WO2013170778A1 - Composé intermédiaire pour la préparation d'ambrisentan, son procédé de préparation et procédé de préparation d'ambrisentan - Google Patents

Composé intermédiaire pour la préparation d'ambrisentan, son procédé de préparation et procédé de préparation d'ambrisentan Download PDF

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WO2013170778A1
WO2013170778A1 PCT/CN2013/075782 CN2013075782W WO2013170778A1 WO 2013170778 A1 WO2013170778 A1 WO 2013170778A1 CN 2013075782 W CN2013075782 W CN 2013075782W WO 2013170778 A1 WO2013170778 A1 WO 2013170778A1
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compound
group
reaction
acid
solvent
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PCT/CN2013/075782
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Chinese (zh)
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林峰
朱晓峰
陈建丽
徐秋龙
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上海医药工业研究院
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/28—Preparation of ethers by reactions not forming ether-oxygen bonds from acetals, e.g. by dealcoholysis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/03—Ethers having all ether-oxygen atoms bound to acyclic carbon atoms
    • C07C43/14—Unsaturated ethers
    • C07C43/178—Unsaturated ethers containing hydroxy or O-metal groups
    • C07C43/1782—Unsaturated ethers containing hydroxy or O-metal groups containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/18—Radicals substituted by singly bound oxygen or sulfur atoms
    • C07D317/22—Radicals substituted by singly bound oxygen or sulfur atoms etherified

Definitions

  • This invention relates to the field of medicinal chemistry, and in particular to intermediate compounds for the preparation of ambrisentan, as well as processes for the preparation of these intermediates and processes for the preparation of ambrisentan. Background technique
  • Pulmonary arterial hypertension is a type of disease characterized by abnormally elevated pulmonary vascular pressure and progressive occlusion of the pulmonary vascular bed pathology, which ultimately leads to an increase in progressive vascular resistance and right heart failure.
  • pulmonary hypertension drugs are mainly classified into phosphodiesterase-5 (PDE-5) inhibitors, prostacyclin and endothelin receptor antagonists depending on the mechanism of action.
  • PDE-5 phosphodiesterase-5
  • prostacyclin phosphodiesterase-5
  • endothelin receptor antagonists can completely bind to endothelin receptors, thereby delaying the progression of the disease. Therefore, in recent years, studies on pulmonary hypertension drugs have tended to be endothelin receptor antagonists.
  • Ambrisentan is a selective endothelin receptor A antagonist developed by Myogen Biopharmaceutical Company of the United States. Its chemical name is (+)-(2S)-2-[(4, 6-II) Methylpyrimidin-2-yl)oxy] 3-methoxy-3,3-diphenylpropionic acid having the formula C 22 H 22 N 2 O 4 and a relative molecular weight of 378.42. The drug was approved by the US FDA in June 2007 with the S-active configuration, and August 2008 Chinese pulmonary hypertension. Its structural formula is as follows:
  • Anrishengtan has a significant effect on the treatment of pulmonary hypertension, and its synthesis is of great significance.
  • U.S. Patent No. 5,703,017 discloses the synthesis of a series of 3-aromatic propionic acid derivatives. Starting from benzophenone, a Darzens condensation reaction, a ring opening reaction, and a substitution reaction are carried out to obtain a compound I. The synthetic route is as follows: This patent does not report the method by which Compound I resolves Anrientan (S-I).
  • U.S. Patent No. 5,932,730 discloses a synthesis method similar to that of US5703017, which uses benzophenone as a raw material, undergoes Darzens reaction, alcoholysis, alkaline hydrolysis, and utilizes L-valine methyl ester or (S)-l-( The enantiomer of 4-nitro-1.
  • the method is:
  • the yield of the method is 36.4%.
  • the method overcomes the disadvantage of the difficulty of crystallization in the amplification of the patent US5932730, the resolving agent is relatively expensive, increases the cost, and is not suitable for industrialization.
