The method of receiving deisopentanisation in the reaction mixture, the recovery method prehiring ketone

 

(57) Abstract:

The present invention relates to an improved method of obtaining deisopentanisation formula I in the reaction mixture, which includes the interaction of sodium borohydride and trichloride boron-pinene in an inert solvent. Thus obtained, diazepamonlinepharmacy can be used without isolation for the recovery properally ketones to their corresponding alcohols with high optical purity. A method of recovering prehiring ketone of the formula (II) to obtain the optically active alcohol of formula (III), where a is-CH=CH-S - or - CH = CH - CH = CH-; R1and R2are hydrogen or halogen; R3are groups of CO2R6, R6C(R7)2- OR8; R6is hydrogen or lower alkyl; R7is lower alkyl; R8is hydrogen or hydroxyamino group; with high optical purity by contacting sodium borohydride and trichloride boron-pinene, having an optical purity of 70% or higher in an inert organic solvent to obtain the reaction mixture containing deisopentanisation, which is then p is ritel is polyalkoxysiloxanes ether. 2 c. and 5 C.p. f-crystals.

Art

The invention relates to the production of deisopentanisation. The invention also relates to the use of raw dietenoniddibretre product when restoring properally ketones.

Deisopentanisation is a well-known chiral regenerating agent and described several ways of obtaining it. In one of the early works (Brown N. S. and Jadhav, P. K., J. Am. Chem. Soc., 1983, 105, 2092-2093), deisopentanisation get a reaction epirate of monochloroborane with a-pinene in diethyl ether. Athirat of monochloroborane in turn derived from lithium borohydride and trichloride boron (Brown N. With. and N. Ravindran, J. Am. Chem. Soc., 1972, 94, 2112-3). In U.S. patent 5043479 reported that the above method leads to a mixture of products, which is unsatisfactory for achieving asymmetric recovery ketones with high enantiomeric excess.

In U.S. patent 5043479 also described a new method of obtaining deisopentanisation. In this way, you must first receive intermediate diazepinonelor and highlight its crystallization. This intermediate product is highly sensitive to oxygen and water, which complicates e is when the original optical purity-pinene approximately 90%. This increase the enantiomeric purity of deisopentanisation when crystallization is considered the limit for maximum enantioselectivity when restoring ketones to alcohols (See. Brown N. C. et al, J. Org. Chem., 1987, 52, 5406 and references in this work; Brown N. With. et al, J. Org. Chem., 1986, 51, 3394; Srebnick M. et al, J. Org. Chem., 1988, 53, 2916; and Brown, H. C. et al, J. Am. Chem. Soc., 1988, 1539).

In U.S. patent 5292946 shown that the obtained in situ, deisopentanisation, without selection or separate treatment as the final product and intermediate diazepinonelor, behaves similarly selected reagent. Both are described in U.S. patents 5043479 and 5292946 method require the use of corrosive reagent hydrogen chloride, and, therefore, not ideal from the point of view of industrial applications.

In another method (King, A. O. et al, J. Org. Chem., 1993, 58, 3731-5) deisopentanisation get from monochloroethylene complex and a-pinene. The source of boron in this way contains foul-smelling compound dimethyl sulfide, which makes it unsuitable reagent for use in large quantities.

All previously known methods require the use or borane or monochloroborane, both of which are DTI in cheap, convenient and efficient method of obtaining dietenoniddibretre product used for recovering properally ketones with getting hydroxycodone with high optical purity.

Brief description of the invention

The present invention is directed to obtaining deisopentanisation in situ and its use in the recovery properally ketones to alcohols with high optical purity.

Detailed description of the invention

The present invention provides a method of obtaining deisopentanisation, which includes:

- contacting sodium borohydride and-pinene with trichloride boron in an inert solvent to obtain a composition containing deisopentanisation.

In a preferred embodiment of the invention-pinene is a (1R)-(+)--pinene, deisopentanisation has the formula I:

< / BR>
As used in this description, the expression "composition containing deisopentanisation" serves to show that the aforementioned reaction product of deisopentanisation in any way or in any degree is not distinguished from substances such as solvent, unreacted ukrashenie "EI" ("her") means the enantiomeric excess. The term "high optical purity" means the ratio of enantiomeric pairs, at least 95:5 in favor of the desired enantiomer.

