CN102807516A - Intermediate in amisulpride and method for preparing amisulpride by using intermediate - Google Patents
Intermediate in amisulpride and method for preparing amisulpride by using intermediate Download PDFInfo
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- CN102807516A CN102807516A CN2012102922758A CN201210292275A CN102807516A CN 102807516 A CN102807516 A CN 102807516A CN 2012102922758 A CN2012102922758 A CN 2012102922758A CN 201210292275 A CN201210292275 A CN 201210292275A CN 102807516 A CN102807516 A CN 102807516A
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- 229960003036 amisulpride Drugs 0.000 title claims abstract description 58
- NTJOBXMMWNYJFB-UHFFFAOYSA-N amisulpride Chemical compound CCN1CCCC1CNC(=O)C1=CC(S(=O)(=O)CC)=C(N)C=C1OC NTJOBXMMWNYJFB-UHFFFAOYSA-N 0.000 title claims abstract description 56
- 238000000034 method Methods 0.000 title abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 25
- 238000006482 condensation reaction Methods 0.000 claims abstract description 7
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 23
- 238000003756 stirring Methods 0.000 claims description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- 238000002360 preparation method Methods 0.000 claims description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 13
- 239000007787 solid Substances 0.000 claims description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- 238000004821 distillation Methods 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- MFPWEWYKQYMWRO-UHFFFAOYSA-N tert-butyl carboxy carbonate Chemical compound CC(C)(C)OC(=O)OC(O)=O MFPWEWYKQYMWRO-UHFFFAOYSA-N 0.000 claims description 10
- 239000000543 intermediate Substances 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 238000001953 recrystallisation Methods 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- 235000017550 sodium carbonate Nutrition 0.000 claims description 5
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Chemical group CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- BQFCCCIRTOLPEF-UHFFFAOYSA-N chembl1976978 Chemical compound CC1=CC=CC=C1N=NC1=C(O)C=CC2=CC=CC=C12 BQFCCCIRTOLPEF-UHFFFAOYSA-N 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 3
- 230000001105 regulatory effect Effects 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 abstract description 6
- 239000012535 impurity Substances 0.000 abstract description 5
- 239000005711 Benzoic acid Substances 0.000 abstract 3
- 235000010233 benzoic acid Nutrition 0.000 abstract 3
- UNRBEYYLYRXYCG-UHFFFAOYSA-N (1-ethylpyrrolidin-2-yl)methanamine Chemical compound CCN1CCCC1CN UNRBEYYLYRXYCG-UHFFFAOYSA-N 0.000 abstract 1
- DYHSDKLCOJIUFX-UHFFFAOYSA-N Di-tert-butyl dicarbonate Substances CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 abstract 1
- -1 di-tert-butyl dicarbonate ester Chemical class 0.000 abstract 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 abstract 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000002585 base Substances 0.000 description 4
- 230000002194 synthesizing effect Effects 0.000 description 4
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- PQLFROTZSIMBKR-UHFFFAOYSA-N ethenyl carbonochloridate Chemical compound ClC(=O)OC=C PQLFROTZSIMBKR-UHFFFAOYSA-N 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- FFFHBHWCZONDKN-UHFFFAOYSA-N (1-ethylpyrrol-2-yl)methanamine Chemical class CCN1C=CC=C1CN FFFHBHWCZONDKN-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-LWMBPPNESA-L D-tartrate(2-) Chemical compound [O-]C(=O)[C@@H](O)[C@H](O)C([O-])=O FEWJPZIEWOKRBE-LWMBPPNESA-L 0.000 description 1
- 101150049660 DRD2 gene Proteins 0.000 description 1
- KIWBPDUYBMNFTB-UHFFFAOYSA-N Ethyl hydrogen sulfate Chemical compound CCOS(O)(=O)=O KIWBPDUYBMNFTB-UHFFFAOYSA-N 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
- PFUQSACCWFVIBW-UHFFFAOYSA-N [C].C1=CC=CC=C1 Chemical compound [C].C1=CC=CC=C1 PFUQSACCWFVIBW-UHFFFAOYSA-N 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 239000003693 atypical antipsychotic agent Substances 0.000 description 1
