CN1931837A - Prepn process of cadotril - Google Patents
Prepn process of cadotril Download PDFInfo
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- CN1931837A CN1931837A CN 200510029735 CN200510029735A CN1931837A CN 1931837 A CN1931837 A CN 1931837A CN 200510029735 CN200510029735 CN 200510029735 CN 200510029735 A CN200510029735 A CN 200510029735A CN 1931837 A CN1931837 A CN 1931837A
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- 238000000034 method Methods 0.000 title claims abstract description 18
- ODUOJXZPIYUATO-UHFFFAOYSA-N 2-[[2-[(acetylthio)methyl]-1-oxo-3-phenylpropyl]amino]acetic acid (phenylmethyl) ester Chemical compound C=1C=CC=CC=1COC(=O)CNC(=O)C(CSC(=O)C)CC1=CC=CC=C1 ODUOJXZPIYUATO-UHFFFAOYSA-N 0.000 title abstract description 14
- 229960002281 racecadotril Drugs 0.000 title abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 24
- RDUHFHDKXQBHMH-UHFFFAOYSA-N 2-benzyl-3-hydroxypropanoic acid Chemical compound OCC(C(O)=O)CC1=CC=CC=C1 RDUHFHDKXQBHMH-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000006467 substitution reaction Methods 0.000 claims abstract 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 13
- 239000003153 chemical reaction reagent Substances 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 9
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 8
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 239000012046 mixed solvent Substances 0.000 claims description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 4
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 235000015320 potassium carbonate Nutrition 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 3
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 3
- 150000004820 halides Chemical class 0.000 claims description 3
- 230000026045 iodination Effects 0.000 claims description 3
- 238000006192 iodination reaction Methods 0.000 claims description 3
- 239000002994 raw material Substances 0.000 claims description 3
- HFRXJVQOXRXOPP-UHFFFAOYSA-N thionyl bromide Chemical compound BrS(Br)=O HFRXJVQOXRXOPP-UHFFFAOYSA-N 0.000 claims description 3
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 2
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 238000005100 correlation spectroscopy Methods 0.000 claims description 2
- XKBGEWXEAPTVCK-UHFFFAOYSA-M methyltrioctylammonium chloride Chemical compound [Cl-].CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC XKBGEWXEAPTVCK-UHFFFAOYSA-M 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 2
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 2
- 235000007715 potassium iodide Nutrition 0.000 claims description 2
- 229960004839 potassium iodide Drugs 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 229950004288 tosilate Drugs 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- 229940059260 amidate Drugs 0.000 claims 4
- NPUKDXXFDDZOKR-LLVKDONJSA-N etomidate Chemical compound CCOC(=O)C1=CN=CN1[C@H](C)C1=CC=CC=C1 NPUKDXXFDDZOKR-LLVKDONJSA-N 0.000 claims 4
- 230000002140 halogenating effect Effects 0.000 claims 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims 3
- JXYACYYPACQCDM-UHFFFAOYSA-N Benzyl glycinate Chemical compound NCC(=O)OCC1=CC=CC=C1 JXYACYYPACQCDM-UHFFFAOYSA-N 0.000 claims 2
- OGFAWKRXZLGJSK-UHFFFAOYSA-N 1-(2,4-dihydroxyphenyl)-2-(4-nitrophenyl)ethanone Chemical compound OC1=CC(O)=CC=C1C(=O)CC1=CC=C([N+]([O-])=O)C=C1 OGFAWKRXZLGJSK-UHFFFAOYSA-N 0.000 claims 1
- MOMFXATYAINJML-UHFFFAOYSA-N 2-Acetylthiazole Chemical group CC(=O)C1=NC=CS1 MOMFXATYAINJML-UHFFFAOYSA-N 0.000 claims 1
- 241000196324 Embryophyta Species 0.000 claims 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims 1
- 239000000376 reactant Substances 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 235000009518 sodium iodide Nutrition 0.000 claims 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 10
- 230000026030 halogenation Effects 0.000 abstract description 6
- 238000005658 halogenation reaction Methods 0.000 abstract description 6
- 238000009776 industrial production Methods 0.000 abstract description 4
- 230000009435 amidation Effects 0.000 abstract description 3
- 238000007112 amidation reaction Methods 0.000 abstract description 3
- 239000000463 material Substances 0.000 abstract 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 239000012230 colorless oil Substances 0.000 description 6
