WO2019127902A1 - 一种5r-苄氧氨基哌啶-2s-甲酸或其衍生物的制备方法 - Google Patents

一种5r-苄氧氨基哌啶-2s-甲酸或其衍生物的制备方法 Download PDF

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WO2019127902A1
WO2019127902A1 PCT/CN2018/078072 CN2018078072W WO2019127902A1 WO 2019127902 A1 WO2019127902 A1 WO 2019127902A1 CN 2018078072 W CN2018078072 W CN 2018078072W WO 2019127902 A1 WO2019127902 A1 WO 2019127902A1
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compound
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benzyloxyaminopiperidine
base
sodium
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PCT/CN2018/078072
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English (en)
French (fr)
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戚聿新
李新发
徐欣
王保林
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解顺根
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新发药业有限公司
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Priority to AU2018344100A priority Critical patent/AU2018344100B2/en
Priority to US16/345,765 priority patent/US11142499B1/en
Priority to KR1020197008541A priority patent/KR102212496B1/ko
Priority to RU2019121138A priority patent/RU2730006C1/ru
Priority to JP2019515843A priority patent/JP6792069B2/ja
Priority to CA3042925A priority patent/CA3042925A1/en
Priority to EP18877299.0A priority patent/EP3733648B1/en
Publication of WO2019127902A1 publication Critical patent/WO2019127902A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B57/00—Separation of optically-active compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/02—Preparation by ring-closure or hydrogenation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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, directly attached to ring carbon atoms
    • C07D211/78—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a green preparation method of 5R-benzyloxyaminopiperidine-2S-carboxylic acid or a derivative thereof, which is a key intermediate for preparing avibactam and Relebactam.
  • Pharmaceutical biochemical industry a green preparation method of 5R-benzyloxyaminopiperidine-2S-carboxylic acid or a derivative thereof, which is a key intermediate for preparing avibactam and Relebactam.
  • Avibactam and Relebactam are non- ⁇ -lactam inhibitors of the novel diazabicyclooctyl ketone compounds, which can inhibit type A (including ESBL and KPC) and C.
  • Type ⁇ -lactamase, avidabartin combined with various cephalosporin and carbapenem antibiotics, has broad-spectrum antibacterial activity, especially for Escherichia coli and Cray containing extended-spectrum ⁇ -lactamase
  • 5R-benzyloxyaminopiperidine-2S-formate (II a ), 5R-benzyloxyaminopiperidine-2S-formate oxalate (II c ), 5R-benzyloxyaminopiperidine-2S-formic acid (II b ) is a key intermediate in the preparation of avivatan and rilibatan.
  • Patent document WO2012172368 discloses a synthesis method of 5R-benzyloxyaminopiperidine-2S-formate (II a ), 5R-benzyloxyaminopiperidine-2S-formic acid and avivatan, and US Patent No.
  • the raw material of the method uses N-protected L-pyroglutamic acid ester, trimethylsulfoxonium sulfoxide and methanesulfonic acid at a high price, and uses dimethyl sulfoxide as a solvent, and the post-treatment produces a large amount of waste water, which is poor in environmental protection and additionally The yield is low (59%).
  • U.S. Patent No. US20140275001 provides a further synthesis of 5R-benzyloxyaminopiperidine-2S-formate (II a ) (see Scheme 2), the technical solution of which is still N-protected L-pyroglutamic acid
  • the acid ester is the starting material, and the trimethyl iodide sulfoxide is opened to increase the carbon chain; the difference is that the US20140275001 patent document first uses a ruthenium catalyst to close the ring, chiral reduction of the carbonyl group to obtain an S-configuration alcohol, and then N -Benzyloxy-2-nitrobenzenesulfonamide achieves the SN2 configuration flip and converts the hydroxyl group to an amino group; first removes the 2-nitrobenzenesulfonyl chloride group under the action of lithium hydroxide and thioglycolic acid, and then trifluoroacetic acid Removal of the N-protecting group affords product IIa.
  • the method is cumber
  • Both Reaction Scheme 1 and Scheme 2 employ relatively expensive starting materials and trimethylsulfoxonium iodide as a method of increasing the carbon chain, and the method of Scheme 2 uses an expensive rhodium catalyst.
  • the two reaction processes require protection and deprotection.
  • the operation is extremely cumbersome, the amount of solvent used is large, the “three wastes” have large emissions, and the atomic utilization rate is low, which is not conducive to environmental protection.
  • the yield of the product obtained by the above prior art method is low, which is not conducive to green industrial production.
  • the present invention provides a 5R-benzyloxyaminopiperidine-2S-formate (II a ), 5R-benzyloxyaminopiperidine-2S-A, which is inexpensive and easy to obtain and has a simple process.
  • the method uses L-glutamic acid as a starting material to prepare compound III by esterification in the presence of an acidic reagent, and the compound III is subjected to "one-pot method" and 2-haloacetate, N- under basic conditions.
  • the protective reagent reaction or the N-protecting reagent, 2-haloacetate is reacted to obtain the compound IV, and the compound IV is intramolecularly condensed into a ring under the action of a strong base to obtain N-protected piperidin-5-one-2S-formic acid.
  • Ester (V) The resulting N-protected piperidin-5-one-2S-formate (V) was prepared by the preparation of 5R-benzyloxyaminopiperidine-2S-carboxylic acid.
  • Route 1 Compound V deprotection group, benzyloxy ammonia hydrochloride condensation, imine reduction-chiral resolution, neutralization, hydrolysis
  • Route 2 Compound V hydrolysis, deprotection, benzyloxy ammonia hydrochloride Condensation, imine reduction-chiral resolution, neutralization
  • Route 3 compound V and benzyloxy ammonia hydrochloride condensation, imine reduction-chiral resolution, deprotection, neutralization, hydrolysis.
  • a method for preparing 5R-benzyloxyaminopiperidine-2S-carboxylic acid and a derivative thereof, 5R-benzyloxyaminopiperidine-2S-carboxylic acid and a derivative thereof are 5R-benzyloxyaminopiperidine- Green preparation method of 2S-formate (II a ), 5R-benzyloxyaminopiperidine-2S-formate oxalate (II c ), 5R-benzyloxyaminopiperidine-2S-formic acid (II b ) ,Proceed as follows:
  • the acidic reagent is thionyl chloride, phosgene, diphosgene, triphosgene, oxalyl chloride;
  • the esterification reaction temperature is 30-100 ° C;
  • the alcohol is selected from the group consisting of C 1-6 saturated fat Alcohol, substituted C 6-9 aromatic alcohol or alkyl substituted aromatic alcohol, the alcohol
  • Step (1) After the completion of the reaction, the excess acidic reagent and the alcohol are distilled off, and the same alcohol as in the step (1) is added to the residue, followed by the addition of the base, 2-haloacetate, N-
  • the protective reagent or the base, the N-protecting reagent, the 2-haloacetate, the compound IV is obtained by two substitution reactions, and the reaction temperature is preferably 20-85 ° C;
  • Compound IV is condensed into a ring under the action of a solvent and a strong base to obtain a compound V; preferably, the solvent is tetrahydrofuran, 2-methyltetrahydrofuran, methoxycyclopentane, toluene, and the solvent and the compound IV
  • the solvent is tetrahydrofuran, 2-methyltetrahydrofuran, methoxycyclopentane, toluene
  • the mass ratio is 4-20:1; the reaction temperature of the intramolecular condensation ring is -20 to 50 ° C, and the reaction time is 2-7 hours.
