WO2024037485A1 - 一种来特莫韦无定形的制备方法 - Google Patents

一种来特莫韦无定形的制备方法 Download PDF

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WO2024037485A1
WO2024037485A1 PCT/CN2023/112849 CN2023112849W WO2024037485A1 WO 2024037485 A1 WO2024037485 A1 WO 2024037485A1 CN 2023112849 W CN2023112849 W CN 2023112849W WO 2024037485 A1 WO2024037485 A1 WO 2024037485A1
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solvent
letermovir
solution
another preferred
amorphous
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PCT/CN2023/112849
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English (en)
French (fr)
Inventor
刘天杰
申淑匣
张良
张国彬
祁道冉
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上海迪赛诺化学制药有限公司
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Publication of WO2024037485A1 publication Critical patent/WO2024037485A1/zh

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    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
    • C07D239/84—Nitrogen atoms

Definitions

  • the invention belongs to the field of pharmaceuticals, and specifically relates to a method for preparing amorphous letermovir.
  • Cytomegalovirus belongs to the DNA virus family, family Herpesviridae, and betaherpes subfamily viruses. CMV has obvious species specificity. Human cytomegalovirus (HCMV) can only infect the human body and proliferate in human fibroblasts. Although they can be present throughout the body, HCMV infections are most commonly associated with the salivary glands. HCMV infection is often overlooked in healthy people. But it can be life-threatening for immunocompromised subjects such as HIV-infected patients, organ transplant recipients or newborns. In particular, HCMV remains a major viral cause of birth defects and a life-threatening disease in transplant recipients.
  • HCMV Human cytomegalovirus
  • letermovir (S)- ⁇ 8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-(2-methoxy-5- Trifluoromethylphenyl)-3,4-dihydroquinazolin-4-yl ⁇ acetic acid, its structural formula is represented by Formula I.
  • Letermovir belongs to a new class of non-nucleoside CMV inhibitors (3,4-dihydroquinazoline), which inhibits viral replication by targeting the viral terminase complex. This compound is only active against human cytomegalovirus and therefore has high potential as a specific human anti-HCMV drug.
  • Patent WO2013/127971A1 mentions the calcium salt and sodium salt of letermovir; patent WO2013/127968A1 mentions the benzenesulfonate and tosylate of letermovir; patent WO2021/170882A1 mentions the potassium salt of letermovir .
  • No crystalline form of letermovir appears in the existing literature.
  • WO2014/202737A1 mentions the preparation method of letermovir amorphous form, and clarifies that acetonitrile or acetone solvent can be used to obtain letermovir amorphous form suitable for preparations.
  • the amorphous product prepared by this method may have the potential risk of increased impurities.
  • the production efficiency may be low and cannot meet the needs of industrial production.
  • the impurity mesityl oxide will be produced; if it is necessary to control this impurity to a lower limit, it is necessary to replace MTBE (methane) with acetone under low temperature conditions for a long time. (tert-butyl ether) solvent, the production efficiency is extremely low; if acetonitrile is used as the solvent, racemization will occur due to heating or alkali, and acetonitrile is highly toxic, has a low dissolved residue limit, and cannot meet the requirements of industrial production.
  • MTBE methane
  • the present invention provides a kind of 4(S)- ⁇ 8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3
  • a new method for the preparation of amorphous -(2-methoxy-5-trifluoromethylphenyl)-3,4-dihydroquinazolin-4-yl ⁇ acetic acid In this method, letermovir is dissolved in a specific solvent and the amorphous form of letermovir is obtained by dripping water back.
  • the technical problems of potential impurity generation and low production efficiency are solved. Therefore, the method of the present invention has more significant advantages in terms of resources and cost, and is more suitable for industrial production.
  • a method for preparing letermovir amorphous which is characterized in that it includes the steps:
  • the preparation method of the first solution includes the steps:
  • the third solvent is methyl tert-butyl ether MTBE.
  • the base is an inorganic base.
  • step (b) before performing the extraction, part of the third solvent is distilled off.
  • the distillation temperature in step (b) and step (c) is 20-60°C.
  • the method for preparing the first solution described in step (1) includes the step of dissolving temovir in the first solvent.
  • the mixture is filtered and the filtrate is retained, so The filtrate is the first solution.
  • the system is heated and/or stirred.
  • the heating temperature is 0-80°C.
  • the heating temperature is 20-60°C.
  • the first solvent is an organic solvent.
  • the first solvent is dimethyl sulfoxide or isopropyl alcohol.
  • the second solvent is water.
  • the temperature of the second solvent is 0-80°C.
  • the temperature of the second solvent is 20-60°C.
  • step (2) the solution is added by slow dripping, and the precipitation is generated during the dripping process.
  • the separation and purification described in step (3) includes the steps:
  • the suspension was filtered, and the filter cake was rinsed with deionized water and dried under vacuum at 40-80°C.
  • a pharmaceutical composition in a second aspect of the present invention, characterized in that the pharmaceutical composition includes: (1) amorphous letermovir prepared by the method described in the first aspect of the present invention; (2) Optionally, a pharmaceutically acceptable carrier.
  • letermovir amorphous prepared by the method of the first aspect of the present invention or the pharmaceutical composition of the second aspect of the present invention, which is characterized in that , for the preparation of medicines for preventing or treating diseases related to the herpes virus group.
  • the herpesvirus-related disease is a cytomegalovirus CMV-related disease.
  • Figure 1 is an XRPD pattern of amorphous letermovir prepared according to the preparation method of one embodiment of the present invention.
  • the inventor unexpectedly discovered that letermovir was dissolved in a specific solvent and the amorphous form of letermovir was obtained by dripping water back.
  • the amorphous product has high purity, low dissolved residue, low hygroscopicity, good powder properties, and greatly reduces the time for solvent replacement, so it is very suitable for the industrial production of the amorphous product. Based on this, the inventor completed the present invention.
  • amorphous refers to the amorphous form of letermovir.
  • the method of the present invention can increase the temperature during the solvent replacement process and improve production efficiency.
  • the time efficiency is significantly better than the method using acetone as the solvent in WO2014/202737A1.
  • the amorphous powder produced by the method of the present invention has high purity, low dissolved residue, and good powder properties.
  • letermovir can be commercially available or prepared according to methods known in the art, such as the method described in WO2004/096778.
  • solvents and reagents such as dimethyl sulfoxide, isopropyl alcohol, etc.
  • solvents and reagents such as dimethyl sulfoxide, isopropyl alcohol, etc.
  • the X-ray powder diffraction pattern (XRPD) described in the present invention is collected on a Bruker D2Phaser X-ray powder diffraction diffractometer.