  • Patent WO2010070658 discloses a preparation of Anrishengtan using L-valine methyl ester as a resolving agent Method, the method is:
  • Patent WO2011004402 discloses a novel intermediate for the synthesis of ambrisentan and a process for the preparation thereof. Using a chiral amine as a resolving agent, the obtained diastereomer (IX) is strongly basic and 4,6-dimethyl-2-
  • the total route yield of the method is 24%, but the resolving agents are relatively expensive.
  • the object of the present invention is to provide an intermediate compound for preparing ambrisentan, which is a compound of the S configuration, which can directly synthesize ambrisentan without resolution, overcomes the defects of the prior art, and improves the synthesis. Atomic utilization, reduced costs, and suitable for industrial production.
  • the invention utilizes cheap and readily available D-mannitol as a raw material, and constructs a 2-S-chiral center of ambrisentan using a chiral configuration naturally occurring in D-mannitol, and directly obtains high optics without being separated.
  • a chiral intermediate of purity optical purity ee value greater than 99.9%
  • the method of the present invention is a green chemical method to improve the atomic utilization and synthesis of the synthesis.
  • Efficiency the method is simple in operation, mild in reaction conditions, high in yield, and suitable for industrial mass production.
  • the invention also provides a method for preparing ambrisentan using the above intermediate, the raw material used in the method is cheap and easy to obtain, the operation is simple, the yield is high, and the product is suitable for industrial mass production.
  • the present invention provides a compound represented by IV,
  • the present invention provides a process for the preparation of a compound of formula IV, which comprises obtaining a compound of formula IV by reverse deprotection of a compound of formula III,
  • R 2 are each independently selected from a hydrogen atom, C r C 6 fluorenyl, C r C 6 halodecyl, phenyl or phenyl substituted by ⁇ -decyloxy, halogen, hydroxy, or The attached carbon atoms together form a C 3 -C 6 cyclodecyl group.
  • the attached carbon atoms together form a cyclohexyl or cyclopentyl group.
  • ⁇ is both methyl, both ethyl or all 11.
  • reaction solvent is one or more of organic solvents or a mixed solvent of an organic solvent and water.
  • the organic solvent is selected from the group consisting of methanol, ethanol, tetrahydrofuran, acetonitrile,
  • the reaction is carried out under the catalysis of a protic acid or a solid super acid, and the amount of the protonic acid is 0.1 to 2 eq, preferably 0.2 to 1.8 eq, based on the equivalent of the compound III. More preferably, it is 0.3 ⁇ 0.8 eq; the amount of solid super acid is 0.1 eq ⁇ 2.5 eq, preferably 0.3 ⁇ leq; the reaction temperature is 0 °C ⁇ 100 °C, preferably 20 °C ⁇ 80 °C; the reaction time is lh ⁇ 60h, preferably 2h ⁇ 60h.
  • the protic acid is selected from the group consisting of concentrated sulfuric acid, concentrated hydrochloric acid, glacial acetic acid, trifluoroacetic acid, p-toluenesulfonic acid or a mixture thereof
  • the solid super acid is selected from the group consisting of phosphotungstic acid, phosphomolybdic acid, Nafion or a mixture thereof.
  • the present invention provides an intermediate compound III for the preparation of a compound of the formula IV, which has the structural formula:
  • R 2 are each independently selected from a hydrogen atom, C r C 6 fluorenyl, C r C 6 halodecyl, phenyl or phenyl substituted by ⁇ -decyloxy, halogen, hydroxy, or The attached carbon atoms together form a C 3 -C 6 cyclodecyl group.
  • the attached carbon atoms together form a cyclohexyl or cyclopentyl group.
  • the present invention provides a method of preparing a compound of Formula III, the method comprising
  • the compound represented by II is subjected to methylation reaction in the presence of a reaction solvent to obtain a compound of the formula III.
