CN102976985A - New method for synthesis of (diphenylmethyl)sulfinyl-acetamide and analogues thereof by using one-pot method. - Google Patents
New method for synthesis of (diphenylmethyl)sulfinyl-acetamide and analogues thereof by using one-pot method. Download PDFInfo
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Abstract
The present invention proposes a new method for synthesis of (diphenylmethyl)sulfinyl-acetamide (modafinil) and analogues thereof by using a one-pot method. The method comprises that: benzhydrol is used to react with reacthiourea, an acid, an alkali, and chloroacetamide or a derivative thereof; and without isolation or via one time isolation, diphenylmethyl thioacetamide and derivatives thereof obtained via the above reaction are directly oxidized with an oxidant by using the one-pot method, and (diphenylmethyl)sulfinyl-acetamide (modafinil) and analogues thereof are obtained. By using the method, isolation of intermediates can be omitted and one only need to treat products of the last step, thereby decreasing intermediate operation steps greatly, simplifying the production process, and reducing labor intensity and production cost. The method has the advantages of being low in pollution and cost, easy in operation, and affordable, facilitating industrial production.
Description
Technical field
The present invention relates to the synthetic method of central stimulant benzhydrylsulfinyl yl acetamide and analogue thereof (modafinil class).
Background technology
Modafinil is to be applied to clinical treatment lethargy and hypnolepsy by the novel central nervous stimulant thing that French Lafon company at first develops, and improves Alcoholic organic brain syndrome symptom.Show clinically dysthymia disorders, multiple sclerosis, attention deficit hyperactivity disorder (ADHD), appetite, sexuality and schizophrenia symptom, good improvement is arranged and have tolerance.
(I) US Patent 4177290 (1979) has reported the synthetic method of this compound the earliest.Adopting benzhydrol and thiocarbamide is raw material, synthetic two beneze methane thiols separate, and obtain hexichol methylthio group acetic acid with chloroacetate reaction again, after separating through the sulfur oxychloride chloride, separate after the ammonia solution, after separating, use hydrogen peroxide oxidation, synthesize diphenyl-methyl thionyl ethanamide; Or synthetic diphenyl-methyl thioacetic acid, oxidation, resterification, last ammonia solution obtain diphenyl-methyl thionyl ethanamide.The sulfur oxychloride that the mercaptan that this method generates has foul smell, use has deep-etching, ammoniacal liquor has strong and stimulating.
(II) Wang Qiaoling etc., fine-chemical intermediate, 2003,33 (3): 26-27, reported with benzhydrol and Thiovanic acid reaction to obtain the diphenyl-methyl thioacetic acid, and then the synthetic modafinils of multistep such as chlorination, ammonia solution, oxidation; Gu Zhengbing etc., novel central stimulant modafinil improvement in synthesis, Chinese Pharmaceutical Journal, 2002,37 (3): 236-237, Chen Meijun etc., synthesizing of novel central stimulant modafinil, print 2004 during chemical industry, 18 (4): 33-34, reported that with chlorination and a synthetic step of ammonia solution simplified technological operation, Thiovanic acid also has pungent niff in this synthetic forwarding method.
(III) EP Patent 1260501A1 (2002) and the CA 378418A1 such as Naddaka V; (2002) and the kindhearted CN 1432565A (2003) of woods; all with having synthesized hexichol first sulfydryl carbonamidine hydrobromate under benzhydrol and thiocarbamide and the acidic conditions; separate; and then in the basic solution, direct and chlor(o)acetamide reaction under the nitrogen protection is after the separation; last hydrogen peroxide oxidation obtains modafinil, has shortened synthetic route.This method temperature variation is frequent, adds chlor(o)acetamide in batches, and technique is difficult to control.
(IV) Bicherov A V etc.; RU Patent 2313520C1 (2006); report reacts to get benzhydryl thioacetamide with benzhydrol again with the product that chlor(o)acetamide and Sulfothiorine reaction obtain, and obtains the benzhydrylsulfinyl yl acetamide with hydrogen peroxide oxidation again.
