CN101538222B - Preparation method for N-(2-phenyl)ethyl-2-[(2,2-dimethoxyethyl)amino]acetamide halate - Google Patents
Preparation method for N-(2-phenyl)ethyl-2-[(2,2-dimethoxyethyl)amino]acetamide halate Download PDFInfo
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- CN101538222B CN101538222B CN 200810034808 CN200810034808A CN101538222B CN 101538222 B CN101538222 B CN 101538222B CN 200810034808 CN200810034808 CN 200810034808 CN 200810034808 A CN200810034808 A CN 200810034808A CN 101538222 B CN101538222 B CN 101538222B
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- ethyl
- phenyl
- acetamide
- dme
- aminoacetaldehyde
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- KOMKLFDEPKFXBU-UHFFFAOYSA-N COC(CNCC(NCCc1ccccc1)=O)OC Chemical compound COC(CNCC(NCCc1ccccc1)=O)OC KOMKLFDEPKFXBU-UHFFFAOYSA-N 0.000 description 1
- LNWWGHNQLOXRTF-UHFFFAOYSA-N O=C(CCl)NCCc1ccccc1 Chemical compound O=C(CCl)NCCc1ccccc1 LNWWGHNQLOXRTF-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses a preparation method for N-(2-phenyl)ethyl-2-[(2,2-dimethoxyethyl)amino]acetamide halite, which comprises the following steps: mixing N-(2-phenyl)ethyl-2-chloracetamide and aminoacetaldehyde dimethyl acetal, and in the presence of alkali and a phase transfer catalyst, reacting the mixture in an organic solvent and a water system; and separating an organic layer after finishing the reaction, boiling off a menstruum, and introducing dried chlorine hydride or hydrogen bromide gas after the obtained concentrate is dissolved by a solvent to salify. The method has the following advantages of simple operation, mild reaction conditions, low consumption of raw material, namely the aminoacetaldehyde dimethyl acetal, and higher yield (the yield can be up to 72 percent); and the product is non-hygroscopic after being placed in air for a long time, has good stability, can greatly reduce the production cost and is easy to realize the industrialization.
Description
Technical field
The present invention relates to chemical field, relate in particular to the pharmaceutical chemistry field, more specifically, the present invention provides a kind of N-(2-phenyl) ethyl-2-[(2, the 2-dimethoxy ethyl) amino] preparation method of acetamide halate.
Background technology
PRAZIQUANTEL BP 98 is the broad-spectrum anti-parasite medicine.Its anthelmintic spectrum is very wide, and is all very effective to 5 kinds of main schistosomicide of human body (Man, Egypt, Japan, river bank is public and ask and insert schistosomicide) disease.In addition, it also has killing action to lung fluke, clonorchis sinensis, Echinococcus hydatid cyst, cysticercus, Meng Shi pleroceroid, fasciloopsis, tapeworm etc.Its effect characteristics are that curative effect is high, dosage is little, short treating period, metabolism is fast, toxicity is little and convenient oral.The appearance of PRAZIQUANTEL BP 98 is an important breakthrough on the parasitosis chemotherapy, and it has become the choice drug of the multiple parasitosis of treatment now.
N-(2-phenyl) ethyl-2-[(2, the 2-dimethoxy ethyl) amino] acetamide hydrochloride is the important intermediate of preparation PRAZIQUANTEL BP 98.To synthesizing of its; The general method that adopts does in the prior art; The aminoacetaldehyde of N-(2-phenyl) ethyl-2-chlor(o)acetamide and 2.2 times of molar weights is contracted dme earlier reflux in toluene 2 hours, filter back evaporate to dryness toluene, residue is logical exsiccant hydrogen chloride gas salify and getting in methylene dichloride again.The contract consumption of dme of this method yield lower (67%), raw material ammonia ethylhexanal is big, and production cost is high, and the unstable products that obtains, very easily suction.