  • the instrument parameters are as follows:
  • the particle size is detected by Mastersizer 2000 dry method, and the specific detection parameters (refer to patent WO2014/202737A1 method) are as follows:
  • Sample pan microvolume; small sieve with balls
  • the dissolved residue (solvent residue) is detected by gas chromatography, and the detection method is as follows:
  • the purity is detected by high performance liquid chromatography, and the detection method (refer to patent WO2014/202737A1
  • the liquid phase detection method is as follows:
  • the mixture of organic and aqueous phases was heated under reflux. The mixture was distilled to remove MTBE. The aqueous phase of the reactor was stirred at 55-60°C for a further 5 hours. MTBE (320 mL) and water (130 mL) were added to the mixture while stirring at 22°C. The resulting phases were separated again and the organic phase was extracted with the aid of 6% aqueous sodium chloride solution (60 mL).
  • the separated aqueous phase and the 6% sodium chloride solution from which the organic phase was extracted were recombined and stirred with water (50 mL) and MTBE (320 mL).
  • the pH was adjusted to 6.5 with the aid of 1 mol/L hydrochloric acid, the organic phase was separated, and the solvent was gently distilled to dryness.
  • the residue was dissolved in DMSO (approximately 120 mL). Distill at 35-40°C for 2.0 hours to replace MTBE with DMSO to obtain a DMSO solution.
  • the product was subsequently precipitated by adding DMSO solution with stirring (250 rpm) in excess water (960 mL) at 35-40°C.
  • the dried solid was a white powder, and XRPD was shown in Figure 1, showing that the obtained product was amorphous.
  • the amorphous form has high purity, low dissolved residue and low hygroscopicity.
  • Example 2 The amorphous letermovir obtained in Example 1 (1.0 g) and DMSO (3.5 mL) were added at once to a 10 mL glass bottle. The mixture was stirred and clarified at 20-25°C. Add 28 mL of purified water to a 50 mL three-necked flask and heat it to 20-25°C. At this temperature, slowly add the insulated DMSO solution dropwise. The total dropping time is 2 hours to obtain a white turbid solid suspension. Continue after the dropwise addition. Stir for 1 hour, filter with suction, rinse with 5 mL of purified water and collect the solid. Place it in a 50°C vacuum oven to dry for 24 hours to obtain 0.90 g of white solid, with a molar yield of 90.0%.
  • Letermovir amorphous form (1.0 g) obtained in Example 1 and DMSO (2.0 mL) were added to a 10 mL glass bottle at one time. The mixture was stirred and clarified at 35-40°C. Hot filter with 0.45 ⁇ m filter membrane, rinse with 0.5mL DMSO, mix the filtrate and eluent and keep it warm at 35-40°C. Add 20 mL of purified water to a 50 mL three-necked flask and heat it to 35-40°C. At this temperature, slowly add the insulated DMSO solution dropwise. The total dropping time is 2 hours to obtain a white suspended solid suspension. Cool down after the dropwise addition.
  • the mixture of organic and aqueous phases was heated under reflux. The mixture was distilled to remove MTBE. The aqueous phase of the reactor was stirred at 55-60°C for a further 5 hours. MTBE (160 mL) and water (65 mL) were added to the mixture while stirring at 22°C. The resulting phases were separated again and the organic phase was extracted with the aid of 6% aqueous sodium chloride solution (30 mL).
  • the separated aqueous phase and the 6% sodium chloride solution from which the organic phase was extracted were recombined and stirred with water (25 mL) and MTBE (160 mL).
  • the pH was adjusted to 6.5 with the aid of 1 mol/L hydrochloric acid, the organic phase was separated, the solvent was gently distilled to dryness and the residue was dissolved in IPA (approximately 60 mL). Distill at 35-40°C for 2.0 hours and repeat once to replace MTBE with IPA to obtain an IPA solution.
  • the product was subsequently precipitated by adding an IPA solution with stirring (250 rpm) in excess water (480 mL) at 35-40°C.
  • Letermovir amorphous form (1.0 g) and IPA (5.5 mL) obtained in Example 1 were added to a 10 mL glass bottle at one time. The mixture was stirred and clarified at 20-25°C. Add 44 mL of purified water to a 100 mL three-necked flask and heat it to 20-25°C. At this temperature, slowly add the insulated IPA solution dropwise. The total dropping time is 2 hours to obtain a white suspended solid suspension. Continue after the dropwise addition. Stir for 1 hour, filter with suction, rinse with 5 mL of purified water and collect the solid. Place it in a 50°C vacuum oven to dry for 24 hours to obtain 0.89 g of white solid, with a molar yield of 89.0%.
  • Letermovir amorphous form (1.0 g) and IPA (3.0 mL) obtained in Example 1 were added to a 10 mL glass bottle at one time. The mixture was stirred and clarified at 35-40°C. Hot filter with 0.45 ⁇ m filter membrane, rinse with 0.5mL IPA, mix the filtrate and eluent and keep it warm at 35-40°C. Add 28 mL of purified water to a 50 mL three-necked flask and heat it to 35-40°C. At this temperature, slowly add the insulated IPA solution dropwise. The total dropping time is 2 hours to obtain a white suspended solid suspension. Cool down after the dropwise addition.
  • Example 1 The letermovir amorphous form obtained in Example 1 was used as a raw material, dissolved in the solvent in the table below, and then water was added dropwise. The results are shown in Table 1.
  • the specific implementation methods are as follows:
  • Letermovir amorphous (0.2g) and DMSO (0.7mL) obtained in Example 1 were added in sequence to a 5mL glass bottle. The mixture was heated to 35-40°C and then stirred for 15 minutes. The solution became clear. Add 5.6 mL of purified water to a 50 mL three-necked flask and heat to 35-40°C. At this temperature, slowly add the dissolved DMSO solution dropwise. The total dropping time is 2 hours to obtain a white suspended solid suspension. Add dropwise After completion, cool to room temperature, continue stirring for 1 hour, filter with suction, rinse with 1 mL of purified water and collect the solid, place it in a 50°C vacuum oven and dry for 24 hours to obtain a white solid.
  • the method for preparing letermovir amorphous form from other solvents is similar to DMSO solvent, except DMSO is replaced with other solvents.
  • the preparation method is the same as that in Example 3, except that the dissolving solvent is replaced with the dissolving solvent in the table, and the water is replaced with the alkane in the table.
  • Example 3 The letermovir amorphous form obtained in Example 1 was used as raw material, dissolved in the solvent in the table below, and then water was added dropwise to the solution. The results are shown in Table 3.
  • the specific implementation methods are as follows:
  • Letermovir amorphous (0.2g) and DMSO (0.7mL) obtained in Example 1 were added in sequence to a 5mL glass bottle. The mixture was heated to 35-40°C and then stirred for 15 minutes. The solution became clear. Add 5.6 mL of purified water to a 25 mL three-necked flask and heat it to 35-40°C. At this temperature, slowly add water dropwise to the DMSO solution. The total dropping time is 2 hours to obtain a white suspended solid suspension. Add dropwise After completion, cool to room temperature, continue stirring for 1 hour, filter with suction, rinse with 1 mL of purified water and collect the solid, place it in a 50°C vacuum oven and dry for 24 hours to obtain a white solid.
