CN110818676A

CN110818676A - Crystal form of cyclohexane derivative

Info

Publication number: CN110818676A
Application number: CN201810915855.5A
Authority: CN
Inventors: 黄悦; 傅啸云; 徐辉
Original assignee: SHANGHAI JINGXIN BIOLOGICAL MEDICAL CO Ltd; Zhejiang Jingxin Pharmaceutical Co Ltd
Current assignee: SHANGHAI JINGXIN BIOLOGICAL MEDICAL CO Ltd; Zhejiang Jingxin Pharmaceutical Co Ltd
Priority date: 2018-08-13
Filing date: 2018-08-13
Publication date: 2020-02-21

Abstract

The invention relates to a cyclohexane derivative N' - [ trans-4- [2- [7- (benzo [ b ]) as shown in a formula I]Thiophene) -7-piperazinyl]Ethyl radical]Cyclohexyl radical]Crystalline form of (E) -N, N-dimethylurea exhibiting, using CuK α radiation, diffraction peaks at least at 9.151 DEG + -0.2 DEG, 13.856 DEG + -0.2 DEG, 16.219 DEG + -0.2 DEG and 18.585 DEG + -0.2 DEG in an XRPD spectrum expressed in degrees 2 theta and a process for its preparationLow hygroscopicity, good stability, and convenient long-term storage and transportation.

Description

Crystal form of cyclohexane derivative

Technical Field

The invention belongs to the field of medicinal chemistry, and particularly relates to a crystal form of a cyclohexane derivative for treating mental diseases and a preparation method thereof.

Background

The present inventors have disclosed in CN106518841A compound 1 having the structural formula of formula I, whose chemical name is N '- [ trans-4- [2- [7- (benzo [ b ] thiophene) -7-piperazinyl ] ethyl ] cyclohexyl ] -N, N-dimethylurea, and cyclohexane derivative N' - [ trans-4- [2- [7- (benzo [ b ] thiophene) -7-piperazinyl ] ethyl ] cyclohexyl ] -N, N-dimethylurea represented by the structural formula of formula I has D2/D3 antagonist effect and 5-hydroxytryptamine absorption inhibition effect as well as anti-schizophrenia effect, and particularly has high selectivity of D3/D2 receptor and small side effects. However, CN106518841A only mentions that the compound of formula I is in amorphous form, and does not disclose that the compound of formula I exists in crystalline form.

In order to improve the stability of the compound in the preparation process and the storage process, a physical form with stable physicochemical properties is needed, and the quality of the compound is still ensured to be stable and reliable for a long time even in a high-temperature and high-humidity environment.

Disclosure of Invention

Based on the existing compound shown in the formula I, the inventor develops a crystal form which is named as crystal form A through intensive research, improves the stability of the compound I and reduces the hygroscopicity of the compound I. Specifically, the present invention provides the following technical solutions.

The invention provides a crystal form of cyclohexane derivative N' - [ trans-4- [2- [7- (benzo [ b ] thiophene) -7-piperazinyl ] ethyl ] cyclohexyl ] -N, N-dimethylurea shown as a formula I, named as a crystal form A, which is characterized in that an X-ray powder diffraction spectrum radiated by CuK α and expressed by a 2 theta angle has diffraction peaks at least at 9.151 DEG +/-0.2 DEG, 13.856 DEG +/-0.2 DEG, 16.219 DEG +/-0.2 DEG and 18.585 DEG +/-0.2 DEG, preferably at least at 9.151 DEG +/-0.1 DEG, 13.856 DEG +/-0.1 DEG, 16.219 DEG +/-0.1 DEG and 18.585 DEG +/-0.1 DEG, and more preferably at least at 9.151 DEG, 13.856 DEG, 16.219 DEG and 18.585 deg.

Preferably, said form a also has diffraction peaks at 2 Θ values of 16.929 ° ± 0.2 °, 17.652 ° ± 0.2 °, 20.355 ° ± 0.2 ° and 37.939 ° ± 0.2 °; diffraction peaks are preferably present at 16.929 ° ± 0.1 °, 17.652 ° ± 0.1 °, 20.355 ° ± 0.1 ° and 37.939 ° ± 0.1 °; more preferably, there are diffraction peaks at 16.929 °, 17.652 °, 20.355 ° and 37.939 °.

