WO2017120729A1 - Procédé et intermédiaire pour la préparation de chlorhydrate d'épirubicine - Google Patents

Procédé et intermédiaire pour la préparation de chlorhydrate d'épirubicine Download PDF

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WO2017120729A1
WO2017120729A1 PCT/CN2016/070566 CN2016070566W WO2017120729A1 WO 2017120729 A1 WO2017120729 A1 WO 2017120729A1 CN 2016070566 W CN2016070566 W CN 2016070566W WO 2017120729 A1 WO2017120729 A1 WO 2017120729A1
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Prior art keywords
compound
reaction
solvent
acid
base
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Chinese (zh)
Inventor
张福利
贾淼
裘鹏程
倪国伟
朱津津
汪有贵
毛文纲
严伟
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Shanghai Institute of Pharmaceutical Industry
Zhejiang Hisun Pharmaceutical Co Ltd
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Shanghai Institute of Pharmaceutical Industry
Zhejiang Hisun Pharmaceutical Co Ltd
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Priority to CN201680078413.9A priority Critical patent/CN108473523B/zh
Priority to PCT/CN2016/070566 priority patent/WO2017120729A1/fr
Publication of WO2017120729A1 publication Critical patent/WO2017120729A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C07H1/06—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/24—Condensed ring systems having three or more rings
    • C07H15/252—Naphthacene radicals, e.g. daunomycins, adriamycins

Definitions

  • the invention belongs to a process for chemically synthesizing a medicament, in particular to a preparation method of epirubicin hydrochloride and an intermediate thereof. Background technique
  • Epirubicin hydrochloride also known as epirubicin hydrochloride, chemical name (8 & 105 10-[(3'-amino-2',3',6'-tripleoxy- ⁇ -J-arabinopyranosyl) oxygen -6,8,11-trihydroxy-8-hydroxyethyl-1-methoxy-7,8,9, 10-tetrahydrotetracene-5,12-dione hydrochloride, molecular formula C 27 H 3 .C1N0 U , molecular weight 579.15, CAS registration number 56390-09-1. It is famasiapu strong
  • Anthracycline anti-tumor antibiotics developed for the treatment of breast cancer, lung cancer and liver cancer listed in Europe in 1984 and listed in the US in 1999.
  • the synthetic routes of epirubicin hydrochloride are mainly as follows:
  • DE2510866 discloses a method for synthesizing epirubicin hydrochloride. The method has a total of 11 steps of reaction, and the crude product yield of epirubicin hydrochloride is only 8.6%, the route is long, and the yield is low.
  • Polish Journal of Chemistry, 2005, 79(2): 349-359 discloses a method for synthesizing epirubicin hydrochloride.
  • the method has a total of 10 steps of reaction, and the crude product yield of epirubicin hydrochloride is 22%, the route is long, and the yield is low.
  • the reaction raw materials of the method are not easily obtained, and are prepared by a two-step reaction, so that the synthetic route of epirubicin hydrochloride is extended to 12 steps.
  • WO2006096665 discloses a method for synthesizing epirubicin hydrochloride.
  • the method has a total of seven steps of reaction. Although the reaction route is shortened compared with the methods 1 and 2, the crude yield of epirubicin hydrochloride is 26%, and the yield is low. Further, in this method, the sulphur oxidation in which dimethyl sulfoxide and trifluoroacetic acid are involved is required to be carried out at a low temperature of -70 ° C, which is industrially difficult to achieve, and is disadvantageous for industrial production.
  • a method for synthesizing epirubicin hydrochloride is disclosed in W09629335A1.
  • the yield of epirubicin hydrochloride is 41%, but there are still 11 steps and the route is long.
  • a method for preparing epirubicin hydrochloride is disclosed in W09629335A1.
  • Doxorubicin hydrochloride As a raw material, it is soluble in hydrazine, dimethyl-dimethylformamide, which is difficult to recover by boiling point, triethyl orthoformate as a bishydroxy protecting agent, and trifluoroacetic acid as a catalyst to carry out bishydroxyprotection to obtain compound 29, due to trifluoroacetic acid.
  • the technical problem to be solved by the present invention is to overcome the existing long route in the preparation method of epirubicin hydrochloride, the yield is low, the reaction raw material is expensive, difficult to obtain, high in cost, harsh in reaction conditions, complicated in operation, and difficult
  • a preparation method of epirubicin hydrochloride and an intermediate thereof are provided.
