CN104829532A - Method for preparing lorcaserin hydrochloride single crystal - Google Patents

Abstract

The invention relates to a method for preparing large single crystals of greencaserin hydrochloride, which is characterized in that it comprises the following steps: using a mixed solvent of water, acetonitrile and ethanol as the recrystallization medium at room temperature, wherein the mass ratio of water, acetonitrile and ethanol is 1: (0.5~5): (0.5~1), dissolve the crude greencaserin hydrochloride in a mixed solvent, raise the temperature of the system to 40~60°C, put it in a closed container and pressurize it to 2~5 atmospheres, lower the temperature to 0~10°C and let it stand for recrystallization for 1~3 days, and finally filter and dry to obtain large single crystals with large size and complete crystal form. The invention has the advantages of simple and convenient operation, suitability for industrial production, environmental protection, high product purity and high yield.

Description

a preparation Method for green caserin hydrochloride single crystal

technical field

The invention belongs to the field of preparation of crude drugs, in particular to a method for preparing large-particle single crystals of green caserin hydrochloride.

Background technique

Lorcaserin Hydrochloride is a kind of R-configuration cyclic amine hydrochloride, its chemical name is (R)-chloro-1-methyl-2,3,4,5-tetrahydro-1H -3-Benzazepine hydrochloride, the molecular formula is C ₁₁ H ₁₅ Cl ₂ N · 0.5H ₂ O. The structure is as follows:

Lvcaserin is a drug that acts on the central nervous system to suppress appetite. It was developed by the American Enina Pharmaceutical Company in 2005. Its specific target is 5-HT _2C , which has a strong effect on appetite control. There was no role for -HT _2A or 5-HT _2B receptors, which are associated with cardiovascular disease and hallucinations, respectively. The latest results of a large-scale phase III clinical trial showed that greencaserin has a weight-loss effect and has no effect on heart valves and pulmonary arteries. Different from other weight-loss drugs, Greencaserin can also improve heart rate, blood pressure and low-density lipoprotein cholesterol (LDL-C) levels while losing weight. The advantage of lvcaserin for weight loss is not in its efficacy, but in its safety, which is significantly better than existing drugs. In addition, it also has clear benefits for people with type 2 diabetes and cardiovascular risk factors. Therefore, the development of lvcaserin has a good market prospect .

The green caserin drug currently sold in the United States is called Belviq. US Patent US8168624B2 discloses three crystal forms of green caserin, crystal form I, crystal form II and crystal form III. The present invention prepares its large grain single crystal based on the stable crystal form III. The crystal form of the drug product will greatly affect the dissolution rate and bioavailability of the drug. In addition, according to the requirements of the preparation, the particle size of the raw material drug is easy to prepare within a reasonable range. Therefore, how to adopt a simple, reliable, and high-yield method to re-extract chlorocaserin hydrochloride crystals to obtain single crystals with high purity so as to achieve the best drug efficacy is an urgent problem to be solved.

Contents of the invention

The invention provides a new method for greencaserin hydrochloride single crystal which is easy to operate, suitable for industrial production, and has large crystal particles and complete structure, which is convenient for preparation.

The purpose of the present invention is achieved through the following technical solutions:

The method for preparing large-particle single crystals of greencaserin hydrochloride provided by the present invention is to finally obtain greencaserin hydrochloride by recrystallizing with water, acetonitrile and ethanol as solvents through the selection of various solvents and recrystallization conditions. Large-grain single crystal, the specific steps are as follows:

1) Dissolve the crude greencaserin hydrochloride in a mixed solvent of water, acetonitrile and ethanol according to a certain ratio at a temperature of 40~60°C, and stir evenly until clarification.

2) Put the obtained solution in a closed container and pressurize it to 2~5 atmospheres, cool down to 0~10°C and let it stand for recrystallization for 1~3 days. After the large crystals are precipitated in the solution, filter it with suction;

3) The crystals obtained in step 2) were vacuum-dried at 50-80°C for 2-5 hours to obtain large single crystals of greencaserin hydrochloride.

The green caserin hydrochloride prepared by the above method is a colorless and transparent large particle single crystal, which has been analyzed by differential scanning calorimetry, scanning electron microscope, polarizing microscope and single crystal X-ray diffraction. The large single crystal of green caserin hydrochloride belongs to the orthorhombic crystal system, the space group is: P2 ₁ 2 ₁ 2 ₁ , and the unit cell parameters are a=8.2396(4)Å; b=11.5169(7)Å; c=26.5462 (13)Å; α=90°; β=90°; γ=90°, Z=4, and the unit cell volume is 2519.1(2)Å ³ .

