WO2019015312A1 - Cristal de sel sodique de danoprévir et procédé pour sa préparation - Google Patents

Cristal de sel sodique de danoprévir et procédé pour sa préparation Download PDF

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Publication number
WO2019015312A1
WO2019015312A1 PCT/CN2018/075917 CN2018075917W WO2019015312A1 WO 2019015312 A1 WO2019015312 A1 WO 2019015312A1 CN 2018075917 W CN2018075917 W CN 2018075917W WO 2019015312 A1 WO2019015312 A1 WO 2019015312A1
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Prior art keywords
crystal
sodium
temperature
solution
reaction
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PCT/CN2018/075917
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English (en)
Chinese (zh)
Inventor
吴劲梓
古德蒙森·克里斯蒂安
杨百灵
单波
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歌礼药业（浙江）有限公司
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Publication of WO2019015312A1 publication Critical patent/WO2019015312A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/14—Extraction; Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/14—Extraction; Separation; Purification
    • C07K1/30—Extraction; Separation; Purification by precipitation

Definitions

  • the invention relates to the technical field of pharmacy, in particular to a crystal of a hepatitis C treatment drug danovir sodium (ASC08) and a preparation method thereof.
  • ASC08 hepatitis C treatment drug danovir sodium
  • Danofrevir sodium English name Danoprevir Sodium Salt, code ASC08
  • ASC08 is a highly effective anti-hepatitis C virus drug whose chemical structure is as follows:
  • the rememberivir sodium crystal of the present invention uses Cu-K ⁇ radiation, and the X-ray powder diffraction pattern expressed by 2 ⁇ angle is 5.086 ⁇ 0.1, 7.231 ⁇ 0.1, 8.004 ⁇ 0.1, 9.524 ⁇ 0.1, 10.199 ⁇ 0.1, 13.089 ⁇ 0.1, 14.561 ⁇ 0.1, 17.517 ⁇ 0.1, and 19.325 ⁇ 0.1 have diffraction peaks; more preferably, the crystal uses Cu-K ⁇ radiation, and the X-ray powder diffraction pattern expressed in 2 ⁇ angle is 5.086 ⁇ 0.1, 7.231 ⁇ 0.1 , 8.004 ⁇ 0.1, 9.524 ⁇ 0.1, 10.199 ⁇ 0.1, 11.511 ⁇ 0.1, 13.089 ⁇ 0.1, 14.561 ⁇ 0.1, 16.590 ⁇ 0.1, 17.517 ⁇ 0.1, 18.283 ⁇ 0.1, 19.325 ⁇ 0.1, 19.844 ⁇ 0.1 and 20.589 ⁇ 0.1 Diffraction peaks.
  • the Xanthrene sodium crystal of the present invention uses Cu-K ⁇ radiation, and the X-ray powder diffraction pattern expressed in 2 ⁇ angle is as shown in FIG. 1 .
  • Dannuoruiwei sodium crystal of the present invention KBr tablet method using a measured infrared spectrum 3545cm -1, 1710cm -1, 1672cm -1 , 1235cm -1, 1117cm -1 at a characteristic absorption peaks; more preferably, the present
  • the infrared spectrum of the invented danovir sodium crystals measured by the KBr tablet method is shown in FIG.
  • the DSC spectrum of the dismissivir sodium crystal of the present invention measured at a rate of 10 ° C / minute is shown in FIG. 5 .
  • the TGA spectrum of the danovir sodium crystal of the present invention is shown in Fig. 6.
  • the invention also provides a method for preparing crystals of consequenceivir sodium, wherein the synthetic route of rememberivir sodium is as follows:
  • the preparation method of the danovir sodium sodium crystal of the invention comprises the following steps:
  • step (1) the 32 wt% aqueous NaOH solution is fed in an amount of from 1.0 to 14 equivalents of rememberivir.
  • the preparation process of the Dannoribe sodium of the present invention is as follows:
  • the invention prepares the hepatitis C treatment drug danovir sodium crystal, and the crystal is characterized.
  • the crystal of essenceivir sodium provided by the invention provides an important foundation and reference value for the research of the subsequent pharmaceutical dosage form and therapeutic effect.
  • Figure 1 is an X-ray powder diffraction pattern of the crystal of the present invention
  • Figure 2 is an X-ray powder diffraction pattern of the crystal of the present invention labeled 2 ⁇ position;
  • Figure 3 is an X-ray powder diffraction data sheet of the crystal of the present invention.
  • FIG. 4 is an infrared spectrum (IR) of the crystal of the present invention.
  • FIG. 5 is a differential scanning calorimetry (DSC) pattern of the crystal of the present invention.
  • FIG. 6 is a thermogravimetric analysis (TGA) of the crystal of the present invention.
  • step 1