  • the preparation method of the invention has the advantages of short route, high yield, easy availability of reaction raw materials, no need to use other expensive reagents, low cost, mild reaction conditions, simple operation and favorable industrial production.
  • the present invention mainly solves the above technical problems by the following technical solutions.
  • the invention provides a preparation method of the compound 4', which comprises the following steps: in an organic solvent, the compound 4 and the trifluoromethanesulfonic anhydride are subjected to an esterification reaction as shown below under the action of a base to obtain a compound 4 ';
  • the esterification reaction preferably comprises the following steps: after the compound 4, the organic solvent and the base are mixed, trifluoromethanesulfonic anhydride is added to carry out the esterification reaction.
  • the esterification reaction requires the addition of trifluoromethanesulfonic anhydride at a temperature of -5 V -0 V.
  • the organic solvent may be a conventional solvent for such a reaction in the art, and is preferably a halogenated hydrocarbon solvent.
  • the halogenated hydrocarbon solvent is preferably dichloromethane, more preferably anhydrous methylene chloride.
  • the base may be a conventional base for such reaction in the art, preferably an organic base.
  • the organic base is preferably pyridine, more preferably anhydrous pyridine.
  • the trifluoromethanesulfonic anhydride is preferably used in the form of an organic solution of trifluoromethanesulfonic anhydride.
  • the amount of the trifluoromethanesulfonic anhydride and the organic solvent may not be specifically limited.
  • the manner of adding trifluoromethanesulfonic anhydride is preferably dropwise.
  • the speed of the dropwise addition may be not particularly limited as long as the temperature of the reaction system is controlled to be between -5 ° C and 0 ° C.
  • the amount of the base to be used may be a conventional amount for such a reaction in the art, and preferably, the molar ratio thereof to the compound 4 is from 3:1 to 10:1, more preferably from 5:1 to 8:1.
  • the amount of the trifluoromethanesulfonic anhydride used may be a conventional amount for such a reaction in the art, and preferably, the molar ratio thereof to the compound 4 is 1: 1-5: 1, more preferably 2: 1-3. : 1.
  • the amount of the organic solvent to be used is not particularly limited as long as the reaction is not affected, and preferably, the volume-to-mass ratio of the compound to the compound 4 is from 5 mL/g to 20 mL/g.
  • the temperature of the esterification reaction is preferably from -5 ° C to 0 ° C.
  • the progress of the esterification reaction can be monitored by conventional detection methods in the art (e.g., TLC, HPLC or GC), generally as the end of the reaction when Compound 4 disappears.
  • the period of the esterification reaction is preferably from 0.5 to 3 hours, more preferably 1 hour.
  • the method of preparing the compound 4' can also be carried out in gas protection.
  • the gas in the gas protection may be a conventional protective gas in the field of organic synthesis, preferably N 2 .
  • the post-treatment operation may be further included.
  • the post-treatment operation preferably comprises the steps of: adding a terpene hydrocarbon solvent to the reaction liquid after completion of the esterification reaction, precipitating the solid, and filtering.
  • the terpene hydrocarbon solvent may be a conventional terpene hydrocarbon solvent in the organic field, preferably n-glycol.
  • the amount of the terpene hydrocarbon solvent to be used may be not particularly limited, so that no solid precipitation is preferable.
  • the subsequent reaction can be carried out directly without post-treatment.
  • the method for preparing the compound 4' preferably further comprises the steps of: exemplifying the compound 3 and the triisopropyl orthoformate in the organic solvent under the catalysis of an acid and/or an acid salt; a condensation reaction to produce the compound 4;
  • the condensation reaction preferably comprises the steps of: suspending the compound 3 in an organic solvent, adding an acid and/or an acid salt, triisopropyl orthoformate, and performing the Condensation reaction.
  • the acid or acid salt may be a conventional acid or acid salt of the reaction in the art, and the acid is preferably an organic acid, more preferably camphorsulfonate.
  • the acid salt is preferably a pyridine hydrochloride salt and/or a pyridine p-toluenesulfonate.
  • the organic solvent is preferably an anhydrous organic solvent.
  • the organic solvent may be a conventional organic solvent for such a reaction in the art, preferably an ether solvent and/or a 3 ⁇ 4 hydrocarbon solvent.
  • the ether solvent is preferably tetrahydrofuran and/or 2-methyltetrahydrofuran.
  • the halogenated hydrocarbon solvent is preferably dichloromethane.