-Pinene used in this way, can be a (1R)-(+)--pinene or (1S)-(-)--pinene, in which the enantiomeric excess may be low, up to approximately 70%. Thus, even-pinene with an optical purity of about 70% usually leads to end alcohol with an optical purity of about 94%. -Pinene with an optical purity of less than about 70% can also be used with little loss of optical purity of the target alcohol. In a preferred embodiment of the invention is used (1R)-(+)--pinene with EI 70% or above.

The organic solvent used in the present method can be any, which is almost never interferes with the desired reaction. Preferred solvents are polyoxyalkylene esters. Examples polyoxyphenylene esters include, but are not limited to, 1,2-dimethoxyethane, diglyme, trislim and similar compounds. Preferred polyoxyphenylene solvent is 1,2-dimethoxyethane.

The reaction can be conducted at a temperature of from peagents the temperature of the reaction mixture is supported at approximately 0oC or below, and thereafter the temperature may be raised to approximately 40oC. the Reaction allowed to proceed essentially to completion, what happens over time from about 15 minutes to about 2 hours; typically, the reaction is essentially completed within approximately 30 minutes. The course of the reaction can be monitored by methods known in the art; for example, consumption-pinene can be monitored by high performance liquid chromatography (HPLC) or by defining the relationship isopinocampheol (obtained by oxidation of deisopentanisation hydrogen peroxide) to a-pinene using gas chromatographic analysis.

The reaction is preferably carried out in an inert atmosphere, for example under nitrogen atmosphere.

The molar ratio of sodium borohydride to trichloride boron is preferably 1:1.1. The molar ratio of a-pinene to the sodium borohydride and trichloride boron is at least 4:1:1.1.

Obtained by the above method, the composition comprising deisopentanisation, can be used without additional purification for chiral restoration properally ketones.

Thus, in soorta optically active alcohol with high optical purity, which includes:

(a) contacting sodium borohydride and trichloride boron-pinene, having an optical purity of 70% or higher in an inert organic solvent to obtain a composition containing deisopentanisation;

(b) interaction prehiring ketone composition obtained in stage (a), to obtain the corresponding optically active alcohol with high optical purity.

In a preferred variant embodiment of the invention specified-pinene is a (1R)-(+)--pinene, this deisopentanisation has the formula I:

< / BR>
specified ketone has the formula II:

< / BR>
and the said alcohol has the formula III:

< / BR>
And represents-CH=CH-S - or-CH=CH-CH=CH-;

the substituents R1and R2independently represent hydrogen or halogen;

Deputy R3is a CO2R6, COR6or CO(R7)2-O-R8;

Deputy R6represents hydrogen or lower alkyl;

Deputy R7represents lower alkyl; and

Deputy R8represents hydrogen or hydroxyamino group; and said solvent is polyoxylene , R2and the bicyclic heterocycle to which they are attached together represent a 7-chlorinolysis fragment.

In the method of the present invention stage (a) is carried out in accordance with the previously described methodology. Stage (b) of the method is preferably carried out in an ether solvent. More specifically, the ether solvents include, but are not limited to, ethers such as diethyl ether, di-ad-butyl and diisopentyl ethers, anisole, cyclic ethers, such as tetrahydropyran, 4-methyl-1,3-dioxane, dihydropyran, tetrahydrofuran, furan, 2-methyl-tetrahydrofuran and 2-ethoxyacrylate, most preferably tetrahydrofuran.

The reaction may be conducted at temperatures from -25 to 25oC, preferably from about -20 to about 0oC. the Reaction allowed to proceed essentially to completion in a period of from about 1 to 100 hours; when using prehiring ketone and deisopentanisation preferred variant of the invention, the conversion to optically active alcohol, as a rule, 90% for about 3 hours at a temperature of approximately -20oC; further transformation can be the lead in the ambient pressure and in an inert atmosphere, for example in nitrogen. At the end of the desired optically active alcohol can be isolated by conventional means, for example, by means of crystallization, which leads to the desired optical isomer with enantiomeric excess up to 99%.