  • Example 1 The amorphous forms obtained in Example 1 were added to the solvent solution in the following table, and were placed at corresponding temperatures to examine the solution stability. The results are shown in Table 4.
  • New impurities will be produced in both methanol and ethanol solutions, and the impurities will grow rapidly. They are presumed to be methyl ester or ethyl ester impurities, resulting in a significant decrease in purity. However, no new impurities will be produced in the dimethyl sulfoxide solution, and a small amount of impurities will be produced in the isopropyl alcohol solution, which is presumed to be impurities from the esterification of isopropyl alcohol. Dimethyl sulfoxide and isopropanol solutions have no or less new impurities and are suitable as solvents for preparing amorphous materials.
  • the mixture of organic and aqueous phases was heated under reflux. The mixture was distilled to remove MTBE. The aqueous phase of the reactor was stirred at 55-60°C for a further 5 hours. MTBE (160 mL) and water (65 mL) were added to the mixture while stirring at 22°C. The resulting phases were separated again and the organic phase was extracted with the aid of 6% aqueous sodium chloride solution (30 mL).
  • the separated aqueous phase and the 6% sodium chloride solution from which the organic phase was extracted were recombined and stirred with water (25 mL) and MTBE (160 mL).
  • the pH was adjusted to 6.5 with the aid of 1 mol/L hydrochloric acid.
  • the organic phase was separated, the solvent was gently distilled to dryness and the residue was dissolved in acetone (approximately 75 mL).
  • the solution was exchanged into acetone (20-25°C) by means of 6 distillation steps of 130 mL each to obtain an acetone solution.
  • the product was subsequently precipitated by adding an acetone solution (ca. 60 mL) with stirring (250 rpm) in excess water (492 mL) at 20-25°C.
  • the mixture of organic and aqueous phases was heated under reflux. The mixture was distilled to remove MTBE. The aqueous phase of the reactor was stirred at 55-60°C for a further 5 hours. MTBE (160 mL) and water (65 mL) were added to the mixture while stirring at 22°C. The resulting phases were separated again and the organic phase was extracted with the aid of 6% aqueous sodium chloride solution (30 mL).
  • the separated aqueous phase and the 6% sodium chloride solution from which the organic phase was extracted were recombined and stirred with water (25 mL) and MTBE (160 mL).
  • the pH was adjusted to 6.5 with the aid of 1 mol/L hydrochloric acid.
  • the organic phase was separated, the solvent was gently distilled to dryness and the residue was dissolved in acetone (approximately 75 mL).
  • the acetone solution was obtained by changing the solution to acetone (35-40°C) by means of 6 distillation steps of 130 mL each, which was subsequently added by stirring (250 rpm) in excess water (492 mL) at 35-40°C. solution (approximately 60 mL) to precipitate the product.
  • the mixture of organic and aqueous phases was heated under reflux. The mixture was distilled to remove MTBE. The aqueous phase of the reactor was stirred at 55-60°C for a further 5 hours. MTBE (160 mL) and water (65 mL) were added to the mixture while stirring at 22°C. The resulting phases were separated again and the organic phase was extracted with the aid of 6% aqueous sodium chloride solution (30 mL). The separated aqueous phase and the 6% sodium chloride solution from which the organic phase was extracted were recombined and stirred with water (25 mL) and MTBE (160 mL). The pH was adjusted to 6.5 with the aid of 1 mol/L hydrochloric acid.
  • the mixture of organic and aqueous phases was heated under reflux. The mixture was distilled to remove MTBE. The aqueous phase of the reactor was stirred at 55-60°C for a further 5 hours. MTBE (160 mL) and water (65 mL) were added to the mixture while stirring at 22°C. The resulting phases were separated again and the organic phase was extracted with the aid of 6% aqueous sodium chloride solution (30 mL).
  • the separated aqueous phase and the 6% sodium chloride solution from which the organic phase was extracted were recombined and stirred with water (25 mL) and MTBE (160 mL).
  • the pH was adjusted to 6.5 with the aid of 1 mol/L hydrochloric acid.
  • the organic phase was separated and the solvent was gently distilled to dryness. Dissolve the residue in acetone (approximately 75 mL).
  • the solution was exchanged into acetone (20-25°C) by means of a 1-step distillation of 130 mL of acetone to obtain an acetone solution, which was subsequently added by stirring (250 rpm) in excess water (492 mL) at 20-25°C to precipitate the product.
  • the yields of letermovir prepared by the six methods of Examples 1, 4 and Comparative Examples 1, 2, 3 and 4 are consistent, with high purity, low dissolved residues and basically consistent particle sizes. However, the boiling points of acetone and MTBE are close. If low-temperature replacement is used in industrial production, it will take a long time and use a large amount of solvent, which seriously affects production efficiency. If high-temperature replacement is used, the impurity mesityl oxide may not be effectively controlled, and there will be larger impurities. Risk; if only one replacement of acetone is used according to Comparative Example 4, the product will be light yellow. For solids, the dissolved MTBE residue exceeded the ICH limit ( ⁇ 0.5%), failed to meet quality requirements, and the yield was significantly smaller.
  • Acetonitrile has low solubility limit, high toxicity, and the risk of producing racemic impurities.
  • DMSO and isopropyl alcohol have no risk of increased impurities or residual dissolution.
  • DMSO has a large difference in boiling point and MTBE.
  • MTBE can be completely replaced by one distillation, which greatly improves production efficiency. Therefore, DMSO and isopropanol are more suitable as replacement and dissolving solvents for letermovir amorphous form.
  • the amorphous exposure obtained from different solvent systems was placed under accelerated conditions of 40°C/75% RH to observe changes in crystal form and purity.
  • the amorphous shape prepared by the five methods has good stability and does not change after being placed at 40°C/75%RH for 3 months.