  • the molar ratio of the triisopropyl orthoformate to the compound 3 is preferably from 4:1 to 10:1, more preferably from 5:1 to 6:1.
  • the amount of the acid and/or acid salt (if the acid and the acid salt are co-catalyzed, the amount used herein refers to the total amount of the acid and the acid salt) is a catalytic amount, preferably, the mass is a compound. 3% by mass of 0.01% to 0.2%, more preferably 0.05% to 0.08%.
  • the amount of the organic solvent to be used is not particularly limited as long as it does not affect the progress of the reaction, and preferably, the volume-to-mass ratio of the solvent to the compound 3 is from 1 mL/g to 50 mL/g, more preferably from 5 mL/g to 20 mL. /g.
  • the temperature of the condensation reaction is preferably from 25 ° C to the reflux temperature of the solvent at normal pressure.
  • the progress of the condensation reaction can be monitored by conventional detection methods in the art (e.g., TLC, HPLC or GC), generally as the end of the reaction when Compound 3 disappears.
  • the condensation reaction comprises a first-stage reaction and a second-stage reaction, wherein the temperature of the first-stage reaction is preferably from 25 ° C to 30 ° C ; the second-stage reaction The temperature is preferably the solvent reflux temperature at normal pressure.
  • the time of the condensation reaction is preferably from 1 to 6 hours, wherein the first stage reaction time is preferably 0.5
  • the second stage reaction time is preferably from 0.5 hours to 3 hours, in hours to 5 hours.
  • a post-treatment operation is further included.
  • the method and conditions for the post-treatment operation may be a conventional method and condition for post-treatment in the field of organic synthesis, and preferably include the following steps: adding water, a base (for example, 22.7 mL of water) to the reaction liquid after the end of the condensation reaction , 0.2g sodium bicarbonate), added to the extraction with an organic solvent (such as ethyl acetate) extraction layering (extraction, the general operation is the organic phase washed with water (114mLx2), combined with the aqueous phase, extraction with organic solvents (such as ethyl acetate) Wash (227 mL x 2)), combine all the organic phases, remove the organic solvent (for example, steam under reduced pressure), and dry (for example, vacuum drying at 35 ° C to constant weight) to obtain Compound 4.
  • a base for example, 22.7 mL of water
  • an organic solvent such as ethyl acetate
  • extraction layering extraction, the general operation is the
  • the base can be a post-treatment conventional base in the art for such reaction, preferably sodium bicarbonate.
  • the temperature at which the reaction liquid after the completion of the condensation reaction is mixed with water and alkali is preferably from 20 ° C to 40 ° C, preferably from 25 ° C to 30 ° C.
  • the reaction liquid after completion of the condensation reaction may be treated with an organic acid having a pKa value of 3-5 (25 ° C).
  • the organic acid is preferably one or more of formic acid, acetic acid, n-propionic acid, n-butyric acid, citric acid, fumaric acid and tartaric acid.
  • the amount of the organic acid to be used is not particularly limited as long as it does not affect the progress of the reaction, and preferably, the molar ratio thereof to the compound 3 is 5:1 to 20:1, more preferably 10:1 to 20 : 1.
  • the temperature of the organic acid treatment is preferably from 10 ° C to 30 ° C.
  • the organic acid treatment time is preferably from 10 hours to 20 hours, more preferably from 15 hours to 18 hours.
  • the reaction liquid after completion of the condensation reaction is treated with an organic acid, it is preferred to further comprise a step of mixing the reaction liquid after completion of the condensation reaction with water or a base.
  • the base can be a post-treatment conventional base in the art for such reactions, preferably sodium bicarbonate.
  • the relationship between the amount of water and the amount of the base may not be specifically limited.
  • the temperature at which the reaction liquid after completion of the condensation reaction is mixed with water and alkali is preferably 20 ° C to 40 ° C, preferably 25 ° C to 30 ° C.
  • the post-treatment operation preferably includes The following steps: To the reaction solution treated with an organic acid having a pKa value of 3-5 (25 ° C), an aqueous solution of sodium hydrogencarbonate (for example, 67.8 g of sodium hydrogencarbonate plus 784 mL of water) is added, and an organic solvent for extraction is added (for example, Ethyl acetate) extraction stratification (extraction, the organic phase is usually washed with water (114 mL x 2), the aqueous phase is combined, the extraction is washed with an organic solvent (such as ethyl acetate) (227 mL> ⁇ 2), and all organic phases are combined.
