CN1721400A - Process for synthesizing 2-(diphenyl methyl sulfinyl) acetamide - Google Patents

Process for synthesizing 2-(diphenyl methyl sulfinyl) acetamide Download PDF

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CN1721400A
CN1721400A CN 200510049330 CN200510049330A CN1721400A CN 1721400 A CN1721400 A CN 1721400A CN 200510049330 CN200510049330 CN 200510049330 CN 200510049330 A CN200510049330 A CN 200510049330A CN 1721400 A CN1721400 A CN 1721400A
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methyl
ethanamide
diphenyl
synthetic method
sulfinyl
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CN100393699C (en
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裴文
孙莉
陶文伟
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Zhejiang University of Technology ZJUT
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Zhejiang University of Technology ZJUT
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Abstract

The present invention relates to the synthesis process of 2-(dibenzylmethylthionyl) acetylamide. The synthesis process includes the first reaction of benzyl mercaptol and chloroacetate inside ionic liquid to obtain the compound as shown in expression I; the subsequent aminolysis of the compound as shown in expression I to obtain amide compound as shown in expression II; and final oxidation of the amide compound to obtain the product. The synthesis process has simple operation, high yield and less environmental pollution.

Description

The synthetic method of 2-(diphenyl methyl sulfinyl) ethanamide
(1) technical field
The present invention relates to the synthetic method of a kind of 2-(diphenyl methyl sulfinyl) ethanamide.
(2) background technology
Modafinil (Modafinil, CRL-40476, trade(brand)name Provigil), chemistry 2-(diphenyl methyl sulfinyl) ethanamide by name is a kind of novel medicine that produces refreshing effect to the mind that acts on central nervous system by the exploitation of French Lafon company.In succession in France, Britain, Germany's listing, getting permission the listing in the U.S. in December, 1998 after 1994, be mainly used in treatment narcolepsy and spontaneous hypersomnia, is first medicine that is used for the treatment of lethargy.Modafinil has wide application prospect from now on its good central excitation effect and very little toxic side effect and enjoy favor.
At present, the synthesis route of the modafinil that relates among the present invention has four kinds.One, sets out by benzhydrol, make two beneze methane thiols, then with chloroacetate reaction, be substituted, chlorination, ammonia are separated, four steps of oxidation obtain product with thiocarbamide reaction; Two, to be raw material separated for four steps through oxidation, esterification, ammonia obtains product with two beneze methane thiols and Mono Chloro Acetic Acid; Three, benzhydrol and Thiovanic acid be raw material under strong acidic condition, be substituted, chlorination, ammonia are separated, oxidation makes product; Four, be raw material with diphenyl-chloromethane and ethyl thioglycolate, be substituted, ammonia is separated, oxidation three step obtains product.In above-mentioned synthesis technique, use highly corrosive agents sulfur oxychloride and huge drugs methyl-sulfate, operate cumbersomely, and need discharging to contain the trade effluent of bronsted lowry acids and bases bronsted lowry in a large number, environment there is bigger pollution.
(3) summary of the invention
The object of the invention is to provide a kind of method of simple to operate, yield is high, environmental pollution is little Synthetic 2-(diphenyl methyl sulfinyl) ethanamide.
Described 2-(diphenyl methyl sulfinyl) ethanamide is suc as formula shown in (I), described synthetic method is included in the ionic liquid, make formula (II) compound by two beneze methane thiols and chloracetate reaction earlier, separate the amide compound that makes suc as formula (III) by formula (II) compound through ammonia again, at last amide compound is carried out oxidation and get described product;
