WO2016015596A1 - Process for preparing 2, 3-disubstituted-5-oxopyran compound - Google Patents

Process for preparing 2, 3-disubstituted-5-oxopyran compound 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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compound
formula
sodium
lithium
optionally substituted
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French (fr)
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/en
Publication of WO2016015596A1 publication Critical patent/WO2016015596A1/en
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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)
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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract

A process of preparing 2, 3-disubstituted-5-oxopyran compounds, comprising cyclizing a compound in the presence of a base and an organic solvent is provided.

Description

PROCESS FOR PREPARING 2, 3-DISUBSTITUTED-5-OXOPYRAN COMPOUND
CROSS-REFERENCE TO RELATED APPLICATION
The present application is based upon and claims priority to Chinese Patent Application No. 201410367961.6, filed on July 29, 2014, the entirety contents of which are incorporated herein by reference.
FIELD
The present invention relates to a process for preparing 2,3-disubstituted-5-oxopyran compounds.
BACKGROUND
A 2, 3-disubstituted 5-oxopyran compound of formula (04) :
Figure PCTCN2015084977-appb-000001
in which Ar is phenyl optionally substituted with R4, R4 is F, Cl, C1-C6 alkyl unsubstituted or substituted with fluorine, or C1-C6 alkoxy unsubstituted or substituted with fluorine； each of R1 and R2 is independently hydrogen, or an amino-protecting group； is useful in the synthesis of Omarigliptin or other compounds, is an important intermediate.
US Patent No. 7902376 and PCT Publication WO2007097931 disclose methods to prepare compounds of formula (04) , but both of the methods disclosed are complex to operate and need a special catalyst. So it is necess ary to explore an easy process.
SUMMARY
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.
DETAILED DESCRIPTION OF THE INVENTION
According to embodiments of present invention, the term “about” used in association with the number disclosed herein intended to mean that the unmber may be approximate values and the value of each number may differ by 0.1％, 0.5％, 1％, 2％, 3％, 5％, 7％, or 10％.
The present invention provides a process of preparing a compound of formula (04) . The compound of formula (04) is represented below:
Figure PCTCN2015084977-appb-000002
in which Ar is phenyl optionally substituted with at least one R4；
each of R1 and R2 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. ； 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；
R4 is F, Cl, C1-C6 alkyl unsubstituted or substituted with fluorine, or C1-C6 alkoxy unsubstituted or substituted with fluorine.
According to embodiments of present invention, the process of preparing the compound of formula (04) includes: cyclizing a compound of formula (03) to obtain the compound of formula (04) :
Figure PCTCN2015084977-appb-000003
in which Ar, R1, R2 are as defined above； R3 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.
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 (DBU) , and combinations thereof.
In some embodiments, 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.
In some embodiments, the organic solvent is tetrahydrofuran. In some embodiments, the organic solvent is dichloromethane.
In the cyclization reaction of the compound of formula (03) to obtain the compound of formula (04) , the reaction temperature is from about -10 ℃ to about 130 ℃. In some embodiments, the reaction temperature is from about 40 ℃ to about 100 ℃. In some embodiments, the reaction temperature is from about 0 ℃ to about 60 ℃. In some embodiments, the reaction temperature is from about 10 ℃ to about 60 ℃. In some embodiments, the reaction temperature is from about 20 ℃ to about 60 ℃. In some embodiments, the reaction temperature is from about 20 ℃ to about 40 ℃. In some embodiments, the reaction temperature is from about 15 ℃ to about 35 ℃.
In the cyclization reaction of the compound of formula (03) to obtain the compound  of formula (04) , 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.
In some embodiments, 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 ℃ to about 35 ℃.
The compound of formula (03) can be prepared by performing a ring-opening reaction to a compound of formula (02) :
Figure PCTCN2015084977-appb-000004
in which Ar, R1, R2, and R3 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.
In some embodiments, 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 C1-C4 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 and the like.