  • the obtained compound VI is condensed with benzyloxy ammonia hydrochloride in the presence of a solvent and triethylamine to obtain a compound VII; preferably, the solvent is ethyl acetate, dichloromethane, chloroform, 1,2-di One of ethyl chloride, benzene, toluene or a combination thereof, the reaction temperature is 40-80 ° C;
  • the obtained compound V is condensed with benzyloxy ammonia hydrochloride in the presence of a solvent and a triethylamine base to give compound XI, N-protecting group 5-benzyloxyiminopiperidine-2S-formate (XI)
  • the solvent is ethyl acetate, dichloromethane, chloroform, 1,2-dichloroethane, benzene, toluene or a combination thereof, the reaction temperature is 40-80 ° C;
  • the obtained compound XI is reduced in the presence of concentrated sulfuric acid in ethyl acetate, reduced with a reducing agent, and added with oxalic acid, and subjected to chiral resolution to obtain compound XII, N-protecting group -5R-benzyloxyaminopiperidine-2S-A Acid ester (XII);
  • step (1) when step (1) uses thionyl chloride or phosgene as an acidic reagent, the molar ratio of thionyl chloride or phosgene to L-glutamic acid is (2.1-4.5): 1, preferably ester.
  • the reaction temperature is 40-80 ° C, the reaction time is 1-8 hours; when using diphosgene or oxalyl chloride as the acidic reagent, the molar ratio of diphosgene or oxalyl chloride to L-glutamic acid is (1.1-2.5) :1, preferably the esterification reaction temperature is 40-80 ° C, the reaction time is 1-8 hours; when the triphos is used as the acidic reagent, the molar ratio of triphosgene to L-glutamic acid is (0.7-1.5): 1,
  • the esterification reaction temperature is from 60 to 80 ° C and the reaction time is from 1 to 8 hours.
  • the mass ratio of the alcohol to L-glutamic acid in step (1) is from 8:1 to 30:1.
  • the above C 1-6 saturated fatty alcohol is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, n-pentanol, isoamyl alcohol, tert-amyl alcohol, hexanol;
  • the above substituted C 6-9 aromatic alcohol or alkyl substituted aromatic alcohol is selected from the group consisting of benzyl alcohol, o-methylbenzyl alcohol, and p-methylbenzyl alcohol.
  • the addition of the same alcohol as in the step (1) in the step (2) means that the kind and quality of the alcohol are the same as in the step (1).
  • the base in the step (2) is an inorganic base or an organic base
  • the inorganic base is selected from the group consisting of potassium carbonate, sodium carbonate, calcium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, calcium hydrogencarbonate, potassium acetate, and sodium acetate.
  • the organic base being selected from one or a combination of trimethylamine, triethylamine, tri-n-butylamine;
  • the 2-haloacetate of step (2) is methyl 2-chloroacetate, methyl 2-bromoacetate, methyl 2-iodoacetate, methyl 2-iodoacetate, 2- Ethyl chloroacetate, ethyl 2-bromoacetate, ethyl 2-iodoacetate, ethyl 2-iodoacetate, benzyl 2-chloroacetate, benzyl 2-bromoacetate, benzyl 2-iodoacetate, 2-iodine Benzyl acetate;
  • the N-protecting reagent in the step (2) is benzyl chloride, benzyl bromide, benzoyl chloride, methyl chloroformate, ethyl chloroformate, tert-butyl chloroformate, benzyl chloroformate, chloroformic acid. -9-mercaptomethyl ester, di-tert-butyl dicarbonate;
  • step (2) the molar ratio of 2-haloacetate, N-protecting reagent, base and L-glutamic acid is (1.0-2.0): (1.0-2.0): (2.0 -4.0): 1;
  • the reaction temperature is 40-70 ° C, and the two substitution reaction times are 1-5 hours.
  • the strong base is sodium hydride, sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium t-butoxide or sodium benzylate; further preferably the strong base and the compound IV
  • the molar ratio is (1.0-2.0): 1.
  • the compound V in the step (1.1) is subjected to de-N-protecting group to obtain the compound VI.
  • the N-protecting group can be selected in the following manner; when the N-protecting group is When benzyl, catalytic hydrogenolysis debenzylation; when the N-protecting group is benzoyl or alkoxycarbonyl, the corresponding N-protecting group is hydrolyzed under basic conditions; preferably, the catalytic hydrogen described in step (1.1)
  • the catalyst used for the solution is palladium carbon or Raney nickel.
  • the preferred amount of the palladium carbon catalyst is 0.5% to 5% by mass of the compound V, and further preferably the amount of the catalyst is 1% to 3% by mass; the preferred amount of Raney nickel catalyst is The compound V is 1% to 20% by mass, and further preferably the catalyst is used in an amount of 5% to 10% by mass.
  • the solvent described in the step (1.1) is one of methanol, ethanol, propanol, butanol, ethyl acetate, tetrahydrofuran, acetonitrile or a mixed solvent thereof, and further preferably a mass ratio of the solvent to the compound V.
  • the hydrogen pressure is 0.1-1.0 MPa
  • the reaction temperature is 20-85 ° C
  • the reaction is 3-10 hours.
  • the N-protecting group is a benzoyl group or an alkoxycarbonyl group
  • the corresponding N-protecting group is hydrolyzed under basic conditions; preferably, the base in the step (1.1) is potassium hydroxide, sodium hydroxide or lithium hydroxide.
  • the solvent described in step (1.1) is one of water, methanol, ethanol, propanol, butanol, ethyl acetate, tetrahydrofuran, acetonitrile Or a mixed solvent thereof, further preferably, the mass ratio of the solvent to the compound V is from 3:1 to 15:1; in the preferred step (1.1), the hydrolysis reaction temperature is from 10 to 100 ° C, and the reaction is carried out for 2 to 10 hours.
  • the solvent in the solvent in the step (1.2) is one of methanol, ethanol, propanol, butanol, ethyl acetate, tetrahydrofuran, acetonitrile or a mixed solvent thereof, and further preferably The mass ratio of the solvent to the compound VI is from 3:1 to 15:1;
  • the molar ratio of the benzyloxyamine hydrochloride to the compound VI is from 0.9 to 1.5:1; preferably, the reaction temperature is from 10 to 80 ° C, and the reaction time is from 2 to 5 hours.
  • the concentrated sulfuric acid is a sulfuric acid having a mass fraction of 95-98%, and the molar ratio of the concentrated sulfuric acid to the compound VII is (3.0-6.0): 1, and most preferably the concentrated sulfuric acid. For a mass fraction of 98% sulfuric acid.
  • the mass ratio of ethyl acetate to the compound VII is from 5 to 20:1; further preferably, the mass ratio of ethyl acetate to the compound VII is from 10 to 14:1.