  • an organic solvent for extraction for example, Ethyl acetate
  • the organic solvent is removed (e.g., under reduced pressure) and dried (e.g., dried under vacuum at 35 ° C to constant weight) to afford compound 4.
  • the temperature at which the reaction solution treated with the organic acid having a pKa value of 3-5 (25 ° C) is mixed with the aqueous sodium hydrogencarbonate solution is preferably -5 ° C - 0 ° C.
  • the method for preparing the compound 4' preferably further comprises the steps of: acylating the compound 2 with trifluoroacetic anhydride in the organic solvent A, and then, in the solvent, after the acylation reaction is completed.
  • the reaction solution is treated with a base to obtain the compound 3;
  • the acylation reaction preferably comprises the steps of: suspending the compound 2 in the organic solvent A, and then adding trifluoroacetic anhydride to carry out the acylation reaction, preferably, The acylation reaction requires the addition of trifluoroacetic anhydride at a temperature between 0 ° C and 25 ° C (e.g., 10 ° C to 25 ° C).
  • the organic solvent A is preferably an anhydrous organic solvent.
  • the organic solvent A may be a conventional organic solvent for such a reaction in the art, preferably an ether solvent and/or a hydrocarbon solvent.
  • the ether solvent is preferably tetrahydrofuran and/or 2-methyltetrahydrofuran.
  • the halogenated hydrocarbon solvent is preferably dichloromethane.
  • the molar ratio of the trifluoroacetic anhydride to the compound 2 is preferably from 3:1 to 10:1, more preferably from 4:1 to 6:1.
  • the amount of the organic solvent A to be used is not particularly limited as long as it does not affect the progress of the reaction, and preferably, the volume-to-mass ratio of the organic solvent to the compound 2 is 5 mL/g to 30 mL/g, more preferably 5 mL/g- 10 mL/g.
  • the temperature of the acylation reaction is preferably from 0 ° C to 25 ° C, more preferably from 10 ° C to 20 ° C.
  • the progress of the acylation reaction can be monitored by conventional detection methods in the art (e.g., TLC, HPLC or GC), generally as the end of the reaction when Compound 2 disappears.
  • the acylation reaction time is preferably from 3 hours to 10 hours, more preferably from 4 hours to 6 hours.
  • the treatment of the reaction liquid after completion of the acylation reaction with a base preferably includes the following steps: adding a base and an organic solvent B to the reaction liquid after completion of the acylation reaction, and adding water , carry out the reaction.
  • the organic solvent B may be a conventional solvent for such a reaction in the art, preferably one or more of an ether solvent, a 3 ⁇ 4 hydrocarbon solvent, an ester solvent, and an alcohol solvent, and more preferably A mixed solvent of one or more of an ether solvent, a halogenated hydrocarbon solvent, and an ester solvent with an alcohol solvent.
  • the ether solvent is preferably tetrahydrofuran and/or 2-methyltetrahydrofuran.
  • the halogenated hydrocarbon solvent is preferably dichloromethane.
  • the ester solvent is preferably ethyl acetate.
  • the alcohol solvent is preferably methanol.
  • the base is preferably an inorganic base.
  • the inorganic base is preferably one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate and sodium phosphate.
  • the amount of the base to be used may be a conventional amount for such a reaction in the art, and preferably, the molar ratio thereof to the compound 2 is from 15 to 25:1.
  • the amount of water and organic solvent B used may be a conventional amount for such reactions in the art.
  • the relationship between the mixed solvent of the water and the organic solvent B and the amount of the compound 2 is not particularly limited as long as the reaction is not affected.
  • the temperature at which the reaction solution after the completion of the acylation reaction is treated with a base is preferably from 30 ° C to 35 ° C.
  • the time at which the reaction solution after the completion of the acylation reaction is treated with a base is preferably 10 hours to 25 hours, more preferably 15 hours to 20 hours.
  • the method and conditions for the post-treatment may be the conventional methods and conditions for post-treatment in the field of organic synthesis, and preferably include the following steps: adding to the reaction solution after the end of the acylation reaction is completed with a base, An aqueous solution of hydrochloric acid (14.2 mL of concentrated hydrochloric acid and 150 mL of water is mixed), the layers are separated, the organic phase is washed with water, and the aqueous phase is combined with an organic solvent (for example ethyl acetate) for extraction, and all the organic phases are combined with an acid having a pH of 4.0.
