JPH01230567A - Stereochemical inversion of optically active epichlorohydrin - Google Patents

Abstract

PURPOSE:To carry out the mutual stereochemical inversion of both antipodes of the subject compound in high efficiency, by opening the ring of an optically active epichlorohydrin with an alcohol, sulfonating the product, converting the ether bond into an alcohol and finally carrying out intramolecular cyclization. CONSTITUTION:An optically active epichlorohydrin is made to react with an alcohole of formula I (R<1> is C6H5CH2-, etc.) to obtain an optically active glycerol derivative of formula II, which is converted into an optically active glycerol derivative of formula III (R is alkyl, aryl, etc.) by reacting with a sulfonic acid halide in the presence of a base. The obtained derivative is reacted in the presence of an acidic catalyst, a metal catalyst or an acidic catalyst and a metal catalyst and the resultant optically active glycerol derivative of formula IV is subjected to intramolecular cyclization in the presence of a base to obtain an optically active epichlorohydrin different from the starting compound. An arbitrary antipode between both antipodes of optically active epichlorohydrin can be easily and freely prepared in high purity by this process.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to a method for inverting the stereochemistry of optically active epichlorohydrin.

Optically active epichlorohydrin is an extremely important compound as a raw material for the synthesis of new materials such as medical mulberry plants, agricultural chemicals, other physiologically active substances, and even ferroelectric liquid crystal materials. These synthetic UA
If a preferable optical isomer as FI can be freely selected, the steps for obtaining the target compound can be shortened, and in general, the target compound with higher optical purity can be obtained. The present invention provides a method for easily producing both enantiomers of optically active epichlorohydrin with high purity.

(Prior art and its a! problem) In recent years, the usefulness of optically active substances has been increasing in the field of new materials as mentioned above, and it is necessary to obtain optically active substances with high optical purity that serve as raw materials for these materials. has become an extremely important issue.

Conventionally, optically active epichlorohydrin (R) form and (S
) As a method for preparing the body, it is known to make it separately from D-mannitol (J.

Org, Chem, 43.4876 (1978))
However, this method requires a large number of steps and is not a practical method.

Recently, microorganisms have been used to increase i! T! The present applicant has provided a method for producing highly optically active epichlorohydrin (Japanese Unexamined Patent Publication No. Sho G1-1321969, Japanese Unexamined Patent Publication No. Sho 62-6697), but the optical isomer mainly obtained by this method is the (R) isomer. be.

It cannot be said that the technology for economically producing the highly pure (S) form of optically active epichlorohydrin has yet been established.

(Means for Solving the Problems) The present invention provides a method for easily and freely producing both enantiomers of highly pure optically active epichlorohydrin.

The present invention provides the following methods (I) to (IV
This is a method for stereochemical inversion of optically active epichlorohydrin, which is characterized in that it is carried out by the following steps.

(I> Optically active epichlorohydrin and the following - deceased (i>
Step R1OH (I> F-1) of producing an optically active glycerol derivative (II> represented by the following - deceased (II>) by reacting the alcohol represented by II>, R1 is C6 to Is CH2-, CH2=CH-CH2-.

Ct-12=C(Ct-h) -CI-12.

(CH3) 3 0 +, (Co tis
>2CH- and (C6H5)3C-. Moreover, in -deceased person (II), the symbol * represents an asymmetric carbon atom.

(II) Step 03O2R of producing the optically active glycerol derivative (1) represented by the following - deceased (I[I) by reacting the optically active glycerol derivative (I [>) with a sulfonic acid halide in the presence of a base - In the deceased (III), R is an alkyl group having 1 to 3 carbon atoms which may have a halogen, and an alkyl group having 6 to 1 carbon atoms.
2, R1 is a group selected from the aryl groups of 2, and R1 has the general formula (
It has the same meaning as R1 in I>, and the symbol * represents an asymmetric carbon atom.

(I[l) The above optically active glycerol derivative (■) is reacted in the presence of an acidic catalyst, a metal catalyst, or an acidic catalyst and a metal catalyst to produce an optically active glycerol derivative (1v) represented by the general formula (IV). Manufacturing process SO2R In the above-decedent (IV), R has the same meaning as R in general formula (III), and the symbol * represents an asymmetric carbon atom.

