WO2016015596A1 - Procédé de préparation d'un composé 5-oxopyrane 2, 3-disubstitué - Google Patents

Procédé de préparation d'un composé 5-oxopyrane 2, 3-disubstitué Download PDF

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Publication number
WO2016015596A1
WO2016015596A1 PCT/CN2015/084977 CN2015084977W WO2016015596A1 WO 2016015596 A1 WO2016015596 A1 WO 2016015596A1 CN 2015084977 W CN2015084977 W CN 2015084977W WO 2016015596 A1 WO2016015596 A1 WO 2016015596A1
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Prior art keywords
compound
formula
sodium
lithium
optionally substituted
Prior art date
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Ceased
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PCT/CN2015/084977
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English (en)
Inventor
Guodong SUN
Yongjun Liu
Mingjie WEI
Cailang LAI
Dasheng LI
Shouhua ZHANG
Zhongqing Wang
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Sunshine Lake Pharma Co Ltd
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Sunshine Lake Pharma Co Ltd
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Priority to CN201580039019.XA priority Critical patent/CN106660981B/zh
Publication of WO2016015596A1 publication Critical patent/WO2016015596A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/18—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by doubly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/30—Oxygen atoms, e.g. delta-lactones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention relates to a process for preparing 2,3-disubstituted-5-oxopyran compounds.
  • Ar is phenyl optionally substituted with R 4
  • R 4 is F, Cl, C1-C6 alkyl unsubstituted or substituted with fluorine, or C1-C6 alkoxy unsubstituted or substituted with fluorine
  • each of R 1 and R 2 is independently hydrogen, or an amino-protecting group; is useful in the synthesis of Omarigliptin or other compounds, is an important intermediate.
  • the present invention provides a novel process for the preparation of 2,3-disubstituted-5-oxopyran compounds having the structure formula (04) described above.
  • the present invention also provides some important novel intermediates.
  • the present invention provides a process of preparing a compound of formula (04) .
  • the compound of formula (04) is represented below:
  • Ar is phenyl optionally substituted with at least one R 4 ;
  • each of R 1 and R 2 is independently hydrogen, or an amino-protecting group, such as alkoxy carbonyl class amino-protecting groups: benzyloxycarbonyl (Cbz) , t-butyloxycarbonyl (Boc) , fluorenylmethoxycarbonyl (Fmoc) , trimethylsilylethoxycarbonyl (Teoc) , methoxycarbonyl, ethoxycarbonyl, allyloxycarbonyl (Alloc) , etc.
  • an amino-protecting group such as alkoxy carbonyl class amino-protecting groups: benzyloxycarbonyl (Cbz) , t-butyloxycarbonyl (Boc) , fluorenylmethoxycarbonyl (Fmoc) , trimethylsilylethoxycarbonyl (Teoc) , methoxycarbonyl, ethoxycarbonyl, allyloxycarbonyl (Alloc)
  • acyl class amino-protecting groups acetyl (Ac) , phthaloyl (Pht) , methylsulfonyl, phenylsulfonyl, p-toluenesulfonyl (Tos) , trifluoroacetyl (Tfa) , o-nitrophenylsulfonyl, p-nitrophenylsulfonyl, pivaloyl and the like; alkyl class amino-protecting groups: trityl (Trt) , 2, 4-dimethoxybenzyl (Dmb) , p-methoxybenzyl (PMB) , benzyl (Bn) , etc;
  • R 4 is F, Cl, C1-C6 alkyl unsubstituted or substituted with fluorine, or C1-C6 alkoxy unsubstituted or substituted with fluorine.
  • the process of preparing the compound of formula (04) includes: cyclizing a compound of formula (03) to obtain the compound of formula (04) :
  • R 3 is a group can react with a hydroxy to form an ether, such as F, Cl, Br, I, mesyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, methanesulfonyloxy, p-nitrophenylsulfonyloxy, trifluoromethanesulfonyloxy, hydroxy or onium salt thereof, or diazonium salt thereof, etc.
  • an ether such as F, Cl, Br, I, mesyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, methanesulfonyloxy, p-nitrophenylsulfonyloxy, trifluoromethanesulfonyloxy, hydroxy or onium salt thereof, or diazonium salt thereof, etc.
  • the cyclization reaction of the compound of formula (03) to obtain the compound of formula (04) is carried out in the presence of a first base (base B2) in an organic solvent.
  • the base B2 is an organic or inorganic base selected from sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, potassium tert-butoxide, lithium tert-butoxide, sodium methoxide, sodium ethoxide, sodium amide, sodium hydride, sodium bis (trimethylsilyl) amide, lithium bis (trimethylsilyl) amide, potassium bis(trimethylsilyl) amide, lithium diethylamide, lithium diisopropylamide, oxide silver, ammonia, methylamine, diethylamine, triethylamine, ethylenediamine, diisopropylethylamine, pyridine, pyrrole, N-methylmorpholine, and 1, 8-diazabicyclo [5.4.0] undec-7-ene