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Abstract

本发明涉及一种制备式I化合物的无定形方法。具体地，本发明提供了一种制备式I化合物来特莫韦无定形的方法，本发明的方法减少了杂质增加的潜在风险，生产效率高，制得的无定形纯度高、溶残低、粉体性质好，并且制备过程中无油状物产生。

Description

一种来特莫韦无定形的制备方法 技术领域
本发明属于制药领域，具体涉及一种制备来特莫韦无定形的方法。
背景技术
巨细胞病毒(cytomegalovirus，CMV)属DNA病毒，疱疹病毒科，β疱疹亚科病毒。CMV有明显的种属特异性，人巨细胞病毒(human cytomegalovirus，HCMV)只能感染人体及在人纤维细胞中增殖。虽然它们可存在于整个身体内，但HCMV感染通常与唾液腺相关。HCMV感染在健康人中通常被忽视。但对于免疫受损的受试者如HIV感染者、器官移植受者或新生儿来说可能是危及生命的。特别是，HCMV仍是出生缺陷的主要病毒原因和在移植受者中威胁生命的疾病。
来特莫韦的化学名为(S)-{8-氟-2-[4-(3-甲氧基苯基)哌嗪-1-基]-3-(2-甲氧基-5-三氟甲基苯基)-3,4-二氢喹唑啉-4-基}乙酸，其结构式由式I表示。
来特莫韦属于一类新的非核苷类CMV抑制剂(3,4-二氢喹唑啉)，通过靶向病毒终止酶(terminase)复合物抑制病毒的复制。该化合物仅针对人类巨细胞病毒有活性并且因此具有作为特异性人类抗HCMV药物的高潜力。
专利WO2013/127971A1提及来特莫韦的钙盐和钠盐；专利WO2013/127968A1提及来特莫韦的苯磺酸盐和甲苯磺酸盐；专利WO2021/170882A1提及来特莫韦钾盐。现有的文献未出现来特莫韦晶型。WO2014/202737A1提及了来特莫韦无定形制备方法，明确了采用乙腈或者丙酮溶剂可以得到适用于制剂的来特莫韦无定形。但采用该方法制备得到的无定形可能存在杂质增加的潜在风险，另外也可能出现生产效率较低，无法满足工业化生产。若按照WO2014/202737A1中的方法采用溶剂丙酮，将会产生异亚丙基丙酮杂质；如需要控制该杂质在较低限度，需要在低温条件下用丙酮长时间替换MTBE(甲 基叔丁基醚)溶剂，生产效率极低；若采用乙腈作为溶剂，升温或者碱都会产生外消旋化并且乙腈的毒性较大，溶残限度较低，亦无法满足工业化生产要求。
综上所述，本领域迫切需要一种既能够保证产品的质量(纯度，溶残和杂质等质量指标合格)，又能够降低成本，提高生产效率的简便易行且易于工业化生产的来特莫韦无定形制备方法。
发明内容
本发明为了解决现有技术存在的问题，本发明提供了一种4(S)-{8-氟-2-[4-(3-甲氧基苯基)哌嗪-1-基]-3-(2-甲氧基-5-三氟甲基苯基)-3,4-二氢喹唑啉-4-基}乙酸无定形新的制备方法。该方法通过使来特莫韦溶解在特定溶剂，通过反滴入水的方法得到来特莫韦无定形。解决了潜在杂质产生和生产效率低的技术问题。因此，本发明的方法在资源和成本方面具有更显著的优势，更适宜工业化生产。
在本发明的第一方面，提供了一种制备来特莫韦无定形的方法，其特征在于，包括步骤：
(1)提供来特莫韦在第一溶剂中的第一溶液；
(2)向第二溶剂中加入第一溶液，产生沉淀，得到悬浮液；
(3)对悬浮液进行分离和纯化，得到来特莫韦无定形。
在部分实施方式中，所述的第一溶液的制备方法包括步骤：
(a)将来特莫韦的盐、碱、第二溶剂、第三溶剂混合；
(b)萃取得到的混合物，加入第一溶剂，蒸馏除去第三溶剂；
(c)任选地，加入第一溶剂，蒸馏去除第三溶剂，重复一次或多次；
(d)得到来特莫韦在第一溶剂中的溶液。
在另一优选例中，所述的第三溶剂为甲基叔丁醚MTBE。
在另一优选例中，所述的碱为无机碱。
在另一优选例中，在步骤(b)中，在进行所述的萃取前，蒸馏除去部分第三溶剂。
在另一优选例中，步骤(b)和步骤(c)中的蒸馏的温度为20-60℃。
在部分实施方式中，步骤(1)中所述的第一溶液的制备方法包括步骤：将来特莫韦溶解在第一溶剂中。
在另一优选例中，将来特莫韦溶解在第一溶剂之后，将混合物过滤，保留滤液，所 述的滤液即第一溶液。
在另一优选例中，将来特莫韦溶解在第一溶剂之后，对体系进行加热和/或搅拌。
在另一优选例中，加热的温度为0-80℃。
在另一优选例中，加热的温度为20-60℃。
在部分实施方式中，所述的第一溶剂为有机溶剂。
在另一优选例中，所述的第一溶剂为二甲亚砜或异丙醇。
在部分实施方式中，所述的第二溶剂为水。
在部分实施方式中，步骤(2)中，第二溶剂温度为0-80℃。
在另一优选例中，第二溶剂的温度为20-60℃。
在部分实施方式中，步骤(2)中，所述加入溶液的方式为缓慢滴加，并且所述的沉淀在滴加过程中产生。
在部分实施方式中，步骤(3)中所述的分离和纯化包括步骤：
将悬浮液过滤，滤饼用去离子水淋洗，并于40-80℃真空干燥。
在本发明的第二方面，提供了一种药物组合物，其特征在于，所述的药物组合物包括：(1)如本发明第一方面所述的方法制备的来特莫韦无定形；(2)任选地，药学上可接受的载体。
在本发明的第三方面，提供了一种如本发明第一方面所述的方法制得的来特莫韦无定形或者如本发明第二方面所述的药物组合物的用途，其特征在于，用于制备预防或治疗疱疹病毒群相关疾病的药物。
在另一优选例中，所述的疱疹病毒群相关疾病为巨细胞病毒CMV相关疾病。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1为根据本发明的一个实施例的制备方法制备的来特莫韦无定形XRPD图。
具体实施方式
发明人经过广泛而深入的努力，意外地发现使来特莫韦溶解在特定溶剂，通过反滴入水的方法得到来特莫韦无定形。而且该无定形纯度高、溶残低、引湿性小，粉体性质好，且大大减少了溶剂替换的时间，因而十分适合用于该无定形的工业化生产。基于此，发明人完成了本发明。
术语
除非另外定义，否则本文中所用的全部技术与科学术语均具有如本发明所属领域的普通技术人员通常理解的相同含义。
除非特别说明，在本发明中，无定形是指来特莫韦无定形。
本发明的主要优点包括：
(a)与现有技术相比，本发明提供的制备来特莫韦无定形的方法减少了杂质增加的潜在风险。
(b)本发明的方法在溶剂替换过程可以升高温度，提高生产效率，时间效率明显优于WO2014/202737A1中采用丙酮作为溶剂的方法。
(c)本发明的方法制得的无定形纯度高、溶残低、粉体性质好。
(d)本发明方法制备无定形过程中无油状物产生，溶残风险低，收率高。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数。