  • R 2 is independently selected from hydrogen atoms, C r C 6 alkyl with, C r C 6 alkyl with haloalkyl, or phenyl ⁇ - embankment alkoxy, halo, hydroxy-substituted phenyl group, or and a The carbon atoms to which they are attached together form a C 3 -C 6 cyclodecyl group.
  • a cyclohexyl or cyclopentyl group is formed.
  • it is hydrogen, R 2 trichloromethyl, tert-butyl, phenyl or 4-methoxyphenyl.
  • Both ⁇ and R 2 are methyl, both ethyl or all 11.
  • the reaction solvent is an aprotic solvent, preferably selected from the group consisting of tetrahydrofuran, dichloromethane, ethyl acetate, N,N-dimethylformamide, toluene, cyclohexane, chloroform, xylene;
  • the methylating agent is selected from the group consisting of iodoformin, dimethyl sulfate or dimethyl carbonate;
  • the reaction temperature is 0 ° C ⁇ 80 ° C, preferably 20 V ⁇ 40 ° C;
  • the reaction time is lh ⁇ 32 h, preferably 4h ⁇ 16h.
  • the present invention provides a process for the preparation of ambrisentan, which comprises the steps of: a) selectively oxidizing an oxidizing agent in the presence of a buffer salt and a solvent and TEMPO, and then acidifying to form a compound V. ;
  • the compound V is subjected to a substitution reaction with 4,6-dimethyl-2-methylsulfonylpyrimidine in a solvent under basic conditions and in the presence of a phase transfer catalyst;
  • step b) acidifying the product obtained in step b) to obtain ambrisentan S-I, the reaction route is as follows
  • the solvent is selected from the group consisting of acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dioxane, preferably acetonitrile, tetrahydrofuran, more preferably tetrahydrofuran;
  • the oxidizing agent is sodium chlorite, and the equivalent of the compound IV is 1 equivalent.
  • the oxidizing agent is used in an amount of from 1 to 10 eq, preferably from 2 to 6 eq, more preferably from 3 to 5 eq.
  • the TEMPO is used in an amount of from 0.001 to 0.5 eq, preferably from 0.01 to 0.3 eq, more preferably from 0.01 to 0.1, based on 1 equivalent of the compound IV.
  • Eq; the acid used in the acidification in step a) is selected from the group consisting of dilute hydrochloric acid, dilute sulfuric acid or dilute phosphoric acid; more preferably dilute hydrochloric acid.
  • the selective oxidation of 1,2 diol is a problem.
  • the decarboxylated product is easily formed according to the prior art.
  • the TEMPO-NaClO 2 method of the present invention can produce compound V in a high yield. .
  • the solvent is selected from the group consisting of acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dioxane, preferably acetonitrile, tetrahydrofuran, more preferably tetrahydrofuran, the basicity
  • the condition is achieved by adding a base selected from the group consisting of potassium carbonate, sodium carbonate, sodium hydroxide, sodium amide, more preferably sodium hydroxide
  • the phase transfer catalyst is selected from the group consisting of tetrabutylammonium chloride, tetrabutyl Ammonium bromide, tetrabutylammonium iodide, tetrabutylammonium hydrogen sulfate, benzyltrimethylammonium chloride or methyltrioctyl ammonium chloride (Aliquat 336), more preferably tetrabutylammonium hydrogen sulfate.
  • the acid used in the acidification reaction is selected from the group consisting of dilute hydrochloric acid, dilute sulfuric acid, dilute phosphoric acid, and more preferably dilute hydrochloric acid.
