Crystal form of cyclohexane derivative

A technology of cyclohexane and derivatives, applied in the crystal form of cyclohexane derivatives and the field of preparation thereof, can solve the problems such as undisclosed crystal form of the compound of formula I, reduce production costs, facilitate long-term storage and transportation, The effect of low hygroscopicity

Inactive Publication Date: 2020-02-21
ZHEJIANG JINGXIN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the patent CN106518841A only mentions that the compound of formula I is in an amorphous form, and does not disclose that the compound of formula I exists in a crystal form

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Embodiment 1: N'-[trans-4-[2-[7-(benzo[b]thiophene)-7-piperazinyl]ethyl]cyclohexyl]-N,N-dimethylurea ( Formula I compound) preparation

[0046] Refer to the preparation of Example 5 of CN106518841A.

[0047] Preparation of 1-benzo[b]thiophene-4-piperazine hydrochloride

[0048]

[0049] 7.20g 7-bromobenzo[b]thiophene, 19.9g piperazine anhydride, 4.70g sodium tert-butoxide, 0.32g (R)-(+)-2,2′-bis(diphenylphosphino)- A mixture of 1,1'-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 as a yellow ...

Embodiment 2

[0059] Preparation and identification of embodiment 2 crystal form A

[0060] Dissolve 200 mg of the amorphous product from Example 1 in ethyl acetate, reflux at 77°C, cool to room temperature (20-25°C) and stir for 1 hour, filter with suction, and recrystallize to obtain a crystal form, which is named as the compound of formula I Form A.

[0061] figure 1 The X-ray diffraction pattern (XRPD) of Form A is shown and the corresponding spacing values ​​at 2θ are provided in Table 1 characteristic peaks.

[0062] Table 1

[0063]

[0064] figure 2 The DSC chart of Form A is shown, showing an absorption peak, and the result shows that the sample has an endothermic peak at 161.6°C.

[0065] image 3 The TGA diagram of Form A is shown, and the TG shows that the sample has 0.1% weight loss when the sample is heated to 150°C.

Embodiment 3

[0066] Embodiment 3 Solubility experiment

[0067] Accurately weigh 20 mg of the crystal form A of Example 2 into a 4ml centrifuge tube, add 4ml of water, rotate and mix (25rpm) at 37°C for 1, 2, 4 and 24 hours, take samples at each time point and centrifuge, and measure Filtrate HPLC concentration and solubility, as shown in table 2 through HPLC measurement result:

[0068] Table 2

[0069] sample / time 1 hour 2 hours 4 hours 24 hours Example 2 Crystal Form A 0.028mg / ml 0.046mg / ml 0.031mg / ml 0.031mg / ml

[0070] Regarding Form A of the compound of formula I, the solubility in water is less than 0.1 mg / ml.

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Abstract

The invention relates to a crystal form of a compound, namely a cyclohexane derivative N'-[trans-4-[2-[7-(benzo[b]thiophene)-7-piperazinyl] ethyl] cyclohexyl]-N,N-dimethyl urea of a formula I shown inthe description, and a preparation method of the compound. An XRPD (X-ray powder diffraction) spectrum which has CuKalpha radiation and is presented by 2theta angles, of the crystal form, has diffraction peaks at 9.151+ / -0.2 degrees, 13.856+ / -0.2 degrees, 16.219+ / -0.2 degrees and 18.585+ / -0.2 degrees at least. The crystal form is low in dehumidification, good in stability and 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 crystal form 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)-7-piperazinyl ]ethyl]cyclohexyl]-N,N-dimethylurea, the cyclohexane derivative N'-[trans-4-[2-[7-(benzo[b]thiophene) represented by formula I -7-Piperazinyl]ethyl]cyclohexyl]-N,N-Dimethylurea has D2 / D3 antagonist action and serotonin uptake inhibition and anti-schizophrenia effect, especially at its D3 / D2 receptors The selectivity is high and the side effects are small. However, the patent CN106518841A only mentions that the compound of formula I is in an amorphous form, and does not disclose that the compound of formula I exists in a crystal form. [0...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D333/54A61K31/496A61P25/18A61P25/24A61P25/22A61P25/28A61P25/00
CPCA61P25/00A61P25/18A61P25/22A61P25/24A61P25/28C07B2200/13C07D333/54
Inventor 黄悦傅啸云徐辉
Owner ZHEJIANG JINGXIN PHARMA
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