JPH0717568B2 - Method for separating optically active glycol derivative - Google Patents

Description

Description of the Invention The present invention [relates to] the general formula 1 ^* (In the formula, R ₁ represents an aliphatic hydrocarbon group having ₁ to 16 carbon atoms,
R ₂ represents an aliphatic hydrocarbon group having 1 to 6 carbon atoms, R ₃ represents an allyl sulfonyloxy group or a halogen atom, and * represents an asymmetric carbon. ) Optically active represented by the ester body 1 ^* and Formula 2 ^* (Wherein R ₁ , R ₃ and * are the same as above), the mixture of the optically active alcohol 2 ^* is treated under basic conditions to selectively react the alcohol 2 ^* with the general formula 3 ^*. (R ₁ and * are the same as the above), and the optically active epoxy compound 3 ^* is converted, and the resulting mixture of ester compound 1 ^* and epoxy compound 3 ^* is first distilled by distillation using the boiling point difference to obtain epoxy compound 3 ^{*. The present} invention relates to a method for separating an optically active glycol derivative, characterized in that ^* is separated, and then ester 1 ^* is collected from the residue. For example, racemic ester of glycol derivative is asymmetric using an enzyme such as lipase. Unreacted ester 1 ^* obtained by hydrolysis and alcohol 2 ^{* of} hydrolyzate
Is effective for separating. The ester 1 ^* can be easily converted into an epoxy compound 3 ^* by reacting with an alcoholate after isolation.

These optically active esters 1 ^* , alcohols 2 ^* and 3 ^* are all highly versatile compounds as starting materials for antibiotics, insect pheromones, liquid crystals and the like.

[Conventional technology and problems]

The present inventors have already disclosed in JP-A-61-227797 that a racemic compound represented by the general formula (RS) -1 (In the formula, R ₁ , R ₂ and R ₃ are the same as the above), a lipase having stereoselective hydrolysis ability is allowed to act on the ester to selectively hydrolyze the (R) form, (S) -1 _{(Wherein, R 1, R 2, R} 3 are as defined above) unreacted ester represented by [(S) - 1] and general formula (R) - 2 Have revealed that - [2 (R)] can be taken (in formula, R _1, R ₃ is the same as) hydrolyzate alcohol represented by. However, both 1 and 2 are lipophilic, and complete separation is difficult only with an organic solvent, and we have carried out separation and purification by silica gel column chromatography. However, the development of a simpler method for separating ester and alcohol is desired. It was rare.

[Means and Actions for Solving Problems]

The present invention is (Wherein R ₁ , R ₂ , R ₃ and * are the same as above), and Studies have been conducted in order to establish a simple method for separation from the alcohol represented by (wherein R ₁ , R ₃ and * are the same as above). As a result, the ester 1 ^* is stable under strongly basic conditions above pH 12, while the alcohol 2 ^* is readily available under basic conditions above pH 11. In can be converted into represented epoxide, thus 1
By treating the mixture of ^* and 2 ^* with base, 1 ^* and 3 ^*
It can be converted into a mixture containing ^*, and the epoxy compound 3 ^* in this mixture can be easily recovered by a distillation operation,
Furthermore, when R ₃ is a halogen group from the residue, it is distilled by R ₃
In the case where is an allylsulphonyloxy group, the present invention has been completed by finding that 1 ^* can be easily recovered only by concentrating.

Note that when the 1 ^* obtained by separating reacted with an alcoholate converted easily into 3 ^*, 3 by connexion high purity further distilled
You can get ^* .

The present invention uses a microorganism or lipase to form a racemic ester. As an example, a mixture of ester (S) -1 and alcohol (R) -2 obtained by asymmetric hydrolysis of

General formula (RS) -1 , (S) -1 , 1, ^* , (R) -2 , 2
Substituents R ₁ and R of the compound represented by ^* , (R) -3 , 3 ^*
The combinations of ₂ and R ₃ are as follows.

R ₁ is, for example, an aliphatic hydrocarbon group having 1 to 16 carbon atoms,
R ₂ is, for example, an aliphatic hydrocarbon group having 1 to 6 carbon atoms, and preferably 1 to 4 carbon atoms in consideration of the difference in boiling point from the organic solvent. Examples of R ₃ include a halogen group such as chlorine and bromine, a p-toluenesulfonyloxy group, a phenylsulfonyloxy group, and an allylsulfonyloxy group such as a naphthylsulfonyloxy group.