- 229940127236 atypical antipsychotics Drugs 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000007859 condensation product Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229940103494 thiosalicylic acid Drugs 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an intermediate in amisulpride and a method for preparing amisulpride by using an intermediate. The method comprises the following steps: reacting 4-amino-2-methoxy group-5-ethylsulfonyl benzoic acid and di-tert-butyl dicarbonate ester so as to obtain the intermediate (4-(N-tert-tert-butoxycarbonyl)amino-2-methoxy group-5-ethylsulfonyl benzoic acid) of the amisulpride; and carrying out condensation reaction on the intermediate (4-(N-tert-butoxycarbonyl)amino-2-methoxy group-5-ethylsulfonyl benzoic acid) of the amisulpride and N-ethyl-2-aminomethyl pyrrolidine so as to obtain 4-(N-tert-tert-butoxycarbonyl)amino-N-((1-ethyl-2-pyrrolidyl)methyl)-5-ethylsulfonyl-2-methoxy benzamide, and carrying out deprotection of tert-butoxycarbonyl group (BOC) so as to obtain the amisulpride. According to the method, the process processing is simple, impurities which are hard to remove are avoided, the reaction yield is high and can be up to 76%, the purity of the obtained amisulpride is high, and the medical quality of the amisulpride is greatly improved.
Description
Technical field
The present invention relates to the synthetic field of medicine, be specifically related to a kind of midbody of amisulpride: the method for 4-(N-tert-butoxycarbonyl) amino-2-methoxyl group-5-ethylsulfonyl phenylformic acid and preparation method thereof and the intermediate preparation amisulpride that utilizes this amisulpride.
Background technology
Amisulpride (amisulpride; 1); Chemical name: 4-amino-N-((1-ethyl-2-pyrrolidyl) methyl)-5-ethylsulfonyl-2-methoxy benzamide; Be novel atypical antipsychotic, be widely used in clinical benzene carbon amide verivate in Europe and world wide with significant curative effect by the exploitation of Sanifi-Synthelabo company.Its main mechanism is that selectivity antagonism d2 dopamine receptor and D3 acceptor play a role, and is used to treat chronic clinically and acute progressive schizophrenia, and its structural formula is following:
Document " synthesizing of amisulpride " has been reported the preparation method of two kinds of amisulprides:
Method 1:
With 4-amino-2-methoxyl group-5-Thiosalicylic acid (2) is raw material; Under alkaline condition, obtain 4-amino-2-methoxyl group-5-ethyl phenyl sulfide formic acid (3) through the ethyl sulfate ethylization; Make 4-amino-2-methoxyl group-5-ethylsulfonyl phenylformic acid (4) with the Peracetic Acid oxidation again; 4 under Vinyl chloroformate, triethylamine catalysis with 2, the condensation of 5-dichloro amylamine gets 4-amino-N-(2,5-dichloro amyl group)-5-ethylsulfonyl-2-methoxy benzamide; At last become pyrrolidine ring, make target compound 1 with the ethamine closed loop.This method complex steps, and the product impurity of gained is more, is difficult for purifying, total recovery low (total recovery 10.9%).
Method 2:
On the basis of method 1 synthetic 4, directly use 4 under Vinyl chloroformate, triethylamine catalysis, to make target compound 1, total recovery 22.5% with side chain side chain N-ethyl-2-aminomethylpentazaneand (5) condensation.
Chinese patent CN200910069064.6 discloses the compound method of a kind of (S) (-)-amisulpride D-(-)-tartrate; This method comprises: 2-methoxyl group-4-amino-5-ethylsulfonyl phenylformic acid and lower alcohol are reacted the ester that obtains its lower alcohol; The ester of gained lower alcohol and S) (-)-1-ethyl-2-aminomethyl pyrroles reaction, get (S) (-)-amisulpride.
In above-mentioned three kinds of methods, all be to adopt directly 4-amino-2-methoxyl group-5-ethylsulfonyl phenylformic acid (4) and N-ethyl-2-aminomethylpentazaneand (5) are carried out condensation reaction, make amisulpride; But in above-mentioned reaction; The active amino and the carboxyl that exist in 4-amino-2-methoxyl group-5-ethylsulfonyl benzoic acid compounds are easy to take place condensation reaction under the katalysis of catalyzer Vinyl chloroformate, triethylamine; The character of the condensation product that makes is similar with amisulpride; In later stage removal of impurities process, be difficult to Ex-all, not only influenced the quality of product, but also reduced yield.