  • the compound represented by P3 (82.5-90.0 kg, 1.1-1.2X was added to the reaction vessel (Note: in the present application, the charge ratio X is expressed as DPC-based mass multiple, the same below), tetrahydrofuran (525-540 kg) , 7.0-7.2X), start stirring. Control the reaction temperature below 0 ° C, add pivaloyl chloride (22.5-23.3kg, 0.30-0.31X) into the reaction vessel. Adjust the temperature to 0 ⁇ 5 ° C under nitrogen protection. , stirring time 90 ⁇ 120 minutes.
  • process water 225-240 kg, 3.0-3.2X
  • temperature of the reaction vessel was controlled to be 40 ° C or lower, and concentrated under reduced pressure.
  • Toluene 653-675 kg, 8.7-9.0X
  • 2N hydrochloric acid 66.0-67.5 kg, 0.88-0.90X
  • the organic phase was washed with process water (128-135 kg, 1.7-1.8X) and 4 wt% NaOH solution (156-173 kg, 2.1-2.3X), allowed to stand for stratification, and the aqueous phase was removed; finally, a 25 wt% NaCl solution was used ( 225-232 kg, 3.0-3.1X) Wash.
  • the internal temperature of the reactor was controlled to be below 60 ° C.
  • the solution in the reaction vessel was concentrated under reduced pressure, and then toluene was added to continue distillation under reduced pressure until the moisture of the feed liquid did not exceed 0.05%. If the water is unsatisfactory, the toluene is continuously distilled under reduced pressure until it is passed, and a toluene solution of the compound (TPC) of the formula II is obtained.
  • the temperature of the feed liquid was controlled to be 10 ° C or lower, benzoyl chloride (27.8-28.5 kg, 0.37-0.38X) was added, and then stirred at -3 to 3 ° C for at least 0.5 hours.
  • the temperature of the reaction vessel was controlled at -3 to 3 ° C, and solid lithium t-butoxide (15.0-15.8 kg, 0.20-0.21X) was added thereto in portions.
  • the reaction vessel is kept stirring at -3 to 3 ° C for at least 1 hour, sampled, and the reaction end point is detected by HPLC.
  • the remaining amount of TPC is not more than 3.0%, and the reaction is considered complete. If the reaction is not complete, it is supplemented at -3 to 3 ° C.
  • the benzoyl chloride and lithium t-butoxide were added and stirring was continued until the reaction was completed.
  • toluene (330-345 kg, 4.4-4.6X) and 4 wt% NaOH solution (188-203 kg, 2.5-2.7X) were added to the reaction vessel, stirred, and allowed to stand for separation, and the organic layer was treated with process water (90). -105kg, 1.2-1.4X), 4wt% NaOH solution (90-105kg, 1.2-1.4X), then wash with process water (67.5-82.5kg, 0.9-1.1X), then process water (203-218kg) Washed with 2.7-2.9X) and 35wt% hydrochloric acid (11.3-12.0kg, 0.15-0.16X) and finally washed with 25wt% NaCl solution (75.0-82.5kg, 1.0-1.1X).
  • catalyst Catalyst-5065 (0.150-0.190 kg, 0.0020-0.0025X) with dichloromethane (12.0-14.25 kg, 0.16-0.19X) and toluene (20.3-22.5) Kg, 0.27-0.30X) Dissolved and ready for use.
  • the benzoyl-TPC toluene solution in the reactor was bubbled through the nitrogen gas for 2-3 hours. The temperature was then adjusted to 68-75 °C.
  • the Catalyst-5065 dichloromethane/toluene solution to be used was transferred to the reaction kettle. Stir at 68-75 ° C for at least 20 minutes. Sampling, HPLC reaction method to detect the end of the reaction, the remaining amount of benzoyl-TPC is not more than 3.0%, the reaction is considered complete, if the reaction is not complete, the catalyst solution is added, and stirring is continued until the reaction is completed.
  • reaction vessel was quenched by adding process water (1.13-1.43 kg, 0.015-0.020X), stirred for at least 10 minutes, controlled to an internal temperature of 55 ° C or lower, and the reaction solution was concentrated under reduced pressure.
  • process water (1.13-1.43 kg, 0.015-0.020X)
  • tetrahydrofuran (405-420 kg, 5.4-5.6X)
  • tetrahydrofuran (67.5-82.5 kg, 0.9-1.1X) and ethanol (488-503 kg, 6.5 -6.7X)
  • ethanol 488-503 kg, 6.5 -6.7X
  • Process water (98-113 kg, 1.3-1.5X) was added to the mixed solution of the compound of the formula IV in the reaction vessel, and the temperature was adjusted to 20-25 ° C and stirred for at least 1 hour. Under the protection of nitrogen, the temperature was controlled to 0-10 ° C, and a 30 wt% NaOH solution (330-345 kg, 4.4-4.6X) was added to the mixed solution of the compound of the formula IV in the reaction kettle, and the temperature was adjusted to 5-10 ° C after the completion of the dropwise addition. The mixture was stirred for 9 hours or more, sampled, and the reaction end point was detected by HPLC. The residual amount of the compound represented by the formula IV was not more than 1.0%, and the reaction was completed. If the reaction was incomplete, stirring was continued at 5 to 10 ° C until the reaction was completed.
