KR900004908B1 - Alpha-(hydroxy) -1,3-oxathiolune derivatives and their preparation - Google Patents

Abstract

A method for preparing alpha-(hydroxy)-1,3-oxathiolane derivs. of formual (I) comprises, (a) reacting alphahaloacetic acid with metal salts of acetic acid or tetraalkylammonium acetate in organic solvent to form alpha-acetoxyacetoacetic acid derivs. (III); (b) reacting (III) with 2-mercaptoethanol in the presence of acid catalyst to form a cpd. of formula (II); (c) hydrolyzing the cpd. of formula (II). In the formulas, R= methoxy or phenylamino gp.. (I) are useful as intermediates in the prodn. of agricultural chemicals and medicines.

Description

알파-(히드록시)-1, 3-옥사티올란 유도체 및 그 제조방법Alpha- (hydroxy) -1,3-oxathiolane derivatives and preparation method thereof

본 발명은 일반식(I)로 표시되는 신규화합물 알파-(히드록시)-1, 3-옥사티올란 유도체와 그리고 그것의 제조에 관한 것이다.The present invention relates to novel compounds alpha- (hydroxy) -1, 3-oxathiolane derivatives represented by general formula (I) and to their preparation.

일반식(I)에 있어서 R은 메톡시 또는 페닐아미노기를 표시한다.In general formula (I), R represents a methoxy or phenylamino group.

일반식(I)의 알파-(히드록시)-1, 3-옥사티올란 유도체는 농약 또는 의약품 제조에 사용될 수 있는 유용한 중간체인바, 이의 제조공정을 간단히 설명하면 공지화합물인 일반식(II)의 알파-할로아세토아세트산 유도체와 아세트산금속염 또는 테트라알킬암모늄아세테이트를 유기용액 중에서 반응시켜 일반식(III)의 알파-아세톡시아세토아세트산 유도체를 제조한 후 일반식(III)의 화합물과 2-메르캅토에탄올을 산촉매 존재하에 유기용액중에서 탈수하여 일반식(IV)의 알파-(아세톡시)-1,3-옥사티올란을 제조한 다음 일반식(IV)의 화합물을 촉매 존재하에 가수분해하여 일반식(I)의 알파-(아세톡시)-1,3-옥사티올란을 제조한 다음 일반식(IV)의 화합물을 촉매 존재하에 가수분해하여 일반식(I)의 알파-(히드록시)-1, 3-옥사티올란 유도체를 제조하는 것이다. 이의 제조공정을 구조식으로 표시하면 다음과 같다.Alpha- (hydroxy) -1 and 3-oxathiolane derivatives of general formula (I) are useful intermediates that can be used in the manufacture of pesticides or pharmaceuticals. -The alpha-acetoxyacetoacetic acid derivative of the general formula (III) is prepared by reacting a haloacetoacetic acid derivative with a metal acetate or a tetraalkylammonium acetate in an organic solution, and then a compound of the general formula (III) and 2-mercaptoethanol Dehydration in an organic solution in the presence of an acid catalyst to prepare alpha- (acetoxy) -1,3-oxathiolane of formula (IV), followed by hydrolysis of the compound of formula (IV) in the presence of a catalyst Alpha- (acetoxy) -1,3-oxathiolane was prepared, followed by hydrolysis of the compound of formula (IV) in the presence of a catalyst to produce alpha- (hydroxy) -1, 3-oxa of formula (I). It is to prepare a thiolane derivative. The manufacturing process thereof is expressed as follows.

일반식(II), (III) 및 (IV)에 있어서 R은 메톡시 또는 페닐아미노기를 표시한다.In General Formulas (II), (III) and (IV), R represents a methoxy or phenylamino group.

본 발명에 있어서 일반식(II)의 알파-할로아세토아세트산 유도체를 제외한 일반식(III)의 알파-아세톡시아세토아세트산 유도체와 일반식(IV)의 알파-(아세톡시)-1, 3-옥사티올란 및 일반식(I)의 알파-(히드록시)-1, 3-옥사티올란 유도체들은 신규한 화합물이다. 다만 일반식(III)의 알파-아세톡시아세토아세트산 유도체와 유사한 공지의 화합물인 알파-아세톡시아세토아세트산 에틸에스테르는 전문잡지(J. Am. Chem. Soc., 70 2812(1948))에서와 같이 에틸아세토아세테이트와 아세트산납을 반응시켜 낮은 수율(34%)로 제조된 바 있다.Alpha-acetoxyacetoacetic acid derivatives of general formula (III) and alpha- (acetoxy) -1, 3-oxa of general formula (IV) excluding alpha-haloacetoacetic acid derivatives of general formula (II) in the present invention Thiolanes and alpha- (hydroxy) -1, 3-oxathiolane derivatives of general formula (I) are novel compounds. However, alpha-acetoxyacetoacetic acid ethyl ester, a known compound similar to the alpha-acetoxyacetoacetic acid derivative of general formula (III), may be used as in the magazine (J. Am. Chem. Soc., 70 2812 (1948)). Ethyl acetoacetate and lead acetate was reacted to produce a low yield (34%).

본 발명자들은 공지화합물인 알파-아세톡시아세토아세트산 에틸에스테르의 제조원리를 토대로 새롭고도 유용한 화합물을 제조하기 위해 연구를 거듭하던 차 기대이상으로 간편하고도 고수율의 목적화합물을 제조하기에 이르렀다.The present inventors have come to produce a simple and high yield of the desired compound beyond the expected expectations, which has been studied to prepare new and useful compounds based on the production principle of alpha-acetoxyacetoacetic acid ethyl ester which is a known compound.

본 발명을 보다 자세히 설명하면 일반식(III)의 알파-아세톡시아세토아세트산 유도체는 일반식(II)의 알파-클로로아세토아세트산, 알파-브로모아세토아세트산등의 알파-할로아세토아세트산 유도체를 아세트산칼륨염, 아세트산나트륨염등의 아세트산금속염(CH₃COOM) 또는 테트라메틸암모늄아세테이트, 테트라에틸암모늄아세테이트등의 테트라알킬암모늄아세테이트(R₁)₄NOAc)와 반응시켜 간편하고 경제적이며 높은 수율로 제조된다. 이때 용매로는 염화메틸렌, 아세톤, 클로로포름, 에틸아세테이트, 벤젠, 아세토니트릴, 톨루엔, 크실렌 등의 비활성 유기용매를 사용할 수 있으며 가능한 반응온도는 20-150℃이나 바람직한 온도는 50-100℃이다.In more detail, the alpha-acetoxyacetoacetic acid derivative of the general formula (III) is an alpha-haloacetoacetic acid derivative such as alpha-chloroacetoacetic acid and alpha-bromoacetoacetic acid of the general formula (II) It is prepared in a simple, economical and high yield by reacting with a metal acetate salt (CH ₃ COOM) such as salt, sodium acetate salt or tetraalkylammonium acetate (R ₁ ) ₄ NOAc such as tetramethylammonium acetate, tetraethylammonium acetate. In this case, an inert organic solvent such as methylene chloride, acetone, chloroform, ethyl acetate, benzene, acetonitrile, toluene, and xylene may be used, and a possible reaction temperature is 20-150 ° C., but a preferable temperature is 50-100 ° C.