R is C in its Chinese style (II) 1～C 10Alkyl or aromatic base, also be that chloracetate is C for the aliphatics carbon number 1～C 10Alkyl ester or aromatic ester.
Described ionic liquid is alkyl imidazole a tetrafluoro borate or alkyl-imidazole hexafluorophosphate, and described alkyl is C for the aliphatics carbon number 1～C 10Alkyl substituent is preferably the alkyl imidazole a tetrafluoro borate.Below be described more preferably ion liquid: 1-butyl-3-methyl imidazolium tetrafluoroborate, 1-ethyl-3-methyl imidazolium tetrafluoroborate, 1-butyl-3-Methylimidazole hexafluorophosphate.
Described use 1-butyl-3-methyl imidazolium tetrafluoroborate ionic liquid is during as reaction medium, and the aftertreatment of product is that ionic liquid can continue to recycle with behind the organic solvent extraction product.
Described oxidation preferably adopts inorganic oxide as oxygenant, more preferably hydrogen peroxide.
The beneficial effect of synthetic modafinil Green Chemistry method of the present invention is mainly reflected in:
(1) use ionic liquid, not volatile, nonflammable explosive security is good, and organism and inorganics are all had good solubility, is reflected under the homogeneous phase condition and carries out, and is convenient to operation and handles the product yield height.
(2) ionic liquid easily reclaims use.
(3) avoid having used highly corrosive agents sulfur oxychloride and huge drugs methyl-sulfate, simplified technological operation, reduced the quantity discharged of trade effluent, solved the pollution of sewage environment.
(4) embodiment
The invention will be further described below by specific embodiment, but protection scope of the present invention is not limited to this.
Embodiment 1
(1) preparation of hexichol methylthioglycolic acid methyl esters: in three mouthfuls of round-bottomed flasks of the 100ml that thermometer and prolong are housed, add diphenyl-methyl mercaptan (2g successively, 10mmol), 1-butyl-3-methyl imidazolium tetrafluoroborate (4ml), methyl chloroacetate (1.08g, 10mmol), stirred 4 hours at 100 ℃, the TLC detection reaction is complete.Cooling, with product with toluene extraction (2 * 10ml), water washing 2 times, drying concentrates, and obtains oily liquids 2.26g, yield 83.1%, bp=370.1 ℃.
IR(KBr)v：1736(C＝O)，1600，1493(Ar)，702(C-S)cm -1。
MS (m/e): 272 (M +), 258,199,167 (base peaks), 152,87,72,45.
(2) preparation of diphenyl-methyl sulphur ethanamide: in three mouthfuls of round-bottomed flasks of the 100ml that thermometer and prolong are housed, add hexichol methylthioglycolic acid methyl esters (2.72g successively, 10mmol), 1-butyl-3-methyl imidazolium tetrafluoroborate (10ml), continuously logical ammonia 3 hours, stir under the room temperature and spend the night, the TLC detection reaction is complete.Then with product with extracted with diethyl ether (2 * 10ml), water washing 2 times, drying concentrates, white powder solid 1.9g, yield 73.9%.Fusing point: 108～109 ℃ (literature value is 110 ℃).
IR(KBr)v：1687(N-C＝O)，1600(Ar)，699(C-S)cm -1。
MS (m/e): 257 (M +), 199,167 (base peaks), 152,121,115.
(3) preparation of diphenyl-methyl thionyl ethanamide: in three mouthfuls of round-bottomed flasks of the 100ml that thermometer and prolong are housed, add diphenyl-methyl sulphur ethanamide (2.57g successively, 10mmol), 1-butyl-3-methyl imidazolium tetrafluoroborate (10ml), hydrogen peroxide (0.34g, 10mmol), stirred 3 hours at 60 ℃, the TLC detection reaction is complete.Cooling, and usefulness extracted with diethyl ether product (2 * 10ml), water washing 2 times, drying concentrates, and gets white powder solid 2.06g with ethyl alcohol recrystallization, yield 75.4%, fusing point: 162.5～165 ℃ (literature value: 164～166 ℃).
IR(KBr)v：1687(N-C＝O)，1495(Ar)，1034(S-O)，702(C-S)cm -1。
MS (m/e): 274 (M +), 167 (base peaks), 152,115.
1H?NMR(500MHz?CDCl 3)δ：7.28，7.52(m，10H，Ar)，5.24(s，1H)，3.15，3.51(d，J＝14Hz，2H，CH 2)，5.78，7.11(s，2H)。
Ionic liquid in the reaction system can continue to recycle.
Embodiment 2