Summary of the invention
The method that the purpose of this invention is to provide preparation N-(2-phenyl) ethyl-2-[(2, the 2-dimethoxy ethyl) amino] acetamide halate of a kind of high yield, low cost and constant product quality.
Synthetic route provided by the invention is:
In this reaction, the raw material ammonia ethylhexanal contracts between dme and N-(2-phenyl) ethyl-2-chlor(o)acetamide mainly with bimolecular nucleophilic substitution mechanism (S
N2) react, concrete reaction mechanism is following:
Should react; There is not negatively charged ion to occur in speed of response control stage (formation transition state); Therefore reaction is prone in non-protonic solvent (like toluene, methylene dichloride, chloroform, acetone, DMSO 99.8MIN. (DMSO), N, dinethylformamide (DMF), hexamethylphosphoramide (HMPA) etc.), carry out.Protic solvent (like water, alcohol, formic acid etc.) is prone to and the raw material ammonia ethylhexanal amino (NH in the dme that contracts
2) mutually combine through hydrogen bond, produce solvation effect, reduced-NH
2Nucleophilie nucleus ability, reduced the S between itself and N-(2-phenyl) ethyl-2-chlor(o)acetamide
N2 speed of response; And aprotic solvent right-NH
2Therefore the solvent free effect can make-NH
2Be in free state, help the carrying out of nucleophilic reaction.
In reaction, also generate the hydrogenchloride of a part, the general employing increases 2-2.2 doubly with the contract consumption of dme of aminoacetaldehyde in the prior art, makes it participate in S as nucleophilic reagent
NIn the time of 2 reactions, served as again and attached the hydrogenchloride of sour agent, promoted that balance moves right, improved reaction yield to generate in the absorption reaction.Dme causes production cost high but the very high aminoacetaldehyde of mass consumption industry price contracts, and the product salify that makes the by this method moisture absorption very easily, and stability is very poor.
In preparation method of the present invention, adopt alkali to substitute the aminoacetaldehyde dme that contracts and come the hydrogenchloride that generates in the absorption reaction, make the contract consumption of dme of aminoacetaldehyde descend greatly, be merely 0.45 times of prior art consumption, make production cost greatly descend.
Because most of alkali solubleness in reaction solvent is less, the speed that the hydrogenchloride that generates in the reaction is adsorbed is slow, and molecular balance moves slowly, and finally causes reaction process slow.For this reason; In technology of the present invention, adopted the phase-transfer catalysis method, changed alkali over to reaction solvent effectively, thereby increased the speed that the concentration of alkali has accelerated to adsorb hydrogenchloride in the reaction solvent with phase-transfer catalyst; Improve speed of reaction, made the reaction times shorten to about 10 hours.This phase-transfer catalyst can comprise: quaternary ammonium salt, a kind of in the for example following material or appoint multiple: palmityl trimethyl ammonium chloride, cetyl trimethylammonium bromide, tetrabutylammonium chloride, Tetrabutyl amonium bromide, tetramethyl ammonium chloride, 4 bromide etc.; Polyethylene glycols, for example, a kind of in the following material or appoint multiple: PEG 400, Polyethylene Glycol-600, polyoxyethylene glycol 800, cetomacrogol 1000 etc.
Preferably, according to the method for the invention, can in the presence of alkali, react; Alkali can adsorb to fall the hydrogenchloride that produces in the reaction; Promote molecular balance to move right, improved reaction conversion ratio, the existence of alkali simultaneously greatly reduces the contract consumption of dme of raw material ammonia ethylhexanal.Particularly, said alkali can comprise, organic bases, a kind of in the for example following material or appoint multiple: triethylamine, N, accelerine, N, N-Diethyl Aniline, pyridine etc.; Inorganic base, a kind of in the for example following material or appoint multiple: sodium hydroxide, Pottasium Hydroxide, salt of wormwood, yellow soda ash, saleratus, sodium hydrogencarbonate etc.