  • the reducing agent is sodium borohydride, sodium tricyanoborohydride, sodium triacetoxyborohydride, sodium tripropionyl borohydride, potassium borohydride, three. Potassium cyanoborohydride, potassium triacetoxyborohydride or potassium tripropionyl borohydride.
  • the molar ratio of the reducing agent to the compound VII is (2.0-4.0):1.
  • the obtained 5R-benzyloxyaminopiperidine-2S-formate oxalate is neutralized in a solvent to obtain 5R-benzyloxyaminopiperidine-2S-A.
  • Acid ester (II a ) is obtained in the step (1.4).
  • the solvent in the step (1.4) is ethyl acetate, dichloromethane, chloroform, 1,2-dichloroethane, benzene, toluene or a mixture thereof; preferably the solvent and the compound II b
  • the mass ratio is 4:1 to 12:1.
  • the base in the step (1.4) is one or a combination of potassium carbonate, sodium carbonate, calcium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, calcium hydrogencarbonate, aqueous ammonia; preferably the base and 5R-benzyl
  • the molar ratio of oxyaminopiperidine-2S-formate oxalate was (1.5-3.0):1.
  • the neutralization reaction temperature is 10 to 40 ° C, and the reaction time is 2 to 5 hours.
  • the obtained 5R-benzyloxyaminopiperidine-2S-formate (II a ) is hydrolyzed in a solvent to obtain 5R-benzyloxyaminopiperidine-2S-formic acid. (II b ).
  • the solvent in the step (1.5) is water, ethyl acetate, dichloromethane, chloroform, 1,2-dichloroethane, benzene, toluene or a mixture thereof; preferably the solvent and the compound IIa
  • the mass ratio is 4:1 to 12:1.
  • the base in the step (1.5) is one or a combination of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, calcium carbonate, potassium hydrogencarbonate or sodium hydrogencarbonate;
  • the molar ratio of the base to 5R-benzyloxyaminopiperidine-2S-formate (II a ) is (1.5-3.0):1.
  • the hydrolysis reaction temperature is 10 to 80 ° C, and the reaction time is 2 to 5 hours.
  • step (2.1) the compound V is hydrolyzed in a solvent to obtain a compound VIII, N-protected piperidin-5-one-2S-carboxylic acid (VIII);
  • the solvent in the step (2.1) is water, ethyl acetate, dichloromethane, chloroform, 1,2-dichloroethane, benzene, toluene or a mixture thereof; preferably the solvent and the compound V
  • the mass ratio is 4:1 to 12:1.
  • the base in the step (2.1) is one or a combination of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, calcium carbonate, potassium hydrogencarbonate or sodium hydrogencarbonate;
  • the molar ratio of the base to the compound V is (1.5 - 3.0): 1.
  • the hydrolysis reaction temperature is from 10 to 80 ° C, and the reaction time is from 2 to 5 hours.
  • the compound VIII obtained in the step (2.2) is subjected to deprotection of the N-protecting group to obtain the compound IX, that is, piperidin-5-one-2S-carboxylic acid (IX); depending on the N-protecting group,
  • the N-protecting group is selected in the following manner; when the N-protecting group is a benzyl group, catalytic dehydrolysis of the benzyl group is employed; when the N-protecting group is a benzoyl group or an alkoxycarbonyl group, the corresponding N- is hydrolyzed under basic conditions.
  • the protecting group preferably, the catalyst for catalytic hydrogenolysis in the step (2.2) is palladium carbon or Raney nickel, and the preferred palladium carbon catalyst is used in an amount of 0.5% to 5% by mass of the compound VIII, and further preferably the amount of the catalyst is 1 % to 3% by mass; a preferred amount of Raney nickel catalyst is from 1% to 20% by mass of the compound VIII, and a further preferred amount of the catalyst is from 5% to 10% by mass.
  • the solvent described in the step (1.1) is one of methanol, ethanol, propanol, butanol, ethyl acetate, tetrahydrofuran, acetonitrile or a mixed solvent thereof, and further preferably a mass ratio of the solvent to the compound VIII. It is 4:1 to 15:1; in the preferred step (1.1), the hydrogen pressure is 0.1-1.0 MPa, the reaction temperature is 20-85 ° C, and the reaction is 3-10 hours.
  • the N-protecting group is a benzoyl group or an alkoxycarbonyl group
  • the corresponding N-protecting group is hydrolyzed under basic conditions; preferably, the base in the step (1.1) is potassium hydroxide, sodium hydroxide or lithium hydroxide.
  • the solvent described in step (1.1) is one of water, methanol, ethanol, propanol, butanol, ethyl acetate, tetrahydrofuran, acetonitrile Or a mixed solvent thereof, further preferably, the mass ratio of the solvent to the compound VIII is from 3:1 to 15:1; in the preferred step (1.1), the hydrolysis reaction temperature is from 10 to 100 ° C, and the reaction is carried out for 2 to 10 hours.
  • the solvent in the solvent in the step (2.3) is one of methanol, ethanol, propanol, butanol, ethyl acetate, tetrahydrofuran, acetonitrile or a mixed solvent thereof, and further preferably The mass ratio of the solvent to the compound IX is from 3:1 to 15:1;
  • the molar ratio of the benzyloxyamine hydrochloride to the compound IX is from 0.9 to 1.5:1; preferably, the reaction temperature is from 10 to 80 ° C, and the reaction time is from 2 to 5 hours.
  • the concentrated sulfuric acid is a sulfuric acid having a mass fraction of 95-98%, the molar ratio of the concentrated sulfuric acid to the compound X is (3.0-6.0): 1, and most preferably the concentrated sulfuric acid. For a mass fraction of 98% sulfuric acid.
  • the mass ratio of ethyl acetate to compound X is from 5 to 20:1; further preferably, the mass ratio of ethyl acetate to compound X is from 10 to 14:1.
  • the reducing agent is sodium borohydride, sodium tricyanoborohydride, sodium triacetoxyborohydride, sodium tripropionyl borohydride, potassium borohydride, three. Potassium cyanoborohydride, potassium triacetoxyborohydride or potassium tripropionyl borohydride.
  • the molar ratio of the reducing agent to the compound X is (2.0-4.0):1.
  • the compound V obtained in the step (3.1) is condensed with benzyloxy ammonia hydrochloride in the presence of a solvent and a base to give the compound XI, N-protecting group-5-benzyloxyiminopiperidine- 2S-formate (XI);
  • the solvent described in the step (3.1) is methanol, ethanol, propanol, butanol, ethyl acetate, tetrahydrofuran, acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, benzene. a toluene or a mixed solvent thereof, further preferably a mass ratio of the solvent to the compound V is from 3:1 to 15:1;
  • the base in the step (3.1) is an organic base such as triethylamine, tri-n-butylamine, diisopropylethylamine, pyridine or an inorganic base potassium carbonate, sodium carbonate or a mixture thereof.
  • the molar ratio of base to compound V is (1.0-2.0); 1;
  • the molar ratio of the benzyloxyamine hydrochloride to the compound V is from 0.9 to 1.5:1; preferably, the reaction temperature is from 10 to 80 ° C, and the reaction time is from 2 to 5 hours.
