New method for preparing 5-(4-fluorophenyl)-1-[2-(2r,4r)-4-hydroxy-6-oxotetrahydropyran-2-yl)ethyl]-2-isopropyl-4-phenyl-1h-pyrrol-3-carboxyli9c acid phenylamide

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a new method for preparing 5-(4-fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxotetrahydropyran-2-yl)ethyl]-2-isopropyl-4-phenyl-1H-pyrrol-3-carboxylic acid phenylamide that involves conversion of methylcyano acetate to the end compound for 8 or less stages. Also, invention relates to value intermediate compounds that are synthesized as result of realization of above indicated stages of the claimed method. 5-(4-Fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxotetrahydropyran-2-yl)ethyl]-2-isopropyl-4-phenyl-1H-pyrrol-3-carboxylic acid phenylamide is a value intermediate compound used in synthesis of the drug atorvastatin calcium that is used as hypolipidemic and/or hypocholesterolemic agent. Proposed method allows avoiding usage of expensive chiral parent substances and to reduce the synthesis process time.

EFFECT: improved preparing method.

12 cl, 3 ex

 

The technical field

Described an improved method of producing phenylamide 5-(4-forfinal)-1-[2-((2R,4R)-4-hydroxy-6-oxitetraciclina-2-yl)ethyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acids by synthesis, in which methylcinnamic converted into the desired product in eight or less stages, and describes other valuable intermediate compounds used in this method.

The level of technology

Phenylamide 5-(4-forfinal)-1-[2-((2R,4R)-4-hydroxy-6-oxitetraciclina-2-yl)ethyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid is a useful intermediate compound used in the synthesis of Lipitor® (atorvastatin calcium), known under the chemical name of the trihydrate of the calcium salt (2:1) [R-(R*,R*)]-2-(4-forfinal)-β ,δ -dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-heptane acid. The above compound is useful as an inhibitor of the reductase enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA reductase) and are thus useful as hypolipidemic and/or hypocholesterolemic agent.

In U.S. patent No. 4681893, which is included in this description by reference, describes certain TRANS-6-[2-(3 - or 4-carboxamido-substituted-pyrrol-1-yl)alkyl]-4-hydroxyfuran-2-ones, including TRANS(±)-5-(4-propenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[(2-tetrahydro-4-hydroxy-6-oxo-2H-Piran-2-and is)ethyl]-1H-pyrrol-3-carboxamide.

In U.S. patent No. 5273995, which is included in this description by reference, describes the enantiomer with (R,R) form of the acid with an open ended ring TRANS-5-(4-forfinal)-2-(1-methylethyl)-N,4-diphenyl-1-[(2-tetrahydro-4-hydroxy-6-oxo-2H-Piran-2-yl)ethyl]-1H-pyrrol-3-carboxamide, ie [R-(R*,R*)]-2-(4-forfinal)-β ,δ -dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-heptane acid.

In U.S. patents№№5003080; 5097045; 5103024; 5124482; 5149837; 5155251; 5216174; 5245047; 5248793; 5280126; 5397792; 5342952; 5298627; 5446054; 5470981; 5489690; 5489691; 5510488; 5998633 and 6087511, which are included in this description by reference, describes various methods and key intermediate compounds for receiving atorvastatin.

Crystalline forms of atorvastatin calcium are described in U.S. patent No. 5969156 and 6121461, which are included in this description by reference.

The method of synthesis of obtaining phenylamide 5-(4-forfinal)-1-[2-((2R,4R)-4-hydroxy-6-oxitetraciclina-2-yl)ethyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid described in U.S. patent No. 5273995.

Asymmetric restoring β -ketoesters, and β -diketones, represents a transformation is well known in organic synthesis. However, the complexity of these reactions increases in the case of 1,3,5-tricarbonyl systems, and often result in poor yield and poor stereoselectivity. In fact, research is research, conducted Saburi (Tetrahedron, 1997, 1993; 49) and Carpentier (Eur. J. Org. Chem. 1999; 3421) independently showed that GeoStereo - and/or enantioselectivity in asymmetric hydrogenation dictaphone is low or medium. Moreover, the fact that the methods of the prior art require hydrogenation at high pressure and significant reaction time, makes these methods impractical and unsuitable for industrial production processes.

However, it was unexpectedly discovered that esters of diol of the present invention, esters of (R)-7-[2-(4-forfinal)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-1-yl] - for 3,5-dihydroxyheptanoic acid, can be obtained directly from the corresponding 1,3,5-tricarbonyl predecessors with high stereoselectivity through easy and effective response of asymmetric hydrogenation catalyzed by ruthenium, the use of chiral narramissic diphosphine ligands in the presence of secondary activating agents, such as proton acid.

The object of this invention is a quick and effective way to get phenylamide 5-(4-forfinal)-1-[2-((2R,4R)-4-hydroxy-6-oxitetraciclina-2-yl)ethyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid. This method avoids the use of expensive chiral starting materials (ethyl ester of (R)-4-cyano-3-is hydroxy-butyric acid) and low-temperature diastereoselective recovery borane. Moreover, key stage condensation Paal-Knorr common to this method and methods of the prior art, improved by a significant reduction in reaction time.

Thus, the method of the present invention has significant advantages over methods of the prior art and is applicable for synthesis on an industrial scale.

Brief description of the invention

Therefore, the first aspect of the present invention includes an improved method for obtaining compounds of formula (13)

which includes:

Stage (a) interaction of the compounds of formula (1)

where R is alkyl, aryl, arylalkyl or heteroaryl, in a solvent, with a compound of the formula (2)

where R1is XR, where

X is Oh,

S or

Se, or R1is

where R2or R3independently are

the alkyl,

cycloalkyl,

arylalkyl or

by aryl, or

R2and R3together are

-(CH2)4-,

-(CH2)5-,

-(CH(R4)-CH2)3-,

-(CH(R4)-CH2)4-,

-(CH(R4)-(CH2)2-CH(R4))-,

-(CH(R4)-(CH2)3-CH(R4))-,

-CH2-CH 2-A-CH2-CH2-,

-CH(R4)-CH2-A-CH2-CH2-,

-CH(R4)-CH2-A-CH2-CH(R4)-

where R4is alkyl having 1-4 carbon atoms, a is O, S or N, and R such as defined above, to obtain compounds of formula (3)

where R1such as defined above;

Stage (b) interaction of the compounds of formula (3) with hydrogen in the presence of a catalyst and a strong acid, in a solvent, to obtain the compounds of formula (4)

where Y is Cl, Br, TsO, MsO, or HSO4and R1such as defined above;

Stage (C) interaction of the compounds of formula (4) with a base in a solvent and then adding the compounds of formula (5)

where R such as defined above, in a solvent, to obtain the compounds of formula (6)

where R and R1such as defined above;

Stage (d) interaction of the compounds of formula (6) with the compound of the formula (7)

in a solvent with removal of water to obtain the compounds of formula (8)

where R1such as defined above;

Stage (e) interaction of the compounds of formula (8) with the compound of the formula (9)

where M is sodium, lithium, potassium, zinc, magnesium, copper, calcium or aluminum, and R1such as defined above, in a solvent, in the presence of a strong base, to obtain the compounds of formula (10)

where R1such as defined above;

Stage (f) interaction of the compounds of formula (10) with hydrogen in the presence of a catalyst, in a solvent, in the presence of acid to obtain the compounds of formula (11)

where R1such as defined above, or the compounds of formula (11a)

Stage (g) interaction of the compounds of formula (11b)

where R1ais HE, -XR, where

X is Oh,

S or

Se, or R1Ais

where R2or R3independently are

the alkyl,

cycloalkyl,

arylalkyl or

by aryl, or

R2and R3together are

-(CH2)4-,

-(CH2)5-,

-(CH(R4)-CH2)3-,

-(CH(R4)-CH2)4-,

-(CH(R4)-(CH2)2-CH(R4))-,

-(CH(R4)-(CH2)3-CH(R4))-,

-CH2-CH2-A-CH2-CH2-,

-CH(R4)-CH2-A-CH2-CH2-,

-CH(R4)-CH2-A-CH -CH(R4)-

where R4is alkyl having 1-4 carbon atoms, a is O, S or N, and R such as defined above, in a solvent, in the presence of acid, with subsequent interaction with the bottom, allermuir agent and catalyst for the acylation, solvent, obtaining the compounds of formula (12)

and;

Stage (h) interaction of the compounds of formula (12) with BUT-M in alcohol of the formula (17) or (17b)

or

where M is sodium, lithium, potassium, zinc, magnesium, copper, calcium or aluminum; or with a compound of formula (16) or (16b)

or

where M, such as defined above for the alcohol of formula (17) or (17b), where the aryl or allyl in the compounds of the formula (16) or (16b) and (17) or (17b) is the same, in a solvent, followed by adding hydrogen in the presence of a catalyst and acid, to obtain the compounds of formula (13).

The second aspect of the present invention includes an improved method for obtaining compounds of formula (8).

where R1such as defined above, which includes:

the interaction of the compounds of formula (4)

where Y is Cl, Br, TsO, MsO, or HSO4and R1this ka is defined above, with the compound of the formula (20)

where R and M are such as defined above, with compound (7)

in a solvent with removal of water, to obtain the compounds of formula (8).

The third aspect of the present invention includes an improved method for obtaining compounds of formula (13)

which includes:

Stage (a) interaction of the compounds of formula (11) with an acetal of the formula (15)

where R5and R5Athe same or different and are independently stands, ethyl, or -(CH2)n-where n is an integer from 2 to 4 and R such as defined above, in a solvent, in the presence of acid, and then adding the aldehyde corresponding to the previous acetal, in the presence of a base, to obtain the compounds of formula (14)

where R1and R such as defined above;

Stage (b) interaction of the compounds of formula (14) in a nucleophilic solvent, in the presence of acid, or an optional interaction with hydrogen in the presence of a catalyst and an acid in a solvent to obtain compounds of formula (13); and

Stage (C) alternative interaction of the compounds of formula (11) or (11a) in dinucleophiles solvent, in the presence of acid, the obtaining the compounds of formula (13).

A fourth aspect of the present invention includes a method of obtaining the compounds of formula (11b)

where R1ais HE, -XR, where

X is Oh,

S or

Se, or R1Ais

where R2or R3independently are

the alkyl,

cycloalkyl,

arylalkyl or

by aryl, or

R2and R3together are

-(CH2)4-,

-(CH2)5-,

-(CH(R4)-CH2)3-,

-(CH(R4)-CH2)4-,

-(CH(R4)-(CH2)2-CH(R4))-,

-(CH(R4)-(CH2)3-CH(R4))-,

-CH2-CH2-A-CH2-CH2-,

-CH(R4)-CH2-A-CH2-CH2-,

-CH(R4)-CH2-A-CH2-CH(R4)-

where R4is alkyl having 1-4 carbon atoms, a is O, S or N, and R is alkyl, aryl, arylalkyl or heteroaryl, which includes:

Stage (a) interaction of the compounds of formula (10)

where R1such as defined above, with one mole of hydrogen, in the presence of a catalyst, in a solvent, in the presence of acid, to obtain the compounds of formulas (18) and/or (18a)

and

where R1such as defined above; and

is Tadeu (b) interaction or the compounds of formula (18), or (18a) with hydrogen in the presence of a catalyst, in a solvent, in the presence of acid to obtain the compounds of formula (11b).

The fifth aspect of the present invention includes a compound of the formula (6)

where R is alkyl, aryl, arylalkyl or heteroaryl, and

R1is XR, where

X is Oh,

S or

Se, or R1is

where R2or R3independently are

the alkyl,

cycloalkyl,

arylalkyl or

by aryl, or

R2and R3together are

-(CH2)4-,

-(CH2)5-,

-(CH(R4)-CH2)3-,

-(CH(R4)-CH2)4-,

-(CH(R4)-(CH2)2-CH(R4))-,

-(CH(R4)-(CH2)3-CH(R4))-,

-CH2-CH2-A-CH2-CH2-,

-CH(R4)-CH2-A-CH2-CH2-,

-CH(R4)-CH2-A-CH2-CH(R4)-

where R4is alkyl having 1-4 carbon atoms, a is O, S or N, and R such as defined above.

Especially preferred is the compound of formula (6)where R is the PhCH2or (CH3)3-C - R1is

More preferred is a compound of the formula (6)where R is the PhCH2and R1is the tsya

The sixth aspect of the present invention includes a compound of the formula (8)

where R1such as defined above.

Especially preferred is the compound of formula (8), in which R1is

The seventh aspect of the present invention includes a compound of formula (10) or its pharmaceutically acceptable salt

where R1such as defined above.

Especially preferred is the compound of formula (10), in which R1is-O-tertiary bootrom, -O-isopropyl, -O-ethyl, -O-stands,

or-NMe2.

