Method of producing hydrochloride of n,n-dimethyl-1-[1-(4-chlorophenyl)

专利摘要:
N,N-Dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine hydrochloride monohydrate is a non-hygroscopic material which can be used as a pharmaceutical in the treatment of depression.
公开号:SU1443796A3
申请号:SU4028642
申请日:1986-12-15
公开日:1988-12-07
发明作者:Эдвард Джеффери Джеймс；Вайбрау Дерек
申请人:Дзе Бутс Компани Плс(Фирма)；
IPC主号:

专利说明:

The invention relates to a process for the preparation of therapeutically active N, N-dimethyl-1-1- (4-chlorophenyl) -cyclobutyl-3-methyl 1-butylamine as its monohydrate.
The purpose of the invention is to develop a process for the preparation of N, N-dimethyl-1-1- (4-chlorophenip) -Hlp-butyl-3-methyl-butylamine hydrochloride in the form of its monohydrate, which allows to obtain a non-hygroscopic product.
Example 1. N, N-Dimethyl-1-C 1- (4-chlorophenyl) -cyclobutyl-3-methyl butylamine-g. Hydrochloride (0.5 g) is dissolved in 5 MP of boiling water. This solution was filtered hot, and the filtrate was cooled. The crystallized product from the cooled filtrate is collected by filtration and dried in vacuo at room temperature to give N5N-dimethyl-1-P (4-chlorophenyl) -hesia-butyl-3-methylbutylamine-hydrochloride monohydrate (m.p. 193- 195).
Example 2. M, N-Dimethyl-1-1- (A-chlorophenyl) -cI Shobutyl-3-methylamine hydrochloride (5 g) is dissolved in a boiling mixture of toluene (126 ml) and water (12.6 ml) The solution is filtered hot and the filtrate is cooled. The product crystallized from the cooled filter was collected by filtration and dried in vacuo at room temperature. N, N-dimethyl-1-G1- (4-chlorophenyl) -cyclobutyl-3-methylbutylamine hydrochloride monohydrate (t.p. 194-196 ° C).
Example 3.- M, N-Dimethyl-1-1- (4-chlorophenyl) -cyclobutyl-3-methylbu-Ti-shamnn-hydrochloride (10 g) is dissolved in a boiling mixture of acetone (110 mp) and water (ml ). The solution is filtered hot and the volume of the filtrate is reduced by distilling off 80 ml of solvent. The product, collected by filtration of the cooled concentrate, is dried in vacuo at room temperature to give N5N-dimethyl-1 1- (4-chlorophenyl) monohydrate — hclglobutyl-3-methylbutylamine hydrochloride (mp. 195 ° C) .
0
which is dehydrated
70 ° C for 7 hours, dissolve
Examples 4-6. Sample (1 g) K, H-dimenp-1- 1- (4-chlorophyll) cyclobutyl 1-3-methylbutylamine hydrochloride,
under vacuum in a boiling mixture of water (0.5 mp) and an organic solvent (4.5 ml). The solution is allowed to cool to room temperature and then stored at 4 ° C for 3 days. The solid is collected by filtration, washed with an organic solvent and dried under vacuum at room temperature for 18 hours to give N, N-dimethyl-1-1- (4-hlcp phenyl) -cyclobutythyl-3-methylbutylamine hydrochloride monohydrate m.p. which is given below.
Example Solvent Industrial Methylated Alcohol
one
M.p. C 195-198 (shrinkage at 160)
Propane-2-ol
195-198 (shrinkage at 163)
0
5 Q
0
five
2-Ethoxyethanol
194-198 (shrinkage at 166)
Examples 7-11. Sample (1g) H, L-dimethyl-1- 1- (4-chlorophenyl) -cyclobutyl-3-methylbutylamine hydrochloride, which is dehydrated in vacuum at 70 ° C for 7 hours, treated with an organic solvent indicated below (x, mp ). Water (ump) is then added. The mixture is boiled, the resulting solution is allowed to cool to room temperature, then stored at 4 ° C for 3 hours. In examples 10 and 11, the solution is stored at room temperature for 18 hours, and crystallization is caused by decreasing the volume of solution in air flow. . The solid is collected by filtration, washed with an organic solvent, and dried in vacuo at room temperature for 18 hours to give N, N-dimethyl-1-L1 (4-chlorophenyl) -cyclobutyl-3-methIl-butylamine-hydrochloride monohydrate, m.p. which is given below.
Example Solvent x 7 1,2-Dimethoxyethane 10 1
8 xylene
9 Cyclohexane 30 2
10 1,4-Dioxane 25 1
1 Methyl acetate 25 2
at
one
one
2
one
2
So pl., ° C 196-198 (shrinkage at
185;
196-198 (shrinkage at 166)
193-197 (shrinkage at 160)
196-199 (shrinkage at 160)
197-202
Examples 12 and 13. Sample (1 g) K, N-dimethyl-1-1- (4-chlorophenyl) -cyclobutyl 1-3-methylbutylamine is treated with 5 M hydrochloric acid (1 mp) and the mixture is dissolved in a minimum amount boiling organic solvent indicated below. The resulting solution is allowed to cool to room temperature. The solid is collected by filtration, washed with an organic solvent, washed and dried in vacuo at room temperature for 18 h, yielding dimethyl -1-1- (4-chlorophenyl) cyclobut monohydrate, yl-3-methylbusht1amin hydrochloride, T .pl which is shown below. Example Solvent, m.p.
12 Acetone194-197
13 Ethanol196-201
Example 14. A sample of (5 g) S, K-dimethyl-1-1- (4-chlorophenyl) -cyl-butyl 3-3-methylbutydamine-hydrochloride is heated with a mixture of toluene (30 ml) and propan-2-ol (3 ml) to 90 ° C and allowed to cool to 72 ° C. Add 0.9 MP of water, cool the mixture to, then place in an ice-water bath for 30 minutes. The solid is collected by filtration, washed with cold toluene, and dried by suction at room temperature to give N, N-dimethyl-1-1- (4-chlorophenyl) cyclobutyl-3-methyl 1-butylamine hydrochloride monohydrate. M.p. 193-195 ° C (shrinkage at 150-155 s)
5 o
five
0
g Q g
Example 15. A sample (24.1 g) of N, N-dimethyl-1-Li - (4-chlorophenyl) -cyclobutyl-3-methylbutylamine hydrochloride was dissolved in a boiling mixture of water (72 ml) and tetrahydrofuran (7 ml), the mixture is allowed to cool. The solid is collected by filtration, dried at 40 ° C to give N, N-dimethyl-1-1- (4-chlorophenyl) -cyclobutyl-3-methylbutylamine hydrochloride monohydrate (mp. 193-195 ° C ).
Example 16. A sample (48.2 g) of N, N-dimethyl-1- 1- (4-chl orphenyl) -cyclobutyl-3-methylbutylamine hydrochloride is suspended while stirring with water (145 ml) for 24 hours at 25 C. The solid is collected by filtration and dried by suction at room temperature, yielding dimethyl -1-1- (4-chlorophenyl) -cyclobutyl} -3-methylbutylamine hydrochloride monohydrate (mp. 191-195.5 ° C ).
The non-hygroscopic nature of the products obtained in the examples given is illustrated by the following comparative experiment. A sample of N, N-dimethyl-1-1- (4-chlorophenyl) cyclobutyl-3-methylbutylamine hydrochloride is deposited in a vacuum oven at 60 ° C for 16 hours and stored in a desiccator over phosphorus pentoxide. The analysis showed that this material does not contain water. When this sample is exposed to the atmosphere for 1 month, the analysis shows that the water content is approximately 3%, which corresponds to about 0.6 molar equivalent of water. However, when the sample of monohydrate H, H-dimethyl-1- (1- (4-chlorofensh1) -cyclobutyl-3-metshgbutylamine-hydrochloride is exposed to the atmosphere for 5 months, no increase in the water content is observed, which indicates the absence of water absorption by sample.
Thus, the proposed method eliminates the disadvantage of the known method, according to which a hygroscopic product is formed, which is inconvenient in obtaining a pharmaceutical preparation.
The product obtained in accordance with the invention, when exposed to the atmosphere for 5 months, does not absorb water.