  • an organic solvent for example ethyl acetate
  • the aqueous solution is washed, washed with water, and the organic solvent is removed (for example, under reduced pressure), and dried (for example, vacuum drying at 35 ° C to constant weight).
  • the acid in the aqueous acid solution having a pH of 4.0 may be a conventional acid in the art as long as the pH in the aqueous acid solution is controlled to 4.0.
  • the temperature at which the reaction liquid after completion of the acylation reaction is mixed with the aqueous hydrochloric acid solution after completion of the alkali treatment is preferably -5 °C - 0 °C.
  • the invention also provides a preparation method of the compound 5, which comprises the following steps: in the organic solvent, the compound 4' and the formic acid prepared according to the preparation method as described above are subjected to the following steps under the action of a base; Nucleophilic substitution reaction to produce compound 5;
  • the nucleophilic substitution reaction preferably comprises the steps of: adding a mixed solution of a base, a formic acid and an organic solvent to a mixed solution of the compound 4' and an organic solvent; Nucleophilic substitution reaction.
  • the amount of the organic solvent in the mixed solution of the compound 4' and the organic solvent and the mixed solution of the alkali, formic acid and the organic solvent is not particularly limited as long as the reaction is not affected.
  • the formic acid is preferably anhydrous formic acid.
  • the organic solvent may be a conventional organic solvent for such a reaction in the art, preferably a 3 ⁇ 4 generation hydrocarbon solvent.
  • the 3 ⁇ 4 generation hydrocarbon solvent is preferably methylene chloride (for example, anhydrous dichloromethane).
  • the base may be a conventional base for such reactions in the art, preferably triethylamine.
  • the base may be used in an amount conventionally used in the art, and preferably, the molar ratio thereof to formic acid is 1:1-5:1, more preferably 1:1-3:1.
  • the molar ratio of the compound 4' and the formic acid is preferably 1:10-1:15, more preferably 1:12.5.
  • the amount of the solvent to be used is not particularly limited as long as it does not affect the progress of the reaction.
  • the volume-to-mass ratio of the solvent to the formic acid is from 1 mL/g to 50 mL/g, more preferably from 1 mL/g to 30 mL/g.
  • the temperature of the nucleophilic substitution reaction may be a conventional temperature for such a reaction in the art, preferably from 20 ° C to 25 ° C.
  • the process of the nucleophilic substitution reaction can be carried out Conventional detection methods in the field are monitored (eg, TLC, HPLC, or GC), typically as the endpoint of the reaction when Compound 4' disappears.
  • the time of the nucleophilic substitution reaction is preferably from 10 hours to 20 hours, more preferably from 15 hours to 20 hours.
  • the method and conditions of the post-treatment operation may be a conventional method and condition for post-treatment in the field of organic synthesis, and preferably include the following steps: adding a base to the reaction solution after the end of the nucleophilic substitution reaction (for example Sodium bicarbonate) and water, layered, the organic phase is washed with an aqueous acid solution (for example, 8% aqueous acetic acid) (for example, 300 mL ⁇ 2), and the aqueous acid layer is combined, and the extraction is carried out with an organic solvent (the organic solvent for extraction is generally reacted with a nucleophilic substitution reaction).
  • a base for example Sodium bicarbonate
  • an aqueous acid solution for example, 8% aqueous acetic acid
  • an organic solvent for extraction is generally reacted with a nucleophilic substitution reaction.
  • the organic solvent used is the same, for example, methylene chloride, combined with all the above organic phases, washed with an aqueous alkali solution (for example, 5% sodium hydrogencarbonate, 300 mL), and the aqueous alkali solution is washed with an organic solvent for extraction (the organic solvent for extraction is generally
  • the nucleophilic substitution reaction uses the same organic solvent, for example, methylene chloride.
  • the organic phase is combined, washed with water, and the organic solvent is removed (for example, under reduced pressure) to obtain compound 5.
  • the compound 4' and the formic acid are directly subjected to the action of a base without post-treatment.
  • the nucleophilic substitution reaction is carried out to prepare the compound 5; more preferably, the nucleophilic substitution reaction is carried out by directly adding the mixed solution of the base, formic acid and an organic solvent without post-treatment.
  • the present invention also provides a process for the preparation of the compound 5', which comprises the steps of: deprotecting the compound 5 obtained according to the preparation method as described above under the action of a base in a solvent. , obtaining compound 5';
  • the deprotection reaction preferably comprises the following steps: after mixing the compound 5 with a solvent, adding a base to carry out the deprotection reaction; preferably, the The deprotection reaction is controlled by adding a base at a temperature of -25 °C to -5 °C.