- 230000006837 decompression Effects 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- -1 amino acid ester Chemical class 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000004809 thin layer chromatography Methods 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 238000010792 warming Methods 0.000 description 4
- SSQJZGZDIKJZSR-UHFFFAOYSA-N C(CC)(=O)Cl.ClCC1=CC=CC=C1 Chemical compound C(CC)(=O)Cl.ClCC1=CC=CC=C1 SSQJZGZDIKJZSR-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- DYUQAZSOFZSPHD-UHFFFAOYSA-N Phenylpropyl alcohol Natural products CCC(O)C1=CC=CC=C1 DYUQAZSOFZSPHD-UHFFFAOYSA-N 0.000 description 3
- 108700040249 racecadotril Proteins 0.000 description 3
- PLPVOVXBFICNLL-UHFFFAOYSA-N CCl.C1=CC=CC=C1.NCC(=O)O Chemical compound CCl.C1=CC=CC=C1.NCC(=O)O PLPVOVXBFICNLL-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 206010012735 Diarrhoea Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 238000006683 Mannich reaction Methods 0.000 description 1
- 238000006845 Michael addition reaction Methods 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- QQJYOLKVSSXIMT-UHFFFAOYSA-N S(C)(=O)(=O)OC.C1=CC=CC=C1.NCC(=O)O Chemical compound S(C)(=O)(=O)OC.C1=CC=CC=C1.NCC(=O)O QQJYOLKVSSXIMT-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 201000009840 acute diarrhea Diseases 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000012320 chlorinating reagent Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- SDJHDRMYZQFJJO-UHFFFAOYSA-N ethanethioic s-acid;potassium Chemical compound [K].CC(S)=O SDJHDRMYZQFJJO-UHFFFAOYSA-N 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 229940030980 inova Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 230000001360 synchronised effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention discloses preparation process of cadotril. The material 2-benzyl-3-hydroxypropionic acid is prepared into cadotril through halogenation, amidation and substitution. The process has cheap materials, less wastes, simple operation, less reaction steps and high yield, and is suitable for industrial production.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, be specifically related to the preparation method of medicine cadotril (acetorphan, 4).
Background technology
Cadotril (acetorphan, acetorphan, 4), chemistry N-(2-acetyl thiomethyl-1-oxo-3-phenyl propyl) glycine benzene methyl by name, develop by Bioprojet company, at first went on the market with trade(brand)name Tiorfan in 1993, in other market listing, be used for the treatment of adult's acute diarrhea subsequently in France.The listing of calendar year 2001 approval children's diarrhae indication.
The synthetic route of the cadotril of document US 5786494 reports obtains through alkylation, single hydrolysis, Mannich reaction, Michael addition from Benzyl Chloride:
Used toxic reagent formaldehyde in this route; Used condensation reagent DCC in addition, although can remove by product DCU with the way of column chromatography in the laboratory, DCU is difficult to remove in industrial production, thereby is impractical in industrial production.
Summary of the invention
In order to solve the problems referred to above that synthetic cadotril exists in the prior art, the present invention has been born.Technical problem to be solved by this invention is to disclose a kind of method for preparing cadotril, and this method is a raw material with 2-phenmethyl-3-hydroxy-propionic acid (5), through two halogenations, amidation, replacement, and synthetic cadotril.
Synthetic route is as follows:
According to the present invention, synthesize and form by following steps:
(a) 2-phenmethyl-3-hydroxy-propionic acid obtains the compound shown in the formula (1) through the activation of the synchronous functional group of halide reagent:
X=Cl, Br etc. in the formula
Chlorinating agent comprises sulfur oxychloride, oxalyl chloride, phosphorus pentachloride, phosphorus trichloride, phosphorus oxychloride etc.
Brominated reagent comprises thionyl bromide, phosphorus tribromide, boron tribromide etc.
Solvent comprises one or more mixtures among methylene dichloride, ethylene dichloride, toluene, acetone, DMF, the DMSO, or without solvent.
Temperature of reaction-20～120 ℃.
(b) compound shown in the formula (1) and amino acid ester or its salt (6) amidation, or react the compound shown in the formula of obtaining (2) in the lump with iodination reagent more with this understanding:
Formula (2) is raceme or individual isomer
X=Cl, Br, I etc. in the formula.