  • the present invention provides a process for the preparation of ambrisentan, which comprises the steps of: a) reacting compound IV with an acid chloride R 3 -C1 in the presence of a solvent and a base to form compound VI, wherein is selected from the group consisting of pivaloyl At the 4-position of the benzoyl or phenyl ring, hydroxy, halogen, C r C 6 fluorenyl or C r C 6 ⁇ An oxy-substituted benzoyl group, more preferably a pivaloyl group or a benzoyl group;
  • the compound VI is substituted with 4,6-dimethyl-2-methylsulfonylpyrimidine to form the compound ⁇ ;
  • the solvent is selected from the group consisting of dichloromethane, ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, chloroform, tetrahydrofuran, acetonitrile or a mixture thereof, more preferably Dichloromethane, tetrahydrofuran;
  • the basic condition is achieved by the addition of a base selected from the group consisting of pyridine, triethylamine, potassium carbonate, sodium carbonate, more preferably pyridine, triethylamine.
  • the solvent is selected from the group consisting of acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dioxane, preferably acetonitrile, tetrahydrofuran or a mixture thereof, more preferably tetrahydrofuran;
  • the basic condition is achieved by adding a base selected from the group consisting of potassium carbonate, sodium carbonate, sodium hydroxide, sodium amide, more preferably sodium hydroxide;
  • the phase transfer catalyst is preferably tetrabutylammonium chloride, four Butyl ammonium bromide, tetrabutylammonium iodide, tetrabutylammonium hydrogen sulfate, benzyltrimethylammonium chloride or methyltrioctyl ammonium chloride (Aliquat 336), more preferably tetrabutylammonium hydrogen sulfate .
  • the solvent is selected from the group consisting of dichloromethane, ethyl acetate, methanol, ethanol or a mixture thereof, more preferably methanol, methanol and dichloromethane;
  • the basicity Condition is by adding
  • the base is selected from the group consisting of sodium hydroxide, potassium carbonate, sodium carbonate, sodium methoxide or sodium ethoxide, more preferably sodium methoxide.
  • the solvent is selected from the group consisting of chloroform, chloroform or a mixture thereof
  • the oxidizing agent is selected from the group consisting of a Dess-Martin oxidizing agent or Pt.
  • the present invention provides an intermediate compound VI or ⁇ or sapon for the preparation of S-I, the structural formulas of which are as follows:
  • the 4-position is preferably a pivaloyl group, a benzoyl group, or a benzene ring substituted by hydroxy, halo, C r C 6 alkyl with or ⁇ - embankment substituted benzoyl group, more preferably a pivaloyl group, a benzoyl group.
  • alkyl as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having a straight chain, branched chain.
  • C r C 6 alkyl such as methyl, ethyl, propyl, t-butyl.
  • Cycloalkyl means a cyclic saturated monovalent hydrocarbon group, preferably a c 3 -c 2Q cycloalkyl group, more preferably a c 3 -c 6 cycloalkyl group such as a cyclopropyl group, a cyclobutyl group, a cyclohexyl group or a cyclopentyl group.
  • haloalkyl group means an alkyl group as defined above which is substituted by a halogen atom, preferably a c r c 6 haloalkyl group such as a trifluoromethyl group, a trichloromethyl group or the like.
  • aryl as used herein, unless otherwise specified, includes an organic group, such as phenyl or naphthyl, obtained by removal of one hydrogen from an aromatic hydrocarbon.
  • alkyl Unless otherwise specified, “alkyl”, “cycloalkyl”, “aryl”, as used herein, are each optionally independently substituted with from 1 to 3 substituents selected from the group consisting of: cyano, 3 ⁇ 4 Or a hydroxy, nitro or dC 6 hospital base or. wide. 6 hospital oxygen.
  • R and “S” refer to a specific stereochemical configuration of a substituent on an asymmetric carbon atom in the chemical structure depicted.
  • Me means a methyl group.
  • the present invention provides the preparation of ambrisentan and a compound IV having the following structural formula:
  • the intermediate is used to prepare ambrisentan, which has high atomic economy without being separated.