After treating these compounds with an asymmetrically hydrolyzable enzyme such as lipase or a microorganism, extraction with a hydrophobic organic solvent such as ether, melene chloride or ethyl acetate, as shown in JP-A-61-227797, approximately equimolar amounts of the ester [(S) - 1] and alcohol - extract containing [(R) 2] is obtained.

The organic solvent to be used is selected such that the difference in boiling point from (S) -1 or (R) -3 can be large, and the organic solvent is (S).
-1 or (R) -3 needs to be considered to prevent it from being mixed. The reverse combination, namely the ester [(R)-
1] and an alcohol [(S) - 2] the mixture be subjected to the reaction similar to the above is of course also possible.

These extracts can be used as they are in the next reaction. For example, add NaOH or Ca (OH) to the extract obtained above.
An alkaline aqueous solution such as _{2 is} added in excess (about 1.1 to 3.0 times the molar equivalent) with respect to the alcohol 2 ^* . Then too much
Adjust the pH range from 10 to 13, preferably
Gradually drop it so that it is kept around 12. Also, when the organic solvent is once distilled off and the concentrated mixture containing no solvent is used, the same method may be used.

The reaction temperature can be room temperature to the boiling point of the solvent. The end point of the reaction is high performance liquid chromatography (HP
LC, detection: UV) and thin layer chromatography (TLC, detection: I)
₂ ), it can be easily determined by the disappearance of the 2 ^* peak by analysis using gas chromatography. After the reaction, the organic solvent layer is dehydrated with anhydrous sodium sulfate or the like,
Fractionation is performed to collect the epoxide 3 ^* fraction.
On the other hand, the ester 1 ^* can be obtained by further distilling when R ₃ is a halogen group and concentrating when R ₃ is an allylsulphonyloxy group.

In particular, when ester 1 ^* is fixed, easily increase the ester 1 ^* chemical purity by crystallization using an organic solvent, a high quality ester 1 ^* is obtained.

Also, instead of using an alkaline solution, by treating with a basic compound in an organic solvent, similarly, only 2 ^* can be selectively converted into epoxide 3 ^* . More specifically, as the organic solvent, for example, benzene, toluene, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, methylene chloride, chloroform,
Using a solvent such as hexane and ethyl acetate, the basic compound is selected from, for example, alcohol metal salts, amines, inorganic bases, etc., if these are added in a range of 1.1 to 2.0 times the theoretical molar amount. good.

The reaction is carried out in the temperature range of −80 ° C. to the boiling point used for dissolution. The treatment after the reaction may be performed according to the case of using an alkaline solution.

〔Example〕

Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited to these examples.

Reference Example 1 the asymmetric solution matrix (RS) with lipase -2-acetyloxy -1-p-toluenesulfonyloxy Huo oxy propane (RS) - 1a ₁ 27.2g, City version lipase "Amano P" [Amano Pharmaceutical Co., Ltd.]
The reaction solution containing 0.3 g and 150 ml of 0.1 M phosphate buffer (pH 7.2) was subjected to an asymmetric hydrolysis reaction while maintaining the pH at 7.2 with a 5N-NaOH aqueous solution at a temperature of 40 ° C. The reaction is completed in about 4 hours,
After cooling, extraction operation was performed twice with 150 ml of toluene. When the toluene layer is dehydrated with anhydrous sodium sulfate (S)-
2-Acetyloxy-1-p-toluenesulphonyloxypropane (S) -1a ₁ and (R) -2-hydroxy-
1-p-toluenesulphonyloxypropane R- 2a A toluene solution containing approximately equimolar amount of was obtained.

Reference Example 2 Instead of the substrate (RS) -1a ₁ , (RS) -2-butanoyloxy-1-p-toluenesulphonyloxypropane (R
S) -1a ₂ (S) -1a ₂ and (R) -in accordance with Reference Example 1 except that
A toluene solution containing approximately equimolar amount of 2a was prepared.