일반식(IV)의 알파-(아세톡시)-1, 3-옥사티올란 유도체는 산 촉매 존재중에서 일반식(III)의 알파-아세톡시아세토아세트산 유도체와 2-메르캅토에탄올을 비활성 유기용액중에서 탈수하여 제조할 수 있다. 이때 산 촉매로는 황산, 염산, 질산등의 무기산, 벤젠술폰산, 파라톨루엔술폰산, 메탄술폰산등의 유기산, 또는 알루미늄클로라이드, 삼불화붕소, 사염화주석, 삼불화붕소·디에틸에테르, 사염화티타늄등의 루이스산이 가능하나 부산물의 생성을 최소화하기 위해서 벤젠술폰산, 파라톨루엔술폰산, 사염화주석, 삼불화붕소·디에틸에테르, 사염화티탄등이 바람직하다. 용매로는 에틸에테르, 메틸렌클로라이드, 클로로포름, 에틸아세테이트, 벤젠, 톨루엔, 크실렌등의 비활성유기용매를 사용할 수 있다. 가능한 반응온도는 0-150℃이나 바람직하기는 25-130℃이다.The alpha- (acetoxy) -1 and 3-oxathiolane derivatives of general formula (IV) dehydrate the alpha-acetoxyacetoacetic acid derivatives of general formula (III) and 2-mercaptoethanol in an inert organic solution in the presence of an acid catalyst. Can be prepared. At this time, examples of the acid catalyst include inorganic acids such as sulfuric acid, hydrochloric acid and nitric acid, organic acids such as benzene sulfonic acid, paratoluene sulfonic acid and methanesulfonic acid, or aluminum chloride, boron trifluoride, tin tetrachloride, boron trifluoride diethyl ether and titanium tetrachloride. Lewis acids are possible, but benzenesulfonic acid, paratoluenesulfonic acid, tin tetrachloride, boron trifluoride, diethyl ether, and titanium tetrachloride are preferred to minimize the formation of by-products. As a solvent, an inert organic solvent such as ethyl ether, methylene chloride, chloroform, ethyl acetate, benzene, toluene, xylene and the like can be used. Possible reaction temperatures are 0-150 ° C. but preferably 25-130 ° C.

끝으로 일반식(I)의 알파-(히드록시)-1, 3-옥사티올란 유도체는 일반식(IV)의 알파-(아세톡시)-1, 3-옥사티올란 유도체를 산 또는 염기 촉매 존재하에서 가수분해하여 제조할 수 있다. 이때 산 촉매로는 황산, 염산, 질산등의 무기산, 벤젠술폰산, 파라톨루엔술폰산, 메탈술폰산등의 유기산이 가능하다. 염기촉매로는 탄산소다, 중탄산소다, 탄산칼륨, 중탄산칼륨등의 약염기 또는 수산화칼륨, 수산화나트륨, 수산화바륨, 수산화칼슘 등의 강염기가 가능하다. 그러나 산 촉매보다는 염기촉매를 사용하는 것이 부산물도 적고 간편하며 수율도 높아 경제적이다. 용매로는, 물, 메탄올, 에탄올, 프로판올, 아세톤, 디옥산, 아세토니트릴, 아세트산에틸, 메틸렌클로라이드, 클로로포름, 벤젠, 톨루엔등의 비활성유기용매의 단독용매 또는 이들의 혼합용매가 가능하다. 반응온도는 0-100℃가 가능하나 바람직하기는 0-50℃이다.Finally, the alpha- (hydroxy) -1,3-oxathiolane derivatives of general formula (I) can be used to convert the alpha- (acetoxy) -1,3-oxathiolan derivatives of general formula (IV) in the presence of an acid or base catalyst. It can be prepared by hydrolysis. The acid catalyst may be inorganic acids such as sulfuric acid, hydrochloric acid, nitric acid, organic acids such as benzenesulfonic acid, paratoluenesulfonic acid, and metalsulfonic acid. The base catalyst may be a weak base such as sodium carbonate, sodium bicarbonate, potassium carbonate or potassium bicarbonate, or a strong base such as potassium hydroxide, sodium hydroxide, barium hydroxide or calcium hydroxide. However, using a base catalyst rather than an acid catalyst is economical because there are few by-products, it is simple and the yield is high. As the solvent, a single solvent of an inert organic solvent such as water, methanol, ethanol, propanol, acetone, dioxane, acetonitrile, ethyl acetate, methylene chloride, chloroform, benzene, toluene, or a mixed solvent thereof may be used. The reaction temperature may be 0-100 ° C, but preferably 0-50 ° C.