Summary of the invention
The present invention is intended to solve provides a kind of new, preparation method of benzhydrylsulfinyl yl acetamide and analogue thereof easily.Obtain yield height, benzhydrylsulfinyl yl acetamide and analogue thereof that purity is high with easy method, the white powder that the method obtains namely is benzhydrylsulfinyl yl acetamide and analogue thereof.
In order to achieve the above object, the invention provides the method for the synthetic benzhydrylsulfinyl yl acetamide of a kind of one kettle way and analogue thereof, under temperature 20-240 ℃, pH value 4-14 condition, take benzhydrol, thiocarbamide, acid, alkali, halogen ethanamide or derivatives thereof, oxygenant as raw material, intermediate product obtains benzhydryl thioacetamide or does not separate direct oxidation one kettle way sintetics through step separation;
Chemical equation is:
Wherein, described R
1, R
2Be identical or different aliphatic group, alicyclic hydrocarbon radical, such as hydrogen, methyl, ethyl, propyl group, butyl, amyl group, hexyl, benzyl, cyclopentyl, cyclohexyl, piperidyl, morpholinyl, and aryl radical and the fragrant heterocyclic radical of all kinds of groups replacements, such as phenyl, tolyl, chloro-phenyl-, sulphenyl, nitrophenyl, aminophenyl, pyridyl, pyrryl, pyrimidyl, 4,6-dichloro pyrimidine base, 4-chloropyrimide base;
Halogen in described halogen ethanamide and the derivative thereof is chlorine, bromine;
The solvent of selecting is water, acetonitrile, methyl alcohol, ethanol, chloroform, methylene dichloride, 1,2-ethylene dichloride, acetone, butanone, tetrahydrofuran (THF), DMF, benzene, toluene, tetracol phenixin, perhaps any mixed system of water and described organic solvent;
Described alkali is selected sodium hydroxide, potassium hydroxide, calcium hydroxide, yellow soda ash, salt of wormwood, calcium carbonate, sodium bicarbonate, saleratus solid or their alkaline solution, or pyridine, or triethylamine;
Mineral acid or organic acid are selected in described acid; Mineral acid is selected any one of hydrochloric acid, Hydrogen bromide, sulfuric acid, chlorsulfonic acid, the above-mentioned mineral acid of the various loads of phosphoric acid, and described load agent is silicon-dioxide, aluminium sesquioxide, diatomite, kaolin or carclazyte; Described organic acid is Phenylsulfonic acid, tosic acid, trifluoromethanesulfonic acid or various acidic resins;
Described oxygenant is specifically selected a kind of or mixed solution among hydrogen peroxide, perchloric acid, Periodic acid, Sodium peroxoborate, clorox, sodium periodate or the organic peroxide acid; Described organic peroxide acid is Peracetic Acid, peroxy trifluoroacetic acid or peroxide m-chlorobenzoic acid;
Reaction times is 1-36 hour.
Under the optimal way, temperature of reaction is 40-150 ℃ of lower reaction; The pH value is transferred under the 9-10 condition and is reacted.
A kind of optimal way is; with benzhydrol, thiocarbamide, the reaction of chlor(o)acetamide or derivatives thereof obtain benzhydryl thioacetamide, again through the hydrogen peroxide oxidation; do not separate direct oxidation perhaps; be poured into water; resulting solid is used recrystallizing methanol more after filtration, obtains white powder and is benzhydrylsulfinyl yl acetamide and analogue thereof.
Among the above-mentioned preparation method, under the optimal way, described benzhydrol: thiocarbamide: acid: alkali: halogen ethanamide and derivative thereof: the mol ratio of oxygenant=1: 1.0-10: 1.0-8: 1.0-10.0: 1.0-8.
