New intermediate products and the method of obtaining derivatives of camptothecin (cpt-11) and related compounds

 

(57) Abstract:

Describes the new intermediate products of camptothecin General formula (I), where Rarepresents a chlorine atom, a lower alkoxygroup, Rbrepresents a hydrogen atom, a C1-8alkyl, hydroxys1-8alkyl, a group-C(O)H or a group (a), Rcrepresents a group selected from a number of formulas (II-IX), or Rband Rctogether form a residue of formula-CH2-O-C(O)-C(OH)(R6)- or-CH2-O-CH(OH)-C(OH)(R6)-, Rdrepresents a chlorine atom or a group C(O)OR4, R3represents a hydrogen atom or benzyl, R4represents a C1-8alkyl, R5represents a hydrogen atom, R6represents a C1-8alkyl, R7represents a hydrogen atom. The compounds are effective anti-cancer drugs. Also described is a method of obtaining derivatives of camptothecin (CPT-11) and related compounds.

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6 C. and 50 C.p. f-crystals.

The present invention is described and claimed a new intermediate products and methods of synthesis of derivatives of camptothecin, such as irinotecan, and other compounds related to SS="ptx2">

Art

The connection, which is given the designation SR in this document is mentioned in M. Shamma, D. A. Smithers, V. St. George, Tetrahedron, 1973, 1949-1954.

Asymmetric synthesis of this compound, SR, described in the following publications (grouped by author):

Group 1.

N. Terasawa, M. Sugimori, A. Ejima, Y. Tagawa, Chem. Pharm. Bull., 1989, 37, 3382-3385.

A. Ejima, N. Terasawa, M. Sugimori, N. Tagawa, J. C. S. Perkin I, 1990, 27-31.

H. Tagawa, N. Terasawa, A. Ejima, US Patent 4778891 (Oct. 18, 1988).

H. Tagawa, H. Terasawa, A. Ejima, EP 220601 (Oct 14, 1986).

Group 2.

M. C. Wani, A. W. Nicholas, M. E. Wall, J. Med. Chem. 1987, 2317-2319.

M. C. Wani, A. W. Nicholas, M. E. Wall, US Patent 5053512 (Oct. 1, 1990).

M. E. Wall, M. C. Wani, A. W. Nicholas, G. Manikumar, US Patent 4894456 (Jan. 16, 1990).

M. E. Wall, M. C. Wani, A. W. Nicholas and G. Manikumar, WO 90/03169 (Sep. 28, 1988).

Background of the invention

Derivatives camptothecin, such as irinotecan, are effective anti-cancer drugs. The present invention describes an effective way of synthetic obtain various derivatives of camptothecin, including irinotecan or CPT-11, and other useful compounds, such mappila.

Summary of the invention

The invention includes compounds, methods, re can be used to obtain derivatives of camptothecin, for example, CPT-11, and other related compounds, for example mappila.

Specific compounds selected from the compounds described and identified herein, are compounds indicated in the DIAGRAMS as 2G, 3G, 4G, 5G, 6G, 7GG, 7GA, 8GG, 8GA, 8GB, 9GG, 9GA, 10G, 10G(S), 10G(R), 11G, 11G(S), 11G(R), 12GA-1, 12GA-1(S), 12GA-1(R), 12GA-2, 12GA-2(S), 12GA-2(R), 12GB-1, 12GB-1(S), 12GB-1(R), 12GB-2, 12GB-2(S), 12GB-2(R), 12G, 12G(S), 12G(R), 13G, 13G(S) or 13G(R),

where R1is any optionally substituted C1-8alkyl, including lower alkyl, C3-10cycloalkyl, lower alkyl - C3-10cycloalkyl, alkenyl, aryl, substituted aryl, alkylaryl or substituted alkylaryl, including benzyl or substituted benzyl;

where R2represents H,

(a) any optionally substituted alkyl, including C1-8alkyl, alkylaryl, including C1-6alkylaryl, C1-8alkyl-C6aryl, substituted benzyl and unsubstituted benzyl;

b) -C(O)-R3or

C) -C(R7)2-O-R3where each R7independent from the other;

where R3represents H, optionally substituted C1-8alkyl, including lower alkyl, cycloalkyl, alkenyl, aryl, substituted aryl and alkylaryl, or substituted alkylaryl, including benzyl and substituted benzyl;

where R4not only is -10 cycloalkyl, alkenyl, aryl, substituted aryl, alkylaryl or substituted alkylaryl, including benzyl and substituted benzyl;

where R5represents H, optionally substituted C1-8alkyl, including lower alkyl, aryl, substituted aryl, or two groups R5can be connected with the formation of cyclopentane, or cyclohexane, or their substituted derivatives;

where R6represents optionally substituted C1-8alkyl, lower alkyl, including ethyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, including benzyl and substituted benzyl, C3-10cycloalkyl, lower alkyl-C3-10cycloalkyl, heteroaryl or substituted heteroaryl,

where R7independently represents H, optionally substituted C1-8alkyl, including lower alkyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, or two R7can be connected with the formation of cyclopentane, or cyclohexane, or their substituted derivatives;

where R8represents optionally substituted C1-6alkyl, including lower alkyl, including tert-butyl, C3-10cycloalkyl, lower alkyl-C3-10cycloalkyl, alkenyl, aryl, substituted aryl, alkylaryl or substituted alkylaryl, including benzyl and zamienieny in the description as SRT, SRT, 4CPT, 5CPT, 6CPT, 7CPT, 7CPTA, 8CPTG, 8CPTA, 8CPTAB, 9CPTG, 9CPTA, 9CPTB, 10CPT, 10CPT(S), 10CPT(R), 11CPT, 11CPT(S), 11CPT(R), 12CPTA-1, 12CPTA-1(S), 12CPTA-1(R), 12CPTA-2, 12CPTA-2(S), 12CPTA-2(R), 12CPTB-1, 12CPTB-1(S), 12CPTB-1(R), 12CPTB-2, 12CPTB-2(S), 12CPTB-2(R), 12CPT, 12CPT(S), 12CPT(R), 13CPT, 13CPT(S) and 13CPT(R), where R1-R9are defined above.

Other specific compounds according to the invention is selected from compounds described and indicated in the description as 6MG, 7MG, 8MG, 9MG, 10MG, 11MG, 12MG, 13MG except 13MG, in which R6represents C1-2alkyl, where the radicals have the same meanings as the above radicals.

Other specific compounds according to the invention is selected from compounds described and indicated in the description as 5MM, 6MM, 7MM, 8MM, 9MM, 10MM, 11MM or 12MM.

In addition to the compounds in this invention are described and claimed various ways, denoted as STAGE. These STAGES include STAGE, described and designated in the description of how the SCHEME G, including STAGE 2, or STAGE 3, or STAGE 4 or STAGE 5 or STAGE 5A STAGE or 5b, or STAGE 6 or STAGE 7GG, or STAGE 7GA, or STAGE 8GG, or STAGE 8GA, or STAGE 8GB, or STAGE 9GG, or STAGE 9GA, or STAGE 9GB, or STAGE 10GG, or STAGE 10GA, or splitting the enantiomers STAGE 10, or STAGE 11 STAGE 12, or STAGE 13, or STAGE 14, or any , and indicated in the description of how the SCHEME CPT, includes STAGE 7G or STAGE 7A, or STAGE 8G, or STAGE 8A, or the STAGE 8B, or STAGE 9G, or STAGE 9A, or STAGE 9, STAGE or 10G, or STAGE 10A, or STAGE 11 STAGE 12, STAGE or 13, or STAGE 14, or any combination of them containing two or more STAGES.

In addition, described and claimed STAGE, described and designated in the description of the SCHEME as M-G, including STAGE 5 or STAGE 6 or STAGE 7 or STAGE 8 or STAGE 9 and STAGE 10, or STAGE 11 STAGE 12, STAGE or 13, or any combination of them containing two or more STAGES.

In addition, described and claimed STAGE, described and designated in the description of how the CIRCUIT M-M, including STAGE 5 or STAGE 6 or STAGE 7 or STAGE 8 or STAGE 9 and STAGE 10, or STAGE 11 STAGE 12, STAGE or 13, or any combination of them containing two or more STAGES.

Additional description of the invention and description of preferred implementations of the invention.

DETAILED DESCRIPTION OF THE INVENTION

Compounds according to this invention identifies two ways: descriptive names and identifying structures showing different chemical structural elements. In appropriate cases, the inherent stereokhimiya center, indicate the stereochemistry of only one chiral center, if the stereochemistry of the other chiral center is not considered, the stereochemistry of the other chiral center presents unsplit or racemic mixture. All temperatures are given in degrees Celsius, regardless of whether they are like "o" or "oC" or not. Minutes can be written as m or min H can be written as H or h Abbreviation in the description of the standard or clear chemist, unless otherwise stated. When the connection type or subject in any manner to the effects of other compounds, can be say that they are "mixed" with these compounds. Usually, the mixing of compounds is the promotion of chemical reactions among the one or more mixed compounds. You can also apply the following terms.

OPTIONALLY SUBSTITUTED. The term "substituted" or "optionally substituted" usually means first of all "C1-8alkyl", but note that it includes all the options of all groups. The term can refer to a group or radical that is substituted with halogen, lower alkyl, mono - or di(lower alkyl)substituted lower alkyl, (lower alkyl)thio, halogen-substituted lower alkyl is sludge, halogen, lower alkoxy, aryloxy, aryl(lower alkyl), hydroxy, cyano, amino, mono - and di(lower alkyl)amino or nitro, and the like. A chemist, a specialist in this area, usually need to know when and how to conduct such an obvious substitution.

ALKYL. Bracketed term (Cn-Cmalkyl) includes values such that the compound (C1-C8must include compounds containing from 1 to 8 carbons and their isomeric forms. Different carbon residues are aliphatic hydrocarbon radicals and include branched and unbranched forms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl and n-octyl and its isomeric form.

n-ALKYL. Bracketed term (Cn-Cmn-alkyl) has such a value that the compound (C1-C8) include compounds containing from 1 to 8 carbon atoms and had unbranched form a chain.

LOWER ALKYL. The term "lower alkyl" refers to branched or unbranched saturated hydrocarbon radicals having from one to six carbon atoms. Representatives of such groups is Mernie forms of hexyl and the like.

(LOWER ALKYL)THIO. The term "(lower alkyl)thio" refers to a lower alkyl group, as defined above, attached to the original molecular residue through a sulfur atom. Typical (lower alkyl)diography include methylthio, ethylthio, propylthio, isopropylthio and the like.

ALKOXY. The alkoxy represented by the formula-OR1where R1is (C1-C8)alkyl, refers to the alkyl radical, which is attached to the rest of the molecule by oxygen and includes branched or unbranched forms such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentox, isopentane, n-hexose, isohexane, n-heptose, isoheptane and n-actoxy and the like.

LOWER ALKOXY. The term "lower alkoxy" denotes an alkyl group, as defined above, attached to the original molecular residue through an oxygen atom. Representatives of such groups include methoxy, ethoxy, butoxy and the like.

ALKENYL. Alkenyl refers to the radical of aliphatic unsaturated hydrocarbon having at least one double bond and includes both branched and unbranched forms, the Tennille, 2-methyl-1-butenyl, 1-pentenyl, allyl, 3-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl, 3-methyl-1-pentenyl, 3-methylallyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 1-methyl-4-hexenyl, 3-methyl-1-hexenyl, 3-methyl-2-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-methyl-4-heptenyl, 3-methyl-1-heptenyl, 3-methyl-2-heptenyl, 1-octenyl, 2-octenyl or 3-octenyl and the like.

QUINIL. The term quinil refers to a monovalent branched or unbranched hydrocarbon radical containing at least one carbon-carbon triple bond, such as atenolo, PROPYNYL and the like.

CYCLOALKYL. Bracketed term (Cn-mcycloalkyl) includes values such that the compound (C3-10) included the radical of a saturated cyclic hydrocarbon containing from 3 to 10 carbons in its cyclic chain. The term may also include the alkyl substituted cycloalkyl, such as cyclopropyl, 2-methylcyclopropyl, 2,2-dimethylcyclopropane, 2,3-diethylcarbamyl, 2-butylcyclohexyl, cyclobutyl, 2-methylcyclohexyl, 3-propylcyclohexyl, cyclopentyl, 2,2-dimethylcyclobutyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclodecyl and the like. Each of these residues, when feasible, morettin, two or three lesosecnyh carbon atoms substituted by heteroatoms, such as nitrogen, sulfur and oxygen.

ARYL. The term (C6-12)aryl refers to the basic structure, containing from 6 to 12 carbon atoms, one or two condensed or unfused aromatic rings which can be optionally substituted or substituted by 1-3 hydroxy groups, C1-C3alkoxy, C1-C3alkyl, trifluoromethyl, fluorine, chlorine or bromine. Examples of "aryl" are phenyl, m-were p-triptoreline, -naphthyl, -naphthyl, - (o -, m-, p-)tolyl, (o-, m-, p-)ethylphenyl, 2-atitool, 4-ethyl-o-tolyl, 5-ethyl-m-tolyl, (o-, m - or p-)propylphenyl, 2-propyl-(o-, m - or p-)tolyl, 4-isopropyl-2,6-xylyl, 3-propyl-4-ethylphenyl, (2,3,4-, 2,3,6 -, or 2,4,5- )trimetilfenil, (o-, m - or p-)forfinal, (o-, m - or p-trifluoromethyl)phenyl, 4-fluoro-2,5-xylyl, (2,4-, 2,5-, 2,6-, 3,4- or 3,5-)differenl, (o-, m - or p-)chlorophenyl, 2-chloro-p-tolyl, (3-, 4- , 5- or 6-)chloro-o-tolyl, 4-chloro-2-propylphenyl, 2-isopropyl-4-chlorophenyl, 4-chloro-3-forfinal, (3 - or 4-)chloro-2-forfinal, (o-, m - or p-)tryptophanyl, (o-, m - or p-)ethoxyphenyl, (4 - or 5-)chloro-2-methoxyphenyl, and 2,4-dichloro-(5 or 6)were and the like. Each of these residues, when appropriate, can be substituted.

ALKYLARYL. The term is emeny aryl groups, containing from 6 to 12 carbon atoms, as described above.