  • the base B2 is potassium carbonate. In some embodiments, the base B2 is triethylamine.
  • the organic solvent is a solvent which does not react with the reactants or products of the reaction, selected from esters, alkane solvents, ether solvents, ketone solvents, and combinations thereof.
  • the ester solvent is selected from ethyl acetate, methyl acetate, isopropyl acetate and the like;
  • the alkane solvent is selected from n-hexane, n-heptane, cyclohexane, dichloromethane, toluene, xylene, acetonitrile and the like;
  • the ether solvent is selected from isopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, 1, 4-dioxane and the like;
  • the ketone solvent is selected from acetone, methyl ethyl ketone, 3-pentanone and the like.
  • the organic solvent is tetrahydrofuran. In some embodiments, the organic solvent is dichloromethane.
  • the reaction temperature is from about -10 °C to about 130 °C. In some embodiments, the reaction temperature is from about 40 °C to about 100 °C. In some embodiments, the reaction temperature is from about 0 °C to about 60 °C. In some embodiments, the reaction temperature is from about 10 °C to about 60 °C. In some embodiments, the reaction temperature is from about 20 °C to about 60 °C. In some embodiments, the reaction temperature is from about 20 °C to about 40 °C. In some embodiments, the reaction temperature is from about 15 °C to about 35 °C.
  • the reaction time is 1 hour to 24 hours. In some embodiments, the reaction time is 4 hours to 16 hours. In some embodiments, the reaction time is about 8 hours to about 12 hours.
  • the cyclization of the compound of formula (03) to obtain the compound of formula (04) is performed in the presence of potassium carbonate and tetrahydrofuran at a temperature from about 15 °C to about 35 °C.
  • the compound of formula (03) can be prepared by performing a ring-opening reaction to a compound of formula (02) :
  • R 1 , R 2 , and R 3 are as defined above.
  • the ring-opening reaction of the compound of formula (02) may be carried out under the condition of adding an acid or an acid hydrate.
  • the acid is an inorganic acid or an organic acid selected from formic acid, acetic acid, propionic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, benzoic acid, lactic acid, malic acid, oxalic acid, citric acid, salicylic acid, tartaric acid, mandelic acid, fumaric acid, maleic acid, succinic acid, hydrochloric acid, sulfuric acid, phosphoric acid, sodium bisulfate, potassium bisulfate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, and combinations thereof.
  • the molar ratio of the acid to the compound of formula (02) is from about 0.1: 1 to about 3.0: 1. In some embodiments, the molar ratio of the acid to the compound of formula (02) is from about 0.5: 1 to about 2.0: 1. In some embodiments, the molar ratio of the acid to the compound of formula (02) is from about 1.0: 1 to about 2.0: 1.
  • the acid is sodium hydrogensulfate or a hydrate thereof. In some embodiments, the acid is sodium dihydrogen phosphate. In some embodiments, the acid is acetic acid. In some embodiments, the acid is oxalic acid.
  • the reaction solvent of the ring-opening reaction of the compound having formula (02) is selected from alcohol solvents, ester solvents, alkane solvents, ether solvents, ketone solvents, water, and combinations thereof.
  • the alcohol solvent is selected from C 1 -C 4 alcohols
  • the ester solvent is selected from ethyl acetate, methyl acetate, isopropyl acetate and the like
  • the alkane solvent is selected from n-hexane, n-heptane, cyclohexane, dichloromethane, toluene, xylene, acetonitrile and the like
  • the ether solvent is selected from isopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, 1, 4-dioxane and the like
  • the ketone solvent is selected from acetone, methyl ethyl ketone, 3-pentanone
  • the reaction temperature of the ring-opening reaction of the compound having formula (02) is from about -10 °C to about 60 °C. In some embodiments, the reaction temperature is from about 0 °C to about 40 °C. In some embodiments, the reaction temperature is from about 15 °C to about 30 °C. In some embodiments, the reaction temperature is from about 20 °C to about 28 °C.
  • the reaction time of the ring-opening reaction of the compound having formula (02) is 1 hour to 24 hours. In some embodiments, the reaction time is about 4 hours to about 20 hours. In some embodiments, the reaction time is about 8 hours to about 15 hours.
  • the resulting reaction mixture containing the compound of formula (03) can be used directly to prepare the compound of formula (04) without a separation.
  • the compound of formula (02) can be prepared by cyclizing a compound of formula (01) :
  • R 1 , R 2 , and R 3 are as defined above.
  • the compound of formula (02) can be obtained via one reaction step, also can be obtained via multistep reaction.