The eighth aspect of the present invention includes a compound of the formula (12)

The ninth aspect of the present invention includes a compound of formula (18) or its pharmaceutically acceptable salt

where R1such as defined above.

Especially preferred is the compound of formula (18), in which R1is-O-tertiary bootrom, -O-isopropyl, -O-ethyl, -O-stands,

or-NMe2.

The tenth aspect of the present invention includes a compound of formula (18a) or its pharmaceutically als is salt

where R1such as defined above.

Especially preferred is the compound of formula (18a), in which R1is-O-tertiary bootrom, -O-isopropyl, -O-ethyl, -O-stands,

or-NMe2.

Detailed description of the invention

The term “alkyl” means a straight or branched hydrocarbon radical having from 1 to 8 carbon atoms, and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl and the like.

“Alkoxy” and “dialkoxy include O-alkyl or S-alkyl having from 1 to 6 carbon atoms as defined above for “alkyl”.

The term “cycloalkyl” means a saturated hydrocarbon ring having 3-8 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

The term “aryl” means an aromatic radical which is a phenyl group, phenylalkyl group, phenyl group, substituted by 1-4 substituents selected from alkyl, as defined above, alkoxy, as defined above, dialkoxy defined above, halogen, trifloromethyl, dialkylamino defined above for alkyl, nitro, cyano,such as the definition is but above for alkyl, -(CH2)

2
n
-N(alkyl)2where n2is an integer from 1 to 5 and alkyl such as defined above, andsuch as defined above for alkyl and n2.

The term “allyl” means a hydrocarbon radical having 3-8 carbon atoms containing a double bond between carbon atoms 2 and 3, unsubstituted or substituted by 1-3 substituents at carbon atoms having a double bond, selected from alkyl or aryl, such as defined above, and includes, for example, propenyl, 2-butenyl, cinnamyl and the like.

The term “arylalkyl” means an aromatic radical attached to the alkyl radical, where the aryl and alkyl such as defined above, for example, benzyl, phenethyl, 3-phenylpropyl, (4-chlorophenyl)methyl and the like.

“Alkali metal” is a metal of group IA of the periodic table and includes, for example, lithium, sodium, potassium and the like.

“Alkaline earth metal” is a metal of group IIA of the periodic table and includes, for example, calcium, barium, strontium, magnesium and the like.

The term “heteroaryl” means 5 - and 6-membered heteroaromatic radical, which may be optionally condensed with benzene ring containing 3 heteroatoms, selected from N, O and S, and includes, for example, a heteroaromatic radical which is 2 - or 3-tanila, 2 - or 3-TuranAlem, 2 - or 3-pyrrolidon, 2-, 3 - or 4-pyridinyl, 2-pyrazinium, 2-, 4 - or 5-pyrimidinyl, 3 - or 4-pyridazinyl, 1H-indol-6-yl, 1H-indol-5-yl, 1H-benzimidazole-6-yl, 1H-benzimidazole-5-yl, 2-, 4 - or 5-thiazolyl, 3-, 4 - or 5-isothiazoline, 2-, 4 - or 5-imidazolyl, 3-, 4 - or 5-pyrazolyl or 2 - or 5-thiadiazolyl, and may be optionally substituted by a Deputy selected from alkyl such as defined above, alkoxy, such as defined above, dialkoxy, such as defined above, halogen, trifloromethyl, dialkylamino, such as defined above for alkyl, nitro, cyano,such as defined above for alkyl, -(CH2)

2
n
-N(alkyl)2where n2is an integer from 1 to 5 and alkyl such as defined above, andsuch as defined above for alkyl and n2.

Pharmaceutically acceptable acid additive salts of the compounds of this invention include salts derived from inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, Hydrobromic, uudistoodetena, hydrofluoric, f is stricta and the like, as well as salts derived from nontoxic organic acids, such as aliphatic mono - and dicarboxylic acids, phenylsilane alcamovia acid, hydroxyalkanoate acid, alcantarilla, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such salts include the sulfate, persulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydratefast, dihydrophosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, triptorelin, propionate, kaprilat, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate,

benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, bansilalpet, toluensulfonate, phenyl acetate, citrate, lactate, maleate, tartrate, methanesulfonate and the like.

Also included are salts of amino acids such as arginate and the like and gluconate, galacturonic (see, for example, Berge S. M. et al., “Pharmaceutical Salts” J. of Pharma. Sci., 1977;66:1).

Acid additive salts of these basic compounds is produced by interaction of the free base with a sufficient amount of the desired acid to obtain the salt in the usual way. The free base can be regenerated by the interaction of the salt with the base and the release of free bases in the usual way. The free base is slightly different from its corresponding salts of certain physical SV is isthmi, such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free bases for the purposes of this invention.

Pharmaceutically acceptable basic additive salts get with metals or amines, such as alkali and alkaline earth metals or organic amines. Examples of metals used as cations include sodium, potassium, magnesium, calcium and the like. Examples of suitable amines include N,N’-dibenziletilendiaminom, chloroprocaine, choline, diethanolamine, dicyclohexylamine, Ethylenediamine, N-methylglucamine, and procaine (see, for example, S.M. Berge et al., “Pharmaceutical Salts” J. of Pharma. Sci., 1977; 66:1).

Basically additive salts of these acidic compounds produced by interaction of the free acid with a sufficient amount of the desired base with obtaining salt in the usual way. The free acid can be recovered by the interaction of the salt with acid and allocation of free acid in the usual way. The free acid is slightly different from its corresponding salts of certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free acid for purposes of this invention.

In addition, the compounds of this invention can exist as in not solvated forms, and in alfatronix forms, including hydrated forms. In General, the solvated forms, including hydrated forms, are equivalent nonsolvated forms and included in the scope of this invention.

The following list includes abbreviations and letter abbreviations used in the diagrams and the text:

H2SO4sulfuric acid
NaOMethe sodium methoxide
MeOHmethanol
MtBEmethyl tert-butyl ether
GCgas chromatography
Pt/Cplatinum on carbon
Pd/Cpalladium on carbon
H2hydrogen
HClhydrochloric acid
Hgmercury
psipound per square inch
iPrOH (IPA)isopropyl alcohol
HPLChigh performance liquid chromatography
NaOHsodium hydroxide
CH2Cl2dichloromethane (methylene chloride)
DMSO-d6deuterated dimethyl sulfoxide
THFtetrahed furan
Na2SO4the sodium sulfate
nBuLin-utility
NaClsodium chloride
KtButert-piperonyl potassium
NaHCO3sodium bicarbonate
BnOHbenzyl alcohol :
Pd(OH)2/Cthe palladium hydroxide on carbon
H2Aboutwater
PivOHpavlikova acid
PhCHObenzaldehyde
PhCH3toluene
CDCl3deuterated chloroform
BnONabenzilate sodium
NH4OHthe ammonium hydroxide
PhCH(OMe)2dimethylacetal benzaldehyde
MsOHmethansulfonate
PTsOHa pair of toluensulfonate
CSAcamphorsulfacid
Phphenyl
NaHsodium hydride
KHthe potassium hydride
EtOActhe ethyl acetate
tBuOH(HOtBu)tert-butanol
PhCH2CO2Hfinely Usna acid
NaNH2amide sodium
KHMDShexamethyldisilazide potassium
'lahsocialogical
Pd/Al2O3palladium on aluminium oxide
APCIchemical ionization at atmospheric pressure
ESIelectrospray ionization
PCIdirect chemical ionization
direct chemical ionizationH NMRspectroscopy proton nuclear magnetic resonance
spectroscopy proton nuclear magnetic resonanceWith NMRspectroscopy13carbon nuclear magnetic resonance
BINAP(R)-(+)-2,2’-bis(diphenylphosphino)-1,1’-binaphthyl
pTol-BINAP(R)-(+)-bis(di-p-tolylphosphino)-1,1’-binaphthyl
Cl-MeO-BIPHEP[(R)-(+)-5,5’-dichloro-6,6’-dimethoxy[1,1’-biphenyl]-2,2’-diyl]misdefinition
C2-TunaPhos[12aR)-6,7-dihydrobenzo[e,g][1,4]dioxin-1,12-diyl]misdefinition
C4-TunaPhos[14aR)-6,7,8,9-tetrahydrobenzo[b,d][1,6]dioxazine-1,14-diyl]misdefinition
MeO-BIPHEP[(1S)-(-)-6,6’-dimethoxy[1,1’-biphenyl]-2,2’-diyl]misdefinition
p-cYmen4-isopropyltoluene
eithe enantiomeric excess
HRMSmass spectrometry, high-resolution
m/zthe ratio of mass-to-charge
the ratio of mass-to-chargeRthe retention time

The method of the present invention in the first aspect is a new, improved, economical and industrially applicable method for obtaining compounds of formula (13)

The method of the present invention in the first aspect is depicted in figure 1. Thus, the compound of formula (1), where R is alkyl, aryl, arylalkyl or heteroaryl, is subjected to the interaction with the compound of the formula (2), where R1is XR, where

X is Oh,

S or

Se, or R1is

where R2or R3independently are

the alkyl,

cycloalkyl,

arylalkyl or

by aryl, or

R2and R3together are

-(CH2)4-,

-(CH2)5-,

-(CH(R4)-CH2)3-,

-(CH(R4)-CH2)4-,

-(CH(R4)-(CH2)2-CH(R4))-,

-(CH(R4)-(CH2)3-CH(R4))-,

-CH2-CH2-A-CH2-CH2-,

-CH(R4-CH 2-A-CH2-CH2-,

-CH(R4)-CH2-A-CH2-CH(R4)-

where R4is alkyl having 1-4 carbon atoms, a is O, S or N, and R such as defined above, in a solvent such as, for example, methyl tert-butyl ether and the like, to obtain the compounds of formula (3), where R1such as defined above. Preferably, the reaction is carried out with the compound of the formula (2), in which R1-N is morpholine, methyl tert-butyl ether.

The compound of the formula (3) is subjected to interaction with hydrogen in the presence of a catalyst, such as, for example, Pt/C, Pd/C, in the presence of acid, such as, for example, a strong acid, for example hydrochloric acid, Hydrobromic acid, p-toluensulfonate, methanesulfonate, sulfuric acid and the like (optional recovery is carried out with the use of Sponge Ni/NH4OH, metal hydrides and the like, to obtain the free base of compounds of formula (4)) in a solvent such as, for example, methanol, ethanol and the like, to obtain the compounds of formula (4)in which Y is Cl, Br, TsO, MsO, or HSO4and R1such as defined above.

Preferably, the reaction is carried out in the presence of Pt/C, hydrochloric acid and hydrogen in methanol.

The compound of the formula (4) is subjected to interaction with the bottom, such as nab, the emer, the sodium methoxide and the like, in a solvent such as, for example, tetrahydrofuran, toluene, methyl tert-butyl ether and the like, and in alcohol, such as, for example, isopropanol, ethanol, methanol and the like, to obtain the free base, followed by interaction with the compound of the formula (5), where R such as defined above, in a solvent such as, for example, isopropanol, tetrahydrofuran and the like, to obtain the compounds of formula (6)in which R such as defined above. Optional, free base of compounds of formula (4) may be subjected to interaction with the compound of the formula (5) to obtain the compounds of formula (6). Preferably the reaction is carried out with sodium methoxide in methyl tert-butyl ether and methanol to obtain the free base with subsequent interaction with phenylacetate in tetrahydrofuran.

The compound of formula (6) is subjected to interaction with the compound of the formula (7) in a solvent such as, for example, proton, aprotic, polar or non-polar solvent, for example, tetrahydrofuran and the like, with removal of water using a chemical drying agent, such as, for example, molecular sieves and the like, or by using a water trap Dean-stark or using azeotropic distillation with a suitable solvent, such as, for example, toluene and the like, n is the receiving of the compounds of formula (8), where R1such as defined above. Preferably, the reaction is carried out with activated 3A molecular sieves in tetrahydrofuran.

The compound of formula (8) is subjected to interaction with the compound of the formula (9), where M is sodium, lithium, potassium, zinc, magnesium, copper, calcium or aluminum, and R1such as defined above, in a solvent such as, for example, directionspanel aprotic solvent, for example tetrahydrofuran, toluene and the like, in the presence of a strong base, such as, for example, n-utility, lithium or hexamethyldisilazide potassium, diisopropylamide lithium and the like, to obtain the compounds of formula (10), in which R1such as defined above. Preferably the reaction is carried out with the compound of the formula (9)in which M is sodium, where the basis is n-utility and the solvent is tetrahydrofuran.

The CARBONYLS compounds of the formula (10) in scheme 1 is shown in the keto form. However, the compound of formula (10) can undergo “keto-enol” tautomerism and, thus, can exist in several tautomeric forms, which are included in the scope of this invention.