(1) preparation of hexichol methylthioglycolic acid methyl esters: in three mouthfuls of round-bottomed flasks of the 100ml that thermometer and prolong are housed, add diphenyl-methyl mercaptan (2g successively, 10mmol), 1-ethyl-3-methyl imidazolium tetrafluoroborate (4ml), (1.08g 10mmol), stirred 6 hours at 60 ℃ methyl chloroacetate.Cooling, with product with toluene extraction (2 * 10ml), water washing 2 times, drying concentrates, and obtains oily liquids 1.89g, yield 69.5%, bp=370.1 ℃.
IR(KBr)v：1736(C＝O)，1600，1493(Ar)，702(C-S)cm -1。
MS (m/e): 272 (M +), 258,199,167 (base peaks), 152,87,72,45.
(2) preparation of diphenyl-methyl sulphur ethanamide: in three mouthfuls of round-bottomed flasks of the 100ml that thermometer and prolong are housed, add hexichol methylthioglycolic acid methyl esters (2.72g successively, 10mmol), 1-ethyl-3-methyl imidazolium tetrafluoroborate (10ml), the ammoniacal liquor 20ml of adding 25% stirred 10 hours under 20 ℃ of conditions.Then with product with extracted with diethyl ether (2 * 10ml), water washing 2 times, drying concentrates, white powder solid 1.71g, yield 66.5%.Fusing point: 107.5～108.5 ℃ (literature value is 110 ℃).
IR(KBr)v：1687(N-C＝O)，1600(Ar)，699(C-S)cm -1。
MS (m/e): 257 (M +), 199,167 (base peaks), 152,121,115.
(3) preparation of diphenyl-methyl thionyl ethanamide: in three mouthfuls of round-bottomed flasks of the 100ml that thermometer and prolong are housed, add diphenyl-methyl sulphur ethanamide (2.57g successively, 10mmol), 1-ethyl-3-methyl imidazolium tetrafluoroborate (10ml), hydrogen peroxide (0.34g, 10mmol), stirred 8 hours at 40 ℃.Cooling, and usefulness extracted with diethyl ether product (2 * 10ml), water washing 2 times, drying concentrates, and gets white powder solid 1.64g with ethyl alcohol recrystallization, yield 60.1%, fusing point: 162.5～165 ℃ (literature value: 164～166 ℃).
IR(KBr)v：1687(N-C＝O)，1495(Ar)，1034(S-O)，702(C-S)cm -1。
MS (m/e): 274 (M +), 167 (base peaks), 152,115.
1H?NMR(500MHz?CDCl 3)δ：7.28，7.52(m，10H，Ar)，5.24(s，1H)，3.15，3.51(d，J＝14Hz，2H，CH 2)，5.78，7.11(s，2H)。
Ionic liquid in the reaction system can continue to recycle.
Embodiment 3
(1) preparation of hexichol methylthioglycolic acid methyl esters: in three mouthfuls of round-bottomed flasks of the 100ml that thermometer and prolong are housed, add diphenyl-methyl mercaptan (2g successively, 10mmol), 1-butyl-3-Methylimidazole hexafluorophosphate (4ml), methyl chloroacetate (1.08g, 10mmol), stirred 4 hours at 120 ℃, the TLC detection reaction is complete.Cooling, with product with toluene extraction (2 * 10ml), water washing 2 times, drying concentrates, and obtains oily liquids 2.23g, yield 82.9%, bp=370.1 ℃.
IR(KBr)v：1736(C＝O)，1600，1493(Ar)，702(C-S)cm -1。
MS (m/e): 272 (M +), 258,199,167 (base peaks), 152,87,72,45.
(2) preparation of diphenyl-methyl sulphur ethanamide: in three mouthfuls of round-bottomed flasks of the 100ml that thermometer and prolong are housed, add hexichol methylthioglycolic acid methyl esters (2.72g successively, 10mmol), 1-butyl-3-Methylimidazole hexafluorophosphate (10ml), the ammoniacal liquor 20ml of adding 25% stirred 10 hours under 40 ℃ of conditions.Then with product with extracted with diethyl ether (2 * 10ml), water washing 2 times, drying concentrates, white powder solid 1.82g, yield 70.2%.Fusing point: 107～108.5 ℃ (literature value is 110 ℃).
IR(KBr)v：1687(N-C＝O)，1600(Ar)，699(C-S)cm -1。
MS (m/e): 257 (M +), 199,167 (base peaks), 152,121,115.
(3) preparation of diphenyl-methyl thionyl ethanamide: in three mouthfuls of round-bottomed flasks of the 100ml that thermometer and prolong are housed, add diphenyl-methyl sulphur ethanamide (2.57g successively, 10mmol), 1-butyl-3-Methylimidazole hexafluorophosphate (10ml), hydrogen peroxide (0.34g, 10mmol), stirred 4 hours at 80 ℃.Cooling, and usefulness extracted with diethyl ether product (2 * 10ml), water washing 2 times, drying concentrates, and gets white powder solid 1.54g with ethyl alcohol recrystallization, yield 56.4%, fusing point: 163～165 ℃ (literature value: 164～166 ℃).
IR(KBr)v：1687(N-C＝O)，1495(Ar)，1034(S-O)，702(C-S)cm -1。
MS (m/e): 274 (M +), 167 (base peaks), 152,115.
1H?NMR(500MHz?CDCl 3)δ：7.28，7.52(m，10H，Ar)，5.24(s，1H)，3.15，3.51(d，J＝14Hz，2H，CH 2)，5.78，7.11(s，2H)。
Ionic liquid in the reaction system can continue to recycle.