Deisopentanisation is a useful reagent for the recovery properally ketones to the corresponding chiral hydroxycodone. The compounds of formula III illustrate the usefulness of chiral hydroxycodone. The compounds of formula III are intermediate when receiving leukotriene antagonists of formula IV:

< / BR>
where a takes the values defined previously;

the substituents Ra, Rbrepresent, among other things, hydrogen or halogen; and

Deputy Rccan be a CO2Rd, CORdor C(Re)2-OH;

Deputy Rdcan represent hydrogen or lower alkyl;

Deputy Remay be a lower alkyl;

ALK represents, for example, cyclopropyl-1,1-(bis)methylene, isopropyl, etc. of Compounds of formula IV are useful as anti-asthma, anti-allergic, anti-inflammatory and chitosamine therapeutic agents. These antagonist is iscoe published Patent application 604114, and located on the simultaneous consideration of the patent application U.S. serial number 08/174931. The above-mentioned U.S. patent, the European Patent application and based on the simultaneous consideration of the patent application U.S. also describe getting predecessors properally ketones of the formula II.

The following examples are provided to illustrate the present invention and are in no way intended to limit the scope of the invention which is defined solely by the claims.

Example 1

Getting deisopentanisation in situ

In a round bottom flask of 250 ml is placed NaBH4(1.89 g, 50.0 mmol) and replacing with nitrogen air. Add dimethoxyethane (30 ml) and (+)--pinene (85% EI, 31.8 ml, 200 mmol) and the resulting mixture is cooled to -20oC. Add a solution of BCl3(55 ml, 1.0 M in heptane, 55.0 mmol) at such a speed that the temperature of the reaction mixture did not exceed 0oC (15 min). The mixture was incubated sequentially at 0oC for 15 minutes, at room temperature for 1 hour and at 40oC for 1 hour to obtain chiral reducing agent, deisopentanisation.

Example 2

Recovery of 2-(hydroxypropyl)benzoate.

In a separate flask in a nitrogen atmosphere to prepare a suspension of methyl 2-(3-(3-(2-(7-chloro-2-chinoline)ethynyl)phenyl)-3-oxopropyl)-benzoate (hereinafter - ketoester, 25.77 g, 97.3% of the weight. , 55 mmol) in tetrahydrofuran (200 ml) and then cooled to -20oC. To ketoether add the cooled suspension of chiral reducing reagent of example 1 (at -20oC) and the mixture was incubated at -20oC for several hours and then at 0oC for 1 hour.

The reaction is quenched with benzaldehyde (15 ml), the mixture is heated to 40oC and incubated for 1.5 hours. After cooling to 20oC the mixture is slowly poured in intensively mixed aqueous solution of K2CO3(30% wt., 100 ml). Stirring is continued until, until all the solid has dissolved. The organic layer is separated, filtered and then concentrated to 1/3 of its original volume (vacuum 20-23 inches (508-584.2 mm), bath temperature of 40-50oC). Add heptane (120 ml), then water (3 ml) to induce crystallization. Add heptane (120 ml) and the mixture was incubated at room temperature for 4 hours to complete the crystallization. After filtering and washing the precipitate with a mixture of THF/heptane (1/5, until the filtrate becomes p is monohydrate (S)-hydroxyether in the form of a yellow solid (yield 94.7%, in terms of the degree of purity of 98 wt%. ) EI% 99.0%.

1. The method of receiving deisopentanisation in the reaction mixture, characterized in that exercise contacting sodium borohydride and-pinene with trichloride boron in an inert solvent.

2. The method according to p. 1, characterized in that a-pinene is a (1R)-(+)--pinene, deisopentanisation has the formula I

< / BR>
3. The method according to p. 1, characterized in that the solvent is polyalkoxysiloxanes ether.

4. The method according to p. 1, characterized in that the solvent is a 1,2-dimethoxyethan.

5. Method of recovering prehiring ketone with obtaining optically active alcohol with high optical purity, characterized in that the conducting contacts sodium borohydride and trichloride boron-pinene, having an optical purity of 70% or higher in an inert organic solvent to obtain the reaction mixture containing deisopentanisation, which is then subjected to interaction with prochiral ketone.

