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CN-121991077-A - Method for preparing didanosine crystal form

CN121991077ACN 121991077 ACN121991077 ACN 121991077ACN-121991077-A

Abstract

The invention relates to a method for preparing a crystalline form of didodesine, which comprises the steps of dissolving didodesine in a first organic solvent, cooling to separate out part of didodesine crystals, and adding a second organic solvent to further separate out the crystals.

Inventors

  • ZHOU XINBO
  • ZHANG MIN

Assignees

  • 浙江京新药业股份有限公司

Dates

Publication Date
20260508
Application Date
20251106
Priority Date
20241106

Claims (10)

  1. 1. A process for the preparation of a crystalline form of didanosine comprising the steps of: (1) Dissolving didanosine in a first organic solvent; (2) Cooling to separate out part of Darcy crystals, and adding a second organic solvent to further separate out crystals; in the step (1), the first organic solvent is selected from one or more of ethyl formate, methyl acetate, propyl acetate, isopropyl acetate, butyl acetate and isobutyl acetate, preferably, the first organic solvent is isopropyl acetate or butyl acetate; in the step (2), the weight of the second organic solvent is 0.1-0.5 times of that of the first organic solvent in the step (1); in the step (1), the weight ratio of the didanosine to the first organic solvent is 1 (3-15).
  2. 2. The process for the preparation of crystalline form of didanosine of claim 1, wherein the second organic solvent is n-heptane.
  3. 3. The process for the preparation of crystalline form of didanosine according to claim 1, wherein in step (1), didanosine is dissolved in the first organic solvent by heating, preferably at a temperature of 30-60 ℃.
  4. 4. The process for the preparation of crystalline form of didanosine according to claim 1, wherein in step (2), the temperature is reduced to 0-10 ℃.
  5. 5. The process for the preparation of crystalline form of didanosine according to claim 1, wherein the weight ratio of didanosine to the first organic solvent is 1 (7-12).
  6. 6. The process for the preparation of crystalline form of didanosine according to claim 1, wherein in step (2) the weight of the second organic solvent is 0.3-0.4 times, more preferably 0.3-0.32 times the weight of the first organic solvent in step (1).
  7. 7. The process for preparing crystalline form of didanosine according to claim 1, wherein, between step (1) and step (2), a step of decolorizing is further included, preferably using activated carbon.
  8. 8. The process for the preparation of crystalline form of didanosine according to claim 7, wherein the weight ratio of activated carbon to didanosine is (0.01-0.02): 1, preferably 0.015:1.
  9. 9. The process for the preparation of crystalline form of didanosine according to claim 8, wherein the activated carbon decolorization time is 15-45 minutes, preferably 30 minutes.
  10. 10. The process for the preparation of crystalline form of didanosine according to any one of claims 1-9, wherein the prepared crystalline form of didanosine is didanosine form a.

Description

Method for preparing didanosine crystal form Technical Field The invention belongs to the field of drug crystal forms, and particularly relates to a method for preparing a didaxib crystal form. Background The chemical name of the didanosine is 7-chloro-3- (5-dimethylaminomethyl- [1,2,4] oxadiazol-3-yl) -5-methyl-4, 5-dihydro-imidazo [1,5-a ] [1,4] benzodiazepin-6-one, which is a partial agonist/partial positive allosteric modulator (pPAM) of gamma-aminobutyric acid A (GABAA) receptor, selectively acts on (GABA) A receptor alpha 1 subtype, can activate the receptor and rapidly inhibit the nervous system, can avoid overactivating the receptor and produce deep inhibition, and causes nerve side effects, has been developed for treating insomnia disorder, is an important improvement of traditional insomnia treatment medicines, and improves the daytime mental state of users. Patent document CN1350538A, CN113045574A, CN111620834a and the like sequentially disclose a preparation method of didanosine and an intermediate thereof and a non-sedative effect of the didanosine and the intermediate thereof on insomnia. These documents do not address polymorphism. Patent document CN109134471a discloses the solid form of didanosine and its corresponding preparation method, but it does not carefully study the preparation method of the didanosine crystal form. Disclosure of Invention The drugs used for pharmaceuticals are required to have high quality and stable crystal forms from the industrial production point of view, and the production method is also required to be safe, simple, high in yield, high in purity and capable of being produced in a large scale for a long time. However, the process of preparing crystalline forms of didodeoxycholic acid in patent document CN109134471a has some drawbacks, for example, chemical purity, yield and reproducibility of these crystalline forms in industrial production are not involved, while the preparation process of example 1 involves a step of high Wen Dijia methyl tert-butyl ether, which has serious safety hazards in industrial production, is prone to splash and explosion accidents, and the high-volume volatilization of methyl tert-butyl ether at high temperature seriously affects the physical health of workers. The preparation method can overcome the defects of the prior art, is safe to operate, is friendly to workers, and is suitable for industrial production. The invention provides a preparation method of a didanosine crystal form (preferably a crystal form A), which comprises the following steps: (1) Dissolving didanosine in a first organic solvent; (2) Cooling to separate out part of Darcy crystals, and adding a second organic solvent to further separate out crystals; in the step (1), the first organic solvent is selected from one or more of ethyl formate, methyl acetate, propyl acetate, isopropyl acetate, butyl acetate and isobutyl acetate, preferably, the first organic solvent is isopropyl acetate or butyl acetate; In the step (1), the weight ratio of the didanosine to the first organic solvent is 1 (3-15), preferably, the weight ratio of the didanosine to the first organic solvent is 1 (7-12), and can be specifically 1:9.6 or 1:12; optionally, in step (1), the didanosine is dissolved in the first organic solvent by heating, preferably at a temperature of 30-60 ℃; in the step (2), the temperature is reduced to 0-10 ℃ preferably; In step (2), the second organic solvent is preferably n-heptane; In step (2), the weight of the second organic solvent is 0.1 to 0.5 times, preferably 0.3 to 0.4 times, more preferably 0.3 to 0.32 times that of the first organic solvent in step (1); Optionally further comprising a step of decolorizing between step (1) and step (2), preferably using activated carbon; In some embodiments, the weight ratio of activated carbon to didanosine is (0.01-0.02): 1, preferably 0.015:1; in some embodiments, the activated carbon decolorization time is 15 to 45 minutes, preferably 30 minutes; In some embodiments, the step of decolorizing further comprises filtering, etc.; In some embodiments, in step (2), further comprising filtering, washing, drying; In some embodiments, the preparation process of the present invention prepares crystalline form a of didanosine; In some embodiments, the didanosine form A has characteristic peaks in an X-ray powder diffraction pattern measured using a Cu-K alpha ray form at least at diffraction angles 2θ of 6.6+ -0.2 °, 9.1+ -0.2 °, 16.9+ -0.2 °, 19.6+ -0.2 °, 19.8+ -0.2 °, 21.0+ -0.2 °, 22.9+ -0.2 °, 23.7+ -0.2 °, 27.4+ -0.2 °, preferably, the diffraction angles 2θ are also at least 12.5±0.2°, 12.9±0.2°, 14.7±0.2°, 15.9±0.2°, 18.5±0.2°, 20.0±0.2°, 20.5±0.2°, 22.6±0.2°, 23.4±0.2°, 24.5±0.2°, and more preferably the deviation of the diffraction angles is ±0.1°; in the specific embodiment of the invention, the characteristic spectral line of the X-ray powder diffraction pattern of the didanosine crystal form A is shown in table 1, and pr