The reaction temperature of the ring-opening reaction of the compound having formula (02) is from about -10 ℃ to about 60 ℃. In some embodiments, the reaction temperature is from about 0 ℃ to about 40 ℃. In some embodiments, the reaction temperature is from about 15 ℃ to about 30 ℃. In some embodiments, the reaction temperature is from about 20 ℃ to about 28 ℃.
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.
When the ring-opening reaction of the compound of formula (02) to obtain the compound of formula (03) is completed, 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) :
Figure PCTCN2015084977-appb-000005
in which Ar, R1, R2, and R3 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.
In the transformation of the compound of formula (01) to the compound of formula (02) , it is able to add a second base (base B1) or silver nitrate. 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.
In some embodiments, 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.
In some embodiments, 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 ℃ to about 40 ℃. 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 ℃ to about 30 ℃. 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 ℃ to about 20 ℃.
In some embodiments, the compound of formula (01) is cyclized at a temperature from -20 ℃ to 40 ℃ 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.
In some embodiments, 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:
Figure PCTCN2015084977-appb-000006
wherein Ar, R1, R2, and R3 are as defined above.
In some embodiments, R3 is Br or I. In some embodiments, Ar is phenyl substituted with fluorine, R1 is hydrogen, R2 is t-butoxycarbonyl, R3 is Br or I. In some embodiments, Ar is phenyl substituted with fluorine, R1 is hydrogen, R2 is a benzyloxycarbonyl, R3 is Br. In some embodiments, Ar is phenyl substituted with fluorine, R1 is hydrogen, R2 is trimethylsilylethoxycarbonyl, R3 is Br. In some embodiments, Ar is 2, 5-difluorophenyl, R1 is hydrogen, R2 is t-butoxycarbonyl, R3 is I. In some embodiments, Ar is 2, 5-difluorophenyl, R1 is hydrogen, R2 is t-butoxycarbonyl, R3 is Br.
In some embodiments, the compound of formula (03) is represented below:
Figure PCTCN2015084977-appb-000007
In some embodiments, the compound of formula (03) is represented below: 
Figure PCTCN2015084977-appb-000008
In some embodiments, the compound of formula (02) is represented below:
Figure PCTCN2015084977-appb-000009
In some embodiments, the compound of formula (02) is represented below:
Figure PCTCN2015084977-appb-000010
In some embodiments, the compound of formula (04) is represented below:
Figure PCTCN2015084977-appb-000011
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.
EXAMPLES
In order that the skilled in the art to understand the present invention, some non-limiting examples are disclosed and described in detail.
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 following abbreviations are used throughout the application:
BOC or Boc              butyloxycarbonyl；
BuO                      tert-butoxy；
CDCl3                   chloroform deuterated；
KOH                     potassium hydroxide；
K2CO3                   potassium carbonate；
THF                     tetrahydrofuran；
MTBE                    methyl tert-butyl ether；
g                       gram；
mL                      milliliter；
MS                      mass specturm；
NMR                     nuclear magnetic resonance.
Example 1:
tert-butyl ( (2R, 3S) -2- (2, 5-difluorophenyl) -5- (iodomethylene) tetrahydrofuran-3-yl) carbamate
Figure PCTCN2015084977-appb-000012
To a mixture of methanol (42 mL) and tert-butyl ( (1R, 2S) -1- (2, 5-difluorophenyl) -1-hydroxypent-4-yn -2-yl) carbamate (7.0 g) cooled to-5℃ was added a solution of KOH (3.2 g) in methanol (28 mL) dropwise. After dropwise addition, the resulting mixture was stirred for 30 minutes, then iodine (5.7 g) was added to the mixture. The reaction mixture was stirred at 0 ℃ for 10 minutes, followed by 25 ℃ for 6 hours, and then quenched with water (140 mL) . Then the mixture was stirred at 25 ℃ for 2 hours. The precipitate was collected by filtration and washed sequentially with methanol/water (40 mL, v: v＝1: 1) . The resulting solid was dried at 45 ℃ in vacuo to give the title compound as awhite solid (8.8 g, purity: 95.0％) .