본 발명의 일반식(I)과 일반식(IV)의 옥사티올란 유도체는 각각 두개의 비대칭탄소원자(asymmetric carbon)을 갖고 있어서 각각 4개의 입체이성질체(enantiomer)로 구성될 수 있으며 각각 두개의 부분입체이성질체(diastereomer)는 분리가능하다. 본 발명에서 제조된 일반식 IV의 옥사티올란 유도체는 부분입체이성질체의 혼합물로 생성되었으며 이들은 박층크로마토그래피, 관크로마토그래피 또는 분별결정(fractional crystallization)에 의해서 분리가능하다. 일반식(IV)의 알파-(아세톡시)-1, 3-옥사티올란 유도체로부터 일반식(I)의 알파-(히드록시)-1, 3-옥사티올란 유도체로의 가수분해과정에서 비대칭중심(asymmetriccentre)의 입체화학(stereochemistry)은 변하지 않고 유지된다. 따라서 일반식(IV)의 알파-(아세톡시)-1, 3-옥사티올란 유도체의 두개의 부재탄소원자에 특정한 입체화학을 갖고 있는 입체이성질체를 가수분해하여 생성된 일반식(I)의 알파-(히드록시)-1, 3-옥사티올란 유도체의 두개의 부재탄소원자의 입체화학은 출발물질인 일반식(IV)의 알파-(아세톡시)-1, 3-옥사티올란 유도체의 입체화학과 동일하다.The oxathiolane derivatives of general formula (I) and general formula (IV) of the present invention each have two asymmetric carbons, and thus may be composed of four stereoisomers and two diastereomers, respectively. Isomers are separable. The oxathiolane derivatives of formula IV prepared in the present invention are produced as a mixture of diastereomers and are separable by thin layer chromatography, tube chromatography or fractional crystallization. Asymmetric centers in the hydrolysis of alpha- (acetoxy) -1, 3-oxathiolane derivatives of general formula (IV) to alpha- (hydroxy) -1, 3-oxathiolan derivatives of general formula (I) The stereochemistry of the asymmetric centre remains unchanged. Therefore, alpha- of general formula (I) generated by hydrolyzing stereoisomers having a specific stereochemistry to two absent carbon atoms of alpha- (acetoxy) -1 and 3-oxathiolane derivatives of general formula (IV) The stereochemistry of the two absent carbon atoms of the (hydroxy) -1,3-oxathiolane derivatives is the same as the stereochemistry of the alpha- (acetoxy) -1,3-oxathiolane derivatives of the general formula (IV) as starting materials.

필요에 따라서 일반식 I과 일반식 IV의 1, 3-옥사티올란 유도체의 부분입체이성질체를 분리할 수도 있다.If necessary, diastereomers of the 1,3-oxathiolane derivatives of the general formulas I and IV may be separated.

다음 실시예는 본 발명을 더 자세히 예시한 것이나, 본 발명은 특허청구범위에서 이탈하지 않는 한 다음 실시예에 한정되지 않는다.The following examples illustrate the invention in more detail, but the invention is not limited to the following examples unless departing from the claims.

[실시예 1]Example 1

[알파-아세톡시아세토아세트아닐리드(III, R=페닐아미노)의 제조][Production of alpha-acetoxyacetoacetanilide (III, R = phenylamino)]

아세톤(500ml)에 아세트산칼륨(59g, 0.6몰)을 현탁시키고 가열환류하면서 알파-클로로아세토아세트아닐리드(II, X=Cl, R=페닐아미노)(64g, 0.3몰)을 30분간에 걸쳐 조금씩 가하였다. 1시간동안 더 가열환류한 다음 반응혼합물을 실온으로 식히고 생성된 백색고체를 여과하여 제거하고 용매를 감압증발로 제거하였다. 생성된 미황색의 기름상의 액체를 염화메틸렌에 녹이고 찬물로 씻고 건조(Na₂SO₄)시킨 다음 용매를 감압증발로 제거하여 미황색의 기름상의 액체(68g)를 얻었다. 이것을 벤젠과 석유에테르에서 결정화하여 백백색의 결정인 알파-아세톡시아세토아세트아닐리드(III, R=페닐아미노)(65g, 수율91%)를 얻었다.Suspend potassium acetate (59 g, 0.6 mol) in acetone (500 ml) and add alpha-chloroacetoacetanilide (II, X = Cl, R = phenylamino) (64 g, 0.3 mol) little by little over 30 minutes while heating under reflux. It was. After further heating at reflux for 1 hour, the reaction mixture was cooled to room temperature, the resulting white solid was filtered off, and the solvent was removed by evaporation under reduced pressure. The resulting pale yellow oily liquid was dissolved in methylene chloride, washed with cold water, dried (Na ₂ SO ₄ ), and the solvent was removed by evaporation under reduced pressure to obtain a pale yellow oily liquid (68 g). This was crystallized in benzene and petroleum ether to obtain alpha-acetoxyacetoacetanilide (III, R = phenylamino) (65 g, 91% yield) as white crystals.

녹는점:78-80℃Melting Point: 78-80 ℃

원소분석:C₁₂H₁₃O₄N에 대한Elemental Analysis: for C ₁₂ H ₁₃ O ₄ N

이론치(실험치):C;61.3(61.3), H;5.57(5.54), N;5.95(6.01)Theoretical value (experimental value): C; 61.3 (61.3), H; 5.57 (5.54), N; 5.95 (6.01)

[실시예 2]Example 2

클로로포름(200ml)에 알파-클로로아세토아세트아닐리드(II, X=Cl, R=페닐아미노)(21.2g, 0.1몰)과 테트라에틸암모늄아세테이트·사수화물(31.4g, 0.12몰)을 가하고 1시간 반동안 가열환류한 다음 반응혼합물을 실온으로 식히고 찬물로 씻은 다음 건조(Na₂SO₄)하고 용매를 감압증발로 제거하였다.Alpha-chloroacetoacetanilide (II, X = Cl, R = phenylamino) (21.2 g, 0.1 mol) and tetraethylammonium acetate and tetrahydrate (31.4 g, 0.12 mol) were added to chloroform (200 ml) for 1 hour and a half. The reaction mixture was cooled to room temperature, cooled to room temperature, washed with cold water, dried (Na ₂ SO ₄ ), and the solvent was removed by evaporation under reduced pressure.

생성된 미황색 기름상의 액체(22g)를 벤젠과 석유에테르에서 결정화하여 백색의 결정인 알파-아세톡시아세토아세트아닐리드(III, R=페닐아미노)(17.9g, 수율 76%)를 얻었다. 이것은 실시예 1에서 제조한 것과 녹는점, 수소핵자기공명스펙트럼, 적외선흡수스펙트럼에서 동일하였다.The resulting pale yellow oily liquid (22 g) was crystallized in benzene and petroleum ether to obtain alpha-acetoxyacetoacetanilide (III, R = phenylamino) as a white crystal (17.9 g, yield 76%). This was the same in melting point, hydrogen nuclear magnetic resonance spectrum, infrared absorption spectrum as prepared in Example 1.