  • the solvent may be a conventional solvent for such a reaction in the art, preferably a halogenated hydrocarbon solvent and/or an alcohol solvent of dC 4 .
  • the halogenated hydrocarbon solvent is preferably dichloromethane.
  • the alcohol solvent of d- is preferably methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and tert-butanol.
  • the base may be a conventional base for such reactions in the art, preferably an inorganic base.
  • the inorganic base is preferably sodium hydroxide and/or potassium hydroxide.
  • the base is preferably used in the form of an aqueous solution of a base.
  • the molar concentration of the aqueous solution of the base is not particularly limited as long as it does not affect the progress of the reaction.
  • the molar concentration of the aqueous alkali solution is from 1 mol/L to 3 mol/L.
  • the amount of the base to be used is not particularly limited as long as it does not affect the progress of the reaction.
  • the mass ratio of the compound 5 to the base is 1:1-1:3, more preferably 1:2.
  • the amount of the solvent to be used may not be specifically limited as long as it does not affect the progress of the reaction.
  • the temperature of the deprotection reaction is preferably -25 5 °C.
  • the progress of the deprotection reaction can be monitored by conventional detection methods in the art (e.g., TLC, HPLC or GC), generally as the end of the reaction when Compound 5 disappears.
  • the time of the deprotection reaction is preferably from 5 hours to 20 hours, more preferably from 8 hours to 15 hours.
  • the post-treatment operation may be a conventional post-treatment operation for preparing such a reaction in epirubicin hydrochloride, and the present invention preferably comprises the following steps: in the reaction liquid after the end of the deprotection reaction, The organic acid and the inorganic base are sequentially added, and the organic solvent (the organic solvent may be extracted by a conventional organic solvent in the art, preferably a halogenated hydrocarbon solvent) may be extracted (extractable two or more times).
  • the aqueous phase is extracted with an organic solvent
  • the organic solvent may be a conventional organic solvent for extraction in the art, preferably a halogenated hydrocarbon solvent or a mixed solvent of a halogenated hydrocarbon solvent and a dC 4 alcohol solvent (for example).
  • Dichloromethane: Methanol 4: 1 (v/v))
  • all organic phases are combined, washed with water, and the organic solvent is removed (for example, steam distillation under reduced pressure).
  • the organic acid may be a post-treatment conventional organic acid, preferably acetic acid, for such reactions in the art.
  • the organic acid is preferably used in the form of an aqueous solution of an organic acid.
  • the mass fraction of the organic acid in the aqueous solution of the organic acid is preferably from 5% to 15%, more preferably 8%.
  • the inorganic base can be post-treated to a conventional inorganic base, preferably sodium bicarbonate, for such reactions in the art.
  • the amount of the organic acid and the inorganic acid to be used may be a conventional amount for such post-treatment in the art, and is not specifically limited herein.
  • the removal is carried out directly in a solvent under the action of a base without post-treatment.
  • the reaction was protected to prepare compound 5'.
  • the invention also provides a preparation method of epirubicin hydrochloride compound 1, which comprises the following steps: in the solvent, under the action of hydrochloric acid, the compound 5' obtained according to the above preparation method is subjected to the deprotection reaction shown below. , obtaining compound 1 ;
  • the solvent may be a conventional solvent for such a reaction in the art, and is preferably a halogenated hydrocarbon solvent and/or an alcohol solvent of dC 4 .
  • the halogenated hydrocarbon solvent is preferably dichloromethane.
  • the alcohol solvent of dC 4 is preferably one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and tert-butanol.
  • the hydrochloric acid preferably participates in the reaction in the form of an aqueous solution of hydrochloric acid.
  • the molar concentration of the aqueous hydrochloric acid solution is not particularly limited as long as it does not affect the progress of the reaction.
  • the aqueous hydrochloric acid solution has a molar concentration of 2 mol/L to 4 mol/L.
  • the amount of the hydrochloric acid to be used is not particularly limited as long as it does not affect the progress of the reaction, and preferably, the molar ratio thereof to the compound 5' is from 26:1 to 52:1.
  • the amount of the solvent to be used may not be specifically limited as long as it does not affect the progress of the reaction.
  • the temperature of the deprotection reaction is preferably from 0 to 25 °C.
  • the progress of the deprotection reaction can be monitored by conventional detection methods in the art (e.g., TLC, HPLC or GC), generally as the end of the reaction when compound 5' disappears.
