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3-cyclohexyl-1,1-dimethylurea compound as well as preparation method and application thereof

A technology of dimethyl urea and compound, which is applied in the field of 3-cyclohexyl-1,1-dimethyl urea compounds, can solve the problem of difficult synthesis of 4-aminocyclohexanoic acid, unfavorable industrial production, severe reaction conditions, etc. problems, to achieve the effect of controllable product quality, stable yield and high purity

Active Publication Date: 2015-04-08
SHANGHAI INST OF PHARMA IND CO LTD +1
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in this route, the carboxylic acid form of the starting material 8, i.e. trans-4-aminocyclohexanoic acid, is difficult to synthesize and is not commercially available.
Patent CN101778820 respectively describes the preparation method of trans-4-aminocyclohexanoic acid, but the reaction conditions are severe, the reaction temperature is 130°C, the pressure is 140bar, and the reaction time is long (5 days), which is not conducive to industrial production

Method used

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  • 3-cyclohexyl-1,1-dimethylurea compound as well as preparation method and application thereof
  • 3-cyclohexyl-1,1-dimethylurea compound as well as preparation method and application thereof
  • 3-cyclohexyl-1,1-dimethylurea compound as well as preparation method and application thereof

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Experimental program
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Effect test

Embodiment 1

[0090] Preparation of 1,1-dimethyl-3-(trans-4-(2-oxoethyl)cyclohexyl)urea (I-1);

[0091] (1) Synthesis of 1,1-Dimethyl-3-(4-oxocyclohexyl)urea (1)

[0092] Combine 4-aminocyclohexanone (113.16g, 1.0mol), dichloromethane (566mL), tetra-n-butylammonium bromide (0.6g, 1.9mmol), DMAP (0.6g, 4.9mmol), 40% NaOH aqueous solution (NaOH:60g) was added to a 1000mL four-necked flask, cooled to 0℃ in an ice bath, slowly added dimethylcarbamoyl chloride (129g, 1.2mol) dropwise, the temperature did not exceed 10℃, after the addition, stirred at room temperature for 2h, reflux React for 6h, cool to room temperature, add H 2 O (200mL) was stirred and separated, the organic layer was washed with 10% HCl (20mL×2), saturated brine (200mL×1), anhydrous MgSO 4 Evaporate to dryness, filter, and evaporate to dryness to obtain 159.16 g of white solid with a yield of 86.5%, which is directly used in the next reaction.

[0093] (2) Synthesis of 2-(4-(3,3-dimethylureido)cyclohexylalkenyl) ethyl acetate (2)

...

Embodiment 2

[0102] Preparation of Cariprazine (Cariprazine)

[0103] 1,1-Dimethyl-3-(trans-4-(2-oxoethyl)cyclohexyl)urea (I-1) (9.0g, 42.39mmol), 1-(2,3-di Chlorophenyl) piperazine (9.8g, 42.39mmol), sodium triacetoxyborohydride (13.1g, 61.8mmol), 1,2-dichloroethane (300mL) were added to a 500mL single-necked flask and stirred at room temperature for 18h , Add potassium carbonate aqueous solution (250mL), separate the layers, extract the aqueous layer with 1,2-dichloroethane (150mL×1), combine the organic layers, wash with saturated brine (150mL×1), and dry with anhydrous sodium sulfate , Filter, concentrate, remove most of the solvent, filter, wash the filter cake with ethyl acetate (50 mL×3), combine the filtrate, and concentrate to obtain 16.2 g of white solid with a yield of 89.5%. The obtained white solid, ethanol (160 mL), and 10% HCl (39.84 mmol) were added to a 250 mL single-neck flask, refluxed for 1 h, cooled to room temperature, and filtered to obtain 16.7 g of cariprazine (white...

Embodiment 3

[0107] Preparation of 3-(trans-4-(2-hydroxyethyl)cyclohexyl)-1,1-dimethylurea (II-1)

[0108] The trans-2-(4-(3,3-dimethylureido) cyclohexyl) ethyl acetate (3) (51.27g, 0.2mol), NaBH 4 (37.8g, 1mol), THF (190mL) were added to a 500mL single-necked flask, refluxed for 1h, cooled to 50℃, methanol (80mL) was added in batches, after the addition, refluxed for 7h, the reaction solution was cooled to room temperature and concentrated Adjust the reaction solution to pH 1-2 with hydrochloric acid, stir for 1 hour, adjust the reaction solution to pH 7-8 with 20% NaOH aqueous solution, stir for 1 hour, extract with dichloromethane (200mL×3), and wash with saturated brine (100×1) , Anhydrous MgSO 4 After drying, filtering, and concentrating, a colorless oil was obtained, which was allowed to stand and solidified to obtain 37.7 g of white solid with a yield of 88%.

[0109] 1 H NMR(DMSO-d 6 ,δ:ppm):0.89-0.95(m,2H,A-H),1.13-1.19(m,5H,A-H),1.67-1.75(m,4H,A-H),2.75(s,6H,CH 3 ), 3.35-3.44(m,3H,A-H...

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Abstract

The invention discloses a 3-cyclohexyl-1,1-dimethylurea compound as well as a preparation method and application thereof. The 3-cyclohexyl-1,1-dimethylurea compound is used for preparing an antischizophrenic drug cariprazine. Compared with the prior art and report literatures, the preparation method of the 3-cyclohexyl-1,1-dimethylurea compound has the remarkable advantages of being free of removal of protecting groups such as Boc group, high in atom economy, low in cost and easy in getting of raw materials, mild in reaction condition, stable in yield, simple and convenient to operate, controllable in product quality, high in product purity, less in three waste pollution and easy to produce industrially. The structure formula of the 3-cyclohexyl-1,1-dimethylurea compound is as shown in (I) in the specification.

Description

Technical field [0001] The invention relates to a 3-cyclohexyl-1,1-dimethylurea compound and a preparation method and application thereof. Background technique [0002] Cariprazine, the chemical name is trans-1-{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl }-3,3-Dimethylurea hydrochloride, developed by Hungarian Gedeon Richter Ltd and Forest Laboratories, USA 3 / D 2 Receptor partial agonist, used to treat schizophrenia (pre-registration), mania (pre-registration), and major depression (phase III). It is expected to be marketed in the United States in early 2015 as an anti-schizophrenia drug. Its structural formula is as follows: [0003] [0004] Schizophrenia is a disease that seriously affects human health. It currently affects the normal life of about 1% of the world’s population and brings serious consequences to patients and their families. It is the seventh disease with the largest social burden. [0005] Antipsychotic drugs are mainly divided into typical a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C275/26C07C309/66C07C309/73C07C273/18C07C303/28C07D295/135
CPCY02P20/55
Inventor 李建其陈晓文张飞龙董堃华
Owner SHANGHAI INST OF PHARMA IND CO LTD
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