Summary of the invention
The technical problem that the present invention will solve is: the deficiency that is directed to prior art; Midbody of a kind of amisulpride and preparation method thereof is provided; And a kind of technological process is simple, avoids the impurity that is difficult to remove, the preparation method of the amisulpride that yield is high, purity is good.
In order to reach the foregoing invention purpose, the technical scheme that the present invention adopts is: the midbody that a kind of amisulpride is provided: 4-(N-tert-butoxycarbonyl) amino-2-methoxyl group-5-ethylsulfonyl phenylformic acid, and structural formula is shown in formula III:
The present invention also provides a kind of intermediates preparation of amisulpride, it is characterized in that, comprises with structural formula being the compound of formula IV: 4-amino-2-methoxyl group-5-ethylsulfonyl phenylformic acid and tert-Butyl dicarbonate react;
In the above-mentioned reaction, 4-amino-2-methoxyl group-5-ethylsulfonyl phenylformic acid (IV) is dissolved in the solvent orange 2 A, adds alkali; Down reaction 0.5-5 hour is passable at 5-60 ℃ to add tert-Butyl dicarbonate again, and cooling reaction thing to room temperature is again in the impouring frozen water; Standing demix is regulated water layer pH to 3-4, stirs and separates out solid; Filter, drying makes the midbody of amisulpride: 4-(N-tert-butoxycarbonyl) amino-2-methoxyl group-5-ethylsulfonyl phenylformic acid (III).
The mol ratio of said 4-amino-2-methoxyl group-5-ethylsulfonyl phenylformic acid and tert-Butyl dicarbonate is 1:1-1:2.
Said solvent orange 2 A is at least a in ethanol, methyl alcohol, DMF and the acetonitrile.
Said alkali is yellow soda ash.
The present invention also provides a kind of method of utilizing the intermediate preparation amisulpride of above-mentioned amisulpride, it is characterized in that: may further comprise the steps:
A, with the midbody of amisulpride: 4-(N-tert-butoxycarbonyl) amino-2-methoxyl group-5-ethylsulfonyl phenylformic acid (III) carries out condensation reaction with the N-ethyl-2-aminomethylpentazaneand, makes 4-(N-tert-butoxycarbonyl) amino-N-((1-ethyl-2-pyrrolidyl) methyl)-5-ethylsulfonyl-2-methoxy benzamide (II);
In the above-mentioned reaction; 4-(N-tert-butoxycarbonyl) amino-2-methoxyl group-5-ethylsulfonyl phenylformic acid (III) is dissolved among the solvent B; Add DCC again, reacted 10-13 hour down at 10-40 ℃, with frozen water washing reaction thing with the N-ethyl-2-aminomethylpentazaneand; Distillation removes the B that desolvates, and makes 4-(N-tert-butoxycarbonyl) amino-N-((1-ethyl-2-pyrrolidyl) methyl)-5-ethylsulfonyl-2-methoxy benzamide (II);
B, the 4-that makes (N-tert-butoxycarbonyl) amino-N-((1-ethyl-2-pyrrolidyl) methyl)-5-ethylsulfonyl-2-methoxy benzamide (II) is carried out deprotection reaction;
In the above-mentioned reaction, 4-(N-tert-butoxycarbonyl) amino-N-((1-ethyl-2-pyrrolidyl) methyl)-5-ethylsulfonyl-2-methoxy benzamide (II) is dissolved in the solvent C, adds acid again and at room temperature reacted 10-40 minute; Solvent C is removed in underpressure distillation, adds entry again, stirs; Separate out solid; Filter, recrystallization makes amisulpride (I).
Among the step a, said 4-(N-tert-butoxycarbonyl) amino-2-methoxyl group-5-ethylsulfonyl phenylformic acid (III) is 1:1:1-1:2:2 with the mol ratio of N-ethyl-2-aminomethylpentazaneand and DCC.
