JPS6019289B2 - Method for producing optically active sulfoximines - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing novel optically active sulfoximines having optical activity on the sulfur atom. More specifically, N-halosulfilimines [1] having optical activity on the sulfur atom are hydrolyzed to produce the corresponding sulfoximines.

It relates to a method of manufacturing [0]. Organic compounds with a sulfoximine skeleton are used as pharmaceuticals, surfactants, resin additives, etc. due to their unique chemical structures.
Although it is a useful compound as a solvent, paint, agricultural chemical, organic synthesis intermediate, etc., sufficient knowledge has not yet been obtained regarding its optically active form. However, in addition to the above-mentioned various uses, optically active compounds having a sulfoximine skeleton can be used as optical resolution reagents, pharmaceuticals with selective or exclusive medicinal effects, etc. due to their specific property of being optically active substances. They have additive or complementary uses as reagents for asymmetric synthesis, model compounds for various enzymes, etc., and therefore there is a need for a production method that provides these useful optically active compounds. There are a few known examples of optically active sulfoximine obtained by (1) iminization of optically active sulfoxide and permanganate acidification of optically active sulfoximine, but the practicality is extremely poor. For example, m The '21 method requires the use of chemicals that are dangerous to handle, such as sodium azide, and the '21 method involves both an oxidation reaction and a reductive deimino reaction, so the yield of the target sulfoximine is extremely low or It is necessary to use permanganate, which cannot be obtained at all and has problems in waste liquid treatment.The present inventors have already discovered that sulfoximine can be obtained by treating N-halosulfimine with an alkali. In general, it is difficult to predict whether an optically active form is stable or unstable, and optically unstable active forms will racemize even if left at room temperature. This occurs due to physical causes such as heat, light, and dissolution in solvents, or chemical causes such as alkalis and acids.For this reason, chemical reactions involving certain optically active substances, especially in the case of organic sulfur compounds, involve sulfur vacancies in the reaction. It is also possible that the red orbit of
This is generally extremely difficult. In view of these facts, the present inventors conducted extensive research and surprisingly found that optically active sulfoximines can be obtained without racemization by hydrolyzing optically active N-halosulfilimines. They discovered this and completed the present invention. That is, the present invention has the following formula: [In the formula, R1 and R2 optionally represent a phenyl group or a lower alkoxy-substituted phenyl group, and X represents a halogen atom. ] N-halosulfimines having optical activity on the sulfur atom represented by the formula are mixed with water or (and) an alkali and hydrolyzed, optionally in the presence of a solvent. : [In the formula, R1 and R2 are the same as above. ] This is a method for producing sulfoximines having optical activity on the sulfur atom. Although the hydrolysis mechanism of optically active N-halosulfimine is not clear, (i) N
- Hydrolysis reaction of halosulfilimine [1] {1}'
Sulfoximine thus obtained

(ii
) Deimination reaction of sulfoximine with nitrite {
It is known that the reaction proceeds with steric retention on the sulfur atom. Sulfoximine obtained by the present invention

When [0] undergoes a deimization/conversion reaction ■, it usually becomes N-halosulfimine [
Since a sulfoxide [m] having an optical rotation opposite to that of [1] can be obtained in good optical yield, the reaction in the hydrolysis reaction of [1] usually occurs with steric retention without racemization on the sulfur atom. progress, sulfoximine