[실시예 3]Example 3

알파-브로모아세토아세트아닐리드(II, X=Br, R=페닐아미노)(2.56g, 10밀리몰)과 아세트산나트륨(1.23g, 15밀리몰)을 에틸아세테이트(30ml)에 가하고 5시간동안 가열환류하였다. 반응혼합물을 실온으로 식히고 생성된 미황색고체를 여과하여 제거한 다음 찬물로 씻고 건조(Na₂SO₄) 시키고 용매를 감압증발로 제거하여 미황색의 기름상의 액체(2.23g)를 얻었다. 이것을 벤젠과 석유에테르에서 결정화하여 백색의 결정인 알파-아세톡시아세토아세트아닐리드(III, R=페닐아미노)(2.04g, 수율 87%)를 얻었다. 이것은 실시예 1에서 제조한 것과 녹는점, 수소핵자기공명스펙트럼, 적외선 흡수스펙트럼에서 동일하였다.Alpha-bromoacetoacetanilide (II, X = Br, R = phenylamino) (2.56 g, 10 mmol) and sodium acetate (1.23 g, 15 mmol) were added to ethyl acetate (30 ml) and heated to reflux for 5 hours. . The reaction mixture was cooled to room temperature, the resulting pale yellow solid was filtered off, washed with cold water, dried (Na ₂ SO ₄ ), and the solvent was removed by evaporation under reduced pressure to obtain a pale yellow oily liquid (2.23 g). This was crystallized in benzene and petroleum ether to obtain alpha-acetoxyacetoacetanilide (III, R = phenylamino) (2.04 g, 87% yield) as white crystals. This was the same in melting point, hydrogen nuclear magnetic resonance spectrum, infrared absorption spectrum as prepared in Example 1.

[실시예 4]Example 4

[알파-아세톡시아세토아세트산 메틸에스테르(III, R=메톡시)의 제조][Production of alpha-acetoxyacetoacetic acid methyl ester (III, R = methoxy)]

알파-클로로아세토아세트산 메틸에스테르(II, X=Cl, R=메톡시)(45.2g, 0.03몰)의 에틸아세테이트(200ml) 용액에 아세트산나트륨(3.7g, 0.045몰)을 가하고 3시간 반동안 가열환류한 다음 반응혼합물을 실온으로 식히고 생성된 백색고체를 여과하여 제거하였다. 반응혼합물을 찬물로 두번 씻고 건조(Na₂SO₄)시킨 다음 용매를 감압증발로 제거하여 미황백의 기름상의 액체인 알파-아세톡시아세토아세트산 메틸에스테르(III, R=메톡시)(5.01g, 수율 96%)를 얻었다.To a solution of ethyl acetate (200 ml) of alpha-chloroacetoacetic acid methyl ester (II, X = Cl, R = methoxy) (45.2 g, 0.03 mol) was added sodium acetate (3.7 g, 0.045 mol) and heated for 3 and a half hours. After refluxing, the reaction mixture was cooled to room temperature and the resulting white solid was removed by filtration. The reaction mixture was washed twice with cold water and dried (Na ₂ SO ₄ ), and the solvent was removed by evaporation under reduced pressure. Alpha-acetoxyacetoacetic acid methyl ester (III, R = methoxy) (5.01 g, Yield 96%).

[실시예 5]Example 5

[알파-아세톡시아세토아세트산 메틸에스테르(III, R=메톡시)의 제조][Production of alpha-acetoxyacetoacetic acid methyl ester (III, R = methoxy)]

알파-브로모아세토아세트산 메틸에스테르(II, X=Br, R=메톡시)(1.95g, 10밀리몰)의 아세톤(50m) 용액에 테트라메틸 암모늄아세테이트(1.33g, 10밀리몰)과 물(10ml)을 가하고 5시간 반동안 가열환류하였다. 반응혼합물을 감압증발하여 용매를 제거한 다음 벤젠에 녹이고 찬물로 씻고 건조(Na₂SO₄)하였다. 용매를 감압증발로 제거하여 미황백의 기름상의 액체인 알파-아세톡시아세토아세트산 메틸에스테르(III, R-메톡시)(132g, 수율 76%)를 얻었다. 이것은 실시예 4에서 제조한 것과 녹는점, 수소핵자기공명스펙트럼에서 동일하였다.Tetramethyl ammonium acetate (1.33 g, 10 mmol) and water (10 ml) in an acetone (50 m) solution of alpha-bromoacetoacetic acid methyl ester (II, X = Br, R = methoxy) (1.95 g, 10 mmol) Was added and heated to reflux for 5 and a half hours. The reaction mixture was evaporated under reduced pressure to remove the solvent, which was dissolved in benzene, washed with cold water and dried (Na ₂ SO ₄ ). The solvent was removed by evaporation under reduced pressure to obtain alpha-acetoxyacetoacetic acid methyl ester (III, R-methoxy) (132 g, yield 76%) as a pale yellow oily liquid. This was the same in melting point and hydrogen nuclear magnetic resonance spectrum as prepared in Example 4.

[실시예 6]Example 6

[알파-(아세톡시)-2-메틸-1, 3-옥사티올란-2-아세트아닐리드(IV, R=페닐아미노)의 제조][Production of alpha- (acetoxy) -2-methyl-1, 3-oxathiolane-2-acetanilide (IV, R = phenylamino)]

알파-아세톡시아세토아세트아닐리드(III, R=페닐아미노)(30g, 0.13몰), 2-메르캅토에탄올(9.8ml, 0.14몰), 파라톨루엔술폰산·일수화물(0.25g)의 벤젠(150ml) 용액을 19시간동안 가열환류하면서 생성되는 물을 딘-스타크(Dean-Stark) 물 분리장치를 이용하여 제거하였다.Alpha-acetoxyacetoacetanilide (III, R = phenylamino) (30 g, 0.13 mol), 2-mercaptoethanol (9.8 ml, 0.14 mol), benzene (150 ml) of paratoluenesulfonic acid monohydrate (0.25 g) The resulting water was removed using a Dean-Stark water separator while the solution was heated to reflux for 19 hours.

반응혼합물을 실온으로 식히고 0.5N 가성소다수와 찬물로 각각 씻고 건조(Na₂SO₄)한 다음 용매를 감압 증발로 제거하여 미황색 기름상의 액체인 알파-(아세톡시)-2-메틸-1, 3-옥사티올란-2-아세트아닐리드(IV, R=페닐아미노)(23.4g, 수율62%)를 얻었다. 박층크로마토그래피와 수소핵자기공명스펙트럼에 의하면 이것은 부분입체이성질체의 혼합물이었다. 두 부분입체이성질체는 실리카겔(Kiesel gel 60, 70-230mesh)과 벤젠-아세트산에틸을 용리액(eluent)으로 사용하는 관크로마토그래피로 분리하였다.The reaction mixture was cooled to room temperature, washed with 0.5 N caustic soda water and cold water, dried (Na ₂ SO ₄ ), and the solvent was removed by evaporation under reduced pressure to give a pale yellow oily liquid, alpha- (acetoxy) -2-methyl-1, 3 -Oxathiolane-2-acetanilide (IV, R = phenylamino) (23.4 g, yield 62%) was obtained. According to thin layer chromatography and hydrogen nuclear magnetic resonance spectra, this was a mixture of diastereomers. The two diastereomers were separated by column chromatography using silica gel (Kiesel gel 60, 70-230mesh) and benzene-ethyl acetate as eluent.