  • the compound XI is reduced in the presence of concentrated sulfuric acid in ethyl acetate, reduced by a reducing agent, added with oxalic acid, and subjected to chiral resolution to obtain a compound XII, N-protected.
  • 5-R-benzyloxyaminopiperidine-2S-formate (XII) is reduced in the presence of concentrated sulfuric acid in ethyl acetate, reduced by a reducing agent, added with oxalic acid, and subjected to chiral resolution to obtain a compound XII, N-protected.
  • the concentrated sulfuric acid is a sulfuric acid having a mass fraction of 95-98%, and the molar ratio of the concentrated sulfuric acid to the compound XI is (3.0-6.0): 1, and most preferably the concentrated sulfuric acid. For a mass fraction of 98% sulfuric acid.
  • the mass ratio of ethyl acetate to compound XI is from 5 to 20:1; further preferably, the mass ratio of ethyl acetate to compound XI is from 10 to 14:1.
  • the reducing agent is sodium borohydride, sodium tricyanoborohydride, sodium triacetoxyborohydride, sodium tripropionyl borohydride, potassium borohydride, and the like. Potassium cyanoborohydride, potassium triacetoxyborohydride or potassium tripropionyl borohydride.
  • the molar ratio of the reducing agent to the compound XI is (2.0-4.0):1.
  • the compound XII obtained in the step (3.3) is subjected to N-protecting agent, neutralized to obtain 5R-benzyloxyaminopiperidine-2S-formate (II a );
  • the compound XII in the step (3.3) is subjected to de-N-protecting group and neutralized to obtain the compound IIa.
  • the N-protecting group can be selected in the following manner; when N-protecting When the benzyl group is a benzyl group, catalytic hydrogenolysis is used to debenzylate; when the N-protecting group is a benzoyl group or an alkoxycarbonyl group, the corresponding N-protecting group is hydrolyzed under basic conditions; preferably, the step (3.3)
  • the catalyst used for catalytic hydrogenolysis is palladium carbon or Raney nickel.
  • the preferred palladium carbon catalyst is used in an amount of 0.5% to 5% by mass of the compound XII, and further preferably the catalyst is used in an amount of 1% to 3% by mass; a preferred Raney nickel catalyst The amount is from 1% to 20% by mass based on the mass of the compound XII, and further preferably the amount of the catalyst is from 5% to 10% by mass.
  • the solvent described in the step (3.3) is one of methanol, ethanol, propanol, butanol, ethyl acetate, tetrahydrofuran, acetonitrile or a mixed solvent thereof, and further preferably a mass ratio of the solvent to the compound XII.
  • the hydrogen pressure is 0.1-1.0 MPa
  • the reaction temperature is 20-85 ° C
  • the deprotection and neutralization reaction time are 3-10 hours.
  • the N-protecting group is a benzoyl group or an alkoxycarbonyl group
  • the corresponding N-protecting group is hydrolyzed under basic conditions; preferably, the base in the step (3.3) is potassium hydroxide, sodium hydroxide or lithium hydroxide.
  • the molar ratio of the base to the compound XII (2.0-3.0): 1; preferably, the solvent described in the step (3.3) is one of water, methanol, ethanol, propanol, butanol, ethyl acetate, tetrahydrofuran, acetonitrile. Or a mixed solvent thereof, further preferably, the mass ratio of the solvent to the compound XII is from 3:1 to 15:1; in the preferred step (1.1), the hydrolysis reaction temperature is from 10 to 100 ° C, and the reaction is carried out for 2 to 10 hours.
  • the solvent described in the step (3.3) is one of water, methanol, ethanol, propanol, butanol, ethyl acetate, tetrahydrofuran, acetonitrile.
  • the mass ratio of the solvent to the compound XII is from 3:1 to 15:1; in the preferred step (1.1), the hydrolysis reaction temperature is from 10 to 100 ° C, and the reaction is
  • the step (3.4) is carried out by hydrolysis and acidification of the obtained 5R-benzyloxyaminopiperidine-2S-formate (II a ) in a solvent to obtain 5R-benzyloxyaminopiperidine-2S-carboxylic acid (II). b );
  • the solvent in the step (3.4) is water, ethyl acetate, dichloromethane, chloroform, 1,2-dichloroethane, benzene, toluene or a mixture thereof; preferably the solvent and the compound IIa
  • the mass ratio is 4:1 to 12:1.
  • the base in the step (3.4) is one or a combination of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, calcium carbonate, potassium hydrogencarbonate or sodium hydrogencarbonate;
  • the molar ratio of the base to the compound IIa is (1.5 - 3.0): 1.
  • the hydrolysis reaction temperature is from 10 to 80 ° C, and the reaction time is from 2 to 5 hours.
  • different routes can be selected to prepare the desired desired product.
  • 5R-benzyloxyaminopiperidine-2S-formate oxalate (II c )
  • 5R-benzyloxyaminopiperidine-2S-formate (II a )
  • 5R-benzyloxyaminopiperidine prepared by the present invention -2S-formic acid (II b ) is used as a raw material, and avivatan (I a ) and rilibate (I b ) can be prepared according to a known method.
  • the reaction formula is as follows (Scheme 4):
  • the present invention relates to a 5R-benzyloxyaminopiperidine-2S-formate (II a ), 5R-benzyloxyaminopiperidine-2S-formate oxalate (II c ), 5R-benzyloxy Green preparation method of aminopiperidine-2S-formic acid (II b ).
  • the invention develops and prepares a novel preparation method for preparing 5R-benzyloxyaminopiperidine-2S-carboxylic acid and its derivatives, and uses L-glutamic acid as a starting material, which is cheap and easy to obtain, and the types of reactions involved in each step are involved.
  • the reaction conditions are easy to control, the operability is strong, the process is simple, the atomic economy is high, the total yield can reach more than 60.0%, and the ratio is increased by 0.5 times to 3 times compared with the prior art, and the obtained product has high purity and low cost.
  • the method of the invention is easy to recycle, reduces waste liquid discharge, and is green in process.
  • Figure 2 is a nuclear magnetic carbon spectrum of the product obtained in Example 18 of the present invention.
  • reaction process and product purity were monitored by gas phase or liquid chromatography, and the optical purity (area ratio %) was measured by a liquid chromatograph equipped with a chiral column (ES-OVS, 150 mm ⁇ 4.6 mm, Agilent), and the calculation was performed. Rate and ee% value.
  • the layer and the aqueous layer were extracted with 1,2-dichloroethane, 50 g each time, and the organic layer was combined, and the solvent was distilled under atmospheric distillation, and then distilled under reduced pressure to obtain 24.4 g of a colorless transparent liquid N-benzylpiperidine-5-
  • the ketone-2S-formic acid ethyl ester had a GC purity of 99.7% and a yield of 93.5%.
  • Example 9 250 g of 1,2-dichloroethane and 26.0 g (0.15 mol) of piperidin-5-one-2S-carboxylate were added to a 500 ml four-necked flask equipped with a stirring, a thermometer and a reflux condenser.
  • Example 9 was prepared), 26.0 g (0.16 mol) of benzyloxyamine hydrochloride, 17.2 g (0.17 mol) of triethylamine.