6. The method according to p. 5, characterized in that a-pinene is a (1R)-(+)--pinene, deisopentanisation has the formula I

< / BR>
the ketone is BR>R1and R2independently represents hydrogen or halogen;

R3is a CO2R6, COR6or C(R7)2-O-R8;

R6represents hydrogen or lower alkyl;

R7represents lower alkyl;

R8represents hydrogen or hydroxyamino group

and the said solvent is polyalkoxysiloxanes ether.

7. The method according to p. 6, wherein R1, R2and the bicyclic heterocycle to which they are attached together represent a 7-chlorinolysis fragment.

 

Same patents:

The invention relates to a new organoboron compound having catalytic activity, of the formula I

[RjM-Xd-MRj]a-bAc+(I)

in which R are, independently of one another, identical and denote C1-C40alkyl; X is, independently from each other, equal or different and denote C1-C40alkyl; M is, independently of one another, identical or different and denote an element of IIIa, IVa, Va group of the Periodic system of elements, provided that one M is boron, a is a cation of an element Ia, IIa and IIIa groups of the Periodic system of elements, carbene-hydronium - or sulfonyl - cation or compound Quaternary ammonium, and a is an integer from 0 to 10, b is an integer from 0 to 10, C is an integer from 0 to 10 and a = C; d is 1; j is an integer from 1 to 3
The invention relates to the technology of organoboron compounds, in particular amine-Baranov, namely morpholine-borane, which can be used as a selective reducing agent in aqueous and organic media, as well as hydroporinae agent in fine organic synthesis

The invention relates to methods of producing a cyclic boron compounds which may find application in the synthesis of 1,4-butandiol, cyclic ketones, tertiary alcohols, ethers and other products used in thin organic and ORGANOMETALLIC synthesis

The invention relates to methods of producing a cyclic boron compounds which may find application in the synthesis of TRANS-2,3-dialkyl-1,4-butandiol, substituted cyclic ketones, alcohols, esters, and other practically important compounds used in thin organic and ORGANOMETALLIC synthesis

The invention relates to a new method of obtaining sulfur-containing imidazole derivatives of General formula (I) possess valuable pharmacological properties, and new intermediate products of the formula III, IV and V

(I)

where

R1- C1-C4-alkyl;

R2- alkylthiol containing 1-4 carbon atoms, possibly substituted by one or more substituents selected from halogen, hydroxyl, alkoxy, benzyloxy, and means phenylthio or mercapto;

R3- carboxyl, free or converted into a salt or an ester of linear or branched C1-C4-alkyl, or hydroxyalkyl;

R4- radical (CH2)m-SO2-X-R10where X is - NH-, NHCONH-, NHCO-O-; R10is hydrogen or C1-C3-alkyl, m = 0, 1;

the interaction of imidazole formula II

(II)

with the corresponding halogen derivatives - a compound of formula III

(III)

where

B is a boron atom;

X1and X2is hydroxyl or X1with X2form together with the boron atom to which they relate, zatem subjected to interaction with the compound of the formula V

(V)

where

X4is a halogen atom

The invention relates to inhibitors of glycogen phosphorylase, pharmaceutical compositions containing such inhibitors and the use of such inhibitors to treat diabetes, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis and myocardial ischemia in mammals

The invention relates to new heterocyclic compounds having therapeutic activity, to processes for their preparation and intermediate compounds used for their production, to pharmaceutical preparations containing these compounds and to the use of these compounds in medicine

The invention relates to compounds of the following formula 1, which inhibit the enzyme glycinamide ribonucleotide the formyl transferase (GARFT)

The invention relates to new derivatives of hydroxamic acids, possessing valuable pharmacological properties, in particular showing the properties of an inhibitor of collagenase, which can be used to delay the development or prevention of diseases of degeneration of the joints, such as rheumatoid arthritis or osteoarthritis, or in the treatment of invasive tumors, atherosclerosis or multiple sclerosis, as well as the way they are received, intermediate products for their production, pharmaceutical preparation and method thereof
Up!