Reference Example 3 Substitute for Substrate 1a ₁ (RS) -2-Butanoyloxy-1-
p-toluenesulphonyloxybutane (RS) -1b ₁ (S) -1b ₁ and (R) -in accordance with Reference Example 1 except that
2-Hydroxy-1-p-toluenesulphonyloxybutane (R) -2b ₁ A toluene solution containing approximately equimolar amount of was prepared.

Reference Example 4 Substrate (RS) -1-Bromo-2-acetoxypropane (RS) - 1a ₃ 18.1g, commercially available Lipase "Amano P" [Amano Pharmaceutical Co.] 0.91g and 0.1M- phosphate buffer (pH 7.2) 10
While maintaining the reaction liquid containing 0 ml at 35 ° C, an asymmetric hydrolytic reaction was carried out. The reaction reached 50% in about 6 hours. About 20 after cooling
The extraction operation was performed twice with 0 ml of diisopropyl ether. When the isopropyl ether layer was dehydrated with anhydrous sodium sulfate, (S) -1-bromo-2-acetoxypropane (S) -1a ₃ and (R) -1-bromo-2-propanol An ether solution containing almost equimolar amounts of (R) -2a ₃ was obtained.

Reference Example 5 Instead of the substrate (RS) -1-bromo-2-acetoxypropane, (RS) -1-bromo-2-acetoxybutane (RS) - the other was used 1b ₂ is according to Reference Example 4 (S) -1
-Bromo-2-acetoxybutane (S) - 1b ₂ and (R)-1-bromo-2-butanol An isopropyl ether solution containing (R) -2b ₂ in an approximately equimolar amount was prepared.

Reference Example 6 Instead of the substrate (RS) -1-bromo-2-acetoxypropane, (RS) -1-chloro-2-hexanoyloxypropane (RS) - except for using 1a ₄ are according to Reference Example 4 (S) -1
-Chloro-2-hexanoyloxypropane (S) - 1a ₄ and (R)-1-chloro-2-propanol A diisopropyl ether solution containing almost equimolar amount of (R) -2a ₄ was prepared.

Example 1 100 ml of water was added to about 300 ml of a toluene solution containing about 0.05 mol of each of (S) -ester (S) -1a ₁ and (R) -alcohol (R) -2a obtained in Reference Example 1, and 30 Keep the temperature at ℃ and add 5N-NaOH aqueous solution dropwise with vigorous stirring. Adjust the dropping rate of the alkaline solution so that the pH will be 12.0. The reaction is HPLC
In the toluene layer (R) - 2a Track peaks was confirmed that the completely disappeared in about 2 hours.

The toluene layer is dehydrated with anhydrous sodium sulfate, (R)
-Propylene oxide (R) -3a The content of was measured by gas chromatography (GC) and found to be equivalent to 2.30 g (79% of theoretical yield).
Furthermore, the bath temperature was 70 ° C, and 1.53 g (theoretical yield of 53
%) Of (R) -3a was obtained.

▲ [α] ²² _D ▼ ＝ + 12.8 ° (neat) ¹ H NMR (90MHz, CDCl ₃ ) δ (ppm): 1.3 (3H, d, J = 5.0H
z), 2.3-2.45 (1H, m), 2.6-2.75 (1H, m), 2.8-3.
05 (1H, m) [literature; LR Hillis et al., Journal of Organic Chemistry (J.Org.Chem.), 46 , 3348 (19)
81).

(R) - 3a: ▲ [α] ²² _D ▼ = + 13.0 ° (neat)] On the other hand, it is concentrated while evaporated under reduced under reservoir toluene residue.
This concentrate was washed twice with 100 ml of 1N-NaOH aqueous solution, once dissolved with 50 ml of ether, dehydrated with anhydrous sodium sulfate, and about 200 ml of hexane was gradually added (S)- 1a ₁ white powder 9.8g (theoretical yield of 72
%)was gotten. ▲ [α] ²² _D ▼ ＝ -13.0 ° (c = 2.0,
CHCl ₃ ), mp 39-40 ° C. ¹ H NMR (90 MHz, CDCl ₃ ) δ (ppm): 1.23 (3H, d, J = 6.4
_{Hz, C H 3 CH (O} -) -), 1.95 (3H, s, CH 3 CO -), 2.45
(3H, s, CH ₃ −Ar−), 4.03 (2H, d, J = 5.1Hz, −CH
_2- ), 4.82-5.17 (1H, m, -CH-), 7.33, 7.77 (each
2H, 2d, J = 8.1Hz, Ar-H) obtained in Example 2 Reference Example 2 (S) - ester (S) - 1a ₂ and (R) - and 2a each about 0.05 moles - alcohol (R) Preparation was carried out according to Example 1 using 300 ml of a toluene solution containing the same.