The compound of formula (10) is treated with hydrogen in the presence of a catalyst, such as, for example, chiral narozeniny complex of ruthenium (II)-diphosphine. For example, the complex predecessors is tenika ruthenium catalyst, such as oligomer [dichloro(1, 5cyclooctadiene)]ruthenium (II) and chiral diphosphines ligand, such as [(R)-(+)-2,2’-bis(diphenylphosphino)-1,1’-binaphthyl]. However, in this reaction recovery can be used any chiral narozeniny complex of ruthenium (II)/diphosphine. For example, precursors of the catalyst based on ruthenium (II) include dimer [dibromo(1,5-Dicyclopentadiene)] ruthenium (II)complex [bis(2-methallyl)cycloocta-1,5-diene]ruthenium (II) dimer [dichloro(p-cYmen)]ruthenium (II) and the like. Examples of effective chiral diphosphine ligands include

2,2’-bis(di-p-tolylphosphino)-1,1’-binaphthyl,

2-diphenylphosphinomethyl-4-diphenylphosphino-1-tert-butoxycarbonylamino,

derivatives tricyclo[8.2.2.24,7]hexadeca-4,6,10,12,13,15-hexane-5,11-diylbis(diphenylphosphine),

4,4’-bidimensional-3,3’-diylbis(diphenylphosphine),

6,6’-dimethoxy[1,1’-biphenyl]-2,2’-diyl]misdefinition,

[5,5’-dichloro-6,6’-dimethoxy[1,1’-biphenyl]-2,2’-diyl]misdefinition and

derivatives of 1,2-bis(2,5-dimethylphosphino) and the like,

in a solvent such as, for example, methanol, ethanol, isopropanol and the like, optionally in the presence of co-solvent, for example dichloromethane, tetrahydrofuran, toluene and the like, in the presence of acid, such as hydrochloric acid, Hydrobromic acid, Dowex® ion exchange resin and the like is Oh, obtaining the compounds of formula (11) or the compounds of formula (11a), where R1such as defined by

above. Preferably, the reaction is carried out with the dimer dichloro(p-cYmen)ruthenium (II) and [(R)-(+)-5,5’-dichloro-6,6’-dimethoxy[1,1’-biphenyl]-2,2’-diyl]misdefinition in methanol in the presence of hydrochloric acid.

The compound of the formula (11b), in which R1ais HE, -XR, where

X is Oh,

S or

Se, or R1Ais

where R2or R3independently are

the alkyl,

cycloalkyl,

arylalkyl or

by aryl, or

R2and R3together are

-(CH2)4-,

-(CH2)5-,

-(CH(R4)-CH2)3-,

-(CH(R4)-CH2)4-,

-(CH(R4)-(CH2)2-CH(R4))-,

-(CH(R4)-(CH2)3-CH(R4))-,

-CH2-CH2-A-CH2-CH2-,

-CH(R4)-CH2-A-CH2-CH2-,

-CH(R4)-CH2-A-CH2-CH(R4)-

where R4is alkyl having 1-4 carbon atoms, a is O, S or N, and R is alkyl, arylalkyl or heteroaryl, is subjected to the interaction with acid, such as, for example, p-toluensulfonate, camphorsulfacid, sulfuric acid, hydrogen chloride and the like, in dinucleophiles a solvent such as, for example, toluene, clonicel, dichloromethane, methyl tert-butyl ether and the like, with subsequent interaction with a base, such as, for example, triethylamine, pyridine, diisopropylethylamine and the like, and allermuir agent such as, for example, acetic anhydride, benzoyl chloride, benzylchloride and the like, in the presence of 4-dimethylaminopyridine, obtaining the compounds of formula (12). Preferably, the reaction is carried out in toluene in the presence of p-toluenesulfonic acid, followed by treatment with triethylamine, acetic anhydride and 4-dimethylaminopyridine in toluene.

The compound of the formula (12) is subjected to interaction with the BUT-M in alcohol of the formula (17) or (17b), where M is sodium, lithium, potassium, zinc, magnesium, copper, calcium or aluminum, or with the compound of the formula (16) or (16b), where M, such as defined above, in the alcohol of the formula (17) or (17b), where the aryl or allyl in the compounds of formula (16) or (16b) and (17) or (17b) are the same, the optional co-solvent such as, for example, dinucleophiles solvent, for example acetone, tetrahydrofuran, 1,2-dimethoxyethane and the like, followed by the addition of hydrogen in the presence of a catalyst, such as Pd(OH)2A /C, Pd/C, Pd/Al2O3and the like, in the presence of acid, such as hydrochloric acid, Hydrobromic acid, sulfuric acid and the like, to obtain the compounds of formula (13). Preferably, the reaction is carried out with sodium hydroxide in benzyl alcohol and subsequent hydrogenation in the presence of Pd(OH)2/C and sulfuric acid.

The method of the present invention in the second aspect presented in figure 2. Thus, the compound of formula (4)obtained as described in scheme 1, is subjected to the interaction with the compound of the formula (20), where R and M are such as defined above, and a compound of formula (7), with removal of water using a chemical drying agent, such as, for example, molecular sieves and the like, or by using a water trap Dean-stark or using azeotropic distillation with a suitable solvent, such as, for example, tetrahydrofuran, toluene and the like, to obtain the compounds of formula (8), where R1such as defined above. Preferably the reaction is carried out with the compound of the formula (20), in which R is PhCH2and M is sodium, in the presence of activated 3A molecular sieves in tetrahydrofuran.

The method of the present invention in the third aspect shown in figure 3. Thus, the compound of formula (11) is subjected to interaction with the acetal of the formula (15), where R5and R5Athe same or different are independently stands, ethyl, or -(CH2)nwhere n is an integer from 2 to 4, and R such as defined above, in the presence of acid, Taco is how, for example, hydrochloric acid, p-toluensulfonate pyridinium, n-toluensulfonate and the like, in a solvent such as, for example, toluene, dichloromethane, methyl tert-butyl ether and the like, and then adding the aldehyde corresponding to the previous acetal of the formula (15), in the presence of a strong base, such as, for example, dinucleophiles basis, for example, tertiary piperonyl potassium bis(trimethylsilyl)amide, potassium, 1,8-diazabicyclo[5.4.0]undec-7-ene and the like, to obtain the compounds of formula (14), in which R1and R such as defined above. Preferably, the reaction is carried out in dimethylacetal benzaldehyde in toluene in the presence of p-toluenesulfonic acid followed by the addition of benzaldehyde and tertiary butoxide potassium in tetrahydrofuran.

The compound of formula (14) is subjected to interaction with hydrogen in the presence of a catalyst, such as palladium on carbon or platinum on carbon and the like, in the presence of acid, such as hydrochloric acid and the like, in a solvent such as, for example, toluene, tetrahydrofuran, methyl tert-butyl ether, ethyl acetate, and the like, and in alcohol, such as, for example, methanol, ethanol and the like, to obtain the compounds of formula (13). Preferably, the reaction is carried out in toluene in the presence of platinum on carbon, when outstay methanol, in the presence of hydrochloric acid.

Optional compound of formula (14) is subjected to interaction with acid, such as, for example, hydrochloric acid, p-toluensulfonate pyridinium, n-toluensulfonate and the like, in a solvent such as, for example, toluene, dichloromethane, methyl tert-butyl ether and the like, to obtain the compounds of formula (13). Preferably the reaction is carried out in methylene chloride in the presence of p-toluenesulfonic acid.

Alternatively, the compound of formula (11) is subjected to interaction with acid, such as, for example, hydrochloric acid, Hydrobromic acid, p-toluensulfonate and the like, in dinucleophiles a solvent such as, for example, toluene, acetonitrile, methyl tert-butyl ether, tetrahydrofuran and the like, to obtain the compounds of formula (13). Preferably the reaction is carried out in toluene in the presence of p-toluenesulfonic acid.

The method of the present invention in the fourth aspect presented in figure 4. Thus, the compound of formula (1), where R1such as defined above, is subjected to the interaction with one molar equivalent of hydrogen in the presence of a catalyst, using the methodology described above for the conversion of compounds of formula (10) compound of formula (11) to obtain either the compounds of formula (18)or the compounds of formula 18 is), where R1such as defined above, or mixtures thereof. The mixture of compounds of the formula (18) and (18a) can be separated by conventional methods, such as, for example, chromatography and the like. Preferably the mixture of compounds of formulas (18) and (18a) is shared by HPLC.

The compound of formula (18) or (18a) or their mixture is subjected to interaction with hydrogen in the presence of a catalyst, as described for obtaining the compounds of formula (11), obtaining the compounds of formula (11b), where R1asuch as described above. Preferably, the reaction is carried out using at least one molar equivalent of hydrogen.

The compound of formula (13) can be transformed into atorvastatinalso (19) using the techniques described in U.S. patent No. 5273995 and 5969156.

The following non-limiting examples illustrate the preferred methods for producing the compounds of this invention.

SCHEME 1

SCHEME 2

SCHEME 3

SCHEME 4

Example 1

Phenylamide 5-(4-forfinal)-1-[2-((2R,4R)-4-hydroxy-6-oxitetraciclina-2-yl)ethyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid

Stage 1: Morpholine-4-yl-3-oxopropionate

In the reactor with inert nitrogen, equipped with skim milk is the first refrigerator, inlet for nitrogen and a mechanical stirrer, download morpholine (1.2 mol), medicinehat (1.0 mol) and MtBE (52 ml). The homogeneous solution is heated to about 55° C and stirred at this temperature for 12-18 hours. MtBE (33 ml) is added over approximately 15 minutes and the solution is slowly cooled to a temperature below 50° where there is a clear emergence of centers of crystallization. Add MtBE (66 ml) over 1 hour. During this time the reaction mixture is cooled to a temperature close to ambient temperature. When you are finished adding MtBE reaction mixture is cooled with stirring to about 0° C. the precipitate is collected by filtration and the filter cake washed with additional MtBE (about 40 ml). The solid is dried in vacuum at a temperature of about 45° with 3-morpholine-4-yl-3-oxopropanenitrile (139 g). This product is used in a later stage without further purification.

m/z (APCI(m+1)) 154,9; calculated for C7H10N2O2154,07

Stage 2: 3-Amino-1-morpholine-4-improper-1-he; hydrochloride

In the reactor with an inert nitrogen load 5% Pt-C (43 g; 58% are wetted with water) followed by addition of 3-morpholine-4-yl-3-oxopropanenitrile (2.8 mol). Add a solution of MeOH (3.4 l) and n HCl (is 3.08 mol) of such with what speed, in order to maintain the internal temperature at about 25° C. the Vessel and its contents Tegaserod three blowdown N2under pressure (50 psi). The atmosphere replaced with hydrogen three blowdown H2under pressure (50 psi) and the reaction mixture is vigorously stirred at a temperature of about 25° maintaining the hydrogen pressure (50 psi) for approximately 24 hours. Pressure H2reduce and replace N2. The reaction mixture is passed through a filtering agent, which is then washed with Meon (500 ml). The reaction mixture was concentrated in vacuo to a volume of about 1.4 l and add IPA (2.2 l). The reaction mixture was cooled to 0° and filtered. The filter cake was washed with MtBE (500 ml) and dried in vacuum at a temperature of about 30° obtaining hydrochloride 3-amino-1-morpholine-4-improper-1-it is in the form of a white solid (439 g). This product is used in the following stage without further purification.

1H NMR (400 MHz, DMSO) δ of 2.72 (t, 2H, J=6,78), 2,96 (t, 2H, J=6,77), 3,83-3,44 (m, 2H), 3,52-to 3.58 (m, 2H), 8,08 (CL, 3H).

13With NMR (100 MHz, DMSO) δ 168,4, 65,9, 45,1, 41,45, 35,1, 29,6.

Free base: m/z (APCI(m+1)) 159,2; calculated for C7H14N2O2158,11.

Stage 3: 3-Amino-1-morpholine-4-improper-1-he; connection with phenylacetic acid

In the reactor load hydrochlor the d 3-amino-1-morpholine-4-improper-1-he (765 mmol). Add Meon (380 ml) and the mixture vigorously stirred at room temperature for about 10 minutes. Add MtBE (380 ml) and the resulting suspension is cooled to -10° slowly add 25% (V/V) solution of NaOMe in Meon (765 mmol) via addition funnel with such a rate as to maintain the internal temperature at about -10° C. the resulting suspension is vigorously stirred in an atmosphere of N2and heated to a temperature of 0° C. the Solids are removed by filtration, washing with additional MtBE (50 ml). The solvent is removed in vacuo to obtain the free base in the form of crude oil, which is placed in MtBE (600 ml). The mixture is cooled with vigorous stirring at a temperature of approximately 0° slowly adding phenylacetic acid (765 mmol) in solution in MtBE (300 ml). After complete addition, the reaction mixture is stirred for another 10 minutes, during which time the product precipitates from solution. The solids are collected by filtration, washing with additional MtBE (100 ml), and dried in a vacuum at a temperature of ≤ 40° with 3-amino-1-morpholine-4-improper-1-it, connect with phenylacetic acid (191 g). This product is used in a later stage without further purification, it may be re-deposited from MtBE.

