JPH0421662B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Field of Application] The present invention relates to a method for producing (S)-(-)-1-benzyl-3-hydroxypyrrolidine, which is useful as a synthetic intermediate for optically active pharmaceuticals. [Background of the invention] 1-benzyl-3-hydroxypyrrolidine has the following structural formula: It has an asymmetric carbon atom at the 3-position of the pyrrolidine ring. Until now, stereochemical considerations have not been added1
-Benzyl-3-hydroxypyrrolidine itself is already known from British Patent No. 831934 [Chemical Abstracts (CA), 54 , 24800c (1960)]. Also, Synthetic Communications, 13 (13), 1117
-1123 (1983) describes the following reaction formula as an improved method for producing 3-hydroxypyrrolidine, which is useful as a synthetic intermediate for various peptides. Developed a reaction route via 1-benzyl-3-hydroxypyrrolidine as an intermediate;
It is also stated that this reaction route is a method in which it is expected that the corresponding optically active target product can be obtained by using d- or l-malic acid instead of dl-malic acid as the starting compound. However, this document does not describe any experiments or results of the asymmetric synthesis method. Therefore, although it is recognized that the existence of optically active 1-benzyl-3-hydroxypyrrolidine was presumed from a stereochemical standpoint due to the presence of an asymmetric carbon atom, there is no evidence that optically active 1-benzyl-3-hydroxypyrrolidine exists not only in this document but also in actual production. There have been no reports of this happening, so it can be said that it is, in fact, a new substance. On the other hand, the present inventors have previously synthesized 2,6-dimethyl-
4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-(1-benzylpyrrolidin-3-yl) ester-5-methyl ester (Patent No. 1137506, Japanese Patent Publication No. 1983-30111)
See publication. diastereomer A and diastereomer B of (hereinafter referred to as YM-09730) were separated for the first time, and diastereomer A was separated from diastereomer B.
They found that it has a unique pharmacological effect that is far superior to that of a mixture of both diastereomers, and filed a patent application. (Special Application No. 59-75998). In addition, the above diastereomer is YM-
This occurs due to the presence of two asymmetric carbon atoms at 09730. Diastereomer A itself (dl mixture) has a melting point (decomposition) of its hydrochloride.
It shows a melting point of 200-206°C, and is distinguished from diastereomer B, which shows a melting point of 180-185°C of the same hydrochloride. The present inventors further determined that diastereomer A was L-
(−)-Malic acid etc. are used to optically resolve the right-handed optical isomer of diastereomer A (hereinafter referred to as YM-
09730-d-A), and that this isomer has unique pharmacological effects that are far superior to its left-handed optical isomer and the mixture of both isomers. I applied (Tokugansho)
59-114098). The present inventors have developed this new and useful YM-09730
As a result of intensive research aimed at increasing the optical yield of -d-A, we found that YM-09730 has a specific configuration at the 3-position of the pyrrolidine ring among the asymmetric carbon atoms present in YM-09730. From YM−09730−
We planned to separate d-A, and in order to produce optically active 1-benzyl-3-hydroxypyrrolidine as a raw material compound, the Synthetic Communica Co., Ltd.