(R) -Propylene oxide (R) -3a : of theoretical yield
42% ▲ [α] ²² _D ▼ ＝ + 12.7 ° (neat) (S) -2-butanoyloxy-1-p-toluenesulphonyloxypropane (S) -1a ₂ : 65% of theoretical yield Syrup, ▲ [α] ²² _D ▼ ＝ -10.0 ° (c = 2.0,
CHCl ₃ ) ¹ H NMR (90 MHz, CDCl ₃ ) δ (ppm): 0.90 (3H, t, J = 6.3
_{Hz, C H 3 -CH 2 -} ), 1.16-1.83 (5H, m, C H 3 CH (O-)
_{-, CH 3 C H 2 CH} 2 -), 2.18 (2H, t, J = 7.5Hz, CH 3 CH 2 C H 2
−), 2.45 (3H, s, C H ₃ −Ar−), 4.05 (2H, d, J = 4.8H
z, -CH (O-) C H 2 O -), 4.86-5.22 (1H, m, -CH
(O-)-), 7.35, 7.77 (each 2H, d, J = 8.4Hz, Ar-
H) Example 3 (S) in NaH (0.05 mol) suspended in 50 ml of toluene.
- ester (S) - 1a ₁ and (R) - alcohol (R) -
2a A toluene (50 ml) solution of a mixture of about 0.05 mol each is added dropwise and stirred. The reaction is monitored by HPLC, TLC and GC. After reacting for 12 hours at room temperature, the (R) -2a peak disappeared and the (R) -3a peak was observed by HPLC and TLC. (GC yield 92%). The reaction was stopped by adding water under ice-cooling, washed with water, dried, and distilled under atmospheric pressure at a bath temperature of 70 ° C to give 1.29 g (4
4%) of (R) -3a was obtained. ▲ [α] ²² _D ▼ ＝ + 12.7 ° (neat). Furthermore, (S) -1a ₁ was collected according to Example 1.

Yield 9.1 g (theoretical yield of 67%) ▲ [α] ²⁰ _D ▼ = -12.9 DEG (c = 2.0, CHCl ₃₎ obtained in Example 4 Reference Example 3 (S) - ester (S) - 1b ₁ and (R) - alcohol (R) - 2b KoTsuta prepared except for using a toluene solution in the same manner as in example 1 containing each from about 0.05 mol.