Generally speaking; Above-mentioned being reflected in the organic solvent carried out; This organic solvent is the product of dissolving raw material and generation preferably generally, and it comprises, a kind of in the for example following material or appoint multiple: methylene dichloride, chloroform, toluene, MIBK, ether, hexanaphthene, THF, ethylene dichloride, tetracol phenixin, sherwood oil, normal hexane, N; Dinethylformamide, DMAC N,N, acetone, DMSO 99.8MIN., dioxane etc.
Preparation in accordance with the present invention can reduce the raw material ammonia ethylhexanal dme consumption that contracts, and can use aminoacetaldehyde about N-(2-phenyl) ethyl-2-chlor(o)acetamide and the 1 times of molar weight dme that contracts to react more completely usually.For example, in actual fabrication process, preferred feed ratio can be; The contract feed ratio of dme of N-(2-phenyl) ethyl-2-chlor(o)acetamide and aminoacetaldehyde is 1: 0.8～1.2 (in the present invention; If no special instructions, all ratios that relate to all refer to mol ratio, rather than weight ratio).Preferred temperature of reaction is 0～100 ℃.
Particularly, preparation method provided by the invention may further comprise the steps:
N-(2-phenyl) ethyl-2-chlor(o)acetamide and the aminoacetaldehyde dme (for example 1 times of molar weight) that contracts is mixed, in the presence of alkali and phase-transfer catalyst, in the system of organic solvent and water, react.Said alkali and phase-transfer catalyst, and organic solvent, temperature of reaction etc. can be with reference to content mentioned above.Tell organic layer after reaction finishes, boil off solvent, the gained enriched material feeds exsiccant hydrogenchloride or bromize hydrogen gas salify after with dissolution with solvents.
The invention has the advantages that the method that is provided is simple to operate, reaction conditions is gentle; The raw material ammonia ethylhexanal dme consumption that contracts is little, and yield higher (being up to 72%), product place for a long time that air is also nonhygroscopic, good stability; Production cost can decline to a great extent, and is easy to realize industriallization.
Embodiment
Further specify the present invention through embodiment below, but these embodiment do not constitute any restriction to the present invention.
Embodiment one:
Aminoacetaldehyde is contracted after dme 21 gram, yellow soda ash 16 grams, tetrabutylammonium chloride 2.76 grams, 100 milliliters of MIBKs and 100 ml waters mix, be heated to 90 ℃, drip the mixed solution of N-(2-phenyl) ethyl-2-chloracetyl amido 39.6 grams and 50 milliliters of MIBKs; Drip off in 90 ℃ of insulations 8 hours, be as cold as room temperature, branch vibration layer; Organic layer with washing once; The evaporate to dryness MIBK gets yellow oil, after 100 milliliters of methylene dichloride dissolvings, feeds the exsiccant hydrogen chloride gas to pH=1～2 at 0-5 ℃; Filter; Filter cake is washed after drying with a small amount of freezing methylene dichloride, gets white solid 41.2 grams (HPLC content is greater than 98%), yield: 68.3%.
Embodiment two:
Aminoacetaldehyde is contracted after dme 10.5 gram, yellow soda ash 8.0 grams, tetrabutylammonium chloride 1.38 grams, 50 milliliters of MIBKs and 50 ml waters mix, be cooled to 0 ℃, drip the mixed solution of N-(2-phenyl) ethyl-2-chlor(o)acetamide 19.8 grams and 30 milliliters of MIBKs; Drip off in 0 ℃ of insulation 2 hours, be raised to stirred overnight at room temperature then, branch vibration layer; Organic layer with washing once; The evaporate to dryness MIBK gets yellow oil, after 50 milliliters of methylene dichloride dissolvings, feeds the exsiccant hydrogen chloride gas to pH=1-2 at 0-5 ℃; Filter; Filter cake is washed after drying with a small amount of freezing methylene dichloride, gets white solid 20.8 grams (HPLC content is greater than 98%), yield: 69.0%.
