WO2016146048A1 - Procédé de fabrication industrielle de dérivé du midazolam - Google Patents

Procédé de fabrication industrielle de dérivé du midazolam Download PDF

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Publication number
WO2016146048A1
WO2016146048A1 PCT/CN2016/076318 CN2016076318W WO2016146048A1 WO 2016146048 A1 WO2016146048 A1 WO 2016146048A1 CN 2016076318 W CN2016076318 W CN 2016076318W WO 2016146048 A1 WO2016146048 A1 WO 2016146048A1
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WO
WIPO (PCT)
Prior art keywords
compound
midazolam
hydroxypropane
reaction
molar ratio
Prior art date
Application number
PCT/CN2016/076318
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English (en)
Chinese (zh)
Inventor
王志训
Original Assignee
王志训
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 王志训 filed Critical 王志训
Publication of WO2016146048A1 publication Critical patent/WO2016146048A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
    • C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to the field of organic synthesis, and in particular to an industrial manufacturing method of a midazolam derivative.
  • Midazolam as a drug for anti-anxiety, sedation, sleep, muscle relaxation, anticonvulsant effect. Because of its rapid pharmacological action, rapid metabolic inactivation and short duration, it is widely used in the treatment of various insomnia and sleep rhythm disorders. Injectables are also widely used for endoscopy and preoperative administration. Therefore, its prodrugs are often widely concerned in the pharmaceutical field.
  • the present invention aims to overcome the above drawbacks and to provide a manufacturing method which is simple in operation, low in cost, convenient in post-treatment, high in yield, and suitable for industrial production.
  • the industrial production method of the midazolam derivative provided by the present invention is characterized in that a ring-forming reaction occurs between the compound A and the compound B under the condition of a catalyst,
  • R is a hydroxyl group or a halogen.
  • the molar ratio of the above compound A to the compound B is 1:1-2.
  • the industrial production method of the midazolam derivative provided by the present invention has the following characteristics: the above compound B can be replaced by a mixture of 1,3-diamino-2-hydroxypropane and acetyl halide; The molar ratio of 3-diamino-2-hydroxypropane to acetyl halide is 1:0.8-1.
  • the industrial production method of the midazolam derivative provided by the present invention has the following characteristics: the above compound B can be replaced by a mixture of 1,3-diamino-2-hydroxypropane and compound C;
  • R is an alkyl group and derivatives or aryl groups thereof and derivatives thereof;
  • the molar ratio of the above 1,3-diamino-2-hydroxypropane to the compound C is 1:0.8-1.
  • the industrial production method of the midazolam derivative provided by the present invention has the following feature: the above compound B can be replaced with a mixture of 1,3-diamino-2-hydroxypropane and acetonitrile; The molar ratio of diamino-2-hydroxypropane to acetonitrile is 1:0.8-1.
  • the industrial production method of the midazolam derivative provided by the present invention has the following feature: the above compound B can be replaced with a mixture of 1,3-diamino-2-hydroxypropane and the compound D;
  • the structure of Compound D is as follows:
  • R is an alkyl group and derivatives or aryl groups thereof and derivatives thereof;
  • the molar ratio of the above 1,3-diamino-2-hydroxypropane to the compound D is 1:0.8-1.
  • the reaction is preferably carried out under neutral or basic conditions.
  • the industrial production method of the midazolam derivative provided by the present invention has the following characteristics: the above compound B can be replaced by a mixture of 1,3-dihalo-2-hydroxypropane, ammonia and compound E;
  • the above compound E may be selected from one of acetyl halide, compound C, acetonitrile, and compound D;
  • the molar ratio of the above 1,3-dihalo-2-hydroxypropane, ammonia gas, and compound E is 1:1 to 10:0.8-1.
  • the industrial production method of the midazolam derivative provided by the present invention has the following characteristics: the above compound B can be replaced by a mixture of 2-halomethyl propylene oxide, ammonia gas and compound E;
  • the above compound E may be selected from one of acetyl halide, compound C, acetonitrile, and compound D;
  • the molar ratio of the above 2-halomethyl propylene oxide, ammonia gas, and compound E is 1:1 to 10: 0.8-1.
  • the present invention also provides a specific manufacturing process for the industrial manufacturing method of the above midazolam derivative, characterized in that the raw material and the organic solvent are put into the reaction vessel, and the catalyst is refluxed for 2-8 hours to complete the reaction.
  • the product is obtained by filtration, hydrolysis, concentration and recrystallization or distillation to obtain a pure product;
  • the inputs of various raw materials may be performed sequentially or out of order;
  • composition of the substitute B raw material When a three-component raw material is used, it is preferred to subject the composition of the substitute B raw material to a mixture reaction for 0.5 to 1 hour, and then to introduce the compound A into the reaction.
