Crystal form of p-hydroxyphenyl hydantoin and preparation method thereof

Abstract

The invention relates to the technical field of crystal form research, in particular to a p-hydroxyphenyl hydantoin crystal form and a preparation method thereof, the crystal form is SMeOH or SEtOH, the SMeOH has characteristic absorption peaks at the following 2 theta angles in an XRD diffraction pattern: 17.0 + / -0.3, 18.0 + / -0.3, 19.0 + / -0.3, 20.0 + / -0.3, 22.0 + / -0.3, 24.0 + / -0.3, 25.0 + / -0.3, 27.0 + / -0.3, 2.0 + / -0.3 and 29.0 + / -0.3, and the SEtOH has characteristic absorption peaks at the following 2 theta angles in an XRD diffraction pattern: 17.0 + / -0.3, 18.0 + / -0.3, 20.0 + / -0.3, 23.0 + / -0.3 and 27.0 + / -0.3. According to the crystal form of p-hydroxyphenyl hydantoin and the preparation method thereof, the problems that at present, p-hydroxyphenyl hydantoin is unstable in quality, and the yield of D-p-hydroxyphenylglycine produced through enzyme catalysis is low are solved.

Description

Technical Field

[0001] The invention relates to the technical field of crystal form research, and in particular to a crystal form of p-hydroxyphenylhydantoin and a preparation method thereof. Background Art

[0002] Polymorphism is the phenomenon that the chemical composition of a substance is the same, but the crystal structure is different. Although each crystal form of the same substance has the same molecular composition, the arrangement of the molecules and the interaction between the molecules may be very different. The discovery of polymorphism has a long history. The earliest discovery of polymorphism of inorganic substances was in 1788, when scientists discovered that aragonite and calcite were both calcium carbonate, but their structures were different. The study of polymorphism of organic matter began in 1832, when Russian scientist Uller and others discovered that benformamide had polymorphism. In recent years, with the advancement of science and technology, more and more substances have been found to have polymorphism, and different crystal forms have completely different properties. For example, diamond, graphite, fullerene and nanotubes are all different crystal forms of carbon, showing different properties respectively. Therefore, it can be said that the different properties and characteristics of polymorphism affect the application of substances in life. Among them, the greatest impact is solid organic drugs. Drugs with the same chemical composition may exhibit different physical and chemical properties in different crystal forms, such as density, crystal morphology, hardness, melting point and solubility. As a result, polymorphism can directly affect the efficacy, bioavailability and toxic side effects of drugs, which further affects the production and preparation process of drugs. Some scholars have also studied the therapeutic effects of different glycine crystal forms on hereditary systemic rigidity in mice and found that the therapeutic effect of the γ crystal form is relatively better than that of the α crystal form. Typical polymorphic drugs also include odorless chloramphenicol, an antibiotic used for children. It has three different crystal forms and an amorphous form. The metastable B crystal form is more easily and quickly hydrolyzed by enzymes than the other two crystal forms. During the use of ritonavir produced by Abbott, the metastable crystal form I that has been on the market will be converted into the stable crystal form II. Since the solubility of the metastable crystal form is greater than that of the stable crystal form, it ultimately leads to a decrease in drug efficacy. Since polymorphism can affect the efficacy and safety of drugs, in the United States Pharmacopoeia, the crystal form has been listed as one of the quality control indicators of drugs, and my country's drug research and development has gradually listed the crystal form control of drugs as an indispensable part.

[0003] In recent years, with the continuous expansion of the domestic production scale of p-hydroxyphenyl hydantoin, there have been many reports on the technical improvement of the p-hydroxyphenyl hydantoin production process, and the related literature and patents have been reported. The improvement work is mainly focused on improving the reaction yield and the treatment of three wastes, and there are few reports on the research of product crystal form. At the same time, due to the differences in various production processes and post-treatments, the obtained p-hydroxyphenyl hydantoin product crystal form is not uniform, which causes a series of problems such as unstable enzyme catalytic efficiency conversion rate and low yield in the subsequent enzymatic synthesis of D-p-hydroxyphenylglycine.