Embodiment three:
Aminoacetaldehyde is contracted after dme 10.5 gram, sodium hydroxide 6.0 grams, palmityl trimethyl ammonium chloride 1.6 grams, 50 milliliters of methylene dichloride and 50 ml waters mix, and room temperature drips the mixed solution of N-(2-phenyl) ethyl-2-chlor(o)acetamide 19.8 grams and 30 milliliters of methylene dichloride, drips off stirred overnight; Branch vibration layer; Organic layer with washing once, concentrate part methylene chloride after, feed the exsiccant hydrogen chloride gas to pH=1-2 at 0-5 ℃; Filter; Filter cake is washed after drying with a small amount of freezing methylene dichloride, gets white solid 19.1 grams (HPLC content is greater than 98%), yield: 63.4%.
Embodiment four:
Aminoacetaldehyde is contracted after dme 12.6 gram, Pottasium Hydroxide 8.4 grams, Polyethylene Glycol-600 1.0 grams, 50 milliliters of methylene dichloride and 50 ml waters mix, and room temperature drips the mixed solution of N-(2-phenyl) ethyl-2-chlor(o)acetamide 19.8 grams and 30 milliliters of methylene dichloride, drips off and is warmed up to 40 ℃; Be incubated 10 hours, branch vibration layer, organic layer are with washing once; After concentrating part methylene chloride; Feed the exsiccant hydrogen chloride gas to pH=1-2 at 0-5 ℃, filter, filter cake is washed after drying with a small amount of freezing methylene dichloride; Get white solid 19.8 grams (HPLC content is greater than 98%), yield: 65.7%.
Embodiment five:
Aminoacetaldehyde is contracted after dme 10.5 gram, sodium hydrogencarbonate 12.6 grams, tetramethyl ammonium chloride 0.55 gram, 50 milliliters of toluene and 50 ml waters mix, be heated to 60 ℃, drip the mixed solution of N-(2-phenyl) ethyl-2-chlor(o)acetamide 19.8 grams and 30 milliliters of toluene; Drip off in 60-80 ℃ of insulation 10 hours, be as cold as room temperature, branch vibration layer; Organic layer is with washing once, and evaporate to dryness toluene gets yellow oil, after 50 milliliters of methylene dichloride dissolvings; Feed the exsiccant hydrogen chloride gas to Ph=1-2 at 0-5 ℃, filter, filter cake is washed after drying with a small amount of freezing methylene dichloride; Get white solid 21.7 grams (HPLC content is greater than 98%), yield: 72%.
Embodiment six:
Aminoacetaldehyde is contracted after dme 10.5 gram, sodium hydrogencarbonate 12.6 grams, 4 bromide 0.77 gram, 50 milliliters of toluene and 50 ml waters mix, be heated to 60 ℃, drip the mixed solution of N-(2-phenyl) ethyl-2-chlor(o)acetamide 19.8 grams and 30 milliliters of toluene; Drip off in 60-80 ℃ of insulation 10 hours, be as cold as room temperature, branch vibration layer; Organic layer is with washing once, and evaporate to dryness toluene gets yellow oil, after 50 milliliters of methylene dichloride dissolvings; Feed the exsiccant hydrogen chloride gas to pH=1-2 at 0-5 ℃, filter, filter cake is washed after drying with a small amount of freezing methylene dichloride; Get white solid 21.5 grams (HPLC content is greater than 98%), yield: 71.3%.
Embodiment seven:
Aminoacetaldehyde is contracted after dme 8.4 gram, saleratus 15 grams, tetramethyl ammonium chloride 0.55 gram, 50 milliliters of toluene and 50 ml waters mix, be heated to 60 ℃, drip the mixed solution of N-(2-phenyl) ethyl-2-chlor(o)acetamide 19.8 grams and 30 milliliters of toluene; Drip off in 60-80 ℃ of insulation 10 hours, be as cold as room temperature, branch vibration layer; Organic layer is with washing once, and evaporate to dryness toluene gets yellow oil, after 50 milliliters of methylene dichloride dissolvings; Feed the exsiccant hydrogen chloride gas to pH=1-2 at 0-5 ℃, filter, filter cake is washed after drying with a small amount of freezing methylene dichloride; Get white solid 19.6 grams (HPLC content is greater than 98%), yield: 65%.