Regarding the asymmetric synthesis method shown in tions), L-(-)
-Examined using malic acid. However, although this method yields a product with a high S-isomer content [80% enantioexcess (ee)] with some racemization, the optical purity cannot be increased by ordinary means such as distillation, and YM −
It was still insufficient to be used as a synthetic intermediate for 09730-d-A. We also investigated asymmetric reduction using 1-benzyl-3-pyrrolidinone as a raw material, and found that this method also yielded a product containing a large amount of S-form (30% ee), but YM-09730-d In order to use it as a synthetic intermediate for -A, it was necessary to develop a method to increase its optical purity. The present inventors further investigated the optical resolution method by fractional recrystallization and found that L-(+)-tartaric acid, L-(-)-malic acid, D-(-)-quinic acid, D-
-(+)-camphoric acid, D-(+)-10-camphorsulfonic acid, L-aspartic acid, N-acetyl-L-tryptophan, N-acetyl-D-β
-phenylalanine, N-(4-hydroxy-6
-Methylnicotinoyl)-D-parahydroxyphenylglycine, which has been used for optical resolution of racemates, is used, and methanol, ethanol, isopropanol, acetonitrile, acetone, chloroform, dioxane, methyl ethyl ketone, and these acids are used. Crystallization was attempted from solvents considered suitable for optical resolution of YM-09730, such as water-containing solvents, but crystalline salts could not be obtained in any case, and optical resolution could not be performed. Furthermore, (-)-dibenzoyl-L-tartaric acid,
(-)-Diacetyl-L-tartaric acid, N-acetyl-
As a result of examining D-valine and N-acetyl-L-glutamic acid in the same solvent system, (-)-dibenzyl-L-tartaric acid and (-)-diacetyl-L-
- For tartaric acid, crystals could be isolated with a small amount of acetone, for N-acetyl-D-valine with only acetonitrile, and for N-acetyl-L-glutamic acid, crystals could be isolated using isopropanol, acetonitrile, and acetone, but in all cases, crystals were isolated in the dl form. The problem was that only crystals could be obtained. [Means for Solving] As a result of further intensive research aimed at solving the above problems, the present inventors found that 1-benzyl-3-
In the case of hydroxypyrrolidine, (S)-
The present invention was completed by discovering that (-)-1-benzyl-3-hydroxypyrrolidine can be isolated in a pure manner. That is, the present invention provides (S)-(-)-1-benzyl- which crystallizes after adding optically active mandelic acid to dl-1-benzyl-3-hydroxypyrrolidine.
It is characterized by separating the mandelic acid salt of 3-hydroxypyrrolidine and then treating it with an alkali. Here, dl-1-benzyl-3-hydroxypyrrolidine is usually a mixture of equal amounts of d-form and l-form, but
In the production method of the present invention, even if one optically active substance is contained in an amount equal to or more than its enantiomer, it can be separated, and such a mixture is also meant. Therefore, even if dl-1-benzyl-3-hydroxypyrrolidine is a racemic product produced by a known method, it can also be obtained by reacting (S)-(-)-malic acid with benzylamine. Become (S)
-(-)-A non-equivalent mixture containing a large amount of S-form produced by an asymmetric synthesis method to reduce 1-benzyl-3-hydroxysuccinimide, or an asymmetric reduction to reduce 1-benzyl-3-pyrrolidinone It may also be a non-equivalent mixture with a slightly larger amount of the S-isomer produced by the method. The cyclization reaction in the first step of the asymmetric synthesis method proceeds without a solvent, but it can be carried out using an organic solvent. Such solvents include methanol,
Examples include ethanol, benzene, toluene, etc.
Preferably, it does not contain water. The reaction is carried out under heating, preferably at 170°C, under azeotropic dehydration. The second step of reduction is carried out by heating in an organic solvent such as tetrahydrofuran, dioxane, ether, diglyme, preferably an anhydrous organic solvent, together with a hydride reducing agent such as lithium aluminum hydride or sodium borohydride. will be achieved. On the other hand, in the asymmetric reduction reaction, reduction using a chiral borohydride is preferable, and 1-benzyl-3-pyrrolidinone is reacted with tetrahydrofuran, dioxane,
Advantageously, the reaction product of 9-borabicyclo[3.3.1]nonane and 2-(+)-pinene is added in an organic solvent such as ether and the reaction is carried out at room temperature. Using the 1-benzyl-3-hydroxypyrrolidine thus obtained as a raw material, it is reacted with optically active mandelic acid. This method uses dl−
This method takes advantage of the fact that at least one of the salts of 1-benzyl-3-hydroxypyrrolidine and optically active mandelic acid is crystalline and has a different solubility in a solvent.
