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Crystal form of cyclohexane derivative maleate

A maleate and derivative technology, applied in the field of medicinal chemistry, can solve the problems of the preparation process and the drug-forming process, chemical stability, poor crystal stability, etc., and achieve the effects of good hygroscopicity and good crystal stability.

Inactive Publication Date: 2020-05-01
ZHEJIANG JINGXIN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The inventor also found that the maleate salt of the compound of formula I has unique advantages in numerous bases in the subsequent research and development process. For example, experiments have shown that its pharmacokinetic properties have small individual differences and have a stable therapeutic effect It has a high development value for druggability, but there are many problems in the physical properties of maleic acid in the preparation of pharmaceutical forms during the salt-forming process, such as the easy formation of solvates in the preparation of bases, chemical stability, and crystal form stability. Poor, bring unnecessary trouble to the preparation process and the drug-making process, so there is an urgent need for a better physical form of maleate

Method used

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  • Crystal form of cyclohexane derivative maleate
  • Crystal form of cyclohexane derivative maleate
  • Crystal form of cyclohexane derivative maleate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] Example 1: N'-[trans-4-[2-[7-(benzo[b]thiophene)-4-yl-1-piperazine]ethyl]cyclohexyl]-N,N-dimethyl Preparation of urea (compound of formula I)

[0064] The preparation of the free base refers to Example 5 of CN106518841A.

[0065] Preparation of 1-benzo[b]thiophene-4-piperazine hydrochloride

[0066]

[0067] 7.20g 7-bromobenzo[b]thiophene, 19.9g piperazine, 4.70g sodium tert-butoxide, 0.32g (R)-(+)-2,2'-bis(diphenylphosphino)-1 , a mixture of 1′-binaphthalene (BINAP), 0.63 g of dipalladium tris(dibenzylideneacetone) and 150 ml of toluene was refluxed for 1 hour under a nitrogen atmosphere. Pour 150ml of water into the reaction solution, then extract with 100ml×3 ethyl acetate, wash with water, dry over anhydrous magnesium sulfate, and evaporate the solvent under reduced pressure (0.01MPa, 45°C). The residue was purified by silica gel column chromatography (dichloromethane:methanol:25% aqueous ammonia=100:10:1) to obtain 4.60 g of 1-benzo[b]thiophen-4-yl-piperazine...

Embodiment 2

[0075] Example 2: N'-[trans-4-[2-[7-(benzo[b]thiophene)-4-yl-1-piperazine]ethyl]cyclohexyl]-N,N-dimethyl Preparation of urea (formula I compound) maleate

[0076] 200 mg of the product from Example 1 and maleic acid in a molar ratio of 1.05 were stirred in 5 ml of acetone (Acetone) to precipitate a solid, and the maleate salt was isolated.

Embodiment 3

[0077] Example 3: N'-[trans-4-[2-[7-(benzo[b]thiophene)-4-yl-1-piperazine]ethyl]cyclohexyl]-N,N-dimethyl Preparation of urea (formula I compound) maleate crystal form I

[0078] According to the salt 200mg obtained in Example 2 in 5 milliliters of H 2 After being suspended and stirred in O at room temperature for 3 days, the crystal form I of the maleate salt of the compound of formula I was obtained by centrifugation at room temperature.

[0079] Figure 1A Powder X-ray Diffraction Pattern (XRPD) is shown and corresponding spacing values ​​at 2θ are provided in Table 1 characteristic peaks. Figure 1B The DSC results show that the sample has two endothermic peaks at 110.5°C and 192.8°C; Figure 1B The TGA showed that the sample had a weight loss of 5.64% when the sample was heated to 150 °C. 1 H-NMR conforms to 1:1 stoichiometry (base: maleic acid), see the results Figure 1C .

[0080] Regarding the maleate salt crystal form I of the compound of formula I, the solubil...

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Abstract

The invention relates to a novel crystal form of maleate of a cyclohexane derivative N'-[trans-4-[2-[7-(benzo[b]thiophene)-4-yl-1-piperazine]ethyl]cyclohexyl]-N,N-dimethyl urea as shown in a formula Iwhich is described in the specification. The crystal form has good chemical stability and crystal form stability, is suitable for being made into a preparation, and is convenient for long-term storage and transportation.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a new crystal form of a salt of a cyclohexane derivative used for treating diseases in the mental field and a preparation method thereof. Background technique [0002] The present inventor once disclosed in CN106518841A the compound 1 of formula I structural formula, and its chemical name is N'-[trans-4-[2-[7-(benzo[b]thiophene)-4 base-1- Piperazine] ethyl] cyclohexyl] -N, N- dimethylurea Cyclohexane derivative N'-[trans-4-[2-[7-(benzo[b]thiophene represented by the structural formula I )-4-yl-1-piperazine]ethyl]cyclohexyl]-N,N-dimethylurea has D2 / D3 antagonist effect and 5-hydroxytryptamine absorption inhibitory effect, and has application prospects in related fields of antipsychotic diseases, especially It is anti-schizophrenic. [0003] [0004] The inventor also found that the maleate salt of the compound of formula I has unique advantages in numerous bases...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D333/54A61P25/00A61P25/22A61P25/24A61P25/28A61P25/18C07C57/145C07C51/41A61K31/496
CPCA61P25/00A61P25/18A61P25/22A61P25/24A61P25/28C07B2200/07C07B2200/13C07D333/54
Inventor 黄悦傅啸云唐春兰朱丹
Owner ZHEJIANG JINGXIN PHARMA