More preferably, the crystal form A also has diffraction peaks at 2 theta values of 4.472 DEG +/-0.2 DEG, 11.498 DEG +/-0.2 DEG, 18.086 DEG +/-0.2 DEG, 19.271 DEG +/-0.2 DEG, 21.725 DEG +/-0.2 DEG, 23.676 DEG +/-0.2 DEG, 23.981 DEG +/-0.2 DEG, 24.805 DEG +/-0.2 DEG, 25.604 DEG +/-0.2 DEG, 28.026 DEG +/-0.2 DEG, 29.604 +/-0.2 DEG, 30.521 +/-0.2 DEG, 31.726 +/-0.2 DEG, 33.014 +/-0.2 DEG, 35.474 +/-0.2 DEG and 36.165 DEG +/-0.2 DEG; diffraction peaks preferably exist at 4.472 DEG + -0.1 DEG, 11.498 DEG + -0.1 DEG, 18.086 DEG + -0.1 DEG, 19.271 DEG + -0.1 DEG, 21.725 DEG + -0.1 DEG, 23.676 DEG + -0.1 DEG, 23.981 DEG + -0.1 DEG, 24.805 DEG + -0.1 DEG, 25.604 DEG + -0.1 DEG, 28.026 DEG + -0.1 DEG, 29.604 + -0.1 DEG, 30.521 + -0.1 DEG, 31.726 + -0.1 DEG, 33.014 + -0.1 DEG, 35.474 + -0.1 DEG and 36.165 DEG + -0.1 DEG; more preferably, there are diffraction peaks at 4.472 °, 11.498 °, 18.086 °, 19.271 °, 21.725 °, 23.676 °, 23.981 °, 24.805 °, 25.604 °, 28.026 °, 29.604, 30.521, 31.726, 33.014, 35.474 and 36.165 °; most preferably, the XRPD pattern of form a is as shown in figure 1.

In one embodiment of the crystalline form of the present invention, the crystalline form has an endothermic peak at 150 to 170 ℃ in DSC analysis; preferably, the DSC pattern of said crystalline form is as shown in figure 2.

In one embodiment of the crystalline form of the present invention, the weight loss at 150 ℃ in TGA analysis is between 0.08 and 0.12%; preferably, the TGA profile is as shown in figure 3.

The invention discloses a method for preparing the crystal form, which comprises the following steps: recrystallizing the amorphous compound shown in the formula I in an organic solvent to obtain the crystal form of the compound shown in the formula I.

In one embodiment of the preparation method of the crystal form a of the present invention, the compound of formula I in amorphous form is refluxed and dissolved in an organic solvent, and then cooled, stirred, filtered, and recrystallized to obtain the crystal form a.

In one embodiment of the preparation method of the crystal form, the reflux temperature is 60-80 ℃; preferably, the cooling temperature is up to 20-25 ℃.

In one embodiment of the method for preparing the crystalline form of the present invention, the organic solvent is selected from ethyl acetate, toluene, acetonitrile, isopropyl acetate, isopropanol or a mixture of two or more thereof.

The invention also provides a pharmaceutical composition for treating or improving schizophrenia, psychotic disorder, confusion, mood disorder, bipolar disorder, depression, phobia, obsessive-compulsive disorder, anxiety disorder or cognitive disorder, which comprises the crystal form A and pharmaceutical excipients.

The crystal form A of the compound of the formula I has low hygroscopicity and good stability, and is convenient to store and transport for a long time, so that the production cost is reduced.

Drawings

FIG. 1 is an X-ray powder diffraction pattern (XPRD pattern) of form A of the compound of formula I in one embodiment of the present invention.

Figure 2 is a differential scanning calorimetry trace (DSC plot) of form a of the compound of formula I in one embodiment of the invention. The abscissa is temperature (. degree. C.); the ordinate represents the heat flow rate (W/g).

Figure 3 is a thermogravimetric analysis (TGA) profile of form a of the compound of formula I in one embodiment of the present invention.

Detailed Description

The invention is further illustrated by the following examples. It is to be understood that these examples are for illustrative purposes only and are not limiting upon the present invention. Various changes or modifications thereof, which may occur to those skilled in the art based on the teachings of the present invention, are within the scope of the present invention.

N' - [ trans-4- [2- [7- (benzo [ b ]) of the invention]Thiophene) -7-piperazinyl]Ethyl radical]Cyclohexyl radical]X-ray powder diffractogram of form A of N, N-dimethylurea, tableNow the diffraction peak position, i.e. diffraction angle 2 theta (DEG), interplanar spacing

The relative intensities of the diffraction peaks (I/I0) are summarized in Table 1.

