WO2014108011A1 - Intermédiaires de l'entécavir et procédé de préparation correspondant - Google Patents

Intermédiaires de l'entécavir et procédé de préparation correspondant Download PDF

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Publication number
WO2014108011A1
WO2014108011A1 PCT/CN2013/089175 CN2013089175W WO2014108011A1 WO 2014108011 A1 WO2014108011 A1 WO 2014108011A1 CN 2013089175 W CN2013089175 W CN 2013089175W WO 2014108011 A1 WO2014108011 A1 WO 2014108011A1
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compound
formula
group
give
reaction
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PCT/CN2013/089175
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English (en)
Chinese (zh)
Inventor
刘念
牟祥
李倩
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重庆康施恩化工有限公司
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Publication of WO2014108011A1 publication Critical patent/WO2014108011A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/36—Compounds containing oxirane rings with hydrocarbon radicals, substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages

Definitions

  • the invention relates to a hepatitis B drug intermediate and a preparation method thereof, in particular to a key intermediate of entecavir, a methylene cyclopentane compound and a preparation method thereof.
  • Entecavir an antiviral (HBV) prescription drug, was first marketed in the United States in April 2005 by Bristol-Myers Squibb.
  • the chemical name is: [IS- (1 ⁇ , 3 ⁇ , 4 ⁇ )]-2-yl-1,9-dihydro[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclo] ⁇ 611- ⁇ -6-one;
  • JOC 1985 (50) 755, CN1061972, WO9809964, CN1747959, etc. describe the preparation method thereof, the key is to synthesize the key intermediate cyclopentane compound, and the intermediate has the following problems.
  • the preparation method is achiral cyclopentane.
  • the olefin is the starting material, and the chiral group is constructed by using an expensive chiral ligand or chiral resolution, and the introduction of the chiral group is low in efficiency and high in cost.
  • CN1747959 also reports the use of silane as a precursor of a hydroxyl group. After completing the basic structural synthesis of the target molecule, the conversion of the silane group to a hydroxyl group is accomplished using very severe oxidation conditions, so that the purity and yield are not high, and A special resin is required to separate.
  • Tetra edron 59 (2003) 9013-9018 reports a synthesis method for the synthesis of entecavir intermediate methylene cyclopentane.
  • the core of the method is to open the epoxy through chlorotitanium titanate and combine with acetylene to obtain a ring-closing product.
  • the ring closure yield is as high as 82%.
  • this method has the following problems - First, it is necessary to use a highly toxic organotin to remove the 2-position hydroxyl group of glucose.
  • nucleophilic attack can occur due to the positions of 9-N and 7-N. Although the 9-N selectivity is greater than 7-N, the reaction product of 7-N is unavoidable.
  • alkyl denotes a straight or branched monovalent glucone and a hydrocarbon group consisting of carbon and hydrogen atoms.
  • C1-6 alkyl means a branched or straight-chain alkyl group of 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, ft butyl , n-hexane.
  • Haloalkyl means an alkyl group as defined above substituted by one or more halogens, for example trifluoromethyl.
  • alkoxy alone or in combination with other groups, denotes a group R-0-, wherein R is alkyl as defined above.
  • C1-6 alkoxy means a group R'-0-, wherein R' is a C1-6 fluorenyl group as captured above.
  • Aryl means a monocyclic or fused ring bicyclic aromatic ring containing a carbon atom.
  • C5-10 aryl means an aryl group having 5 to 10 carbon atoms.
  • the C5-10 aryl group can be phenyl or naphthyl.
  • Alkyl means an alkyl group as described above substituted with an aryl group as described above.
  • Acyl refers to the group -CO-R, wherein R is alkyl, aryl, aralkyl as described above.
  • aryl groups described above may be optionally substituted with one or more substituents.
  • the substituent is preferably selected from the group consisting of C1-6 alkyl, Cl>6 alkoxy, halogen, aryl and nitro, more preferably selected from methoxy, ethoxy, Halogen, phenyl and nitro.
  • the present invention provides new synthetic methods including -
  • PI and P3 may be the same or different and each represent hydrogen, an alkoxycarbonyl or an aralkoxy-Wei group;
  • P2 is selected from the group consisting of C1-6 alkyl, haloalkyl, benzyl, t-BuMe 2 Si, t-BuP3 ⁇ 4Si, Et 3 Si, benzoyl, tetrapyran-2-yl, substituted with a phenyl ring Benzoyl, biphenyl "4-formyl"; the epoxy stereo configuration of the compound of Formula 2 may be in the R-configuration, the S-configuration or the 3 ⁇ 4S-configuration.
  • the preparation method of the compound 1 is prepared by the following method - preparing the compound of the formula 13 by double-base protection under Lewis acid catalysis,
  • R1 is a hydrogen atom, a C1-6 alkyl group, a phenyl group or a substituted phenyl group, and the substituent on the phenyl group is preferably selected from the group consisting of a methoxy group, an ethoxy group, a halogen group, a phenyl group and a nitro group;
  • the compound of formula 12 is selectively deprotected from a hydroxy protecting group under polar conditions in a polar protic solvent.
  • Rl, P4 are defined as described above;
  • the compound of the formula 11 is obtained by the oxidation reaction and the elimination reaction in the polar preparation to obtain the formula 10
  • R1 is defined as described above;
  • R1 is defined as described above;
  • R2 is methylsulfonyl or p-toluenesulfonyl, and P1 and P3 are as defined above;
  • PK P3 is defined as above;
  • PI, P3 are defined as described above;
  • a compound of the formula 3 is reacted with a hydroxy protecting reagent to give a compound of the formula 1.
  • Another preparation method of compound 5 is as follows - a base protecting reagent is reacted to obtain a compound of formula 22, Wherein: R1 is a C1-6 alkyl group, an aryl group, a substituted aryl group, and an aralkyl group;
  • ⁇ is a 3 ⁇ 4-based activating group, and R1 is as defined above;
  • the compound is reacted with a halogenating reagent to prepare a compound of the formula 20,
  • R1 is defined as described above;
  • X is a halogen, and P1 and P3 are defined as defined above;
  • Compound 1 can also be prepared by the following method.
  • the compound is hydrolyzed by a Mitsunobu reaction to give a compound of the formula 32.
  • PI, P2 are defined as described above;
  • R2 is hydrogen, an organometallic ion such as sodium, a weight, a potassium ion, and a 'grac group, an aralkyl group, an substituted aralkyl group on the aromatic ring, and R1, P1, and ⁇ 2 are as defined above;
  • Rl, Pl, P2, P3 are defined as above;
  • Rl, PI, P2, P3 are defined as described above;
  • PI, P2, P3 are defined as described above;
  • the compound of the formula 24 is oxidized to give a compound of the formula 2.
  • the epoxy stereo configuration can be R-configuration, S-configuration or R, S-configuration.
  • reaction temperature 20-3 (TC).
  • Ethyl diethylaminoethyl malonate (258 g l. Wmol, leq), 3 L of tetrahydrofuran, potassium tert-butoxide (146 g, 1.30 mol, 1.09 eq), refluxed for 1 hour, and added 5 (M) mL of tetrahydrogen
  • the 19a (300 g, l, 19 mol, l eq) dissolved in the sputum was added for 10 minutes, refluxed for 2.5 hours, and the remaining 20% of TLC was still added, supplemented with diethyl acetamidomalonate (100 g 0.47 mol, 0.39eq) and butanol C58g, 0.417mol, 0.39eq), after refluxing for 10 hours, no T2 in TLC, cooled to room temperature, filtered, concentrated under reduced pressure to 1L, then added 2L ethyl acetate, 0.1N 1 L of hydrochloric acid was washed, was
  • 29a (30 g, 72.18 mmol» leq) was added, 300 g of tetrahydrofuran was added, and the temperature was lowered to 0. °C, add lithium oxide (11.6g, 277.8mmol, 3.84 eq), add and maintain at this temperature for 2-3 hours, HPLC control without 29a, 0.5N potassium hydrogen sulfate solution to adjust the pH to 6- After concentrating between methanol, ethyl acetate was extracted, dried, and concentrated to give 28 g of white solid 28a, yield 85%.
  • potassium tert-butoxide (7 g, 62.9 mmol, 1.61 eq) was added to a 500 mL reaction flask, and anhydrous 100 mL of tetrahydrofuran was added to cool to 5-10 ° C, and methyltriphenyl bromide (23.6 g was added).