除非特别说明，在本发明中，来特莫韦可通过市售获得或按照本领域公知的方法制得如WO2004/096778记载的方法。
除非特别说明，实施例中所用溶剂和试剂(如二甲亚砜、异丙醇等)可通过市售获得。
检测方法
本发明所述的X-射线粉末衍射图(XRPD)是在Bruker D2Phaser X-射线粉末衍射衍射仪上采集。仪器参数如下：
射线:单色Cu-Ka射线λ＝1.5418)
扫描方式：θ/2θ
扫描范围：2-35°
电压：30KV
电流：10mA
本发明中，粒度用Mastersizer 2000干法检测，具体检测参数(参照专利WO2014/202737A1方法)如下：
称入量：0.3-0.4g
测量时间：20秒
背景时间：6秒
遮蔽限度：0.5％至6％
样品盘：微体积；具有球的小筛
进料速率：45-55％
分散压力：2.5Bar
进行四次独立分析并且将结果取平均值。
本发明中，溶残(溶剂残留)采用气相色谱检测，检测方法如下：
直接进样气相色谱法：
装置：                   气相色谱法，例如Agilent 6890
柱：                     DB-WAX:30m长度，0.53mm内径，1μm膜厚度
载气，流速：             氮气，2mL/mL(恒定流)
注射器温度：             160℃
检测器/温度：            FID/260℃
                         氢气30mL/min
燃烧气体：               空气300mL/min
                         构成气体(N2)25mL/min
                         起始温度50℃
                         保温时间2分钟
烘箱温度程序：           加热速率20K/min
                         最终温度230℃
                         保温时间15分钟
注射体积                 1μL
本发明中，纯度采用高效液相色谱检测，检测方法(参考专利WO2014/202737A1 的液相检测方法)如下：
梯度反向HPLC-纯度
实施例1 DMSO(二甲亚砜)35-40℃制备来特莫韦无定形
将(2S,3S)-2,3-双[(4-甲基苯甲酰基)氧基]琥珀酸-{(4S)-8-氟-2-[4-(3-甲氧基苯基)哌嗪-1-基]-3-[2-甲氧基-5-(三氟甲基)苯基]-3,4-二氢喹唑啉-4-基}乙酸甲酯(1:1盐)(61.6g)、碳酸氢钠(32.8g)和水(630mL)的混合物与MTBE(320mL)一起搅拌。分离所得各相并且用70mL的7％碳酸氢钠溶液处理有机相。再次分离所得各相并且用250mL的4％氢氧化钠溶液处理有机相。
在回流条件下加热有机相和水相的混合物。将混合物蒸馏以除去MTBE。将反应器的水相在55-60℃再搅拌5小时。在22℃下搅拌的同时向混合物中添加MTBE(320mL)和水(130mL)。再次分离所得各相并且借助于6％氯化钠水溶液(60mL)萃取有机相。
将分离的水相和萃取有机相后的6％氯化钠溶液重新合并，并且与水(50mL)和MTBE(320mL)一起搅拌。借助于1mol/L盐酸将pH调节至6.5，分离有机相，将溶剂轻轻蒸馏以干燥。将残余物溶解在DMSO(约120mL)中。在35-40℃蒸馏2.0小时，实现DMSO对MTBE的替换，获得DMSO溶液。随后通过在35-40℃下在过量水(960mL)中的搅拌条件(250rpm)下，添加DMSO溶液，来沉淀产物。
在抽滤后加入170mL水淋洗。分离得到的湿滤饼在装备有螺旋破碎辊的真空干燥器 中在40-80℃下干燥。
通过这个程序，获得产量为31.6g的作为无定形的(S)-{8-氟-2-[4-(3-甲氧基苯基)哌嗪-1-基]-3-(2-甲氧基-5-三氟甲基苯基)-3,4-二氢喹唑啉-4-基}乙酸，摩尔收率为92.3％。
烘干后的固体为白色粉末，XRPD如图1所示，显示得到的产物为无定形。该无定形纯度高，溶残低，引湿性小。
实施例2 DMSO溶液20-25℃反滴工艺制备来特莫韦无定形
在10mL玻璃瓶中一次加入实施例1得到的来特莫韦无定形(1.0g)、DMSO(3.5mL)。混合物在20-25℃搅拌澄清。在50mL三口烧瓶中加入28mL纯化水加热至20-25℃，在此温度下缓慢滴加保温的DMSO溶液，总滴加时间为2小时，获得白色悬浊的固体悬浮液，滴加完毕后继续搅拌1小时，抽滤，5mL纯化水淋洗并收集固体，放入50℃真空烘箱干燥24小时后得到白色固体0.90g，摩尔收率为90.0％。
该工艺得到产品的性状及XRPD与实施例1相同。
实施例3 DMSO溶液35-40℃反滴工艺制备来特莫韦无定形
在10mL玻璃瓶中一次加入实施例1得到的来特莫韦无定形(1.0g)、DMSO(2.0mL)。混合物在35-40℃搅拌澄清。0.45μm滤膜热过滤，0.5mL DMSO淋洗，滤液及淋洗液混合后在35-40℃保温。在50mL三口烧瓶中加入20mL纯化水加热至35-40℃，在此温度下缓慢滴加保温的DMSO溶液，总滴加时间为2小时，获得白色悬浊的固体悬浮液，滴加完毕后降温至室温，继续搅拌1小时，抽滤，5mL纯化水淋洗并收集固体，放入50℃真空烘箱干燥24小时后得到白色固体0.91g，摩尔收率为91.0％。
该工艺得到产品的性状及XRPD与实施例1相同。
实施例4 IPA(异丙醇)55-60℃制备来特莫韦无定形
将(2S,3S)-2,3-双[(4-甲基苯甲酰基)氧基]琥珀酸-{(4S)-8-氟-2-[4-(3-甲氧基苯基)哌嗪-1-基]-3-[2-甲氧基-5-(三氟甲基)苯基]-3,4-二氢喹唑啉-4-基}乙酸甲酯(1:1盐)(30.8g)、碳酸氢钠(16.4g)和水(315mL)的混合物与MTBE(160mL)一起搅拌。分离所得各相并且用35mL的7％碳酸氢钠溶液处理有机相。再次分离所得各相并且用125mL的4％氢氧化钠溶液处理有机相。
在回流条件下加热有机相和水相的混合物。将混合物蒸馏以除去MTBE。将反应器的水相在55-60℃再搅拌5小时。在22℃下搅拌的同时向混合物中添加MTBE(160mL)和水(65mL)。再次分离所得各相并且借助于6％氯化钠水溶液(30mL)萃取有机相。
