ITMI940697A1 - BICYCLE PREPARATION PROCESS 2. 2. 1. OPTICALLY ACTIVE EPTAN-2-ONE. - Google Patents

Description

in addition to those described in the documents already cited.

For example, the enzymatic redox described by Anthony J. Irwin et al. in J. Am. Chem. Soc., 2H. 8476-82 (1976), the resolution of norcamphor through the formation of clathrates (Deruent Abstract of the Japanese patent application No. 05/178780 - Daicel Chem. Ind. Ltd.), the kinetic resolution described in Chemical Abstracts Il3: 39997g [ Cho et al. in Bull. Korean Chem. Soc., 10. (6), 618-19, (1989)], the reduction of the corresponding bicycle [2.2.1] hept-5-en-2-one described by Johnson et al. in Tetrahedron, 40. (8), 1225-33 (1984) and the kinetic resolution described by Conan et al. in Bull. Soc. Chim.Fr., 1405-10 (1974).

All these synthetic routes are rather complex or lead to the obtainment of norcamphor with an extremely low optical purity.

We have now found that norcanfora can be obtained with good yields and high optical purity by resolution of the ketal diastereomers obtained by ketaiization of racemic norcamphor with tartaric acid derivatives.

Therefore, the object of the present invention is a process for the preparation of optically active norcamphor which comprises the ketaiization of the racemic norcamphor with an optically active tartaric acid derivative of formula "Bicycle preparation process [2.2.1] heptan-2-one optically active"

Description

The present invention relates to a process for the preparation of the optically active bicycle [2.2.13eptan-2-one and, more particularly, relates to a process for the preparation of the optically active bicycle [2.2.1] ep_ tan-2-one for resolution of the ketals derived from tartaric acid.

The bicycle [2.2.1] heptan-2-one, more commonly known as norcamphor or 2-oxonorbornane, is a known compound of formula I.

In particular, two optically active forms of norcamphor are known: the (+) form with configuration (1S, 4R) and the (-) form with configuration (1R, 4S).

Both norcamphor enantiomers are useful as intermediates, for example for the preparation of the 2-norbornanones-3 - substituted described in the European patent application n.

528694 (Chisso Corporation), of the norbornylaminines described in the European patent application n. 452000 (Shionogi Co. Ltd.) or the β-santalol and β-santalene derivatives described by Krotz et al. in Tetrahedron: Asymmetry, 1_ (8), 537-40 (1990). Various methods have been described in the literature for the preparation of norcamphor in optically active form.

(II)

where R is an -ORi group, in which Ri is a linear or branched C, -C3 alkyl, or a -NR2R3 group, in which R2 and R3, the same or different, are hydrogen atoms or linear C1-C3 alkyls or branched, aryl or possibly substituted alkylaryl and the carbon atoms marked with an asterisk are both in S or R configuration, to obtain a mixture of two diastereomeric ketals of formula

in which R has the above meanings and the carbon atoms marked with an asterisk are both in S or R configuration, the possible transformation of the mixture of diastereoisomers ketals of formula III in which R is an -ORi group in the corresponding mixture of ketals diastereomers of formula

CIII-A)

in which R2 and R3 have the meanings already reported, the resolution of the mixture of ketal diastereomers of formula III-A by crystallization in a suitable solvent and the acid hydrolysis of the diastereomer of formula III-A to obtain the optically active norcamphor.

The optically active compounds of formula I obtained with the process of the invention are useful as intermediates.

Among the meanings of R1, R2 and R3 specific examples of linear or branched alkyls are methyl, ethyl, propyl and isopropyl; specific examples of aryls and alkylaryls are phenyl and benzyl. Preferably, in the process object of the present invention the compounds of formula III in which R1 is methyl or ethyl and the compounds of formula III-A in which one or both groups R2 and R3 are methyl or ethyl are used.

The ketalization is carried out according to conventional methods such as direct ketalization or transketalization.

The ketalization reaction is preferably carried out by reaction of the racemic norcamphor with a derivative of tartaric acid of formula II in an acid medium in a suitable solvent selected, for example, from toluene, xylene, dichloroethane and chlorobenzene.

The derivative of the tartaric acid of fonnula II can have configuration (R, R) or (S, S).

The derivative of formula II can also be prepared "in situ", before the ketaiization reaction, for example by esterification of tartaric acid according to conventional techniques. When the ketaiization is carried out using a tartaric acid amide (II, R = NR2R3), a diastereoisomeric mixture of the ketals of formula III-A is obtained which are then directly separated by crystallization.

The separation of the ketal diastereoisomers of formula III-A by crystallization, according to the process of the present invention, is preferably carried out in a solvent selected from methanol, ethanol, isopropanol, dimethylformamide, water, heptane, toluene, acetonitrile, methyl chloride, dichloroethane and their blends.