The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z : 460.2, [M+Na] +；
1H NMR (600 MHz, CDCl3) δ (ppm) : 7.09-6.90 (m, 3H) , 5.46 (s, 1H) , 4.92 (d, 1H) , 4.86 (d, 1H) , 4.36 (s, 1H) , 2.95 (ddd, 1H) , 2.62 (dd, 1H) , 1.43 (s, 9H) .
Example 2:
tert-butyl ( (2R, 3S) -5- (bromomethylene) -2- (2, 5-difluorophenyl) tetrahydrofuran- 3-yl) carbamate
Figure PCTCN2015084977-appb-000013
To a mixture of methanol (150 mL) and sodium methoxide (13.0 g) cooled to -10 ℃ was added a solution of tert-butyl ( (1R, 2S) -1- (2, 5-difluorophenyl) -1-hydroxypent-4-yn-2-yl) carbamate (31.1 g) in methanol (200 mL) dropwise. After dropwise addition, N-bromosuccinimide (21.5 g) was added to the resulting mixture. The mixture was stirred at 0 ℃ for 10 minutes, followed by 25 ℃ for 6 hours, and then quenched with water (350 mL) and stirred for 30 minutes. The mixture was concentrated in vacuo until the precipitate appeared. After stirring at 25 ℃ for 30 minutes, the precipitate was collected by filtration and washed sequentially with methanol (80 mL) and water (80 mL) . The resulting solid was dried at 45 ℃ in vacuo to give the title compound as a white solid (35.4 g, purity: 92.8％) .
The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 414.0, [M+Na] +；
1H NMR (600 MHz, CDCl3) δ (ppm) : 7.11 -6.87 (m, 3H) , 5.53-5.30 (m, 1H) , 5.13-5.06 (m, 1H) , 4.33 (s, 1H) , 2.95-2.86 (m, 1H) , 2.62-2.56 (m, 1H) , 1.43 (s, 9H) .
Example 3:
tert-butyl ( (2R, 3S) -5- (bromomethylene) -2- (2, 5-difluorophenyl) tetrahydrofuran-3-yl) carbamate
Figure PCTCN2015084977-appb-000014
To a mixture of water (42 mL) , methanol (100 mL) and KOH (15.0 g) cooled to -10 ℃ was added a solution of tert-butyl ( (1R, 2S) -1- (2, 5-difluorophenyl) -1-hydroxypent-4-yn-2-yl) carbamate (41.6 g) in methanol (550 mL) dropwise. After dropwise addition, dibromohydantoin (23.1 g) was added to the resulting mixture. The reaction mixture was stirred at 0 ℃ for 30 minutes, followed with a temperature  from 20 ℃ to 25 ℃ for 8 hours, and then quenched with water (650 mL) and stirred for 1.5 hours. The precipitate was collected by filtration and washed sequentially with methanol/water (400 mL, v: v＝1: 1) . The resulting solid was dried at 50 ℃ in vacuo to give the title compound as a white solid (46.5 g) .
The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 414.0, [M+Na] +.
Example 4:
tert-butyl ( (1R, 2S) -1- (2, 5-difluorophenyl) -1-hydroxy-5-iodo-4-oxopentan-2-yl) carbamate
Figure PCTCN2015084977-appb-000015
A solution of sodium hydrogen sulfate monohydrate (2.2 g) and tert-butyl ( (2R, 3S) -2- (2, 5-difluorophenyl) -5- (iodomethylene) tetrahydrofuran-3-yl) carbamate (7.2 g) in THF/water (35 mL/7 mL) was stirred at a temperature from 28 ℃ to 33 ℃ for 12 hours. Then the organic phase of the reaction mixture was separated and concentrated in vacuo at 40 ℃ to remove THF. Isopropyl acetate (35 mL) and water (28 mL) was added to the residue and the resulting mixture was stirred for 10 minutes. The seperated organic phase was concentrated in vacuo to give the title compound as brown oil (8.6 g) , which could be used for the next step without purification.
The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 477.8, [M+Na] +, 381.8, [M-BuO] + .