Benzhydrylsulfinyl yl acetamide of the present invention and analogue synthetic method thereof, namely " one kettle way " obtains the finished product.Be starting raw material with benzhydrol and thiocarbamide, after reaction under the condition of acidity, directly add the basic hydrolysis neutralization, add again afterwards the reaction of chlor(o)acetamide or derivatives thereof, obtain benzhydryl thioacetamide and carry out oxidation and obtain the finished product through separating or do not separate direct adding oxygenant.This method has not only been avoided the shortcomings such as sharp aroma of the deep-etching of sulfur oxychloride in the literature method, sulfhydryl compound and ammoniacal liquor, has also reduced the complicacy of technological operation, workman's labour intensity etc.This method has and has reduced cost, has shortened synthesis technique, is suitable for the advantages such as suitability for industrialized production.
The present invention compared with prior art; one step of present method intermediate product separates or does not separate; only process the final step product; all reduced widely middle-chain, simplified the technological process of production, reduced labour intensity and production cost, thereby central nervous stimulant thing benzhydrylsulfinyl yl acetamide (modafinil) and the analogue thereof of high-quality low-cost are provided for market.
Embodiment
The present invention's usefulness benzhydrol and thiocarbamide, Hydrogen bromide, sodium hydroxide solution, chlor(o)acetamide or derivatives thereof; obtain hexichol first thioacetamide through separating or without separation, directly obtaining benzhydrylsulfinyl yl acetamide (modafinil) and analogue thereof with the hydrogen peroxide oxidation one pot reaction.
A kind of new synthetic method of benzhydryl thioacetamide and analogue thereof among embodiment one, the present invention.Take by weighing the benzhydrol of 18.4g, thiocarbamide and the 30mL water of 9.2g joins in the there-necked flask of 500mL, stirring and dissolving, be warmed up to 70-80 ℃, drip the dense HBr reaction of 5mL 1-2h, add the 6mL 45%NaOH aqueous solution, then the chlor(o)acetamide reaction 2-3h that adds 10.0g, stopped reaction is poured into water, and the adularescent solid generates, filtration obtains white solid 25.0g, and productive rate is 98.6%.Re-crystallizing in ethyl acetate.Mp 108-109 ℃ (110 ℃ in document).
1H?NMR(CDCl
3)：δ7.2-7.4(m，10H，Ar)；6.49(s，1H，NH
2)；5.71(s，1H，NH
2)；5.14(s，1H，-CH)；3.06，(s，2H，CH
2)；
IR(KBr)：3375cm
-1(-NH
2)，3180(-NH
2)，2952(-CH
2)，1629(-C＝O)，1494(-Ph)，1373(-Ph)，688(C-S)；
MS(m/e)：257(M
+)，199，167，152，139，121，77。
A kind of new synthetic method of hexichol first thioacetamide and analogue thereof among embodiment two, the present invention.Take by weighing the benzhydrol of 18.4g, thiocarbamide and the 35mL water of 12.1g joins in the there-necked flask of 500mL, stirring and dissolving, be warmed up to 70-80 ℃, drip the dense HBr reaction of 5mL 1-2h, add the 20mL 45%NaOH aqueous solution, then the chlor(o)acetamide reaction 2-3h that adds 11.0g, stopped reaction is poured into water, and the adularescent solid generates, filtration obtains white solid 25.0g, and productive rate is 98.4%.Re-crystallizing in ethyl acetate.Mp 106-107 ℃ (110 ℃ in document).