The advantage of the method for preparing the large particle single crystal of greencaserin hydrochloride provided by the invention is:

1) The operation is simple, the cost is low, and the yield is as high as 85% or more;

2) The obtained single crystal has high purity, complete crystal form, and large particles, which are convenient for preparation.

Schedule Notes

Fig. 1 is the spectrogram of the differential scanning of the large particle single crystal of green caserin hydrochloride prepared by embodiment 1 of the present invention;

Fig. 2 is the spectrogram of the polarizing microscope of the large particle single crystal of green caserin hydrochloride prepared by embodiment 6 of the present invention;

Fig. 3 is the crystal structure diagram of the large particle single crystal of green caserin hydrochloride prepared in Example 6 of the present invention.

Fig. 4 is the X-ray diffraction spectrum of the green caserin hydrochloride polycrystalline powder prepared in Example 7 of the present invention.

Detailed ways

Example 1

Weigh 1g of greencaserin hydrochloride sample, add 3g of water + 8g of acetonitrile mixed solvent at room temperature, raise the temperature of the system to 50°C, stir evenly, remove impurities by suction filtration after dissolution, and place in a closed container to pressurize to 2 Atmospheric pressure, lower the temperature to 10°C and stand for recrystallization for 3 days to obtain large single crystals with a size of 500-800 microns. After suction filtration, it was dried in a vacuum oven for 5 hours, and the calculated yield was 86% after weighing. Samples were taken for thermal analysis testing, and its melting point was 200±1°C, and its enthalpy value was 67.62 J/g. The thermal analysis curve is shown in Figure 1.

Example 2

Weigh 1g of green caserin hydrochloride sample, add 3g of water + 2.5g of methanol mixed solvent at room temperature, raise the temperature of the system to 50°C, stir evenly, after the solution is clear, remove the impurities by suction filtration, place in a closed container and pressurize to 2 atmospheres, lower the temperature to 10°C and stand for recrystallization for 3 days to obtain large single crystals larger than 500-700 microns in size. After suction filtration, it was dried in a vacuum oven for 5 hours, and the calculated yield was 88% after weighing.

Example 3

Weigh 1g of greencaserin hydrochloride sample, add 8g of acetonitrile + 2.5g of methanol mixed solvent at room temperature, raise the temperature of the system to 50°C, stir evenly, after the solution is clear, remove the impurities by suction filtration, place in a closed container and pressurize to 2 atmospheres, lower the temperature to 10°C and stand for recrystallization for 3 days to obtain large single crystals with a size of 300-600 microns. After suction filtration, it was dried in a vacuum oven for 5 hours, and the calculated yield was 87% after weighing.

Example 4

Weigh 1g of green caserin hydrochloride sample, add 3g of water + 8g of acetonitrile + 2.5g of methanol mixed solvent at room temperature, raise the temperature of the system to 50°C, stir evenly, after the solution is clear, remove impurities by suction filtration and place in a closed container Pressurize to 2 atmospheres, cool down to 10°C and stand for recrystallization for 3 days to obtain large single crystals larger than 400-800 microns in size. After suction filtration, it was dried in a vacuum oven for 5 hours, and the calculated yield was 91% after weighing.

Example 5

Weigh 1g of greencaserin hydrochloride sample, add 2g of water + 8g of acetonitrile + 1g of methanol mixed solvent at room temperature, raise the temperature of the system to 50°C, stir evenly, after it dissolves, filter it to remove impurities and place it in an airtight container Pressurize to 2 atmospheres, cool down to 10°C and stand for recrystallization for 3 days to obtain large single crystals larger than 500-800 microns in size. After suction filtration, it was dried in a vacuum oven for 5 hours, and the calculated yield was 86% after weighing.

Example 6

Weigh 1g of green caserin hydrochloride sample, add 3g of water + 6g of acetonitrile + 1g of methanol mixed solvent at room temperature, raise the temperature of the system to 50°C, stir evenly, remove impurities by suction filtration, place in a closed container and pressurize to 2 Atmospheric pressure, the temperature was lowered to 10°C and left to stand for recrystallization for 3 days, and a large number of large single crystals with a size of 500-1000 microns were obtained. After suction filtration, it was dried in a vacuum oven for 5 hours, and the calculated yield was 93% after weighing. A single crystal particle with a size of 0.75 mm × 0.85 mm × 1.1 mm was selected through polarizing microscope observation for testing and analysis on an X-ray diffractometer, as shown in the polarizing microscope photo in FIG. 2 . The results show that the crystal belongs to the orthorhombic crystal system, the space group is: P2(1)P2(1)P(1), and the unit cell parameters are a=8.2396(4)Å; b=11.5169(7)Å; c=26.5462 (13) Å; α=90°; β=90°; γ=90°; Z=4. The schematic diagram of its crystal structure is shown in Fig. 3 .