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

Abstract

La présente invention concerne un intermédiaire important (2) de l'entécavir et un procédé pour préparer le composé (1) intermédiaire de l'entécavir par réaction de fermeture de cycle du composé (2) en présence de radicaux libres avec des métaux de transition en tant que centre.
PCT/CN2013/089175 2013-01-14 2013-12-12 Intermédiaires de l'entécavir et procédé de préparation correspondant WO2014108011A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201310011620.0A CN103387587B (zh) 2013-01-14 2013-01-14 恩替卡韦中间体及其制备方法
CN201310011620.0 2013-01-14

Publications (1)

Publication Number Publication Date
WO2014108011A1 true WO2014108011A1 (fr) 2014-07-17

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WO (1) WO2014108011A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103387587B (zh) * 2013-01-14 2015-12-09 重庆康施恩化工有限公司 恩替卡韦中间体及其制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003106477A1 (fr) * 2002-06-01 2003-12-24 Isis Pharmaceuticals, Inc. Composes oligomeres contenant des nucleosides carbocycliques et leur utilisation dans la modulation genique
CN101130542A (zh) * 2006-08-24 2008-02-27 江苏正大天晴药业股份有限公司 抗病毒核苷类似物的合成方法
CN101148450A (zh) * 2007-11-02 2008-03-26 严红芳 一种核苷化合物的制备方法
CN103387587A (zh) * 2013-01-14 2013-11-13 重庆康施恩化工有限公司 恩替卡韦中间体及其制备方法

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102417506B (zh) * 2010-09-27 2016-04-06 杭州赛利药物研究所有限公司 一种抗病毒药物恩替卡韦的制备方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003106477A1 (fr) * 2002-06-01 2003-12-24 Isis Pharmaceuticals, Inc. Composes oligomeres contenant des nucleosides carbocycliques et leur utilisation dans la modulation genique
CN101130542A (zh) * 2006-08-24 2008-02-27 江苏正大天晴药业股份有限公司 抗病毒核苷类似物的合成方法
CN101148450A (zh) * 2007-11-02 2008-03-26 严红芳 一种核苷化合物的制备方法
CN103387587A (zh) * 2013-01-14 2013-11-13 重庆康施恩化工有限公司 恩替卡韦中间体及其制备方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DONDONI, A. ET AL.: "A convenient synthesis of iminosugar-C-glycosides via organometallic addition to N-benzyl-N-glycosy lhydroxylamines", TETRAHEDRON, vol. 59, no. 24, 2003, pages 4261 - 4273 *

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CN103387587A (zh) 2013-11-13

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