权利要求:
Claims (3)
[1]
1. A process for the preparation of H, L-dimesh1-1- {1 (chlorophenyl) -cyclobutyl-J-3-methylbutylamine hydrochloride as a monohydrate, characterized in that; that K, H-dimethyl-1- 1- (4-chlorophenyl) -cyclobutyl-3-methylbutylamine hydrochloride is suspended in water or recrystallized from water or a mixture of water and a solvent which is immiscible or miscible with water.
[2]
2. The method according to p. 1, u and with the fact that
different qualities of a water-immiscible solvent are toluene, xylene or cyclohexane.
[3]
3. A method according to claim 1, characterized in that acetone, propan-2-ol5 industrial methylated alcohol, 2-ethoxyethanol, 1,2 dimethoxytane, tetrahydrofuran, 1-4-dioxane are used as a water-miscible solvent. or methyl acetate.

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UY34194A|2011-07-15|2013-02-28|Astrazeneca Ab|?METHYL) PHENOXI) AZETIDIN-1-IL)-1,3,4-OXADIAZOL-2-IL) METHANONE IN THE TREATMENT OF OBESITY?|

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CA2922849A1|2012-08-31|2014-03-06|Ixchel Pharma, Llc|Agents useful for treating obesity, diabetes and related disorders|

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CN110372522B|2019-07-30|2020-10-02|南京工业大学|Method for stripping and recovering pentamethylene diamine from pentamethylene diamine-containing solid phase|

法律状态:
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优先权:

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申请号 | 申请日 | 专利标题

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GB858531071A|GB8531071D0|1985-12-17|1985-12-17|Therapeutic compound|LTRP1012A| LT2520B|1985-12-17|1993-09-20|N, N-DIMETHYL-1-CIKLOBUTIL) -3-M MONITORING METHOD OF HYDROCHLORIDE OF ETHYLBUTYLAMIN|

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LV931268A| LV5455A3|1985-12-17|1993-11-25|Method of Acquisition of N, N-dimethyl-1-yl--cyclobutyl-3-methylbutylamine hydrochloride monohydrate|