The term "relative intensity" refers to the ratio of the intensity of the other peak to the intensity of the peak having the highest intensity when the intensity of the peak having the highest intensity among all diffraction peaks of an X-ray powder diffraction pattern is 100%.

In a preferred embodiment, form a of the present invention has an X-ray powder diffraction pattern substantially the same as the X-ray powder diffraction spectrum shown in fig. 1.

The term "substantially the same" means that at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% of the peaks in the X-ray powder diffraction pattern appear in the exemplary X-ray powder diffraction spectrum given in figure 1.

In addition, the crystal form is analyzed by a differential scanning calorimetry technology, when the differential scanning calorimetry technology is used for analysis, the temperature rise rate is 10 ℃ per minute, 1 endothermic peak exists in a DSC spectrum at 150-170 ℃, and the DSC spectrum is basically shown in figure 2. It is to be understood that the values quoted by differential scanning calorimetry are not to be interpreted as absolute values, in analogy to the possible deviations of the X-ray powder diffraction pattern values.

In a preferred embodiment, the crystalline form of the present invention has a Differential Scanning Calorimetry (DSC) spectrum substantially the same as that of figure 2.

In addition, the crystal form is analyzed by a TGA thermogravimetric analysis technology, and when the TGA technology is used for analysis, the weight loss at 150 ℃ in a TGA graph reaches 0.10%, and the TGA graph is basically shown as figure 3. It should be understood that there is a similarity in possible deviations from the X-ray powder diffraction pattern values, and that the values quoted by TGA thermogravimetric analysis techniques are not to be interpreted as absolute values either.

Examples

Reagent: the reactants and the catalyst used in the embodiment of the invention are chemically pure, and can be directly used or simply purified according to the requirement; the organic solvent and the like are analytically pure and are directly used. The reagents were purchased from Shanghai chemical reagent company, China medicine (group).

Amorphous forms of the compounds of formula I are prepared according to the methods reported in the prior art such as example 5 in CN106518841A, and are not limited thereto.

X-ray powder diffraction:

CuK α rays are adopted to perform X-ray powder diffraction analysis on an X-ray powder diffractometer produced by PANalytacal, the test power is 45kV multiplied by 40mA, the scanning speed is 5 DEG/min, the step width is 0.02 DEG, and theta-2 theta continuous scanning within the scanning range of 3-40 DEG (2 theta) is performed.

Differential Scanning Calorimetry (DSC) characterization:

the measurement was carried out by using a Q2000/2500 differential scanning calorimeter of TA under the condition that the protective gas was nitrogen, the temperature rise rate was 10 ℃/min, and the temperature gradually increased from 25 ℃ to the set end point.

Thermogravimetric analysis (TGA):

the measurement was carried out by using a Q5000/5500 thermogravimetric analyzer manufactured by TA under the condition that the protective gas is nitrogen, the temperature rise rate is 10 ℃/min, and the temperature gradually rises from room temperature to a set terminal point.

Content detection method (HPLC):

chromatographic conditions

Solution preparation

Diluent (blank solution) acetonitrile/water 1/1(V/V)

Test solution: precisely weighing 5mg of a sample, placing the sample in a 10ml measuring flask, adding 2ml of methanol for dissolving, adding a diluent (blank solution) for constant volume, and uniformly mixing to obtain the product.

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

Reference was made to the preparation of example 5 of CN 106518841A.

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

A mixture of 7.20g of 7-bromobenzo [ b ] thiophene, 19.9g of piperazine anhydride, 4.70g of sodium tert-butoxide, 0.32g of (R) - (+) -2,2 '-bis (diphenylphosphino) -1, 1' -Binaphthyl (BINAP), 0.63g of dipalladium tris (dibenzylideneacetone) and 150ml of toluene was refluxed for 1 hour under a nitrogen atmosphere. 150ml of water was poured into the reaction solution, followed by extraction with 100ml of X3 ethyl acetate, washing with water, drying over anhydrous magnesium sulfate, and evaporation of 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 4.60g of 1-benzo [ b ] thiophen-4-yl-piperazine as a yellow oil. 2ml of concentrated hydrochloric acid was added to a methanol solution (25ml) containing 4.6g of 1-benzo [ b ] thiophen-4-yl-piperazine and the solvent was evaporated under reduced pressure (0.01MPa, 45 ℃). To the residue was added ethyl acetate (50ml), and the precipitated crystals were filtered, dissolved in 15ml of methanol under reflux and then cooled to room temperature (25 ℃) to be recrystallized to obtain colorless needle-like crystals of 1-benzo [ b ] thiophen-4-yl-piperazine hydrochloride.