  • the reaction was stirred at 50-55 ° C for 4 hours, cooled, 100 g of water was added, the layers were separated, and the organic layer was washed twice with brine, 25 g each.
  • the filter cake was washed first with 60 g of a mixture of ethyl acetate/methanol (2:1) and then washed with 50 g of ethyl acetate. Drying under vacuum, 18.0 g of a single isomer, 5R-benzyloxyaminopiperidine-2S-formic acid methyl ester, a chiral HPLC purity of 99.5%, a yield of 63.5%, and a total yield of 50.0% based on L-glutamic acid. .
  • the filter cake was washed first with 60 g of a mixture of ethyl acetate/methanol (2:1) and then washed with 50 g of ethyl acetate. Drying under vacuum gave 19.3 g of a single isomer, 5R-benzyloxyaminopiperidine-2S-ethyl ester, chiral HPLC purity 99.6%, yield 65.4%, total yield of 54.7% based on L-glutamic acid .
  • the nuclear magnetic data of the obtained product are as follows: 1 H NMR (400 MHz, DMSO-d 6 ) ⁇ : 1.26 (m, 1H), 1.45 (q, 1H), 1.80 (m, 1H), 2.11 (m, 1H), 3.03 (m, 2H), 3.20 (d, 1H), 4.58 (s, 2H), 6.77 (d, 1H), 7.29-7.37 (m, 5H).
  • thermometer To a 500 ml four-necked flask equipped with a stirring, a thermometer was charged with 100 g of water, 50 g of ethanol, and 27.8 g (0.10 mol) of 5R-benzyloxyaminopiperidine-2S-carboxylate (manufactured by the method described in Example 17). It is obtained, 24 g (0.12 mol) of 20% aqueous sodium hydroxide solution, and stirred at 40-45 ° C for 3 hours. After completion of the hydrolysis reaction, the pH is adjusted to 2.5-3.0 with 30% hydrochloric acid, filtered, and dried to obtain 24.5 g of light. Yellow powder solid 5R-benzyloxyaminopiperidine-2S-carboxylic acid, HPLC purity 99.9%, yield 98.0%.
  • the filter cake was washed first with 60 g of a mixture of ethyl acetate/methanol (2:1) and then washed with 50 g of ethyl acetate.
  • the obtained filter cake was added to another 500 ml four-necked flask, and 100 g of water, 100 g of methanol, 80 g (0.4 mol) of a 20% aqueous sodium hydroxide solution were added, and the reaction was stirred at 30-35 ° C for 4 hours, and the hydrolysis reaction was completed.

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Abstract

本发明涉及一种 5R-苄氧氨基哌啶-2S-甲酸或其衍生物的绿色制备方法。该方法以 L-谷氨酸为起始原料，在酸性试剂存在下经酯化反应，然后在碱性条件下依次和 2-卤代乙酸酯、N-保护试剂或 N-保护试剂、2-卤代乙酸酯反应得化合物 IV，然后在强碱作用下经分子内缩合成环得到 N-保护基哌啶-5-酮-2S-甲酸酯 (V) 。所得化合物V经下列途径之一制备 5R-苄氧氨基哌啶-2S-甲酸(或酯)。途径 1：化合物V脱保护基、苄氧基氨盐酸盐缩合、亚胺还原-手性拆分、中和、水解；途径 2：化合物V水解、脱保护基、苄氧基氨盐酸盐缩合、亚胺还原-手性拆分、中和；途径 3：化合物 V 和苄氧基氨盐酸盐缩合、亚胺还原-手性拆分、脱保护基、中和、水解。以上途径可以"一锅法"实现。

Description

一种5R-苄氧氨基哌啶-2S-甲酸或其衍生物的制备方法 技术领域
本发明涉及一种5R-苄氧氨基哌啶-2S-甲酸或其衍生物的绿色制备方法，该化合物是制备阿维巴坦(Avibactam)和瑞利巴坦(Relebactam)的关键中间体，属于医药生物化工领域。
背景技术