Among the step a, said solvent B is methylene dichloride or DMF or acetonitrile or THF; Among the step b, said solvent C is ethanol or methyl alcohol or acetonitrile or DMF.
Among the step b, said acid is hydrochloric acid.
In sum; Midbody of amisulpride provided by the invention and preparation method thereof and the method for utilizing this intermediate preparation amisulpride are through making 4-(N-tert-butoxycarbonyl) amino-2-methoxyl group-5-ethylsulfonyl phenylformic acid with 4-amino-2-methoxyl group-5-ethylsulfonyl phenylformic acid and tert-Butyl dicarbonate reaction; Active 4 bit aminos are protected; Again protected 4-(N-tert-butoxycarbonyl) amino-2-methoxyl group-5-ethylsulfonyl phenylformic acid and N-ethyl-2-aminomethylpentazaneand are carried out condensation reaction; Remove the protection base again, make amisulpride; Condensation reaction takes place in active amino and the carboxyl having avoided in the above-mentioned reaction existing in 4-amino-2-methoxyl group-5-ethylsulfonyl benzoic acid compounds under the effect of catalyzer, generate other material with the amisulpride similar performance; The preparation method of amisulpride provided by the invention has avoided the generation of impurity, has improved the quality of amisulpride, and the yield of amisulpride can reach 76%.
Embodiment
Do below in conjunction with the specific embodiment specific embodiments of the invention and to describe in detail:
Embodiment 1
The midbody of amisulpride: 4-(N-tert-butoxycarbonyl) amino-2-methoxyl group-5-ethylsulfonyl is benzoic synthetic:
After 26g 4-amino-2-methoxyl group-5-ethylsulfonyl phenylformic acid (IV) and 150ml ethanol stirring and dissolving, add 12g yellow soda ash, add the 30g tert-Butyl dicarbonate down at 20 ℃; Be heated to 30 ℃ of reactions 5 hours; Cooling reaction liquid is to room temperature, layering in the impouring frozen water again, water layer with the Hydrogen chloride adjust pH to 3-4; Solid is separated out in stirring; Filter and, the gained solid at 40 ℃ of following drying under reduced pressure, is made 31g 4-(N-tert-butoxycarbonyl) amino-2-methoxyl group-5-ethylsulfonyl phenylformic acid (III) with a small amount of distilled water wash filter cake.
Embodiment 2
Synthesizing of amisulpride: with adding 100ml methylene dichloride stirring and dissolving in 31g 4-(N-tert-butoxycarbonyl) amino-2-methoxyl group-5-ethylsulfonyl phenylformic acid and the 12g N-ethyl-2-aminomethylpentazaneand; Add 19.5g DCC 30 ℃ of following stirring reactions 12 hours; Reaction solution is washed with frozen water; Methylene dichloride is removed in distillation, makes 44g 4-(N-tert-butoxycarbonyl) amino-N-((1-ethyl-2-pyrrolidyl) methyl)-5-ethylsulfonyl-2-methoxy benzamide; Add 50ml ethanol in the above-mentioned 4-that makes (N-tert-butoxycarbonyl) amino-N-((1-ethyl-2-pyrrolidyl) methyl)-5-ethylsulfonyl-2-methoxy benzamide and at room temperature stir with 5ml2M hydrochloric acid and sloughed BOC protection base in 30 minutes, ethanol is removed in underpressure distillation, adds the stirring of 100ml zero(ppm) water in the residue; Separate out solid; Filter, and use acetone recrystallization, make the 29.3g amisulpride; Yield is 74.8%, and purity is 99.6%.
Embodiment 3
The midbody of amisulpride: 4-(N-tert-butoxycarbonyl) amino-2-methoxyl group-5-ethylsulfonyl is benzoic synthetic:
After 26g4-amino-2-methoxyl group-5-ethylsulfonyl phenylformic acid (IV) and 150mlDMF stirring and dissolving, add 12g yellow soda ash, add the 28g tert-Butyl dicarbonate down at 20 ℃; Be heated to 60 ℃ of reactions 0.5 hour; Cooling reaction liquid is to room temperature, layering in the impouring frozen water again, water layer with the Hydrogen chloride adjust pH to 3-4; Solid is separated out in stirring; Filter and, the gained solid at 45 ℃ of following drying under reduced pressure, is made 31.4g 4-(N-tert-butoxycarbonyl) amino-2-methoxyl group-5-ethylsulfonyl phenylformic acid (III) with a small amount of distilled water wash filter cake.