  • the cyclization reaction of the compound of formula (01) to obtain the compound of formula (02) may be carried out under conditions of adding a halogenating agent.
  • the halogenating agent is selected from N-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide, iodine, bromine, chlorine, 1, 3-dibromo-5, 5-dimethyl-hydantoin (dibromohydantoin) , thionyl chloride, sodium dichloroisocyanurate acid, potassium dichloroisocyanurate, chloroisobromine cyanuric acid, trichloroisocyanuric uric acid, and combinations thereof.
  • the base B1 is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, potassium tert-butoxide, lithium tert-butoxide, sodium methoxide, sodium ethoxide, sodium amide, sodium hydride, sodium bis (trimethylsilyl) amide, lithium bis (trimethylsilyl) amide, potassium bis(trimethylsilyl) amide, lithium diethylamide, lithium diisopropylamide, ammonia, methylamine, diethylamine, triethylamine, ethylenediamine, diisopropylethylamine, pyridine, pyrrole, N-methylmorpholine, and combinations thereof.
  • the molar ratio of the halogenating agent to the compound of formula (01) is from about 0.3: 1 to about 3.0: 1. In some embodiments, the molar ratio of the halogenating agent with the compound of formula (01) is from about 0.5: 1 to about 2.0: 1. In some embodiments, the molar ratio of the halogenating agent to the compound of formula (01) is from about 0.5: 1 to about 1.0: 1. In some embodiments, the molar ratio of the halogenating agent with the compound of formula (01) is from about 1.0: 1 to about 2.0: 1.
  • the molar ratio of the base B1 to the compound of formula (01) is from about 0 to 3.0: 1. In some embodiments, the molar ratio of the base B1 to the compound of formula (01) is from about 0 to about 2.0: 1. In some embodiments, the molar ratio of the base B1 to the compound of formula (01) is from about 1.0: 1 to about 3.0: 1. In some embodiments, the molar ratio of the base B1 to the compound of formula (01) is from about 1.0: 1 to about 2.0: 1.
  • the halogenating agent is iodine. In some embodiments, the halogenating agent is N-bromosuccinimide. In some embodiments, the halogenating agent is 1,3-dibromo-5, 5-dimethyl-hydantoin.
  • the base B1 is potassium hydroxide. In some embodiments, the base B1 is potassium carbonate.
  • the transformation of the compound of formula (01) to the compound of formula (02) is performed at a temperature from about -20 °C to about 40 °C. In some embodiments, the transformation of the compound of formula (01) to the compound of formula (02) is performed at a temperature from about -10 °C to about 30 °C. In some embodiments, the transformation of the compound of formula (01) to the compound of formula (02) is performed at a temperature from about 0 °C to about 20 °C.
  • the compound of formula (01) is cyclized at a temperature from -20 °C to 40 °C to obtain the compound of formula (02) under the conditions of adding a halogenating agent and a base B1, wherein the halogenating agent is iodine or 1,3-dibromo-5, 5-dimethyl-hydantoin.
  • the process of preparing the compound of formula (04) includes cyclizing the compound of formula (01) to obtain the compound of formula (02) under the conditions of adding a halogenating agent, ring-opening the compound of formula (02) to obtain the compound of formula (03) in the presence of an acid, cyclizing the compound of formula (03) to obtain the compound of formula (04) in the presence of a base B2:
  • R 1 , R 2 , and R 3 are as defined above.
  • R 3 is Br or I.
  • Ar is phenyl substituted with fluorine, R 1 is hydrogen, R 2 is t-butoxycarbonyl, R 3 is Br or I.
  • Ar is phenyl substituted with fluorine, R 1 is hydrogen, R 2 is a benzyloxycarbonyl, R 3 is Br.
  • Ar is phenyl substituted with fluorine, R 1 is hydrogen, R 2 is trimethylsilylethoxycarbonyl, R 3 is Br.
  • Ar is 2, 5-difluorophenyl, R 1 is hydrogen, R 2 is t-butoxycarbonyl, R 3 is I.
  • Ar is 2, 5-difluorophenyl, R 1 is hydrogen, R 2 is t-butoxycarbonyl, R 3 is Br.
  • the compound of formula (03) is represented below:
  • the compound of formula (03) is represented below:
  • the compound of formula (02) is represented below:
  • the compound of formula (02) is represented below:
  • the compound of formula (04) is represented below:
  • the process provided by the present invention easy to obtain the raw materials, is convenient to prepare the intermediate compound of formula (04) , and can be used for industrial production.
  • Reagents used in the present invention are commercially available on the market or can be prepared by the process of the present invention.
  • the compound of formula (01) can be prepared referring to the method described in United States patent No. 7902376 or other prior art.
  • the compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 350.0.