It can be seen that [0] can be obtained with good optical yield. The present invention can be implemented, for example, as follows. The optically active N-halosulfimines used as raw materials can be obtained by, for example, treating optically active N-halofonylsulfimines with an acid and then treating them with an alkali. It can be obtained by a method such as The optically active N-halosulfimine thus obtained is mixed with water or/and an alkali, if necessary in the presence of a solvent, and hydrolyzed. After the reaction, it is optional to separate and, if necessary, purify according to a conventional method. Optically active N is usually used as a raw material.
- Conditions such as reaction temperature are appropriately selected in consideration of the optical stability of the halosulfimines or the optically active sulfoximines to be produced. The reaction is usually carried out at around room temperature, but may be cooled if necessary. In addition, to prevent racemization, the entire reaction system was kept at 60°C.
It is preferable to deal with it below. , Water and/or alkali according to the present invention are usually used in a stoichiometric amount or more with respect to N-halosulfuilimine, and it is preferable to use alkali in consideration of reaction rate and the like. As the alkali, ordinary alkalis are preferably used, such as alkoxides, ammonium hydroxide, hydroxides of alkali metals such as sodium and potassium, and hydroxides of alkali metals such as calcium and barium. Can be mentioned. Examples of RI and/or R2 of compounds [1] and [B] according to the present invention include methyl group, ethyl group, propyl group, butyl group, rt-butyl group, hexyl group, 2-ethylhexyl group, Saturated alkyl groups such as dodecyl group, cyclopropyl group, saturated silulohexyl alkyl group such as cyclohexyl group, vinyl group, 1-
Examples include unsaturated alkyl groups such as propenyl group, 4-hexenyl group, and 9-bentadecenyl group, unsaturated cycloalkyl groups such as cyclohexenyl group, and aryl groups such as phenyl group and naphthyl group. Further, RI and R2 may form a ring, and the skeleton of the sulfur-containing cyclic compound in which RI and R2 form a ring includes thiolane,
Examples include thian, oxathian, 1,2-dihydrothionaphthene, benzothian, thiabicycloheptane, phenoxatine, phenothiazine, thioxanthene, penicillin, and cephalosporin. Compound [1] according to the present invention and