When ketalization is carried out using an ester of tartaric acid (II, R = OR,), a diastereoisomeric mixture of the corresponding ketals of formula III is obtained which are then transformed into the corresponding ketals of formula III-A before carrying out the separation for crystallization.

The possible transformation of the ketal of formula III in which R is an -ORi group into the corresponding ketal of formula III-A is carried out by reaction with a suitable amine of formula NHR2H3, in which R2 and R3 have the meanings already reported, in a suitable solvent, preferably water, lower alkaline or mixtures thereof.

Specific examples of amines of formula NHR2R * are ammonia, methylamine, dimethylamine, ethylamine, diethylamine, propylamine, dipropylamine, isopropylamine, aniline and benzylamine.

Exclusively for practical and economic reasons it is preferred to use ammonia, methylamine or dimethylamine.

Even more preferably ammonia is used.

By acid hydrolysis, preferably carried out by treatment with a dilute aqueous solution of an inorganic acid such as, for example, hydrochloric acid, optically active norcamphor is obtained in pure form.

The most characterizing aspect of the process object of the present invention is the resolution by crystallization of the ketals of formula III-A, or of the ketals of norcanfora with amml of tartaric acid.

This resolution is peculiar in that only the ketals of formula III-A allow the separation of the two diastereomeric ketals and therefore the obtainment of norcamphor in optically active form.

Attempts to carry out the resolution by crystallization of ketals of norcamphor with other derivatives of tartaric acid, for example of the esters of formula III, have given completely unsatisfactory results.

A preferred practical embodiment of the process object of the present invention is the following.

The racemic norcamphor is ketaiized by treatment with an ester of the CS, S) -tartaric acid in an acid medium, obtaining a substantially 1: 1 mixture of the two diastereoisomers having respectively UR, 4S, 4'S, 5'S) and (1S, 4R, 4'S) configurations. , 5'S).

The mixture of ketal diastereoisomers is then treated with an aqueous solution of an amine of formula NHR2R3 thus obtaining the corresponding mixture of ketal diastereoisomers of formula III-A which is crystallized from a mixture of methanol and water.

The ketal of (1S, 4R) - (+) - norcamphor is separated by precipitation which by hydrolysis with dilute hydrochloric acid gives the optically pure (+) - norcamphor.

The process for preparing the optically active norcamphor object of the present invention has numerous advantages which differentiate it from known processes.

These advantages are above all the good yields and the easy industrial applicability of the process.

As far as we know, in fact, the only industrial processes for the preparation of optically active norcamphor involve a microbiological synthesis and are characterized by high costs and low yields.

The process object of the invention, on the other hand, uses easily available tartaric acid derivatives and allows to obtain optically pure norcamphor in a few simple steps. In order to better illustrate the present invention, the following examples are now provided.

Example 1

Preparation of the ketal of the (t) -norcanfora with the methyl diester of the D (-) - tartaric acid.

Toluene (32 ml), methyl diester of D (-) - tartaric acid (46.4 g; 0.26 moles), trimethylorthoformate (31 g; 0.29 moles) and 96% sulfuric acid were charged into a reactor. (w / w) (1.22 g; 0.012 mol).

The mixture was stirred at 85 ° C for about two hours and then at 110 ° C for another two hours, collecting the developed methanol. The solution was cooled to room temperature and then toluene (50 ml) and (t) -norcanfora (22 g; 0.20 mol) were charged.

The solution was left under stirring at 70 ° C for 12 hours.

After cooling to room temperature, the reaction mixture was poured into a solution of K2CO320% (w / w) in water.

The organic phase was separated and washed three times with water (3 x 100ml).

By evaporation of the solvent under reduced pressure an oily product was obtained (51.2 g; yield 95%) consisting of a 1: 1 mixture of the two desired diastereomers.

4.67 (d, 1H, J = 5.12 Hz, diastereomer B); 4.70 (d, 1H, J = 5.13 Hz, diastereomer A); 4.73 (d, 1H, J = 5.12 Hz, diastereomer B).

Keepnet: (m / e) 270 (Μ *).

Example 2

Preparation of the ketal of the_ (±) -norcanfora with the methyl diester of D (-) - tartaric acid.

Methanol (565 ml) and D (-) - tartaric acid (300 g; 2.0 moles) were charged to a reactor at 20 ° C and thionyl chloride (485 g; 4.07 moles) was added dropwise. in 4 hours. After 1 hour from the end of the addition, toluene (795 ml) was added and a part (100 ml) of the solution was distilled under vacuum (15-20 mmHg) at 20 ° C.

After loading 96% sulfuric acid (3 g; 0.03 moles) and toluene (250 ml), the resulting solution was heated to 80 ° C.