HETEROCYCLES. Examples of heterocycles include: (2-, 3 - or 4-)pyridyl, imidazolyl, indolyl, Nin-formylindole, Nin-C2-C5alkyl-C(O)-indolyl, [1,2,4] -triazolyl, (2-, 4-, 5-)pyrimidinyl, (2-, 3-) thienyl, piperidinyl, pyrrolyl, pyrrolidyl, pyrrolidinyl, pyrazolyl, pyrazolyl, pyrazolidine, imidazole, imidazoline, imidazolidine, pyrazinyl, piperazinil, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidine, morpholine, thiazolyl, diazolidinyl, isothiazolin, isothiazolinones, chinoline, ethenolysis, benzimidazolyl, benzothiazolyl, benzoxazolyl, furyl, peril, fedasil, carbazolyl, thienyl and sensational, thienyl, indolyl, ethanolic and the like. Each of these residues, when appropriate, can be substituted.

HETEROARYL. Heteroaryl refers to mono - or bicyclic structure containing ring of 5-12 atoms, where at least one ring is aromatic, but only where one, two or three lesosecnyh carbon atoms substituted by heteroatoms, such as nitrogen atom, sulfur and oxygen. Examples may include pyridine, thiophene, furan, pyrimidine, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyridineboronic, 4-hintline, 2-honokalani, 1-phthalazine, 2-imidazolyl, 4-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-indolyl, 3-indolyl, 3-indazole, 2-benzoxazolyl, 2-benzothiazolyl, 2-benzimidazolyl, 2-benzofuranyl, 3-benzofuranyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,4-thiadiazole-3-yl, 1,2,4-thiadiazole-5-yl, 1,2,4-triazole-3-yl, 1,2,4-triazole-5-yl, 1,2,3,4-tetrazol-5-yl, 5-oxazolyl, 1-pyrrolyl, 1-pyrazolyl, 1,2,3-triazole-1-yl, 1,2,4-triazole-1-yl, 1-tetrazolyl, 1-indolyl, 1-indazole, 2-isoindolyl, 1-purinol, 3-isothiazole, 4-isothiazole and 5-isothiazolin. Each of these residues, when appropriate, can be substituted.

CHIRALITY. Skilled in the art, it is obvious that the compounds according to this invention may contain one or more chiral centers and may exist in optically active forms, including CIS-/TRANS - and/or R - and S-isomeric forms and their mixtures. Scope of this invention includes all these forms, enantiomeric or diastereomeric form compounds, including optically active form, in pure form or in the form of a mixture of enantiomers, or a diastereoisomer is neither dependent on the stereochemistry of the individual compounds. The splitting of the enantiomers can be accomplished by means of splitting the enantiomers of funds, for example optically active dibenzoyltartaric acid, camphorsulfonate, bis-o-toluylene acid, tartaric acid, and diatsetilvinny acid.

OPTICAL PURITY is sometimes referred to as"%" (% enantiomeric excess).

The methods and compounds of the invention

The following examples relate to compounds and formulas identified in the SCHEMA.

METHODS, REACTIONS AND CONNECTION DIAGRAMS G

General description of reactions

All values radicals to the methods described below are defined above in the summary of the invention and definitions. Below reveal more preferred substituents.

STAGE 1. (Carsinoma acid ---> 1 G)

Source material, dichloroaniline acid, is a known compound and can be obtained from the commercially available carsinoma acid.

Methods of obtaining and the range of acceptable conditions are known and are listed in the following link: M. E. Baizer, M. Dub, S. Gister, N. G. Steinberg, J. Am. Pharm. Assoc., 1956, 45, 478-480. The use of tetraalkylammonium salts and tertiary amines in reactions of this type is described in Chemical Ab 44, 466.

The preferred method carsinoma acid is heated with phosphorus oxychloride and of tetraalkylammonium chloride or hydrochloride of the tertiary amine, most preferably chloride Tetramethylammonium, at a temperature between 120oand 140owithin about 12 to 24 hours. The mixture is then subjected to reaction with water, getting the product 1CPT.

STAGE 2. (1 G ---> 2 G)

2,6-Dichlorophenylamino acid is dissolved or suspended in an ethereal solvent such as diethyl ether, tetrahydrofuran or 1,2-dimethoxyethane, and subjected to interaction with an excess of ethylaniline or utility in solution in diethyl ether or tetrahydrofuran at a temperature between about - 30oand +10o. Excess ethylaniline or utility decompose by reaction with dilute acid, such as hydrochloric acid, or by reaction first with a complex ether, such as methylformate, or a ketone, such as acetone, and subsequent reaction with dilute acid, for example hydrochloric acid.

In accordance with another variant of 2,6-dichloroaniline acid can be converted into its acid chloride by reaction with thionyl chloride or pentachloride phosphorus and then prerna solvent, for example, dimethyl ether, tetrahydrofuran or 1,2-dimethoxyethane, and subjected to interaction with an excess of ethylaniline or utility in solution in diethyl ether or tetrahydrofuran at a temperature between about -30oand about +10o. The product is then emit after the reaction intermediate complex with a dilute acid, such as hydrochloric acid. Preferred R6represents lower alkyl, including C1-4alkyl and ethyl, aryl and substituted aryl, alkylaryl and substituted alkylaryl, including benzyl and substituted benzyl, C3-10cycloalkyl, heteroaryl or substituted heteroaryl, preferably C1-4alkyl, ethyl, benzyl.

STAGE 3. (2 G ---> 3G)

Alkylation indicated in the DIAGRAM G (see end of description) as 2G, is subjected to interaction with alcohol or diola in the presence of trimethylchlorosilane. The alcohols can be dialami (diatomic alcohols, for example ethylene glycol, 1,3-propane diol or 2,2-dimethyl-1,3-propane diol, or monohydroxy alcohols, such as methanol. The preferred alcohol is ethylene glycol. When using ethylene glycol, get atlantal, other ketals can be obtained by using other alcohols. You can add the solution is preferably at approximately 40o. Preferred R6represents lower alkyl, including C1-4alkyl and ethyl, aryl and substituted aryl, alkylaryl and substituted alkylaryl, including benzyl and substituted benzyl, C3-10cycloalkyl, heteroaryl or substituted heteroaryl, preferably C1-4alkyl, ethyl, benzyl.

STAGE 4. (3 G ---> 4G)

Connection DIAGRAM G (see the end of the description), denoted 3G, is subjected to the interaction with the sodium alkoxide or potassium or an excess of alcohol, or solvent, such as tetrahydrofuran or 1,2-dimethoxyethane. The reaction can be conducted at a temperature between about 20oand 80o. The alkoxide, or a preferred group R1SCHEME G, can be any of the pre-defined lower alkyl, cycloalkyl, C3-10cycloalkyl, alkenyl, aryl and arylalkyl groups including benzyl and substituted benzyl. The most preferred groups R1are methyl and benzyl.

STAGE 5A (optional) and STAGE 5b. (4G ---> 5G)

STAGE 5A. Review ortho-directed metallation reactions was published, see V. Snieckus, Chem. Rev., 1990, vol. 90, pp. 879-933, it is included here as a reference.

Connection DIAGRAM G (see the end of the description), denoted as W for the formation of pyridylamine. The resulting anion is then subjected to interaction with the electrophile and the product emit after further reaction with dilute acid. Suitable solvents for the reaction are ethers such as diethyl ether, tetrahydrofuran or 1,2-dimethoxyethane, or hydrocarbons, such as toluene, hexane, heptane, cyclohexane or isooctane, or mixtures of any of these or similar solvents.

Alkyllithium can be motility, n-utility, second-utility or tert-utility. The reaction temperature may be between about -40oand about +50o. The electrophile may be alkylhalogenide, such as methyliodide, dimethylsulfate, chloromethylation ether, benzylcarbamoyl ether or benzylbromide aldehydes or ketones such as formaldehyde, acetone, benzaldehyde, or other similar compounds; or amides such as formamide, including dimethylformamide, N-formylpiperidine or N-formylmorpholine or N-methylformamide or similar formamide. The acid used for highlighting product may be hydrochloric acid, acetic acid, sulfuric acid or other acids from the average force to strong.

The preferred solvent is heptane, the preferred base I is at a temperature of between about -5oand about +5o. Purification of the product can be carried out by crystallization, chromatography or through the formation of bisulfite additive compounds which can be decomposed by reaction with either acid or base.

Note that STAGE 5A can be omitted to obtain 5G STAGE 5b can be performed without STAGE 5A.

STAGE 5b.

The aldehyde STAGE 5A restore in alcohol hydride reducing agent, such as borohydride sodium. The reaction can be carried out with the use of alcohol, for example methanol or 2-propanol as solvent, or it can be done in two phase medium with water and the organic phase consisting of heptane, methylene chloride or methyl tert-butyl ether or mixtures of these and similar solvents. You can add a phase transfer catalyst transfer, such as tetrabutylammonium chloride, but this is optional.

STAGE 5A STAGE 5b (4G ---> 5G)

Preferred R2shown in the DIAGRAM G can be H or a) any optionally substituted C1-8alkyl, alkylaryl, C1-8alkylaryl, including C1-8alkyl-C6aryl, substituted benzyl and unsubstituted benzyl: b) -C(O)-R3or-C(R7)2-O-R3, the tee of the invention. This sequence of reactions should be directly below the specified STAGE 6 SCHEME G, see the end of the description, only when R2is b) -C(O)-R3or-C(R7)2-O-R3where each R7not dependent on another. When R2represents H or any optionally substituted C1-8alkyl, alkylaryl, C1-8alkylaryl, including C1-8alkyl-C6aryl, substituted benzyl and unsubstituted benzyl, the reactions proceed in accordance with the SCHEME of M-G and SCHEME M-M and can lead to mappila or analogues mappila.

STAGE 6. (5 G ---> 6 (G) (CXEMA G - continued)

Alcohol is subjected to interaction with the substrate and alkylating agent in a suitable solvent to obtain the product. Grounds can be hydrides such as sodium hydride or potassium hydride, or alkoxide base, such as tert-piperonyl potassium.

Suitable solvents are the ether solvents such as tetrahydrofuran or 1,2-dimethoxyethane, or alcohols, such as tert-butanol. The temperature may be between about 15oand about 80o. Preferred is tert-piperonyl potassium and the preferred solvents are THF or MTBE (methyl-whom accordance with another alternative, the reaction can be carried out in conditions of the transfer phase, using water and an organic solvent, such as methylene chloride or hydrocarbons, for example hexane, heptane or toluene, or similar solvents. May be a hydroxide such as sodium hydroxide or potassium hydroxide, or carbonate of sodium or potassium. You can add a phase transfer catalyst transfer, for example tetrabutylammonium chloride, and the preferred temperature range is between about 10oand about 30o.

ALTERNATIVE STAGE

There are 2 different reactions of the Stage 7, the series 7GG and 7GA; 3 different reaction Stage 8, the series 8GG, 8GA, 8GB: 3 different reactions of the Stage 9, the series 9GG, 9GA, 9GB and 2 different reactions of the Stage 10, the series 10GG and 10GA, followed by the procedure of splitting the enantiomers Stage 10. See Diagram G in the end of the description.

STAGE 7 GG and STAGE 10GA. (6G ---> 7 (GG) and (9GA ---> 10 G).

The carbonylation reaction of aryl halides catalyzed by palladium with zero valency, are well known, see J. K. Stille and P. K. Wong, J. Org. Chem., 1975, 40, 532-534, but irishlady usually have low reactivity in these reactions. It is known that in contrast to the simple arylhalides, 2-chloropyridine easily undergo reactions introduction involving palladium with zero valency. Izvesti not described carbonylation reaction of 2-chloropyridine, catalyzed by palladium with zero valency.

Compounds indicated 6G, is subjected to reaction with carbon monoxide and an alcohol in the presence of soluble salts of palladium II (such as palladium acetate), phosphine ligand (such as 1,3-bidimensional) and bases, such as sodium acetate or potassium carbonate, sodium or potassium, triethylamine or tri-n-butylamine, in a polar aprotic solvent such as dimethylformamide or acetonitrile.

A preferred group R3shown in the DIAGRAM G (see the end of the description), can be any of the previously defined, H, lower alkyl, cycloalkyl, alkenyl, aryl and arylalkyl groups including benzyl and substituted benzyl groups. Preferred groups R3are methyl and benzyl.

A preferred group R4alcohol shown in the DIAGRAM G (see the end of the description), can be any of the previously defined, H, lower alkyl, cycloalkyl, alkenyl, aryl and arylalkyl groups including benzyl and substituted benzyl groups. A more preferred group R4is n-propyl. The temperature range is between about 50oand about 100o.

7can be connected with the formation of cyclopentane or cyclohexane or their substituted derivatives.

Some links describing the reaction of implementation indicated in the above STAGE 7, the following: a) K. Isobe and S. Kawaguchi, Heterocycles, 1981, 16, 1603-1612; b) N. Sato, A. Hayakaws and R. Takeuchi, J. Het. Chem., 1990, 503-506; C) M. Ishikura, M. Kamada and M. Terashima, Synthesis, 1984, 936-938 and g) K. Isobe, K. Nanjo, Y. Nakamura and S. Kawaguchi, Bul. Chem. Soc. Japan, 1986, 59, 2141-2149.

STAGE 7 GA and STAGE 8 GG. (6 G ---> 7 GA), for (7 GG ---> 8 (GG)

Ketal hydrolyzing reaction with water in the presence of a strong acid, such as triperoxonane acid. Concentration triperoxonane acid may be between about 50% and 90% and the reaction temperature between about 15oand about 30o. In accordance with another variant of ketal can be removed by exchange reaction with a ketone, such as acetone or 2-butanone, catalyzed by a strong acid, such as p-toluensulfonate or acidic ion-exchange resin, such as resin amberlyst a-15. For the exchange reaction, the preferred temperature is about the temperature phlegmy ketone.

STAGE 8GA. (7GA ---> 8GA)

Connection 8GA is dissolved in a solvent and subjected to reaction with vinyllithium or wikimanialang. Suitable solvents are prostide mixtures, or as mixtures with hydrocarbons, such as toluene, heptane or cyclohexane. The reaction temperature may be between about -78oC and about 25o. The product emit after subsequent reaction with dilute acid, such as hydrochloric, sulfuric or acetic acid. The preferred reagent is vinylmania in tetrahydrofuran used as a solvent, at a temperature of from about -40oup to about 25oafter that the reaction is quenched with hydrochloric acid. Preferred R5independently represents H, lower alkyl, aryl, substituted aryl, or two groups R5can be connected with the formation of cyclopentane or cyclohexane or their substituted derivatives.