  • the present invention further provides a process for the preparation of a compound of the formula IV, which comprises obtaining a compound of the formula IV from a compound of the formula III in a reaction-soluble protecting group,
  • R 2 are each independently selected from a hydrogen atom, C r C 6 fluorenyl, C r C 6 halodecyl, phenyl or phenyl substituted by ⁇ -decyloxy, halogen, hydroxy, or
  • the attached carbon atoms together form a C 3 -C 6 cyclodecyl group, more preferably, and each independently selected from a hydrogen atom, a methyl group, an ethyl group, a propyl group, a t-butyl group, a trichloromethyl group, a phenyl group or 4-methoxyphenyl, or together with the carbon atom to which they are attached, form a cyclohexyl or cyclopentyl group; further preferably, hydrogen, R 2 trichloromethyl, tert-butyl, phenyl or 4-methyl Most preferably, R n is a methyl group, both ethyl or all
  • the reaction solvent described above is one or more of an organic solvent or a mixed solvent of an organic solvent and water, and the organic solvent is selected from the group consisting of methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, acetone. , dioxane.
  • the reaction described above is carried out under the catalysis of a protic acid or a solid super acid selected from the group consisting of concentrated sulfuric acid, concentrated hydrochloric acid, glacial acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, preferably concentrated sulfuric acid, glacial acetic acid, and Toluenesulfonic acid; the solid super acid is selected from the group consisting of phosphotungstic acid, phosphomolybdic acid, Nafion and the like.
  • the amount of the protonic acid is 0.1 to 2 eq, preferably 0.2 to 1.8 eq, more preferably 0.3 to 0.8 eq, based on the equivalent of the compound III.
  • the amount of the solid super acid is 0.1 eq based on the equivalent of the compound III. ⁇ 2.5 eq, preferably 0.3 ⁇ leq.
  • the reaction temperature is from 0 ° C to 100 ° C, preferably from 20 ° C to 80 ° C.
  • the reaction time is from 1 h to 60 h, preferably from 2 h to 60 h.
  • the present invention further provides an intermediate compound III for the preparation of a compound of the formula IV, which has the formula:
  • R 2 are each independently selected from a hydrogen atom, C r C 6 fluorenyl, C r C 6 halodecyl, phenyl or phenyl substituted by ⁇ -decyloxy, halogen, hydroxy, or
  • the attached carbon atoms together form a c 3 -c 6 cyclodecyl group, more preferably, and each independently selected from a hydrogen atom, a methyl group, an ethyl group, a propyl group, a t-butyl group, a trichloromethyl group, a phenyl group or 4-methoxyphenyl, or together with R 2 and the carbon atom to which they are attached, form a cyclohexyl or cyclopentyl group; further preferably, hydrogen, trichloromethyl, tert-butyl, phenyl or 4-methyl Oxyphenyl groups, most preferably, !
  • Both ⁇ and R 2 are methyl, both ethyl or all 11.
  • the present invention also provides a process for the preparation of the compound of the formula III, which comprises subjecting a compound of the formula II to methylation in the presence of a reaction solvent to obtain a compound of the formula III.
  • R 2 is independently selected from hydrogen atoms, C r C 6 alkyl with, C r C 6 alkyl with haloalkyl, or phenyl ⁇ - embankment alkoxy, halo, hydroxy-substituted phenyl group, or and a The carbon atom to which they are attached Forming a C 3 -C 6 cyclodecyl group, more preferably, and each independently selected from a hydrogen atom, a methyl group, an ethyl group, a propyl group, a t-butyl group, a trichloromethyl group, a phenyl group or a 4-methoxy group Phenyl, or R 2 together with the carbon atom to which they are attached form a cyclohexyl or cyclopentyl group; further preferably, hydrogen, R 2 trichloromethyl, tert-butyl, phenyl or 4-methoxybenzene Most preferably,
  • the compound of the formula II can be obtained by a method disclosed in the prior art.