  • the reaction time may vary from 2 to 8 hours, preferably from 2 to 8 hours, depending on the starting materials of the reaction, and the end point of the central control reaction is detected by HPLC.
  • the above extract and recrystallization solvent are selected from a mixture of one or more of ethers, aromatics, alcohols, and alkanes having a boiling point of less than 120 °C.
  • a mixture of one or more of a molecular sieve, a metal catalyst, and a metal Lewis acid may be added during the above reaction.
  • the molar ratio of the above catalyst to the reactant is from 0.1 to 2.
  • the above organic solvent may be selected from aromatic, heteroaryl or alkane organic solvents having a boiling point of 40 to 100 ° C, such as toluene, benzene, tetrahydrofuran, n-hexane, cyclohexane and the like.
  • the above catalyst may be selected from the group consisting of Lewis acids/bases, metal halides, metal coordination compounds, and steroidal compounds.
  • One of the above; the above catalyst is most preferably titanium tetrachloride.
  • the production method provided by the invention is simple, and is different from the complicated production mode in the prior art, and the severe production conditions, the synthesis of the target product can be realized in one step of the invention. And the yield can be increased by at least 50% relative to the multi-step synthesis of the prior art. And because the invention optimizes the production process and the synthetic route, in the production process of the invention, the side reaction is less, the post-treatment is convenient, the production condition is mild, and the three waste discharge in the reaction process is greatly reduced, which is Suitable for industrial, green and environmentally friendly production models.
  • the preferred starting materials selected namely, the compounds A and B and their substitutes, are inexpensive, and the whole reaction process is realized in one pot, and the post-treatment and It is simple and can be purified by simple recrystallization to achieve a purity of 98.5% or more.
  • the present invention is a manufacturing method suitable for large-scale industrial production.
  • the molar ratio of the compound A to the compound B may also be 1:1 or 1:1.2 or 1:1.5 or 1:1.8 or 1:2, and the solvent may also be a boiling point such as cyclohexane.
  • the molar ratio of the compound A, B and C may also be 1:1:1 or 1:1.2:1 or 1:1.5:1.1 or 1:1.8:1.5 or 1:2:1.6, and the solvent may also be selected.
  • the reaction an attempt was made to carry out the reaction by a one-pot input method or the raw materials A and B were first reacted and then the raw material C was added, and the yield was comparable to that of the one-step one-pot method.
  • the molar ratio of the compound A, B and C may also be 1:1:1 or 1:1.2:1 or 1:1.5:1.1 or 1:1.8:1.5 or 1:2:1.6, etc.
  • the C compound may also Selected from, for example, ethyl acetate, phenyl acetate, benzyl acetate, etc.
  • reaction vessel A250g, B80g, C30g and 500ml of ethanol were put into the reaction vessel, and 80 g of zinc chloride was added to reflux reaction for 8 hours, and the reaction was terminated.
  • the reaction product was filtered, hydrolyzed, concentrated, and recrystallized from maleic acid to obtain 351 g of pure product.
  • the molar ratio of the compound A, B and C may also be 1:1:1 or 1:1.2:1 or 1:1.5:1.1 or 1:1.8:1.5 or 1:2:1.6, and the solvent may also be selected.
  • A250g, B90g, C120g and n-hexane 250ml were put into the reaction vessel, 100g of molecular sieve was added, 25g of titanium tetrachloride was refluxed for 5 hours, and the reaction was terminated. The reaction product was filtered, hydrolyzed, concentrated and recrystallized from maleic acid to obtain pure product. 353g.
  • the molar ratio of the compound A, B and C may also be 1:1:1 or 1:1.2:1 or 1:1.5:1.1 or 1:1.8:1.5 or 1:2:1.6, etc., and the C compound may also be used.
  • reaction product 250 ml of tetrahydrofuran and B90g were put into the reaction vessel, about 17 g of ammonia gas was introduced, and reacted at room temperature for 1.5 hours to absorb excess gas.
  • 80 g of pyridine was added to the reaction vessel, and D78.5 g was slowly added dropwise, after no gas was released.
  • A260g was added, and 60 g of titanium tetrachloride was added thereto for refluxing for 1 hour, and the reaction was terminated.
  • the reaction product was filtered, hydrolyzed, extracted with ethyl acetate, concentrated, and recrystallized from ethanol to obtain 251 g of pure product.
  • the molar ratio of compounds A, B, C and D can also be 1:1:1:1 or 1:1.2:2:1 or 1: Different ratios of 1.5:5:1.1 or 1:1.8:10:1.5 or 1:2:3:1.6, in addition, compound D can also be replaced with compound C and its substitutes in Examples III, IV and V,
  • the selected catalyst can be determined according to the properties of different raw materials, and other Lewis acid/base, metal halide, metal complex compound which is commonly used for ring formation reaction other than titanium tetrachloride can also be selected. a mixture of one or more of the steroid compounds.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Catalysts (AREA)