Embodiment 4
Synthesizing of amisulpride: with adding 100ml acetonitrile stirring and dissolving in 31.4g 4-(N-tert-butoxycarbonyl) amino-2-methoxyl group-5-ethylsulfonyl phenylformic acid and the 17g N-ethyl-2-aminomethylpentazaneand; Add 29gDCC 40 ℃ of following stirring reactions 10 hours; Reaction solution is washed with frozen water; Acetonitrile is removed in distillation, makes 44g 4-(N-tert-butoxycarbonyl) amino-N-((1-ethyl-2-pyrrolidyl) methyl)-5-ethylsulfonyl-2-methoxy benzamide; Add 50ml methyl alcohol in the above-mentioned 4-that makes (N-tert-butoxycarbonyl) amino-N-((1-ethyl-2-pyrrolidyl) methyl)-5-ethylsulfonyl-2-methoxy benzamide and at room temperature stir with 2ml 2M hydrochloric acid and sloughed BOC protection base in 40 minutes, methyl alcohol is removed in underpressure distillation, adds the stirring of 100ml zero(ppm) water in the residue; Separate out solid; Filter, and use acetone recrystallization, make the 29.6g amisulpride; Yield is 76%, and purity is 99.7%.
Embodiment 5
The midbody of amisulpride: 4-(N-tert-butoxycarbonyl) amino-2-methoxyl group-5-ethylsulfonyl is benzoic synthetic:
After 50g 4-amino-2-methoxyl group-5-ethylsulfonyl phenylformic acid (IV) and 300ml acetonitrile stirring and dissolving, add 24g yellow soda ash, add the 27g tert-Butyl dicarbonate down at 20 ℃; Be heated to 5 ℃ of reactions 3 hours; Cooling reaction liquid is to room temperature, layering in the impouring frozen water again, water layer with the Hydrogen chloride adjust pH to 3-4; Solid is separated out in stirring; Filter and, the gained solid at 40 ℃ of following drying under reduced pressure, is made 59.4g 4-(N-tert-butoxycarbonyl) amino-2-methoxyl group-5-ethylsulfonyl phenylformic acid (III) with a small amount of distilled water wash filter cake.
Embodiment 6
Synthesizing of amisulpride: with adding 100ml THF stirring and dissolving in 29.7g 4-(N-tert-butoxycarbonyl) amino-2-methoxyl group-5-ethylsulfonyl phenylformic acid and the 23g N-ethyl-2-aminomethylpentazaneand; Add 36g DCC 10 ℃ of following stirring reactions 13 hours; Reaction solution is washed with frozen water; THF is removed in distillation, makes 43g 4-(N-tert-butoxycarbonyl) amino-N-((1-ethyl-2-pyrrolidyl) methyl)-5-ethylsulfonyl-2-methoxy benzamide; Add the 60ml acetonitrile in the above-mentioned 4-that makes (N-tert-butoxycarbonyl) amino-N-((1-ethyl-2-pyrrolidyl) methyl)-5-ethylsulfonyl-2-methoxy benzamide and at room temperature stir with 2ml2M hydrochloric acid and sloughed BOC protection base in 60 minutes, acetonitrile is removed in underpressure distillation, adds the stirring of 100ml zero(ppm) water in the residue; Separate out solid; Filter, and use acetone recrystallization, make the 28.2g amisulpride; Yield is 74.8%, and purity is 99.5%.
Though describe in detail, be not to be qualification to this patent protection domain in conjunction with the specific embodiment specific embodiments of the invention.In claims institute restricted portion, various modifications that those skilled in the art can make without creative work or adjustment still receive the protection of this patent.