Example 7

Weigh 2g of greencaserin hydrochloride sample, add 3g of water + 6g of acetonitrile + 1g of methanol mixed solvent at room temperature, raise the temperature of the system to 50°C, stir evenly and directly cool down to 10°C for 3 days to stand for recrystallization, and a large amount of less than 200 micron size powder crystals. After suction filtration, it was dried in a vacuum oven for 5 hours, and the calculated yield was 73% after weighing. According to polycrystalline X-ray diffraction analysis, it is a polycrystalline form of Form III, as shown in FIG. 4 .

The chlorocaserin hydrochloride crystal form III single crystal prepared by the present invention is ground to obtain a polycrystalline powder, which is tested by a powder X-ray diffractometer when the Bragg 2θ angle is 3-40° (Cukα, λ=1.5418Å). The powder diffraction pattern is shown in Figure 4, and its characteristic spectral line data are listed in Table 1. In Table 1 d is the lattice spacing, I/I. Represents the relative intensity, expressed as a percentage of the strongest spectral line. The results show that the crystal form of the single crystal obtained by the present invention is consistent with the crystal form III reported in the literature after being ground into polycrystalline powder.

Table 1 Characteristic lines of Figure 4

d(Å) I/I. 23.9 100 31.2 21.4 26.5 21.2 22.8 19.7 18.9 19.2 28.6 18.6 15.4 17.5 14.9 12.0 13.7 8.92 10.2 8.79 16.7 5.3

For the greencaserin hydrochloride single crystal obtained in the present invention, detailed crystallographic data can be obtained by means of a single crystal diffractometer, and its unit cell parameters, crystal system and space group and other information are listed in Table 2.

Table 2 Crystallographic data and other structural determinations of Form Ⅲ

molecular formula C ₁₁ H ₁₅ Cl ₂ N 1/2H ₂ O Molecular mass 241.15 space group P2 ₁ 2 ₁ 2 ₁ crystal system Orthorhombic system a 8.2396(4)Å b 11.5169(7)Å c 26.5462(13)Å alpha 90° beta 90° gamma 90° unit cell volume 2519.1(2)Å ³ Molecular number of unit cell (Z) 4 density 1.272 g/ ^cm3 Scan Angle (Max) 25.350° R factor R1=0.0434, WR2=0.1024

The atomic coordinates of the single crystal are listed in Table 3, the bond lengths are listed in Table 4, and the bond angles are listed in Table 5 through analysis and calculation of the single crystal structure.

Table 3 Atomic position parameters of crystal form Ⅲ

atom x Y Z U(Å ² ) Cl1 0.2658(1) 0.8919(1) 1.07690 N1 -0.0518(3) 1.0023(2) 0.8325(1) H1A -0.12810 0.95200 0.82190 0.0700 H1B -0.05660 1.06470 0.81220 0.0700 C1 0.0823(3) 0.9132(3) 0.9934(1) H1 0.00500 0.94470 1.01490 0.0560 C2 0.2306(4) 0.8790(3) 1.0124(1) C3 0.3469(4) 0.8333(3) 0.9817(1) H3 0.44680 0.81050 0.99460 0.0720 C4 0.3137(4) 0.8217(3) 0.9313(1) H4 0.39310 0.79160 0.91010 0.0710 C5 0.1642(4) 0.8538(3) 0.9111(1) C6 0.0471(3) 0.9011(3) 0.9429(1) C7 -0.1151(3) 0.9403(3) 0.9218(1) H7 -0.16110 0.87450 0.90320 0.0610 C8 -0.0954(4) 1.0403(3) 0.8843(1) H8A -0.19630 1.08360 0.88280 0.0640 H8B -0.01190 1.09240 0.89660 0.0640 C9 0.1089(4) 0.9469(3) 0.8256(1) H9A 0.19230 1.00210 0.83520 0.0700 H9B 0.12340 0.92960 0.79010 0.0700 C10 0.1335(4) 0.8372(3) 0.8552(1) H10A 0.22480 0.79550 0.84090 0.0750 H10B 0.03800 0.78880 0.85110 0.0750 C11 -0.2385(4) 0.9750(4) 0.9620(2) H11A -0.24360 0.91570 0.98730 0.1190 H11B -0.34330 0.98400 0.94670 0.1190 H11C -0.20600 1.04700 0.97710 0.1190 Cl2 0.1102(1) 1.2225(1) 1.00070 N2 0.5229(3) 1.4701(2) 0.7934(1) H2A 0.59640 1.52750 0.79050 0.0650 H2B 0.48350 1.45590 0.76240 0.0650 C12 0.1920(3) 1.3217(3) 0.9129(1) H12 0.11500 1.37760 0.92120 0.0700 C13 0.2192(4) 1.2302(3) 0.9448(1)