1H NMR (400 MHz, DM is On) δ to 2.55 (t, 2H, J=6,78), of 2.86 (t, 2H, J=6,78), 3,62 (t, 2H), 3,42 (t, 2H), 6.22 per (CL, 3H), 7,25 for 7.12 (m, 5H).

13With NMR (100 MHz, DMSO) δ 174,2, 169,0, 138,2, 129,2, 127,8, 125,5, 66,0, 45,2, 44,4, 41,4, 35,7, 31,6.

Stage 4: Phenylamide 5-(4-forfinal)-2-isopropyl-1-(3-morpholine-4-yl-3-oxopropyl)-4-phenyl-1H-pyrrole-3-carboxylic acid

Method And

In the reactor with inert nitrogen, equipped with a suitable reflux and Soxhlet extraction apparatus containing freshly activated 3A molecular sieves (4-8 mesh; 97,2 g), download 3-amino-1-morpholine-4-improper-1-he, the connection with phenylacetic acid (765 mmol) and phenylamide 2-[2-(4-forfinal)-2-oxo-1-phenylethyl]-4-methyl-3-oxopentanoic acid (450 mmol). Add THF (360 ml) and the resulting solution was vigorously stirred by heating at the boiling point under reflux for about 24 hours, during which the product begins to precipitate. Add Polynesians aqueous NaHCO3(100 ml) and the reaction mixture is cooled with constant stirring to a temperature of about 0° C. Add MtBE (100 ml) and the solids collected by filtration. The solid is washed with distilled water (100 ml) and MtBE (2× 100 ml), collected and dried in vacuum at a temperature of ≤ 50° obtaining phenylamide 5-(4-forfinal)-2-isopropyl-1-(3-morpholine-4-yl-3-oxopropyl)-4-phenyl-1H-pyrrole-3-carboxylic what islote in the form of a white solid (194 g). This product is used in a later stage without further purification.

m/z (APCI(m-1)) 538,2; (APCI(m+1)) 540,2; calculated for

With33H34FN3O3539,26.

Method In

In the reactor with inert nitrogen, equipped with a suitable reflux condenser and the extractor Soxhlet containing freshly activated 3A molecular sieves (4-8 mesh; 36 g), download hydrochloride 3-amino-1-morpholine-4-improper-1-she (170 mmol), sodium salt of phenylacetic acid (170 mmol) and phenylamide 2-[2-(4-forfinal)-2-oxo-1-phenylethyl]-4-methyl-3-oxopentanoic acid (100 mmol). Add THF (150 ml) and the resulting solution was vigorously stirred by heating at the boiling point under reflux for about 24 hours, during which the product begins to precipitate. Slowly add water NaHCO3(100 ml) and the reaction mixture is cooled with constant stirring to a temperature of about 0° C. Add MtBE (100 ml) and the solids collected by filtration. The solid is washed with distilled water (15 ml) and MtBE (2× 15 ml), collected and dried in vacuum at a temperature of ≤ 50° obtaining phenylamide 5-(4-forfinal)-2-isopropyl-1-(3-morpholine-4-yl-3-oxopropyl)-4-phenyl-1H-pyrrole-3-carboxylic acid as a white solid (42,1 g). This product is used on subsequent with adiah without further purification.

m/z (APCI(m-1)) 538,2; (APCI(m+1)) 540,2; calculated for C33H34FN3O3539,26.

Way

In the reactor with inert nitrogen, equipped with a reflux condenser, an inlet for nitrogen and a mechanical stirrer download morpholine (1.2 mol), medicinehat.ca (1.0 mol) and MtBE (52 ml). The homogeneous solution is heated to about 55° C and stirred at this temperature for 12-18 hours. MtBE (33 ml) is added over approximately 15 minutes and the solution is slowly cooled to a temperature below 50° where there is a clear emergence of centers of crystallization. Add MtBE (66 ml) over 1 hour. During this time the reaction mixture is cooled to a temperature close to ambient temperature. When you are finished adding MtBE reaction mixture is cooled with stirring to about 0° C. the precipitate is collected by filtration and the filter cake washed with additional MtBE (about 40 ml).

The crude 3-morpholine-4-yl-3-oxopropionate placed in the Meon (2 l) and transferred into the reactor with inert nitrogen gas under pressure, loaded with 5% Pt-C (55 g; 58% hydrated water). Add HCl (n; 1.1 mol) with such a rate as to maintain the internal temperature at about 25° C. the Vessel and its contents Tegaserod three blowdown N22under pressure (50 psi) and the reaction mixture is vigorously stirred at a temperature of about 25° maintaining the hydrogen pressure (50 psi) for approximately 24 hours. Pressure H2reduce and replace N2. The reaction mixture is passed through a filtering agent, which is then washed with Meon (500 ml). The reaction mixture is concentrated until moistened Meon solids, which re-suspended in IPA (100 ml). The suspension is cooled to 0° and filtered. The filter cake was washed with cold (0° (C) the IPA and re-suspended in the Meon (500 ml) and MtBE (500 ml). The suspension is cooled with stirring to -10° With added dropwise 25% (V/V) solution of NaOMe in Meon (1 mol) with such a rate as to maintain the internal temperature of ≤ -5° C. the resulting suspension is filtered to obtain a clear solution of the free base. The solvent is removed in vacuum to obtain crude oil, which is placed in THF (450 ml) and cooled to about 0aboutC. the resulting solution was transferred into the reactor with inert nitrogen gas, which contains phenylacetic acid (1.0 mol) and phenylamide 2-[2-(4-forfinal)-2-oxo-1-phenylethyl]-4-methyl-3-oxopentanoic acid (590 mmol). The reactor is equipped with a suitable reflux and Soxhlet extraction apparatus containing freshly and tigerbunny 3A molecular sieves (4-8 mesh. 125 g). The resulting solution was vigorously stirred while boiling under reflux in an atmosphere of N2within about 24 hours, during which the product begins to precipitate. Add Polynesians aqueous NaHCO3(130 ml) and the reaction mixture is cooled with constant stirring to a temperature of about 0° C. Add MtBE (130 ml) and the solids collected by filtration. The solid is washed with distilled water (130 ml) and MtBE (2× 130 ml), collected and dried in vacuum at a temperature of ≤ 50° obtaining phenylamide 5-(4-forfinal)-2-isopropyl-1-(3-morpholine-4-yl-3-oxopropyl)-4-phenyl-1H-pyrrole-3-carboxylic acid as a white solid (223 g). This product is used in a later stage without further purification.

m/z (APCI(m-1)) 538,2; (APCI(m+1)) 540,2; calculated for C33H34FN3O3539,26.

Stage 5: ethyl ester of 7-[2-(4-forfinal)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-1-yl] - for 3,5-dioxopentanoate acid

Method And

In the dry reactor with inert nitrogen loads sodium hydride (300 mmol). Add anhydrous THF (150 ml) and the resulting mixture is cooled in a nitrogen atmosphere to about -20° C. Add ethylacetoacetate (307 mmol) with such a rate as to maintain the internal reaction temperature at the level of ≤ -10° C. After D. is bauleni washed with THF (30 ml) and the resulting solution was stirred for approximately 45 minutes when ≤ -10aboutC. the Temperature is reduced to approximately -18° C. Add A 10.0 M solution of n-BuLi in hexane (300 mmol) with such a rate as to maintain the internal reaction temperature at the level of ≤ -4° C. After the addition was washed with THF (30 ml) and the resulting orange solution is stirred for about 90 minutes at a temperature of ≤ -4° C. the Temperature is reduced to about -25° C. To a solution of girolata add phenylamide 5-(4-forfinal)-2-isopropyl-1-(3-morpholine-4-yl-3-oxopropyl)-4-phenyl-1H-pyrrole-3-carboxylic acid (74 mmol), the resulting suspension is stirred at about -23° C for 20 hours. The reaction mixture is quenched in a mixture of 18% aqueous HCl (898 mmol) and MtBE (20 ml) at such a rate as to maintain the internal reaction temperature at the level of ≤ -2° C. the Reactor and transferring the system was washed with THF (30 ml) and transferred into the reaction mixture. Two-phase solution is heated to about 20° under stirring. The mixture is transferred into a separating funnel and the phases are separated. The organic layer was washed with water (33 ml) and saturated aqueous NaCl (33 ml). All aqueous layers are re-extracted with MtBE (40 ml). Two organic layers are combined and concentrated in vacuo to crude oil, maintaining the internal temperature of the product at the level of ≤ 60° C. To the oil is added EtOH (24 ml) and the mixture is again concentrated in vacuo. It received the WMD oil and immediately add EtOH (330 ml) and water (33 ml) and a solution of the product stand at a temperature of ≤ 10° C for about 14 hours. The obtained solid is collected, washed with cold 20% aqueous EtOH (100 ml) and dried in vacuo to obtain ethyl ester of 7-[2-(4-forfinal)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-1-yl] - for 3,5-dioxopentanoate acid (35,6 g) as a white solid. This product is used in a later stage without further purification, or, optionally, it can be re-deposited from IPA/N2O.

HRMS m/z (ESI(m-1)) 581,2463; calculated for C35H35FN2O5582,2530.

By the procedure similar to stage 5, method a, replacing ethylacetoacetate corresponding complex ether or Amida acetoacetic acid, receive the following connections:

Tert-butyl ester of 7-[2-(4-forfinal)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-1-yl] - for 3,5-dioxopentanoate acid.

HRMS m/z (ESI(m-1)) 609,2772; APCI (m+1) 611,3; calculated for C37H39FN2O5610,2843.

Isopropyl ester of 7-[2-(4-forfinal)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-1-yl] - for 3,5-dioxopentanoate acid.

m/z (PCI(m+1)) 597; calculated for C36H37FN2O5596,27.

Methyl ester of 7-[2-(4-forfinal)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-1-yl] - for 3,5-dioxopentanoate acid.

m/z (PCI(m+1)) 569; calculated for C34H33FN2O5568,24.

Morphodynamic 7-[2-(4-forfinal)-5-isopropyl-3-phenyl-4-phenylcarbamoyl Errol-1-yl] - for 3,5-dioxopentanoate acid.

HRMS m/z (ESI(m-1)) 622,2715; calculated for C37H38FN3O5623,2795.

N,N-dimethylamide 7-[2-(4-forfinal)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-1-yl] - for 3,5-dioxopentanoate acid.

m/z (PCI(m+1)) 582; calculated for C35H36FN3O4581,27.

Method In

Tert-butyl ester of 7-[2-(4-forfinal)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-1-yl] - for 3,5-dioxopentanoate acid

In the reactor with an inert nitrogen loads sodium salt of tert-butylacetoacetate (100 mmol). Add anhydrous toluene (71,5 ml) and THF (8.2 ml, 101 mmol) and the resulting solution is cooled at a positive pressure of nitrogen to a temperature of about -10° C. Add 10 M solution of n-BuLi in hexane (104 mmol) with such a rate as to maintain the internal reaction temperature at the level of ≤ 1° C. After complete addition, the resulting solution is stirred for an additional 20-30 minutes and the temperature is reduced to approximately -6° C. Simultaneously, phenylamide 5-(4-forfinal)-2-isopropyl-1-(3-morpholine-4-yl-3-oxopropyl)-4-phenyl-1H-pyrrole-3-carboxylic acid (25 mmol) load into the second reactor with inert nitrogen. Add anhydrous THF (50 ml) at room temperature and the resulting suspension is cooled to about -10° C and stirred for 15-90 minutes. The solution dienoate added to a suspension of morphodynamic with talislanta, in order to maintain the internal reaction temperature at about -5° C. After the addition the suspension is stirred at a temperature of about -5° for ≥ 2 hours. With vigorous stirring, water (35 ml) at such a rate as to maintain the internal reaction temperature at the level of ≤ 0° C. Add concentrated 37% hydrochloric acid (19,0 ml, 229 mmol) with such a rate as to maintain the internal reaction temperature at the level of ≤ 0° C. two-layer reaction mixture distil under vacuum, removing >50% organic solvents. The distillation is stopped and the lower aqueous layer was removed. Add water (55 ml) and distilled in vacuo continue up until the main part of the organic solvent is removed. [Note: it is Preferable to drain and replace the water layer before vacuum distillation.] Add IPA (100 ml) followed by addition of water (100 ml). The mixture is stirred for ≥ 6 hours, during which the product hardens. The solid is collected by filtration and the filter cake is washed with pre-mixture 1:1 IPA:H2O. the Obtained solid is dried in vacuum at a temperature of 35aboutWith obtaining tert-butyl ester of 7-[2-(4-forfinal)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-1-yl] - for 3,5-dioxole Lanovoy acid (14.1 g) as a white solid. The product is used in a later stage without further purification or, optionally, it can be re-deposited from toluene.