Claims (8)

1, the synthetic method of a kind of 2-(diphenyl methyl sulfinyl) ethanamide, be included in the ionic liquid, make formula (I) compound by two beneze methane thiols and chloracetate reaction earlier, separate the amide compound that makes suc as formula (II) by formula (I) compound through ammonia again, at last amide compound is carried out oxidation and get described product;
R is C in its Chinese style (I) 1～C 10Alkyl or aromatic base.
2, the synthetic method of 2-as claimed in claim 1 (diphenyl methyl sulfinyl) ethanamide is characterized in that described ionic liquid is alkyl imidazole a tetrafluoro borate or alkyl-imidazole hexafluorophosphate.
3, the synthetic method of 2-as claimed in claim 2 (diphenyl methyl sulfinyl) ethanamide is characterized in that described ionic liquid is C 1～C 10The alkyl imidazole a tetrafluoro borate.
4, the synthetic method of 2-as claimed in claim 2 (diphenyl methyl sulfinyl) ethanamide is characterized in that described ionic liquid is one of following: 1-butyl-3-methyl imidazolium tetrafluoroborate, 1-ethyl-3-methyl imidazolium tetrafluoroborate, 1-butyl-3-Methylimidazole hexafluorophosphate.
5,, it is characterized in that described R is a methyl as the synthetic method of the described 2-of one of claim 1～4 (diphenyl methyl sulfinyl) ethanamide.
6, the synthetic method of 2-as claimed in claim 1 (diphenyl methyl sulfinyl) ethanamide is characterized in that described oxidation employing inorganic oxide is as oxygenant.
7, the synthetic method of 2-as claimed in claim 6 (diphenyl methyl sulfinyl) ethanamide is characterized in that described oxidation employing hydrogen peroxide is as oxygenant.
8, the synthetic method of 2-as claimed in claim 7 (diphenyl methyl sulfinyl) ethanamide is characterized in that comprising:
In 100 ℃ of stirring reactions, cooling extracts product with toluene in 1-butyl-3-methyl imidazolium tetrafluoroborate for (1) two beneze methane thiol and methyl chloroacetate, washing, and drying concentrates, and obtains hexichol methylthioglycolic acid methyl esters;
(2) hexichol methylthioglycolic acid methyl esters led to ammonia 3 hours continuously in 1-butyl-3-methyl imidazolium tetrafluoroborate, and stirring reaction is complete, then with the product extracted with diethyl ether, and washing, drying concentrates, and gets diphenyl-methyl sulphur ethanamide;
(3) diphenyl-methyl sulphur ethanamide in 1-butyl-3-methyl imidazolium tetrafluoroborate in 60 ℃ complete through hydrogen peroxide oxidation, the extracted with diethyl ether product use in cooling, washing, drying, concentrated, get 2-(diphenyl methyl sulfinyl) ethanamide with ethyl alcohol recrystallization.
CNB2005100493300A 2005-03-10 2005-03-10 Process for synthesizing 2-(diphenyl methyl sulfinyl) acetamide Expired - Fee Related CN100393699C (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10221147B2 (en) 2014-08-13 2019-03-05 Red Bull Gmbh Heterocyclic compounds with working memory enhancing activity

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1584462A (en) * 1977-03-31 1981-02-11 Lafon Labor N-diaryl-malonamide and diarylmethyl-sulphinyl-acetamide derivatives and pharmaceutical compositions containing them
DK1309547T3 (en) * 2000-07-27 2007-05-21 Teva Pharma Crystalline and pure modafinil and process for making the same
EP1437345A1 (en) * 2003-01-13 2004-07-14 Organisation de Synthese Mondiale Orsymonde Novel method for preparing methyl 2-diphenylmethylsulfinylacetate
WO2004075827A2 (en) * 2003-01-31 2004-09-10 Alembic Limited Process for the preparation of 2-[(diphenylmethyl) thio] acetamide

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10221147B2 (en) 2014-08-13 2019-03-05 Red Bull Gmbh Heterocyclic compounds with working memory enhancing activity

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