Embodiment eight:
Aminoacetaldehyde is contracted after dme 12.6 gram, salt of wormwood 10.3 grams, 4 bromide 0.77 gram, 50 milliliters of toluene and 50 ml waters mix, be heated to 60 ℃, drip the mixed solution of N-(2-phenyl) ethyl-2-chlor(o)acetamide 19.8 grams and 30 milliliters of toluene; Drip off in 60-80 ℃ of insulation 10 hours, be as cold as room temperature, branch vibration layer; Organic layer is with washing once, and evaporate to dryness toluene gets yellow oil, after 50 milliliters of methylene dichloride dissolvings; Feed the exsiccant hydrogen chloride gas to pH=1-2 at 0-5 ℃, filter, filter cake is washed after drying with a small amount of freezing methylene dichloride; Get white solid 21.7 grams (HPLC content is greater than 98%), yield: 72.0%.
Embodiment nine:
Aminoacetaldehyde is contracted after dme 12.6 gram, salt of wormwood 10.3 grams, 4 bromide 0.77 gram, 50 milliliters of toluene and 50 ml waters mix, be heated to 60 ℃, drip the mixed solution of N-(2-phenyl) ethyl-2-chlor(o)acetamide 19.8 grams and 30 milliliters of toluene; Drip off in 60-80 ℃ of insulation 10 hours, be as cold as room temperature, branch vibration layer; Organic layer is with washing once, and evaporate to dryness toluene gets yellow oil, after 50 milliliters of methylene dichloride dissolvings; Feed the exsiccant bromize hydrogen gas to pH=1-2 at 0-5 ℃, filter, filter cake is washed after drying with a small amount of freezing methylene dichloride; Get white solid 24.7 grams (HPLC content is greater than 98%), yield: 71.2%.
Embodiment ten:
Aminoacetaldehyde is contracted after dme 12.6 gram, salt of wormwood 10.3 grams, 4 bromide 0.77 gram, 50 milliliters of toluene and 50 ml waters mix, be heated to 60 ℃, drip the mixed solution of N-(2-phenyl) ethyl-2-chlor(o)acetamide 19.8 grams and 30 milliliters of toluene; Drip off in 60-80 ℃ of insulation 10 hours, be as cold as room temperature, branch vibration layer; Organic layer is with washing once, and evaporate to dryness toluene gets yellow oil, behind 20 milliliters of anhydrous alcohol solutions; Feed the exsiccant bromize hydrogen gas to pH=1-2 at 0-5 ℃, filter, filter cake is washed after drying with a small amount of freezing absolute ethyl alcohol; Get white solid 23.8 grams (HPLC content is greater than 98%), yield: 68.6%.
Claims (6)
1. the preparation method of N-shown in the formula (I) (2-phenyl) ethyl-2-[(2, the 2-dimethoxy ethyl) amino] ethanamide halogen acid salt,
It is characterized in that this method comprises: make aminoacetaldehyde shown in N-shown in the formula (II) (2-phenyl) ethyl-2-chlor(o)acetamide and the formula (III) contract dme in the presence of the alkali organic solvent with in react,
Use phase-transfer catalyst when reacting; This phase-transfer catalyst is one or more following materials: palmityl trimethyl ammonium chloride, cetyl trimethylammonium bromide, tetrabutylammonium chloride, Tetrabutyl amonium bromide, tetramethyl ammonium chloride, 4 bromide; PEG 400; Polyethylene Glycol-600, polyoxyethylene glycol 800, cetomacrogol 1000;
Said alkali is one or more following materials: triethylamine, N, accelerine, N, N-Diethyl Aniline, pyridine, sodium hydroxide, Pottasium Hydroxide, salt of wormwood, yellow soda ash, saleratus, sodium hydrogencarbonate;
Said organic solvent is one or more following materials: methylene dichloride, chloroform, toluene, MIBK, ethylene dichloride, tetracol phenixin;
Reaction product is with the HX salify, and wherein X is Cl or Br, obtains N-(2-phenyl) ethyl-2-[(2, the 2-dimethoxy ethyl) amino] ethanamide halogen acid salt.
