JPH02131461A - Production of optically active glycerol derivative - Google Patents

Abstract

PURPOSE:To obtain the aimed product by reacting an optically active epichlorohydrin with an alcohol in the presence of an acidic catalyst to give an optically active glycerol derivative, reacting the resultant glycerol derivative with a sulfonyl halide and deprotecting the resultant sulfonate in the presence of an acidic catalyst, metallic catalyst, etc. CONSTITUTION:(R)-Epichlorohydrin is reacted with an alcohol expressed by the formula R<1>OH (R<1> is benzyl, CH2=CHCH2-, etc.) in the presence of an acidic catalyst (e.g., Lewis acid) at 30-80 deg.C to give a compound expressed by formula I, which is then reacted with a sulfonyl halide (e.g., chloromethane sulfonic acid) at 0-70 deg.C to afford a compound expressed by formula II. The compound expressed by formula II is reacted in the presence of an acidic catalyst (e.g., p-toluenesulfonic acid) and/or metallic catalyst (e.g., Pd) at 20-100 deg.C to give a compound expressed by formula III, which is then subjected to intramolecular cyclization reaction to provide the (S)-bichlorohydrin.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to a method for producing an optically active glycerol derivative which is a precursor of optically active epichlorohydrin.

(Prior art and its problems) Optically active epichlorohydrin is an extremely important compound as a raw material for the synthesis of new materials such as medicines, agricultural chemicals, other physiologically active substances, and even ferroelectric liquid crystal materials. If a preferable optical isomer can be freely selected as a raw material for synthesis, the steps for obtaining the target compound can be shortened, and further, the target compound with higher optical purity can be obtained.

Conventionally, optically active epichlorohydrin (R) form and (S
) is known to be produced separately from D-mannitol (J, Org. Chem.
43, 4876 (197B>), this method requires a large number of steps and is not a practical method.

Recently, the present applicant has provided a method for producing highly pure optically active epichlorohydrin using microorganisms (Japanese Patent Application Laid-Open No. 1983-1972-1).
132196, JP-A-62-6697), the optical isomer mainly obtained by this method is the (R> isomer).

In recent years, the usefulness of optically active epichlorohydrin has been increasing in the field of new materials as mentioned above, and it has become an extremely important problem to obtain both enantiomers of the optically active substances that serve as raw materials with high optical purity. ing.

(Means for Solving the Problems) The present inventors have discovered a method for producing optically active epichlorohydrin with high purity by mutually inverting the stereochemistry in response to the above-mentioned needs. I applied. The present invention provides an optically active glycerol derivative as an intermediate produced in this manufacturing process.

The present invention is a method for producing an optically active glycerol derivative represented by the general formula (I>), which is obtained by the reaction of the following steps (a) to (c).

OSO2 R In the above general formula (I), R is a group selected from an alkyl group having 1 to 3 carbon atoms and an aryl group having 6 to 12 carbon atoms, which may have a halogen. The symbol * represents an asymmetric carbon atom.

(a) Optically active epichlorohydrin and the following general formula (n)
Step R10H of producing an optically active glycerol derivative (III) represented by the following general formula (nl) by reacting the alcohol represented by ), R1 is Cs
H5 CH2-, CH2 = CH-CH2 +, CH2
=C (OH3)-CH2-(CH3)3G
−, (Cs Hs ) 2 0H and (Cs H
s) A group selected from 30. Also, the general formula (I
II>, the symbol * represents an asymmetric carbon atom.

(Ex) The above optically active glycerol derivative (III) is reacted with a sulfonic acid halide in the presence of a base to obtain an optically active glycerol derivative represented by the following general formula (IV) (
0802 R In the above general formula (1v), R represents the same meaning as R in the general formula (I>), and R1 represents the same meaning as R1 in the general formula (II). represents an asymmetric carbon atom.

(c) A step of producing an optically active glycerol derivative (I> represented by the general formula (I>) by reacting the optically active glycerol derivative (IV) in the presence of an acidic catalyst, a metal catalyst, or an acidic catalyst and a metal catalyst. The method for producing the optically active glycerol derivative (I>) of the present invention will be explained using the following reaction formula.

The reaction formula below shows the reaction steps for mutual stereochemical inversion of each isomer of optically active shrimp chlorohydrin, and for convenience, the optically active (R) isomer is shown as the raw material shrimp chlorohydrin. Ta. Of course, if the optically active (S) isomer is used as the raw material epichlorohydrin, the corresponding optical isomers will be obtained in each step, and the final product will be (R
) It goes without saying that one epichlorohydrin can be obtained.