  • the time of the deprotection reaction is preferably from 3 hours to 15 hours, more preferably from 5 hours to 10 hours.
  • the method and conditions for the post-treatment may be the conventional methods and conditions for post-treatment in the field of organic synthesis, and preferably include the following steps: the reaction solution after the end of the deprotection reaction is layered, and the aqueous phase is extracted with an organic solvent. (for example, dichloromethane), the organic phase is combined, washed with water, and the aqueous phase is combined to obtain a crude aqueous solution of epirubicin hydrochloride, which is then separated and purified by column chromatography.
  • an organic solvent for example, dichloromethane
  • the method for separating and purifying can be a conventional method for separating and purifying epirubicin hydrochloride in the field, for example, a method for separating and purifying epirubicin hydrochloride disclosed in patents IT01237202 and US4861870, and the application number is CN201510744980.0, the application date is Chinese Patent Application, Nov. 5, 2015, the entire contents of which is incorporated herein by reference.
  • the hydrochloric acid is directly added to the deprotection reaction without post-treatment to obtain the compound 1.
  • the invention also provides a preparation method of the compound 4, which comprises the following steps: in the organic solvent, the compound 3 and the triisopropyl orthoformate are subjected to a condensation reaction as shown below under the catalysis of an acid and/or an acid salt; , the compound 4 is prepared;
  • the invention also provides a preparation method of the compound 5, which comprises the following steps: in an organic solvent, in a base Under the action, the compound 4' and the formic acid are subjected to a nucleophilic substitution reaction as shown below to prepare a compound.
  • the invention also provides a preparation method of the compound 5', which comprises the following steps: in a solvent, under the action of a base, the compound 5 is subjected to a deprotection reaction as shown below to obtain a compound 5';
  • the present invention also provides a preparation method of epirubicin hydrochloride compound 1, which comprises the following steps: in a solvent, under the action of hydrochloric acid, the compound 5' is subjected to a deprotection reaction as shown below to obtain a compound 1;
  • the present invention also provides a compound of Formula 4, a compound of Formula 4', a compound of Formula 5, or a compound of Formula 5':
  • the configuration of the "one" attached carbon atom in the structure of each compound is racemic or non-racemic. When it is non-racemic, it is in the S configuration or the R configuration.
  • temperature means operating at room temperature, and the room temperature means ambient temperature, generally 10 ° C - 30 ° C o
  • the temperature of the added materials, the mixing temperature of the materials, and the like refer to the temperature of the reaction system (or the reaction liquid).
  • the post-treatment without treatment generally means that the reaction liquid after the completion of the reaction is not post-treated.
  • the preparation method of the invention has short route, easy to obtain reaction raw materials, no need to use other expensive reagents, low cost, mild reaction conditions, simple operation, yield greater than 65%, purity greater than 85%, high yield and purity , is conducive to industrial production. detailed description
  • the doxorubicin hydrochloride described in the present invention is provided by Zhejiang Hisun Pharmaceutical Co., Ltd.
  • the purity of the compound 3, the compound 4, the compound 4-1, the compound 4-2, the compound 4', the compound 5, the compound 5', the compound 29, the compound 30, the compound 32 and the compound 30' in the present invention is normalized by HPLC.
  • method was measured, chromatographic conditions: Fortis H 2 0 column (4.6mm X 250mm, 5um); mobile phase: 20mmol / L potassium dihydrogen phosphate solution (pH 4.0) (A), acetonitrile (B), gradient ( 0 ⁇ 8 min, A 95%; 8 ⁇ 15 min, A 95% ⁇ 25%; 15
  • the concentration of epirubicin hydrochloride is determined by HPLC, and the sample is diluted to a suitable concentration in epirubicin hydrochloride, and the concentration of epirubicin hydrochloride in the sample is obtained by a regression equation.
  • the regression equation is derived from the standard curve.
  • Standard curve drawing Precisely weigh a certain amount of epirubicin hydrochloride reference substance in a volumetric flask, add mobile phase to dissolve and volume, and use it as a reference stock solution. Accurately measure the appropriate amount of stock solution, and dilute with the mobile phase to prepare a series of standard solutions with concentrations of 26.3, 52.6, 105.2, 210.4, 315.6, 420.8, and 526.0 g/mL, respectively, and inject them separately, with a peak area of epirubicin hydrochloride ( mAUxmin) is the ordinate, the concentration c ( ⁇ g/mL) is the abscissa, and the linear regression is performed.