STAGE 8GB and STAGE 9GG. (7 GA ---> 8GB and 8 GG ---> 9 GG)

The Wittig reaction is conducted by reacting the ketone with a solution of the ylides derived from salt methyldiphenylphosphine, preferably bromide and a strong base, such as n-utility, tert-piperonyl potassium or bestremembered potassium in a solvent, for example diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane or DMF. The preferred base is bestremembered potassium, the preferred solvent is DMF. The reaction Ave is CLASS="ptx2">

STAGE 9GA. (8GA ---> 9GA)

9GA dissolved in a solvent and subjected to interaction with ozone to produce an intermediate product. Depending on the composition of the solvent, this intermediate product can be ozonid or a mixture of hydroperoxides. This intermediate product is subjected to interaction with a suitable reducing agent to obtain a product, either directly or Paladino through the formation of an intermediate aldehyde. The reaction temperature may be between about -78oand about 25o. Suitable solvents for the reaction are chlorinated hydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane or other polychlorinated derivatives of ethane or ethylene, either alone or as mixtures or as mixtures with alcohols, for example methanol. The preferred solvent is a mixture of methylene chloride and methanol at a temperature from about -78oto about -40ofor the initial reaction with ozone and temperature from aboutoup to 25oto restore the intermediate product. The preferred reducing agent is borohydride sodium.

STAGE 9GB and STAGE 10GG. (8 GB ---> 9 GA and 9 GG ---> 10 (GG)

talities by osmium tetroxide and stoichiometric sookielee, for example, N-oxide, trimethylamine N-oxide N-methylmorpholine or in aqueous THF or preferably in tert-butanol used as solvent. The reaction temperature may be between about 15oand about 50opreferably about 40o, for about 12-48 hours.

An alternative to the racemic ominirovaniya is the use of asymmetric ominirovaniya, as described by Sharpless, for turning SRT directly in 10G (R) or (S). Specific references for asymmetric ominirovaniya by Sharpless following:

G. A. Crispino, A. Makita, Z.-M. Wang, K. C. Sharpless, Tet. Lett., 1944, 543-546.

G. A. Crispino, K.-S. Jeong, H. C. Kolb, Z.-M. Wang, D. Xu, K. B. Sharpless, J. Org. Chem., 1993, 3785-3786 and many of the references listed in this article.

K. B. Sharpless, W. K. Amberg, U. S. Patent 5227543.

K. B. Sharpless, M. Beller, C. Blackburn, Y. Kawanami, H.-L. Kwong, Y. Ogino, T. Shibata, T. Ukita, L. Wang, PCT WO 92/20677.

J. Hartung, K. B. Sharpless, PCT WO 93/07142.

STAGE 10. The splitting of the enantiomers (10 G ---> 10 G (R or S))

Racemic diol, such 10g, you can handle azetiliruet reagent such as vinyl acetate, isopropenylacetate, acetic anhydride or ethyl acetate, in an organic solvent in the presence of lipase. Possible solvents include simple ether or the social acetate isomer and individual diology isomer. The reaction is usually carried out at a temperature between 25o45oC when the concentration of the substrate 15-40 mg/ml of the reaction Products can be separated by crystallization using conventional organic solvents or by chromatography on silica gel. Optical purity (% EE) of each enantiomer can be determined by analysis of NMR with chiral shift-reagents or chiral HPLC.

STAGE 11-14

The following reactions can be conducted with individual enantiomer or racemic mixtures or mixtures with other relations of enantiomers. The product of the reaction will depend on the source material. SCHEME G (see end of description) and the following stages are for convenience to the individual enantiomer and cited as example. Individual enantiomer is usually denoted by the capital letter "R" or "S". One example of this enantiomer is 10 G (R)". The racemic mixture is usually designated by a number, followed by capital letter "G". One example of a racemic mixture is "10G". See DIAGRAM G. the Reaction according to this invention, of course, not limited to those given in the Schemes, for example, the DIAGRAM G shows the STAGES from 11 to 13 reaction of racemic mixtures, but these units the visual AIDS and do not represent the full invention.

STAGE 11. (10G ---> 11G)

Diol can oxidize in hydroxyaldehyde using oxidation conditions such as Swern, for example DMSO, oxalicacid and triethylamine in an aprotic solvent such as methylene chloride, at a temperature in the range of from about -78oup to about 25o. In accordance with another variant of the oxidation can be carried out by a solution of sodium hypochlorite catalyzed by TEMPO or substituted TEMPO, such as 4-acetoxy-TAMRA, in the two-phase system consisting of water and an aprotic solvent, such as methylene chloride. The preferred reaction temperature between about -5oand about +25oand the reaction time is between about 30 minutes and about 2 hours.

Conditions of Swern type described in A. J. Mancuso and D. Swern Synthesis, 1981, 165-185. The two-phase system consisting of water and an aprotic solvent, is described in P. L. Anelli, C. Biffi, F. Montanari and S. Quici, J. Org. Chem. , 1987, 52, 2559-2562. These publications are entered here as a reference.

STAGE 12. (11G ---> 12G)

For turning hydroxyaldehyde, 11G, 12G used several variants. In the first method, hydroxyaldehyde, 11G, oxidizes in gidrokshikislotu 12GA-1, the sodium chlorite. Gidrokshikislotu can then be turned into a 12G reaction with trimethylsilylimidazole in the same vessel. The advantage is dostatkom this one-step transformation is a relatively low output and variable reaction times.

According to the method with a higher yield, first remove the benzyl group or the hydrogenation or reaction with tribromide boron and then remove the methoxy group by reaction with trimethylsilylimidazole. Cm. SCHEME G at the end of STAGE 12, the Path a, Part 2, path b-1 and b-2. Obviously, the stages of removal of the protective groups can be changed " on the reverse.

The second way of turning 11G 12G changes the order of the stages of the oxidation and removal of the protective groups. Cm. SCHEME G at the end of STAGE 12, the Path C. the Benzyl group is removed by hydrogenation, getting lactol. Lactol then oxidized with sodium hypochlorite catalyzed by TEMPO. Cleavage metoxygroup conduct, as before, trimethylsilylimidazole. Cm. SCHEME G at the end of STAGE 12, the Path, Part 1, 2 and 3. The advantage of this sequence is the lack of phase oxidation with sodium chlorite and the associated danger.

Paths a and b are described in more detail below, the Path is preferable. See DIAGRAM G in the end of the description.

STAGE 12. Path A. (11G ---> 12G, Path)

Path And has two parts, part 1 and part 2. Part 2 follows part 1. Part 2 of the Road And has 2 paths, path a and path b. The path and the Paths a, part 2, has only one stage. Path b Path a, part 2,practical mixture is assumed.

Part 1

Oxidation to form the hydroxy acid is preferably carried out with sodium chlorite using the conditions described in the literature. See B. S. Bal, W. E. Childers, H. W. Pinnick, Tetrahedron, 1981, 2091-2096. To prevent the formation of chlorine dioxide also used other additives, such as hydrogen peroxide or sulfamic acid. So get 12 GA-1.

Part 2

The path and

Single-stage removal of the benzyl and methyl groups spend trimethylsilylimidazole or previously received or generated in situ from trimethylsilylpropyne and sodium iodide in methylene chloride or acetonitrile. See T. Morita, Y. Okamoto, H. Sakurai, J. C. S. Chem. Comm. 1978, 874-875, and M. E. Jung and M. A. Lyster, J. Am. Chem. Soc., 1977, 99, 968. You can add pyridine, but this is not required. The reaction temperature is between about 15oand 50oduring the time between 12 and 48 hours. Thus obtained 12 G.

Path b

Part 1 path b-1. Two-stage removal of the benzyl and methyl groups can be performed in two ways. Benzyl group is removed by hydrogenation over a catalyst, preferably a palladium catalyst deposited on coal or other porous substrate, or palladium black. The solvent suppose the to about 40oin an atmosphere of hydrogen at a pressure from about 1 atmosphere to about 4 atmospheres for about 2-4 hours.

In accordance with another variant of the benzyl group can be removed by reaction with tribromide boron in a solvent such as methylene chloride, at a temperature of from about -5oto about 20owithin about 30 minutes to about 2 hours. Thus obtained product 12 GA-2, differently marked 12 GB-2.

Part 2 path b-2. Cleavage metoxygroup with getting 12G can be trimethylsilylimidazole, as described above. (This stage is the same as the third stage following the Path).

STAGE 12. Path C. (11G ---> 12G, Path)

The path has 3 stages.

Part 1. Benzyl or other suitable group is removed by hydrogenation over a catalyst, preferably a palladium catalyst deposited on coal or other porous substrate, or palladium black. As a solvent, the preferred alcohol is most preferable methanol. The reaction is carried out at a temperature of from about 15oto about 40oin an atmosphere of hydrogen at a pressure from about 1 atmosphere to about 4 atmospheres for from about 12 to about 96 hours. So get 12 GB-1.

Chav Swern conditions, for example DMSO, oxalicacid and triethylamine in an aprotic solvent, such as methylene chloride, at a temperature range from -78 to about 25.

In accordance with another variant, the oxidation is performed with sodium hypochlorite catalyzed by TEMPO or substituted TEMPO, such as 4-acetoxy-TEMPO, two-phase system consisting of water and an aprotic solvent, such as methylene chloride. The reaction temperature is between about -5oand about +25oand the reaction time is between about 30 minutes and 2 hours. So get 12 GB-2, differently marked 12 GB-1.

Part 3. The removal of a methyl group to spend trimethylsilylimidazole or previously received or generated in situ from trimethylsilylpropyne and sodium iodide, methylene chloride or acetonitrile. The conditions described above. Thus obtained 12 G.

STAGE 13. (12G --->13G)

12G is subjected to reaction with acrylate ester, for example methyl-, ethyl - or tert-butyl acrylate, in the presence of a base such as potassium hydride, sodium hydride, tert-piperonyl potassium, sodium carbonate, potassium carbonate, cesium carbonate, or tertiary amines, such as diisopropylethylamine, in a polar aprotic solvent such as dimethyls who I am. The preferred conditions is the reaction with tert-butyl acrylate and cesium carbonate in DMSO at about 50o. The product can be isolated in the form of MES with toluene. So get keeeper, connection 13G.

STAGE 14. (13G ---> 14G)

Ketoester, which can be mainly or exclusively in the form of enol transform in 14G by reaction with a strong acid, such as triperoxonane acid, at a temperature of from about 80oup to about 110owithin about 10 minutes to about 6 hours. You can add a solvent, for example toluene. The preferred conditions are a mixture of toluene and three-forexpros acid at 100-110owithin 1-4 hours.

All references listed in the description of the Schema is included here as a reference. Using the methods described above and the substitution of appropriate starting materials any average person skilled in the art can obtain the connection and to carry out the reaction according to this invention. One of the implementations of this invention is described by reactions, methods and SCHEMA structures CPT-11. This implementation only illustrates the invention and should not limit it in any way.

METHODS, REACTIONS AND CONNECTION SCHEMES is monia (107,71 g, of 1.02 mol) is suspended in phosphorus oxychloride (450 g, 273 ml, 2.9 mol) and heated at a bath temperature of 130oC. Solid materials are dissolved with a weak exothermic effect when the internal temperature reaches about 75oC, forming a transparent brown solution. The reaction mixture is heated at 130oC for 18 hours, then heated to 145oC for 2 hours. The mixture is cooled to room temperature, poured onto 2 kg of ice and stirred for 2 hours. The hard part is dissolved in 1.5 liters of ethyl acetate. The organic solution is dried over sodium sulfate, filtered and evaporated, getting 146,9 g (78%) of light brown solid product.

So pl. 195-197oC (decomposition). (Liter.1so pl. 205-207oC).

1H NMR (300,13 MHz, DMSO-d6) 7,80 (s, 2H).

13C NMR (75,47 MHz, DMSO-d6) 122,87, 144,60, 150,13, 163,66.

Nominal mass spectrum: calculated m/z 192, found m/z 192.

Links:

1. M. E. Baizer, M. Dub, S. Gister, N. G. Steiberg, J. Am. Pharm. Assoc, 1956, 45, 478-480.

2. The use of tetraalkylammonium salts in this type of reactions is described in the patent GDR 154538.

STAGE 2. (1PCT ---> 2CPT)

1CPT (6.6 g, 0,034 mol) is mixed with 82 ml of THF and the mixture is cooled to -40oC. In the course is the reaction at less than -30oC. the Cooling bath is removed and the resulting dark-brown mixture is allowed to warm to 0oC and stirred at 0owithin one hour. The reaction mixture is again cooled to -25oC and add methylformate (3.2 ml, 52 mmol). After incubation for 15 min at -25oC add 20 ml of 6 M hydrochloric acid and the mixture is allowed to warm to room temperature. The phases are separated and the lower aqueous phase is extracted with 3 x 10 ml THF. The combined THF phase is washed 2 times with a mixture of 15 ml of 1 n NaOH and 15 ml saturated NaCl solution and then once with 15 ml saturated NaCl solution. The organic phase is dried over sodium sulfate and then concentrated to obtain oil. Add toluene (50 ml) and the mixture concentrated to obtain oil and this procedure is repeated, getting 6,01 g (84%) of a brown oil which crystallized under vacuum.

So pl. 60-63oC.

1H NMR (300,13 MHz, CDCl3) of 1.17 (t, J = 7,1 Hz, 3H), 2,88 (kV, J = 6,6 Hz, 2H), to 7.61 (s, 2H).

13C NMR (75,47 MHz, CDCl3) 7,50, 32,61, 120,88, 147,66, 151,83, 197,15.

Nominal mass spectrum: calculated m/z 204, found m/z

204.

STAGE 3. (2CPT ---> 3CPT)

2CPT (90,2 g, 0.44 mol), ethylene glycol (650 ml) and trimethylsilane (140 ml, 1.1 mol) are mixed and pereia ends. The reaction mixture is neutralized by adding 1 l of 1 n NaOH solution and extracted with 3 x 250 ml of a mixture of ethyl acetate/heptane (1:1). The organic extracts are combined, dried over sodium sulfate and evaporated. The crystalline residue is dried in high vacuum, receiving 109,71 g (100%) of product.

So pl. 91oC.

1H NMR (300,13 MHz, CDCl3) to 0.80 (t, J = 7.4 Hz, 3H), 1,78 (kV, J = 7,4 Hz, 2H), and 3.72 (t, J = 7,0 Hz, 2H), 3,99 (t, J = 7,0 Hz, 2H), 7,27 (s, 2H).

13C NMR (75,47 MHz, CDCl3) 7,45, 32,77, 65,10, 108,94, 120,30, 150,57, 158,06.

Nominal mass spectrum: calculated m/z 248, found m/z 248.