Crystallization is performed by cooling or concentrating, or by adding a solvent that reduces solubility, and only the less soluble optically active salts are selectively crystallized, resulting in a solid state. Separate the liquid. Solvents that can be used for this fractional recrystallization include methanol, ethanol, acetone, acetonitrile, toluene, and mixed solvents thereof, and it is also possible to reduce solubility by adding water. The collection of (S)-(-)-1-benzyl-3-hydroxypyrrolidine is carried out according to a conventional method, and can be easily accomplished by treatment with a base. [Effects of the Invention] (S)-(-)-1-benzyl-3-hydroxypyrrolidine, which is the object of the present invention, has the above-mentioned YM-
It is useful as a synthetic intermediate for various peptides, including 09730-dA. YM-09730-d-A is a new compound, and the rate of increase in coronary blood flow when directly administered into the coronary artery is
Its left-handed optical isomer (YM-09730-l-A)
It is significantly superior to the racemic compound (YM-09730-dl-A) and has a high affinity for coronary arteries (see Japanese Patent Application No. 114098/1983). There are various methods for producing YM-09730-d-A using (S)-(-)-1-benzyl-3-hydroxypyrrolidine, which is the object of the present invention, as a raw material compound. An example of the synthesis method is shown below. That is, the object compound of the present invention () diketene () is reacted to form acetoacetic acid (1-benzylpyrrolidin-3-yl) ester, which is then reacted with m-nitrobenzaldehyde () and 3-aminocrotonic acid methyl ester (). YM-09730-
d-A() can be produced. Furthermore, the object compound of the present invention () is subjected to catalytic reduction to remove the benzyl group to form (S)-(-)-3-hydroxypyrrolidine, which is used as a proline analog component of various peptides. The present invention relates to a substantially novel object compound of the present invention ()
According to the present invention, it is possible to produce a pure compound () with high optical purity, which could not be achieved by most methods conventionally known as means for separating or synthesizing other optically active compounds. This makes it possible to obtain this technology and has a significant industrial effect. Moreover, when YM-09730-d-A is produced using the object compound () of the present invention as a raw material, the desired compound can be obtained in a yield about twice as high as that of the conventional method using a racemate as a raw material. [Example] The present invention will be explained in more detail by referring to Examples below. Note that an experiment conducted using L-(-)-malic acid for the asymmetric synthesis method described in Synthetic Communications is shown as a reference example. Furthermore, the absolute configuration of optically active mandelic acid is as follows.

【formula】

[Formula] The optical purity of D-(-)-mandelate of (S)-(-)-1-benzyl-3-hydroxypyrrolidine is determined by the nuclear magnetic resonance spectrum ( 100M
Hz), and when the 3-position of the hydroxypyrrolidine is S coordination, it is measured as a singlet at 4.03 ppm,
In the case of R coordination, it is observed as a quartet (J = 12.5 Hz) at 4.01 ppm. Furthermore, (S)-(-)-1-benzyl-3-hydroxypyrrolidine was produced by focusing on the methine proton at the 3-position of pyrrolidine, which was observed as a multiplet at 4.32 ppm, and adding a shift reagent [Eu-TFMC()] little by little. The absolute configuration and optical purity can be confirmed based on the empirical rule that the S-coordinated methine proton is shifted to a lower magnetic field to a smaller extent by adding S-coordinated methine protons. Reference example (S)-(-)-malic acid 75g and benzylamine
75ml was reacted at 170℃ for 3 hours to form (S)-(-)-1.
-Benzyl-3-hydroxysuccinimide [melting point 99-101°C, specific light intensity [α] ²⁰ _D -51.1° (C=1,
52.7 g of methanol) was obtained. Lithium aluminum hydride in 340ml of anhydrous tetrahydrofuran
9.73 g of imide was suspended, and a solution of 20.5 g of this imide in 200 ml of anhydrous tetrahydrofuran was added dropwise while cooling with ice water.
After heating under reflux for 3 hours, cool, add 100 g of sodium sulfate decahydrate, and stir overnight under ice cooling. Insoluble materials are removed, the solvent is distilled off under reduced pressure, and the boiling point is 109-115℃/0.8mmHg, specific light intensity [α]
13.8 g of (S)-(-)-1-benzyl-3-hydroxypyrrolidine with ²⁰ _D -3.0° are obtained. The (S)-(-)-isomer obtained here contained 10% R-(+)-isomer from the nuclear magnetic resonance spectrum obtained by adding a hydrogen shift reagent [Eu-TFMC()] at the 3rd position. The optical purity was 80%ee. Example 1 (1) 17.7 g of l-1-benzyl-3-hydroxypyrrolidine and 15.2 g of (D)-(-)-mandelic acid were heated and dissolved in 66 ml of acetone and allowed to stand overnight at 4°C to precipitate 8.5 g of crystals. was recrystallized from 26 ml of acetone to obtain the (D)-(-)mandelate of (S)-(-)-1-benzyl-3-hydroxypyrrolidine.