첫째 띠, R_f=0.8(용리액; 벤젠:에틸아세테이트=7:3)First band, R _f = 0.8 (eluent; benzene: ethyl acetate = 7: 3)

녹는점:107-108℃Melting Point: 107-108 ℃

원소분석:C₁₄H₁₇O₄NS에 대한Elemental Analysis: for C ₁₄ H ₁₇ O ₄ NS

이론치(실험치):C;56.9(57.0), H;5.80(5.81), N;4.74(4.73).Theoretical (experimental): C; 56.9 (57.0), H; 5.80 (5.81), N; 4.74 (4.73).

두번째 띠, R_f=0.7(용리액; 벤젠:에틸아세테이트=7:3)Second band, R _f = 0.7 (eluent; benzene: ethyl acetate = 7: 3)

녹는점:108-109℃Melting Point: 108-109 ℃

원소분석:C₁₄H₁₇O₄NS에 대한Elemental Analysis: for C ₁₄ H ₁₇ O ₄ NS

이론치(실험치):C;56.9(56.8), H;5.80(5.79), N;4.74(4.81).Theoretical (experimental): C; 56.9 (56.8), H; 5.80 (5.79), N; 4.74 (4.81).

[실시예 7]Example 7

[알파-(아세톡시)-2-메틸-1, 3-옥사티올란-2-아세트아닐리드(IV, R=페닐아미노)의 제조][Production of alpha- (acetoxy) -2-methyl-1, 3-oxathiolane-2-acetanilide (IV, R = phenylamino)]

알파-아세톡시아세토아세트아닐리드(III, R=페닐아미노)(18.8g, 0.08몰)의 에테르(400ml)용액에 2-메르캅토에탄올(8.4ml, 0.12몰)과 삼플루오르화붕소·디에틸에테르(9.84ml)를 가하고 20시간 동안 가열환류하였다. 반응혼합물을 실온으로 식히고 용매를 감압증발로 제거한 다음 생성된 기름상의 액체를 벤젠(400ml)에 녹여 1N 가성소다수와 찬물로 각각 씻고 건조(Na₂SO₄)한 다음 용매를 감압증발로 제거하여 미황색 기름상의 액체인 알파-(아세톡시)-2-메틸-1, 3-옥사티올란-2-아세트아닐리드(IV, R₁=페닐아미노)(19.3g, 수율 82%)를 얻었다. 박층크로마토그래피와 수소핵자기공명스펙트럼에 의하면 이것은 부분입체이성질체의 혼합물이었다. 각각의 부분입체이성질체는 실시예 6와 동일한 방법으로 분리하였으며, 이들은 녹는점, 수소핵자기공명스펙트럼, 적외선스펙트럼에서 실시예 6에서 제조한 것과 각각 동일하였다.2-mercaptoethanol (8.4 ml, 0.12 mol) and boron trifluoride diethyl ether in an ether (400 ml) solution of alpha-acetoxyacetoacetanilide (III, R = phenylamino) (18.8 g, 0.08 mol) (9.84 ml) was added and heated to reflux for 20 hours. The reaction mixture is cooled to room temperature, the solvent is removed by evaporation under reduced pressure, the resulting oily liquid is dissolved in benzene (400 ml), washed with 1N caustic soda water and cold water, dried (Na ₂ SO ₄ ) and the solvent is removed by evaporation under reduced pressure. Alpha- (acetoxy) -2-methyl-1, 3-oxathiolane-2-acetanilide (IV, R ₁ = phenylamino) (19.3 g, yield 82%) was obtained as an oily liquid. According to thin layer chromatography and hydrogen nuclear magnetic resonance spectra, this was a mixture of diastereomers. Each diastereomer was separated in the same manner as in Example 6, and they were identical to those prepared in Example 6 at melting point, hydrogen nuclear magnetic resonance spectrum, and infrared spectrum.

[실시예 8]Example 8

[알파-(아세톡시)-2-메틸-1, 3-옥사티올란-2-아세트산 메틸에스테르(IV, R=메톡시)의 제조][Production of alpha- (acetoxy) -2-methyl-1, 3-oxathiolane-2-acetic acid methyl ester (IV, R = methoxy)]

알파-아세톡시아세토아세트산 메틸에스테르(III, R=메톡시)(70g, 0.4몰)와 2-메르캅토에탄올(42.5ml, 0.6몰)의 에테르(350ml)용액에 삼불화붕소·디에틸에테르(50ml)를 가하고 19시간동안 가열환류하였다. 반응혼합물을 감압증발하여 생성된 기름상의 액체를 메틸렌클로라이드에 녹이고 1N가성소다수(30ml)로 두번 씻고 물로 씻은 다음 건조(무수황산나트륨)하고 용매를 감압증발로 제거하였다. 생성된 기름상의 액체(65g)를 분별감압증류(bp 128-134℃/1mmHg)하여 순수한 알파-(아세톡시)-2-메틸-1, 3-옥사티올란-2-아세트산 메틸에스테르(IV, R=메톡시)(40.5g, 수율 43%)를 얻었다.In a solution of alpha-acetoxyacetoacetic acid methyl ester (III, R = methoxy) (70 g, 0.4 mol) and 2-mercaptoethanol (42.5 ml, 0.6 mol) in an ether (350 ml) boron trifluoride diethyl ether ( 50 ml) was added and heated to reflux for 19 hours. The reaction mixture was evaporated under reduced pressure, and the oily liquid was dissolved in methylene chloride, washed twice with 1N caustic soda water (30 ml), washed with water, dried (sodium sulfate anhydride), and the solvent was removed by evaporation under reduced pressure. Fractional distillation (bp 128-134 ° C./1 mmHg) of the resulting oily liquid (65 g) gave pure alpha- (acetoxy) -2-methyl-1,3-oxathiolane-2-acetic acid methyl ester (IV, R = Methoxy) (40.5 g, yield 43%) was obtained.