2. preparation method according to claim 1 is characterized in that, the contract feed ratio of dme of said N-(2-phenyl) ethyl-2-chlor(o)acetamide and aminoacetaldehyde is 1: 0.8～1.2.
3. preparation method according to claim 1 and 2 is characterized in that, the contract temperature of reaction of dme of said N-(2-phenyl) ethyl-2-chlor(o)acetamide and aminoacetaldehyde is 0～100 ℃.
4. preparation method according to claim 1 and 2 is characterized in that, comprises the following steps:
A mixes N-(2-phenyl) ethyl-2-chlor(o)acetamide and the aminoacetaldehyde dme that contracts;
B adds alkali and phase-transfer catalyst, make said N-(2-phenyl) ethyl-2-chlor(o)acetamide and aminoacetaldehyde contract dme organic solvent and system in react;
C reaction is told organic layer after finishing, and boils off solvent, and the gained enriched material feeds exsiccant hydrogenchloride or bromize hydrogen gas salify after with dissolution with solvents.
5. preparation method according to claim 4 is characterized in that, among the said step a, the contract feed ratio of dme of N-(2-phenyl) ethyl-2-chlor(o)acetamide and aminoacetaldehyde is 1: 0.8～1.2.
6. preparation method according to claim 5 is characterized in that, the temperature of reaction among the said step b is 0～100 ℃.
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| CN 200810034808 CN101538222B (en) | 2008-03-18 | 2008-03-18 | Preparation method for N-(2-phenyl)ethyl-2-[(2,2-dimethoxyethyl)amino]acetamide halate |
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| CN 200810034808 CN101538222B (en) | 2008-03-18 | 2008-03-18 | Preparation method for N-(2-phenyl)ethyl-2-[(2,2-dimethoxyethyl)amino]acetamide halate |
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| CN101538222B true CN101538222B (en) | 2012-12-26 |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5196583A (en) * | 1989-12-04 | 1993-03-23 | Nippon Paint Co., Ltd. | Propargyl amino compounds |
| CN1683346A (en) * | 2005-03-01 | 2005-10-19 | 江苏工业学院 | Praziquantel synthetic process |
| CN101037394A (en) * | 2006-03-16 | 2007-09-19 | 上海佰伦精细化工有限公司 | Preparation method of alkoxy benzamides |
| WO2007119463A1 (en) * | 2006-03-15 | 2007-10-25 | Mitsubishi Tanabe Pharma Corporation | 2-(cyclic amino)-pyrimidone derivatives as tpk1 inhibitors |
-
2008
- 2008-03-18 CN CN 200810034808 patent/CN101538222B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5196583A (en) * | 1989-12-04 | 1993-03-23 | Nippon Paint Co., Ltd. | Propargyl amino compounds |
| CN1683346A (en) * | 2005-03-01 | 2005-10-19 | 江苏工业学院 | Praziquantel synthetic process |
| WO2007119463A1 (en) * | 2006-03-15 | 2007-10-25 | Mitsubishi Tanabe Pharma Corporation | 2-(cyclic amino)-pyrimidone derivatives as tpk1 inhibitors |
| CN101037394A (en) * | 2006-03-16 | 2007-09-19 | 上海佰伦精细化工有限公司 | Preparation method of alkoxy benzamides |
Non-Patent Citations (1)
| Title |
|---|
| Joong Hyup Kim et al.Formation of Pyrazinoisoquinoline Ring System by the Tandem Amidoalkylation and N-Acyliminium Ion Cyclization: An Efficient Synthesis of Praziquantel.《Tetrahedron》.1998,第54卷7395-7400. * |
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