  • the aqueous phase was extracted again with dichloromethane (142.5-157.5 kg, 1.9-2.1X) and the organic layers were combined and transferred to a kettle. Control the internal temperature below 60 ° C, concentrate at atmospheric pressure, add tetrahydrofuran (143-158 kg, 1.9-2.1X), adjust the temperature to 50-55 ° C. RCM carboxylic acid seed crystals were added, the temperature was adjusted to 63-68 ° C, tetrahydrofuran (743-758 kg, 9.9-10.1X) was added to the reactor in batches, and the jacket hot water temperature was controlled below 80 ° C for atmospheric distillation. Under nitrogen protection, slowly adjust the temperature to 0-5 ° C and stir for at least 12 hours.
  • the contents of the kettle were filtered and the filter cake was washed with tetrahydrofuran.
  • the filter cake was sampled and tested. If it was unqualified, it was beaten with tetrahydrofuran (113-225 kg, 1.5-3.0X) and filtered.
  • the wet product is dried under reduced pressure at 30-50 ° C for 15-21 hours. The moisture and solvent residues are sampled. If it is not allowed to continue to dry until it is qualified, the compound of formula V (RCM carboxylic acid) is obtained.
  • the compound of formula V (34.7-35.4 kg, 0.99-1.01X net weight) and tetrahydrofuran (175-182 kg, 5.0-5.2X) were added to the reaction vessel. The temperature was adjusted to 60-70 ° C under nitrogen protection. Tetrahydrofuran (140-175 kg, 4.0-5.0X) was added to the reactor in batches, and the jacket hot water temperature was controlled to be 80 ° C or less, and concentrated under normal pressure. The water and ethanol residues were taken by sampling, and the moisture and ethanol residues were not more than 0.05%, which was considered to be acceptable. If it was not qualified, the above distillation operation was repeated.
  • cyclopropylsulfonamide (8.8-9.1 kg, 0.25-0.26X) and tetrahydrofuran (105-140 kg, 3.0-4.0X) were added, and the temperature was adjusted to 60-70 °C.
  • the temperature of the reaction vessel was adjusted to 10-15 ° C, and purified water (245-280 kg, 7.0-8.0X) and toluene (70-105 kg, 2.0-3.0X) were added to the reaction vessel, stirred, and allowed to stand for stratification. .
  • the aqueous phase was extracted with toluene (70-105 kg, 2.0-3.0X).
  • the organic phases were combined, and the internal temperature of the reaction vessel was controlled to be 25 ° C or lower, and concentrated under reduced pressure.
  • the organic phase in the autoclave was washed with purified water (123-158 kg, 3.5-4.5X) and 18 wt% sulfuric acid (29.8-33.6 kg, 0.85-0.96X).
  • the material in the crystallization kettle was filtered. After filtration, the wet product was beaten with n-heptane (70-84 kg, 2.0-2.4X) and absolute ethanol (42-56 kg, 1.2-1.6X) for at least 1.0 hour and filtered. The wet cake was washed with a mixed solution of n-heptane (11-14 kg, 0.3-0.4X) and absolute ethanol (8-10 kg, 0.24-0.28X). Sampling wet product analysis, if the test result exceeds the warning line, continue to be beaten once with n-heptane and absolute ethanol, and the wet product test results are qualified and dried.
  • the wet product is dried under reduced pressure at 60-70 ° C for 12-16 hours, and the water and solvent residues are sampled. If the result is unsatisfactory, the pressure is dried under reduced pressure until the result meets the requirements, and the dried product of assignivir sodium is obtained.
  • the results of the analysis are shown in Figure 5.
  • the DSC curve of the Dannovir sodium sample showed that the thermal spectrum analysis was characterized by two endothermic peaks with peaks of 162.6 ° C and 240.0 ° C respectively; when the temperature was higher than 204.6 ° C, the sample of Danolone sodium decomposed.
  • the results of the analysis are shown in Figure 6.
  • the TG curve showed a weight loss peak in the TG curve of the Dannoribe sodium sample in the region of about 64 to 169 ° C, indicating that H 2 O and ethanol were continuously lost.