bp:128-134℃/1mmHgbp: 128-134 ℃ / 1mmHg

[실시예 9]Example 9

[알파-(아세톡시)-2-메틸-1, 3-옥사티올란-2-아세트산 메틸에스테르(IV, R=메톡시)의 제조][Production of alpha- (acetoxy) -2-methyl-1, 3-oxathiolane-2-acetic acid methyl ester (IV, R = methoxy)]

알파-아세톡시아세토아세트산 메틸에스테르(III, R=메톡시)(35g, 0.2몰)와 2-메르캅토에탄올(14ml, 0.2몰)의 건조 메틸렌클로라이드(200ml)용액에 사염화티타늄(11ml)를 가하고 상온(20-25℃)에서 48시간 동안 교반하였다. 반응혼합물을 찬물로 3회 씻은 다음 건조(무수황산나트륨)하고 용매를 감압증발로 제거하였다. 생성된 기름상의 액체(29.5g)를 분별감압증류(bp 130-135℃/1mmHg)하여 순수한 알파-(아세톡시)-2-메틸-1, 3-옥사티올란-2-아세트산 메틸에스테르(IV, R=메톡시)(16.8g, 수율 34%)를 얻었다. 이것은 실시예 8에서 제조한 것과 끓는점, 수소핵자기공명스펙트럼에서 동일하였다.Titanium tetrachloride (11 ml) was added to a dry methylene chloride (200 ml) solution of alpha-acetoxyacetoacetic acid methyl ester (III, R = methoxy) (35 g, 0.2 mol) and 2-mercaptoethanol (14 ml, 0.2 mol). Stirred at room temperature (20-25 ° C.) for 48 hours. The reaction mixture was washed three times with cold water, dried (sodium sulfate anhydride) and the solvent was removed by evaporation under reduced pressure. Fractional distillation (bp 130-135 ° C./1 mmHg) of the resulting oily liquid (29.5 g) gave pure alpha- (acetoxy) -2-methyl-1, 3-oxathiolane-2-acetic acid methyl ester (IV, R = methoxy) (16.8 g, yield 34%). This was the same in boiling point, hydrogen nuclear magnetic resonance spectrum as prepared in Example 8.

[실시예 10]Example 10

[알파-(하이드록시)-2-메틸-1, 3-옥사티올란-2-아세트아닐리드(I, R=페닐아미노)의 제조][Production of alpha- (hydroxy) -2-methyl-1, 3-oxathiolane-2-acetanilide (I, R = phenylamino)]

알파-(아세톡시)-2-메틸-1, 3-옥사티올란-2-아세트아닐리드(IV, R=페닐아미노)의 부분입체이성질체의 혼합물(1g, 3.4밀리몰)의 메탄올(20ml)용액에 수산화칼륨(0.1g)의 수용액(20ml)를 가하고 30분 동안 교반하였다.Hydroxide in a methanol (20 ml) solution of a mixture of diastereomers of alpha- (acetoxy) -2-methyl-1, 3-oxathiolane-2-acetanilide (IV, R = phenylamino) (1 g, 3.4 mmol) An aqueous solution of potassium (0.1 g) (20 ml) was added and stirred for 30 minutes.

반응혼합물을 찬물(200ml)에 붓고 염화메틸렌으로 추출한 다음 유기층을 물로 씻고 건조(무수황산나트륨)한 후 용매를 감압증발로 제거하여 백색의 고체인 알파-(히드록시)-2-메틸-1, 3-옥사티올란-2-아세트아닐리드(I, R=페닐아미노)(0.85g, 수율 99%)를 얻었다. 수소핵자기공명스펙트럼에 의하면 이것은 부분입체이성질체의 혼합물이었다.The reaction mixture was poured into cold water (200 ml), extracted with methylene chloride, the organic layer was washed with water and dried (sodium sulfate), and the solvent was removed by evaporation under reduced pressure. The white solid alpha- (hydroxy) -2-methyl-1, 3 -Oxathiolane-2-acetanilide (I, R = phenylamino) (0.85 g, yield 99%) was obtained. According to the hydrogen nuclear magnetic resonance spectrum, this was a mixture of diastereomers.

녹는점:102-118℃Melting Point: 102-118 ℃

[실시예 11]Example 11

[알파-(히드록시)-2-메틸-1, 3-옥사티올란-2-아세트아닐리드(I, R=페닐아미노)의 제조][Production of alpha- (hydroxy) -2-methyl-1, 3-oxathiolane-2-acetanilide (I, R = phenylamino)]

알파-(아세톡시)-2-메틸-1, 3-옥사티올란-2-아세트아닐리드(IV, R=페닐아미노)(0.5g, 1.7밀리몰)의 부분입체이성질체(벤젠-에틸아세테이트(7:3) 전개액과 실리카겔을 사용한 박층크로마토그래피에 R_f=0.8)의 메탄올(10ml) 용액에 탄산칼륨(0.2g)의 수용액(10ml)을 가하고 상온에서 10분동안 교반하였다. 용매를 감압증발로 제거한 다음 생성된 백색고체를 클로로포름으로 추출하고 유기층을 물로 씻은 다음 용매를 감압증발로 제거하여 백색의 고체인 알파-(히드록시)-2-메틸-1, 3-옥사티올란-2-아세트아닐리드(I, R=페닐아미노)(0.43g, 수율 100%)를 얻었다.Diastereomer (benzene-ethylacetate (7: 3) of alpha- (acetoxy) -2-methyl-1, 3-oxathiolane-2-acetanilide (IV, R = phenylamino) (0.5 g, 1.7 mmol) ) To a thin layer chromatography using a developing solution and silica gel, an aqueous solution of potassium carbonate (0.2 g) was added to a methanol (10 ml) solution of R _f = 0.8) and stirred at room temperature for 10 minutes. The solvent was removed by evaporation under reduced pressure, the resulting white solid was extracted with chloroform, the organic layer was washed with water, and the solvent was removed by evaporation under reduced pressure to give the white solid alpha- (hydroxy) -2-methyl-1, 3-oxathiolane- 2-Acetanilide (I, R = phenylamino) (0.43 g, 100% yield) was obtained.