RI or/and R2 in [0] may be a substituted alkyl group, a substituted aryl group, or a sulfur-containing cyclic compound, and examples of these substituents include:
In addition to hydrocarbon groups such as alkyl groups, cycloalkyl groups, and aryl groups, examples include halogen, alkoxy groups, aryloxy groups, alkylthio groups, arylthio groups, nitro groups, cyano groups, acyl groups, and sulfonyl groups. Examples of halogens related to the present invention include chlorine, bromine, iodine, and the like. More specifically, examples of optically active sulfoximines obtained according to the present invention include S-methyl-S-isopropylsulfoximine, S-methyl-S-phenylsulfoximine, and S-cyclopropylsulfoximine. -Phenylsulfoximine, S-ethyl-S-cyclohexylsulfoximine, S-o-
Methoxyphenyl-S-ethylsulfoximine, S-
ethyl-S-p-ethoxyphenyl sulfoximine,
S-o-tri-S-phenylsulfoximine, S-
o-Methylthiophenyl-S-phenylsulfoximine, S1o-nitrophenyl-S-phenylsulfoximine, S1o-methoxyphenyl-S1p tolylsulfoximine, S-o-chloro. Phenyl-S-phenylsulfoximine, S-phenyl-S-2.6-dic. lofuenyl sulfoximine,
S-phenyl-S-p-cyanophenylsulfoximine, S-tolyl-S1p-tolylsulfoximine, S-phenyl-S-p-acetylphenylsulfoximine, S-methyl-S1o- Methylsulfonylphenylsulfoximine, S-imino-S-oxy-2-cyanothiolane, S-imino-S-oxy-2-methoxythiane, S-imino-S-oxy-1,2-dihydrothionaphthene, S-imino-S-oxy-4,4-dimethylbenzo [b] Thiane, S-imino S-oxy-2-chloro-7-thiabicyclo[2.2.1]hebutane, S
-Iminor S-oxy-4-methylphenoxatin, S
- imino S - oxy-1-chlorophenothiazine, S
-Iminor S-oxythioxanthene, S-Iminor S
Examples include optically active substances such as -oxybenicillin and S-imino-S-oxycephalosporin. In the present invention, all solvents used if necessary are preferably used, except those that are involved in the reaction and have an adverse effect, and the reaction system may be a homogeneous system or a suspension system. Examples of the solvent used in the present invention include water,
Alcohols such as methyl alcohol and ethyl alcohol, ethers such as ethyl ether, dioxane and tetrahydrofuran, ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, hydrocarbons such as benzene and hexane, methylene chloride, Halogenated hydrocarbons such as chloroform, carbon tetrachloride, and ethylene chloride, esters such as ethyl acetate and ethyl acetoacetate, polyhydric alcohols and their derivatives such as ethylene glycol and ethylene glycol ethyl ether, dimethylformamide, Nitrogen compounds such as acetamide, acetonitrile, pyridine,
Examples include sulfur compounds such as dimethyl sulfoxide, propane sultone, and sulfolane, and phosphorus compounds such as hexamethylphosphoramide. Even if these solvents are used alone,
Alternatively, they may be used in combination. The present invention provides an optical resolution reagent,
The purpose of the present invention is to easily and safely provide optically active sulfoximines useful as enigmatic agents for asymmetric synthesis, intermediates for the synthesis of various pharmaceuticals having selective or exclusive medicinal efficacy, etc.
There is something huge to contribute to this industry. Reference example 1 (1) 1(S)-S1o-methoxyphenyl-S-phenylsulfyl imine ([Q] Customer: 194o (C=1
．． Dissolve 10.1 parts of 00, CHC13)) in 100 parts of acetone, cool in an ice-water bath, quickly add 6.3 parts of N-chlorosuccinimide, dissolve, remove the casing, and stir at room temperature for 10 minutes. continue. After the reaction, pour the reaction solution into ice water to remove the precipitated solid (pal).
(e-yellow color) was collected in a furnace, dried, and recrystallized from benzene/n-hexane to obtain (1)-(S)-S.
-o-methoxyphenyl-S-phenyl-N-chlorosulfimine (paleyellowchistal)
8. Obtain 4 parts. [Q] Color 5: 1790 (C=○-29
, CHC13). m-p. 79-80ko0 (decom
p. ). Yield: 67%. IR (KBr); Les SN Engineering 86
0ka-1 Example 1 8 parts of (1)-(S)-S-methoxyphenyl-S-phenyl-N-chlorosulfimine synthesized according to Reference Example 1 and 1.8 parts of caustic soda were added to 65 parts of methanol. and incubate for 2 hours at room temperature. The reaction solution was poured into ice water, extracted with chloroform, washed,
After drying, chloroform was distilled off to obtain (10)1(R)1S1o-methoxyphenyl-S-phenylsulfoximine6. $ part (yield 93%, mp131-13 is o) is obtained. Recrystallize from benzene-hexane. [q]. 12.40 (C=2.1$HCL3), mp132.0
~132,5℃ 1R (in KB) maX Ni 3272・1
240・1123・972-INMR (CDCI3)
6 d3,30 (1st, S, NH), 3. Spots (9 days, s
, o-CH30), 6.78-8.14 legs (group, m, P
h) Elemental analysis C, 3 days, 3NQS Actual value: C, 63. Shigeru; Japan, 5.25:N, 5.65%
Calculated value: C, 63.13; Day, 5.30: N, 5.66
% Reference example 2(1)-(S)-S-methoxyphenyl-S-phenylsulfoylimine ([Q] Color 51.
(1)1(S)1S1o-methoxyphenyl-S-
8.4 parts of phenyl-N-chlorosulfilimine are obtained. [Q] Deprivation-33-r (C=0.29, CHC13). mp79-80 0 (decomp) yield 67% Example 2 8 parts of (1)-1(S)-S-o-methoxyphenyl-S-phenyl-N-chlorosulfimine obtained in Reference Example 2 React in the same manner as in Example 1 to obtain (10)1(R)1S-methoxyphenylsulfoximine.6. $ parts (yield 93%, mp131-132℃ [Q
]. 10030 (C=0.67, CHC13)) is obtained. IR
The results of , NMR, and elemental analysis were consistent with Example 1. Reference Example 3 (10)1(R)-S1o-methoxyphenyl-S-phenylsulfoximine ([Q]) obtained in Example 1. 12.40 (C2.05, CHC13 )) Dissolve 0.25 liters in 10w of 2M sulfuric acid, keep at 5°C and add 0.14 liters of sodium nitrite/2.5 ml of water over 2 minutes. After cooling for 1 hour at room temperature, add ice and sodium carbonate to make alkaline at below 5°C, extract with chloroform, wash, and dry.
The solvent was distilled off to obtain 0.22 g of (10)-(R)-S-o-methoxyphenyl-S-phenyl sulfoxide (oil) (yield: 95%). [Q]D+2750 (Cd1.
03 acetone), [Q]D12190 (C=1.12
, CHC13) Melon, NM old is AuthenticSam
Matched with ple. Reference Example 4 (10)-(R)-S-o obtained in Example 2
-methoxyphenyl-S-phenylsulfoximine (
[Q].

Claims (1)

[Claims] 1 Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^1 and R^2 optionally represent a phenyl group or a lower alkoxy-substituted phenyl group, and X represents a halogen atom. show. It is characterized by hydrolyzing N-halosulfuimines having optical activity on the sulfur atom represented by the following formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^1 and R^2 are the same as above. ] A method for producing sulfoximines having optical activity on the sulfur atom.