CN1125032C - Preparation of monohydrate of N,N-dimethyl-1-[1-(4-chlorophenyl) cyclobutyl]-3-methyl butylamine hydrochloride - Google Patents
Preparation of monohydrate of N,N-dimethyl-1-[1-(4-chlorophenyl) cyclobutyl]-3-methyl butylamine hydrochloride Download PDFInfo
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- CN1125032C CN1125032C CN 00112867 CN00112867A CN1125032C CN 1125032 C CN1125032 C CN 1125032C CN 00112867 CN00112867 CN 00112867 CN 00112867 A CN00112867 A CN 00112867A CN 1125032 C CN1125032 C CN 1125032C
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Abstract
The present invention relates to a preparation process of N, N-dimethyl-1-[1-(4-chlorophenyl) cyclobutyl]-3-methyl butylamine hydrochloride monohydrate, which is characterized in that N, N-dimethyl-1-[1-(4-chlorophenyl) cyclobutyl]-3-methyl butylamine formate is put into water solution containing chlorine ions to prepare the N, N-dimethyl-1-[1-(4-chlorophenyl) cyclobutyl]-3-methyl butylamine hydrochloride monohydrate.
Description
That the present invention relates to is N, N-dimethyl-1-[1-(4-chloro-phenyl-) cyclobutyl]-preparation method of 3-3-methyl butylamine hydrochloride monohydrate.
About related N in No. 2098602 English Patents, N-dimethyl-1-[1-(4-chloro-phenyl-) cyclobutyl]-the 3-3-methyl butylamine hydrochloride, have now found that it is a kind of medicinal compound that in as many medical fields such as treatment of obesity, diabetic obesity, reduction lipid level, uric acid reducing level, treatment disordered brain function, treatment Parkinson's diseases, all has therepic use.Because the water absorbability that this hydrochloride self is had has been brought tangible disadvantageous effect to its use in pharmacy procedure.For this reason, a kind of this N that is used to prepare has been described in the CN86108547A Chinese patent prospectus, N-dimethyl-1-[1-(4-chloro-phenyl-) cyclobutyl]-method of 3-3-methyl butylamine hydrochloride monohydrate (hereinafter to be referred as " monohydrate "), hydrochloride with this easy moisture absorption is a raw material, it is contacted with comprising water or aqueous medium, become non-hygroscopic monohydrate product through hydration.Put down in writing according to the document, this hydrochloride compound as its raw material use, the method that is still according to No. 2098602 british patent specification prepares, that is: to the direct precursor compound N of this hydrochloride, N-dimethyl-1-[1-(4-chloro-phenyl-) cyclobutyl]-3-methylbutylamine formate through comprising alkalization, extraction, dehydration, distillation, dissolve salify, some steps such as concentrated, crystallization, diafiltration, drying are prepared from, and then are changed into the monohydrate of this hydrochloride by its described hydration process.This N from its alleged british patent specification, N-dimethyl-1-[1-(4-chloro-phenyl-) cyclobutyl]-3-methylbutylamine formate begins, to finally preparing required monohydrate product, this process obviously is too tediously long complications, is unsafty from economic angle at least.
Given this, the purpose of this invention is to provide a kind of N, N-dimethyl-1-[1-(4-chloro-phenyl-) cyclobutyl]-the more simple and direct preparation method of 3-3-methyl butylamine hydrochloride monohydrate.
The N that the present invention is alleged, N-dimethyl-1-[1-(4-chloro-phenyl-) cyclobutyl]-preparation method of 3-3-methyl butylamine hydrochloride monohydrate, be will be as the precursor compound N of above-mentioned hydrochloride, [3-methylbutylamine formate places the aqueous solution that contains chlorion directly to make through the single step reaction process to N-dimethyl-1-[1-(4-chloro-phenyl-) cyclobutyl.
The said aqueous solution that contains chlorion can be the aqueous solution of various water miscible alkali metal chlorides or alkaline earth metal chloride in the inventive method.Method is to use at least a saturated aqueous solution in common basic metal such as sodium-chlor, Repone K, calcium chloride, magnesium chloride or bariumchloride or the alkaline-earth metal preferably.Adopt the mode of the water miscible basic metal of this kind or the alkaline earth metal chloride aqueous solution to handle N, N-dimethyl-1-[1-(4-chloro-phenyl-) cyclobutyl]-during 3-methylbutylamine formate, be after making this formate in the aqueous solution, pass through a step salt-salt replacement(metathesis)reaction, can directly transform and obtain above-mentioned monohydrate product.