1H?NMR(CDCl
3)：δ7.2-7.4(m，10H，Ar)；6.49(s，1H，NH
2)；5.71(s，1H，NH
2)；5.14(s，1H，-CH)；3.06，(s，2H，CH
2)；
IR(KBr)：3375cm
-1(-NH
2)，3180(-NH
2)，2952(-CH
2)，1629(-C＝O)，1494(-Ph)，1373(-Ph)，688(C-S)；
MS(m/e)：257(M
+)，199，167，152，139，121，77。
A kind of new synthetic method of benzhydrylsulfinyl yl acetamide and analogue thereof among embodiment three, the present invention.In the round-bottomed flask of 500mL, add embodiment one, benzhydryl thioacetamide 25.7g, the 100mL methylene dichloride, stirring and dissolving is warmed up to 30-40 ℃, the hydrogen peroxide that adds 15mL (150mmol), reaction 5-7h, reaction process is by thin-layer chromatography monitoring (developping agent: sherwood oil: ethyl acetate=1: 1), then pour in the cold water, the adularescent solid is separated out, filtration, drying obtain modafinil solid 27.0g, yield 98.9%.Ethyl alcohol recrystallization, fusing point 163-164 ℃.(literature value: fusing point 164-166 ℃).
1H?NMR(CDCl
3)：δ7.40-7.51(m，10H，-Ar)；5.66(s，1H，-NH
2)；7.07(s，1H，-NH
2)；5.22(s，1H，-CH)3.52(d，J＝14.6，1H，-CH
2)；3.14(d，J＝14.6，1H，-CH
2)；
IR(KBr)：3366(-NH
2)，3187(-NH
2)，2987(-CH
2)，1675(-C＝O)，1430(-Ph)，1400(-Ph)，1030(S-O)，701(C-S)；
MS(m/e)：199，167，152，139，121，77。
A kind of new synthetic method of benzhydrylsulfinyl yl acetamide and analogue thereof among embodiment four, the present invention.Take by weighing the benzhydrol of 18.4g, thiocarbamide and the 30mL second eyeball of 9.2g joins in the there-necked flask of 500mL, stirring and dissolving is warmed up to 70-90 ℃, the HBr that adds 5mL, reaction 3-5h adds the 10mL 45%NaOH aqueous solution, then the chlor(o)acetamide that adds 10.0g, stirring and dissolving, reaction 2-6h, regulate pH=7-8, add again 30% hydrogen peroxide of 20mL, stir, reaction 6-12h, stopped reaction is poured into water, have a large amount of white solids to generate, filter and obtain white solid 19.5g, productive rate is 71.2%.Re-crystallizing in ethyl acetate.Mp=163-166 ℃, (document 164-166 ℃).
1H?NMR(CDCl
3)：δ7.40-7.51(m，10H，-Ar)；5.66(s，1H，-NH
2)；7.07(s，1H，-NH
2)；5.22(s，1H，-CH)3.52(d，J＝14.6，1H，-CH
2)；3.14(d，J＝14.6，1H，-CH
2)；
IR(KBr)：3366(-NH
2)，3187(-NH
2)，2987(-CH
2)，1675(-C＝O)，1430(-Ph)，1400(-Ph)，1030(S-O)，701(C-S)；
MS(m/e)：199，167，152，139，121，77。
A kind of new synthetic method of benzhydrylsulfinyl yl acetamide and analogue thereof among embodiment five, the present invention.18.4g benzhydrol, thiocarbamide and the 30mL second eyeball of 9.2g join in the there-necked flask of 500mL, stirring and dissolving is warmed up to 50-60 ℃, drip the Hydrogen bromide of 5mL40%, reaction 1-2h adds the alkali 7mL45%NaOH aqueous solution, then the chlor(o)acetamide that adds 13.6g, stirring and dissolving, reaction 2-4h, transfer pH=7, add again 30% hydrogen peroxide of 25mL, stir, reaction 7-15h, stopped reaction is poured into water, have a large amount of white solids to generate, filter and obtain white solid 19.0g, productive rate is 70.0%.mp?163-165℃。
1H?NMR(CDCl
3)：δ7.2-7.4(m，10H，Ar)；6.49(s，1H，NH
2)；5.71(s，1H，NH
2)；5.14(s，1H，-CH)；3.06，(s，2H，CH
2)；