Table 4 Intramolecular distances in Form Ⅲ single crystals

atom 1,2 distance 1,2 atom 1,2 distance 1,2 Cl1—C2 1.742(3) N2—H2B 0.9000 N1—H1A 0.9000 N2—C19 1.481(4) N1—H1B 0.9000 N2—C20 1.485(4) N1—C8 1.486(4) C12—H12 0.9300 N1—C9 1.482(4) C12—C13 1.372(5) C1—H1 0.9300 C12—C17 1.393(4) C1—C2 1.379(4) C13—C14 1.359(4) C1—C6 1.379(4) C14—H14 0.9300 C2—C3 1.364(5) C14—C15 1.391(4) C3—H3 0.9300 C15—H15 0.9300 C3—C4 1.371(5) C15—C16 1.379(4) C4—H4 0.9300 C16—C17 1.394(4) C4—C5 1.394(4) C16—C21 1.515(4) C5—C6 1.394(4) C17—C18 1.522(4) C5—C10 1.517(4) C18—H18 0.9800 C6—C7 1.517(4) C18—C19 1.526(4) C7—H7 0.9800 C18—C22 1.536(4) C7—C8 1.531(4) C19—H19A 0.9700 C7—C11 1.527(5) C19—H19B 0.9700 C8—H8A 0.9700 C20—H20A 0.9700 C8—H8B 0.9700 C20—H20B 0.9700 C9—H9A 0.9700 C20—C21 1.515(5) C9—H9B 0.9700 C21—H21A 0.9700 C9—C10 1.501(5) C21—H21B 0.9700 C10—H10A 0.9700 C22—H22A 0.9600 C10—H10B 0.9700 C22—H22B 0.9600 C11—H11A 0.9600 C22—H22C 0.9600 C11—H11B 0.9600 O1—H1C 0.8504 C11—H11C 0.9600 O1—H1D 0.8494 Cl2—C13 1.736(3) H9A—H2Ai 9.9734(5) N2—H2A 0.9000 H9A—C19i 9.3622 (27)