Example 5:
tert-butyl ( (1R, 2S) -5-bromo-1- (2, 5-difluorophenyl) -1-hydroxy-4-oxopentan-2-yl) carbamate
Figure PCTCN2015084977-appb-000016
A solution of sodium hydrogen sulfate monohydrate (6.9 g) and tert-butyl ( (2R, 3S) -5- (bromomethylene) -2- (2, 5-difluorophenyl) tetrahydrofuran-3-yl) carbamate (39.0 g) in THF/water (200 mL/40 mL) was stirred at 60 ℃ for 10 hours to complete the reaction. Then the organic phase of the reaction mixture was separated and concentrated in vacuo to remove THF. The residue was diluted with isopropyl acetate (200 mL) and water (120 mL) , and stirred to dissolve. The organic phase was seperated and concentrated in vacuo to give the title compound as brown oil (43.5 g) , which was used for the next step without purification.
The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 336.1, [M-BuO] +.
Example 6:
tert-butyl ( (2R, 3S) -2- (2, 5-difluorophenyl) -5-oxotetrahydro-2H-pyran-3-yl) carbamate
Figure PCTCN2015084977-appb-000017
To the brown oil (8.6 g) obtained from Example 4 were added THF (40 mL) and K2CO3 (2.6 g) . The reaction was stirred at 30 ℃ for 16 hours. Then the mixture was concentrated in vacuo to remove THF and the resulting residue was diluted with a mixture of ethyl acetate (40 mL) and water (20 mL) . The separated organic phase was concentrated in vacuo and the resulting residue was diluted with ethyl acetate (2.5 mL) , heated to 40 ℃ and stirred to dissolve. Then the mixture was cooled to 20 ℃ and n-heptane (7.5 mL) was added. After sitrring for 4 hours at 20 ℃, the precipitate was collected by filtration to give the title compound as a white solid (4.0 g) .
The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 350.0, [M+Na] +, 368.0, [M+K] +；
1H NMR (600 MHz, CDCl3) δ (ppm) : 7.24 (m, 1H) , 7.04 (m, 2H) , 4.85 (s, 1H) , 4.68 (s, 1H) , 4.31 (dd, 1H) , 4.16-4.11 (m, 1H) , 4.11-4.04 (m, 1H) , 3.10-3.02 (m, 1H) , 2.75 (s, 1H) , 1.64 (s, 1H) , 1.37-1.25 (s, 9H) .
Example 7:
tert-butyl ( (2R, 3S) -2- (2, 5-difluorophenyl) -5-oxotetrahydro-2H-pyran-3-yl) carbamate
Figure PCTCN2015084977-appb-000018
To the brown oil (43.5 g) obtained from Example 5 were added THF (500 mL) and K2CO3 (15.2 g) . The reaction was stirred at 35 ℃ for 16 hours. Then the organic phase was separated and concentrated in vacuo at 40 ℃ to remove THF and the resulting residue was diluted with a mixture of ethyl acetate (500 mL) and water (100 mL) . Then the separated organic phase was concentrated in vacuo and the resulting residue was diluted with ethyl acetate (13 mL) , heated to 40 ℃ and stirred to dissolve. Then the mixture was cooled to 20 ℃ and n-heptane (39 mL) was added. After sitrring for 4 hours at 20 ℃, the precipitate was collected by filtration to give the title compound as a white solid (23.9 g) .
The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 350.0.
Some embodiments of the invention are disclosed herein, obviously, a skilled artisan can make any alterations, changes or combinations thereof appropriately to implement and apply the present invention without departing from the content, spirit and scope of the present invention. The skilled in the art can learn from the present invention and improve the process parameters appropriately. It should be noted that it can be readily apparent to those of ordinary skill in the art that certain modifications may be made thereto within the scope of the invention.