(IV) Manufacturing the other optically active epichlorohydrin, which is an optical isomer, by intramolecularly closing the above optically active glycerol derivative (IV) in the presence of a base. The above J culm is used as a raw material for optically active epichlorohydrin. as (R
) will be explained below using the reaction formula. however,
In the following reaction formula, R is R of the -deceased (I [I)
and R1 has the same meaning as the above-mentioned -deceased (I).

The symbol * represents an asymmetric carbon atom.

(R)-Epichlorohydrin (
R)-(II)(R)-([ff) (I>) This step involves (R)-epichlorohydrin and general formula (I)
This is carried out by reacting an alcohol represented by R1OH in the presence of an acidic catalyst.

As (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 epichlorohydrin with high optical purity obtained by the method described in JP-A No. 196 and JP-A-62-6697.

R101-(alcohol represented by C6H5CH20)-1, CH2=CH- used in this reaction
CH20H, CH2=C(CH3) -CH20H,
(C)-13>30OH.

(C6Hs)2 CHOH and (CsHs)3
COH is mentioned. The amount of alcohol used is 1 to 10 equivalents, preferably 2 equivalents to (R)-epichlorohydrin.
A range of ~5 equim is selected. As the acidic catalyst, a Lewis acid or a Lewis acid button is used. Specifically, boron trifluoride, boron trifluoride ether complex, aluminum trichloride, aluminum tribromide, zinc dichloride, tin tetrachloride, Examples include iron chloride. The amount m of the catalyst used is not particularly limited and can be selected within a wide range, but is generally in the range of 0.0001 to 0.05 equivalent relative to (R)-epichlorohydrin, preferably in the range of o, ooi to 0.02. . Although the reaction temperature is not particularly limited, a range of usually 10 to 100°C, preferably 30 to 80°C is appropriate. For example 80
In the case of ℃, the process is completed in 1.5 hours.

Step (II) This step consists of the step (R)-
This is a step in which the hydroxyl group of the (R)-glycerol derivative represented by (II) is reacted with a sulfonic acid halide and a base to form a sulfonic acid ester (R>) represented by (R)-(I[I). .By this reaction, 1
The R3O2 group of the sulfonate ester q is a residue corresponding to the sulfonic acid halide, which is the above-mentioned reactant, and 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. Examples include alkyl groups such as methyl, ethyl, propyl, trifluoromethyl, trichlormethyl, and tribromomethyl, and aryl groups such as phenyl and 1-lyl. Specific examples of the above sulfonic acid halides include methanesulfonic acid chloride, methanesulfonic acid bromide, methanesulfonic acid iodine, trifluoromethanesulfonic acid chloride, trifluoromethanesulfonic acid bromide, trifluoromethanesulfonic acid iodine, and trifluoromethanesulfonic acid chloride. Trichloromethanesulfonic acid, trichloromethanesulfonic acid bromide, trichloromethanesulfonic acid iodide, tri10momethanesulfonic acid chloride, tribromomethanesulfonic acid bromide, tribromomethanesulfonic acid chloride, benzenesulfonic acid chloride, odor benzenesulfonic acid, iodide benzenesulfonic acid, p-toluenesulfonic acid chloride, p-toluenesulfonic acid bromide, p-iodide
-Toluenesulfonic acid and the like.

The base used in this reaction is preferably 3-treated amines such as i-ethylamine, trimeprj'amine, or pyridine. The amount used is 1 to 3 parts, preferably 1 to 1 part, per the sulfonic acid halide and base co-raw material alcohol.
2 hits H'! or appropriate. Reaction temperature is -20~100°
C1 Normally in the range of 0 to 70°C J: Normally at room temperature (20 to 70°C
(30°C), the reaction is completed in 0.5 to 3 hours. As for the solvent, see below (1) Any solvent may be used, but methylene chloride and chloroform are usually used.

Step of (I[I) This step is (R)-(II
I) The compound is reacted in the presence of a catalyst to form (R)-(IV
) is a process for producing 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 choice of catalyst is (R) −
(III) This is carried out as appropriate based on the R1 substitution of the compound.