  • the above reaction solvent is an aprotic solvent, preferably tetrahydrofuran, dichloromethane, ethyl acetate, N,N-dimethylformamide, toluene, cyclohexane, chloroform, xylene, more preferably tetrahydrofuran, dichloromethane, Toluene;
  • methylating agent is preferably iodonium, dimethyl sulfate, dimethyl carbonate;
  • the reaction temperature is preferably 20 ° C ⁇ 80 ° C, more preferably 20 V - 40 V reaction time is 1 h ⁇ 32 h, preferably 4h ⁇ 16h.
  • the invention also provides two preparation methods of ambrisentan:
  • Step 1 Compound IV is selectively oxidized by an oxidizing agent in the presence of a buffer salt and a solvent and TEMPO catalyzed, and then acidified to form Compound V;
  • Step 2 Under basic conditions and in the presence of a phase transfer catalyst, Compound V and 4,6-Dimethyl-2-methanesulfonylpyrimidine is subjected to a substitution reaction in a solvent;
  • Step 3 The product obtained in the second step is subjected to an acidification reaction to obtain Anritan S-I, and the reaction route is as follows:
  • the solvent used in the reaction is a solvent known to those skilled in the art, and includes acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dioxane, preferably acetonitrile, tetrahydrofuran, more preferably tetrahydrofuran.
  • the oxidizing agent used in the first step is sodium chlorite in an amount of from 1 to 10 eq, preferably from 2 to 6 eq, more preferably from 3 to 5 eq, of the compound IV.
  • the catalyst used in the first step is TEMPO, and the equivalent of the compound IV is 1.
  • the amount of TEMPO used is 0.001 to 0.5 eq, preferably 0.01 to 0.3 eq, more preferably 0.01 to 0.1 eq.
  • the acid used in the first step is preferably dilute hydrochloric acid, dilute sulfuric acid, dilute phosphoric acid, more preferably dilute hydrochloric acid.
  • the solvent used is a solvent known to those skilled in the art, and includes acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dioxane, preferably acetonitrile, tetrahydrofuran, and more preferably tetrahydrofuran.
  • the base used in the second step is selected from the group consisting of potassium carbonate, sodium carbonate, sodium hydroxide, sodium amide, and more preferably sodium hydroxide.
  • the phase transfer catalyst used in the second step is selected from the group consisting of tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium hydrogen sulfate, benzyltrimethylammonium chloride or methyltrisin.
  • Ammonium chloride Aliquat 3366, more preferably tetrabutylammonium hydrogen sulfate.
  • the acid used is preferably dilute hydrochloric acid, dilute sulfuric acid, dilute phosphoric acid, more preferably dilute hydrochloric acid.
  • Method 2 has a four-step reaction.
  • Step 1 Compound IV is reacted with an acid chloride R 3 -C1 in the presence of a solvent under basic conditions to form compound VI, which is selected from the 4-position of pivaloyl, benzoyl or benzene ring by hydroxyl group, halogen, C r C 6 fluorenyl or C r C 6 methoxy-substituted benzoyl group, more preferably pivaloyl or benzoyl;
  • Step 2 Compound VI is substituted with 4,6-dimethyl-2-methylsulfonylpyrimidine in the presence of basic conditions and a phase transfer catalyst to form compound ⁇ ;
  • Step 3 Deprotecting the compound ⁇ to form a compound in the presence of a basic condition and a solvent;
  • Step 4 Compound W is oxidized with an oxidizing agent to obtain a compound S-I in the presence of a solvent, and the reaction route is as follows:
  • the solvent to be used is preferably dichloromethane, ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, chloroform, tetrahydrofuran or acetonitrile, more preferably dichloromethane, tetrahydrofuran.
  • the basic condition of the first step is achieved by adding a base, preferably pyridine, triethylamine, potassium carbonate or sodium carbonate, more preferably pyridine or triethylamine.
  • the 4-position is preferably a pivaloyl group, a benzoyl group, or a benzene ring substituted by hydroxy, halo, C r C 6 alkyl with C r C 6 embankment or substituted benzoyl group, more preferably a pivaloyl group or benzoyl .