HRMS m/z (ESI(m-1)) 609,2772; APCI (M+1) 611,3; calculated for C37H39FN2O5610,2843.

By the procedure similar to stage 5, method, replacing the sodium salt of tert-butylacetoacetate the corresponding sodium salt of ester or acetoacetic acid amide, receive the following connections:

Ethyl ester of 7-[2-(4-forfinal)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-1-yl] - for 3,5-dioxopentanoate acid.

HRMS m/z (ESI(m-1)) 581,2463; calculated for C35H35FN2O5582,2530.

Isopropyl ester of 7-[2-(4-forfinal)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-1-yl] - for 3,5-dioxopentanoate acid.

m/z (PCI(m+1)) 597; calculated for C36H37FN2O5596,27.

Methyl ester of 7-[2-(4-forfinal)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-1-yl] - for 3,5-dioxopentanoate acid.

m/z (PCI(m+1)) 569; calculated for C34H33FN2O5568,24.

Morphodynamic 7-[2-(4-forfinal)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-1-yl] - for 3,5-dioxopentanoate acid.

HRMS m/z (ESI(m-1)) 622,2715; calculated for C37H38FN3O5623,2795.

N,N-dimethylamide 7-[2-(4-forfinal)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-1-yl] - for 3,5-dioxopentanoate acid.

m/z (PCI(m+1)) 582; calculated for C35N 36FN3O4581,27.

Step 6: methyl ether (5R)-7-[2-(4-forfinal)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-1-yl] - for 3,5-dihydroxyheptanoic acid

Method And

In the reactor with an inert nitrogen load ethyl ester of 7-[2-(4-forfinal)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-1-yl] - for 3,5-dioxopentanoate acid (100.0 mmol) and Meon (250 ml). The resulting suspension is heated under stirring at a temperature of approximately 55aboutWith obtaining a homogeneous solution. The vessel and its contents Tegaserod three purging argon at a pressure of 50 psi. With the constant flow of argon was added 1 M HBr in methanol (7.0 mmol) and the catalyst RuCl2(DMF)n[(R)-Cl-MeO-BIPHEP)] (0.5 mmol) and the reactor rinsed with additional quantity of argon at a pressure of 50 psi. The atmosphere replaced with hydrogen three tests at a pressure of 50 psi. The reaction mixture was vigorously stirred at a temperature of 65° when supported hydrogen pressure (50 psi) until then, until there is no further absorption of hydrogen. The reaction mixture was cooled to ambient temperature, the hydrogen pressure will reduce and be replaced by nitrogen. Untreated Meon a solution of methyl ester (5R)-7-[2-(4-forfinal)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-1-yl] - for 3,5-dihydroxyheptanoic acid is used in the following stage without purification or, optionally, it m which may be a dedicated flash chromatography on a column of silica gel, elwira a mixture of ethyl acetate-hexane.

HPLC analysis (YMC ODS AQ S5; 1 ml/min; 30°; 254 nm: CH3CN/H2O, 60:40 (0-22 min) to 100:0 (27-37 min) to 60:40) showed the ratio of SYN:anti isomers of 1:1.5. Chiral HPLC analysis (Chiralcel OD-H column; 5% EtOH:hexane; tR(3R,5R)=23,1 min/tR(3R,5S)=18,0 min/tR(3S,5S)=24,8 min/tR(3S,5R)=19,9 min) showed the enantiomeric excess at C-5 ≥ 98%, predominantly (R) configuration. m/z (PCI(m+1)) 573; calculated for C34H37FN2O5572,27.

By the procedure similar to stage 6, the method And using the solution of the corresponding alcohol instead of the Meon, you receive the following compounds, for example:

Ethyl ester of (5R)-7-[2-(4-forfinal)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-1-yl] - for 3,5-dihydroxyheptanoic acid

m/z (PCI(m+1)) 587; calculated for C35H39FN2O5586,28.

Chiral HPLC analysis (Chiralcel OD-H column; 5% EtOH:hexane; tR(3R,5R)=17,6 min/tR(3R,5S)=14,7 min/tR(3S,5S)=20,9 min/tR(3S,5R)=15,9 min) showed the enantiomeric excess at C-5 ≥ 98%, predominantly (R) configuration.

Isopropyl ether (5R)-7-[2-(4-forfinal)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-1-yl] - for 3,5-dihydroxyheptanoic acid

m/z (PCI(m+1)) 601; calculated for C36H41FN2O5600,30.

By the procedure similar to stage 6, the method And using the appropriate ester or amide from step 5 in dinucleophiles the/ncoordinates solvent (for example,

toluene) instead of the Meon and acetic acid instead of HBr can avoid transesterification and get the following compounds, for example:

Tert-butyl ether (5R)-7-[2-(4-forfinal)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-1-yl] - for 3,5-dihydroxyheptanoic acid

m/z (APCI(m+1)) 615,3; calculated for C37H43FN2O5614,32.

Morpholinoethyl (5R)-7-[2-(4-forfinal)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-1-yl] - for 3,5-dihydroxyheptanoic acid

m/z (APCI(m+1+HCO2N)) 672,3; calculated for C37H42FN3O5627,31.

N,N-dimethylamide (5R)-7-[2-(4-forfinal)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-1-yl] - for 3,5-dihydroxyheptanoic acid

m/z (APCI(m+1)) 586; calculated for C35H40FN3O4585,30.

By the procedure similar to stage 6, method A, using alternative Ru(II)-chiral diphosphine complexes instead of RuCl2(DMF)n[(R)-Cl-MeO-BIPHEP)] as catalyst for the hydrogenation get identical products with different enantiomeric excess at C-5. For example, when recovering the ethyl ester of 7-[2-(4-forfinal)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-1-yl] - for 3,5-dioxopentanoate acid to methyl ester (5R)-7-[2-(4-forfinal)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-1-yl] - for 3,5-dihydroxyheptanoic acid, the following occurs:

RuCl2(DMF)n[(R)-(+)-BINAP] complex yields a product with 0% ei (predominantly the (R) configuration) at C-5, what is defined chiral HPLC analysis.

RuCl2(DMF)n[(R)-(+)-pTol-BINAP] complex yields a product with 91% of ei (predominantly the (R) configuration) at C-5, which is defined chiral HPLC analysis.

RuCl2(DMF)n[(R)-(+)-C4-TunaPhos] complex yields a product with 93% of ei (predominantly the (R) configuration) at C-5, which is defined chiral HPLC analysis.

RuCl2(DMF)n[(R)-(+)-C2-TunaPhos] complex yields a product with 98% of ei (predominantly the (R) configuration) at C-5, which is defined chiral HPLC analysis.

RuCl2(DMF)n[(S)-(-)-MeO-BIPHEP] complex yields a product with 95% ei (predominantly the (S) configuration) at C-5, which is defined chiral HPLC analysis.

RuCl2[(R)-(+)-Cl-MeO-BIPHEP](NEt3)nthe complex gives the product ≥ 98% ei (predominantly the (R) configuration) at C-5, which is defined chiral HPLC analysis.

RuCl2[(R)-(+)-BINAP](NEt3)nthe complex gives a product with 91% of ei (predominantly the (R) configuration) at C-5, which is defined chiral HPLC analysis.

RuCl2[(R)-(+)-pTol-BINAP](NEt3)nthe complex gives a product with 91% of ei (predominantly the (R) configuration) at C-5, which is defined chiral HPLC analysis.

[Ru(TFA)2((R)-(+)-Cl-MeO-BIPHEP)]nthe complex gives the product ≥ 98% ei (predominantly the (R) configuration) at C-5, which is defined chiral HPLC analysis.

[Ru(TFA)2((R)-(+)-BINAP)]nthe complex gives a product with 0% ei (predominantly the (R) configuration) at C-5, what is defined chiral HPLC analysis.

Method In

In the reactor with an inert nitrogen load dimer chloride besaratinia (II) (11 mg) and (R)-(+)-C2-TunaPhos (26 mg). The reactor purge N2when the pressure and added dropwise via syringe Meon, blow N2. The resulting mixture was thoroughly rinsed N2and stirred at a temperature of 25aboutC for 30 minutes. Into the reactor through a syringe add a solution of tert-butyl methyl ether 7-[2-(4-forfinal)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-1-yl] - for 3,5-dioxopentanoate acid (0.5 g) and Meon, blowing N2(4,5 ml)and the resulting mixture is stirred in an atmosphere of N2at a temperature of 60aboutC for 30 minutes. The solution is stirred at a temperature of 60aboutWhen supported by the pressure of the H260 psi for 22 hours. The reaction mixture was cooled to ambient temperature and rinsed again N2. Untreated Meon a solution of methyl ester (5R)-7-[2-(4-forfinal)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-1-yl] - for 3,5-dihydroxyheptanoic acid is used in the following stage without purification or, optionally, it can be a dedicated flash chromatography on a column of silica gel, elwira a mixture of ethyl acetate-hexane.

HPLC analysis (YMC ODS AQ S5; 1 ml/min; 30about; 254 nm: CH3CN/H2O, 60:40 (0-22 min) to 100:0 (27-37 min) to 60:40) showed the ratio of SYN:anti isomers 1:1,4.

Chiral HPLC the analysis (Chiralcel OD-H column; 5% EtOH:hexane; tR(3R,5R)=23,1 min/tR(3R,5S)=18,0 min/tR(3S,5S)=24,8 min/tR(3S,5R)=19,9 min) showed the enantiomeric excess at C-5 ≥ 97%, predominantly (R) configuration.

m/z (PCI(m+1)) 573; calculated for C34H37FN2O5572,27.

Stage 7: phenylamide 5-(4-forfinal)-2-isopropyl-1-[2-((S)-6-oxo-3,6-dihydro-2H-Piran-2-ileti]-4-phenyl-1H-pyrrole-3-carboxylic acid

A suitable reaction vessel with an inert nitrogen load CON (110,0 mmol) and water (300 ml). To the rapidly stirred solution was added the crude solution of methyl ester (5R)-7-[2-(4-forfinal)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-1-yl] - for 3,5-dihydroxyheptanoic acid from step 6 (approximately 100 mmol/>98% of ei) in the Meon (250 ml). The mixture is heated in an atmosphere of nitrogen to an internal temperature of about 85° C. Simultaneously, the Meon removed by distillation. The reaction mixture is cooled to a temperature of 45° and washed With MtBE (2× 150 ml). The MtBE phase separated and removed. To the aqueous phase with a temperature of 45° add toluene (125 ml) followed by slow addition of 6N HCl (20 ml). A two-phase mixture is stirred for 10 minutes and the layers separated. The aqueous phase is extracted with a second portion of toluene (125 ml) and removed. The combined organic phases are heated to the boiling point under reflux in a nitrogen atmosphere. This lie is collected 130 ml of distilled water and removed. The resulting solution is cooled to about 60° and sequentially add NEt3(140 mmol), DMAP (2.0 mmol) and Ac2O (70,0 mmol) at such a speed as to maintain the internal reaction temperature between 55° to 65° C. the Solution is stirred for about 1.5 hours at a temperature of 60° C. the Mixture is cooled to a temperature of 50° and slowly add 1N HCl (100 ml). A two-phase mixture is stirred for 10 minutes, the phases are separated and the aqueous phase is removed. The organic phase is washed with a second portion of 1N HCl (100 ml) and water (100 ml), keeping the temperature 45°-55° C. a Solution in toluene diluted Bu2O (200 ml) and the resulting solution is slowly cooled to a temperature of 0° with constant stirring. The obtained solid is collected on a filter funnel and dried in vacuum to obtain phenylamide 5-(4-forfinal)-2-isopropyl-1-[2-((S)-6-oxo-3,6-dihydro-2H-Piran-2-ileti]-4-phenyl-1H-pyrrole-3-carboxylic acid as a white/whitish solid (34.4 g). This product is used in a later stage without further purification or, optionally, it can be re-deposited from IPA/N2O.

m/z (PCI(m+1)) 523; calculated for C33H31FN2O3522,23.

Chiral HPLC analysis (Chiralpack AD column; 1 ml/min; 30°; 254 nm; 10% IPA:hexane; tR(R)=18 min/tR(S)=16 min) showed enantion the RNA excess > 98%, predominantly (R) configuration.