For example, specific examples of acidic catalysts include p-toluenesulfonic acid and benzenesulfonic acid.

Perchloric acid, UA acid, hydrochloric acid, nitric acid, hydrogen bromide, acetic acid.

trifluoroacetic acid, trichloroacetic acid, tri-10F acetic acid,
Examples of the catalyst include silica gel, aluminum chloride, titanium tetrachloride, tin tetrachloride, and boron trifluoride. Examples of the metal catalyst include platinum and palladium.

When R1 is Cs R5CH2-, hydrogenation using palladium, CH2=CH-CH2- or (J-12=C
(CH3) When CH2-, palladium and p-toluenesulfonic acid seem to be perchloric acid, (CI-13> 3
G- is trifluoroacetic acid, hydrochloric acid or hydrogen bromide mixed acetic acid, (Ce Hs ) 2 C)-1- is palladium and aluminum chloride, (Cs Hs ) 3
When G-, acetic acid, trifluoroacetic acid, silica gel or hydrochloric acid are preferred.

The catalyst m used is 0.1 to 0.1 to the raw material compound of this step.
A range of 30% by weight, preferably from 0.5 to 10% by weight, is suitable. In the case of a mixture catalyst, the amount of 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 needles and water, or water and alcohol as a single solvent. Alcohols include methanol, ethanol, propatool, t
-Butyl alcohol, etc., and ethers include ethyl ether, tetrahydrofuran, dioxane, etc. Generally, 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 in the range of 20 to 100°C.

Step (IV) This step is 1! by step (I[I)! It was rejected (R
)-(IV) In this step, the stereochemistry of the compound is inverted by an intramolecular cyclization reaction in the presence of a base to obtain the other optical isomer of the original raw material epichlorohydrin, that is, (S)-epichlorohydrin.

The base used in this reaction is hydroxylated 1-
Caustic alkalis such as potassium hydroxide and potassium hydroxide are preferred. 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)-epichlorohydrin obtained in this way has an optical purity equivalent to that of the raw material (R)-epichlorohydrin.

In the above, (R> body was explained as a raw material, but (S
) form as a raw material, it goes without saying that the (R) form can be obtained.

(Example) Example 1 (R)-Epichlorohydrin ([α)9-33° (C=
4.5 methanol) ) 31.79(1(343
m mol) and benzyl alcohol 93.05 CI
(861 m mof > was placed in a reactor, stirred at 25°C, and boron trifluoride needle 0.:W (2,4
mm01) was added dropwise and the reaction was allowed to proceed for 1.5 hours (maximum exothermic reaction temperature: 80°C). Next, ethyl ether was added to the reaction solution, saturated water was added until the pH reached γ, water was further added, 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 removed under reduced pressure, and the residue was distilled under reduced pressure (1
34-b 1-benzyloxy-3-chloro-2-propatool 5
1.4 particles (256 m mol, yield 74.7%) was added to 17
is.

The properties of this product are as follows.

[α] Suga -4,90' (C=1.10 methanol) IRνmax cm-13452 NMR (CDC4'3) δ: 2.9-3.15 <IH, br) 3.35-3
．． 65 (411, m') 3.7~4.05 (
ill, m')4.46 (2tl, s
>7.1-7.3 (511, m) 20 g (99,7 mmol) of the above product (R)-1-benzyloxy-3-chloro-2-propatool was dissolved in 70 ml of methylene chloride and heated at 25 °C. While stirring, 16.68 m (119.6 m mol) of triethylamine was added, and then methanesulfone chloride [8.49 m (109 m mol)
, 7 mmol) 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 removed under reduced pressure (R11-benzyloxy-3-chloro-2-methanesulfonyloxypropane 27.5 g (98.7 mmol, yield 99.0%)
It's 19.

The properties of this product are as follows.

(cr) v-3,60' (C=1.29 CH
2Cl2)IRνmax cm-11362,118O
NMR (CDC13) δ: 3.03 (31+, S) 3.55~
3.85 (4tl, m)4.52 (
2tl, S) 4.60-5.05 (II-1,
m ) 7.15 to γ, 40 (511, m ) The above product (R)-1-benzyloxy-3-chloro[1-2-
Methanesulfonyloxypropane 26 (J (93,3
m mol > in 95% ethanol, 10 weight m
m Palladium-carbon 10 (1 (Pd 9.4mn
ot) was added and 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 two-door solution under reduced pressure (R>-3-chloro-2-methanesulfonyloxy-1-propatol 14.6 g (77.2 mmo
1, yield 82.8%).