Abstract

L'invention concerne un procédé de fabrication industrielle d'un dérivé du midazolam, ledit procédé étant caractérisé en ce que : le composé A et le composé B subissent une réaction de cyclisation dans les conditions d'un catalyseur. Le procédé de production décrit est simple, met en œuvre la synthèse du produit cible en une étape, et diffère du moyen de production complexe et des conditions de production difficiles de la technique antérieure. En outre, le rendement peut être augmenté d'au moins 50 % par rapport à la synthèse à plusieurs étapes de la technique antérieure. En outre, étant donné que le procédé de production et la voie de synthèse ont été optimisés, il y a peu de réactions secondaires pendant la production, le post-traitement est pratique, les conditions de production sont douces, et le procédé est approprié pour les modes de production industrielle.
PCT/CN2016/076318 2015-03-16 2016-03-14 Procédé de fabrication industrielle de dérivé du midazolam WO2016146048A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201510115152.0A CN106032381A (zh) 2015-03-16 2015-03-16 一种咪达唑仑衍生物的工业制造方法
CN201510115152.0 2015-03-16

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WO2016146048A1 true WO2016146048A1 (fr) 2016-09-22

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WO (1) WO2016146048A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115385918A (zh) * 2021-08-26 2022-11-25 成都硕德药业有限公司 一种咪达唑仑新晶型及其制备方法
CN114773348B (zh) * 2021-09-02 2024-03-15 成都苑东生物制药股份有限公司 一种咪达唑仑的制备方法及其中间体
CN115232132B (zh) * 2022-07-25 2024-02-13 福安药业集团重庆礼邦药物开发有限公司 一种盐酸咪达唑仑g晶型及其制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5831089A (en) * 1996-07-01 1998-11-03 Pharmacia & Upjohn Company Process to produce midazolam
CN1315953A (zh) * 1999-06-30 2001-10-03 艾博特公司 制备咪唑并二氮杂环庚三烯中间体的方法
CN103319486A (zh) * 2012-03-22 2013-09-25 南京大学 合成4H-咪唑并[1,5-a][1,4]苯二氮卓,特别是咪达唑仑的方法
CN103804384A (zh) * 2014-01-27 2014-05-21 李宏 苯并二氮杂卓类化合物的制备方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5831089A (en) * 1996-07-01 1998-11-03 Pharmacia & Upjohn Company Process to produce midazolam
CN1315953A (zh) * 1999-06-30 2001-10-03 艾博特公司 制备咪唑并二氮杂环庚三烯中间体的方法
CN103319486A (zh) * 2012-03-22 2013-09-25 南京大学 合成4H-咪唑并[1,5-a][1,4]苯二氮卓,特别是咪达唑仑的方法
CN103804384A (zh) * 2014-01-27 2014-05-21 李宏 苯并二氮杂卓类化合物的制备方法

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