녹는점:122-123℃Melting Point: 122-123 ℃

[실시예 12]Example 12

[알파-(히드록시)-2-메틸-1, 3-옥사티올란-2-아세트아닐리드(I, R=페닐아미노)의 제조][Production of alpha- (hydroxy) -2-methyl-1, 3-oxathiolane-2-acetanilide (I, R = phenylamino)]

알파-(아세톡시)-2-메틸-1, 3-옥사티올란-2-아세트아닐리드(IV, R=페닐아미노)(0.5g, 1.7밀리몰)의 부분입체이성질체(벤젠-에틸아세테이트(7:3) 전개액과 실리카겔을 사용한 박층크로마토그래피에서 R_f=0.7)의 에탄올(10ml) 용액에 1N수산화나트륨수용액(10ml)와 아틸아세테이트(20ml)를 가하고 30분동안 상온에서 교반하였다. 반응혼합물에 에틸아세테이트(50ml)를 가하고 유기층을 분리한 다음 찬물로 2회 씻고 건조(무수황산나트륨)한 후 용매를 감압증발로 제거하여 백색의 고체인 알파-(히드록시)-2-메틸-1, 3-옥사티올란-2-아세트아닐리드(I, R=페닐아미노)(0.40g, 수율 92%)를 얻었다.Diastereomer (benzene-ethylacetate (7: 3) of alpha- (acetoxy) -2-methyl-1, 3-oxathiolane-2-acetanilide (IV, R = phenylamino) (0.5 g, 1.7 mmol) ) In a thin layer chromatography using a developing solution and silica gel, an aqueous 1 N sodium hydroxide solution (10 ml) and acyl acetate (20 ml) were added to an ethanol (10 ml) solution of R _f = 0.7), followed by stirring at room temperature for 30 minutes. Ethyl acetate (50 ml) was added to the reaction mixture, the organic layer was separated, washed twice with cold water, dried (sodium sulfate anhydrous), and the solvent was removed by evaporation under reduced pressure to give a white solid alpha- (hydroxy) -2-methyl-1. , 3-oxathiolane-2-acetanilide (I, R = phenylamino) (0.40 g, yield 92%) was obtained.

녹는점:133-135℃Melting Point: 133-135 ℃

원소분석:C₁₂H₁₅O₃NS에 대한Elemental Analysis: for C ₁₂ H ₁₅ O ₃ NS

이론치(실험치):C;56.9(57.1), H;5.97(6.02), N;5.53(5.58)Theoretical value (experimental value): C; 56.9 (57.1), H; 5.97 (6.02), N; 5.53 (5.58)

[실시예 13]Example 13

[알파-(히드록시)-2-메틸-1, 3-옥사티올란-2-아세트산 메틸에스테르(I, R=메톡시)의 제조][Production of alpha- (hydroxy) -2-methyl-1, 3-oxathiolane-2-acetic acid methyl ester (I, R = methoxy)]

알파-(아세톡시)-2-메틸-1, 3-옥사티올란-2-아세트산 메틸에스테르(IV, R=메톡시)의 부분입체이성질체의 혼합물(13.54g, 0.58몰)의 아세토니트릴(20ml)과 클로로포름(80ml) 용액에 무수탄산칼륨(8g)의 수용액(20ml)를 가하고 상온에서 2시간 동안 교반하였다. 반응혼합물을 찬물(200ml)에 가하고 유기층을 분리한 다음 찬물로 씻고 건조(무수황산나트륨)한 후 용매를 감압증발로 제거하여 미황색 기름상의 액체인 알파-(히드록시)-1, 3-옥사티올란-2-아세트산 메틸에스테르(I, R=메톡시)(9.22g, 수율 83%)를 얻었다. 수소핵자기공명스펙트럼에 의하면 이것은 부분입체이성질체의 혼합물이었다.Acetonitrile (20 ml) of a mixture of diastereomers of alpha- (acetoxy) -2-methyl-1,3-oxathiolane-2-acetic acid methylester (IV, R = methoxy) (13.54 g, 0.58 mol) An aqueous solution of anhydrous potassium carbonate (8 g) (20 ml) was added to a solution of chloroform (80 ml) and stirred at room temperature for 2 hours. The reaction mixture was added to cold water (200 ml), the organic layer was separated, washed with cold water, dried (sodium sulfate anhydride), and the solvent was removed by evaporation under reduced pressure. Alpha- (hydroxy) -1, 3-oxathiolane- 2-Acetic acid methyl ester (I, R = methoxy) (9.22 g, yield 83%) was obtained. According to the hydrogen nuclear magnetic resonance spectrum, this was a mixture of diastereomers.

Claims (12)

일반식(I)로 표시되는 신규한 알파-(히드록시)-1, 3-옥사티올란 유도체Novel alpha- (hydroxy) -1,3-oxathiolane derivatives represented by formula (I)

일반식(I)에 있어서 R은 메톡시 또는 페닐아미노기를 표시한다.In general formula (I), R represents a methoxy or phenylamino group. 일반식(II)의 알파-할로아세토아세트산 유도체와 아세트산금속염 또는 테트라알킬암모늄아세테이트를 유기용액 중에서 반응시켜 일반식(III)의 알파-아세톡시아세토아세트산 유도체를 제조하는 제1공정, 일반식(III)의 알파-아세톡시아세토아세트산 유도체와 2-메르캅토에탄올을 산촉매 존재하에 유기용매중에서 반응시켜 일반식(IV)의 알파-아세톡시-1, 3-옥사티올란을 제조하는 제2공정 및 일반식(IV)의 알파-아세톡시-1, 3-옥사티올란을 촉매 존재하에 유기용액 중에서 반응시켜 일반식(I)의 알파-(히드록시)-1, 3-옥사티올란 유도체를 제조하는 제3공정으로 이루어진 것을 특징으로 하는 일반식(I)의 알파-(히드록시)-1, 3-옥사티올란 유도체의 제조방법.A first step of preparing alpha-acetoxyacetoacetic acid derivative of general formula (III) by reacting alpha-haloacetoacetic acid derivative of general formula (II) with a metal acetate or tetraalkylammonium acetate in an organic solution, general formula (III) A second process and a general formula for preparing alpha-acetoxy-1 and 3-oxathiolane of the general formula (IV) by reacting alpha-acetoxyacetoacetic acid derivatives of N 2) and 2-mercaptoethanol in an organic solvent in the presence of an acid catalyst. A third step of preparing alpha- (hydroxy) -1,3-oxathiolane derivative of general formula (I) by reacting alpha-acetoxy-1 and 3-oxathiolane of (IV) in an organic solution in the presence of a catalyst Method for producing alpha- (hydroxy) -1,3-oxathiolane derivative of formula (I), characterized in that consisting of.