Stage 8: phenylamide 5-(4-forfinal)-1-[2-((2R,4R)-4-hydroxy-6-oxitetraciclina-2-yl)ethyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid

Method And

In purged with argon, the reactor load phenylamide 5-(4-forfinal)-2-isopropyl-1-[2-((S)-6-oxo-3,6-dihydro-2H-Piran-2-ileti]-4-phenyl-1H-pyrrole-3-carboxylic acid (0,020 mol/>99% of ei) and benzyl alcohol (52 ml). The reaction mixture is cooled to a temperature of -10° and add NaOH (0.040 mol). After stirring for 19 hours at a temperature of -10° the reaction is quenched with 37% HCl (0,042 mol) and diluted with water (25 ml) and toluene (25 ml). After heating the mixture to ambient temperature, the lower aqueous layer was removed. The upper organic layer is combined with 20% Pd(OH)2/C (1.0 g) and H2SO4(0.01 mol) and hydronaut when the hydrogen pressure of 50 psi at a temperature of 50° C for 16 hours. The reaction mixture is heated to a temperature of 80° and filtered through diatomaceous earth. The reactor and the catalyst was washed with hot toluene (10 ml). The lower aqueous layer was removed. The upper organic layer is washed with a warm solution of aqueous HCl (0.16 g, 37% HCl in 25 ml of hot water) and heated to boiling point under reflux for 2.5 hours in an argon atmosphere with simultaneous azeotropic removal of water. The reaction mixture Oh adut to a temperature of 65° With and contribute seed of phenylamide 5-(4-forfinal)-1-[2-((2R,4R)-4-hydroxy-6-oxitetraciclina-2-yl)ethyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid. After 2 hours the reaction mixture is slowly cooled to ambient temperature. The resulting suspension is cooled to a temperature of about 0aboutC. the Product is collected and washed with cold toluene (25 ml). The obtained solid is dissolved in hot toluene (95 ml), cooled to a temperature of 65° and stand for 2 hours. The reaction mixture is slowly cooled to ambient temperature and then cooled to a temperature of 0° C. the Product is collected, washed with cold toluene (25 ml) and dried in vacuum at a temperature of 70° during the night of obtaining phenylamide 5-(4-forfinal)-1-[2-((2R,4R)-4-hydroxy-6-oxitetraciclina-2-ileti]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid (8,4 g) in the form of a white solid.

HPLC analysis (YMC ODS AQ S5; 1 ml/min; 30°; 254 nm; CH3CN/H2O, 60:40 (0-22 min) to 100:0 (27-37 min) to 60:40) showed the ratio of SYN:anti isomers of >99:1.

Chiral HPLC analysis (Chiralcel OF; 60°; 254 nm; 20% IPA:hexane; tR(3R,5R)=26 min/tR(3R,5S)=59 min/tR(3S,5S)=33 min/tR(3S,5R)=37 min) showed the enantiomeric excess at C-5 >99%, predominantly the (R) configuration.

m/z (PCI(m+1)) 541; calculated for C33H33FN2O4540,24.

According to the method of the ke, similarly, stage 8, the method And substituted derivatives of benzyl alcohol (for example, p-methoxybenzyloxy alcohol) can be used instead of benzyl alcohol to obtain the corresponding compounds.

Method In

In purged with argon, the reactor load phenylamide 5-(4-forfinal)-2-isopropyl-1-[2-((S)-6-oxo-3,6-dihydro-2H-Piran-2-ileti]-4-phenyl-1H-pyrrole-3-carboxylic acid (19,1 mmol/>99% of ei) and allyl alcohol (50 ml). The reaction mixture is cooled to a temperature of -5° and add LiOH (38,2 mmol). After stirring for 1 hour at a temperature of -5° the reaction is quenched with 37% HCl (42 mmol) and toluene (125 ml). After heating the mixture to ambient temperature, the reaction mixture was concentrated to a volume of approximately 75 ml Add toluene (50 ml) and the reaction mixture is concentrated by distillation until the crude oil, which solidified upon maturation. The crude residue is placed in DME (340 ml). To the resulting solution add deionized water (20 ml), p-toluensulfonate (2.25 g) and 5% Pd/C (11 g, 50% water-wetted). The resulting mixture is heated to a temperature of 45° C in an atmosphere of N2for 1.5 hours and at ambient temperature for a further 16 hours. The solution is passed through an auxiliary filtering additive to remove catalyst and the solvent is removed in HAC is the mind. The residue is placed in toluene (50 ml). Add water (75 ml) and KOH (950 mg), the reaction mixture is heated to a temperature of 65° and the layers separated. The aqueous phase is washed with toluene (25 ml) at a temperature of 65° and the combined layers of toluene are removed. To the aqueous phase add toluene (50 ml) followed by addition of 6N HCl (3.8 ml). The mixture is vigorously stirred at a temperature of 65° C for 5 minutes and the phases are separated. Phase toluene is heated to the boiling temperature under reflux for 2.5 hours with simultaneous azeotropic removal of water. The reaction mixture is cooled to a temperature of 65° and contribute seed of phenylamide 5-(4-forfinal)-1-[2-((2R,4R)-4-hydroxy-6-oxitetraciclina-2-yl)ethyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid. After 2 hours the reaction mixture is slowly cooled to ambient temperature. The resulting suspension is cooled to a temperature of about 0° C. the Product is collected and washed with cold toluene (25 ml).

The obtained solid is dissolved in hot toluene (95 ml), cooled to a temperature of 65° and stand for 2 hours. The reaction mixture is slowly cooled to ambient temperature and then cooled to 0° C. the Product is collected, washed with cold toluene (25 ml) and dried in vacuum at a temperature of 70° during the night of obtaining phenylamide 5-(4-forfinal)-1[2-((2R,4R)-4-hydroxy-6-oxitetraciclina-2-ileti]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid as a white solid.

HPLC analysis (YMC ODS AQ S5; 1 ml/min; 30about; 254 nm; CH3CN/H2O, 60:40 (0-22 min) to 100:0 (27-37 min) to 60:40) showed the ratio of SYN:anti isomers of >99:1.

Chiral HPLC analysis (Chiralcel OF; 60°; 254 nm; 20% IPA:hexane; tR(3R,5R)=26 min/tR(3R,5S)=59 min/tR(3S,5S)=33 min/tR(3S,5R)=37 min) showed the enantiomeric excess at C-5 >99%, predominantly the (R) configuration.

m/z (PCI(m+1)) 541; calculated for C33H33FN2O4540,24.

By the procedure similar to stage 8, method, substituted derivatives of allyl alcohol (for example, krotilova alcohol) can be used instead of allyl alcohol to obtain the corresponding compounds.

Way

Operation And

In the reactor with an inert nitrogen load tert-butyl ether (5R)-7-[2-(4-forfinal)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-1-yl] - for 3,5-dihydroxyheptanoic acid (10.0 mmol), dimethylacetal benzaldehyde (to 44.0 mmol), toluene (40 ml) and the monohydrate of p-toluenesulfonic acid (1.0 mmol). The reaction mixture was vigorously stirred under vacuum for about 20 hours, or until completion of the reaction, determined by HPLC analysis of aliquots. The solution is cooled under nitrogen atmosphere to a temperature of about -50° add 1M solution of KOtBu in THF (9.0 mmol) in three equal portions, separated by intervals of 30-45 minutes. The resulting solution was displaced is more of an additional 12-14 hours at a temperature of 0° C. the Reaction is quenched by slow addition of 1N HCl (10 ml). The obtained two-phase mixture is heated to a temperature of about 15° and transferred into a separating funnel where the aqueous phase is removed. The organic phase is washed with saturated aqueous NaCl (100 ml), dried over anhydrous MgSO4(25 g), filtered and concentrated in vacuo to crude oil. This product is used in further steps without purification or, optionally, it can be re-precipitated from a mixture of simple ether/hexane.

m/z (APCI(m+1)) 703,4; calculated for C44H47FN2O5702,35.

By the procedure similar to stage 8, method, operation And using the appropriate ester from step 6 instead of tert-butyl methyl ether (5R)-7-[2-(4-forfinal)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-1-yl] - for 3,5-dihydroxyheptanoic acid will receive the following compounds, for example:

methyl ester of ((4R,6R)-6-{2-[2-(4-forfinal)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-1-yl]-ethyl}-2-phenyl[1,3]dioxane-4-yl)acetic acid

ethyl ester of ((4R,6R)-6-{2-[2-(4-forfinal)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-1-yl]-ethyl}-2-phenyl[1,3]dioxane-4-yl)acetic acid

isopropyl ether ((4R,6R)-6-{2-[2-(4-forfinal)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-1-yl]-ethyl}-2-phenyl[1,3]dioxane-4-yl)acetic acid

Operation

In a reactor containing an inert nitrogen under pressure, load tert-b is tilby ether ((4R,6R)-6-{2-[2-(4-forfinal)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-1-yl]ethyl}-2-phenyl[1,3]dioxane-4-yl)acetic acid from operations And (5.0 g), 5% Pd/C (0.45 g; 50% N2About moist), 2n HCl in the Meon (1.9 ml), toluene (11 ml) and Meon (3.1 ml). The reactor and its contents Tegaserod two cycles of partial pumping gas and creating a high pressure nitrogen (25 mm RT. Art. and 50 psi, respectively). The atmosphere replaced with hydrogen three cycles of partial pumping gas and creating a high pressure of hydrogen (25 mm RT. Art. and 50 psi, respectively). The reaction mixture was vigorously stirred at a temperature of 40° when positive pressure N2(about 50 psi) for approximately 2.5 hours. The reaction mixture was cooled to ambient temperature and the hydrogen pressure dropped and replaced by nitrogen. The reaction mixture is passed through a filtering agent to remove the catalyst, carefully rinsing the Meon (2× 5 ml). To the resulting solution was added KOH (0.6 g) in water (25 ml). The reaction mixture was vigorously stirred in a nitrogen atmosphere and heated to an internal reaction temperature of about 90° With, removing the Meon distillation. A two-phase mixture is cooled to a temperature of 70° and With the upper phase of toluene is separated and removed. The aqueous phase is washed with a second portion of toluene (10 ml) at a temperature of 70° C. the Organic phase is separated and removed. To the aqueous phase add toluene (10 ml) followed by slow addition of 2n HCl (5 ml). A two-phase mixture is stirred for 10 mi the ut and the layers separated. The aqueous phase is extracted with a second portion of toluene (10 ml) and removed. The combined organic phases are heated to the boiling point under reflux with a water trap Dean-stark for 2.5 hours in an argon atmosphere. The reaction mixture is cooled to a temperature of 65° and contribute seed of phenylamide 5-(4-forfinal)-1-[2-((2R,4R)-4-hydroxy-6-oxitetraciclina-2-yl)ethyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid. After 2 hours the reaction mixture is slowly cooled to ambient temperature. The resulting suspension is cooled to a temperature of about 0° C. the Product is collected and washed with cold toluene (5 ml). The obtained solid is dissolved in hot toluene (20 ml), cooled to a temperature of 65° and stand for 2 hours. The reaction mixture is slowly cooled to ambient temperature and then cooled to a temperature of 0° C. the Product is collected, washed with cold toluene (5 ml) and dried in vacuum at a temperature of 70° during the night of obtaining phenylamide 5-(4-forfinal)-1-[2-((2R,4R)-4-hydroxy-6-oxitetraciclina-2-ileti]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid as a white solid matter.

m/z (PCI(m+1)) 541; calculated for C33H33FN2O4540,24.

Method D

In the reactor with inert nitrogen gas under pressure download which indicate the ethyl ester of 7-[2-(4-forfinal)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-1-yl] - for 3,5-dihydroxyheptanoic acid (100.0 mmol) and EtOH (250 ml). The resulting suspension is heated under stirring to a temperature of about 55° obtaining a homogeneous solution. The vessel and its contents Tegaserod three purging argon at a pressure of 50 psi. At constant argon flow add 1M HBr in methanol (7.0 mmol) and the catalyst RuCl2[(R)-BINAP)]NEt3(0.5 mmol) and the reactor rinsed with additional quantity of argon at a pressure of 50 psi. The atmosphere replaced with hydrogen three tests at a pressure of 50 psi. The reaction mixture was vigorously stirred at a temperature of 65° when supported hydrogen pressure (50 psi) until then, until there is no further absorption of H2. The reaction mixture is cooled to a temperature of about 50° C, the pressure of hydrogen is reduced and replaced by nitrogen. The crude EtOH solution of methyl ester (5R)-7-[2-(4-forfinal)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-1-yl] - for 3,5-dihydroxyheptanoic acid diluted with toluene (250 ml). To the resulting solution was added benzaldehyde (150 mmol) and the monohydrate of p-TsOH (5 mmol). The reaction mixture is heated to the temperature of the reactor 110° removing EtOH and water through education azeotrope with toluene. The solution is cooled under nitrogen atmosphere to a temperature of about -5° add 1M solution of KOtBu in THF (90 mmol) in three equal portions, separated by intervals of 30-45 minutes. The resulting solution was stirred for an additional 1214 hours at 0° C. the Reaction is quenched by slow addition of 1N HCl (100 ml). The obtained two-phase mixture is heated to a temperature of about 15° and transferred into a separating funnel where the aqueous phase is removed. The organic phase is washed with saturated aqueous NaCl (25 ml), dried over anhydrous MgSO4(5 g), filtered and concentrated in vacuo to crude oil, which is placed in the Meon (200 ml). The solution is transferred into the reactor with inert nitrogen gas under pressure containing 5% Pd/C (5 g, 50% water-wetted). Add concentrated HCl (2 ml) and the reaction mixture stirred at supported pressure H2(50 psi) for about 3 hours at a temperature of 50° C. the Reaction mixture was cooled to ambient temperature, H2replace N2and the catalyst removed by filtration. The resulting solution of methyl ester (3R,5R)-7-[2-(4-forfinal)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-1-yl] - for 3,5-dihydroxyheptanoic acid is transferred into the reactor with inert nitrogen gas, loaded with KOH (110,0 mmol) and water (300 ml). The reaction mixture is heated in a nitrogen atmosphere until the internal reaction temperature of about 85° C. Simultaneously remove the Meon distillation. The reaction mixture is cooled to a temperature of 45° and washed With MtBE (2× 150 ml). The MtBE phase was separated and removed. To the aqueous phase at a temperature of 45° add toluene (125 ml) with the latter is the criterion by slow addition of 6N HCl (20 ml). A two-phase mixture is stirred for 10 minutes and the layers separated. The aqueous phase is extracted with a second portion of toluene (125 ml) and removed. The combined organic phases are heated to the boiling point under reflux with a water trap Dean-stark for 2.5 hours in an argon atmosphere. The reaction mixture is cooled to a temperature of 65° and contribute seed of phenylamide 5-(4-forfinal)-1-[2-((2R,4R)-4-hydroxy-6-oxitetraciclina-2-yl)ethyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid. After 2 hours the reaction mixture is slowly cooled to ambient temperature. The resulting suspension is cooled to approximately 0° C. the Product is collected and washed with cold toluene (100 ml). The obtained solid is dissolved in hot toluene (350 ml), cooled to a temperature of 65° and stand for 2 hours. The reaction mixture is slowly cooled to ambient temperature and then cooled to 0° C. the Product is collected, washed with cold toluene (100 ml) and dried in vacuum at a temperature of 70° during the night of obtaining phenylamide 5-(4-forfinal)-1-[2-((2R,4R)-4-hydroxy-6-oxitetraciclina-2-ileti]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid as a white solid.