阿维巴坦(Avibactam)和瑞利巴坦(Relebactam)属于新型二氮杂双环辛酮化合物的非β-内酰胺类抑制剂，阿维巴坦能抑制A型(包括ESBL和KPC)和C型的β-内酰胺酶，阿维巴坦与各类头孢和碳青霉烯抗生素联合使用时，具有广谱抗菌活性，尤其是对含有超广谱β-内酰胺酶的大肠杆菌和克雷伯肺炎杆菌、含有超量AmpC酶的大肠杆菌以及同时含有AmpC和超广谱β-内酰胺酶的大肠杆菌的活性显著。瑞利巴坦和亚胺培南-西司他丁钠组合药物的临床二期显示了良好的性能。阿维巴坦Avibactam(Ia)的CAS号为1192491-61-4，化学名称为[(1R,2S,5R)-2-(氨基羰基)-7-氧代-1,6-二氮杂双环[3.2.1]辛-6-基]硫酸钠，瑞利巴坦Relebactam(Ib)的CAS号为1174018-99-5，化学名称为[(1R,2S,5R)-2-(N-(4-哌啶基)氨基羰基)-7-氧代-1,6-二氮杂双环[3.2.1]辛-6-基]硫酸，阿维巴坦、瑞利巴坦和关键中间体的结构式如下：
Figure PCTCN2018078072-appb-000001
5R-苄氧氨基哌啶-2S-甲酸酯(II a)、5R-苄氧氨基哌啶-2S-甲酸酯草酸盐(II c)、5R-苄氧氨基哌啶-2S-甲酸(II b)是制备阿维巴坦和瑞利巴坦的关键中间体。专利文件WO2012172368公开了5R-苄氧氨基哌啶-2S-甲酸酯(II a)、5R-苄氧氨基哌啶-2S-甲酸和阿维巴坦的合成方法，美国专利US2010197928、US2013012712专门报道了5R-苄氧氨基哌啶-2S-甲酸酯(II a)的合成，见反应路线1。其技术方案是：以N-保护的L-焦谷氨酸酯为起始原料，经三甲基碘化亚砜开环增加碳链，苄氧胺将羰基转换为亚胺，酸性条件下脱去保护基，碱性条件下关环，最后利用还原剂还原、手性拆分得到产品5R-苄氧氨基哌啶-2S-甲酸酯(II a)。该方法所用原料N-保护的L-焦谷氨酸酯、三甲基碘化亚砜、甲基磺酸价格高，利用二甲亚砜做溶剂，后处理产生大量废水，环保性差，另外总收率较低(59％)。
Figure PCTCN2018078072-appb-000002
美国专利US20140275001提供了另外一种5R-苄氧氨基哌啶-2S-甲酸酯(II a)的合成方法(见反应路线2)，其技术方案仍然是以N-保护的L-焦谷氨酸酯为起始原料，三甲基碘化亚砜开环增加碳链；所不同的是该US20140275001专利文件先利用铱催化剂关环，手性还原羰基得到S-构型的醇，再以N-苄氧基-2-硝基苯磺酰胺实现SN2构型翻转并将羟基转换为氨基；先在氢氧化锂和巯基乙酸作用下脱去2-硝基苯磺酰氯基，再以三氟乙酸脱去N-保护基得到产品IIa。该方法操作繁琐，且用到了昂贵的铱催化剂和特殊臭味的巯基乙酸，废水量大，总收率仅为15％。
Figure PCTCN2018078072-appb-000003
反应路线1和反应路线2均采用价格较贵的起始原料以及三甲基碘化亚砜作为增加碳链的方法，且反应路线2的方法使用了价格昂贵的铱催化剂。两种反应过程需要保护、脱保护，操作极为繁琐，溶剂使用量大，“三废”排放大，原子利用率低，不利于环保。同时上述现有技术方法得到的产品收率低，不利于绿色工业化生产。
发明内容
针对现有技术的不足，本发明提供一种原料价廉易得、流程简洁的5R-苄氧氨基哌啶-2S-甲酸酯(II a)、5R-苄氧氨基哌啶-2S-甲酸酯草酸盐(II c)、5R-苄氧氨基哌啶-2S-甲酸(II b)的绿色制备方法，且产品收率显著提高。
利用本发明所得5R-苄氧氨基哌啶-2S-甲酸酯(II a)或5R-苄氧氨基哌啶-2S-甲酸(II b)，可制备阿维巴坦和瑞利巴坦。
术语说明：
化合物III，L-谷氨酸二酯盐酸盐(III)；
化合物IV，N-保护基-N-烷氧羰基甲基-L-谷氨酸二酯(IV)；
化合物V，N-保护基哌啶-5-酮-2S-甲酸酯(V)；
化合物VI，哌啶-5-酮-2S-甲酸酯(VI)；
化合物VII，5-苄氧亚氨基哌啶-2S-甲酸酯(VII)；
化合物VIII，N-保护基哌啶-5-酮-2S-甲酸(VIII)；
化合物IX，哌啶-5-酮-2S-甲酸(IX)；
化合物X，5-苄氧亚氨基哌啶-2S-甲酸(X)；
化合物XI，N-保护基-5-苄氧亚氨基哌啶-2S-甲酸酯(XI)；
化合物XII，N-保护基-5R-苄氧氨基哌啶-2S-甲酸酯(XII)；
化合物II a，5R-苄氧氨基哌啶-2S-甲酸酯(II a)；
化合物II b，5R-苄氧氨基哌啶-2S-甲酸(II b)；
化合物II c，5R-苄氧氨基哌啶-2S-甲酸酯草酸盐(II c)
本说明书中的化合物编号与结构式编号完全一致，具有相同的指代关系。
本发明技术方案如下：
一种5R-苄氧氨基哌啶-2S-甲酸酯(II a)、5R-苄氧氨基哌啶-2S-甲酸酯草酸盐(II c)、5R-苄氧氨基哌啶-2S-甲酸(II b)的绿色制备方法，包括步骤：
该方法以L-谷氨酸为起始原料，在酸性试剂存在下经酯化反应制备化合物III，化合物III在碱性条件下经“一锅法”和2-卤代乙酸酯、N-保护试剂反应或N-保护试剂、2-卤代乙酸酯反应得到化合物IV，化合物IV在强碱作用下经分子内缩合成环得到N-保护基哌啶-5-酮-2S-甲酸酯(V)。所得N-保护基哌啶-5-酮-2S-甲酸酯(V)经下列途径之一制备5R-苄氧氨基哌啶-2S-甲酸。途径1：化合物V脱保护基、苄氧基氨盐酸盐缩合、亚胺还原-手性拆分、中和、水解；途径2：化合物V水解、脱保护基、苄氧基氨盐酸盐缩合、亚胺还原-手性拆分、中和；途径3：化合物V和苄氧基氨盐酸盐缩合、亚胺还原-手性拆分、脱保护基、中和、水解。
反应式如下：
更为详细的，一种5R-苄氧氨基哌啶-2S-甲酸及其衍生物的制备方法，5R-苄氧氨基哌啶-2S-甲酸及其衍生物为5R-苄氧氨基哌啶-2S-甲酸酯(II a)、5R-苄氧氨基哌啶-2S-甲酸酯草酸盐(II c)、5R-苄氧氨基哌啶-2S-甲酸(II b)的绿色制备方法，步骤如下：
(1)于酸性试剂存在下，L-谷氨酸和醇经酯化反应制备化合物III(L-谷氨酸二酯盐酸盐)；
优选的，所述酸性试剂为氯化亚砜、光气、二光气、三光气、草酰氯；所述酯化反应温度为30-100℃；所述醇选自C 1-6的饱和脂肪醇、取代的C 6-9的芳醇或烷基取代芳醇，所述醇
Figure PCTCN2018078072-appb-000004
是C 1-6的饱和脂肪醇，或取代的C 6-9的芳醇或烷基取代芳醇；