IR(KBr)：3375cm
-1(-NH
2)，3180(-NH
2)，2952(-CH
2)，1629(-C＝O)，1494(-Ph)，1373(-Ph)，688(C-S)；
MS(m/e)：257(M
+)，199，167，152，139，121，77。
A kind of new synthetic method of benzhydrylsulfinyl yl acetamide and analogue thereof among embodiment six, the present invention.18.4 benzhydrol, thiocarbamide and the 15mL water of 9.2g join in the there-necked flask of 500mL, stirring and dissolving is warmed up to 60-80 ℃, drip 5.0mLHBr, reaction 0.5h adds alkali 6.0mL 45%NaOH, then the chlor(o)acetamide that adds 11.3g, stirring and dissolving, reaction 2h, transfer pH=7, add again 30% hydrogen peroxide of 16mL, stir, reaction 15h, stopped reaction is poured into water, have a large amount of white solids to generate, filter and obtain white solid 10.4g, productive rate is 37.9%.mp＝165-166℃。
1H?NMR(CDCl
3)：δ7.2-7.4(m，10H，Ar)；6.49(s，1H，NH
2)；5.71(s，1H，NH
2)；5.14(s，1H，-CH)；3.06，(s，2H，CH
2)；
IR(KBr)：3375cm
-1(-NH
2)，3180(-NH
2)，2952(-CH
2)，1629(-C＝O)，1494(-Ph)，1373(-Ph)，688(C-S)；
MS(m/e)：257(M
+)，199，167，152，139，121，77。
A kind of new synthetic method of hexichol first thioacetyl aniline and analogue thereof among embodiment seven, the present invention.18.4g benzhydrol, thiocarbamide and the 15mL acetonitrile of 9.2g join in the there-necked flask of 500mL, stirring and dissolving is warmed up to 70 ℃, add 6mLHBr, reaction 2-3h adds the alkali 5-7mL 45%NaOH aqueous solution, then adds the chloroacetanilide of 18.0g, stirring and dissolving, reaction 2-4h is poured into water, and has a large amount of white solids to generate, filtration obtains white solid 31.6g, and productive rate is 94.9%.mp?153-154℃。
1H?NMR(CDCl
3，400MHz)：9.12(s，1H，-CONH-Ph)，7.08-7.46(m，15H，C
6H
5-)，5.15(s，1H，Ph
2CH-)，3.24(d，J＝7.6，1H，-CH
2CO-)。
IR(KBr)：3395(-NH
2)，3241(-NH
2)，2911(-CH
2)，1676(-C＝O)，1596(-Ph)，1488(-Ph)，695(C-S)。
A kind of new synthetic method of benzhydrylsulfinyl base Acetanilide and analogue thereof among embodiment eight, the present invention.In the round-bottomed flask of 500mL, add embodiment seven, diphenyl-methyl thioacetyl aniline 33.3g, the 20mL acetonitrile joins in the there-necked flask of 500mL, and stirring and dissolving is warmed up to 30-50 ℃, the hydrogen peroxide that adds again 10mL, stir reaction 5-7h, stopped reaction, be poured into water, have a large amount of white solids to generate, filter and obtain white solid 3.15g, productive rate is 90.2%.mp?181-182℃
1H?NMR(CDCl
3，400MHz)：9.12(s，1H，-CONH-Ph)，7.08-7.52(m，15H，C
6H
5-)，5.19(S，1H，Ph
2CH-)，3.64(d，J＝14.6，1H，-CH
2CO-)，3.19(d，J＝14.6，1H，-CH
2CO-)；
IR(KBr)：3234(NH
2)，3173(NH
2)，2918(-CH
2)，1676(-C＝O)，1494(-Ph)，1441(-Ph)，1044(S-O)，702(C-S)。
A kind of new synthetic method of benzhydrylsulfinyl base Acetanilide and analogue thereof among embodiment nine, the present invention.18.4g benzhydrol, the thiocarbamide of 9.2g, the 15mL acetonitrile joins in the there-necked flask of 500mL, stirring and dissolving, be warmed up to 70 ℃, add the HBr of 7mL, reaction 2-3h, add the alkali 8mL 45%NaOH aqueous solution, then add the 18.0g chloroacetanilide, stirring and dissolving, react 4-6h, add again the hydrogen peroxide of 22mL, stir, reaction 5-7h, stopped reaction is poured into water, have a large amount of white solids to generate, filter and obtain white solid 29.3g, productive rate is 83.4%.mp?181-182℃。