일반식(I)에 있어서 R은 메톡시 또는 페닐아미노기를 표시한다. 일반식(II)에 있어서 R은 메톡시 또는 페닐아미노기를 그리고 X는 염소 또는 브롬을 표시한다. 일반식(III)에 있어서 R은 메톡시 또는 페닐아미노기를 표시한다. 일반식(IV)에 있어서 R은 메톡시 또는 페닐아미노기를 표시한다.In general formula (I), R represents a methoxy or phenylamino group. In formula (II), R represents a methoxy or phenylamino group and X represents chlorine or bromine. In general formula (III), R represents a methoxy or phenylamino group. In general formula (IV), R represents a methoxy or phenylamino group. 제2항에 있어서, 제1공정의 아세트산금속염으로 아세트산칼륨염 또는 아세트산나트륨염중에서 선택하여 반응시키는 것을 특징으로 하는 일반식(I)의 알파-(히드록시)-1, 3-옥사티올란 유도체의 제조방법.3. The alpha- (hydroxy) -1 and 3-oxathiolane derivatives of general formula (I) according to claim 2, wherein the metal acetate of the first step is reacted by selecting from potassium acetate or sodium acetate salt. Manufacturing method. 제2항에 있어서, 제1공정의 테트라알킬암모늄아세테이트로서 테트라메틸암모늄아세테이트 또는 테트라에틸암모늄아세테이트 중에서 선택하여 반응시키는 것을 특징으로 하는 일반식(I)의 알파-(히드록시)-1, 3-옥사티올란 유도체의 제조방법.The alpha- (hydroxy) -1 and 3- of general formula (I) according to claim 2, wherein the tetraalkylammonium acetate of the first step is selected from tetramethylammonium acetate or tetraethylammonium acetate. Method for preparing an oxathiolane derivative. 제2항에 있어서, 제1공정의 유기용매로 염화메틸렌, 아세톤, 클로로포름, 에틸아세테이트, 벤젠, 아세토니트릴, 톨루엔, 크실렌중에서 선택하여 반응시키는 것을 특징으로 하는 일반식(I)의 알파-(히드록시)-1, 3-옥사티올란 유도체의 제조방법.3. The alpha- (hydride of formula (I) according to claim 2, wherein the organic solvent of the first step is selected from methylene chloride, acetone, chloroform, ethyl acetate, benzene, acetonitrile, toluene, and xylene for reaction. Roxy) -1, 3-oxathiolane derivative. 제2항에 있어서, 제1공정의 반응온도로 50-100℃에서 반응시키는 것을 특징으로 하는 일반식(I)의 알파-(히드록시)-1, 3-옥사티올란 유도체의 제조방법.The method for producing alpha- (hydroxy) -1,3-oxathiolane derivatives of general formula (I) according to claim 2, wherein the reaction is carried out at 50-100 ° C at the reaction temperature of the first step. 제2항에 있어서, 제2공정의 산 촉매로 벤젠술폰산, 파라-톨루엔술폰산, 사염화주석, 삼불화붕소·디에틸에테르, 사염화티탄중에서 선택하여 반응시키는 것을 특징으로 하는 일반식(I)의 알파-(히드록시)-1, 3-옥사티올란 유도체의 제조방법.The alpha of the general formula (I) according to claim 2, wherein the acid catalyst of the second step is selected from benzenesulfonic acid, para-toluenesulfonic acid, tin tetrachloride, boron trifluoride diethyl ether, and titanium tetrachloride. Process for the preparation of-(hydroxy) -1,3-oxathiolane derivatives. 제2항에 있어서, 제2공정의 유기용매로 에틸에테르, 메틸렌클로라이드, 클로로포름, 에틸아세테이트 벤젠, 톨루엔, 크실렌중에서 선택하여 반응시키는 것을 특징으로 하는 일반식(I)의 알파-(히드록시)-1, 3-옥사티올란 유도체의 제조방법.The alpha- (hydroxy)-of the general formula (I) according to claim 2, wherein the organic solvent of the second step is selected from ethyl ether, methylene chloride, chloroform, ethyl acetate benzene, toluene, and xylene. 1, 3-oxathiolane derivatives manufacturing method. 제2항에 있어서, 제2공정의 반응온도로 25-130℃에서 반응시키는 것을 특징으로 하는 일반식(I)의 알파-(히드록시)-1, 3-옥사티올란 유도체의 제조방법.The method for preparing alpha- (hydroxy) -1,3-oxathiolane derivatives of the general formula (I) according to claim 2, wherein the reaction is carried out at 25-130 ° C. at the reaction temperature of the second step. 제2항에 있어서, 제3공정의 촉매로서 황산, 염산, 질산, 벤젠술폰산, 파라-톨루엔술폰산, 메탄술폰산 또는 탄산소다, 중탄산소다, 탄산칼륨, 중탄산칼륨, 수산화칼륨, 수산화나트륨, 수산화바륨, 수산화칼슘으로 구성된 염기촉매중에서 선택하여 반응시키는 것을 특징으로 하는 일반식(I)의 알파-(히드록시)-1, 3-옥사티올란 유도체의 제조방법.The catalyst of claim 3, wherein the catalyst of step 3 is sulfuric acid, hydrochloric acid, nitric acid, benzenesulfonic acid, para-toluenesulfonic acid, methanesulfonic acid or sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium hydroxide, sodium hydroxide, barium hydroxide, A method for producing alpha- (hydroxy) -1,3-oxathiolane derivatives of formula (I), characterized by reacting by selecting from a base catalyst composed of calcium hydroxide. 제2항에 있어서, 제3공정의 용매로 물, 메탄올, 에탄올, 프로판올, 아세톤, 디옥산, 아세토니트릴, 아세트산에틸, 메틸렌클로라이드, 클로로포름, 벤젠, 톨루엔 중에서 단독 또는 2가지 이상 혼합하여 사용하는 것을 특징으로 하는 일반식(I)의 알파-(히드록시)-1, 3-옥사티올란 유도체의 제조방법.The solvent of claim 2, wherein the solvent used in the third step is water, methanol, ethanol, propanol, acetone, dioxane, acetonitrile, ethyl acetate, methylene chloride, chloroform, benzene, toluene, or a mixture of two or more thereof. A process for producing alpha- (hydroxy) -1,3-oxathiolane derivatives of the general formula (I). 제2항에 있어서, 제3공정의 반응온도로 0-50℃에 반응시키는 것을 특징으로 하는 일반식(I)의 알파-(히드록시)-1, 3-옥사티올란 유도체의 제조방법.The method for producing alpha- (hydroxy) -1,3-oxathiolane derivatives of the general formula (I) according to claim 2, wherein the reaction is carried out at 0-50 ° C at the reaction temperature of the third step.