(R) -1,2-butylene oxide (R) -3b 45% of theoretical yield, ▲ [α] ²¹ _D ▼ ＝ + 13.3 ° (c = 2.
0, Ether) ¹ H NMR (90 MHz, CDCl ₃ ) δ (ppm): 0.98 (3H, t, J = 7.0
Hz), 1.25-1.80 (2H, m), 2.38-3.12 (3H, m) [reference value; K. Mori et al., Tetrahedron (Tetrahedro
n), 35 , 1601 (1979). (R) -1,2-butylene oxide, ▲ [α] ²¹ _D ▼ ＝ + 13.6 ° (c = 1.135, Ether
r)] (S) -2-Butanoyloxy-1-p-toluenesulphonyloxybutane (S) -1b ₁ ; 72% of theoretical yield, ▲
[Α] ²⁰ _D ▼ = -18.3 ° (c = 2.0, CHCl ₃ ), shape syrup ¹ H NMR (90 MHz, CDCl ₃ ) δ (ppm): 0.73–1.07 (6H, m,
C H ₃ CH ₂ CH ₂ (O −) −, C H ₃ CH ₂ CH ₂ CO−), 1.35−1.80
_{(4H, m, CH 3 C} H 2 CH 2 (O -) -, CH 3 C H 2 CH 2 CO -), 2.08
_{-2.33 (2H, m, CH 3} CH 2 C H 2 CO -), 2.45 (3H, s, CH 3 -A
r), 4.04 (2H, d , J = 4.2Hz, -CH (O-) CH H 2 O-),
4.76-5.03 (1H, m, -CH (O-)-), 7.30, 7.75 (eac
h 2H, d, J = 8.4Hz , Ar-H) obtained in Example 5 Reference Example 4 (S) -1- bromo-2-acetoxy-propane (S) - 1a ₃ and (R)-1-bromo 2- Buropanoru (R) - 2a ₃ water to the concentrate to about 100ml obtained by distilling off the diisopropyl ether of about 300ml diisopropyl ether solution about 400ml containing each from about 0.05 mole 50ml
Add 5N-NaOH aqueous solution at room temperature with vigorous stirring and add about 20
ml (about 0.1 mol) was added dropwise over 30 minutes, and the reaction was continued for 1 hour. The reaction is 2μ with a microsyringe from the ether layer.
Sampling and gas chromatography (column:
Silicon OV-17, 1 m, 80 ° C., N ₂ : 30 ml / min) was analyzed and followed. After completion of the reaction, normal pressure distillation, first (R) - propylene oxide (R) - 3a 1.05 g (theoretical molar yield 36
%), And the diisopropyl ether fraction was then distilled off. Finally, distill under reduced pressure to (S) -1-bromo-2
- acetoxypropane (S) - 1a ₃ and 5.16 g (57% of theory molar yield) was obtained. (Bp64 ℃ / 12mmHg).

The physical property values are as follows.

(R) -Propylene oxide (R) -3a Shape syrup, 35-36 ℃ / 760mmHg, ▲ [α] ²² _D ▼ =
+ 9.1 ° (neat) ¹ H NMR (90MHz, CDCl ₃ ) δ (ppm): 1.3 (3H, d, J = 5.0H
z), 2.3-2.45 (1H, m), 2.6-2.75 (1H, m), 2.8-3.
05 (1H, m) [Literature; LR Hillis et al., J. Org. Chem., 46 , 3348 (19
81). (R) -propylene oxide, ▲ [α] ²² _D ▼
= + 13.0 ° (neat)] (S) -1-Bromo-2-acetoxypropane (S)-
1a ₃ Shape syrup, 73 ℃ / 26mmHg, ▲ [α] ²³ _D ▼ = -13.3
(C = 5.9, CHCl ₃ ), ¹ H NMR (90 MHz, CDCl ₃ ) δ (ppm): 1.35 (3H, d, J = 7.2)
_{Hz, C H 3 CH (O} -) -), 2.06 (3H, s, CH 3 CO -), 3.4
3 (2H, d, J = 6.3Hz, -CH 2 Br), 4.83-5.23 (1H, m, -CH
(O −) −) [Reference value; BTGolding et al., Journal of Chemical Society Parkin Transition I (JC
S. Perkin.I), 1214 (1973). bp57 ℃ / 11mmHg, ▲ [α]
²³ _D ▼ = -13.55 ° (c = 5.8, CHCl ₃ )] Example 6 (S) -1-bromo-2-acetoxybutane (S) -1b ₂ and (R) -1 obtained in Reference Example 5. -Bromo-2-butanol About 0.05 mol of each isopropyl ether solution containing about 0.05 mol
Preparation was carried out according to Example 1 using 400 ml.