The object of the present invention is (R)- obtained by step <C>
(I) is an optically active glycerol derivative.

In the following reaction formula, R represents the same meaning as R in the general formula (I>), and R1 represents the same meaning as R1 in the general formula (I[>).

(R)-Epichlorohydrin (R)- (II) (R)- (rV) Step (A) This step combines (R)-Epichlorohydrin with the general formula R1
This is carried out by reacting an alcohol represented by 0H in the presence of an acidic catalyst.

As the (R)-epichlorohydrin used in this reaction, the above-mentioned Japanese Patent Application Laid-Open No. 61-132 filed by the present applicant
It is advantageous to use optically active shrimp chlorohydrin with high optical purity obtained by the methods described in JP-A No. 196 and JP-A-62-6697.

The alcohol represented by the general formula R1 0H used in this reaction is Cs Hs CH20H, CH2 =
CH-CH20H. CH2-C (CH:s)-C
H2 0H. (C}13) 3 CO
H. (06 H5 )2 CHOH and (C8 }15
) 3 CoH. The amount of alcohol to be used is selected in the range of 1 to 10 equivalents, preferably 2 to 5 equivalents, relative to (R)-ebichlorohydrin. 'Lewis acids or Lewis acid complexes are used as acidic catalysts, specifically boron trifluoride, boron trifluoride ether complex, aluminum trichloride, aluminum tribromide, zinc dichloride,
Examples include tin tetrachloride and iron trichloride. The amount of the catalyst to be used is not particularly limited and can be selected within a wide range, but generally it is 0.000 to (R)-epichlorohydrin. 0001
~0.05 equivalent, preferably 0.05 equivalent. A range of 001 to 0.02 is preferable. The reaction temperature is not particularly limited, but is usually 10
A range of from 100°C to 100°C, preferably from 30 to 80°C is suitable. For example, if the temperature is 80°C, the process will be completed in 1.5 hours.

Step (1) This step consists of the (R) − obtained by step (A).
In the step of converting the water rti group of the (R) monoglycerol derivative represented by (III) with a sulfonic acid halide and a base, it is converted into a sulfonic acid ester of the (R> form represented by (R>-(IV)). The sulfonic acid ester obtained by this reaction ( (R>- (IV)
) is a residue corresponding to the sulfonic acid halide which is the above-mentioned reactant, and R is an alkyl group having 1 to 3 carbon atoms and an aryl group having 6 to 12 carbon atoms, which may have a halogen. This is the chosen group. For example, methyl, ethyl, proyl, trifluoromethyl, trimethyl,
Examples include alkyl groups such as tribromomethyl, and aryl groups such as phenyl and tolyl. Specific examples of the above-mentioned sulfonic acid halides include methanesulfonic acid chloride, methanesulfonic acid bromide, methanesulfonic acid iodine, trifluoromethanesulfonic acid chloride, trifluoromethanesulfonic acid bromide, trifluoromethanesulfonic acid iodide, and trichloromethanesulfonic acid. Methanesulfonic acid, trichloromethanesulfonic acid bromide, trichloromethanesulfonic acid iodide, tribromomethanesulfonic acid chloride, tribromomethanesulfonic acid bromide,
Iodinated tribromomethanesulfonic acid, chlorinated benzenesulfonic acid, brominated benzenesulfonic acid, iodized benzenesulfonic acid, chlorinated p-toluenesulfonic acid, bromated p-toluenesulfonic acid, iodized p-+luenesulfonic acid, etc. Can be mentioned.

The bases used in this reaction are triethylamine,
Tertiary amines such as trimethylamine and pyridine are preferred. The appropriate amount to be used is 1 to 3 equivalents, preferably 1 to 1.2 equivalents, based on the sulfonic acid halide and base co-raw material alcohol. The reaction temperature is -20 to 100℃, usually θ
The temperature may be in the range of ~70°C, and the reaction is usually completed in 0.5 to 3 hours at room temperature (20 to 30'C). Any inert solvent may be used as the solvent, but methylene chloride and chloroform are usually used.

Step (c) The (R)-(IV) compound obtained in step 1) is reacted in the presence of a catalyst to produce the object of the present invention (
R>- (I> This is a step of obtaining a compound.

As the catalyst, an acidic catalyst, a metal catalyst, or a mixture of an acidic catalyst and a metal catalyst is used. The selection of catalyst is (R)-(
IV) It is carried out as appropriate based on the R1 substituent of the compound. For example, specific examples of acidic catalysts include p-toluenesulfonic acid, benzenesulfonic acid, perchloric acid, sulfuric acid, hydrochloric acid, nitric acid,
Hydrogen bromide, acetic acid, trifluoroacetic acid, trichloroacetic acid,
Examples include tribromoacetic acid, silica gel, aluminum chloride, titanium tetrachloride, tin tetrachloride, boron trifluoride, etc.
Examples of the metal catalyst include platinum and palladium.