Obtain 5.1g. Specific luminosity [α] ²⁰ _D −45.5° (C=1,
methanol). Even after repeated recrystallization, there was no change in the specific light intensity. Melting point 101-102℃. The N- CH ₂ -Ph nuclear magnetic resonance spectrum of the (S)-isomer salt obtained here was observed at 4.03 ppm (singlet, 2H), and the AB type 4 at 4.01 ppm of the (R)-isomer. No double line (J=12.5Hz) was observed. (2) Dissolve 22 g of D-(-)-mandelate of (S)-(-)-1-benzyl-3-hydroxypyrrolidine in 50 ml of chloroform, and remove the chloroform layer from a solution of 14.4 g of anhydrous sodium carbonate in 90 ml of water. After washing with
-1-benzyl-3-hydroxypyrrolidine
Obtain 11.5g. Boiling point 109℃/0.65mmHg, [α] ²⁰ _D
−3.77° (C=5, methanol). Example 2 (S) containing (R)-(+)-isomer obtained in Reference Example
D as in Example 1 using 13.8 g of -(-)-1-benzyl-3-hydroxypyrrolidine (80e.e.).
-(-)-mandelate, 3 volumes of ethanol, then 6 volumes of ethanol-toluene (1:5)
Mandelate obtained by recrystallization from [[α] ²⁰ _D −
45.2°] to produce (S)-(-)-1-benzyl-3-hydroxypyrrolidine [boiling point 115-120°C/
1.2-1.5 mmHg, [α] ²⁰ _D -3.77° (C=5, methanol)] 8.6 g was obtained. Example 3 2-(+) in 50 ml of 9-borabicyclo[3.3.1]nonane (0.5 M tetrahydrofuran solution) in a nitrogen stream
- Add 3.4 g of pinene and stir at 60°C for 5 hours.
Cool to room temperature and add 1-benzyl-3-pyrrolidinone
Add 1.75g. After stirring for 4 days at room temperature, 1.3 ml of acetaldehyde is added at 0°C. The solvent was distilled off under reduced pressure, and 20 ml of ether was added to the residue. Cool to 0°C, add 1.5 ml of 2-aminoethanol, and stir.
Remove the formed precipitate. The ether solution is extracted with 1N hydrochloric acid, and the hydrochloric acid layer is made alkaline with sodium carbonate and extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate and concentrated to yield the crude product 1.1.
get g. The crude product was distilled under reduced pressure to obtain 0.6 g of purified product. Boiling point 106℃/0.9mmHg. Got it here (S)
-(-)-1-benzyl-3-hydroxypyrrolidine was prepared by adding shift reagent [Eu-TFMC()] to 3
The nuclear magnetic resonance spectrum of hydrogen at 30% ee was found to be 30% ee. This was optically resolved using D-(-)-mandelate in the same manner as in Example 1, and the result was (S)-(-)-1-, which showed [α] ²⁰ _D -3.77° (C=5, methanol). benzyl
0.35g of 3-hydroxypyrrolidine was obtained. Example 4 3.8 g of sodium borohydride is suspended in 40 ml of anhydrous dioxane, and a solution of 11.4 g of trifluoroacetic acid in 20 ml of anhydrous dioxane is added dropwise at 10-15°C.