Claims (9)
1. the midbody of an amisulpride: 4-(N-tert-butoxycarbonyl) amino-2-methoxyl group-5-ethylsulfonyl phenylformic acid, structural formula is shown in formula III:
2. the intermediates preparation of an amisulpride is characterized in that, comprises with structural formula being the compound of formula IV: 4-amino-2-methoxyl group-5-ethylsulfonyl phenylformic acid and tert-Butyl dicarbonate react;
In the above-mentioned reaction, 4-amino-2-methoxyl group-5-ethylsulfonyl phenylformic acid (IV) is dissolved in the solvent orange 2 A, adds alkali; Add tert-Butyl dicarbonate again and reacted 0.5-5 hour down at 5-60 ℃, cooling reaction thing to room temperature is again in the impouring frozen water; Standing demix is regulated water layer pH to 3-4, stirs and separates out solid; Filter, drying makes the midbody of amisulpride: 4-(N-tert-butoxycarbonyl) amino-2-methoxyl group-5-ethylsulfonyl phenylformic acid (III).
3. the intermediates preparation of amisulpride according to claim 2, it is characterized in that: the mol ratio of said 4-amino-2-methoxyl group-5-ethylsulfonyl phenylformic acid and tert-Butyl dicarbonate is 1:1-1:2.
4. the intermediates preparation of amisulpride according to claim 2 is characterized in that: said solvent orange 2 A is at least a in ethanol, methyl alcohol, DMF and the acetonitrile.
5. the intermediates preparation of amisulpride according to claim 2, it is characterized in that: said alkali is yellow soda ash.
6. the preparation method of an amisulpride is characterized in that: may further comprise the steps:
A, with the midbody of amisulpride: 4-(N-tert-butoxycarbonyl) amino-2-methoxyl group-5-ethylsulfonyl phenylformic acid (III) carries out condensation reaction with the N-ethyl-2-aminomethylpentazaneand, makes 4-(N-tert-butoxycarbonyl) amino-N-((1-ethyl-2-pyrrolidyl) methyl)-5-ethylsulfonyl-2-methoxy benzamide (II);
In the above-mentioned reaction; 4-(N-tert-butoxycarbonyl) amino-2-methoxyl group-5-ethylsulfonyl phenylformic acid (III) is dissolved among the solvent B; Add DCC again, reacted 10-13 hour down at 10-40 ℃, with frozen water washing reaction thing with the N-ethyl-2-aminomethylpentazaneand; Distillation removes the B that desolvates, and makes 4-(N-tert-butoxycarbonyl) amino-N-((1-ethyl-2-pyrrolidyl) methyl)-5-ethylsulfonyl-2-methoxy benzamide (II);
B, the 4-that makes (N-tert-butoxycarbonyl) amino-N-((1-ethyl-2-pyrrolidyl) methyl)-5-ethylsulfonyl-2-methoxy benzamide (II) is carried out deprotection reaction;
In the above-mentioned reaction, 4-(N-tert-butoxycarbonyl) amino-N-((1-ethyl-2-pyrrolidyl) methyl)-5-ethylsulfonyl-2-methoxy benzamide (II) is dissolved in the solvent C, adds acid again and at room temperature reacted 10-40 minute; Solvent C is removed in underpressure distillation, adds entry again, stirs; Separate out solid; Filter, recrystallization makes amisulpride (I).
7. the preparation method of amisulpride according to claim 6; It is characterized in that: among the step a, said 4-(N-tert-butoxycarbonyl) amino-2-methoxyl group-5-ethylsulfonyl phenylformic acid (III) is 1:1:1-1:2:2 with the mol ratio of N-ethyl-2-aminomethylpentazaneand and DCC.
8. the preparation method of amisulpride according to claim 6, it is characterized in that: among the step a, said solvent B is methylene dichloride or DMF or acetonitrile or THF; Among the step b, said solvent C is ethanol or methyl alcohol or acetonitrile or DMF.
9. the preparation method of amisulpride according to claim 6, it is characterized in that: among the step b, said acid is hydrochloric acid.
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| CN119504547A (en) * | 2025-01-21 | 2025-02-25 | 山东安弘制药有限公司 | A kind of preparation method of amisulpride |
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| CN114230497A (en) * | 2021-10-21 | 2022-03-25 | 广东省科学院生物与医学工程研究所 | A kind of preparation method of 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid |
| CN119504547A (en) * | 2025-01-21 | 2025-02-25 | 山东安弘制药有限公司 | A kind of preparation method of amisulpride |
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