When R1 is Cs f-1s CH2-, hydrogenation using palladium, CH2 = CH-CH2- or CH2
=C (CH3) When CH2-, palladium and p-
Toluenesulfonic acid or perchloric acid, (Chl3)
3 For G-, use trifluoroacetic acid, hydrochloric acid or mixed acetic acid with hydrogen bromide, for (Ca Hs ) 2 Ct-L-, use palladium and aluminum chloride, (Ce Hs ) 3
In the case of G-, acetic acid, trifluoroacetic acid, silica gel, or acetic acid are preferred.

The usage of the catalyst is 0.0% for the raw material compound of this process. 1
~30Nffii%, better<kt O. 5-10 f
fi% (D range is suitable. In the case of a mixture catalyst, the metal catalyst is suitably in the range of 0.01 to 1% by weight based on the acidic catalyst.

The solvent used in the reaction can be a mixture of alcohols and water, a mixture of ethers and water, or water or alcohol as a single solvent. Examples of the [Al] groups include methanol, ethanol, 0/τnol,
Ethers such as t-butyl alcohol include ethyl ether, tetrahydrofuran, dioxane, and the like.

Usually, methanol, ethanol, water, or a mixture of these alcohols and water is preferably used.

The reaction can be carried out at a temperature in the range of 0 to 150°C, and usually a range of 20 to 100°C is appropriate.

The optically active glycerol derivative (R>-(I>) of the present invention thus obtained is then intramolecularly closed as shown in the reaction formula (2) to form the other optical isomer of the raw shrimp chlorohydrin. (S) Can be converted to monochlorohydrin.

Step (2) This step consists of the (R>-(I) obtained in step (c).
> in the presence of a base by an intramolecular cyclization reaction to obtain the other optical isomer of the original raw material epichlorohydrin, that is, (S) monoebichlorohydrin.

The base used in this reaction is preferably a caustic alkali such as sodium hydroxide or potassium hydroxide.

The appropriate amount to be used is 1 to 3 equivalents, preferably 1 to 1.2 equivalents, based on the raw material compound for this step. Although the reaction takes place in a heterogeneous system, the reaction proceeds with or without the use of an organic solvent. When an organic solvent is used, it is preferably an inert solvent, such as ethyl ether, tetrahydrofuran, methylene chloride, chloroform, carbon tetrachloride, and the like.

The reaction temperature may be in the range of 0 to 100°C, usually 0 to 70°C.

The (S) monoepichlorohydrin thus obtained has an optical purity equivalent to that of the raw material (R) monoepichlorohydrin.

The optically active glycerol derivative of the present invention is an important compound as an intermediate in obtaining both enantiomers of highly pure optically active shrimp chlorohydrin.

(Example) Example 1 (R) One epichlorohydrin ([α] tube - 33° (c
= 4.5 methanol)) 31.790 (343
m mol) and benzyl alcohol 93. 05o
(861 mmol>) was put into a reactor, stirred at 25°C, and then 0.3rd<
2. 4m mof> was added dropwise and reacted for 1.5 hours (maximum exothermic reaction temperature 80°C). Next, ethyl ether was added to the reaction solution, and saturated sodium bicarbonate solution was added until the pH reached 7. Water was then added to a colander, extraction with ethyl ether was performed, and the mixture was washed with saturated brine.

After drying the organic layer over anhydrous magnesium sulfate, ethyl ether was distilled off under reduced pressure, and the residue was distilled under reduced pressure (1
34-139℃/4mmtlg) L/te(R)-1
-penzyloxy-3-chloro-2-propanol (
(R) − (I[I) > 51.44a (256
m mol, yield 74.1%.

The properties of this product are as follows.

(α)V -4.90' (C=1.10 methanol)I R ), l lIIaX Cm-1
3452NMR (CDα3) δ: 2.9-3.15 (IH, br) 3.35-3
．． 65 (4H, m > 3.7 ~ 4.05 (
IN, m) 4.46 (2H, s) 7.1 to 7.3 (5H, m) The above product (
R>-1-penzyloxy-3-chloro-2-propanol 20a (99.7 m mol>
> and then methanesulfone chloride! 8.49rrd
! (109.7 mmof) was added dropwise and reacted for 1 hour. 4N hydrochloric acid was added to the reaction solution to adjust the pH to 1, followed by extraction with methylene chloride, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 27.5 g of Ril-penzyloxy-3-chloro-2-methanesulfonyloxypropane ((R>-(IV)).
(9B.7 mmof, yield 99.0%) was obtained.