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  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
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  • Genetics & Genomics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Communicable Diseases (AREA)
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Abstract

L'invention concerne un cristal de sel sodique de danoprévir. Le diagramme de diffraction de poudre aux rayons X du cristal exprimé par l'angle 2θ, à l'aide d'un rayonnement Cu-Kα, a des pics de diffraction à 5 086 ± 0,1, 7 231 ± 0,1, 8 004 ± 0,1, 9 524 ± 0,1, 17,517 ± 0,1 et 19 325 ± 0,1.
PCT/CN2018/075917 2017-07-20 2018-02-09 Cristal de sel sodique de danoprévir et procédé pour sa préparation WO2019015312A1 (fr)

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CN201710595399.6A CN109280074A (zh) 2017-07-20 2017-07-20 丹诺瑞韦钠晶体及其制备方法
CN201710595399.6 2017-07-20

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101903391A (zh) * 2007-12-21 2010-12-01 弗·哈夫曼-拉罗切有限公司 大环化合物的制备方法
CN101970396A (zh) * 2008-04-11 2011-02-09 弗·哈夫曼-拉罗切有限公司 用作复分解反应催化剂的新的钌配合物
CN103200934A (zh) * 2010-11-09 2013-07-10 弗·哈夫曼-拉罗切有限公司 治疗hcv感染的药物组合物

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101921227B (zh) * 2007-04-03 2012-09-05 南京工业大学 5-氯-4-羟基-2(1h)-吡啶酮晶型及其制备方法和应用
CN101318948B (zh) * 2008-04-01 2011-04-27 上海天伟生物制药有限公司 鲁比前列酮晶体、其制备方法及用途
CN102030743B (zh) * 2009-09-30 2013-03-20 天津药物研究院 伊潘立酮晶体、其制备方法及药物组合物
CN102453029B (zh) * 2010-11-02 2014-04-23 上海秀新臣邦医药科技有限公司 帕利哌酮新晶型晶体及其制备方法
CN102344458B (zh) * 2011-09-06 2013-10-16 山东罗欣药业股份有限公司 一种头孢丙烯化合物晶体及其药物组合物

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101903391A (zh) * 2007-12-21 2010-12-01 弗·哈夫曼-拉罗切有限公司 大环化合物的制备方法
CN101970396A (zh) * 2008-04-11 2011-02-09 弗·哈夫曼-拉罗切有限公司 用作复分解反应催化剂的新的钌配合物
CN103200934A (zh) * 2010-11-09 2013-07-10 弗·哈夫曼-拉罗切有限公司 治疗hcv感染的药物组合物

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