  • the solvent used in the reaction is a solvent known to those skilled in the art, and includes acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dioxane, preferably acetonitrile, tetrahydrofuran, and more preferably tetrahydrofuran.
  • the basic condition of step two is achieved by the addition of a base selected from the group consisting of potassium carbonate, sodium carbonate, sodium hydroxide, sodium amide, more preferably sodium hydroxide.
  • the phase transfer catalyst used in the second step is selected from the group consisting of tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium hydrogen sulfate, benzyltrimethylammonium chloride, methyltrisin.
  • the solvent to be used is one or more selected from the group consisting of dichloromethane, ethyl acetate, methanol, and ethanol, and more preferably methanol, methanol, and dichloromethane.
  • the basic condition of step three is achieved by the addition of a base selected from the group consisting of sodium hydroxide, potassium carbonate, sodium carbonate, sodium methoxide or sodium ethoxide, more preferably sodium methoxide.
  • the solvent used is one or more selected from the group consisting of dichloromethane, ethyl acetate, methanol, and ethanol, and more preferably dichloromethane, chloroform.
  • the oxidizing agent used is selected from the group consisting of Dess-Martin Oxidizer or Pt.
  • the present invention further provides an intermediate compound VI, vn, w for preparing S-1, and the structural formulas thereof are as follows:
  • the room temperature described in the examples means 20 to 35. Unless otherwise indicated, the reagents described are used directly without purification. All solvents were purchased from commercial suppliers, such as Aldrich, and were used without treatment. The reaction is judged by TLC analysis and/or by LC-MS, and the termination of the reaction is judged by the consumption of the starting material. Thin layer chromatography (TLC) for analysis was performed on precoated silica gel 60 F254 0.25 mm plate glass plates (EMD Chemicals) using UV light (254 nm) and/or silica gel. Iodine imaging, and/or heating with TLC dyes such as alcoholic phosphomolybdic acid, ninhydrin solution, potassium permanganate solution or sorghum sulfate solution.
  • TLC Thin layer chromatography
  • R 2 is independently selected from hydrogen atoms, C r C 6 alkyl with, C r C 6 alkyl with haloalkyl, or phenyl ⁇ - embankment alkoxy, halo, hydroxy-substituted phenyl, or and Together with the carbon atom to which they are attached, a C 3 -C 6 cyclodecyl group is formed, more preferably, and each independently selected from a hydrogen atom, a methyl group, an ethyl group, a propyl group, a t-butyl group, a trichloromethyl group, a benzene group Or a 4-methoxyphenyl group, or together with R 2 and the carbon atom to which they are attached, form a cyclohexyl or cyclopentyl group; further preferably, hydrogen, R 2 trichloromethyl, tert-butyl, phenyl Or 4-methoxyphenyl, most
  • Both ⁇ and R 2 are methyl, both ethyl or all 11.
  • a method of preparing a compound of the formula II (when RfR ⁇ Me, the compound of the formula II is also a compound represented by the formula ⁇ -a) is provided when RfR ⁇ Me.
  • the reaction route of the example la-3a is as follows:
  • the compound of the formula II is also a method for producing a compound represented by the formula ⁇ -e .
  • the reaction route of the example le-3e is as follows:
  • Inventive Examples lj ⁇ 3j provide a compound of formula II when R 2 forms a six-membered ring with a bonded carbon atom (when Ri, R 2 and associated carbon atoms are formed)
  • the compound of the formula II is also a method for producing a compound represented by the formula ⁇ -j.
  • the reaction route of the examples lj-3j is as follows:
  • Example 8 The crude ambrisentan 30g (0.08mol) and 189ml of isopropanol and 21ml of methanol were heated to reflux. After hot filtration, the filtrate was cooled to 25 ° C, stirred for 45 minutes, filtered, and the filter cake was washed with isopropyl alcohol and methanol at 60 ° C. Dry, ambrisentan (21 g, yield 70%), optical purity 99.97% ee.