Claims (15)

  1. A process for preparing a compoud of formula (04) , comprising:
    cyclizing a compound of formula (03) in presence of a first base in an organic solvent to form the compound of formula (04) :
    Figure PCTCN2015084977-appb-100001
    wherein,
    Ar is phenyl optionally substituted with at least one R4；
    each of R1 and R2 is independently hydrogen, or an amino-protecting group；
    R3 is F, Cl, Br, I, mesyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, sulfonyloxy, p-nitrophenylsulfonyloxy, trifluoromethanesulfonyloxy, or hydroxy；
    each R4 is independently F, Cl, C1-C6 alkyl optionally substituted with at least one fluorine, or C1-C6 alkoxy optionally substituted with at least one fluorine.
  2. The process of claim 1, wherein the first base is 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, 1, 8-diazabicyclo [5.4.0] undec-7-ene, and combinations thereof.
  3. The process of claim 1, wherein the organic solvent is selected from ethyl acetate, methyl acetate, isopropyl acetate, n-hexane, n-heptane, cyclohexane, dichloromethane, toluene, xylene, acetonitrile, isopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, acetone, methyl ethyl ketone, 3-pentanone, and combinations thereof.
  4. The process of claim 1, wherein the cyclization reaction of the compoud of formula (03) is performed at a temperature ranging from about -10 ℃ to about 130 ℃.
  5. The process of claim 1, further comprising performing a ring-opening reaction to a compound  of formula (02) by adding an acid to obtain the compound of formula (03) :
    Figure PCTCN2015084977-appb-100002
  6. The process of claim 5, wherein the molar ratio of the acid to the compound of formula (02) ranges from about 0.1: 1 to about 3.0: 1.
  7. The process of claim 5, the ring-opening reaction is performed at a temperature ranging form about -10 ℃ to about 60 ℃.
  8. The process of claim 5, further comprising:
    cyclizing a compound of formula (01) to obtain the compound of formula (02) :
    Figure PCTCN2015084977-appb-100003
  9. The process of claim 8, wherein cyclizing the compound of formula (01) is performed by adding a halogenating agent selected from N-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide, iodine, bromine, 1, 3-dibromo-5, 5-dimethyl-hydantoin, thionyl chloride, sodium dichloroisocyanurate acid, potassium dichloroisocyanurate, chloroisobromine cyanuric acid, trichloroisocyanuric uric acid, and combinations thereof.
  10. The process of claim 9, the molar ratio of the halogenating agent to the compound of formula (01) ranges from about 0.3:1 to about 3.0:1.
  11. The process of claim 9, wherein cyclizing the compound of formula (01) is performed at a temperature ranging from -20 ℃ to 40 ℃.
  12. The process of claim 9, wherein cyclizing the compound of formula (01) is performed in the presence of a second base or silver nitrate, and the second base 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.
  13. A compound of formula (02) :
    Figure PCTCN2015084977-appb-100004
    wherein,
    Ar is phenyl optionally substituted with at least one R4；
    each of R1 and R2 is independently hydrogen, or an amino-protecting group；
    R3 is F, Cl, Br, I, mesyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, sulfonyloxy, p-nitrophenylsulfonyloxy, trifluoromethanesulfonyloxy, or hydroxy；
    each R4 is independently F, Cl, C1-C6 alkyl optionally substituted with at least one fluorine, or C1-C6 alkoxy optionally substituted with at least one fluorine.
  14. A compound of formula (03) :
    Figure PCTCN2015084977-appb-100005
    wherein,
    Ar is phenyl optionally substituted with at least one R4；
    each of R1 and R2 is independently hydrogen, or an amino-protecting group；
    R3 is F, Cl, Br, I, mesyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, sulfonyloxy, p-nitrophenylsulfonyloxy, trifluoromethanesulfonyloxy, or hydroxy；
    each R4 is independently F, Cl, C1-C6 alkyl optionally substituted with at least one fluorine, or C1-C6 alkoxy optionally substituted with at least one fluorine.
  15. A compound having one of the following structures:
    Figure PCTCN2015084977-appb-100006
PCT/CN2015/084977 2014-07-29 2015-07-23 Process for preparing 2, 3-disubstituted-5-oxopyran compound Ceased WO2016015596A1 (en)

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