[0004] In view of the above-mentioned defects, the inventors of the present invention finally obtained the present invention after a long period of research and practice. Summary of the invention

[0005] The purpose of the present invention is to solve the problem that the quality of p-hydroxyphenylhydantoin is unstable and uncontrollable and the yield of D-p-hydroxyphenylglycine produced by enzyme catalysis is low, and to provide a crystal form of p-hydroxyphenylhydantoin and a preparation method thereof.

[0006] In order to achieve the above object, the present invention discloses a crystalline form of p-hydroxyphenylhydantoin, wherein the crystalline form is S MeOH or S EtOH , the S MeOH The following 2θ angles in the XRD diffraction pattern: 17.0±0.3, 18.0±0.3, 19.0±0.3, 20.0±0.3, 22.0±0.3, 24.0±0.3, 25.0±0.3, 27.0±0.3, 2.0±0.3, 29.0±0.3 have characteristic absorption peaks, and the S EtOH The following 2θ angles in the XRD diffraction pattern: 17.0±0.3, 18.0±0.3, 20.0±0.3, 23.0±0.3, and 27.0±0.3 have characteristic absorption peaks.

[0007] The present invention also discloses a method for preparing a crystalline form of p-hydroxyphenylhydantoin, comprising the following steps:

[0008] S1, mixing p-hydroxyphenyl hydroxydione solid with a solvent, wherein the amount of the solvent is 20 times the volume of the p-hydroxyphenyl hydroxydione solid, heating and stirring;

[0009] S2, after the temperature is raised to 65°C, the stirring rate is maintained at 300 rpm and the mixture is stirred and dissolved for 1 hour;

[0010] S3, cooling to 45°C, evaporating the solvent under reduced pressure and then growing the crystal for 1 hour;

[0011] S4, cooling to 20°C and stirring for 0.5 hour, then filtering, washing and drying to obtain p-hydroxyphenylhydrazone.

[0012] In the step S1, the solvent used is any one of methanol, ethanol, isopropanol and water.

[0013] In the step S1, the solvent used is methanol.

[0014] In step S2, the stirring and dissolving temperature is 45-65°C.

[0015] In step S2, the stirring and dissolving temperature is 60-65°C.

[0016] In step S3, the crystal growing temperature is 35-55°C.

[0017] In step S3, the crystal growing temperature is 40-45°C.

[0018] In step S4, the filtration temperature is 0-30°C.

[0019] In step S4, the filtration temperature is 20-25°C

[0020] Compared with the prior art, the beneficial effect of the present invention is that: the present invention optimizes the crystallization process of p-hydroxyphenylhydantoin crystal form I, investigates the effects of different crystallization methods and the amount of solvent on the product yield and product content, and finally determines the optimized crystallization process conditions of p-hydroxyphenylhydantoin crystal form I. The product obtained by the optimized crystallization process has a higher yield and lower cost for enzymatic production of D-p-hydroxyphenylglycine. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 is the S obtained in Example 1 MeOH XRD diffraction pattern of

[0022] Figure 2 is S obtained in Example 2 EtOH XRD diffraction pattern of

[0023] Figure 3 is the S obtained in Example 1 MeOH The crystal form;

[0024] Figure 4 is S obtained in Example 2 EtOH of crystal form. DETAILED DESCRIPTION

[0025] The above and other technical features and advantages of the present invention are described in more detail below in conjunction with the accompanying drawings.

[0026] Example 1

[0027] Characteristic crystal form S MeOH Preparation:

[0028] The solid content of the raw material p-hydroxyphenylhydrazine used is 98%.

[0029] 1. Weigh 20g of p-hydroxyphenyl hydantoin solid and 100mL of methanol, add them together into a 500mL single-mouth bottle, set the temperature to 65°C, stir at 300rpm to dissolve, and after complete dissolution, maintain the stirring rate, cool to 45°C at a rate of 0.25°C / min, grow crystals at 40-45°C for 1h, cool to 20°C and keep for crystallization for 1h. Filter and wash, dry at 80-85°C to obtain p-hydroxyphenyl hydantoin compound S MeOH Product 18.6g, yield 93%, product content 98.8%.