将分离的水相和萃取有机相后的6％氯化钠溶液重新合并并且与水(25mL)和MTBE(160mL)一起搅拌。借助于1mol/L盐酸将pH调节至6.5.，分离有机相，将溶剂轻轻蒸馏以干燥将残余物溶解在IPA(约60mL)中。在35-40℃蒸馏2.0小时，并重复1次实现IPA对MTBE的替换，获得IPA溶液。随后通过在35-40℃下在过量水(480mL)中的搅拌条件(250rpm)下添加IPA溶液来沉淀产物。
在抽滤后，加入85mL水淋洗。分离得到的湿滤饼在装备有螺旋破碎辊的真空干燥器中在40-80℃下干燥。通过这个程序，获得产量为16.2g的作为无定形的(S)-{8-氟-2-[4-(3-甲氧基苯基)哌嗪-1-基]-3-(2-甲氧基-5-三氟甲基苯基)-3,4-二氢喹唑啉-4-基}乙酸，摩尔收率为94.6％。
该工艺得到产品的性状及XRPD与实施例1相同。
实施例5 IPA溶液20-25℃反滴工艺制备来特莫韦无定形
在10mL玻璃瓶中一次加入实施例1得到的来特莫韦无定形(1.0g)、IPA(5.5mL)。混合物在20-25℃搅拌澄清。在100mL三口烧瓶中加入44mL纯化水加热至20-25℃，在此温度下缓慢滴加保温的IPA溶液，总滴加时间为2小时，获得白色悬浊的固体悬浮液，滴加完毕后继续搅拌1小时，抽滤，5mL纯化水淋洗并收集固体，放入50℃真空烘箱干燥24小时后得到白色固体0.89g，摩尔收率为89.0％。
该工艺得到产品的性状及XRPD与实施例1相同。
实施例6 IPA溶液35-40℃反滴工艺制备来特莫韦无定形
在10mL玻璃瓶中一次加入实施例1得到的来特莫韦无定形(1.0g)、IPA(3.0mL)。混合物在35-40℃搅拌澄清。0.45μm滤膜热过滤，0.5mL IPA淋洗，滤液及淋洗液混合后在35-40℃保温。在50mL三口烧瓶中加入28mL纯化水加热至35-40℃，在此温度下缓慢滴加保温的IPA溶液，总滴加时间为2小时，获得白色悬浊的固体悬浮液，滴加完毕后降温至室温，继续搅拌1小时，抽滤，5mL纯化水淋洗并收集固体，放入50℃真空烘箱干燥24小时后得到白色固体0.90g，摩尔收率为90.0％。
该工艺得到产品的性状及XRPD与实施例1相同。
实施例7以水为反溶剂反滴实验
以实施例1得到的来特莫韦无定形为原料，将其溶解在以下表格溶剂中，之后分别滴加入水，结果如表1所示。具体实施方法如下：
在5mL玻璃瓶中依次加入实施例1得到的来特莫韦无定形(0.2g)、DMSO(0.7mL)。混合物加热至35-40℃，然后搅拌15分钟，溶液澄清。在50mL三口烧瓶中加入5.6mL纯化水加热至35-40℃，在此温度下缓慢滴加溶清后的DMSO溶液，总滴加时间为2小时，获得白色悬浊的固体悬浮液，滴加完毕后降温至室温，继续搅拌1小时，抽滤，1mL纯化水淋洗并收集固体，放入50℃真空烘箱干燥24小时后得到白色固体。
其余溶剂制备来特莫韦无定形的方法与DMSO溶剂类似，将DMSO换成其他溶剂。
表1以水为反溶剂的反滴沉淀反应
除了丙酮、乙腈、甲醇、乙醇、二甲亚砜和异丙醇外，其余溶剂滴加过程都会出现明显的成油现象，不利于无定形固体沉淀。
实施例8以烷烃为反溶剂反滴实验
制备方法与实施例3的方法一致，将溶解溶剂更换为表格中溶解溶剂，水更换为表格中烷烃。
表2以烷烃为反溶剂的反滴沉淀反应

所有正溶剂溶解后滴加至烷烃(环己烷或正庚烷)溶剂后都会出油，不利于无定形固体沉淀。
实施例9以水为反溶剂正滴实验
以实施例1得到的来特莫韦无定形为原料，将其溶解在以下表格溶剂中，之后分别滴加水于溶液中，结果如表3所示。具体实施方法如下：
在5mL玻璃瓶中依次加入实施例1得到的来特莫韦无定形(0.2g)、DMSO(0.7mL)。混合物加热至35-40℃,然后搅拌15分钟，溶液澄清。在25mL三口烧瓶中加入5.6mL纯化水加热至35-40℃，在此温度下将水缓慢滴加至DMSO溶液中，总滴加时间为2小时，获得白色悬浊的固体悬浮液，滴加完毕后降温至室温,继续搅拌1小时，抽滤，1mL纯化水淋洗并收集固体，放入50℃真空烘箱干燥24小时后得到白色固体。
其余溶剂制备来特莫韦无定形的方法与DMSO溶剂类似。将DMSO更换为表格中溶解溶剂。
表3以水为反溶剂的正滴沉淀反应

水滴加至所有溶清液中都会成油，不利于无定形沉淀。
实施例10溶液稳定性考察
将实施例1得到的无定形分别加入到以下表格中溶剂溶清，分别放置于相应温度考察溶液稳定性。结果如表4所示。
表4溶液稳定性结果
在甲醇和乙醇溶液中都会产生新增杂质，且杂质增长较快，推测为甲酯或者是乙酯杂质，导致纯度显著降低。而二甲亚砜溶液中不会产生新增杂质，异丙醇溶液中产生少量杂质，推测是异丙醇酯化杂质。二甲亚砜和异丙醇溶液无新增杂质或新增较少，适合作为制备无定形的溶剂。
对比例1丙酮20-25℃制备来特莫韦无定形(参照专利WO2014/202737A1制备)
将(2S,3S)-2,3-双[(4-甲基苯甲酰基)氧基]琥珀酸-{(4S)-8-氟-2-[4-(3-甲氧基苯基)哌嗪-1-基]-3-[2-甲氧基-5-(三氟甲基)苯基]-3,4-二氢喹唑啉-4-基}乙酸甲酯(1:1盐)(30.8g)、碳酸氢钠(16.4g)和水(315mL)的混合物与MTBE(160mL)一起搅拌。分离所得各相并且用35mL的7％碳酸氢钠溶液处理有机相。再次分离所得各相并且用125mL的4％ 氢氧化钠溶液处理有机相。
在回流条件下加热有机相和水相的混合物。将混合物蒸馏以除去MTBE。将反应器的水相在55-60℃再搅拌5小时。在22℃下搅拌的同时向混合物中添加MTBE(160mL)和水(65mL)。再次分离所得各相并且借助于6％氯化钠水溶液(30mL)萃取有机相。
将分离的水相和萃取有机相后的6％氯化钠溶液重新合并，并且与水(25mL)和MTBE(160mL)一起搅拌。借助于1mol/L盐酸将pH调节至6.5。分离有机相，将溶剂轻轻蒸馏以干燥并且将残余物溶解在丙酮(约75mL)中。借助于每次130mL的6次蒸馏步骤将溶液更换为丙酮(20-25℃)，获得丙酮溶液。随后通过在20-25℃下在过量水(492mL)中的搅拌条件(250rpm)下添加丙酮溶液(约60mL)来沉淀产物。在抽滤后，将分离的产物在装备有螺旋破碎辊的真空干燥器中在40-80℃下干燥。通过这个程序，获得产量为16.0g的作为无定形的(S)-{8-氟-2-[4-(3-甲氧基苯基)哌嗪-1-基]-3-(2-甲氧基-5-三氟甲基苯基)-3,4-二氢喹唑啉-4-基}乙酸，摩尔收率为93.5％。
该工艺得到产品的性状及XRPD与实施例1相同。
对比例2丙酮55-60℃制备来特莫韦无定形