STAGE 4. (3CPT ---> 4CPT)

3CPT (57,5 g, 0.23 mol) is dissolved in methanol (170 ml). Add sodium methoxide (80 ml, 0.35 mol, 25 wt.% solution in methanol) and the reaction mixture was refluxed on an oil bath to 85oC. After 20 hours the reaction mixture is allowed to cool to room temperature and then stewed 250 ml of water. Two-phase mixture is diluted with 200 ml of methylene chloride and separated. The aqueous phase is extracted with two portions of more than 100 ml of methylene chloride. The organic extracts are combined, dried over MgSO4filter and concentrate to the formation of the oil is amber in color, which crystallizes in the entry of the seed produces the 3) to 0.88 (t, J = 7.4 Hz, 3H), of 1.85 (q, J = 7.5 Hz, 2H), 3,78 (t, J = 6.9 Hz, 2H), 3,93 (s, 3H), was 4.02 (t, J = 7,1 Hz, 2H), 6.73 x(s, 1H), 6,98 (s, 1H).

13C NMR (75,47 MHz, CDCl3) 7,62, 32,53, 54,04, 64,79, 106,25, 109,23, 113,83, 148,33, 157,27, 163,94.

Nominal mass spectrum: calculated m/z 243, found m/z 244 (M + 1).

STAGE 5. (4CPT ---> 5CPT)

4CPT (73,05 g, 0,299 mol) is dissolved in 1400 ml of heptane and cooled to -10oC. for 10 minutes add n-utility (294 ml, 0,588 mol, 2.5 M solution in hexane), maintaining the internal temperature < 5oC. After complete addition, utility orange mixture was stirred at 0oC for 30 minutes the Mixture was then cooled to -30oC and add N-formylpiperidine (66,0 ml, 0,588 mol). Mixture is allowed to warm to 0oC and stirred at 0oC for 1 h Dark red mixture stew by adding 600 ml of 1 n HCl. The phases are separated and the aqueous phase extracted with 2 × 250 ml of MTBE. The combined organic phases getting the solution asrt. Part of this solution chromatographic on silica using a mixture of hexane/ethyl acetate (4:1) to give the purified sample art for identification.

To a solution of asrt add water (250 ml), tetrabutylammonium chloride (8,3 g 0,029 mol) and borohydride sodium (11.3 g, 0.29 mol) and the mixture vigorously stirred is on and the mixture is stirred at room temperature for 30 minutes The aqueous phase is removed and the organic phase is washed once with 500 ml of water. The organic phase is evaporated to obtain oil. Oil chromatographic on 800 g of silica, using a mixture of hexane/ethyl acetate (4:1). The product yield 57,30 g, 71%. There is also a 15.0 g (20%) of essentially pure 4CPT.

Asrt

1H NMR (300,13 MHz, CDCl3) to 0.96 (t, J = 9,0 Hz, 3H), 2,03 (kV, J = 9.0 Hz, 2H), 3.75 to (m, 2H), 4.00 points (m, 2H), 4.00 points (s, 3H), 7,13 (s, 1H), 10,44 (s, 1H).

13C NMR (75,47 MHz, CDCl3) 7,32, 33,28, 54,81, 64,78, 109,66, 114,67, 117,20, 150,83, 157,52, 161,75, 190,80.

Nominal mass spectrum: calculated m/z 271, found m/z 271.

5CPT

So pl. 49-56oC.

1H NMR (300,13 MHz, CDCl3) 0,84 (t, J = 7.5 Hz, 3H), 1,87 (kV, J = 7,0 Hz, 2H), 3,74 (m, 2H), 3,92 (s, 3H), of 3.97 (m, 2H), 4.72 in (s, 1H), 7,05 (s, 1H).

13C NMR (75,47 MHz, CDCl3) 7,46, 33,01, 54,50, 56,16, 64,98, 110,25, 114,53, 119,15, 147,39, 154,50, 163,00.

Nominal mass spectrum: calculated m/z 273, found m/z 273.

STAGE 6. (5CPT ---> 6CPT, the CPT SCHEME, see the end of the description)

5CPT (503,98 g 1,841 mol) is dissolved in 1330 ml of THF in the flask 12 l, equipped with a mechanical stirrer, addition funnel and thermocouple with connection device. To the flask add 1188 ml of 20% solution of tert-butoxide potassium in THF, maintaining the internal temperature is ml, 2,117 mol), maintaining the internal temperature below 30o. After adding benzylbromide the mixture is stirred at 20-30owithin 1 hour. After one hour add 38 ml of 40% aqueous dimethylamine and the mixture is stirred at 20-30owithin 30 minutes Add 276 ml of 1 n HCl and 2 l of ethyl acetate and the phases are separated. The organic phase is washed with 3 × 1 l of water and then evaporated to obtain oil. Yield: 663,5 g, 99.3 per cent.

1H NMR (300,13 MHz, CDCl3) to 0.75 (t, J = 7.4 Hz, 3H), 1,82 (kV, J = 7,4 Hz, 2H), 3,61 (m, 2H), 3,82 (s, 3H), 3,85 (m, 2H), 4,48 (s, 2H), 4,57 (s, 2H), 6,97 (s, 1H), 7.23 percent (m, 5H).

13C NMR (75,47 MHz, CDCl3) 7,50, 32,96, 54,47, 62,83, 64,73, 73,20, 110,12, 114,8, 116,42, 127,54, 127,76, 128,24, 138,43, 147,91, 155,62, 163,74.

Nominal mass spectrum: calculated m/z 363, found m/z 364 (M+1).

There are two different possible reactions of the STAGE 7, the rows of G and A, and three different possible reactions of the STAGE 8. See wiring Diagram CPT at the end of the description.

STAGE 7G. (6CPT ---> 7CPTG)

6CPT (66,45 g, 183 mmol), palladium acetate (2,05 g, 9,13 mmol), DPPP (4,14 g, 10.0 mmol), potassium carbonate (37,86 g, 274 mmol), n-propanol (665 ml) and DMF (332 ml) are loaded into the flask. The flask is rinsed with nitrogen and then with carbon monoxide. The mixture is heated to 90oC in an atmosphere of carbon monoxide for 16 hours. The reaction is l THF. The combined filtrate and wash liquid concentrate to a volume of about 400 ml Add water (700 ml) and MTBE (700 ml). The aqueous phase is separated and extracted with 350 ml of MTBE. The combined solution MTBE extracted with 4 x 350 ml of water, dried over sodium sulfate and evaporated, getting 68,03 g (yield 89%) of a light orange oil after column chromatography (silica gel: 230-400 mesh mesh, eluent: a mixture of heptane/ethyl acetate, 80:20).

1H NMR (300,13 MHz, CDCl3) 10,87 (t, J = 7.4 Hz, 3H), and 0.98 (t, J = 7.4 Hz, 3H), 1.77 in (m, 2H), 1.93 and (kV, J = 7,4 Hz, 2H), 3,71 (m, 2H), 3,94 (m, 2H), 3,99 (s, 3H), 4.26 deaths (t, J = 6,7 Hz, 2H), 4,59 (s, 2H), 4,74 (s, 2H), 7,29 (m, 5H), of 7.82 (s, 1H).

13C NMR (75,47 MHz, CDCl3) 7,5, 10,42, 22,02, 33,08, 54,07, 63,08, 64,72, 66,98, 73,29, 110,26, 117,05, 122,14, 127,51, 127,99, 128,22, 138,45, 144,70, 153,62, 163,88, 165,29.

Nominal mass spectrum: calculated m/z 415, found m/z 416 (M + 1).

STAGE 7A. (6CPT ---> 7CPTA)

6CPT (50.0 g 0,137 mol) dissolved in 50% aqueous triperoxonane acid (250 ml) and stirred at room temperature for 48 hours. Add water (200 ml) and ethyl acetate (200 ml). The phases are separated and the aqueous phase extracted with ethyl acetate (3 x 200 ml). The combined organic layers are washed with saturated sodium bicarbonate solution (500 ml) until then, until it is removed the residual quantity of the three filtered and concentrated, getting 42.6 g (97%) of product.

1H NMR (300,13 MHz, CDCl3) was 1.04 (t, 7.2 Hz, 3H), 2,71 (kV, 7.2 Hz, 2H), 3,95 (s, 3H), 4,47 (s, 2H), 4,56 (s, 2H), 6,77 (s, 1H), 7,29 (m, 5H).

13C NMR (75,47 MHz, CDCl3) 7,39, 36,15, 54,56, 63,16, 73,43, 113,35, 115,73, 127,86, 127,97, 128,51, 137,50, 147,81, 153,07, 161,38, 204,47.

Nominal mass spectrum: calculated m/z 319, found m/z 320 (M+1).

There are 3 different possible reaction STAGE 8, the rows of G, A and B, see Scheme CPT at the end of the description.

STAGE 8G. (7CPTG ---> 8CPTG)

7CPTG (68,02 g of 163.7 mmol) is dissolved at room temperature in 384 ml of 50% aqueous triperoxonane acid. The mixture is stirred at room temperature for 21 hours. Add 880 ml of water and the mixture extracted with 2 × 500 ml of ethyl acetate. The combined organic phases are washed with 2 x 500 ml of water and then neutralized with a saturated solution of sodium bicarbonate. The organic phase is then dried over sodium sulfate and evaporated, getting 59,86 g (98,4%) of product as a pale yellow oil.

1H NMR (300,13 MHz, CDCl3) to 0.96 (m, 6N), 1,72 (m, 2H), 2,68 (kV, J = 7.2 Hz, 2H), 3.96 points (s, 3H), 4,23 (t, J = 6,7 Hz, 2H), 4,42 (s, 2H), 4,58 (s, 2H), from 7.24 (m, 5H) of 7.48 (s, 1H).

13C NMR (75,47 MHz, CDCl3) 7,55, 10,41, 21,99, 36,21, 54,13, 63,83, 67,22, 73,56, 115,50, 121,49, 127,86, 127,97, 128,19, 128,37, 137,32, 144,87, 150,96, 161,31, 164,54.

Nomi who mmol) dissolved in 5 ml of THF and cooled to -40oC in nitrogen atmosphere. Add vinylmania (2,9 ml, 4.4 mmol, 1.5 M solution in THF). The reaction mixture was kept at -40oC for one hour and then allowed to warm to room temperature. After incubation for 1 hour at room temperature, the reaction mixture stew saturated aqueous ammonium chloride (10 ml) and diluted with ethyl acetate (10 ml). The aqueous layer was extracted with 10 ml ethyl acetate, the extract combined with the previous organic layer and dried over magnesium sulfate. After filtration and concentration get 1,098 g (yield 100%) oil color light amber.

1H NMR (300,133 MHz, CDCl3) of 0.87 (t, J = to 7.32 Hz, 3H), 1,79 is 2.00 (m, 2H), 3,93 (s, 3H), of 4.54 (s, 2H), a 4.83 (s, 2H), 5,16 (DD, J = 0,99 Hz, 10,59 Hz, 1H), 5.25-inch (DD, J = 0,99, 17,23 Hz, 1H), 6,01 (DD, J = 10,59, 17,23 Hz, 1H), 6,94 (s, 1H), 7,30 - 7,37 (m, 5H).

13C NMR (75,468 MHz, CDCl3) 7,7, 34,2, 54,5, 62,6, 72,4, 78,0, 114,0, 115,6, 115,9, 127,9, 128,0, 137,2, 143,0, 148,2, 159,2, 163,1.

Nominal mass spectrum; calculated m/z 347, found m/z 348 (M+1).

There are three different possible reactions of the STAGE 9, the rows of G, A and B, see SCHEME CTP at the end of the description.

STAGE 9G. (8CPTG ---> 9CPTG)

Bromide methyltriphenylphosphonium (2.14 g, 6.0 mmol) dissolved in 15 ml of DMF and stirred at room temperature. Doba is a private white solid was stirred at room temperature for 10 minutes Immediately add the solution 8CPTG (1.48 g, 4.0 mmol) in 5 ml of THF, receiving a mixture of dark-red color, which quickly turns into a brown mixture. The mixture is stirred for 10 minutes Add additional solution ilide until then, until you used up all 8CPTG. The reaction stew by adding 10 ml of 1 n HCl. Add 20 ml of MTBE and the phases are separated. The aqueous phase is extracted with 2 x 20 ml MTBE. The combined organic phases are washed with 3 x 20 ml of water, dried over sodium sulfate and evaporated to a volume of about 15 ml (is weak crystallization of triphenylphosphine oxide). The solution chromatographic on silica (20 g) using a mixture of hexane/ethyl acetate (4:1) to give 1.39 g of product (yield 92%).

1H NMR (300,13 MHz, CDCl3) of 0.85 (m, 6N), to 1.59 (m, 2H), 2,20 (kV, J = 7,4 Hz, 2H), with 3.89 (s, 3H), of 4.12 (t, J = 6,7 Hz, 2H), 4,33 (s, 2H), 4,42 (s, 2H), 4,89 (s, 1H), is 5.06 (s, 1H), 7,17 (m, 5H), 7,35 (s, 1H).

13C NMR (75,47 MHz, CDCl3) 10,43, 12,07, 22,02, 30,23, 53,95, 63,79, 67,00, 73,03, 114,66, 118,67, 121,40, 127,60, 127,90, 128,26, 138,21, 144,49, 147,58, 155,33, 163,11, 165,25.

Nominal mass spectrum: calculated m/z 369, found m/z 369.

STAGE 9A. (8CPTA ---> 9CPTA)

8CPTA (0,500 g of 1.43 mmol) was dissolved in 40 ml of a mixture methanol:methylene chloride (1: 1) and cooled to -70oC and then rinsed sour is it Welsbach. The solution is then rinsed with oxygen for five minutes to remove excess ozone and then rinsed for ten minutes with nitrogen. At -78oC the solution is then treated with sodium borohydride (0,250 g of 6.61 mmol) in solution in 5 ml of 50% aqueous methanol. After fifteen minutes the reaction mixture is allowed to warm to room temperature for one hour. After incubation for one hour at room temperature, the reaction mixture stew 1 M HCl solution (10 ml) and separated. The aqueous phase is extracted with 20 ml and 10 ml of methylene chloride, the extracts combined with the original organic layer and dried over sodium sulfate. After filtration and concentration get 0,491 g (yield 99%) 9CPTA.