In two hours, trimethylorthoformate (234 g; 2.2 moles) was then added dropwise to the solution, distilling a mixture of methanol, toluene and trimethylorthoformate from the solution.

At the end of the dropping, the reaction mixture was kept at 80 ° C for three hours while continuing the distillation.

After adding further 96% sulfuric acid (2 g; 0.02 moles) and dropping trimethylorthoformate (50 g; 0.47 moles) in 10 minutes, the reaction mixture was kept under reflux for three hours and the distillation continued.

The solution was then cooled to 20 ° C and norcamphor (175 g; 1.6 moles) and toluene (150 ml) were charged.

After heating to 60 ° C under stirring, 96% sulfuric acid (2x2 g; 0.04 moles) was added twice to the solution at intervals of about two hours.

The reaction mixture was cooled and poured into a solution of sodium carbonate (70 g; 0.66 mol) in water (600 ml).

After addition of toluene (500ml), the phases were separated and the organic phase was washed three times with a 10% aqueous solution of sodium chloride (3x500ml).

By evaporation of the solvent at reduced pressure, an oily product (540 g) was obtained consisting of a 1: 1 mixture of the two desired diastereoisomers having the same spectroscopic characteristics reported in Example 1.

Example 3

Preparation of the ketal of the (±) -norcanfora with the diamide of the D (-) - tartaric acid.

To a 32% aqueous solution of ammonia (20 ml; 0.37 moles) the ketal of (±) -norcanfora with the methyl diester of D (-) - tartaric acid (5 g; 0.0185 mol), prepared as described in Example 1 or 2. The solution was left under stirring at 20 ° C for 12 hours.

After filtration of the reaction mixture, the solid obtained was washed three times with water (3 x 30 ml) and dried. Under reduced pressure at 60 ° C for 2 hours obtaining the desired ketal (3.10 g; yield 70%) as a 55:45 mixture of the two diastereomers A and B respectively.

Example 4

Preparation of the ketal of the (1S.4R) - (÷) -norcamphor with the diamide of the D (-) - tartaric acid.

Methanol (50 ml) was added to the ketal of the (t) -norcanphora with the diamide of the D (-) - tartaric acid (5 g; 0.02 moles), prepared as described in Example 3.

The mixture was heated to 60 ° C until complete solubilization.

Water (50 ml) was added and then the mixture was kept at 65 ° C until complete solubilization.

After cooling to 55 ° C, the solution was primed with a small amount of the (1S, 4R) - (+) - norcanfora ketal with pure D (-) - tartaric acid diamide.

After cooling to room temperature for 1 hour under stirring, the suspension was left at room temperature for another 1 hour.

After filtration and washing with methanol (5 ml), a product (2.5 g; yield 50%) was obtained consisting of an 85:15 mixture of the two diastereomers.

By subsequent crystallization the desired pure diastereomer was obtained.

Keepnet: (m / e) 240 (M *)

Operating in a similar manner but using dimethylformamide: water = 3: 4 or diraethylformamide: oiethanol = 1.5: 2 as crystallization solvent, the desired optically pure ketal was obtained.

Example 5

Preparation of the ketal of (1S.4R) - (+) - norcanfora with the diamide of the D (-) - tartaric acid.

Methanol (1380 ml) was added to the ketal of the (±) -norcanfora with the diamide of the D (-) - tartaric acid (230 g; 0.96 moles), prepared as described in Example 3.

The mixture was heated to 60 ° C until complete solubilization.

Water (1600 ml) was added and then the mixture was kept at 65 ° C until complete solubilization.

After cooling to 55 ° C, a ketal primer of (1S, 4R) - (+) - norcamphor with pure D (-) - tartaric acid diamide was added.

After cooling to 20 ° C in 5 hours under stirring, the suspension was left at this temperature for another 2 hours. After filtration and washing twice with a methanol: water = 1: 1 mixture (2x100 ml), a product (113 g; 50% yield) was obtained consisting of a 75:25 mixture of the two diastereomers.

After carrying out three other subsequent crystallizations using the same preparation methods and the same solute / solvent ratio, a product was obtained (47.6 g; yield 21%) consisting of a 97.5: 2.5 mixture of diastereoisomers A and B.

Example 6

Preparation of (lS.4R) - (+) - norcanfora

HCl was added to the ketal of (1S, 4R) - (+) - norcanfora with the diamide of D (-) - tartaric acid (5 g; 0.02 mol), prepared as described in Example 4 or 5. 1N (25 ml) and the heterogeneous mixture was heated at 40 ° C for 12 hours.

After cooling to 15 ° C, the suspension was filtered to obtain (1S, 4R) - (+) - norcanfora (1.1 g; 0.01 moles).

The filtration waters were extracted three times with ethyl ether (3 x 25 ml).