Preparation of trans-4- [2- [7- (benzo [ b ] thiophene) -7-piperazinyl ] ethyl ] cyclohexyl-carbamic acid tert-butyl ester

2.54g (10mmol) of 1-benzo [ b ] thiophene-4-piperazine hydrochloride and 2.40g (10mmol) of trans-2- {1- [4- (N-tert-butoxycarbonyl) amino ] cyclohexyl } -acetaldehyde are dissolved in 120ml of dichloromethane, 1.40ml (10mmol) of triethylamine are added at room temperature (25 ℃ C. + -2 ℃ C.) and stirred slowly for 10 minutes, then 3.16g (14.8mmol) of sodium triacetoxyborohydride are added stepwise, the reaction is stirred further at room temperature for 24 hours, and after the reaction has ended 120ml of a 10% sodium bicarbonate solution is added. The reaction system is directly extracted and separated, the organic phase is dried by anhydrous sodium sulfate, and finally filtered and evaporated to dryness, and the solid is refluxed, dissolved and cooled to room temperature (25 +/-2 ℃) by 15ml of ethyl acetate to obtain 3.70g of target product.

Preparation of trans-4- [2- [7- (benzo [ b ] thiophene) -7-piperazinyl ] ethyl ] cyclohexylamine

In an ice-water bath, 4.43g of trans-4- [2- [7- (benzo [ b ] thiophene) -7-piperazinyl ] ethyl ] cyclohexyl-carbamic acid tert-butyl ester was placed in a reaction flask, 80ml of an ethyl acetate solution of saturated hydrogen chloride was added, and a deprotection reaction was carried out by stirring for 8 hours to give a white precipitate, to obtain 3.42g of the hydrochloride of the title compound. The solid was added to 50ml of a methylene chloride solution, 50ml of a saturated sodium bicarbonate solution was stirred for half an hour, followed by liquid-separation extraction, and the organic phase was concentrated (0.01MPa, 40 ℃ C.) to obtain 3.30g of the objective product.

Preparation of N' - [ trans-4- [2- [7- (benzo [ b ] thiophene) -7-piperazinyl ] ethyl ] cyclohexyl ] -N, N-dimethylurea

1.73g of trans-4- [2- [7- (benzo [ b ] thiophene) -7-piperazinyl ] ethyl ] cyclohexaneamine are dissolved in 50ml of dichloromethane, 1.40ml of triethylamine are added, followed by 5.50mmol of N, N-diformylcarbonyl chloride. Stirred at room temperature (25 ℃ C.. + -. 2 ℃ C.) for 48 hours. After the reaction, 50ml of water was added for extraction and liquid separation, and the organic phase was concentrated (0.01MPa, 45 ℃ C.), and the objective component was collected by 1:10 column chromatography (400 mesh silica gel) using methanol and dichloromethane, and concentrated to obtain 1.89g of an amorphous objective product.

Example 2 preparation and characterization of form a

The amorphous product from example 1, 200mg, was dissolved in ethyl acetate at 77 ℃ under reflux and stirred for 1h, cooled to room temperature (20-25 ℃), filtered with suction, and recrystallized to give the crystalline form, designated form a of the compound of formula I.

FIG. 1 shows the X-ray diffraction pattern (XRPD) of form A, and the corresponding spacing values at 2 θ are provided in Table 1

Characteristic peak of (2).

TABLE 1

Figure 2 shows a DSC plot of form a showing an absorption peak, showing that the sample has an endothermic peak at 161.6 ℃.

Fig. 3 shows a TGA plot of form a, with TG showing 0.1% weight loss of the sample when heated to 150 ℃.

Example 3 solubility test

Form A from example 2 was weighed precisely into a 4ml centrifuge tube, 4ml water was added, spun mixed (25rpm) at 37 ℃ for 1, 2, 4 and 24 hours, samples were taken at each time point and centrifuged to determine the filtrate HPLC concentration and solubility, and the HPLC results are shown in Table 2:

TABLE 2

Sample/time	1 hour	2 hours	4 hours	24 hours
					Example 2 form a	0.028mg/ml	0.046mg/ml	0.031mg/ml	0.031mg/ml

Regarding form A of the compound of formula I, the solubility in water is less than 0.1 mg/ml.