1H NMR (300,133 MHz, CDCl3) of 0.82 (t, J = 7,20 Hz, 3H), of 1.86 (DD, J = 7,20 Hz, 14,71 Hz, 2H), 3,69 (s, 2H), 3.96 points (s, 3H), 4,19 - or 4.31 (m, 2H), 4,28 (s, 2H), 4,59 (s, 2H), 7,20 (s, 1H), 7,40 - 7,29 (m, 5H).

13C NMR (75,468 MHz, CDCl3) 7,61, 35,44, 54,50, 62,97, 73,40, 75,26, 84,72, 113,71, 114,13, 127,91, 128,18, 128,35, 137,48, 148,56, 158,01, 163,46.

Nominal mass spectrum: calculated m/z 351, found m/z.

STAGE 9B (8CPTB ---> 9CPTA)

The use of reagents and conditions similar to those described in STAGE 9CPTG.

STAGE 10G. (9CPTG ---> 10 CPTG)

9CPTG (100.0 g, 0,271 mol), dihydrate N-oxide three is up to the 40o. After 24 hours the mixture is cooled to 20-25o. Add 300 ml of water and 110 g of sodium metabisulfite and the mixture is stirred for 30 min at room temperature. The mixture is extracted with 4 × 200 ml of ethyl acetate. The organic phases are combined and stirred with 50 g of silica 70-230 mesh for 1 hour. Silica is separated by filtration and washed with 100 ml of ethyl acetate. The filtrate is stirred with 100 g of Magnesol for 30 min and then the suspension is filtered through 50 g of Magnesol. The filtrates are combined and concentrated to education oils. Add 200 ml of toluene and 800 ml of heptane and the mixture is allowed to crystallize at -20owithin 18 hours. The hard part is separated by filtration and washed with 200 ml of heptane. Output 10CPT to 83.5 G. of filtrate and washing liquids can be distinguished by chromatography additional amount 10CPT.

1H NMR (300,13 MHz, CDCl3) to 0.74 (t, J = 7.4 Hz, 3H), of 1.03 (t, J = 7.4 Hz, 3H), of 1.80 (m, 4H), of 3.69 (d, J = 11.2 Hz, 1H), 3,86 (d, J = 11.2 Hz, 1H), 4,01 (s, 3H), or 4.31 (t, J = 6,7 Hz, 2H), 4,88 (d, J = 10,7 Hz, 1H), 4,96 (d, J = 10,7 Hz, 1H), 7,33 (m, 5H), to 7.64 (s, 1H).

13C NMR (75,47 MHz, CDCl3) 7,55, 10,41, 22,01, 31,71, 54,16, 62,95, 67,13, 70,86, 72,69, 80,12, 117,83, 122,25, 128,00, 128,42, 137,14, 144,74, 155,82, 163,16, 165,23.

Nominal mass spectrum: calculated m/z 403, found m/z 404 (M + 1).

oC for 15 hours. The reaction mixture is then cooled to room temperature and rinsed with nitrogen. The solution is filtered through celite and the celite washed with ethyl acetate (3 x 50 ml). The combined filtrate and wash liquid was concentrated in vacuo to education oils. The oil was diluted with ethyl acetate (100 ml) and the resulting solution washed with water (50 ml) and then concentrated in vacuo. Product highlight column chromatography (silica gel, 230-400 mesh mesh, eluent is a mixture of ethyl acetate:hexane, 1:4) to give 1.40 g (58%) 10CPT.

After conducting 10 STAGES can be cleavage product to optical isomers (enantiomers), it is called in SCHEMES like splitting optical isomers STAGE 10, see wiring Diagram CPT at the end of the description.

STAGE 10 - Splitting optical isomers

To 10CPT (8.0 g, 20 mmol), suspended in 200 ml of methyl tert-butyl ether, add 8.0 g of catalyst PS-30 (Pseudomonas lipase cepaica immobilized on an equal mass celite 521) and 1.85 ml (20 mmol) of vinyl acetate. The resulting suspension is stirred magnetic meshulam ether (3 x 100 ml), the organic solvent was concentrated in vacuo to approximately the volume of a solution of 25 ml. of the Solution is maintained at 0-5oC, the resulting solid product is collected by filtration and washed with hexane (3 x 25 ml), which gives 2,75 g 10CPT (s-enantiomer), []2D5= +3,25oin chloroform (> 99% by HPLC on a column of Chirapak AD, hexane/ISO-propanol, 90: 10, 1 ml/min, 254 nm).

STAGE 11. (10CPT ---> 11CPT)

10CPT (0.565 g, 1.4 mol), 4-acetoxy-TEMPO (0,006 g, 0,028 mmol), potassium bromide (0,0167 g, 0.14 mmol) and sodium bicarbonate (0,0153 r, of 0.182 mmol) are loaded into the flask. Add methylene chloride (7 ml) and water (1 ml) and the mixture is stirred at room temperature for 5 minutes for about 40 min via syringe add sodium hypochlorite solution (1.6 ml, 0.95 M). After adding the reaction stew by adding 5% aqueous solution of sodium metabisulfite. The aqueous phase is separated and extracted with 2 x 5 ml of methylene chloride. The combined organic phases are dried over sodium sulfate and evaporated, getting 0,601 g of a brown syrup. The chemical yield is essentially 100%.

1H NMR (300,13 MHz, CDCl3) of 0.91 (t, J = 7.5 Hz, 3H), of 1.03 (t, J = 7.5 Hz, 3H) and 1.83 (m, 2H), 2,10 (m, 2H), was 4.02 (s, 3H), 4,35 (t, J = 6.6 Hz, 2H), 4,55 (s, 2H), and 4.68 (d, J = 11.7 Hz, 1H), 4,87 (d, J = 11.7 Hz, 1H), 7,35 (m, 5H), 7,78 136,67, 145,05, 150,55, 162,88, 164,93, 200,14.

Nominal mass spectrum: calculated m/z 401, found m/z 402 (M + 1).

Alternative reactions

There are two different ways of reaction in STAGE 12, named By A or B. the Path And has two parts. The second part of the path a, Part 2, has a two way reaction path and, one way, and the path b, two-stage method. The path has three parts. The second intermediate product obtained through the path a, Part 2, path b-1, 12 GA-2, the same as the second intermediate product obtained through the Path, Part 2, 12 GB-2. The third part of the Path B is the same as the second stage of the Path a, Part 2, path b-2. See wiring DIAGRAM CPT at the end of the description.

STAGE 12, the Path a, Part 1. (11CPT ---> 12CPT A-1)

The solution 11CPT (0,206 g, 0.5 mmol) in 6 ml of tert-butanol is mixed with solution of NaH2PO4(0.035 g) in 2 ml of water and cooled to 0o. Add 50% solution of hydrogen peroxide (0,043 ml) and then all quantity of a solution of sodium chlorite (0,076 g, 0,675 mmol) in 0.5 ml of water. After 5 min the reaction stew by adding 1.8 ml of 10% aqueous solution of sodium metabisulfite. The mixture is partitioned between water and methylene chloride and the aqueous phase is extracted 2 times with methylene chloride. The combined organic phase is evaporated, getting 0,200 g (93%) of product 12hz, 1H), to 4.62 (d, J = 11.7 Hz, 1H), and 4.68 (d, J = 11.7 Hz, 1H), equal to 4.97 (d, J = 11.7 Hz, 1H), 7,32 (m, 5H), of 7.90 (s, 1H).

13C NMR (75,47 MHz, CDCl3) 7,83, 10,41, 22,01, 32,15, 54,36, 62,62, 67,31, 72,95, 79,21, 117,39, 121,82, 128,21, 128,52, 136,52, 145,25 152,55, 162,97, 165,01, 176,06.

Nominal mass spectrum: calculated m/z 417, found m/z 418 (M+1).

STAGE 12, the Path a, Part 2, path a (one-stage) (12CTA A-1 ---> 12CPT)

A solution of 12A-1 CPT (0.17 g, 0.40 mmol) and pyridine (0.05 ml, 0.6 mmol) in 5 ml of acetonitrile is stirred at room temperature. Add trimethylsilylmethyl (0.2 ml, 1.4 mmol) and the mixture is stirred over night at room temperature, then heated at 45owithin 48 hours. Add hydrochloric acid (5 ml, 6 n) and the mixture is stirred at room temperature for 15 minutes the Mixture is extracted with 3 x 5 ml ethyl acetate and the combined extracts washed with 5% solution of sodium bisulfite. The ethyl acetate solution is dried over sodium sulfate and evaporated. The remainder chromatographic on silica using a mixture of methylene chloride/methanol (95:5) to give 0.083 g (69%) of product as a pale yellow oil.

1H NMR (300,13 MHz, CDCl3) of 1.02 (m, 6N), of 1.80 (m, 4H), 4,36 (t, J = 6.0 Hz, 2H), 5,22 (d, J = 16.5 Hz, 1H), ceiling of 5.60 (d, J = 16.5 Hz, 1H), 7,40 (s, 1H).

13C NMR (75,47 MHz, CDCl3) 7,66, 10,33, 21,84, the m/z 296 (M + 1).

STAGE 12, the Path a, Part 2, path b-1. (12 CPT-1 ---> 12CPT A-2)

A solution of hydroxy acid 12 CPT A-1 (2.64 g, 6.3 mmol) in 50 ml of methanol is stirred with 10% palladium on coal (0,264 g) in an atmosphere of hydrogen at atmospheric pressure for 2 hours at room temperature. The catalyst was removed by filtration through celite and washed with 10 ml of methanol. The combined filtrate and wash liquid is evaporated, receiving the product (1,82 g, 93%) as a pale yellow highly viscous oil.

1H NMR (300,13 MHz, CDCl3d to 0.88 (t, J = 7.5 Hz, 3H), of 0.97 (t, J = 7,6 Hz, 3H), of 1.76 (m, 4H), 4,0 (s, 3H), 4,25 (t, J = 6.9 Hz, 2H), 5,23 (d, J = 16.2 Hz, 1H), 5,52 (d, J = 16.2 Hz, 1H), a 7.85 (s, 1H).

13C NMR (75,47 MHz, CDCl3) 7,49, 10,32, 21,89, 31,88, 54,08, 65,53, 67,22, 72,72, 114,79, 115,22, 146,01, 148,91, 158,50, 164,51, 173,53.

STAGE 12, the Path a, Part 2, path b-2 (12 CPT A-2 ---> 12 CPT)

The solution hydroxyacetone 12CPT A-2 (1,93 g, 6.2 mmol) and sodium iodide (1.86 g, 12.4 mmol) in 30 ml of acetonitrile was stirred at 0o. Add trimethylsilylmethyl (1.6 ml, 12.4 mmol) and the mixture is stirred and allowed to warm to room temperature for 12 hours. Add a further quantity of sodium iodide (0.9 g, 6.2 mmol) and trimethylsilylacetamide (0.8 ml, 6.2 mmol) and stirring is continued for more than 6 hours. Add 1 n hydrochloric to the keys in ethyl acetate (30 ml) and the aqueous phase extracted with additional 30 ml of ethyl acetate. The combined organic phases are washed with water, dried over sodium sulfate and evaporated, receiving the product as a pale yellow solid (1.84 g, 100%).

1H NMR (300,13 MHz, CDCl3) of 1.02 (m, 6N), of 1.80 (m, 4H), 4,36 (t, J = 6.0 Hz, 2H), 5,22 (d, J = 16.5 Hz, 1H), ceiling of 5.60 (d, J = 16.5 Hz, 1H), 7,40 (s, 1H).

13C NMR (75,47 MHz, CDCl3) 7,66, 10,33, 21,84, 31,88, 66,07, 68,68, 72,32, 107,10, 124,45, 134,41, 149,99, 159,80, 173,26, 176,63.

Nominal mass spectrum: calculated m/z 295, found m/z 296 (M + 1).

STAGE 12, the Path B, Part 1 (11 CPT ---> 12 CPT B-1)

Hydroxyaldehyde 11CPT (2,62 g, 6.6 mol) is dissolved in 30 ml of methanol and stirred with 10% palladium on coal (0.26 g) in hydrogen atmosphere at atmospheric pressure. The reaction is terminated after 96 hours. The catalyst was removed by filtration through celite and washed with 10 ml of methanol. The combined filtrate and wash liquid is evaporated, receiving of 1.97 g (96%) of product as a white solid.

1H NMR (300,13 MHz, CDCl3) 0,84 (t, J = 7.5 Hz, 3H), of 0.95 (t, J = 7.4 Hz, 3H), at 1.73 (m, 4H), to 3.89 (s, 3H), 4,24 (t, J = 6,7 Hz, 2H), 4,57 (d, J = and 17.2 Hz, 1H), 4,73 (d, J = and 17.2 Hz, 1H), 7,86 (s, 1H).

13C NMR (75,47 MHz, CDCl3) 7,53, 10,36, 21,94, 31,70, 53,69, 58,31, 67,04, 70,68, 93,26, 116,57, 120,38, 143,54, 148,98, 158,48, 165,34.

STAGE 12, the Path B, Part 2 (12CPT B-1 ---> 12CPT B-2)

Rest,04 g 0.25 mmol), sodium bicarbonate (of 0.081 g, 0.96 mmol) and potassium bromide (0,088 g of 0.74 mmol) in 3 ml of water. Within 30 minutes, added dropwise a solution of sodium hypochlorite (12%, approximately 12 ml). To decompose the excess sodium hypochlorite is added sodium bisulfite (1.0 g). The aqueous phase is extracted with methylene chloride (10 ml) and the combined organic phases are washed once with water (10 ml) and dried over sodium sulfate. The solvent is evaporated, receiving the product (1.90 g, 99%) as oil, which solidifies upon standing.

1H NMR (300,13 MHz, CDCl3d to 0.88 (t, J = 7.5 Hz, 3H), of 0.97 (t, J = 7,6 Hz, 3H), of 1.76 (m, 4H), 4,0 (s, 3H), 4,25 (t, J = 6.9 Hz, 2H), 5,23 (d, J = 16.2 Hz, 1H), 5,52 (d, J = 16.2 Hz, 1H), a 7.85 (s, 1H).

13C NMR (75,47 MHz, CDCl3) 7,49, 10,32, 21,89, 31,88, 54,08, 65,53, 67,22, 72,72, 114,79, 115,22, 146,01, 148,91, 158,50, 164,51, 173,53.

STAGE 12, the Path B, Part 3. (12 CPT-2 ---> 12 CPT)

This stage is identical to STAGE 12 and the applied methods are the same as in STAGE 12.