The properties of this product are as follows.

[α)? +4.20' (C=1.43 methanol) IR SillaXcm-' 3560.134
6.1174NMR (CDC13) δ: 3.04 (10, br) 3.15
(3+1.S)3.65~4.00 (4H
, m) 4.60-5.05 (ltl, m) The above product (R)-3-chloro-methanesulfonyloxy-1-propatol 11.6 g (61.7 mmol
), 50 rdl of methylene chloride, and 30 d of water and heated to 25°C.
6. Add 48x AA sodium hydroxide aqueous solution while stirring.
29 (1 (75.5 mmol)) was added dropwise over 15 minutes. After roughly stirring at 25°C for 10 minutes, the mixture was extracted with methylene chloride and dried over anhydrous magnesium sulfate. After distilling off the methylene chloride at normal pressure, Subsequently, (S)-epichlorohydrin 3.89(+ (42.1 mmol, yield 68.2
%) was removed by distillation.

The properties of this product are as follows.

[α)'f +33.0' (cm1.17 methanol) I Rvmax cm-11268 NMR (CDCf13) δ:2.55-3.00 (211, m >3.05
~3.40 (IH,m >3.55 (2
H, d J=/1.811Z) Example 2 94.2 g (1,62 mol) of allyl alcohol and 0.2 d of boron trifluoride ethyl ether (1,62xlO
-3 mol) into a reactor and stirred at 50°C.
(cm1.18 methanol) ) 50g (0,5
4 mol) in 1 hour). 2.50 at the same temperature after completion of dropping. 'i reaction was performed.

After cooling, add saturated sodium bicarbonate solution to the reaction solution to make n117, then add water to a colander and perform extraction with I-pull ether.
Washed with saturated saline. After drying the organic layer with anhydrous magnesium sulfate, Eziel-Del was distilled off under reduced JE.
Vacuum distillation of residual pickles (bp60℃/0.9mm1l)
(]) L/te(R)-1-allyloxy-3-chloro-2-propatol 63.9! II (yield 78.5%)
is 1q.

The properties of this product are as follows.

(α] Sweet -5,73° (cm1.05 methanol) n17 1.4596 IRL) maxcm-13400, 11l100N (
CDCb) δ: 2.90-3.20 (IN, br) 3.40
~3.70 (411,Ill)3.70~4.2
5 (311,m)5.00~6.25 (3H
, m) The above product (R)-1-allyloxy-3-lyrolow 2-propatol 50 (1(Q, 33 mol >
was dissolved in 150 ml of methylene chloride, and while stirring at 25°C, 37 g (0.37 mol) of trini[thylamine] was added.
was added, and then methanesulfone chloride M30rIIIl (
0.39 mol> was added dropwise over 1 hour. After the dropwise addition was completed, the reaction was carried out at the same temperature for 2 hours. After adding 4N hydrochloric acid to the reaction solution to make a pill, it was extracted with methylene chloride, and fjUilM
Anhydrous 'uAr! i Dry with magnesium. The solvent was distilled off under reduced pressure, and the residue was distilled under reduced pressure (bp 125
C/0.8 mm 1 la) L/T(R)-1-allyloxy-3-chloro-2-methanesulfonyloxypropane 74.3 (yield 97.9%).

The properties of this product are as follows.

(α] Sweet +4.22° (cm1.16 methanol) nl 1.4639 IR maxcm-1 1360.1172 NMR (C
DC13) δ:3.10 (3H,s >3.60-3.
85 (4H, m) 3.90-4.15 <21
1. m ) 4.65-5.05 (III, m
) 5.05-6.25 (311, m) The above product (R)-1-allyloxy-3-chloro-2-methanesulfonyl A-xypropane 50 (1 (0,22 mol>
Methanol 2007! Dissolve in 40 g of water, 9.10% by weight palladium-carbon 60 (5,6 x 10-3
mol), p-toluenesulfone M6g (3
, 5×10″″2 mol) and stirred under heating and distant current for 10 hours. The catalyst was removed by filtration, and the solution was concentrated under reduced pressure, extracted with methylene chloride, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure (
R)-3-chloro-2-methanesulfonyloxy-1-
Propatool obtained 33.5 (1 (81,3%)).