1H?NMR(CDCl
3，400MHz)：9.12(s，1H，-CONH-Ph)，7.08-7.52(m，15H，C
6H
5-)，5.19(S，1H，Ph
2CH-)，3.64(d，J＝14.6，1H，-CH
2CO-)，3.19(d，J＝14.6，1H，-CH
2CO-)；
IR(KBr)：3234(NH
2)，3173(NH
2)，2918(-CH
2)，1676(-C＝O)，1494(-Ph)，1441(-Ph)，1044(S-O)，702(C-S)。
The new synthetic method of a kind of benzhydrylsulfinyl yl acetamide of the present invention and analogue thereof.This method under certain condition, take benzhydrol, thiocarbamide, acid, alkali, halogen ethanamide and derivative thereof, oxygenant as raw material, intermediate product separates through a step and obtains benzhydryl thioacetamide or do not separate direct oxidation one kettle way sintetics.The middle R of reaction formula
1, R
2Can be identical or different aliphatic group, alicyclic hydrocarbon radical, such as hydrogen, methyl, ethyl, propyl group, butyl, amyl group, hexyl, benzyl, cyclopentyl, cyclohexyl, piperidyl, morpholinyl etc., and aryl radical and the fragrant heterocyclic radical of all kinds of groups replacements, such as phenyl, tolyl, chloro-phenyl-, sulphenyl, nitrophenyl, aminophenyl, pyridyl, pyrryl, pyrimidyl, 4,6-dichloro pyrimidine base, 4-chloropyrimide base etc.
Temperature can be selected a temperature or a plurality of homo(io)thermism or a plurality of temperature change 20-240 ℃ of scope in reaction process.
The one kettle way sintetics, intermediate product separates or does not separate complete operation through a step.
The solvent of selecting is water, acetonitrile, methyl alcohol, ethanol, chloroform, methylene dichloride, 1,2-ethylene dichloride, acetone, tetrahydrofuran (THF), DMF, benzene, toluene, the perhaps mixed system of water and organic solvent.
The alkali that uses is mainly used in regulating the pH value as solution (oxyhydroxide of K, Na, Ca or carbonate, supercarbonate) or the organic bases (pyridine, triethylamine) of mineral alkali solid or mineral alkali.
Acid comprises hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, chlorsulfonic acid and the acid of various carrying inorganic thereof for mineral acid, and the load agent is silicon-dioxide, aluminium sesquioxide, diatomite, kaolin and carclazyte; Organic acid comprises Phenylsulfonic acid, tosic acid, trifluoromethanesulfonic acid or various acidic resins.
Halogen in halogen ethanamide and the derivative thereof is chlorine, bromine.
Oxygenant is a kind of or mixed solution among hydrogen peroxide, perchloric acid, Periodic acid, Sodium peroxoborate, clorox, sodium periodate or the organic peroxide acid.Organic peroxide acid comprises Peracetic Acid, peroxy trifluoroacetic acid, peroxide m-chlorobenzoic acid.
Reaction times is 1-36 hour.
Under the optimal way, benzhydrol: thiocarbamide: acid: alkali: halogen ethanamide and derivative thereof: the mol ratio of oxygenant=1: 1.0-10: 1.0-8: 1.0-10.0: 1.0-8.