  • R 3 is a benzoyl group, and the reaction formula is as follows:

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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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Abstract

L'invention porte sur un intermédiaire IV pour la préparation d'ambrisentan, sur un procédé de préparation de l'intermédiaire et sur un procédé de préparation d'ambrisentan. Le composé intermédiaire est un composé en configuration S et peut être transformé directement pour synthétiser de l'ambrisentan sans être scindé, ce qui résout les défauts de l'état antérieur de la technique, améliore le taux d'utilisation d'atomes de la synthèse, réduit le coût et est applicable à une production industrielle. L'invention porte également sur d'autres intermédiaires VI, VII, VIII pour la préparation d'ambrisentan et sur deux procédés de préparation d'ambrisentan.
PCT/CN2013/075782 2012-05-18 2013-05-17 Composé intermédiaire pour la préparation d'ambrisentan, son procédé de préparation et procédé de préparation d'ambrisentan WO2013170778A1 (fr)

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CN201210158093.1A CN103420811B (zh) 2012-05-18 2012-05-18 用于制备安立生坦的中间体化合物及其制备方法、以及安立生坦的制备
CN201210158093.1 2012-05-18

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KR20180108367A (ko) * 2017-03-24 2018-10-04 한양대학교 산학협력단 지방족 고리를 갖는 엑시드 화합물, 그의 에스터 유도체 및 고분자 중합체
EP3800184A1 (fr) * 2019-09-24 2021-04-07 Henkel AG & Co. KGaA Composés précurseurs d'agent odoriférant et insectifuge à base d'acétal / de cétal

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CN103709106A (zh) * 2013-12-06 2014-04-09 石家庄博策生物科技有限公司 一种立体选择性制备安立生坦的方法
CN104844524A (zh) * 2015-05-18 2015-08-19 宁波人健医药化工有限公司 一种安倍生坦的合成方法
CN109705042B (zh) * 2017-10-26 2021-12-21 正大天晴药业集团股份有限公司 一种安立生坦的制备方法

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WO2011004402A2 (fr) * 2009-07-10 2011-01-13 Cadila Healthcare Limited Procédé amélioré de préparation d'ambrisentan et nouveaux intermédiaires associés
CN102276536A (zh) * 2011-06-10 2011-12-14 中国科学院化学研究所 一种光学纯的（+）-安倍生坦和光学纯的（+）-达芦生坦的制备方法
WO2012017441A1 (fr) * 2010-08-04 2012-02-09 Natco Pharma Limited Procédé amélioré pour la préparation d'acide s-2-hydroxy-3-méthoxy-3,3-diphénylpropionique

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WO2011004402A2 (fr) * 2009-07-10 2011-01-13 Cadila Healthcare Limited Procédé amélioré de préparation d'ambrisentan et nouveaux intermédiaires associés
WO2012017441A1 (fr) * 2010-08-04 2012-02-09 Natco Pharma Limited Procédé amélioré pour la préparation d'acide s-2-hydroxy-3-méthoxy-3,3-diphénylpropionique
CN102276536A (zh) * 2011-06-10 2011-12-14 中国科学院化学研究所 一种光学纯的（+）-安倍生坦和光学纯的（+）-达芦生坦的制备方法

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20180108367A (ko) * 2017-03-24 2018-10-04 한양대학교 산학협력단 지방족 고리를 갖는 엑시드 화합물, 그의 에스터 유도체 및 고분자 중합체
KR101967532B1 (ko) * 2017-03-24 2019-04-10 한양대학교 산학협력단 지방족 고리를 갖는 엑시드 화합물, 그의 에스터 유도체 및 고분자 중합체
EP3800184A1 (fr) * 2019-09-24 2021-04-07 Henkel AG & Co. KGaA Composés précurseurs d'agent odoriférant et insectifuge à base d'acétal / de cétal

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