STAGE 13, the Path a, Part 2, path b-2. (12 CPT ---> 13 CPT)

12 CPT (10.1 g, 0,339 mol), cesium carbonate (22,0 g 0,067 mol), tert-butyl acrylate (25 ml, 0,169 mol) and DMSO (150 ml) was stirred at 47-50ofor 19 hours. The mixture is cooled and add 20 ml of concentrated hydrochloric acid and 180 ml of water. The mixture is extracted 4 times using pariwat to get the oil. Add 200 ml of toluene and the solution is concentrated and receiving 13CPT in the form of crystalline MES 1:1 with toluene (11,5 g, 67%).

1H NMR (300,13 MHz, CDCl3) to 0.92 (t, J = 7.4 Hz, 3H), 1.50 in (C, N), 1,71-to 1.79 (m, 2H), 2,28 (s, 3H), 4,59 (s, 2H), 5,16 (d, J = 17,8 Hz, 1H), 5,61 (d, J = 17,8 Hz, 1H), 6,94 (s, 1H), 7,0-7,2 (m, 5H).

13C NMR (75,47 MHz, CDCl3) 7,64, 21,38, 28,20, 31,41, 49,27, 66,13, 72,50, 83,55, 97,80, 105,69, 118,59, 125,22, 128,14, 128,95, 137,78, 143,82, 149,48, 156,84, 159,26, 166,02, 173,60.

STAGE 14. (13CPT ---> 14CPT)

MES 13CTP-toluene (70,3 g, 0,153 mol) is dissolved in 1400 ml of toluene and 140 ml triperoxonane acid and heated at 110owithin 2 hours. The solution is cooled and concentrated in vacuo to approximately 350 ml Add ethyl acetate (1 l) and the mixture is cooled to -20o. After filtration receive 14 CPT in the form of a light brown crystalline solid product (37,92 g, 93,4%).

1H NMR (300,13 MHz, CDCl3) and 0.98 (t, J = 7.5 Hz, 3H), 1,80 (kV, J = 6.0 Hz, 2H), 2,96 (m, 2H), 4,36 (t, J = 6 Hz, 2H), 5,24 (d, J = 15 Hz, 1H), to 5.66 (d, J = 15 Hz, 1H), 7,27 (s, 1H).

13C NMR (300,13 MHz, DMSO-d6) to 0.80 (t, J = 7,3 Hz, 3H), of 1.81 (m, 2H), 2,89 (t, J = 6.3 Hz, 2H), 4,13 (t, J = 6.3 Hz, 2H), of 5.34 (d, J = 17,1 Hz, 1H), 5,41 (d, J = 17,1 Hz, 1H), 6,86 (s, 1H).

13C NMR (75,47 MHz, DMSO-d6) 7,52, 30,31, 33,71, 42,56, 65,20, 71,92, 98,49, 123,81, 140,19, 149,05, 156,97, 172,03, 197,93.

But/BR> This invention also includes the following reactions, methods and formulas contained in figure 1 (see end of description)

The following links may be useful for understanding the above described more reactions. Getting U-503 from natural camptothecin described in U.S. patent 4473692 (September 25, 1984), T. Miyasaka, S. Sawada, K. Nokata, M. Mutai. The associated receiving U-440 from U-503 is described in U.S. patent 4604463 (August 5, 1986), T. Miyasaka, S. Sawada, K. Nokata, E. Sugino, M. Mutai. The transformation of the U-440 CPT-11 is described in: S. Sawada, S. Okajima, R. Aiyama, K. Nokata, T. Furuta, T. Yokohura, E. Siguno, K. Yamaguchi, T. Miyasaka, Chem. Pharm. Bull., 1991, volume 39, pp. 1446-1454.

The reaction shown in the above Scheme Disclosed Additional Reactions are described below.

Getting U-503 and U-440

U-727 and U-772 subjected to reaction at a temperature of from 95o100oin a mixture of toluene and acetic acid for about 18-24 hours. Toluene and acetic acid is removed by distillation, obtaining U-503, which turn without purification in the U-440.

Untreated U-503 is dissolved in pyridine and subjected to reaction at a temperature of 20oup to 25o4-piperidinecarbonitrile dissolved in methylene chloride. Methylene chloride and pyridine is removed by distillation and the crude U-440 is again dissolved on silica gel, elwira mixture of methylene chloride and methanol, and isolated in the form of a crystalline solid product by crystallization from a mixture of methylene chloride and ethanol.

U-503. U-727 (of 1.05 g, 4.0 mmol), U-772 (0,62 g, 3.8 mmol) and the monohydrate of p-toluenesulfonic acid (0.02 g) is mixed with toluene (10 ml) and acetic acid (10 ml) and heated for 18 to 24 hours at a temperature of from 95o100o. During the reaction gradually precipitates U-503. When the reaction ends, toluene, and acetic acid is removed by distillation under reduced pressure, obtaining U-503 in the form of a solid mass.

U-440. To the crude U-503 added pyridine (15 ml) and the mixture is stirred for 15 minutes at a temperature of 20oup to 25ofor dissolution of U-503. Add a solution of 4-piperidinecarboxylate (1,32 g, 5.7 mmol) in methylene chloride (5 ml). The mixture was stirred at 20-25owithin 2 hours to complete the reaction. The mixture is distilled to dryness under reduced pressure. Add toluene (20 ml) and the mixture is distilled almost to dryness under reduced pressure.

Untreated U-440 dissolved in methylene chloride (25 ml), add saturated aqueous sodium bicarbonate solution (5 ml) and the mixture is stirred at room temperature for 5 minutes the Phases give a combined and redistilled, give crude solid U-440.

The crude solid U-440 dissolved in a mixture of methylene chloride/methanol (95:5, vol. /about. 10 ml) and chromatographic on a column filled with 30 g of silica 230-400 mesh mesh, elwira a mixture of methylene chloride/methanol (95:5, vol/vol.). The fractions containing the product are combined and distilled to a volume of about 10 ml at atmospheric pressure. At the end of the distillation may be some crystallization of the product. Add ethanol (15 ml) and the suspension allowed to stand at -20oC for 24 hours. The product is filtered, washed with ethanol (10 ml) and dried, obtaining of 1.34 g (yield 62%, counting on 16CPT) U-440.

METHODS, REACTIONS AND CONNECTION DIAGRAMS M-M AND M-G

Chiral restoration for the synthesis mappila and related compounds are shown in SCHEMES M-G and M-M Precursors of these compounds are described previously mentioned reaction SCHEME G.

There are a number of reagents available for recovery ketones for obtaining chiral secondary alcohols. Arylalkylamine, similar in structure to the intermediate product shown in SCHEMES for mappila, are particularly suitable substrates for chiral restoration. Among the reagents which are effective for this type of recovery, there is C>, boranova reductants catalyzed by chiral oxazaborolidine3and complexes of sociallyengaged and alcohol darvon4.

1. R. Noyori, I. Tomino and Y. Tanimoto, J. Am. Chem. Soc, 1979, 101, 3129: R. Noyori. U. S. patent 4284581.

2. S. Itsuno, K. Ito, A. Hirao, and S. Nakahama, J. Chem. Soc. Chem. Comm. , 1983, 469. S. Itsuno, M. Nakano, K. Miyazaki, H. Masuda, K. Ito, A. Hirao, and S. Nakahama. J. Chem. Soc. Perkin I, 1985, 2039.

3. E. J. Corey, R. K. Bakshi, S. Shibate. J. Am. Chem. Soc., 1987, 5551.

4. N. Cohen, R. J. Lopresti, C. Neukom, G. Saucey. J. Org. Chem., 1980, 45, 582.

The above reaction products and intermediate products can then be subjected to reaction for obvious options condensation type Friedlander to obtain the target products, such as foods shown in the charts below.

The following is one specific example, showing in detail the conditions of the reactions shown in SCHEMES M-G and M-m

5MM. 4CPT (10.0 g, 41,0 mmol) is dissolved in 500 ml of heptane. The solution is cooled to 0oC and add to 24.4 ml of n-BuLi in hexane (2.10 M, a 51.2 mmol), maintaining a reaction temperature of 0oC. Bright orange suspension was stirred at 0oC for 1.75 hours. Add dimethylsulfate (4.8 ml, a 51.2 mmol), maintaining the reaction temperature below 10oC. the Reaction mixture was stirred at 0oC for 2 h and ZAT is dobavlaut water (40 ml) and ethyl acetate (EtOAc, 75 ml). After 15 minutes, the phases are separated and the aqueous phase is extracted 3 times with 50 ml EtOAc. The organic extracts are combined, dried over Na2SO4filter and concentrate to obtain a red oil. Purification with flash chromatography (CH2Cl2) get 5MM (6,97 g, 66%) as a clear, colorless oil: MS (electron ionization, EI) m/z 257, 259: MS (chemical ionization, HEE)) m/z (-NH3+) 258, 260;

1H NMR (300,14 MHz, CDCl3) was 7.08 (s, 1H), 4,05-4,01 (m, 2H), of 3.97 (s, 3H), 3,80 of 3.75 (m, 2H), 2,28 (s, 3H), of 1.93 (DD, J = 7,4, and 14.9 Hz), of 0.91 (t, J = 7.4 Hz);13C NMR (75,47 MHz) 162,9, 153,3, 144,9, 116,9, 114,4, 110,1, 64,5, 54,2, 31,5, 12,0, 7,4.

6MM. 5MM (12.0 g, 46 mmol) is dissolved in 25 ml of water triperoxonane acid (64%, about. /about. ) and heated to 40oC. After 4 h the reaction mixture is cooled and stew 50 ml of H2O and 75 ml of a mixture of EtOAc:heptane (2:1, vol/vol.). The phases are separated and the aqueous phase is extracted 3 times with 40 ml of a mixture of EtOAc/heptane (2: 1). The organic extracts are combined and neutralized by washing with 200 ml of 9% (wt./about.) aqueous NaHCO3. The phases are separated and the aqueous phase is extracted 3 times with 50 ml EtOAc. The combined organic phases, dried (Na2SO4), filtered and concentrated to give 10 g of a yellowish oil. The crude product is injected directly into C14, 216:

1H NMR (300,14 MHz, CDCl3) to 6.88 (s, 1H, 3,99 (s, 3H), 2,82 (DD, J = 7,2, 14,5 Hz) of 2.16 (s, 3H), 1,19 (t, J = 7.2 Hz);13C NMR (75,47 MHz) 204,2, 162,6, 150,5, 145,5, 116,3, 113,0, 54,4, 35,9, 11,8, 7,6.

6b. Raw 6MM (10 g, about 46 mmol) is dissolved in 100 ml of MeOH and cooled to 0oC. Immediately add all the number of their solution of 2.18 g of NaBH4(58 mmol) in 20 ml of 50% aqueous MeOH. After 20 min the reaction stew 50 ml of aqueous HCl (1 M, 50 mmol) and then diluted with 100 ml of CH2Cl2and 10 ml of water. The phases are separated and the aqueous phase is extracted 3 times with 50 ml of CH2Cl2. The organic extracts are concentrated to yield a white solid material. This solid material is recrystallized from hexane, getting 6b (8,54 g, 85% from 5MM) in the form of long needles: so pl. = 97,0 - 97,5oC; MS (EI) m/z 215, 217: MS (HEE) m/z (-NH3+) 216, 218;1H NMR (300,14 MHz, CDCl3) 7,05 (s, 1H), 4,85 - to 4.81 (m, 1H), 3,95 (s, 3H), of 2.08 (s, 3H), 1,76 - to 1.63 (m, 2H), and 0.98 (t, J = 7.4 Hz);13C NMR (75,47 MHz) 161,8, 155,6, 145,4, 115,0, 113,1, 71,0, 54,1, 30,4, 10,5, 9,8.

7MM 6b (4,00 g, 18.5 mmol) and sodium hydride (1.55 g, a 64.6 mmol) is stirred with 40 ml of THF for 30 minutes Add benzylbromide (2,3 ml of 18.9 mmol) and the mixture is stirred for 8 hours at room temperature. Add a saturated solution of ammonium chloride (10 ml), cabbage soup 1 M HCl prior to extraction 3 times with 20 ml of CH2Cl2. The combined organic phases, dried (NaSO4), filtered and concentrated to formation of a yellow oil. After flash chromatography on silica gel get 7MM (5,09 g, 90%) as a clear oil: MS (EI) m/z 305, 307; MS (HEE) m/z (-NH3+) 306, 308;1H NMR (300,14 MHz, CDCl3) 7,38 - to 7.32 (m, 5H), 7,07 (s, 1H), 4.53-in - to 4.46 (m, 2H), 4.26 deaths (d, J = 11.7 Hz, 1H), 4.00 points (s, 3H), of 2.09 (s, 3H), 1,83 - of 1.62 (m, 1H), and 0.98 (t, J = 7,3 Hz, 3H);13C NMR (75,47 MHz) 162,0, 154,0, 145,6, 137,9, 128,4, 127,8, 127,7, 116,3, 113,8, 78,0, 71,0, 54,2, 29,5, 10,5, 10,1.

8MM 7MM (of 4.00 g of 13.1 mmol), potassium acetate (1.92 g, a 19.6 mmol), palladium acetate (0,147 g of 0.65 mmol) and DPPP (0,268 g of 0.65 mmol) dissolved in 80 ml of DMF and 40 ml of n-propanol. The flask is rinsed CO and then heated to 85oin an atmosphere of CO. After 25 min the mixture is cooled and rinsed with nitrogen, the solution is filtered through celite and the filtrate is concentrated and then partitioned between 80 ml of water and 160 ml of MTBE. The aqueous phase is then extracted 3 times with 50 ml MTBE. The organic extracts are combined, washed 4 times in portions of 25 ml of water, dried (Na2SO4), filtered and concentrated. After purification with flash chromatography using as eluent CH2Cl2get 8MM (4,14 g, 89%) as a clear, colorless oil: MS (EI) m/z 358; MS (HEE) m/z (-NH3+) 358, 360;109 (C, 3H), of 2.18 (s, 3H), 1,90 and 1.80 (m, 3H), 1,78 - of 1.64 (m, 2H), 1.06 a (t, J = 7.4 Hz), of 0.97 (t, J = 7,4 Hz):13C NMR (75,47 MHz) 165,5, 162,3, 151,5, 142,8, 138,0, 128,3, 127,8, 127,7, 122,9, 116,5, 78,1, 70,9, 66,8, 53,8, 29,5, 22,0, 11,3, 10,4, 10,2.