Be reflected in the solvent and carry out in the presence of alkali, used alkali comprises one or more in triethylamine, pyridine, salt of wormwood, yellow soda ash, saleratus, sodium bicarbonate, sodium hydroxide, the potassium hydroxide.
Solvent is a kind of or its mixed solvent in methylene dichloride, acetone, acetonitrile, DMF, DMSO and the water
Temperature of reaction-10～40 ℃
(c) (2) obtain target molecule with the reaction of displacer reagent shown in (3)
CH
3COSY (3)
Y＝H，K+，Na+
Solvent comprises acetone, acetonitrile, DMF, DMSO etc.
Catalyzer is Aliquat336, benzyltriethylammoinium chloride, CuCl, KI etc.
0～80 ℃ of temperature of reaction
This route is raw materials used and reagent is all inexpensive is easy to get, and the three wastes are less, and simple to operate, and reactions steps is few, and yield is higher, is applicable to industrial production.
Embodiment
The present invention is further elaborated below in conjunction with embodiment, but these embodiment do not constitute any restriction to the present invention.
Fusing point is measured with capillary tube technique, and thermometer is not proofreaied and correct; Varian Inova type nuclear magnetic resonance analyser (interior mark TMS, solvent C DCl
3); Finnign-MAT212 type mass spectrograph; Polarimeter341 type polarimeter.
Embodiment 1:
Preparation 2-chloromethylbenzene propionyl chloride
I halogenation sulfoxide halogenation
Add 1.4ml (19.2mmol) sulfur oxychloride and 3 DMF in three mouthfuls of reaction flasks of 25ml, stir after 5 minutes, the ice bath cooling, add 1.0g (5.6mmol) 2-phenmethyl-3-hydroxy-propionic acid, kept this thermotonus 30 minutes, and be warming up to 60 ℃ of reactions 1 hour, the thin-layer chromatography judgement reacts completely, the solution decompression evaporate to dryness gets colorless oil 1.0g.
II Phosphorates phosphorus Halides halogenation
Add 2.0g (11.2mmol) 2-phenmethyl-3-hydroxy-propionic acid in three mouthfuls of reaction flasks of the 50ml that drying tube is housed, add 20ml ethylene dichloride stirring and dissolving again, ice bath adds 3.5gPCl after being cooled to-10 ℃
5, kept this thermotonus 30 minutes, be warming up to 60 ℃ of reactions 20 minutes, the thin-layer chromatography judgement reacts completely, and the solution decompression evaporate to dryness gets colorless oil 2.0g.
III oxalyl chloride halogenation
Add 2.0g (11.2mmol) 2-phenmethyl-3-hydroxy-propionic acid in three mouthfuls of reaction flasks of 50ml, add 20ml methylene dichloride stirring and dissolving again, the ice bath cooling, in the time of 0 ℃, slowly drip the 2ml oxalyl chloride, keep this thermotonus after 20 minutes, dripped 3 pyridine back flow reaction 20 minutes, the thin-layer chromatography judgement reacts completely, the solution decompression evaporate to dryness gets colorless oil 2.2g.
Embodiment 2:
Preparation 2-brooethyl phenylpropyl alcohol acylbromide
Add 2.0g (11.2mmol) 2-phenmethyl-3-hydroxy-propionic acid in three mouthfuls of reaction flasks of I 25ml, add 10ml methylene dichloride and 1% pyridine, stirring and dissolving.Ice bath is cooled to-5 ℃, and Dropwise 5 .84g (28mmol) thionyl bromide was kept this thermotonus 50 minutes, and the solution decompression evaporate to dryness gets colorless oil 1.8g.MS(EI)：306(M
+)
Add 2.0g (4.5mmol) 2-phenmethyl-3-hydroxy-propionic acid in three mouthfuls of reaction flasks of II 25ml, add the 10ml ethylene dichloride, stirring and dissolving.Add the 4.5g boron tribromide after ice bath is cooled to-10 ℃, kept this thermotonus 30 minutes, be warming up to 60 ℃ of reactions 20 minutes, the thin-layer chromatography judgement reacts completely, and the solution decompression evaporate to dryness gets colorless oil 2.2g.
Add 2.0g (4.5mmol) 2-phenmethyl-3-hydroxy-propionic acid in three mouthfuls of reaction flasks of III 25ml, add 10ml toluene, ice bath is cooled to-5 ℃, drips 1.28ml (13.7mmol) PBr
3, kept this thermotonus 30 minutes, it is complete to be warming up to 120 ℃ of 2 hours afterreactions that reflux, the solution decompression evaporate to dryness, colorless oil 2.4g.