A kind of preferred version; with benzhydrol, thiocarbamide, chlor(o)acetamide and derivatives reaction thereof obtain benzhydryl thioacetamide, again through the hydrogen peroxide oxidation; do not separate direct oxidation perhaps; be poured into water; resulting solid is used recrystallizing methanol more after filtration, obtains white powder and is benzhydrylsulfinyl yl acetamide and analogue thereof.
Chemical equation of the present invention:
Wherein, described R
1, R
2Be identical or different aliphatic group, alicyclic hydrocarbon radical, such as hydrogen, methyl, ethyl, propyl group, butyl, amyl group, hexyl, benzyl, cyclopentyl, cyclohexyl, piperidyl, morpholinyl, and aryl radical and the fragrant heterocyclic radical of all kinds of groups replacements, such as phenyl, tolyl, chloro-phenyl-, sulphenyl, nitrophenyl, aminophenyl, pyridyl, pyrryl, pyrimidyl, 4,6-dichloro pyrimidine base, 4-chloropyrimide base;
The R that the present invention relates to
1, R
2Can be identical or different aliphatic group, alicyclic hydrocarbon radical, such as hydrogen, methyl, ethyl, propyl group, butyl, amyl group, hexyl, benzyl, cyclopentyl, cyclohexyl, piperidyl, morpholinyl etc., and aryl radical and the fragrant heterocyclic radical of all kinds of groups replacements, such as phenyl, tolyl, chloro-phenyl-, sulphenyl, nitrophenyl, aminophenyl, pyridyl, pyrryl, pyrimidyl, 4,6-dichloro pyrimidine base, 4-chloropyrimide base etc.The acid amides that the present invention commonly uses is chlor(o)acetamide and derivative thereof.
Acid in the present invention's reaction can be hydrochloric acid, sulfuric acid, Hydrogen bromide etc.; Alkali can be various mineral alkali solids or solution, organic bases; Solvent can be methylene dichloride, chloroform, acetone, acetonitrile, etc. organic solvent or second alcohol and water, first alcohol and water, water etc. as solvent; The general 20-240 of temperature of reaction ℃; General optimum temps at 40-150 ℃.Oxygenant can be hydrogen peroxide, Periodic acid, clorox, the chiral oxidization agent that occurring in nature exists etc., and the present invention generally uses 30% hydrogen peroxide.The pH value is generally 4-14 among the present invention, usually is transferred to 9-10 for best.
The above; only be the better embodiment of the present invention; but protection scope of the present invention is not limited to this; anyly be familiar with those skilled in the art in the technical scope that the present invention discloses; be equal to replacement or change according to technical scheme of the present invention and inventive concept thereof, all should be encompassed within protection scope of the present invention.
Claims (5)
1. the method for the synthetic benzhydrylsulfinyl yl acetamide of an one kettle way and analogue thereof, it is characterized in that, temperature is under 20-240 ℃, pH value 4-14 condition, take benzhydrol, thiocarbamide, acid, alkali, halogen ethanamide or derivatives thereof, oxygenant as raw material, with " one kettle way " synthetic benzhydrylsulfinyl yl acetamide and analogue thereof;
Chemical equation is:
Wherein, described R
1, R
2Be identical or different aliphatic group, alicyclic hydrocarbon radical, such as hydrogen, methyl, ethyl, propyl group, butyl, amyl group, hexyl, benzyl, cyclopentyl, cyclohexyl, piperidyl, morpholinyl, and aryl radical and the fragrant heterocyclic radical of all kinds of groups replacements, such as phenyl, tolyl, chloro-phenyl-, sulphenyl, nitrophenyl, aminophenyl, pyridyl, pyrryl, pyrimidyl, 4,6-dichloro pyrimidine base, 4-chloropyrimide base;
Halogen in described halogen ethanamide and the derivative thereof is chlorine, bromine;