9MM Solution of sodium iodide (1.89 g, 12.6 mmol) and 8MM (3.00 g, 8.4 mmol) and 30 ml of CH3CN cooled to 0oC and add trimethylsilane (1.6 ml, 12.6 mmol). After 15 min the reaction mixture is allowed to warm to room temperature. After 24 h the reaction stew sequential addition of 4.2 ml of 6 M HCl, with 5.3 ml of a saturated solution of sodium chloride, to 10.6 ml of H2O, 0.4 ml of 38% Na2S2O5(water) and 20 ml of EtOAc. After stirring at room temperature for 30 minutes the phases are separated and the aqueous phase is extracted 3 times with 10 ml EtOAc. The organic solutions are combined and washed with 7 ml of saturated NaHCO3and 0.25 ml of 38% aqueous solution of sodium bisulfite. After stirring for 15 minutes the phases are separated and the organic solution is washed 2 times with 10 ml of a saturated aqueous solution of sodium chloride. The solution is dried over Na2SO4, then filtered and concentrated, obtaining 2,80 g (97%) 9MM in the form of a waxy yellow-white solid: MS (EI) m/z 343, 344; MS (HEE) m/z (-NH3+) 344, 345; 1H NMR (300,14 MHz, CDCl3) 9,82 (Shir. C), 7,39 - 7,29 (m, 6N),0,41, 137,63, 133,04, 130,54, 128,40, 127,87, 108,01, 77,76, 71,13, 67,95, 28,80, 21,84, 12,04, 10,29, 10,06.

10MM. The mixture 9MM (3,22 g, 9.4 mmol), cesium carbonate (6,12 g of 18.8 mmol), tert-butyl acrylate (13,5 ml, was 92.3 mmol) and 50 ml of DMSO is heated to 65oC in nitrogen atmosphere. After 3 hours the reaction mixture was cooled to 0oC and then slowly stewed 60 ml of 0.5 M HCl, while maintaining throughout the internal temperature of the 15oC or below. The mixture is diluted with 30 ml of a mixture of EtOAc/toluene (1:4, vol/about.) and the phases are separated. The aqueous phase is extracted 2 times with 30 ml of the above solvent. The organic extracts are combined and washed 3 times with 30 ml of water, dried over Na2SO4filter and concentrate to obtain of 4.57 g of yellow oil. After purification column chromatography receive 3.28 g 10MM in the form of a foamy whitish solid (85%): MS (EI) m/z 411, 412; MS (HEE) m/z (-NH3+) 412, 413;1H NMR (300,14 MHz, CDCl3) to 9.91 (Shir. C), 7,39 - 7,29 (m, 5H), 6,91 (s, 1H), 4,67 (s, 2H), to 4.52 - 4,48 (m, 2H), 4.26 deaths (d, J = 11.8 Hz, 1H), 2,18 (s, 3H), 1,87 - of 1.78 (m, 1H), 1,73 - of 1.53 (m, 2H), 1,59 (s, N), of 0.97 (t, J = 7.4 Hz, 3H):13C NMR (75,47 MHz) 166,61, 160,77, 160,28, 150,69, 140,25, 137,89, 128,35, 127,77, 127,69, 126,63, 103,99, 99,13, 82,95, 78,02, 70,88, 49,08, 29,01, 28,25, 27,87, 11,84, 10,07.

11MM 10MM Solution (0.25 g, 0.61 mmol), triperoxonane acid (0.45 ml) and toluene (18 ml) is diluted with 20 ml of toluene and concentrated to formation of a thick oil. The oil is purified flash chromatography (5% MeOH in CH2Cl2), receiving was 0.138 g 11MM in the form of a foamy yellow solid (73%): MS (EI) m/z; MS (HEE) m/z (-NH3+); 1H NMR (300,14 MHz, CDCl3) 7,27 - to 7.18 (m, 5H),? 7.04 baby mortality (s, 1H), 4,43 - to 4.38 (m, 2H), 4,23 - 4,13 (m, 3H), 2,80 (t, J = 6.9 Hz), is 2.09 (s, 3H), 1.75 is to 1.47 (m, 2H), 0,86 (t, J = 7.4 Hz, 3H); 13C NMR (75,47 MHz) 196,91, 161,48, 150,48, 137,67, 136,95, 132,94, 128,36, 127,71, 102,40, 77,77, 70,97, 41,92, 33,69, 28,90, 12,41, 9,98.

12MM Solution 11MM (is 0.135 g, 0.43 mmol), N-Boc-o-aminobenzaldehyde (0.14 g, to 0.63 mmol), p-toluenesulfonic acid (0,010 g, 0.06 mmol), glacial acetic acid (5 ml) and toluene (25 ml) is heated to 100oC. After 36 h, the solution was concentrated in vacuo to dryness. The residue is dissolved in 25 ml of toluene and then concentrated to obtain of 0.333 g of red-brown solid material. Material purified flash chromatography (2% MeOH in CH2Cl2), receiving 0,123 g 12MM in the form of a foamy yellow solid product (72%): MS (EI) m/z 396, 398; MS (HEE) m/z (-NH3+) 397, 399;1H NMR (300,14 MHz, CDCl3) of 8.33 (s, 1H), they were 8.22 (d, J = 8.5 Hz, 1H), of 7.90 (d, J = 8,1 Hz, 1H), 7,80 (t, J = 7 Hz, 1H), of 7.64 - EUR 7.57 (m, 2H), 7,38 - 7,29 (m, 5H), 5,28 (s, 2H), with 4.64 - of 4.54 (m, 2H), 4,32 (d, J = 12 Hz, 1H), of 2.25 (s, 3H), 1,99 - to 1.67 (m, 1H), of 1.02 (t, J = 7,3 Hz);13C NMR (75,47 MHz) 161,51, 153,51, 151,30, 148,78, 142,67, 138,12, 130,67, 130,12, 129,56, 128,64, 128,33, 127,98, 127,76, 127,60, 127,29, 126,87, 99,51, 78,18, 70,81, 49,91�are stated here briefly and appear at the end of the description. A detailed description is provided above. SCHEME G is a General description, showing the generic structure included in the reaction. After receiving the connection designated 4G, there are two different ways of reactions by which one can act. One proceeds according to SCHEME G, and ultimately results in camptothecin or related compounds. Another way, the CIRCUIT M-G ultimately results in mappila or related compounds.

SCHEME CPT-11 is a specific embodiment of one type of CIRCUIT G, which indicates the specific reactions and intermediates, leading to the obtaining of camptothecin. SCHEME M-M represents a specific embodiment of one type of CIRCUIT M, which indicates the specific reactions and intermediates leading to mappila.

Stage 10 in the SCHEMES G and CPT-11 shows the breakdown of the enantiomers. Although shown only one enantiomer, you can select other enantiomer using suitable starting materials and by developing the necessary modifications that should be obvious to a person skilled in this field. These methods, moreover, must be suitable, regardless of the metric center, these methods, when necessary, with appropriate modifications, can be applied to obtain any enantiomer. When there are two asymmetric center may be shown stereochemistry only one of the two centers. When the molecule has two asymmetric center, the methods usually lead to the cleavage of only one asymmetric center, the splitting of the second heart does not usually occur. The development of an appropriate modifications to the methods of the present invention in combination with the methods available for ordinary specialist in this area, you can achieve complete separation of all four stereoisomers of molecules having two asymmetric center.

SCHEME M-G and G-G show one enantiomer bold line showing the orientation, however, the other enantiomer is possible as well to receive and allocate using methods well-known specialist in this field. These methods should be applicable regardless of whether you have selected enantiomer or mixture of enantiomers. Other enantiomers SCHEMES M-G and G-G are in some claims, where the orientation shown in bold solid line or a dotted line.

Hydrogen atoms and saedinaiushaia indicated only links instead of the letter "C".

Listed below are the various schemes.

1. Intermediate derivatives camptothecin General formula I

< / BR>
where Rarepresents a chlorine atom, a lower alkoxygroup;

Rbrepresents a hydrogen atom, a C1-8alkyl, hydroxys1-8alkyl, a group-C(O)H or a group

< / BR>
Rcrepresents a group selected from the following range:

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
or Rband Rctogether form a residue of the formula

-CH2-O-C(O)-C(OH)(R6)- or-CH2-O-CH(OH)-C(OH)(R6)-;

Rdrepresents a chlorine atom or a group C(O)or SIG4;

R3represents a hydrogen atom or benzyl;

R4represents a C1-8alkyl;

R5represents a hydrogen atom;

R6represents a C1-8alkyl;

R7represents a hydrogen atom.

2. Connection on p. 1 represented by a formula shown below

< / BR>
where R6represents a C1-8alkyl,

for example, is represented by the formula shown below

< / BR>
3. Connection on p. 1 represented by a formula shown below

< / BR>
where R6before the begins on p. 1, represented by the formula shown below

< / BR>
where R1represents a C1-8alkyl;

R2represents a hydrogen atom, a C1-8alkyl, hydroxys1-8alkyl or a group S(O)R3;

R6represents a C1-8alkyl;

R3represents a hydrogen atom,

for example, is represented by the formula shown below

< / BR>
< / BR>
or bisulfate adduct compounds of formula 5A CPT;

< / BR>
or

< / BR>
5. Connection on p. 1 represented by a formula shown below

< / BR>
where R1represents a C1-8alkyl;

R3represents benzyl;

R6represents a C1-8alkyl;

R7represents a hydrogen atom,

for example, is represented by the formula shown below

< / BR>
6. Connection on p. 1 represented by a formula shown below,

< / BR>
where R1represents a C1-8alkyl;

R3represents benzyl;

R4represents a C1-8alkyl;

R6represents a C1-8alkyl;

R7represents a hydrogen atom,

for example, is represented by the formula shown below

< / BR>
7. The connection is silt;

R3represents benzyl;

R7represents a hydrogen atom,

for example, is represented by the formula shown below

< / BR>
8. Connection on p. 1 represented by a formula shown below

< / BR>
where R1and R6are1-8alkyl;

R3represents benzyl;

R7represents a hydrogen atom,

for example, is represented by the formula shown below

< / BR>
9. Connection on p. 1 represented by a formula shown below

< / BR>
where R1and R6are1-8alkyl;

R3represents benzyl;

R5and R7represents a hydrogen atom,

for example, is represented by the formula shown below

< / BR>
10. Connection on p. 1 represented by a formula shown below

< / BR>
where R1and R6are1-8alkyl;

R3represents benzyl;

R7represents a hydrogen atom,

for example, is represented by the formula shown below

< / BR>
11. Connection on p. 1 represented by a formula shown below

< / BR>
where R1, R4and R6are1-8alkyl;

R3represents the following

< / BR>
12. Connection on p. 1 represented by a formula shown below

< / BR>
where R1and R6are1-8alkyl;

R3represents benzyl;

R7represents a hydrogen atom,

for example, is represented by the formula shown below

< / BR>
13. Connection on p. 1 represented by a formula shown below

< / BR>
where R1, R4and R6submit C1-8alkyl,

R3represents benzyl;

R7represents a hydrogen atom,

for example, is represented by the formula shown below

< / BR>
and optical isomers of compounds of formula 10, CPT, represented by the formulas shown below

< / BR>
< / BR>
14. Connection on p. 1 represented by a formula shown below

< / BR>
where R1, R4and R6submit C1-8alkyl;

R3represents benzyl;

R7represents a hydrogen atom,

for example represented by the formulas shown below

< / BR>
and its optical isomers

< / BR>
< / BR>
15. Connection on p. 1 represented by a formula shown below

< / BR>
where R1, R4and R6submit C1-8alkyl;

R3presti, shown below

< / BR>
and its optical isomers

< / BR>
< / BR>
16. Connection on p. 1 represented by a formula shown below

< / BR>
where R1, R2and R6are1-8alkyl,

for example, is represented by the formula shown below

< / BR>
17. Connection on p. 1 represented by a formula shown below

< / BR>
where R1, R2and R6submit C1-8alkyl;

R3represents benzyl, hydrogen,

for example represented by the formulas shown below

< / BR>
< / BR>
< / BR>
or formulas 7MM

< / BR>
< / BR>
< / BR>
18. Connection on p. 1 represented by a formula shown below

< / BR>
where R1, R2, R4and R6are1-8alkyl;

R3represents benzyl,

for example represented by the formulas shown below

< / BR>
< / BR>
< / BR>
19. Connection on p. 1 represented by a formula shown below

< / BR>
where R1, R4and R6submit C1-8alkyl,

for example represented by the formulas shown below

< / BR>
< / BR>
< / BR>
20. Connection on p. 1 represented by a formula shown below

< / BR>
where R1, R4and R6are1-8
< / BR>
where Rarepresents a hydrogen atom;

Rbrepresents a C1-8alkyl;

Rcrepresents a group

Rdrepresents a group

or Raand Rdtogether form a residue of the formula

-CH2-C(C(O)OR8)=C(OH)-

or

-CH2-CH2-C(O)-,

Rband Rctogether form a residue of the formula

-CH2-O-C(O)-C(OH)(R6)-

or

R3represents benzyl,

R4, R6and R8represent1-8alkyl.

22. Connection on p. 21 represented by the formula shown below

< / BR>
where R4and R6are1-8alkyl,

for example, is represented by the formula shown below

< / BR>
and its optical isomers

< / BR>
< / BR>
23. Connection on p. 21 represented by the formula shown below

< / BR>
where R6and R8are1-8alkyl,

for example, is represented by the formula shown below

< / BR>
and its optical isomers

< / BR>
< / BR>
24. Connection on p. 21 represented by the formula shown below

< / BR>
where R2, R4and R6are1-8alkyl;

R3is b
< / BR>
25. Connection on p. 21 represented by the formula shown below

< / BR>
where R2, R6and R8are1-8alkyl;

R3represents benzyl,

for example, is represented by the formula shown below

< / BR>
and its optical isomers

< / BR>
< / BR>
26. Connection on p. 21 represented by the formula shown below

< / BR>
where R2and R6are1-8alkyl;

R3represents benzyl,

for example, is represented by the formula shown below

< / BR>
and its optical isomers

< / BR>
< / BR>
27. Intermediate derivatives camptothecin General formula III

< / BR>
where Rarepresents a C1-8alkyl;

Rbrepresents a group

R3represents benzyl;

R6represents a C1-8alkyl.