Embodiment 3:
Preparation N-(2-chloromethyl-1-oxo-3-hydrocinnamyl) glycine benzene methyl
Add 33.6g (166.8mmol) glycine benzene methyl hydrochloride and 15ml methylene dichloride in the 100ml there-necked flask, add the 40.0ml pyridine after ice bath is cooled to 0 ℃, stirred 10 minutes, drip 10ml and be dissolved with 22.8g (105.6mmol) 2-chloromethylbenzene propionyl chloride.It is complete to react 2 hours afterreactions, washes 2 times, and anhydrous sodium sulfate drying filters, be concentrated into dried, with the crystallization of 200ml petroleum ether and stirring, solid 33.2g (yield 92.3%).
Embodiment 4:
Preparation N-(2-brooethyl-1-oxo-3-hydrocinnamyl) glycine benzene methyl
Add 33.6g (166.8mmol) glycine benzene methyl hydrochloride and 165ml methylene dichloride in the 250ml there-necked flask, add 27.6g salt of wormwood, behind the stirring 10min, ice bath is cooled to 0 ℃ of dropping 10ml and is dissolved with 22.8g (105.6mmol) 2-brooethyl phenylpropyl alcohol acyl chlorides.It is complete to react 2 hours afterreactions, 200ml washing 2 times, anhydrous sodium sulfate drying filters, be concentrated into dried, with the mixed solvent crystallization of 200ml ethyl acetate and sherwood oil, solid 30.2g (yield 84%).
Embodiment 5:
Preparation N-(2-iodomethyl-1-oxo-3-hydrocinnamyl) glycine benzene methyl
Add 21.2g (105.8mmol) glycine benzene methyl mesylate and 165ml acetone in the 250ml there-necked flask, add 27.6g salt of wormwood and 33.2g potassiumiodide, stir after 10 minutes, ice bath is cooled to 0 ℃ of dropping 10ml and is dissolved with 22.8g (105.6mmol) 2-brooethyl phenylpropyl alcohol acyl chlorides.In 60 ℃ of reactions after 5 hours fully, 200ml10% sodium thiosulfate solution washing 2 times, anhydrous sodium sulfate drying filters, and is concentrated into driedly, use the 200ml alcohol crystal, gets solid 38.2g (yield 88.2%).
Embodiment 6:
Preparation N-(2-chloromethyl-1-oxo-3-hydrocinnamyl) glycine benzene methyl
Add 43.6g (129mmol) glycine benzene methyl tosilate and 300ml methylene dichloride in the 500ml there-necked flask, after being cooled to 0 ℃, ice bath adds the 24.8ml triethylamine, stirred 10 minutes, and dripped 10ml and be dissolved with 22.8g (105.6mmol) 2-chloromethylbenzene propionyl chloride.It is complete to react 2 hours afterreactions, washes 2 times, and anhydrous sodium sulfate drying filters, be concentrated into dried, with the crystallization of 200ml petroleum ether and stirring, solid 28.6g (yield 79.5%).
Embodiment 7:
Preparation N-(2-acetyl thiomethyl-1-oxo-3-hydrocinnamyl) glycine benzene methyl (car coat is many)
Add N-(2-chloromethyl-1-oxo-3-hydrocinnamyl) glycine benzene methyl 20.0g (58.0mmol) in the 50ml single port bottle, 180ml acetonitrile and 1wt%CuCl add 9.91g (87.0mmol) thioacetic acid potassium, room temperature reaction 10 hours again, the thin-layer chromatography judgement reacts completely, add the 200ml ethyl acetate in the reaction system, wash anhydrous sodium sulfate drying 3 times, filter, concentrate,, get white solid 19.3g (yield 86.3%) with the mixed solvent crystallization of 30ml ethyl acetate and sherwood oil.
More than show and described ultimate principle of the present invention and principal character and advantage of the present invention.The technician of the industry should understand; the present invention is not restricted to the described embodiments; that describes in the foregoing description and the specification sheets just illustrates principle of the present invention; the present invention also has various changes and modifications without departing from the spirit and scope of the present invention, and these changes and improvements all fall in the claimed scope of the invention.The claimed scope of the present invention is defined by appending claims and equivalent thereof.