[0030] 2. Weigh 20g of p-hydroxyphenyl hydantoin solid and 200mL of methanol, add them together into a 500mL single-mouth bottle, set the temperature to 65°C, stir at 300rpm to dissolve, and after complete dissolution, maintain the stirring rate, cool to 45°C at a rate of 0.25°C / min, evaporate 100ml of solvent under reduced pressure, grow crystals at 40-45°C for 1h, cool to 20°C and keep warm for 1h. Filter and wash, dry at 80-85°C to obtain p-hydroxyphenyl hydantoin compound S MeOH Product 18.4g, yield 92%, product content 99.1%.

[0031] 3. Weigh 20g of p-hydroxyphenyl hydantoin solid and 300mL of methanol, add them together into a 500mL single-mouth bottle, set the temperature to 65°C, stir at 300rpm to dissolve, and after complete dissolution, maintain the stirring rate, cool to 45°C at a rate of 0.25°C / min, evaporate 200ml of solvent under reduced pressure, grow crystals at 40-45°C for 1h, cool to 20°C and keep warm for 1h. Filter and wash, dry at 80-85°C to obtain p-hydroxyphenyl hydantoin compound S MeOH Product 18.6g, yield 93%, product content 99.3%.

[0032] 4. Weigh 20g of p-hydroxyphenyl hydantoin solid and 400mL of methanol, add them together into a 500mL single-mouth bottle, set the temperature to 65°C, stir at 300rpm to dissolve, and after complete dissolution, maintain the stirring rate, cool to 45°C at a rate of 0.25°C / min, evaporate 300ml of solvent under reduced pressure, grow crystals at 40-45°C for 1h, cool to 20°C and keep warm for 1h. Filter and wash, dry at 80-85°C to obtain p-hydroxyphenyl hydantoin compound S MeOH Product 18.8g, yield 94%, product content 99.5%. XRD diffraction spectrum as shown Figure 1 shown.

[0033] Example 2

[0034] Characteristic crystal form S MeOH Preparation:

[0035] Weigh 20g of p-hydroxyphenyl hydantoin solid 40g, measure 800mL of methanol, add them together into a 2000mL single-mouth bottle, set the temperature to 65°C, stir at 300rpm to dissolve, and after complete dissolution, maintain the stirring rate, cool at a rate of 0.25°C / min, evaporate 300ml of solvent under reduced pressure, grow crystals for 1h, and keep warm for crystallization for 1h after cooling. After filtration and washing, dry at 80-85°C to obtain different batches of p-hydroxyphenyl hydantoin compound S MeOH Product quality is as follows:

[0036] Table 1 Effect of different crystal growth temperatures on product quality

[0037]

[0038] Table 2 Effect of different filtration temperatures on product quality

[0039]

[0040] Example 3

[0041] Characteristic crystal form S EtOH Preparation

[0042] Weigh 20g of p-hydroxyphenyl hydantoin solid, measure 400mL of ethanol, add them together into a 500mL single-mouth bottle, set the temperature to 65°C, stir at 300rpm to dissolve, and after complete dissolution, maintain the stirring rate, cool to 45°C at a rate of 0.25°C / min, evaporate 300ml of solvent under reduced pressure, grow crystals at 40-45°C for 1h, cool to 20°C and keep warm for 1h. Filter and wash, dry at 80-85°C to obtain p-hydroxyphenyl hydantoin compound S MeOH Product 19.1g, yield 95.5%, product content 99.4%. XRD diffraction spectrum as Figure 2 shown.

[0043] Example 4

[0044] The solvent for the enzymatic synthesis of D-p-hydroxyphenylglycine by p-hydroxyphenylhydantoin is purified water, and its solubility in water directly affects the yield of the enzyme-catalyzed product.

[0045] 1. Take 0.5 g of p-hydroxyphenylhydrazine, add purified water to make up to 1 L, and dissolve by ultrasonic. The dissolution effects of p-hydroxyphenylhydrazine with different characteristic crystal forms in purified water are shown in Table 3.