(R) -1,2-butylene oxide (R) -3b 38% of theoretical molar yield, ▲ [α] ²⁰ _D ▼ = + 9.8 ° (c =
1, Ether) ¹ H NMR (90 MHz, CDCl ₃ ) δ (ppm): 0.98 (3H, t, J = 7.0
Hz), 1.25-1.80 (2H, m), 2.38-3.12 (3H, m) [reference value; K. Mori et al., Tetrahedron (Tetrahedro
n), 35 , 1601 (1979). (R) -1,2-butylene oxide (R) -3b , ▲ [α] ²¹ _D ▼ = + 13.6 ° (c = 1.13)
5, Ether)] (S) -1-Bromo-acetoxybutane (S) -1b ₂ 45% of theoretical molar yield, shape syrup, (84-86 ℃ / 22m
mHg), ▲ [α] ²⁰ _D ▼ = −20.5 ° (c = 3, Ether) ¹ H NMR (90 MHz, CDCl ₃ ) δ (ppm): 0.93 (3H, t, J = 9.0
_{Hz, C H 3 CH 2 -} ), 1.54-1.98 (2H, m, CH 3 C H 2 CH (O
−) −), 2.10 (3H, s, CH ₃ CO−), 3.50 (2H, d, J = 6.3H
_{z, -CH 2 Br), 4.80-5.13} (1H, m, -CH (O -) -) [literature value;. K.Mori et al, Tetrahedron (Tetrahedron
n), 35 , 1601 (1979). bp85-92 ℃ / 26mmHg, ▲ [α]
²³ _D ▼ = -21.2 DEG (c = 3.543, Ether)] obtained in Example 7 Reference Example 6 (S) -1- chloro-2-hexanoate acetoxyphenyl propane (S) - and 1a ₄ (R) - 1-chloro-
Preparation was carried out according to Example 1 using about 400 ml of a diisopropyl ether solution containing about 0.05 mol of 2-propanol (R) -2a ₄ each.

(R) -Propylene oxide (R) -3a : 37% of theoretical molar yield, ▲ [α] ²² _D ▼ = + 9.2 ° (neat) (S) -1-chloro-2-hexanoyloxypropane ( S) -1a ₄ Theoretical molar yield 62%, bp 70-71 ° C / 1-2 mmHg, ▲ [α] ²⁰ _D
▼ = −5.6 ° (c = 2.2, Dioxane) ¹ H NMR (90 MHz, CDCl ₃ ) δ (ppm): 0.75−1.00 (3H, t,
_{d = 6.0Hz, C H 3 CH} 2 -), 1.19-1.82 (9H, m, CH 3 - (C H
₂ ) ₃ CH ₂ −, C H ₃ CH (O −) −), 2.32 (2H, t, J = 8.2H
_{z, CH 3 (CH 2)} 3 -C H 2 -), 3.57 (2H, d, J = 6.6Hz, -
_{CH 2 Cl), 4.92-5.27 (1H} , m, CH 3 C H (O -) -).

Claims (9)

[Claims] 1. General formula 1 ^* (In the formula, R ₁ represents an aliphatic hydrocarbon group having ₁ to 16 carbon atoms,
R ₂ represents an aliphatic hydrocarbon group having 1 to 6 carbon atoms, R ₃ represents an allyl sulfonyloxy group or a halogen atom, and * represents an asymmetric carbon. ) Optically active represented by the ester body 1 ^* and Formula 2 ^* (Wherein R ₁ , R ₃ and * are the same as above), the mixture of the optically active alcohol 2 ^* is treated under basic conditions to selectively react the alcohol 2 ^* with the general formula 3 ^*. (R ₁ and * are the same as above), and the mixture is converted into an optically active epoxy body 3 ^* , and the resulting mixture of the ester body 1 ^* and the epoxy body 3 ^* is distilled to distill the ester body 1 ^* and the epoxy body. A method for separating an optically active glycol derivative, characterized in that 3 ^* is separated. 2. The method according to claim 1, wherein the treatment under basic conditions is carried out by adding an alkaline solution to the mixture and maintaining the pH in the range of 10-13. 3. The method according to claim 1, wherein the treatment under basic conditions comprises treating with a basic compound in a non-aqueous solvent. 4. The optically active ester 1 ^* is the (S) isomer, and the optically active alcohol 2 ^* is the (R) isomer. The method described. 5. The method according to any one of claims 1 to 4, wherein R ₁ is a methyl group or an ethyl group. 6. The method according to any one of claims 1 to 5, wherein R ₃ is an allylsulphonyloxy group. 7. The method according to any one of claims 1 to 6, wherein R ₃ is a p-toluenesulphonyloxy group. 8. The method according to any one of claims 1 to 5, wherein R ₃ is a halogen atom. 9. The method according to any one of claims 1 to 5 or 8, wherein R ₃ is chlorine or bromine.