Example 4 stability experiment

Form A of example 2, 20mg, was allowed to stand for 1 week at 25 ℃/60% Relative Humidity (RH) and 40 ℃/75% Relative Humidity (RH), respectively, and the purity results by HPLC are shown in Table 3:

TABLE 3

Sample (I)	Condition	HPLC purity: day 0 (%)	HPLC purity: 1 week (%)
				Example 2 form a	25℃/60％RH	99.69	99.68
Example 2 form a	40℃/75％RH	99.69	99.71
				Amorphous form of CN106518841A	25℃/60％RH	99.28	97.63
Amorphous form of CN106518841A	40℃/75％RH	99.28	97.25

The purity of the crystal form A of the compound shown in the formula I is basically unchanged after the compound is placed under the conditions of 25 ℃/60% relative humidity and 40 ℃/75% relative humidity for one week, and the diffraction pattern of the crystal form is still shown in figure 1, namely the crystal form is also unchanged.

Example 5 hygroscopicity test

Dynamic water adsorption curves were collected on DVS Intrasic in SMS (surface Measurement systems).

20mg of the crystal form A obtained in example 2 was placed in an environment at 25 ℃/80% relative humidity to perform a dynamic moisture sorption (DVS) test, and the HPLC measurement results are shown in Table 4:

TABLE 4

Sample (I)	Moisture adsorption	Moisture-wicking property	Whether the crystal form is changed after DVS test
				Example 2 form a	0.16％	Almost has no hygroscopicity	Whether or not

The above results show that: the crystal form A of the compound related to the formula I has the moisture absorption increment of 0.16%, almost no moisture absorption and stability.

Claims

1. A crystalline form of the cyclohexane derivative N' - [ trans-4- [2- [7- (benzo [ b ] thiophene) -7-piperazinyl ] ethyl ] cyclohexyl ] -N, N-dimethylurea, designated form A, according to formula I, characterized in that it has diffraction peaks at least at 9.151 ° ± 0.2 °, 13.856 ° ± 0.2 °, 16.219 ° ± 0.2 ° and 18.585 ° ± 0.2 ° in an X-ray powder diffraction spectrum expressed in terms of 2 θ using radiation of CuK α, is characterized in that

2. A crystalline form according to claim 1 characterized in that form a further exhibits diffraction peaks at 2 Θ values of 16.929 ° ± 0.2 °, 17.652 ° ± 0.2 °, 20.355 ° ± 0.2 ° and 37.939 ° ± 0.2 °.

3. A crystalline form according to claim 2 characterized in that form a further exhibits diffraction peaks at 2 Θ values of 4.472 ° ± 0.2 °, 11.498 ° ± 0.2 °, 18.086 ° ± 0.2 °, 19.271 ° ± 0.2 °, 21.725 ° ± 0.2 °, 23.676 ° ± 0.2 °, 23.981 ° ± 0.2 °, 24.805 ° ± 0.2 °, 25.604 ° ± 0.2 °, 28.026 ° ± 0.2 °, 29.604 ± 0.2 °, 30.521 ± 0.2 °, 31.726 ± 0.2 °, 33.014 ± 0.2 °, 35.474 ± 0.2 ° and 36.165 ° ± 0.2 °; preferably, the XRPD pattern of form a is as shown in figure 1.

4. The crystalline form according to claim 1, characterized in that it has an endothermic peak at 150-170 ℃ in DSC analysis; preferably, the maximum absorption peak is 161.6 ℃; more preferably, the DSC pattern of said crystalline form is shown in figure 2.

5. A crystalline form according to claim 1, characterized by a weight loss at 150 ℃ of from 0.08 to 0.12% in TGA analysis; preferably, the TGA profile is as shown in figure 3.

6. A process for preparing the crystalline form according to any one of claims 1-5, comprising the steps of: recrystallizing the amorphous compound shown in the formula I in an organic solvent to obtain the crystal form of the compound shown in the formula I.

7. The process according to claim 6, wherein the form A is obtained by refluxing and clarifying the amorphous form of the compound of formula I in an organic solvent, cooling, stirring and filtering with suction.

8. The method according to claim 7, wherein the reflux temperature is 60-80 ℃; preferably, the cooling temperature is up to 20-25 ℃.

9. The method according to claim 6, wherein the organic solvent is selected from ethyl acetate, toluene, acetonitrile, isopropyl acetate, isopropanol, or a mixture of two or more thereof.

10. A pharmaceutical composition for treating or ameliorating schizophrenia, psychotic disorders, confusion, mood disorders, bipolar disorder, depression, phobias, obsessive-compulsive disorders, anxiety disorders or cognitive disorders, which comprises the crystalline form a of any of claims 1-5 and a pharmaceutical excipient.