Except that the aqueous solution of water miscible alkali metal chloride of above-mentioned employing or alkaline earth metal chloride, the said aqueous solution that contains chlorion can also or contain aqueous solution of hydrochloric acid for hydrochloric acid in the inventive method.Wherein saidly contain the dilute aqueous solution that aqueous solution of hydrochloric acid can be a hydrochloric acid, also can be the mixing solutions of hydrochloric acid and water-miscible organic solvent, the mixing solutions of the water-miscible organic solvent that example hydrochloric acid and ethyl acetate, ethanol, acetone, tetrahydrofuran (THF), methyl acetate etc. are commonly used.Adopt this kind mode to handle N, N-dimethyl-1-[1-(4-chloro-phenyl-) cyclobutyl]-3-methylbutylamine formate, be to make this formate in the aqueous solution, go on foot salt-sour replacement(metathesis)reaction by one, equally also can directly transform and obtain above-mentioned monohydrate product.
Except that the above-mentioned said aqueous solution that contains chlorion, there is no too much requirement or restriction for the condition of other reaction or processing.
Be understood that thus, the inventive method is passed through N, N-dimethyl-1-[1-(4-chloro-phenyl-) cyclobutyl]-3-methylbutylamine formate compounds handles with the aqueous solution that contains chlorion, through simple salt of a step-salt displacement or salt-sour replacement process, can directly obtain above-mentioned monohydrate product, and it is such to need not above-mentioned for another example document, make this formate precursor compound earlier through alkalization, extraction, dehydration, distillation, the dissolving salify, concentrate, crystallization, diafiltration, after hydrochloride is made in many operating process such as drying, be converted into this monohydrate through hydro-combination process again, operation sequence and technological process are significantly shortened, simplify, also saved raw material greatly.Through actual detected, has equal quality with the inventive method this monohydrate for preparing and the monohydrate for preparing by above-mentioned literature method.
That below introduce is the embodiment that is described in further detail as to foregoing of the present invention.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following example.Employed raw material is by people such as James E.Jeffery and prepares in " J.Chem.Soc.Perkin Trans.1; 1996 " method described in (p2583-9) in each example: with 1-(4-chloro-phenyl-)-cyclobutyl formonitrile HCN 35 grams behind grignard reaction, reduction amination and the three-step reaction that methylates, obtain being the N that is difficult to form crystalline oily compound form, N-dimethyl-1-[1-(4-chloro-phenyl-) cyclobutyl]-3-methylbutylamine formate.
Embodiment 1
After above-mentioned raw materials is dissolved in 50 milliliters of ethyl acetate, filtering, adding excessive saturated aqueous sodium chloride in 0 ℃-10 ℃ stirs, to separating out crystallization, 60 ℃ of freeze-day with constant temperature are filtered and the washing crystallization in cooling, obtain required N, N-dimethyl-1-[1-(4-chloro-phenyl-) cyclobutyl]-3-3-methyl butylamine hydrochloride monohydrate product 34 grams.Fusing point is 192 ℃-195 ℃.
Embodiment 2
After above-mentioned raw materials was dissolved in 50 milliliters of ethyl acetate, filtering added excessive Repone K saturated aqueous solution jolting under room temperature, and to separating out crystallization, also washing crystallization is filtered in cooling, and 60 ℃ of freeze-day with constant temperature obtain above-mentioned monohydrate product 26 grams.191 ℃-195 ℃ of fusing points.
Embodiment 3
After above-mentioned raw materials was dissolved in 50 milliliters of ethyl acetate, filtering added excessive ammonium chloride saturated aqueous solutions in 40 ℃-45 ℃ and stirs, and to separating out crystallization, also washing crystallization is filtered in cooling, and 60 ℃ of freeze-day with constant temperature obtain above-mentioned monohydrate product 26 grams.189 ℃-193 ℃ of fusing points.