m/z (PCI(m+1)) 541; calculated for C33H33FN2O4540,24.

Stage 9: calcium salt of (R,R)-7-[2-(4-forfinal)-5-isoprop the l-3-phenyl-4-phenylcarbamoyl-1-yl] - for 3,5-dihydroxyheptanoic acid

In purged with argon, the reactor load phenylamide 5-(4-forfinal)-1-[2-((2R,4R)-4-hydroxy-6-oxitetraciclina-2-ileti]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid (14,8 mmol), MtBE (45 ml) and Meon (20 ml). Add a solution of NaOH (to 15.2 mmol) in water (103 ml) and the reaction mixture is heated to a temperature of 52° C. After heating for about 1 hour, the reaction mixture is cooled to a temperature of 34° and the layers separated. The upper organic layer is removed. The lower aqueous layer was washed with MtBE (33 ml) at a temperature of about 33° C. the Lower aqueous layer was diluted with MtBE (2 ml) and heated to a temperature of 52° C in argon atmosphere. Add a warm solution of Ca(OAc)2·H2O (7.5 mmol) in water (44 ml) for about 2 hours. After about 5 minutes after the start of addition of Ca(OAc)2in the reaction mixture make a seed suspension of the calcium salt of (R,R)-7-[2-(4-forfinal)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-1-yl] - for 3,5-dihydroxyheptanoic acid (0.08 mmol) in water (1.2 ml) and methanol (0.4 ml). After the addition of Ca(OAc)2the reaction mixture stand for about 15 minutes at a temperature of 52° and cooled to a temperature of 20° C. the Product is collected, washed successively with a solution of water-methanol 2:1 (48 ml) and water (49 ml). After drying in vacuum at a temperature of 70° the floor shall be given calcium salt of (R,R)-7-[2-(4-forfinal)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-1-yl] - for 3,5-dihydroxyheptanoic acid (8.7 g) as a white solid. Analytical specifications of the obtained product correspond to the values presented in the prior art.

Obtaining catalysts

Example

RuCl2(DMF)n[(R)-(+)-Cl-MeO-BIPHEP] complex

A suitable reaction flask is charged with DMF (17.5 ml). The flask and its contents Tegaserod two cycles of partial pumping gas and creating a high pressure nitrogen (25 mm RT. Art. and 10 psi, respectively). Excess nitrogen pressure drop and add immediately dimer chloride besaratinia(II) (0.50 mmol) and (R)-(+)-Cl-MeO-BIPHEP (1.10 mmol). The flask and its contents again Tegaserod two cycles of partial pumping gas and creating a high pressure nitrogen (25 mm RT. Art. and 10 psi, respectively). The excess pressure of nitrogen discharged and the reactor is heated to a temperature of about 100° C for 10 minutes. The resulting solution was cooled to a temperature of ≤ 50° and the solvent is removed in vacuum to obtain RuCl2(DMF)n[(R)-(+)-Cl-MeO-BIPHEP] in the form of a rusty-brown solid. The crude complex used directly in subsequent reactions without purification or get distinct characteristics or, optionally, stored in an inert atmosphere for future use.

According to the method similar to example A, using the appropriate chiral ligands of diphosphine instead of (R)-(+)-Cl-MeO-BIPHEP on ucaut these complexes, for example:

RuCl2(DMF)n[(R)-(+)-BINAP]ncomplex

RuCl2(DMF)n[(R)-(+)-pTol-BINAP]ncomplex

RuCl2(DMF)n[(R)-(+)-C4-TunaPhos]ncomplex

RuCl2(DMF)n[(R)-(+)-C2-TunaPhos]ncomplex

RuCl2(DMF)n[(S)-(-)-MeO-BIPHEP]ncomplex

The example In

RuCl2[(R)-(+)-BINAP] (NEt3)ncomplex

In a suitable reactor under a pressure of inert nitrogen load dimer, dichloro(1, 5cyclooctadiene)ruthenium (II) (0.15 mmol) and (R)-(+)-BINAP (0.32 mmol). Add toluene (8.0 ml) followed by the addition of triethylamine (4.5 mmol). The reactor and its contents Tegaserod two cycles of partial pumping gas and creating a high pressure nitrogen (25 mm RT. Art. and 10 psi, respectively). Excess nitrogen pressure drop, the reactor is sealed and heated to approximately 140° in which it was incubated for approximately 4 hours. The obtained transparent red solution is cooled to a temperature of ≤ 40° and the solvent is removed in vacuum to obtain RuCl2[(R)-(+)-BINAP](NEt3)ncomplex in the form of a rusty-brown solid. The crude complex used directly in subsequent reactions without purification or get distinct characteristics, or, optionally, stored in an inert atmosphere for future use.

According to the method, similarly, when the ERU, using the appropriate chiral ligands of diphosphine instead of (R)-(+)-BINAP get the following combinations, for example:

RuCl2[(R)-(+)-Cl-MeO-BIPHEP](NEt3)ncomplex

RuCl2[(R)-(+)-BINAP](NEt3)ncomplex

RuCl2[(R)-(+)-pTol-BINAP](NEt3)ncomplex

The example

[Ru(TFA)2((R)-(+)-Cl-MeO-BIPHEP)]ncomplex

A suitable reaction flask is charged with acetone (50 ml). The flask and its contents Tegaserod two cycles of partial pumping gas and creating a high pressure argon (25 mm RT. Art. and 10 psi, respectively). Excess argon pressure drop and add immediately (0.50 mmol) and (R)-(+)-Cl-MeO-BIPHEP (0.51 mmol). The flask and its contents again Tegaserod two cycles of partial pumping gas and creating a high pressure argon (25 mm RT. Art. and 10 psi, respectively). Overpressure of argon and reduce the reactor was vigorously stirred at a temperature of about 30° C. Via syringe add triperoxonane acid (1.2 mmol) and the reaction mixture stirred for further 1 hour. The solvent is removed in vacuum careful when passing About2with the receipt of [Ru(TFA)2((R)-(+)-Cl-MeO-BIPHEP)]ncomplex solids. The crude complex used directly in subsequent reactions without purification or get distinct characteristics, or, optionally, stored in inert atmosf the re for further use.

According to the method similar to example, using an appropriate chiral ligands of diphosphine instead of (R)-(+)-Cl-MeO-BIPHEP get the following combinations, for example:

[Ru(TFA)2((R)-(+)-MeO-BIPHEP)]ncomplex

[Ru(TFA)2((R)-(+)-BINAP)]ncomplex

[Ru(TFA)2((R)-(+)-p-Tol-BINAP)]ncomplex

Example 2 obtaining compounds of formula 18 and 18 (a).

Tert.-butyl ester of 7-[2-(4-Forfinal)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-1-yl]-3-hydroxy-5-exogamous acid

Into the reactor under pressure with inert argon download tert.-butyl ester of 7-[2-(4-forfinal)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-1-yl] - for 3,5-dioxopentanoate acid (14.0 mmol) in 40 ml of methylene chloride. To a stirred suspension add RuCl2(DMF) BINAP. The resulting suspension Tegaserod three purging argon at a pressure of 50 psi. The vessel and its contents are rinsed three purging of hydrogen at a pressure of 50 psi, and the mixture is heated at 55° obtaining a homogeneous solution. The reaction mixture was stirred at supported hydrogen pressure (50 psi) until cessation of hydrogen absorption. The reaction mixture was cooled to ambient temperature and remove the hydrogen pressure. The crude solution of tert.-butyl ester of 7-[2-(4-Forfinal)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-1-yl]-3-hydroxy-5-exogamous is islote concentrated in vacuo and purified column flash chromatography on silica gel, elwira mixtures of ethyl acetate-heptane.

HPLC analysis (YMC ODS AQ S5; 1 ml/min; 30° C, 254 nm:

CH3CN/H2O, 60:40 (0-5 min) to 100:0 (15-22 min) to 60:40 (25 min); tR= 14,8 minutes

13C NMR (DCl3, 100 MHz) δ 21,5, 25,5, 28,3, 39,9, 41,5, 44,6, 48,5, 64,5, 81,5, 115,2, 115,6, 115,7, 120,5, 122,8, 123,6, 126,7, 127,7, 127,8, 128,3, 128,6, 128,7, 130,3, 132,5, 132,9, 134,3, 138,3, 141,3, 161,1, 163,5, 164,5, 171,4, 205,8.

Example 3 obtaining the compounds of formula 11b.

Methyl ester of 7-[2-(4-forfinal)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-1-yl] - for 3,5-dihydroxyheptanoic acid

Into the reactor under pressure with inert argon download tert.-butyl ester of 7-[2-(4-forfinal)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-1-yl]-3-hydroxy-5-exogamous acid (2.5 mmol) in 9 ml of methanol. To a stirred suspension add RuCl2(DMF)BINAP and NWG/Meon (0.1 mmol). The resulting suspension Tegaserod three purging argon at a pressure of 60 psi. The vessel and its contents are rinsed three purging of hydrogen at a pressure of 60 psi, and the mixture is heated at 65° obtaining a homogeneous solution. The reaction mixture was stirred at supported hydrogen pressure (50 psi) until cessation of hydrogen absorption. The reaction mixture was cooled to ambient temperature and remove the hydrogen pressure. The crude solution of the methyl ester of 7-[2-(4-forfinal)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-1-the l]-3-hydroxy-5-exogamous acid was concentrated in vacuo.

HPLC ratio of SYN:anti isomers is 1:1.5,

Chiral HPLC analysis (Chiralcel OD-H column; 5% tO:hexane; tR(3R,5R)=23,1 min/tR(3R,5S)=18,0 min/tR(3S,5R)=19,9 min) showed the enantiomeric excess of the 5=87%, predominantly the (R) configuration.

