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N-cyclohexyl-furan-2-formamide compound as well as preparation method and application thereof

A technology of formamides and compounds, applied in the field of N-cyclohexyl-furan-2-carboxamides, which can solve the problems that are not conducive to environmental protection, and achieve the effects of low cost, stable yield and mild reaction conditions

Inactive Publication Date: 2020-06-12
SHANGHAI ZHONGZE THERAPEUTICS CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In this route, the acetyl group of intermediate 16 is hydrolyzed under the condition of dilute hydrochloric acid (5% HCl), and the key intermediate 9 is obtained, which produces a large amount of waste water, which is not conducive to environmental protection

Method used

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  • N-cyclohexyl-furan-2-formamide compound as well as preparation method and application thereof
  • N-cyclohexyl-furan-2-formamide compound as well as preparation method and application thereof
  • N-cyclohexyl-furan-2-formamide compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0085] Preparation of N-(trans-4-(2-oxoethyl)cyclohexyl)furan-2-carboxamide (I-1);

[0086] (1) Synthesis of N-(4-oxocyclohexyl)furan-2-carboxamide (1)

[0087] Add 4-aminocyclohexanone hydrochloride (1496.2g, 10.0mol), dichloromethane (7481mL), and 20% NaOH aqueous solution (NaOH: 1000g) into a 10L four-neck flask, cool to 0°C in an ice bath, and slowly Add furan-2-formyl chloride (1435.8 g, 11.0 mol) dropwise, control the temperature not to exceed 10°C, after the addition is complete, stir at room temperature for 2 h, add H 2 O (1000mL) was stirred, separated, and the organic layer was washed successively with 5% HCl (200mL×2), saturated brine (2000mL×1), anhydrous NaSO 4 Dry, filter and concentrate to obtain 1968.7 g of white solid with a yield of 95%, which is directly used in the next reaction.

[0088] (2) Synthesis of ethyl 2-(4-(furan-2-carboxamide)cyclohexylenyl)acetate (2)

[0089] Add sodium tert-butoxide (1153.2g, 12mol) and THF (3000mL) into a 10000mL four-neck...

Embodiment 2

[0097] Preparation of SIPI6398

[0098] N-(trans-4-(2-oxoethyl)cyclohexyl)furan-2-carboxamide (I-1) (100.0g, 0.43mol), 3-(piperazin-1-yl)benzene Add [d]isothiazole (94.3g, 0.43mol), sodium triacetoxyborohydride (137.8g, 0.65mol), and 1,2-dichloroethane (1000mL) into a 2000mL single-necked bottle, and stir at room temperature for 15h , add potassium carbonate aqueous solution (2500mL), separate the layers, extract the aqueous layer with 1,2-dichloroethane (1500mL×1), combine the organic layers, wash with saturated brine (1000 mL×1), anhydrous sodium sulfate Dry, filter, concentrate, remove most of the solvent, filter, wash the filter cake with ethyl acetate (200mL×3), combine the filtrates, and concentrate to obtain 188.6g of white solid, yield 91%. The resulting white solid, ethanol (1800 mL), and 10% HCl (0.43 mol) were added to a 3000 mL one-necked flask, refluxed for 0.5 h, cooled to room temperature, stirred for 1 h, and filtered to obtain 171 g of SIPI6398 white solid, w...

Embodiment 3

[0103] Preparation of N-(trans-4-(2-chloroethyl)cyclohexyl)furan-2-carboxamide (II-1)

[0104] 2-(trans-4-(furan-2-carboxamido) cyclohexyl) ethyl acetate (3) (200.0g, 0.72mol), NaBH 4(83.2 g, 2.2 mol) and THF (1000 mL) were added to a 2000 mL single-necked bottle, refluxed for 0.5 h, cooled to 40 ° C, and methanol (160 mL) was added in batches, after addition, refluxed for 5 h, and the reaction solution was cooled to room temperature. Adjust the reaction solution to pH 1-2 with concentrated hydrochloric acid, stir for 0.5h, adjust the reaction solution to pH 8-9 with 10% NaOH aqueous solution, stir for 0.5h, extract with dichloromethane (500mL×3), and saturated saline (500×1) washed, anhydrous Na 2 SO 4 Dry, filter, and concentrate to obtain 158.9 g of N-(trans-4-(2-hydroxyethyl)cyclohexyl)furan-2-carboxamide as a white solid, with a yield of 93%.

[0105] Add N-(trans-4-(2-hydroxyethyl)cyclohexyl)furan-2-carboxamide (50.0g, 0.21mol) and pyridine (18.3g, 0.23mol) into a 500...

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Abstract

The invention discloses an N-cyclohexyl-furan-2-formamide compound as well as a preparation method and application of the N-cyclohexyl-furan-2-formamide compound. The N-cyclohexyl-furan-2-formamide compound can be used for preparing an anti-schizophrenia drug SIPI6398, and has the following remarkable advantages compared with the prior art and reported literatures: 1, when the N-cyclohexyl-furan-2-formamide compound disclosed by the invention is used for synthesizing the SIPI6398 without the need of a reaction process of connecting a protecting group and removing the protecting group so that atom economy is high; 2, when the N-cyclohexyl-furan-2-formamide compound is used for preparing SIPI6398, the raw materials are cheap and easy to obtain, the cost is low, the reaction conditions are mild, the yield is stable, the operation is simple and convenient, the three-waste pollution is little, and the industrial production is easy, and the N-cyclohexyl-furan-2-formamide compound is a compound with the following structural general formula (I) shown in the specification.

Description

technical field [0001] The invention relates to N-cyclohexyl-furan-2-carboxamide compounds and applications thereof. Background technique [0002] SIPI6398, the chemical name is N-(trans-4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)furan-2-methyl Amide hydrochloride, D 3 / D 2 Receptor subtype selective antagonist for the treatment of schizophrenia. Its structural formula is as follows: [0003] [0004] Schizophrenia is a disease that seriously affects human health. It is the most serious mental disease, affecting the normal life of about 1% of the world's population, and bringing serious consequences and economic burdens to patients and their families. [0005] Currently clinical antipsychotics are mainly divided into typical antipsychotics and atypical antipsychotics, the latter being commonly used drugs, such as risperidone, aripiprazole, ziprasidone, etc. These drugs can improve negative symptoms while treating positive symptoms, but they all ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/68C07D417/12A61P25/18
CPCA61P25/18C07B2200/07C07D307/68C07D417/12Y02P20/55
Inventor 李建其陈晓文周爱南浦强齐阳历苏晓静
Owner SHANGHAI ZHONGZE THERAPEUTICS CO LTD
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