将(2S,3S)-2,3-双[(4-甲基苯甲酰基)氧基]琥珀酸-{(4S)-8-氟-2-[4-(3-甲氧基苯基)哌嗪-1-基]-3-[2-甲氧基-5-(三氟甲基)苯基]-3,4-二氢喹唑啉-4-基}乙酸甲酯(1:1盐)(30.8g)、碳酸氢钠(16.4g)和水(315mL)的混合物与MTBE(160mL)一起搅拌。分离所得各相并且用35mL的7％碳酸氢钠溶液处理有机相。再次分离所得各相并且用125mL的4％氢氧化钠溶液处理有机相。
在回流条件下加热有机相和水相的混合物。将混合物蒸馏以除去MTBE。将反应器的水相在55-60℃再搅拌5小时。在22℃下搅拌的同时向混合物中添加MTBE(160mL)和水(65mL)。再次分离所得各相并且借助于6％氯化钠水溶液(30mL)萃取有机相。
将分离的水相和萃取有机相后的6％氯化钠溶液重新合并，并且与水(25mL)和MTBE(160mL)一起搅拌。借助于1mol/L盐酸将pH调节至6.5。分离有机相，将溶剂轻轻蒸馏以干燥并且将残余物溶解在丙酮(约75mL)中。借助于每次130mL的6次蒸馏步骤将溶液更换为丙酮(35-40℃)，获得丙酮溶液，随后通过在35-40℃下在过量水(492mL)中的搅拌条件(250rpm)下添加丙酮溶液(约60mL)来沉淀产物。
在抽滤后，将分离的产物在装备有螺旋破碎辊的真空干燥器中在40-80℃下干燥。 通过这个程序，获得产量为16.0g的作为无定形的(S)-{8-氟-2-[4-(3-甲氧基苯基)哌嗪-1-基]-3-(2-甲氧基-5-三氟甲基苯基)-3,4-二氢喹唑啉-4-基}乙酸，摩尔收率为93.2％。
该工艺得到产品的性状及XRPD与实施例1相同。
对比例3乙腈35-40℃MTBE制备来特莫韦无定形
将(2S,3S)-2,3-双[(4-甲基苯甲酰基)氧基]琥珀酸-{(4S)-8-氟-2-[4-(3-甲氧基苯基)哌嗪-1-基]-3-[2-甲氧基-5-(三氟甲基)苯基]-3,4-二氢喹唑啉-4-基}乙酸甲酯(1:1盐)(30.8g)、碳酸氢钠(16.4g)和水(315mL)的混合物与MTBE(160mL)一起搅拌。分离所得各相并且用35mL的7％碳酸氢钠溶液处理有机相。再次分离所得各相并且用125mL的4％氢氧化钠溶液处理有机相。
在回流条件下加热有机相和水相的混合物。将混合物蒸馏以除去MTBE。将反应器的水相在55-60℃再搅拌5小时。在22℃下搅拌的同时向混合物中添加MTBE(160mL)和水(65mL)。再次分离所得各相并且借助于6％氯化钠水溶液(30mL)萃取有机相。将分离的水相和萃取有机相后的6％氯化钠溶液重新合并，并且与水(25mL)和MTBE(160mL)一起搅拌。借助于1mol/L盐酸将pH调节至6.5。分离有机相，将溶剂轻轻蒸馏以干燥并且将残余物溶解在乙腈(约75mL)中。在35-40℃蒸馏2.0小时，并重复1次实现乙腈对MTBE的替换，获得乙腈溶液。随后通过在35-40℃下在过量水(492mL)中的搅拌条件(250rpm)下添加乙腈溶液(约60mL)来沉淀产物。
在抽滤后，将分离的产物在装备有螺旋破碎辊的真空干燥器中在40-80℃下干燥。通过这个程序，获得产量为15.8g的作为无定形的(S)-{8-氟-2-[4-(3-甲氧基苯基)哌嗪-1-基]-3-(2-甲氧基-5-三氟甲基苯基)-3,4-二氢喹唑啉-4-基}乙酸，摩尔收率为92.3％。
该工艺得到产品的性状及XRPD与实施例1相同。
对比例4丙酮对MTBE一次替换制备来特莫韦无定形
将(2S,3S)-2,3-双[(4-甲基苯甲酰基)氧基]琥珀酸-{(4S)-8-氟-2-[4-(3-甲氧基苯基)哌嗪-1-基]-3-[2-甲氧基-5-(三氟甲基)苯基]-3,4-二氢喹唑啉-4-基}乙酸甲酯(1:1盐)(30.8g)、碳酸氢钠(16.4g)和水(315mL)的混合物与MTBE(160mL)一起搅拌。分离所得各相并且用35mL的7％碳酸氢钠溶液处理有机相。再次分离所得各相并且用125mL的4％氢氧化钠溶液处理有机相。
在回流条件下加热有机相和水相的混合物。将混合物蒸馏以除去MTBE。将反应器的水相在55-60℃再搅拌5小时。在22℃下搅拌的同时向混合物中添加MTBE(160mL)和水(65mL)。再次分离所得各相并且借助于6％氯化钠水溶液(30mL)萃取有机相。
将分离的水相和萃取有机相后的6％氯化钠溶液重新合并，并且与水(25mL)和MTBE(160mL)一起搅拌。借助于1mol/L盐酸将pH调节至6.5。分离有机相，将溶剂轻轻蒸馏以干燥。将残余物溶解在丙酮(约75mL)中。借助于130mL丙酮的1次蒸馏步骤将溶液更换为丙酮(20-25℃)，获得丙酮溶液，随后通过在20-25℃下在过量水(492mL)中的搅拌条件(250rpm)下添加丙酮溶液来沉淀产物。
在抽滤后，将分离的产物在装备有螺旋破碎辊的真空干燥器中在40-80℃下干燥。通过这个程序，获得产量为15.3g的作为无定形的(S)-{8-氟-2-[4-(3-甲氧基苯基)哌嗪-1-基]-3-(2-甲氧基-5-三氟甲基苯基)-3,4-二氢喹唑啉-4-基}乙酸，摩尔收率为89.4％。
该工艺烘干后得到浅黄色固体，XRPD与实施例1一致。
效果实施例1不同溶剂工艺对比研究
实施例1，4和对比例1，2，3，4对比，比较不同制备方法的MTBE替换耗时，纯度，溶残，异亚丙基丙酮杂质，外消旋杂质和粒度。
表5不同溶剂工艺对比结果
实施例1,4和对比例1,2,3和4六种方法制备的来特莫韦收率一致，纯度高，溶残低，粒度基本一致。但丙酮和MTBE的沸点接近，在工业化生产中若采用低温替换，耗时长，溶剂用量大，严重影响生产效率；若采用高温替换，杂质异亚丙基丙酮可能无法得到有效控制，存在较大杂质风险；若按照对比例4只采用1次丙酮替换，产品性状为浅黄色 固体，MTBE溶残超出ICH限度(<0.5％)，无法符合质量要求，并且收率明显偏小。
乙腈存在溶残限度低，毒性大，并可能产生外消旋杂质的风险。DMSO和异丙醇无杂质增加和溶残风险，尤其是DMSO，沸点和MTBE差异较大，可采用一次蒸馏完成对MTBE的完全替换，极大提高生产效率。因此，DMSO和异丙醇更适合作为来特莫韦无定形的替换和溶解溶剂。
效果实施例2不同溶剂工艺加速稳定性研究
将不同溶剂体系得到的无定形敞口放于40℃/75％RH加速条件下，考察晶型及纯度变化。
表6不同制备方法得到的产品加速稳定性结果
五种方法制备得到的无定形稳定性较好，在40℃/75％RH放置3个月不发生改变。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 一种制备来特莫韦无定形的方法，其特征在于，包括步骤：
    (1)提供来特莫韦在第一溶剂中的第一溶液；
    (2)向第二溶剂中加入第一溶液，产生沉淀，得到悬浮液；
    (3)对悬浮液进行分离和纯化，得到来特莫韦无定形。