Table 5 Intramolecular bonding angles of non-hydrogen atoms in crystal form Ⅲ

atom atom atom angle N1 C9 C8 117.199 C1 C6 C3 91.528 C1 C6 C5 30.730 C1 C2 C3 29.341 C1 C2 C5 90.138 C1 C3 C5 60.797 C2 C3 C1 120.944 C2 C3 Cl1 120.204 C2 C3 C4 30.755 C2 C3 C6 91.388 C2 C1 Cl1 118.835 C2 C1 C4 90.189 C2 C1 C6 29.558 C2 Cl1 C4 150.938 C2 Cl1 C6 148.360 C2 C4 C6 60.633 C3 C2 C4 118.701 C3 C2 C1 29.714 C3 C2 C5 89.314 C3 C4 C1 88.987 C3 C4 C5 29.390 C3 C1 C5 59.601 C4 C3 C5 121.712 C4 C3 C2 30.544 C4 C3 C6 91.162 C4 C5 C2 91.171 C4 C5 C6 30.558 C4 C2 C6 60.618 C5 C6 C4 118.873 C5 C6 C10 121.766 C5 C6 C1 30.381 C5 C6 C3 89.982 C5 C4 C10 119.359 C5 C4 C1 88.495 C5 C4 C3 28.898 C5 C10 C1 152.146 C5 C10 C3 148.251 C5 C1 C3 59.601 C6 C1 C5 118.888 C6 C1 C7 120.932 C6 C1 C2 29.574 C6 C1 C2 88.322 C6 C5 C4 120.172 C6 C5 C2 89.314 C6 C5 C4 30.569 C6 C7 C4 150.501 C6 C7 C11 150.714 C6 C2 C8 58.749 C7 C6 C8 113.966 C7 C6 C7 111.739 C7 C11 C11 109.154 C8 N1 C11 113.922 C8 N1 C10 142.264 C8 C7 C5 35.374 C9 N1 C8 114.734 C10 C9 C20 115.356 C11 C7 C17 35.473 N2 C19 C14 117.110 C12 C13 C8 120.625 C12 C13 C10 28.770 C12 C13 C16 89.581 C12 C17 C14 91.861 C12 C17 C16 31.048 C12 C14 C16 60.827 C13 C14 C12 122.168 C13 C14 Cl2 118.970 C13 C14 C15 31.584 C13 C14 C17 92.205 C13 Cl2 Cl2 118.861 C13 Cl2 C15 90.594 C13 Cl2 C17 29.969 C13 Cl2 C15 150.543 C13 Cl2 C17 148.824 C13 C15 C17 60.626 C14 C13 C15 117.682 C14 C13 C12 29.062 C14 C13 C16 88.657 C14 C15 C12 88.629 C14 C15 C16 29.026 C14 C12 C16 59.610 C15 C16 C14 121.645 C15 C16 C13 90.911 C15 C16 C17 30.246 C15 C16 C21 32.009 C15 C14 C13 30.734 C15 C14 C17 91.426 C15 C14 C21 153.504 C15 C13 C17 60.697 C15 C13 C21 122.837 C15 C17 C21 62.250 C16 C15 C17 119.892 C16 C15 C21 119.161 C16 C15 C12 88.885 C16 C15 C14 29.329 C16 C17 C21 120.931 C16 C17 C12 31.041 C16 C17 C14 90.591 C16 C21 C12 151.817 C16 C21 C14 148.369 C16 C12 C14 59.563 C17 C12 C16 117.911 C17 C12 C18 121.966 C17 C12 C15 88.082 C17 C12 C13 29.406 C17 C16 C18 120.095 C17 C16 C15 29.862 C17 C16 C13 88.509 C17 C18 C15 149.784 C17 C18 C13 151.307 C17 C15 C13 58.677 C18 C17 C19 113.273 C18 C17 C22 113.564 C18 C19 C22 107.316 C19 N2 C18 114.585 C19 N2 C22 145.914 C19 C18 C22 36.487 C20 N2 C21 112.986 C21 C16 C20 113.534 C21 C16 C15 28.829 C21 C20 C15 123.394

*Angles are in degrees. Estimated standard deviations to the last decimal place are indicated in parentheses.

Claims (5)

1. prepare the method for green card look woods hydrochloride large-particle monocrystal for one kind, it is characterized in that: comprise the following steps: to attach most importance to crystallization medium with water, acetonitrile and alcohol mixed solvent, green card look woods hydrochloride, crude is dissolved in mixed solvent, system is warming up to 40 ~ 60 DEG C, treat that molten being placed on clearly in encloses container is forced into 2 ~ 5 normal atmosphere, cool to 0 ~ 10 DEG C of standing recrystallization 1 ~ 3 day, the drying of last suction filtration obtains that size is large, the large-particle monocrystal body of complete crystal form.

2. prepare the method for green card look woods hydrochloride large-particle monocrystal as claimed in claim 1, it is characterized in that: solvent for use is water, acetonitrile and ethanol and three's mass ratio is 1:(0.5 ~ 5): (0.5 ~ 1).

3. prepare the method for green card look woods hydrochloride large-particle monocrystal as claimed in claim 1 or 2, it is characterized in that: green card look woods hydrochloride, crude and mixed solvent mass ratio are 1:1 ~ 20.

4. prepare the method for green card look woods hydrochloride large-particle monocrystal as claimed in claim 1, it is characterized in that: green card look woods hydrochloride single crystal has a dehydration peak at 95.0 DEG C of places, and enthalpy is 63.8J/g, and melt temperature is 200.0 ± 1 DEG C, and enthalpy is 67.6J/g.

5. prepare the method for green card look woods hydrochloride large-particle monocrystal as claimed in claim 1, it is characterized in that: the large-particle monocrystal body of green card look woods hydrochloride belongs to rhombic system, and spacer is: P2 ₁2 ₁2 ₁, unit cell parameters is a=8.2396 (4); B=11.5169 (7); C=26.5462 (13); α=90 °; β=90 °; γ=90 °; Z=4, unit cell volume reaches 2519.1 (2) ³.