(2)步骤(1)反应完成后，蒸馏回收过量的酸性试剂和醇，再向剩余物中加入与步骤(1)相同的醇，依次然后加入碱、2-卤代乙酸酯、N-保护试剂或碱、N-保护试剂、2-卤代乙酸酯，经两次取代反应得到化合物IV，反应温度优选20-85℃；
(3)化合物IV在溶剂和强碱作用下缩合成环得到化合物V；优选的，所述溶剂为四氢呋喃、2-甲基四氢呋喃、甲氧基环戊烷、甲苯，所述溶剂与化合物IV的质量比为4-20:1；所述分子内缩合成环的反应温度为-20至50℃，反应时间为2-7小时。
经下列途径之一制备目标产物，根据目标产物选择具体途径及相应步骤；
途径1：
(1.1)所得化合物V经过脱N-保护基，得到化合物VI，哌啶-5-酮-2S-甲酸酯(VI)；
(1.2)所得化合物VI于溶剂和三乙胺存在下，和苄氧基氨盐酸盐缩合得到化合物VII；优选的，所述溶剂为乙酸乙酯、二氯甲烷、氯仿、1,2-二氯乙烷、苯、甲苯之一或其组合，所述反应温度为40-80℃；
(1.3)所得化合物VII在浓硫酸存在下，于乙酸乙酯中，经还原剂还原、添加草酸进行反应并进行手性拆分得到5R-苄氧氨基哌啶-2S-甲酸酯草酸盐(II c)；
(1.4)所得5R-苄氧氨基哌啶-2S-甲酸酯草酸盐经过中和，得到5R-苄氧氨基哌啶-2S-甲酸酯(II a)；
(1.5)所得5R-苄氧氨基哌啶-2S-甲酸酯(II a)经过水解、酸化得到5R-苄氧氨基哌啶-2S-甲酸(II b)。
途径2：
(2.1)所得化合物V经过酯基水解，得到化合物Ⅷ，N-保护基哌啶-5-酮-2S-甲酸(Ⅷ)；(2.2)化合物Ⅷ，即N-保护基哌啶-5-酮-2S-甲酸经过脱N-保护剂，得到化合物IX，哌啶-5-酮-2S-甲酸(IX)；
(2.3)所得化合物IX，哌啶-5-酮-2S-甲酸(IX)于溶剂和三乙胺碱存在下，和苄氧基氨盐酸盐缩合得到化合物Ⅹ，5-苄氧亚氨基哌啶-2S-甲酸(Ⅹ)；优选的，所述溶剂为乙酸乙酯、二氯甲烷、氯仿、1,2-二氯乙烷、苯、甲苯之一或其组合，所述反应温度为40-80℃；
(2.4)所得化合物Ⅹ在浓硫酸存在下，于乙酸乙酯中，经还原剂还原、添加草酸进行反应并进行手性拆分、中和得到5R-苄氧氨基哌啶-2S-甲酸(II b)。
途径3：
(3.1)所得化合物V于溶剂和三乙胺碱存在下，和苄氧基氨盐酸盐缩合得到化合物XI，N-保护基-5-苄氧亚氨基哌啶-2S-甲酸酯(XI)；优选的，所述溶剂为乙酸乙酯、二氯甲烷、氯仿、1,2-二氯乙烷、苯、甲苯之一或其组合，所述反应温度为40-80℃；
所得化合物XI在浓硫酸存在下，于乙酸乙酯中，经还原剂还原、添加草酸进行反应并进 行手性拆分得到化合物XII，N-保护基-5R-苄氧氨基哌啶-2S-甲酸酯(XII)；
(3.3)所得化合物XII经过脱N-保护剂、中和得到5R-苄氧氨基哌啶-2S-甲酸酯(II a)；
(3.4)所得5R-苄氧氨基哌啶-2S-甲酸酯(II a)经过水解、酸化得到5R-苄氧氨基哌啶-2S-甲酸(II b)
根据本发明优选的，步骤(1)使用氯化亚砜或光气为酸性试剂时，氯化亚砜或光气和L-谷氨酸的摩尔比为(2.1-4.5):1，优选酯化反应温度为40-80℃，反应时间为1-8小时；使用双光气或草酰氯为酸性试剂时，双光气或草酰氯和L-谷氨酸的摩尔比为(1.1-2.5):1，优选酯化反应温度为40-80℃，反应时间为1-8小时；使用三光气为酸性试剂时，三光气和L-谷氨酸的摩尔比为(0.7-1.5):1，优选酯化反应温度为60-80℃，反应时间为1-8小时。
根据本发明优选的，步骤(1)所述醇与L-谷氨酸的质量比为8:1至30:1。上述C 1-6的饱和脂肪醇选自甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、正戊醇、异戊醇、叔戊醇、己醇；上述取代的C 6-9的芳醇或烷基取代芳醇，选自苄醇、邻甲基苄醇、对甲基苄醇。
步骤(2)所述加入与步骤(1)相同的醇是指醇的种类及质量和步骤(1)相同。
根据本发明优选的，步骤(2)所述碱为无机碱或有机碱，无机碱选自碳酸钾、碳酸钠、碳酸钙、碳酸氢钾、碳酸氢钠、碳酸氢钙、醋酸钾、醋酸钠、醋酸钙之一或组合，有机碱选自三甲胺、三乙胺、三正丁胺之一或组合；
根据本发明优选的，步骤(2)所述2-卤代乙酸酯为2-氯乙酸甲酯、2-溴乙酸甲酯、2-碘乙酸甲酯、2-碘乙酸甲酯、2-氯乙酸乙酯、2-溴乙酸乙酯、2-碘乙酸乙酯、2-碘乙酸乙酯、2-氯乙酸苄酯、2-溴乙酸苄酯、2-碘乙酸苄酯、2-碘乙酸苄酯；
根据本发明优选的，步骤(2)所述N-保护试剂为氯苄、溴苄、苯甲酰氯、氯甲酸甲酯、氯甲酸乙酯、氯甲酸叔丁酯、氯甲酸苄酯、氯甲酸-9-芴基甲酯、二碳酸二叔丁酯；
根据本发明优选的，步骤(2)中，2-卤代乙酸酯、N-保护试剂、碱和L-谷氨酸的摩尔比为(1.0-2.0)：(1.0-2.0)：(2.0-4.0):1；优选反应温度为40-70℃，两次取代反应时间均为1-5小时。
根据本发明优选的，步骤(3)中，所述强碱为氢化钠、甲醇钠、乙醇钠、叔丁醇钠、叔丁醇钾或苄醇钠；进一步优选所述强碱和化合物IV的摩尔比为(1.0-2.0):1。
根据本发明优选的，途径1的详细步骤描述如下：
根据本发明优选的，步骤(1.1)中所述化合物V经过脱N-保护基，得到化合物VI，根据N-保护基的不同，可以选择以下方式脱N-保护基；当N-保护基为苄基时，采用催化氢解脱苄基；当N-保护基为苯甲酰基或烷氧羰基时，采用碱性条件下水解脱相应N-保护基；优选的，步骤(1.1)中所述催化氢解所用催化剂为钯炭或兰尼镍，优选的钯炭催化剂用量为化合物V质量的0.5％-5％，进一步优选的催化剂用量为1％-3％质量比；优选的兰尼镍催化剂 用量为化合物V质量的1％-20％，进一步优选的催化剂用量为5％-10％质量比。优选的，步骤(1.1)所述的溶剂为甲醇、乙醇、丙醇、丁醇、乙酸乙酯、四氢呋喃、乙腈中的一种或其混合溶剂，进一步优选的所述溶剂与化合物V的质量比为4:1至15:1；优选的步骤(1.1)中氢气压力为0.1-1.0MPa，反应温度为20-85℃，反应3-10小时。当N-保护基为苯甲酰基或烷氧羰基时，采用碱性条件下水解脱相应N-保护基；优选的，步骤(1.1)中所述碱为氢氧化钾、氢氧化钠、氢氧化锂；碱和化合物V摩尔比(2.0-3.0):1；优选的，步骤(1.1)所述的溶剂为水、甲醇、乙醇、丙醇、丁醇、乙酸乙酯、四氢呋喃、乙腈中的一种或其混合溶剂，进一步优选的所述溶剂与化合物V的质量比为3:1至15:1；优选的步骤(1.1)中水解反应温度为10-100℃，反应2-10小时。