Embodiment 4
After above-mentioned raw materials was dissolved in 50 milliliters of ethyl acetate, filtering added excessive calcium chloride saturated aqueous solutions in 50 ℃-60 ℃ and stirs, and to separating out crystallization, also washing crystallization is filtered in cooling, and 60 ℃ of freeze-day with constant temperature obtain above-mentioned monohydrate product 25 grams.191 ℃-195 ℃ of fusing points.
Embodiment 5
After above-mentioned raw materials was dissolved in 50 milliliters of ethyl acetate, filtering adds the magnesium chloride saturated aqueous solutions in 60 ℃-70 ℃ and stirs, and was cold slightly, put in the separating funnel, tell organic layer and leave standstill, separate out crystallization, cooling, filter and the washing crystallization, 60 ℃ of freeze-day with constant temperature obtain above-mentioned monohydrate product 28 grams.190 ℃-193 ℃ of fusing points.
Embodiment 6-10
Above-mentioned raw materials is dissolved in respectively in the following solvent.Filtering slowly drips concentrated hydrochloric acid or dilute hydrochloric acid to pH value of solution 3-4 under the stirring at normal temperature, crystallization is separated out in cooling, water diafiltration crystallization, and 60 ℃ of freeze-day with constant temperature obtain above-mentioned monohydrate product, and survey fusing point.
The fusing point of embodiment solvent monohydrate product (℃)
Embodiment 6 ethyl acetate 192-195.5
Embodiment 7 ethanol 194-195.5
Embodiment 8 acetone 192-195
Embodiment 9 tetrahydrofuran (THF) 193.5-196
Embodiment 10 methyl acetate 191-194
Above-mentioned each routine resulting N, N-dimethyl-1-[1-(4-chloro-phenyl-) cyclobutyl]-3-3-methyl butylamine hydrochloride monohydrate product all can be by the satisfied infrared spectra discriminating and the Analysis and Identification of water content.
Claims (5)
1.N, N-dimethyl-1-[1-(4-chloro-phenyl-) cyclobutyl]-preparation method of 3-3-methyl butylamine hydrochloride monohydrate, it is characterized in that with N N-dimethyl-1-[1-(4-chloro-phenyl-) cyclobutyl]-3-methylbutylamine formate places the aqueous solution that contains chlorion to make.
2. preparation method as claimed in claim 1 is characterized in that the said aqueous solution that contains chlorion is the aqueous solution of water miscible alkali metal chloride or alkaline earth metal chloride.
3. preparation method as claimed in claim 1 is characterized in that the said aqueous solution that contains chlorion is saturated aqueous solution at least a in sodium-chlor, Repone K, calcium chloride, magnesium chloride or the bariumchloride.
4. preparation method as claimed in claim 1 is characterized in that the said aqueous solution that contains chlorion is hydrochloric acid or contains aqueous solution of hydrochloric acid.
5. preparation method as claimed in claim 4 is characterized in that the said mixing solutions that aqueous solution of hydrochloric acid is hydrochloric acid and water-miscible organic solvent that contains.
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| Application Number | Priority Date | Filing Date | Title |
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| CN 00112867 CN1125032C (en) | 2000-04-20 | 2000-04-20 | Preparation of monohydrate of N,N-dimethyl-1-[1-(4-chlorophenyl) cyclobutyl]-3-methyl butylamine hydrochloride |
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| Application Number | Priority Date | Filing Date | Title |
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| CN 00112867 CN1125032C (en) | 2000-04-20 | 2000-04-20 | Preparation of monohydrate of N,N-dimethyl-1-[1-(4-chlorophenyl) cyclobutyl]-3-methyl butylamine hydrochloride |
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| CN1274714A CN1274714A (en) | 2000-11-29 |
| CN1125032C true CN1125032C (en) | 2003-10-22 |
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| CN 00112867 Expired - Fee Related CN1125032C (en) | 2000-04-20 | 2000-04-20 | Preparation of monohydrate of N,N-dimethyl-1-[1-(4-chlorophenyl) cyclobutyl]-3-methyl butylamine hydrochloride |
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Granted publication date: 20031022 Termination date: 20110420 |