The organic phase was concentrated under vacuum at room temperature to obtain another (1S, 4R) - (+) - norcanfora (0.5 g; 0.0045 mol).

Total yield 73%.

Example 7

Preparation of the (1S.4R) - (÷) -norcanfora

At the ketal of (1S, 4R) - (+) - norcanfora with the diamide of D (-) - tartaric acid (47.6 g; 0.20 mol), prepared as described in Example 4 or 5, was 1N HCl (238 ml) was added and the heterogeneous mixture was heated at 40 ° C for 8 hours.

After cooling to 15 ° C and extraction three times with ethyl ether (3x500 ml), the combined organic phases were concentrated under vacuum (15-20 mmHg) at room temperature to obtain (1S, 4R) - (+) - norcanfora ( 18.9 g; 0.17 moles; yield 85%).

[α] D20 = + 28.8 °

Example 8

Preparation of the ketal of the (±) -norcanfora with the di-Cmonomethylamide) of the D (-) - tartaric acid.

A methanol solution was added in one portion to the ketal of (t) -norcamphor with the methyl diester of DC -) - tartaric acid (5 g; 0.0185 mol), prepared as described in Example 1 or 2. 33% methylamine (20ml; 0.22mol).

The solution was left under stirring at 20 ° C for 20 hours.

The reaction mixture was concentrated under reduced pressure to obtain a crude solid (4.80 g) which, by crystallization from toluene (80 ml), gives the desired compound as a mixture of the two diastereomers (3.2 g; yield 64%) .

Mass (m / e) 268 (M <+>).

Example 9

Preparation of the ketal of the (ì) -norcanfora with the di- (dimethylamide) of the D (-) - tartaric acid.

To the ketal of the (±) -norcanfora with the methyl diester of DI -) - tartaric acid (5 g; 0.0185 mol), prepared as described in Example 1 or 2, a methanolic solution was added in one portion. 33% dimethylamine (20 ml; 0.14 mol).

The solution was left under stirring at 20 ° C for 20 hours.

The reaction mixture was concentrated under reduced pressure to obtain a crude solid (4.81 g) which, by crystallization from hexane (80 ml), gives the desired compound as a mixture of the two diastereoisomers (3.0 g; yield 54%) .

Mass (m / e) 296 (M-).

Claims (10)

Claims 1) A process for the preparation of optically active norcamphor which includes the ketaiization of racemic norcamphor with an optically active tartaric acid derivative of the formula (II) where R is an -OR · ,, group in which R1, is a linear or branched C1-Ca alkyl, or a -NR2R3 group, in which R2 and R3, the same or different, are hydrogen atoms or C1- alkyls Linear or branched C3, optionally substituted aryls or alkylaryls and the carbon atoms marked with an asterisk are both in So R configuration, to obtain a mixture of two diastereomeric ketals of formula (III) in which R has the above meanings and the carbon atoms marked with an asterisk are both in S or R configuration, the possible transformation of the mixture of ketal diastereoisomers of formula III in which R is an -OR- group, in the corresponding mixture of ketal diastereoisomers of formula CIII-A) in which R2 and R3 have the meanings already reported, the resolution of the mixture of ketal diastereomers of formula III-A by crystallization in a suitable solvent and the acid hydrolysis of the diastereomer of formula III-A to obtain the optically active norcamphor. 2) A process according to claim 1 in which the compounds of formula III are used in which R, is methyl or ethyl. 3) A process according to claim 1 in which the compounds of formula III-A are used in which one or both groups R2 and R3 are methyl or ethyl. 4) A process according to claim 1 in which the ketaiization is carried out in an acid medium in a solvent selected from among toluene, xylene, dichloroethane and chlorobenzene. 5) A process according to claim 1 in which the crystallization is carried out in a solvent selected from methanol, ethanol, isopropanol, dimethylformamide, water, heptane, toluene, acetonitrile, methyl chloride, dichloroethane and their mixtures. 6) A process according to claim 1 in which the transformation of the ketal of formula III in which R is an -OR group, into the corresponding ketal of formula III-A is carried out by reaction with an amraine of formula NHR2R3, in which R2 and R3 have the meanings reported in claim 1, in a solvent selected from water, lower alcohols and their mixtures. 7) A process according to claim 6 wherein the amine of formula NHR2R3 is selected from ammonia, methylamine, dimethylararaine, ethylamine, diethylamine, propylamine, dipropylamine, isopropylamine, aniline and benzylamine. 8) A process according to claim 7 wherein the amine of formula NHR2R3 is selected from ammonia, methylamine and dimethylamine. 9) A process according to claim 8 wherein the amine is ammonia. 10) A process according to claim 1 in which the acid hydrolysis of the diastereomer of formula III-A is carried out by treatment with a dilute aqueous solution of an inorganic acid.