The solvent of selecting is water, acetonitrile, methyl alcohol, ethanol, chloroform, methylene dichloride, 1,2-ethylene dichloride, acetone, butanone, tetrahydrofuran (THF), DMF, benzene, toluene, tetracol phenixin, perhaps any mixed system of water and above-mentioned organic solvent;
Described alkali is selected sodium hydroxide, potassium hydroxide, calcium hydroxide, yellow soda ash, salt of wormwood, calcium carbonate, sodium bicarbonate, saleratus solid or their alkaline solution, again or triethylamine, or pyridine;
Mineral acid or organic acid are selected in described acid; Mineral acid is selected any one of hydrochloric acid, Hydrogen bromide, sulfuric acid, chlorsulfonic acid, the above-mentioned mineral acid of the various loads of phosphoric acid, and described load agent is silicon-dioxide, aluminium sesquioxide, diatomite, kaolin or carclazyte; Described organic acid is Phenylsulfonic acid, tosic acid, trifluoromethanesulfonic acid or acidic resins;
Described oxygenant is specifically selected a kind of or mixed solution among hydrogen peroxide, perchloric acid, Periodic acid, Sodium peroxoborate, clorox, sodium periodate or the organic peroxide acid; Described organic peroxide acid is Peracetic Acid, peroxy trifluoroacetic acid or peroxide m-chlorobenzoic acid;
Reaction times is 1-36 hour.
2. the method for the synthetic benzhydrylsulfinyl yl acetamide of described one kettle way and analogue thereof according to claim 1 is characterized in that temperature is 40-150 ℃ of lower reaction.
3. the method for the synthetic benzhydrylsulfinyl yl acetamide of described one kettle way and analogue thereof according to claim 1 is characterized in that the pH value is transferred under the 9-10 condition and is reacted.
4. arbitrary described one kettle way synthesizes the method for benzhydrylsulfinyl yl acetamide and analogue thereof according to claim 1-3; it is characterized in that; with benzhydrol, thiocarbamide, the reaction of chlor(o)acetamide or derivatives thereof obtain benzhydryl thioacetamide and analogue thereof, again through oxygenant oxidations such as hydrogen peroxide; do not separate direct oxidation perhaps; be poured into water; resulting solid is used the recrystallizations such as methyl alcohol, ethyl acetate more after filtration, obtains white powder and is benzhydrylsulfinyl yl acetamide and analogue thereof.
5. arbitrary described one kettle way synthesizes the method for benzhydrylsulfinyl yl acetamide and analogue thereof according to claim 1-3; it is characterized in that described benzhydrol: thiocarbamide: acid: alkali: halogen ethanamide or derivatives thereof: the mol ratio of oxygenant=1: 1.0-10: 1.0-8: 1.0-10.0: 1.0-8.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4177290A (en) * | 1977-03-31 | 1979-12-04 | Laboratoire L. Lafon | Acetamide derivatives |
| US20020183552A1 (en) * | 2001-05-13 | 2002-12-05 | Chemagis Ltd. | Process for the preparation of acetamide derivatives |
| CN1656064A (en) * | 2002-05-23 | 2005-08-17 | 赛福伦公司 | Preparations of a sulfinyl acetamide |
| CN101326159A (en) * | 2005-12-09 | 2008-12-17 | 马林克罗特公司 | Processes for the preparation of modafinil and analogs thereof |
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2011
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4177290A (en) * | 1977-03-31 | 1979-12-04 | Laboratoire L. Lafon | Acetamide derivatives |
| US20020183552A1 (en) * | 2001-05-13 | 2002-12-05 | Chemagis Ltd. | Process for the preparation of acetamide derivatives |
| CN1656064A (en) * | 2002-05-23 | 2005-08-17 | 赛福伦公司 | Preparations of a sulfinyl acetamide |
| CN101326159A (en) * | 2005-12-09 | 2008-12-17 | 马林克罗特公司 | Processes for the preparation of modafinil and analogs thereof |
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