1. The method of obtaining the compounds of formula (13)

which includes

stage (a) interaction of the compounds of formula (1)

where R is alkyl, aryl, arylalkyl or heteroaryl, in a solvent, with a compound of the formula (2)

where R1is XR, where

X is Oh,

S or

Se, or R1is

where R2or R3independently are

the alkyl,

cycloalkyl,

arylalkyl or

by aryl, or

R2and R3together are

-(CH2)4-,

-(CH2)5-,

-(CH(R4)-CH2)3-,

-(CH(R4)-CH2)4-,

-(CH(R4)-(CH2)2-CH(R4))-,

-(CH(R4)-(CH2)3-CH(R4))-,

-CH2-CH2"And CH2-CH2-,

-CH (R4)-CH2"And CH2-CH2-,

-Is n(R 4)-CH2-A-CH2-CH(R4)-

where R4is alkyl having 1-4 carbon atoms, a is O, S or N, and R such as defined above, to obtain compounds of formula (3)

where R1such as defined above;

stage (b) interaction of the compounds of formula (3) with hydrogen in the presence of a catalyst and a strong acid, in a solvent, to obtain the compounds of formula (4)

where Y is Cl, Br, TsO, MsO, or HSO4and R1such as defined above;

stage (C) interaction of the compounds of formula (4) with a base in a solvent and then adding the compounds of formula (5)

where R is as defined above, in a solvent, to obtain the compounds of formula (6)

where R and R1such as defined above;

stage (d) interaction of the compounds of formula (6) with the compound of the formula (7)

in a solvent with removal of water to obtain the compounds of formula (8)

where R1such as defined above;

stage (e) interaction of the compounds of formula (8) with the compound of the formula (9)

where M is sodium, lithium, potassium, zinc, magnesium, copper, calcium or aluminum, and R1such as defined above, in a solvent, in the presence of a strong base, to obtain the compounds of formula (10)

where R1such as defined above;

stage (f) interaction of the compounds of formula (10) with hydrogen in the presence of a catalyst based on ruthenium, in a solvent, in the presence of acid to obtain the compounds of formula (11)

where R1such as defined above, or the compounds of formula (11a)

stage (g) interaction of the compounds of formula (11b)

where R1Ais HE, -XR, where

X is Oh,

S or

Se, or R1ais

where R2or R3independently are

the alkyl,

cycloalkyl,

arylalkyl or

by aryl, or

R2and R3together are

-(CH2)4-,

-(CH2)5-,

-(CH(R4)-CH2)3-,

-(CH(R4)-CH2)4-,

-(CH(R4)-(CH2)sub> 2-CH(R4))-,

-(CH(R4)-(CH2)3-CH(R4))-,

-CH2-CH2"And CH2-CH2-,

-CH(R4)-CH2"And CH2-CH2-,

-CH(R4)-CH2-A-CH2-CH(R4)-

where R4is alkyl having 1-4 carbon atoms, a is O, S or N, and R is alkyl, aryl, arylalkyl or heteroaryl, in a solvent, in the presence of acid, with subsequent interaction with the bottom, allermuir agent and catalyst for the acylation, solvent, obtaining the compounds of formula (12)

and

stage (h) interaction of the compounds of formula (12) with BUT-M in alcohol of the formula (17) or (17b)

or

where M is sodium, lithium, potassium, zinc, magnesium, copper, calcium or aluminum; or with a compound of formula (16) or (16b)

or

where M, such as defined above for the alcohol of formula (17) or (17b), where the aryl or allyl in the compounds of the formula (16) or (16b) and (17) or (17b) are the same, in a solvent, followed by adding hydrogen in the presence of a catalyst and acid, to obtain the compounds of formula (13).

2. The method according to claim 1, in which produce the rum on the stage (f) is Rul 2(DMF)n[(R)-(+)-Cl-MeO-BIPHEP]

3. The method of obtaining the compounds of formula (8)

where R1is XR, where

X is Oh,

S or

Se, or R1is

where R2or R3independently are

the alkyl,

cycloalkyl,

arylalkyl or

by aryl, or

R2and R3together are

-(CH2)4-,

-(CH2)5-,

-(CH(R4)-CH2)3-,

-(CH(R4)-CH2)4-,

-(CH(R4)-(CH2)2-CH(R4))-,

-(CH(R4)-(CH2)3-CH(R4))-,

-CH2-CH2"And CH2-CH2-,

-CH(R4)-CH2-A-CH2-CH2-,

-CH(R4)-CH2-A-CH2-CH (R4)-

where R4is alkyl having 1-4 carbon atoms, a is O, S or N, and R is alkyl, aryl, arylalkyl or heteroaryl, which includes

the interaction of the compounds of formula (4)

where Y is Cl, Br, TsO, MsO, or HSO4and R1such as defined above, with a compound of formula (20)

where R such as defined above which M is sodium, lithium, potassium, zinc, magnesium, copper, calcium or aluminum, with compound (7)

in a solvent with removal of water, to obtain the compounds of formula (8).

4. The method of obtaining the compounds of formula (13)

which includes

stage (a) interaction of the compounds of formula (11)

where R1is XR, where

X is Oh,

S or

Se, or R1is

where R2or R3independently are

the alkyl,

cycloalkyl,

arylalkyl or

by aryl, or

R2and R3together are

-(CH2)4-,

-(CH2)5-,

-(CH(R4)-CH2)3-,

-(CH(R4)-CH2)4-,

-(CH(R4)-(CH2)2-CH(R4))-,

-(CH(R4)-(CH2)3-CH(R4))-,

-CH2-CH2"And CH2-CH2-,

-CH(R4)-CH2"And CH2-CH2-,

-CH(R4)-CH2-A-CH2-CH(R4)-

where R4is alkyl having 1-4 carbon atoms, a is O, S or N, and R is alkyl, aryl, arylalkyl or heteroaryl, what acetal of the formula (15)

where R5and R5athe same or different and are independently stands, ethyl, or -(CH2)n-where n is an integer from 2 to 4 and R such as defined above, in a solvent, in the presence of acid, and then adding the aldehyde corresponding to the previous acetal, in the presence of a base, to obtain the compounds of formula (14)

where R1and R such as defined above;

stage (b) interaction of the compounds of formula (14) in a solvent, in the presence of acid, or an optional interaction with hydrogen in the presence of a catalyst and an acid in a solvent to obtain compounds of formula (13); and

stage (C) alternative interaction of the compounds of formula (11) or (11a)

in a solvent, in the presence of a base, to obtain the compounds of formula (13).

5. The method of obtaining the compounds of formula (11b)

where R1ais HE, -XR, where

X is Oh,

S or

Se, or R1ais

where R2or R3independently are

the alkyl,

cycloalkyl,

arylalkyl or

by aryl, or

R2and R3together are

-(CH2)4-,

-(CH2)5-,

-(CH(R4)-CH2)3-,

-(CH(R4)-CH2)4-,

-(CH(R4)-(CH2)2-CH(R4))-,

-(CH(R4)-(CH2)3-CH(R4))-,

-CH2-CH2"And CH2-CH2-,

-CH(R4)-CH2"And CH2-CH2-,

-CH(R4)-CH2-A-CH2-CH(R4)-

where R4is alkyl having 1-4 carbon atoms, a is O, S or N, and R is alkyl, aryl, arylalkyl or heteroaryl, which includes

stage (a) interaction of the compounds of formula (10)

where R1is XR or R1is

where X, R, R2and R3such as defined above, with one mole of hydrogen, in the presence of a catalyst based on ruthenium, in a solvent, in the presence of acid, to obtain the compounds of formulas (18) and/or (18a)

and

where R1such as defined above; and

stage (b) interaction or the compounds of formula (18)or (18a) with hydrogen in the presence of a catalyst based on R the acquisition, in a solvent, in the presence of acid to obtain the compounds of formula (11b).

6. The method according to claim 5, in which the catalyst in stage (a) or (b) is Rul2(DMF)n[(R)-(+)-Cl-MeO-BIPHEP].

7. The compound of formula (6)

where R is the PhCH2or (CH3)3-S -, and R1is

8. The compound of formula (8)

where R1is

9. The compound of formula (10) or its pharmaceutically acceptable salt

where R1is-O-tertiary bootrom, -O-isopropyl, -O-ethyl, -O-stands,

or-NMe2.

10. The compound of the formula (12)

11. The compound of formula (18) or its pharmaceutically acceptable salt

where R1is O-tertiary bootrom, -O-isopropyl, -O-ethyl, -O-stands.

12. The compound of formula (18a) or its pharmaceutically acceptable salt

where R1is O-tertiary bootrom, -O-isopropyl, -O-ethyl, -O-stands.



 

Same patents:

The invention relates to the field of organic chemistry, namely to new individual compounds of class oxazino that exhibit fluorescent properties and can be used as starting products for the synthesis of new heterocyclic systems, as well as substances for sample labeling and additives for reflective paints

The invention relates to chemistry and agriculture, particularly to substituted 1,3,5-triazines as promoters prorostania seeds

The invention relates to novel alkyl-piperazinil benzoxazolinone and alkyl-piperidinyl benzoxazolinone derivative of the formula (I), where S1is hydrogen; Z is =C or N; R1, R2and R4independently represent hydrogen, Q is methyl, ethyl or cyclopropylmethyl, and their salts and prodrugs

The invention relates to 4-hydroxy-3-chinainternational and hydrazides of General formula (I), where a represents a-CH2- or-NH-, a R1, R2, R3and R4such as defined in the claims

The invention relates to new biologically active compounds - substituted 3-methyl-4,5-dihydro-1,2-benzisoxazole formula I, where I

The invention relates to new indole derivative of the formula I

< / BR>
in which R1is hydrogen, (NISS

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to an intermediate compound, i. e. tert.-butyl-(E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidine-5-yl}-(4R,6S)-2,2-dimethyl[1,3]dioxane-4-yl]acetate that can be used in synthesis of compound of the formula (IV)

eliciting inhibitory effect on activity of HMG-CoA-reductase and, therefore, can be used for preparing pharmaceutical agents for treatment, for example, hypercholesterolemia, hyperproteinemia and atherosclerosis. Also, invention relates to a method for preparing indicated intermediate compound by reaction of the new parent compound - diphenyl-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine-5-ylmethyl]phosphine oxide with tert.-butyl-2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxane-4-yl]acetate in the presence of a strong base in simple ether or aromatic solvents or their mixtures at temperature in the range from -200C to -900C. Also, invention relates to a method for preparing of compound of the formula (IV) wherein R1 means hydrogen atom or pharmaceutically acceptable cation and to a method for preparing intermediate compounds of the formula (VI):

wherein each P1 and P2 represents independently (C1-C4)-alkyl or group:

and wherein P3 represents (C1-C8)-alkyl. Applying new intermediate compounds and proposed methods provide enhancing quality and yield of compounds.

EFFECT: improved preparing methods.

9 cl, 1 tbl, 8 ex

The invention relates to new imidazole compounds of the formula I:

where R1represents hydrogen, hydroxy, protected hydroxy, or aryl, optionally substituted with a suitable(and) substituent(s) selected from the group consisting of halogen(lower)alkyl, halogen, hydroxy, protected carboxy, carbamoyl, lower alkylenedioxy, lower alkoxy, optionally substituted aryl, and lower alkyl, optionally substituted by hydroxy or protected carboxy; R2represents hydrogen or lower alkyl; R3is hydroxy or protected hydroxy; R4represents cyano, (hydroxy)minamino(lower)alkyl, carboxy, protected carboxy, N-containing heterocyclic group, optionally substituted amino, or carbarnoyl, optionally substituted with a suitable(s) of the substituent(s) selected from the group consisting of amino, hydroxy, lower alkyl, lower alkylsulfonyl, amidoamine(lower)alkyl, optionally substituted by hydroxy; and-And - is-Q -, or-O-Q-, where Q is a single bond or lower alkylene, or its salt, provided when R2is the lowest Ala the substituent(s), the above, and also provided that the compound of formula I is not 1-(hydroxyethyl)-4-(etoxycarbonyl)imidazole or anilide 1-(2-hydroxyethyl)imidazole-4-carboxylic acid

The invention relates to the use of compounds of formula I to obtain medical drug suitable for the treatment of asthma, seasonal or chronic allergic rhinitis, sinusitis, conjunctivitis, food Allergy, scombroid poisoning, psoriasis, urticaria, pruritus, eczema, rheumatoid arthritis, inflammatory bowel disease, chronic obstructive pulmonary disease, thrombosis and otitis and preferably asthma, seasonal and chronic allergic rhinitis

The invention relates to imidazole derivative of the formula (I), where X, Y, R, R2, R3and R4such as defined in the claims

The invention relates to imidazole derivative of formula (1), where X, Y, R, R2, R3and R4such as defined in the claims

The invention relates to inhibitors tyrosinekinase type bis-indolylmaleimide compounds of the formula I

< / BR>
where Z denotes a group of General formula II

< / BR>
where A, B, X, Z, R1-R10have the meanings indicated in the claims, as well as the way they are received and drug based on these compounds

The invention relates to derivatives of cyclic amines and their use as pharmaceuticals, particularly to a compound represented by the General formula (I), its pharmaceutically acceptable acid additive salts or its pharmaceutically acceptable C1-C6alcaldicios salt, R1-phenyl, C3-8-cycloalkyl, aromatic heterocycle with 1-3 heteroatoms selected from O, S, N, or combinations thereof, and these groups may be condensed with benzene ring or an aromatic heterocyclic group with heteroatoms, selected from O, S or N, or combinations thereof, and may also have different substituents

The invention relates to new effectors dipeptidylpeptidase IV - the dipeptide mimetics (I) formed from amino acids and thiazolidinone or pyrrolidino groups, namely: L-ALLO-isoleucyl-thiazolidine, L-ALLO-isoleucyl-pyrrolidino and their salts, salts of L-threo-isoleucyl-thiazolidine and L - threo-isoleucyl-pyrrolidine; a pharmaceutical composition having the ability to lower blood sugar, containing at least one of the above-mentioned compounds (1)
Up!