  • numerals 1, 2, 3 and 4 are peak numbers indicating the retention time, peak height, peak area, and relative area of each component in the compound 4 obtained in Example 2.
  • the peak No. 2 indicates the compound 4.
  • the numbers 1, 2, 3 and 4 are the peak numbers, indicating the retention time, peak height and peak area of each component in the compound 4-1 obtained by subjecting the compound 4 prepared in Example 2 by column chromatography. , relative area and other information.
  • the peak No. 4 indicates the compound 4-1.
  • the numbers 1, 2, 3 and 4 are the peak numbers, indicating the retention time, peak height and peak area of each component in the compound 4-2 obtained by subjecting the compound 4 prepared in Example 2 to fractional resolution by column chromatography. , relative area and other information.
  • the peak No. 3 indicates the compound 4-2.
  • the numerals 1-18 are the peak numbers, and indicate the retention time, peak height, peak area, and relative area of each component in the crude epirubicin hydrochloride obtained in Example 7.
  • the peak No. 11 indicates epirubicin hydrochloride.
  • the concentration of epirubicin hydrochloride in the crude aqueous solution of epirubicin hydrochloride was 6.6 g/L from the regression equation, and the yield of crude epirubicin hydrochloride from the compound 5' was 94. %.
  • the aqueous phase was combined to obtain 3L of a crude aqueous solution of epirubicin hydrochloride, the purity was 89.0%, and diluted to a suitable concentration.
  • the concentration of epirubicin hydrochloride in the crude aqueous solution of epirubicin hydrochloride was 7.2 g/L by the regression equation. It is 91%.

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Abstract

La présente invention concerne un procédé et un intermédiaire pour la préparation d'un chlorhydrate d'épirubicine. Le procédé comprend l'étape suivante, consistant à : dans un solvant organique et sous l'action d'un alcali, soumettre le composé 4 et un anhydride trifluorométhanesulfonique à une estérification montrée ci-dessous pour obtenir le composé 4'. Le procédé de préparation selon la présente invention présente les avantages de voies de réaction courtes, d'un haut rendement, d'une disponibilité accessible de matières premières de réaction, de ne pas avoir besoin d'utiliser d'autres réactifs onéreux, de faibles coûts, de conditions de réaction douces et d'opérations simples, ce qui facilite la production industrielle.
PCT/CN2016/070566 2016-01-11 2016-01-11 Procédé et intermédiaire pour la préparation de chlorhydrate d'épirubicine Ceased WO2017120729A1 (fr)

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PCT/CN2016/070566 WO2017120729A1 (fr) 2016-01-11 2016-01-11 Procédé et intermédiaire pour la préparation de chlorhydrate d'épirubicine

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CN114262300A (zh) * 2021-12-15 2022-04-01 浙江伟锋药业有限公司 一种2-乙氧基-4,6-二氟嘧啶的制备方法
CN115124578A (zh) * 2021-03-29 2022-09-30 上海医药工业研究院 一种络塞维中间体、其制备方法和用途

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WO1996029335A1 (fr) * 1995-03-22 1996-09-26 Sicor Societa' Italiana Corticosteroidi S.P.A. Procede de preparation d'antibiotiques de la famille des anthracyclines
EP0848009A1 (fr) * 1996-12-16 1998-06-17 Pharmachemie B.V. Procédé pour la préparation d'épirubicin ou leurs sels d'addition en commençant avec du daunorubicin
WO2006096665A1 (fr) * 2005-03-07 2006-09-14 Solux Corporation Epimerisation de liaison 4'-c et modification de 14-ch3-(co)-fragment dans des antibiotiques n anthracyclines
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WO1996029335A1 (fr) * 1995-03-22 1996-09-26 Sicor Societa' Italiana Corticosteroidi S.P.A. Procede de preparation d'antibiotiques de la famille des anthracyclines
EP0848009A1 (fr) * 1996-12-16 1998-06-17 Pharmachemie B.V. Procédé pour la préparation d'épirubicin ou leurs sels d'addition en commençant avec du daunorubicin
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CN115124578B (zh) * 2021-03-29 2024-05-10 上海医药工业研究院 一种络塞维中间体、其制备方法和用途
CN114262300A (zh) * 2021-12-15 2022-04-01 浙江伟锋药业有限公司 一种2-乙氧基-4,6-二氟嘧啶的制备方法

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