The properties of this product are as follows.

[α] tube -3.60° (c=1.29 CH2α
2》IR νmaXcm-' 1362. 118
0NMR (CD(l}3>δ:3.03 (3tl, s)3.55~
3.85 (4]1, m )4.52 (
2H, s) 4.60-5.05 (IH, m) 7.15-7
．． 40 (58, m) 26 g (93.3 mmol) of the above product (Rll-penzyloxy-3-chloro-2-methanesulfonyloxypropane) at 95%
The mixture was dissolved in ethanol, 10 g of 10% palladium-carbon (9.4 mmol of Pd) was added, and the mixture was stirred at 25° C. for 12 hours under a hydrogen atmosphere. The catalyst was removed by filtration, and the solvent was distilled off from the solution under reduced pressure to obtain (R>-3-chloro-2-methanesulfonyloxy-1-propanol ((R) - (I ＞ ＞
14.6 (1 (77.2111 mol, yield 82
, 8%).

The properties of this product are as follows.

[α]萱 +4.20° (C-1.43 methanol) IR νmaxcm-1 3560. 13
46. 1174NMR (CDC13) δ: 3.04 (11, br) 3.15
(311, S) 3.65~4.00 (4
8, m) 4.60~5,05 (IH, m>
The above product (R)-3-chloromethanesulfonyloxy-1-propanol 11.69 (61,7 mmo
f), 50 m of methylene chloride, and 30 m of water and heated to 25°C.
6. 48% by weight aqueous sodium hydroxide solution with stirring.
290 (75.5 mmol) was added dropwise over 15 minutes. After further stirring at 25° C. for 10 minutes, the mixture was extracted with methylene chloride and dried over anhydrous magnesium sulfate. After distilling off methylene chloride at normal pressure, 3.890 (S) monochlorohydrin (42.1 mmol, yield 68.2
%) was obtained by distillation.

The properties of this product are as follows.

[α] Electron +33.0” (c=1.17 methanol) I R l/maX Cll-1 126
8NMR (CDα3) δ: 2.55-3.00 (2H, III)3.
05 ~ 3.40 (IH, m > 3.55
(2H, dJ=4.8HZ') Example 2 Allyl alcohol 94,2a (1.62 mol>) and boron trifluoride ethyl ether 0.2 mi (1.62x
1O-3 mol) was placed in a reactor and (R) monochlorohydrin ([α)IF-32.
5° (c=1.18 methanol) > 50g (
0.54 mol) was added dropwise over 1 hour. After the dropwise addition was completed, the reaction was carried out at the same temperature for 2.5 hours.

After cooling, add saturated sodium bicarbonate solution to the reaction solution to adjust the pH to 7,
Water was added to the colander, extracted with ethyl ether, and washed with saturated brine. After drying the organic layer with anhydrous magnesium sulfate, the ethyl alcohol was removed under reduced pressure, and the residue was distilled under reduced pressure (bp 60°C/0.9 mmlo).
L,te(R)-1-allyloxy-3-chloro-2-
Propanol ( (R) - (nl) > 63.9 g (
A yield of 78.5% was obtained.

The properties of this product are as follows.

[α]v-5, 73° (C, = 1.05 methanol) nv1.4596 IR vmaxcm-13400. 1100NMR
(CDCJ3) δ: 2.90 to 3.20 (IH, br) 3.40
~3.70 (4H, m)3.70~4.25
(3■, m)5.00~6.25 (3H,
m) Dissolve 50 g (0.33 mol) of the above product (R>-1-allyloxy-3-chloro-2-propanol) in 150 d of methylene chloride, add 37 g (0.37 mol) of triethylamine while stirring at 25°C, and then Methanesulfone chloride 130rIdl (0.39m
ol) was added dropwise over 1 hour. After the dropwise addition was completed, the reaction was carried out at the same temperature for 2 hours. 4N hydrochloric acid was added to the reaction solution to make it p-concentrated, followed by extraction with methylene chloride, and the organic layer was dried over anhydrous till magnesium. The solvent was distilled off under reduced pressure, and the residue was further distilled under reduced pressure (bp 125°C/0.8 mmHa).
L/te(Ril-allyloxy-3-chloro-2-methanesulfonyloxypropane ((R)-(IV))
74.3 g (yield 97.9%) was obtained.

The properties of this product are as follows.