[0046] Table 3 Dissolution effect of different characteristic crystal forms of p-hydroxyphenylhydantoin in purified water

[0047]

[0048]

[0049] 2. The enzymatic synthesis of D-p-hydroxyphenylglycine by p-hydroxyphenylhydantoin with different characteristic crystal forms is shown in Table 4

[0050] Table 4 Enzymatic synthesis of D-p-hydroxyphenylglycine catalyzed by p-hydroxyphenylhydantoin with different characteristic crystal forms

[0051] raw material weight Conversion time Conversion rate Product Weight Yield <![CDATA[S MeOH ]]> 10g 20h 95.5％ 7.83g 90％ <![CDATA[S EtOH ]]> 10g 22h 95.3％ 7.22g 83％ <![CDATA[S i-PrOH ]]> 10g 25h 95.2％ 6.61g 76％ <![CDATA[S 水 ]]> 10g 30h 95.4％ 6.52g 75％

[0052] The crystal morphology of the polymorph of p-hydroxyphenylhydantoin was characterized by polarizing microscopy. Figure 3 , Figure 4 shown. Figure 3 Medium S MeOH It is a block-shaped regular crystal. Figure 4 Medium S EtOH It is an irregular crystal; Figure 1 For S MeOH XRD diffraction pattern of Figure 2 For S EtOH XRD diffraction pattern.

[0053] The above description is only a preferred embodiment of the present invention, which is only illustrative and not restrictive of the present invention. Those skilled in the art understand that many changes, modifications, and even equivalences may be made to the present invention within the spirit and scope defined by the claims of the present invention, but all of them will fall within the scope of protection of the present invention.

Claims

1. A crystalline form of p-hydroxyphenylhydrazine, characterized in that: The crystal form is S MeOH or S EtOH , the S MeOH The following 2θ angles in the XRD diffraction pattern: 17.0±0.3, 18.0±0.3, 19.0±0.3, 20.0±0.3, 22.0±0.3, 24.0±0.3, 25.0±0.3, 27.0±0.3, 2.0±0.3, 29.0±0.3 have characteristic absorption peaks, and the S EtOH The following 2θ angles in the XRD diffraction pattern: 17.0±0.3, 18.0±0.3, 20.0±0.3, 23.0±0.3, and 27.0±0.3 have characteristic absorption peaks.

2. A method for preparing the crystalline form of p-hydroxyphenylhydantoin as claimed in claim 1, characterized in that: The following steps are involved: S1, mixing p-hydroxyphenyl hydroxydione solid with a solvent, wherein the amount of the solvent is 20 times the volume of the p-hydroxyphenyl hydroxydione solid, heating and stirring; S2, after the temperature is raised to 65°C, the stirring rate is maintained at 300 rpm and the mixture is stirred and dissolved for 1 hour; S3, cooling to 45°C, evaporating the solvent under reduced pressure and then growing the crystal for 1 hour; S4, cooling to 20°C and stirring for 0.5 hour, then filtering, washing and drying to obtain p-hydroxyphenylhydrazone.

3. A method for preparing a crystalline form of p-hydroxyphenylhydantoin as claimed in claim 2, characterized in that: In the step S1, the solvent used is any one of methanol, ethanol, isopropanol and water.

4. The method for preparing a crystalline form of p-hydroxyphenylhydantoin as claimed in claim 2, characterized in that: In the step S1, the solvent used is methanol.

5. The method for preparing a crystalline form of p-hydroxyphenylhydantoin as claimed in claim 2, characterized in that: In step S2, the stirring and dissolving temperature is 45-65°C.

6. The method for preparing a crystalline form of p-hydroxyphenylhydantoin as claimed in claim 2, characterized in that: In step S2, the stirring and dissolving temperature is 60-65°C.

7. The method for preparing a crystalline form of p-hydroxyphenylhydantoin as claimed in claim 2, characterized in that: In step S3, the crystal growing temperature is 35-55°C.

8. The method for preparing a crystalline form of p-hydroxyphenylhydantoin as claimed in claim 2, characterized in that: In step S3, the crystal growing temperature is 40-45°C.

9. The method for preparing a crystalline form of p-hydroxyphenylhydantoin as claimed in claim 2, characterized in that: In step S4, the filtration temperature is 0-30°C.

10. The method for preparing a crystalline form of p-hydroxyphenylhydantoin according to claim 2, characterized in that: In step S4, the filtration temperature is 20-25°C.

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