The properties of this product are as follows.

[α] Wisdom +4.16° (cm1.18 methanol) nvl, 4693 IRvmax cm-13450, 1340, 117O
NMR (CDα3) δ: 3.04 (ltl, br) 3.15
(3H, s) 3.65~4.00 (4N, m) 4.60~5
．． 05 (ltl, m) The above product (R)-3-
Chloro-methanesulfonyloxy-1-propatool 2
5.5g (0.14mol> of methylene chloride 150Ir
13.5 (1 (0.16 mol)) of 48% sodium hydroxide aqueous solution was added to 30% of sodium hydroxide while stirring at 25°C.
Dropped in minutes. After dropping, the reaction was carried out at the same temperature for 30 minutes. Reaction water was added, extracted with methylene chloride, and dried over anhydrous magnesium sulfate. Methylene chloride is distilled off at normal pressure,
Distill the residue under reduced pressure (bp 40℃/40mm 1l)
(] ) (S)-Epichlorohydrin 8.7! I
t (yield 69.5%) was obtained.

The properties of this product are as follows.

(α) ν +32.2° (cm1.13 methanol) nlj 1.4338 I Rνmax cm-11265 NMR (CDα3) δ: 2.55-3.00 (2H, m) 3.05-
3.40 (IH, m)3.55 (2
+1. d) In the above example, each chrycerol derivative of the (S) form and the (R) form were prepared in the same manner as in the above example using the (S) form instead of the (R) form as the raw material epichlorohydrin.
-Epichlorohydrin was obtained, but in this case as well, there was no decrease in optical purity, and it was confirmed that each highly pure optically purified substance was produced.

(Effects of the Invention) The method of the present invention can stereochemically invert both enantiomers of epichlorohydrin to phase H in terms of optical activity without reducing the optical purity of the raw material epichlorohydrin. The body can be provided at will in any practical way.

Claims (3)

[Claims] (1) Optical activity characterized in that when the stereochemistry of one optically active epichlorohydrin is inverted to produce the other optically active epichlorohydrin which is an optical isomer, the following steps (I) to (IV) are carried out. Stereochemical inversion method for epichlorohydrin. (I) Optically active epichlorohydrin and the following general formula (I
) in the presence of an acidic catalyst to produce an optically active glycerol derivative (II) represented by the following general formula (II) R^1OH (I) ▲ Where the mathematical formula, chemical formula, table, etc. Yes▼(II) In the above general formulas (I) and (II), 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_6H_5)_3C-. Further, in the general formula (II), the symbol * represents an asymmetric carbon atom. (II) The above optically active glycerol derivative (II) is reacted with a sulfonic acid halide in the presence of a base to form the following general formula (
Optically active glycerol derivative (III) represented by III)
▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) In the above general formula (III), R is an alkyl group having 1 to 3 carbon atoms that may have a halogen, and an alkyl group having 6 to 12 carbon atoms, which may have a halogen.
is a group selected from aryl groups, and R^1 has the general formula (
It has the same meaning as R^1 in I), and the symbol * represents an asymmetric carbon atom. (III) A step of producing an optically active glycerol derivative (IV) represented by general formula (IV) by reacting the optically active glycerol derivative (III) in the presence of an acidic catalyst, a metal catalyst, or an acidic catalyst and a metal catalyst. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (IV) In the above general formula (IV), R has the same meaning as R in general formula (III), and the * sign represents an asymmetric carbon atom. (IV) A step of producing the other optically active epichlorohydrin, which is an optical isomer, by intramolecularly closing the optically active glycerol derivative (IV) in the presence of a base. (2) The method according to claim 1, wherein one optically active epichlorohydrin is the (R) form and the other optically active epichlorohydrin is the (S) form. (3) The method according to claim 1, wherein one optically active epichlorohydrin is the (S) form and the other optically active epichlorohydrin is the (R) form.