Claims (12)
1. one kind prepares N-[2-acetyl thiomethyl-1-oxo-3-hydrocinnamyl] method of glycine benzene methyl, it is characterized in that this method comprises following steps:
A) two halogenating reactions: with 2-phenmethyl-3-hydroxy-propionic acid is raw material, with the halide reagent reaction, makes compound as the formula (1):
Wherein, X=Cl, Br;
B) amidate action: compound shown in the formula (1) and glycine benzyl ester or its reactant salt, or react the compound that makes as the formula (2) in the lump with iodination reagent more with this understanding:
Wherein, X=Cl, Br, I;
C) substitution reaction: the compound reaction shown in compound shown in the formula (2) and the formula (3) makes target compound:
CH
3COSY (3)
Y=H wherein, K
+, Na
+
The reaction formula of this reaction is as follows:
2. according to the process of claim 1 wherein that the described halide reagent of step a) comprises sulfur oxychloride, oxalyl chloride, phosphorus pentachloride, phosphorus trichloride, phosphorus oxychloride, thionyl bromide, phosphorus tribromide, phosphorus pentabromide.
3. according to the method for claim 2, the solvent of two halogenating reactions comprises that a kind of or youngster among methylene dichloride, ethylene dichloride, toluene, acetone, DMF, the DMSO plants mixture, perhaps without solvent.
4. according to the method for claim 2, the temperature of two halogenating reactions is-20～120 ℃.
5. according to the process of claim 1 wherein that the described glycine benzyl ester salt of step b) comprises hydrochloride, tosilate, mesylate and other pharmacy acceptable salts.
6. according to the process of claim 1 wherein that the described iodination reagent of step b) comprises potassiumiodide, sodium iodide.
7. according to the method for claim 5, amidate action carries out in the presence of alkali in solvent, and used alkali comprises one or more in triethylamine, pyridine, salt of wormwood, yellow soda ash, saleratus, sodium bicarbonate, sodium hydroxide, the potassium hydroxide.
8. according to the method for claim 5, the solvent of amidate action is a kind of or its mixed solvent in methylene dichloride, acetone, acetonitrile, DMF, DMSO and the water.
9. according to the method for claim 5, the temperature of amidate action-10～40 ℃.
10. according to the process of claim 1 wherein that the solvent of the described substitution reaction of step c) comprises a kind of or its mixed solvents such as acetone, acetonitrile, DMF, DMSO.
11. according to the method for claim 7, the catalyzer of substitution reaction is Aliquat336, benzyltriethylammoinium chloride, Tetrabutyl amonium bromide, CuCl, KI.
12. according to the method for claim 7,0～80 ℃ of the temperature of substitution reaction.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101768095A (en) * | 2008-12-26 | 2010-07-07 | 山东齐都药业有限公司 | Preparation method of racecadotril |
| CN102432870A (en) * | 2011-08-31 | 2012-05-02 | 东北石油大学 | Synthesis method of dendritic complex main antioxidant |
| CN107129450A (en) * | 2017-06-05 | 2017-09-05 | 山东裕欣药业有限公司 | A kind of racecadotril crystalline compounds and preparation method thereof |
| CN110272363A (en) * | 2019-06-11 | 2019-09-24 | 扬子江药业集团江苏海慈生物药业有限公司 | A kind of synthetic method of racecadotril |
-
2005
- 2005-09-16 CN CNB2005100297358A patent/CN100537531C/en active Active
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101768095A (en) * | 2008-12-26 | 2010-07-07 | 山东齐都药业有限公司 | Preparation method of racecadotril |
| CN102432870A (en) * | 2011-08-31 | 2012-05-02 | 东北石油大学 | Synthesis method of dendritic complex main antioxidant |
| CN102432870B (en) * | 2011-08-31 | 2013-12-11 | 东北石油大学 | Synthesis method of dendritic complex main antioxidant |
| CN107129450A (en) * | 2017-06-05 | 2017-09-05 | 山东裕欣药业有限公司 | A kind of racecadotril crystalline compounds and preparation method thereof |
| CN107129450B (en) * | 2017-06-05 | 2019-05-03 | 山东裕欣药业有限公司 | A kind of racecadotril crystalline compounds and preparation method thereof |
| CN110272363A (en) * | 2019-06-11 | 2019-09-24 | 扬子江药业集团江苏海慈生物药业有限公司 | A kind of synthetic method of racecadotril |
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