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

Abstract

Selon l'invention, un procédé de préparation de composés 5-oxopyrane 2, 3-disubstitués comprend la cyclisation d'un composé en présence d'une base et d'un solvant organique.
PCT/CN2015/084977 2014-07-29 2015-07-23 Procédé de préparation d'un composé 5-oxopyrane 2, 3-disubstitué Ceased WO2016015596A1 (fr)

Priority Applications (1)

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CN201580039019.XA CN106660981B (zh) 2014-07-29 2015-07-23 2,3-二取代-5-氧代吡喃化合物的制备方法

Applications Claiming Priority (2)

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CN201410367961 2014-07-29
CN201410367961.6 2014-07-29

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WO2016015596A1 true WO2016015596A1 (fr) 2016-02-04

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112369325A (zh) * 2020-10-21 2021-02-19 甘肃亚盛农业研究院有限公司 一种植物外植体安全低毒高效灭菌的方法

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111320598B (zh) * 2018-12-14 2022-04-26 广东东阳光药业有限公司 一种羟基吡喃酮化合物的制备方法

Citations (4)

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WO2007136603A2 (fr) * 2006-05-16 2007-11-29 Merck & Co., Inc. Aminotétrahydropyranes en tant qu'inhibiteurs de la dipeptidyl peptidase-iv pour le traitement ou la prévention du diabète
WO2008060488A1 (fr) * 2006-11-14 2008-05-22 Merck & Co., Inc. Composés hétéroaromatiques tricycliques en tant qu'inhibiteurs de la dipeptidyle peptidase-iv pour le traitement ou la prévention de diabètes
WO2009014676A1 (fr) * 2007-07-23 2009-01-29 Merck & Co., Inc. Nouvelle forme cristalline d'un sel de dichlorhydrate d'un inhibiteur de la dipeptidyle peptidase iv
US20090187028A1 (en) * 2008-01-23 2009-07-23 Feng Xu Process for preparing Chiral Dipeptidyl Peptidase -IV Inhibitor Intermediates

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WO2007097931A2 (fr) * 2006-02-15 2007-08-30 Merck & Co., Inc. Aminotétrahydropyrannes en tant qu'inhibiteurs de dipeptidylpeptidase-iv dans le traitement prophylactique ou thérapeutique du diabète
CA2838738A1 (fr) * 2011-06-29 2013-01-03 Merck Sharp & Dohme Corp. Nouvelles formes cristallines d'un inhibiteur de peptidase-iv

Patent Citations (4)

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WO2007136603A2 (fr) * 2006-05-16 2007-11-29 Merck & Co., Inc. Aminotétrahydropyranes en tant qu'inhibiteurs de la dipeptidyl peptidase-iv pour le traitement ou la prévention du diabète
WO2008060488A1 (fr) * 2006-11-14 2008-05-22 Merck & Co., Inc. Composés hétéroaromatiques tricycliques en tant qu'inhibiteurs de la dipeptidyle peptidase-iv pour le traitement ou la prévention de diabètes
WO2009014676A1 (fr) * 2007-07-23 2009-01-29 Merck & Co., Inc. Nouvelle forme cristalline d'un sel de dichlorhydrate d'un inhibiteur de la dipeptidyle peptidase iv
US20090187028A1 (en) * 2008-01-23 2009-07-23 Feng Xu Process for preparing Chiral Dipeptidyl Peptidase -IV Inhibitor Intermediates

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112369325A (zh) * 2020-10-21 2021-02-19 甘肃亚盛农业研究院有限公司 一种植物外植体安全低毒高效灭菌的方法

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