28. Connection on p. 27 represented by a formula shown below

< / BR>
where R2and R6submit C1-8alkyl;

R3represents benzyl,

for example, is represented by the formula shown below

< / BR>
and its optical isomers:

< / BR>
< / BR>
29. The method of obtaining compounds of formula I on p. 1, namely, that either: (1) mixed 2,6-who IRNA solvent followed by treatment of the reaction product with dilute acid, or 2) convert 2,6-dichlorophenylamino acid into its acid chloride with subsequent transformation into the Weinreb amide and then mixed with a nucleophile, which is either a Grignard reagent or alkylate, and the ether solvent, followed by treatment of the reaction product with dilute acid, which results in obtaining the compounds of formula 2G, which, if necessary, mixed with diola in the presence of trimethylchlorosilane that leads to obtaining the compounds of formula 3G, which, if necessary, is mixed with sodium alkoxide or potassium in a solvent, which results in obtaining the compounds of formula 4G, where R2represents H, which, if necessary, is mixed with the solvent and alkyllithium base or abillities the basis for education pyridyl anion, which is then mixed with the electrophile, the product of this mixing and then mixed with acid and then produce the final product of formula 5G, in free form or mixed with sodium bisulfite and isolated in the form of a bisulfite adduct, or a compound of formula 4G, where R2represents H, or a compound of formula 5G mixed with a reducing agent that leads to the production of other compounds of formula 4G or 5G (5MG), and, if necessary, the connection is renosa phases using water and an organic solvent, that leads to the production of the compounds of formula 6G, which, if necessary, is mixed with carbon monoxide and an alcohol in the presence of soluble salts of palladium II, phosphine ligand and a base in a polar aprotic solvent, which results in obtaining the compounds of formula 7GG, or in connection formula 6G, if necessary, remove ketal a) mixing of this product with water in the presence of a strong acid or (b) the use of the exchange reaction for removal of ketala that leads to obtaining the compounds of formula 7GA, or, if necessary, in the compound of formula 7GG remove ketal a) by mixing with water in the presence of a strong acid or (b) the use of the exchange reaction for removal of ketala that leads to obtaining the compounds of formula 8GG, or, if desired, the compound of formula 7GA dissolved in a solvent and mixed with vinyllithium or wikimanialang that leads to obtaining the compounds of formula 8GA, or, if desired, the compound of formula 7GA mixed with a solution of ilide and solvent for carrying out the Wittig reaction, which results in obtaining the compounds of formula 8GB, or, if desired, the compound of formula 8GG mixed with a solution of ilide and solvent for the reaction of Wittig which leads to Polly obtain an intermediate product, which restore, either directly or through an intermediate product, 9GA, or, if desired, the compound of formula 9GG turn in the diol of formula 10G-ominirovaniya under standard conditions, or, if desirable, the connection 10G obtained by mixing the compounds of formula 9GA with carbon monoxide and an alcohol in the presence of soluble salts of palladium II, phosphine ligand and a base in a polar aprotic solvent, or, if desired, the compound of formula 10G can be separated into the enantiomers by processing racemic diol azetiliruet reagent, or, if desired, the compound of formula 10G is subjected to oxidation to hydroxyaldehyde either a) in the conditions of Swern type, or b) two-phase system containing water and an aprotic solvent, which results in obtaining the compounds of formula 11G, which, if necessary, is subjected to oxidation, which leads to the production of the compounds of formula 12GA-1, or which is removed leaving group, resulting in the compounds of formula 12GB-1, or, if desirable, in the compound of formula 12GA-1 is removed leaving group, resulting in the compounds of formula 12GA-2 or 12GB-2, or, if desirable, lactol formula 12GB-1 oxidizes, resulting in the compounds of formula 12GA-2 6MG, which, if necessary, restore obtaining the compounds of formula 7MG, where R3represents H, or formula 6b, racemate or any isomer, or, if desired, the compound of formula 7MG where3is H, then mixed with the base and the alkylating agent in a solvent, which results in obtaining the compounds of formula 7MG, where R3does not represent H, or formula 7, racemate or any isomer, or, if desired, the compound of formula 7MG mixed with carbon monoxide and an alcohol in the presence of soluble salts of palladium II, phosphine ligand and a base in a polar aprotic solvent, which results in obtaining the compounds of formula 8MG or formula 8MM or isomer or racemate.

30. The method according to p. 29, characterized in that the process for obtaining compounds of 2G is preferably carried out at a temperature from about -30°to about +10°C, which results in obtaining the compounds of formula SRT.

31. The method according to p. 29, characterized in that in the process of getting a 3G connection diol is a glycol, the process is preferably carried out at about 0 To 60°C and the compound represented by formula SRT.

32. The method according to p. 29, characterized in that when a connection is 4G, where R2onto when the connection is 5G, the solvent is selected from diethyl ether, tetrahydrofuran or 1,2-dimethoxyethane or hydrocarbons, such as toluene, hexane, heptane, cyclohexane or isooctane, or mixtures of any of these solvents, alkality selected from metallice, n-utility, sec-utility or tert-utility, or a mixture of any of these grounds, the electrophile is formamid, including dimethylformamide, N-formylpiperidine, or N-formylmorpholine, or N-methylformamide, or similar formamide, or a mixture of any of these formamido, the interaction is carried out at a temperature between about -40 and about +50°C., preferably at a temperature between about -5 and about +5°C, the product emit diluted acid that is selected from acids from moderate to strong, for example hydrochloric acid, acetic acid, or sulfuric acid, or mixtures of any of these acids, and where the resulting compound may have the formula asrt.

34. The method according to p. 29, wherein the bisulfite adduct asrt then mixed with an acid or a base to obtain a compound represented by the formula asrt.

35. The method according to p. 29, characterized in that for obtaining the compounds of formula 4G or 5G recovery, the reducing agent is a hydride such as sodium borohydride is a two-phase condition is water and organic phase, such as heptane, methylene chloride or methyl tert-butyl ether or mixtures of these solvents, and the resulting compound may have the formula SRT or 5MM.

36. The method according to p. 29, characterized in that for obtaining the compounds of formula 6G by mixing the compounds of formula 5G with the base, the base is a hydride, for example sodium hydride or potassium hydride, or alkoxide basis, for example tert-piperonyl potassium, or a mixture of these bases, preferably, tert-piperonyl potassium, a solvent selected from an ether solvent such as Tetra-hydrofuran (THF), methyl tert-butyl ether (MTBE) or 1,2-dimethoxyethane, or alcohol, such as tert-butanol, preferably THF or MTBE, preferably the temperature of the support is between about 20 and about 40°C, or an organic solvent selected from methylene chloride, or a hydrocarbon, such as hexane, heptane or toluene, and the base is selected from hydroxide, for example sodium hydroxide or potassium hydroxide, or carbonate, for example sodium carbonate or potassium hydroxide, to obtain the compounds of formula SRT.

37. The method according to p. 29, characterized in that as soluble salts of palladium (II choose palladium acetate, as a phosphine ligand selected 1,3-bodyperfect potassium, triethylamine or tri-n-butylamine, the polar aprotic solvent is selected from dimethylformamide and acetonitrile, and the resulting compound may be represented by compounds of formula 7CPTG, 8MG or ST.

38. The method according to p. 29, characterized in that for obtaining the compounds of formula 7GA or the compounds of formula 8GG process temperature is from about 15 to about 80°C, the concentration of the acid is from about 50 to about 90%, a strong acid is preferably triperoxonane acid and in this case, the obtained compound represented by the formula SRTA or formula 8CPTG respectively.

39. The method according to p. 29, characterized in that for obtaining the compounds of formula 7GA or the compounds of formula 8GG the exchange reaction is carried out with the ketone and the reaction catalyze a strong acid or acidic ion-exchange resin, preferably a ketone is acetone or 2-butanone and acidic ion-exchange resin is, for example, resin amberlyst a-15 and in this case, the obtained compound represented by the formula SRTA or formula 8CPTG respectively.

40. The method according to p. 29, characterized in that for obtaining the compounds of formula 8GA dissolution 7GA in a mixture of solvents and processing of the vinyl derivative Rastro separately either as mixtures or as mixtures with hydrocarbons, such as toluene, heptane or cyclohexane, the process is carried out at a temperature from about -78 to about +25°C and the product emit after reaction with dilute acid, where the diluted acid may be, for example, hydrochloric, sulfuric or acetic acid, and in this case, the compound obtained can be represented by the formula SRTA.

41. The method according to p. 29, characterized in that for obtaining the compounds of formula 8GB or formula 9GG solution ylides derived from salt methyltriphenylphosphonium and a strong base, in a solvent, for example diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane or DMF), a strong base can be selected from n-utility, tert-butoxide potassium or bestremembered potassium, for example, methyltriphenylphosphonium salt can be bremena salt, ground - bestremembered potassium, the solvent is DMF, the process temperature can be from about -5 to about +25oC and the reaction time may be from about 5 minutes to about 2 hours, and the obtained compound represented by the formula SRT or formula 9CPTG respectively.

42. The method according to p. 29, characterized in that for obtaining the compounds of formula 9GA solvent selected from chlorite is x polychlorinated derivatives of ethane or ethylene, either individually or in a mixture or in a mixture with alcohols, for example methanol, the temperature of the process can be from about -78 to about -25oWith, the reducing agent may be sodium borohydride, for example, as a solvent choose a mixture of methylene chloride and methanol and the temperature of the initial reaction with ozone from about -78 to -40oC and the temperature recovery of the intermediate product from about 0 to 25°C., and the obtained compound represented by the formula SRTA.

43. The method according to p. 29, characterized in that for obtaining the compounds of formula 10G process temperature is from about 15 to about 50°C and the obtained compound represented by the formula ST.

44. The method according to p. 29, characterized in that for obtaining the compounds of formula 10G acetylide reagent selected from vinyl acetate, isopropenylacetate, acetic anhydride or ethyl acetate and applied in an organic solvent with a suitable lipase, for example Pseudomonas cepaica, preferably, for example, an organic solvent is simple ether or hexane and the lipase is Pseudomonas, or, preferably, the lipase is a Pseudomonas cepaica and the method is carried out at a temperature of 25 - 45°C and substrate concentration of 15-40 mg/ml and RAS is present, however, the conditions of Swern type are DMSO, oxalicacid and triethylamine in an aprotic solvent and a temperature range from about -78 to about +25°C, where the aprotic solvent may be methylene chloride, or a two-phase system containing water and an aprotic solvent, for example a solution of sodium hypochlorite catalyzed by TEMPO or substituted TEMPO, for example, 4-acetoxy-TEMPO, and where the other phase is methylene chloride, and where the process temperature can be from about -5 and about +25°C and time to allow the reaction can be any time from about 30 minutes to about 2 hours, and where the resulting compounds can be compounds of formula ST, 11CPT(R) or 11CPT(S).

46. The method according to p. 29, characterized in that for obtaining the compounds of formula 12GA-1 process temperature is about 10°C or 20oC and the reaction time is about 1 h, the oxidizing agent may be sodium chlorite and the resulting compounds are compounds of formula ST-1, 12CPTA-1(R) or 12CPTA-1(S).

47. The method according to p. 29, wherein the leaving group is removed by hydrogenation over a catalyst, the catalyst may be palladium, and the obtained compound can be a compound of formula ST-1, 12CPTB-1(R), 12CPTB-1(S), RT () -2, RT(C)-2(R) or 12CPTA(B)-2(S).

48. With water and an aprotic solvent, the conditions of Swern type can be DMSO, oxalicacid and trimethylamine in an aprotic solvent and at a temperature of from about -78 to +25oC and proton solvent may be methylene chloride and the resulting compounds can be compounds of formula RF () -2, RT(C)-2(R) or 12CPTA(B)-2(S).

49. The method according to p. 29, characterized in that for obtaining the compounds of formula 5G electrophile is metymirumi agent, including dimethylsulfate, methyliodide, bromide or metalcraft, the reagents are maintained at a temperature of from about -40 to about +50°C., preferably at a temperature of from about -5 to about +5°C, the product emit diluted acid, meteorous agent is preferably dimethylsulfate, dilute acid selected from acids from moderate to strong, such as hydrochloric acid, acetic acid, or sulfuric acid, or a mixture of any of these acids, and the resulting compound may be a compound of the formula 5MM.

50. The method according to p. 29, characterized in that the stage of demetalization carried out in acidic conditions and the product may be a compound of the formula 6MM.

51. The method according to p. 29, characterized in that for obtaining the compounds of formula 7MG base is a hydride, such as Ani, and the alkylating agent is alkylhalogenide, for example, is based on tert-piperonyl potassium and alkylating agent is benzylbromide.

52. The method according to p. 29, wherein the strong acid is triperoxonane acid leaving group is removed by interaction with hydrogen over a catalyst, where the catalyst is palladium.

53. The method of obtaining compounds of formula II according to p. 21, which consists in the fact that the compound of formula 12GA-1 (p. 1) is mixed with trimethylsilylimidazole that leads to obtaining the compounds of formula 12G, or, if desired, the compound of formula 12GA-2 (p. 1) or 12GB-2 (p. 1) is mixed with trimethylsilylimidazole removal of the leaving group, resulting in the compounds of formula 12G, which, if necessary, mixed with acrylate ester in the presence of a base, resulting in the compounds of formula 13G, and if it is desirable, from the connection 8G (p. 1) remove the leaving group and mixed with trimethylsilylimidazole that leads to obtaining the compounds of formula 9MG or formula 9, or if desired, the compound of formula 9MG mixed with acrylate ester in the presence of a base in a polar aprotic solvent, resulting in a compound F. the strong acid, that leads to the production of the compounds of formula 11MG or formula 11MM, racemate and both isomers.

54. The method according to p. 53, characterized in that for obtaining the compounds of formula 9MG or 12G trimethylsilylmethyl or receive advance or generated in situ from trimethylsilylpropyne and sodium iodide in methylene chloride or acetonitrile and the process temperature is from about 15 to 50°C for 12 to 48 h, and the resulting compounds can be compounds of formula 9MM, SR, 12CPT(R) or 12CPT(S).

55. The method according to p. 53, wherein upon receipt of the compounds of formulas 10MG or 13G acrylate ester is a methyl-, ethyl - or tert-butyl acrylate, may be potassium hydride, sodium hydride, tert-piperonyl potassium, sodium carbonate, potassium carbonate, cesium carbonate, or tertiary amine, including diisopropylethylamine, in a polar aprotic solvent such as dimethyl sulfoxide, DMF or acetonitrile, for example, acrylate ester is a tert-butyl acrylate and the base is cesium carbonate in DMSO and the reaction temperature is from about 20 to 100°C., preferably about 50°C and the obtained compound represented by the formula ST, 13CPT(R) or formula 13CPT(S).

56. The way to get connected is an intermediate product of the following formula:

< / BR>
that leads to the production of the compounds of formula 12MG or formula 12MM, racemate or both isomers.

 

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