  2. 如权利要求1所述的方法，其特征在于，所述的第一溶液的制备方法包括步骤：
    (a)将来特莫韦的盐、碱、第二溶剂、第三溶剂混合；
    (b)萃取得到的混合物，加入第一溶剂，蒸馏除去第三溶剂；
    (c)任选地，加入第一溶剂，蒸馏去除第三溶剂，重复一次或多次；
    (d)得到来特莫韦在第一溶剂中的溶液。
    在另一优选例中，所述的第三溶剂为甲基叔丁醚MTBE。
    在另一优选例中，所述的碱为无机碱。
    在另一优选例中，在步骤(b)中，在进行所述的萃取前，蒸馏除去部分第三溶剂。
    在另一优选例中，步骤(b)和步骤(c)中的蒸馏的温度为20-60℃。
  3. 如权利要求1所述的方法，其特征在于，步骤(1)中所述的第一溶液的制备方法包括步骤：将来特莫韦溶解在第一溶剂中。
    在另一优选例中，将来特莫韦溶解在第一溶剂之后，将混合物过滤，保留滤液，所述的滤液即第一溶液。
    在另一优选例中，将来特莫韦溶解在第一溶剂之后，对体系进行加热和/或搅拌。
    在另一优选例中，加热的温度为0-80℃。
    在另一优选例中，加热的温度为20-60℃。
  4. 如权利要求1所述的方法，其特征在于，所述的第一溶剂为有机溶剂。
    在另一优选例中，所述的第一溶剂为二甲亚砜或异丙醇。
  5. 如权利要求1所述的方法，其特征在于，所述的第二溶剂为水。
  6. 如权利要求1所述的方法，其特征在于，步骤(2)中，第二溶剂温度为0-80℃。
    在另一优选例中，第二溶剂的温度为20-60℃。
  7. 如权利要求1所述的方法，其特征在于，步骤(2)中，所述加入溶液的方式为缓慢滴加，并且所述的沉淀在滴加过程中产生。
  8. 如权利要求1所述的方法，其特征在于，步骤(3)中所述的分离和纯化包括步骤：
    将悬浮液过滤，滤饼用去离子水淋洗，并于40-80℃真空干燥。
  9. 一种药物组合物，其特征在于，所述的药物组合物包括：(1)如权利要求1所述的方法制备的来特莫韦无定形；(2)任选地，药学上可接受的载体。
  10. 一种如权利要求1所述的方法制得的来特莫韦无定形或者如权利要求9所述的药物组合物的用途，其特征在于，用于制备预防或治疗疱疹病毒群相关疾病的药物。
    在另一优选例中，所述的疱疹病毒群相关疾病为巨细胞病毒CMV相关疾病。
PCT/CN2023/112849 2022-08-15 2023-08-14 一种来特莫韦无定形的制备方法 WO2024037485A1 (zh)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105555771A (zh) * 2013-06-19 2016-05-04 艾库里斯抗感染治疗有限公司 无定形莱特莫韦及其用于口服施用的固体药物制剂
WO2021108022A1 (en) * 2019-11-30 2021-06-03 Dispersol Technologies, Llc Inclusion complexes of pharmaceuticals and cyclic oligomers
WO2021170879A1 (en) * 2020-02-27 2021-09-02 Aic246 Gmbh & Co. Kg Sodium 2-[(4s)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4h-quinazolin-4-yl]acetate monohydrate, its preparation and use
CN114031560A (zh) * 2021-11-16 2022-02-11 山东诚创蓝海医药科技有限公司 一种来特莫韦钠盐的制备方法
WO2022038457A1 (en) * 2020-08-17 2022-02-24 Lupin Limited A precipitation process for amorphous letermovir

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105555771A (zh) * 2013-06-19 2016-05-04 艾库里斯抗感染治疗有限公司 无定形莱特莫韦及其用于口服施用的固体药物制剂
WO2021108022A1 (en) * 2019-11-30 2021-06-03 Dispersol Technologies, Llc Inclusion complexes of pharmaceuticals and cyclic oligomers
WO2021170879A1 (en) * 2020-02-27 2021-09-02 Aic246 Gmbh & Co. Kg Sodium 2-[(4s)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4h-quinazolin-4-yl]acetate monohydrate, its preparation and use
WO2022038457A1 (en) * 2020-08-17 2022-02-24 Lupin Limited A precipitation process for amorphous letermovir
CN114031560A (zh) * 2021-11-16 2022-02-11 山东诚创蓝海医药科技有限公司 一种来特莫韦钠盐的制备方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MI ZHOU, ZHU YULIAN, YANG YONG: "Research Progress of Novel Antiviral Drugs in the Treatment and Prevention of Cytomegalovirus Infection in Transplant Patients", HERALD OF MEDICINE, HUAZHONG KEJI DAXUE TONGJI YIXUEYUAN FUSHU TONGJI YIYUAN, CN, vol. 41, no. 4, 10 February 2022 (2022-02-10), CN , pages 458 - 461, XP093139522, ISSN: 1004-0781 *

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