[α] +4622° (c=1.16 methanol》nv1.4639 IR νmaxcm-1 1360. 1172N
MR (CDα3》 δ: 3.10 (3M, s) 3.60~3
．． 85 (4H, III) 3.90-4.15
(2H, m) 4.65 ~ 5.05 (IH,
m) 5.05-6.25 (3H, m) 50 g (0.22 mo
Dissolve l) in 200rd methanol, 40d water, 10
Jutan% palladium-carbon 60 (5.6X10-
3 mol), Rani p-toluenesulfone Im6g
(3.5x10-2 mol) was added and stirred under heating and reflux for 10 hours. The catalyst was removed by 1 hour, and the extract was concentrated under reduced pressure, extracted with methylene chloride, and the organic layer was dried over anhydrous magnesium chloride. The solvent was distilled off under reduced pressure to obtain (R)-3-chloroo-2-methanesulfonyloxy-1-propanol ((R)-
(I>>33.5g (81.3%) was obtained.

The properties of this product are as follows.

[α] +4.16° (c=1.18 methanol) n11.4693 IR 1,llIlaX Cm-1 3450.
1340. 1170NMR (CDα3) δ: 3.04 (IH, br) 3.15
(3H, s) 3.65-4.00 (4H, m) 4.60-5.05 (1M, m) The above product (
Add 150 d of methylene chloride to 25.50 mol of R)-3-chloromethanesulfonyloxy-1-propanol and add 13.5 g of a 48 wt% aqueous sodium hydroxide solution (0.16 mol) while stirring at 25°C.
ol) was added dropwise over 30 minutes. After the dropwise addition was completed, the reaction was carried out at the same temperature for 30 minutes. After the reaction, water was added, extracted with methylene chloride, and dried over anhydrous magnesium sulfate. Methylene chloride was distilled off at normal pressure, and the residue was further distilled under reduced pressure (bp 40°C/
40mmllg) L/Te(S) {Bichlorohydrin 8
．． 7a (yield 69.5%) was obtained.

The properties of this product are as follows.

[α]萱 +32.2゜ (c=1.13 methanol》n'ff 1.4338 l R νmax cm-1 1265NMR (
CD (lf3) δ: 2.55-3.00 (2H, ra) 3.0
5-3.40 (IH, In >3.55
(2H, d) In the above examples, (2H, d) was used as the raw material epichlorohydrin.
Proceed in the same manner using (S) body instead of R) body to produce (S) body.
) glycerol derivatives and (R)-epichlorohydrin were obtained, and in this case as well, it was confirmed that there was no decrease in optical purity and that highly pure optical isomers were produced.

(Effects of the Invention) The optically active glycerol derivative of the present invention is a precursor of optically active shrimp chlorohydrin, has high optical purity for both enantiomers, and is important as a raw material for the synthesis of medicines, liquid crystals, etc.

Claims (1)

[Scope of Claims] A method for producing an optically active glycerol derivative represented by general formula (I), which is obtained by the reaction of the following steps (a) to (c). ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I) In the above general formula (I), R is an alkyl group having 1 to 3 carbon atoms, which may have a halogen, and an alkyl group having 6 to 12 carbon atoms.
is a group selected from aryl groups. The symbol * represents an asymmetric carbon atom. (a) Optically active epichlorohydrin and the following general formula (II)
A process of producing an optically active glycerol derivative (III) represented by the following general formula (III) by reacting alcohol represented by the following in the presence of an acidic catalyst R^1OH (II) ▲ Contains mathematical formulas, chemical formulas, tables, etc. ▼(III) In the above general formulas (II) and (III), R^1 is C_
6H_5CH_2-, CH_2=CH-CH_2-, C
H_2=C(CH_3)-CH_2-, (CH_3)_
3C-, (C_6H_5)_2CH- and (C_8H_
5) A group selected from _3C-. Also, the general formula (III
), the symbol * represents an asymmetric carbon atom. (b) The above optically active glycerol derivative (III) is reacted with a sulfonic acid halide in the presence of a base to produce an optically active glycerol derivative (IV) represented by the following general formula (IV).
▲There are mathematical formulas, chemical formulas, tables, etc.▼(IV) In the above general formula (IV), R represents the same meaning as R in general formula (I), and R^1 is the same as R in general formula (II). It has the same meaning as R^1. Further, the symbol * represents an asymmetric carbon atom. (c) A step of producing an optically active glycerol derivative (I) represented by general formula (I) by reacting the optically active glycerol derivative (IV) in the presence of an acidic catalyst, a metal catalyst, or an acidic catalyst and a metal catalyst.