After stirring at the same temperature for 1 hour, 5 ml of a solution of 1.03 g of (S)-(-)-1-benzyl-3-hydroxysuccinimide in anhydrous dioxane was added dropwise. After stirring at room temperature for 2 hours, the mixture was heated under reflux for 5 hours. After cooling,
The solvent was distilled off under reduced pressure, and 150 ml of water was added to the resulting residue.
is added to decompose excess reagent, and then made basic with anhydrous sodium carbonate. Extract with chloroform,
After drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the resulting residue is subjected to silica gel column chromatography. Elute with chloroform:methanol (20:1, volume ratio), (S)-(-)-1-
0.63 g of benzyl-3-hydroxypyrrolidine was obtained. This was processed in the same manner as in Example 1 and (S)-
(-)-1-benzyl-3-hydroxypyrrolidine
0.39g was obtained. [α] ²⁰ _D −3.77° (C=5, methanol). Example 5 3.8 g of sodium borohydride was dissolved in 120 ml of anhydrous diglyme, and 14.91 g of boron trifluoride ethyl ether complex was added to this at 4 to 10°C.
drip. After stirring at the same temperature for 30 minutes, (S)-
A solution of 10.25 g of (-)-1-benzyl-3-hydroxysuccinimide in 30 ml of anhydrous diglyme is added dropwise. After the dropwise addition, stirring was continued at 100°C for 17 hours, and then the solvent was distilled off under reduced pressure. Add 1N hydrochloric acid to the resulting residue.
Add 200ml and extract with chloroform. The 1N hydrochloric acid layer is made basic with anhydrous sodium carbonate, and then extracted with chloroform. The chloroform layer is washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 0.64 g of (S)-(-)-1-benzyl-3-hydroxypyrrolidine. This material was treated in the same manner as in Example 1 (S)
0.46 g of -(-)-1-benzyl-3-hydroxypyrrolidine was obtained. [α] ²⁰ _D −3.77° (C=5, methanol). Example 6 3.8 g of sodium borohydride was dissolved in 120 ml of anhydrous diglyme, and 14.91 g of boron trifluoride ethyl ether complex was added to this at 0 to 5°C.
drip. After stirring at the same temperature for 30 minutes, (S)-
A solution of 10.25 g of (-)-1-benzyl-3-hydroxysuccinimide in 30 ml of anhydrous diglyme is added dropwise. After the dropwise addition, stirring was continued at 100°C for 17 hours, and then the solvent was distilled off under reduced pressure. Add 6N hydrochloric acid to the resulting residue
Add 30ml, heat at 100℃ for 30 minutes, and extract with chloroform. The hydrochloric acid layer is made basic with anhydrous sodium carbonate, and then extracted with chloroform. The chloroform layer is washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 6.70 g of (S)-(-)-1-benzyl-3-hydroxypyrrolidine. This material was treated in the same manner as in Example 1 and (S)-
(-)-1-benzyl-3-hydroxypyrrolidine
4.80g was obtained. [α] ²⁰ _D −3.77° (C=5, methanol).

Claims (1)

[Claims] Mandel of (S)-(-)-1-benzyl-3-hydroxypyrrolidine crystallized after adding optically active mandelic acid to 1 dl-1-benzyl-3-hydroxypyrrolidine. (S)-(-) characterized by separating the acid salt and then removing the acid group with an alkali
-Production method of 1-benzyl-3-hydroxypyrrolidine. 2 (S)-(-)-malic acid and benzylamine are reacted to form (S)-(-)-1-benzyl-3-
hydroxysuccinimide and (S)-(-)-1-benzyl-3-hydroxypyrrolidine obtained by reducing this and a small amount of by-product (R)-(+).
After adding optically active mandelic acid to the mixture with -1-benzyl-3-hydroxypyrrolidine, the crystallized mandelic acid salt of (S)-(-)-1-benzyl-3-hydroxypyrrolidine was separated. , followed by removing the acid group with an alkali (S)-
A method for producing (-)-1-benzyl-3-hydroxypyrrolidine. 3 (S)-(-)-1-benzyl-3- obtained by asymmetric reduction of 1-benzyl-3-pyrrolidinone
Hydroxypyrrolidine and by-product (R)-(+)-
After adding optically active mandelic acid to the mixture with 1-benzyl-3-hydroxypyrrolidine, the crystallized mandelic acid salt of (S)-(-)-1-benzyl-3-hydroxypyrrolidine is separated, (S)-, characterized in that the acid group is then removed with an alkali.
A method for producing (-)-1-benzyl-3-hydroxypyrrolidine.