根据本发明优选的，步骤(1.2)中所述溶剂所述的溶剂为甲醇、乙醇、丙醇、丁醇、乙酸乙酯、四氢呋喃、乙腈中的一种或其混合溶剂，进一步优选的所述溶剂与化合物VI的质量比为3:1至15:1；
根据本发明优选的，步骤(1.2)中，所述苄氧胺盐酸盐和化合物VI的摩尔比为0.9-1.5:1；优选反应温度为10-80℃，反应时间为2-5小时。
根据本发明优选的，步骤(1.3)中，所述浓硫酸为质量分数95-98％的硫酸，该浓硫酸与化合物VII的摩尔比为(3.0-6.0)：1，最优选所述浓硫酸为质量分数98％的硫酸。
根据本发明优选的，步骤(1.3)中，乙酸乙酯与化合物VII的质量比为5-20:1；进一步优选乙酸乙酯与化合物VII的质量比为10-14:1。
根据本发明优选的，步骤(1.3)中，所述还原剂为硼氢化钠、三氰基硼氢化钠、三乙酰氧基硼氢化钠、三丙酰氧基硼氢化钠、硼氢化钾、三氰基硼氢化钾、三乙酰氧基硼氢化钾或三丙酰氧基硼氢化钾。所述还原剂与化合物VII的摩尔比为(2.0-4.0)：1。
根据本发明优选的，步骤(1.4)中，所得5R-苄氧氨基哌啶-2S-甲酸酯草酸盐于溶剂中，经碱中和，得到5R-苄氧氨基哌啶-2S-甲酸酯(II a)。
根据本发明优选的，步骤(1.4)中所述溶剂为乙酸乙酯、二氯甲烷、氯仿、1,2-二氯乙烷、苯、甲苯或其混合物；优选所述溶剂与化合物II b的质量比为4:1至12:1。
根据本发明优选的，步骤(1.4)中所述碱为碳酸钾、碳酸钠、碳酸钙、碳酸氢钾、碳酸氢钠、碳酸氢钙、氨水之一或组合；优选所述碱和5R-苄氧氨基哌啶-2S-甲酸酯草酸盐的摩尔比为(1.5-3.0):1。
根据本发明优选的，步骤(1.4)中，所述中和反应温度为10-40℃，反应时间为2-5小时。
根据本发明优选的，步骤(1.5)中，所得5R-苄氧氨基哌啶-2S-甲酸酯(II a)于溶剂中，经碱水解，得到5R-苄氧氨基哌啶-2S-甲酸(II b)。
根据本发明优选的，步骤(1.5)中所述溶剂为水、乙酸乙酯、二氯甲烷、氯仿、1,2-二 氯乙烷、苯、甲苯或其混合物；优选所述溶剂与化合物IIa的质量比为4:1至12:1。
根据本发明优选的，步骤(1.5)中所述碱为氢氧化钠、氢氧化钾、氢氧化锂、碳酸钾、碳酸钠、碳酸钙、碳酸氢钾、碳酸氢钠之一或组合；优选所述碱和5R-苄氧氨基哌啶-2S-甲酸酯(II a)的摩尔比为(1.5-3.0):1。
根据本发明优选的，步骤(1.5)中，所述水解反应温度为10-80℃，反应时间为2-5小时。
Figure PCTCN2018078072-appb-000005
根据本发明优选的，途径2的详细步骤描述如下：
根据本发明优选的，步骤(2.1)中，所述化合物V于溶剂中，经碱水解，得到化合物Ⅷ，N-保护基哌啶-5-酮-2S-甲酸(VIII)；
根据本发明优选的，步骤(2.1)中所述溶剂为水、乙酸乙酯、二氯甲烷、氯仿、1,2-二氯乙烷、苯、甲苯或其混合物；优选所述溶剂与化合物V的质量比为4:1至12:1。
根据本发明优选的，步骤(2.1)中所述碱为氢氧化钠、氢氧化钾、氢氧化锂、碳酸钾、碳酸钠、碳酸钙、碳酸氢钾、碳酸氢钠之一或组合；优选所述碱和化合物V的摩尔比为(1.5-3.0):1。
根据本发明优选的，步骤(2.1)中，所述水解反应温度为10-80℃，反应时间为2-5小时。
根据本发明优选的，步骤(2.2)中所述得到化合物Ⅷ经过脱N-保护基得到化合物IX，即哌啶-5-酮-2S-甲酸(IX)；根据N-保护基的不同，可以选择以下方式脱N-保护基；当N-保护基为苄基时，采用催化氢解脱苄基；当N-保护基为苯甲酰基或烷氧羰基时，采用碱性条件下水解脱相应N-保护基；优选的，步骤(2.2)中所述催化氢解所用催化剂为钯炭或兰尼镍，优选的钯炭催化剂用量为化合物Ⅷ质量的0.5％-5％，进一步优选的催化剂用量为1％-3％质量比；优选的兰尼镍催化剂用量为化合物Ⅷ质量的1％-20％，进一步优选的催化剂用量为5％-10％质量比。优选的，步骤(1.1)所述的溶剂为甲醇、乙醇、丙醇、丁醇、乙酸乙酯、四氢呋喃、乙腈中的一种或其混合溶剂，进一步优选的所述溶剂与化合物Ⅷ的质量比为4:1至15:1；优选的步骤(1.1)中氢气压力为0.1-1.0MPa，反应温度为20-85℃，反应3-10小时。当N-保护基为苯甲酰基或烷氧羰基时，采用碱性条件下水解脱相应N-保护基；优选的，步骤(1.1)中所述碱为氢氧化钾、氢氧化钠、氢氧化锂；碱和化合物Ⅷ摩尔比(2.0-3.0):1；优 选的，步骤(1.1)所述的溶剂为水、甲醇、乙醇、丙醇、丁醇、乙酸乙酯、四氢呋喃、乙腈中的一种或其混合溶剂，进一步优选的所述溶剂与化合物VIII的质量比为3:1至15:1；优选的步骤(1.1)中水解反应温度为10-100℃，反应2-10小时。
根据本发明优选的，步骤(2.3)中所述溶剂所述的溶剂为甲醇、乙醇、丙醇、丁醇、乙酸乙酯、四氢呋喃、乙腈中的一种或其混合溶剂，进一步优选的所述溶剂与化合物IX的质量比为3:1至15:1；
根据本发明优选的，步骤(2.3)中，所述苄氧胺盐酸盐和化合物IX的摩尔比为0.9-1.5:1；优选反应温度为10-80℃，反应时间为2-5小时。
根据本发明优选的，步骤(2.4)中，所述浓硫酸为质量分数95-98％的硫酸，该浓硫酸与化合物Ⅹ的摩尔比为(3.0-6.0)：1，最优选所述浓硫酸为质量分数98％的硫酸。
根据本发明优选的，步骤(2.4)中，乙酸乙酯与化合物Ⅹ的质量比为5-20:1；进一步优选乙酸乙酯与化合物Ⅹ的质量比为10-14:1。
根据本发明优选的，步骤(2.4)中，所述还原剂为硼氢化钠、三氰基硼氢化钠、三乙酰氧基硼氢化钠、三丙酰氧基硼氢化钠、硼氢化钾、三氰基硼氢化钾、三乙酰氧基硼氢化钾或三丙酰氧基硼氢化钾。所述还原剂与化合物Ⅹ的摩尔比为(2.0-4.0)：1。
根据本发明优选的，途径3的详细步骤描述如下：
根据本发明优选的，步骤(3.1)中所述所得化合物V于溶剂和碱存在下，和苄氧基氨盐酸盐缩合得到化合物XI，N-保护基-5-苄氧亚氨基哌啶-2S-甲酸酯(XI)；
根据本发明优选的，步骤(3.1)中所述的溶剂为甲醇、乙醇、丙醇、丁醇、乙酸乙酯、四氢呋喃、乙腈、二氯甲烷、氯仿、1,2-二氯乙烷、苯、甲苯中的一种或其混合溶剂，进一步优选的所述溶剂与化合物V的质量比为3:1至15:1；
根据本发明优选的，步骤(3.1)中所述碱为有机碱三乙胺、三正丁胺、二异丙基乙胺、吡啶或无机碱碳酸钾、碳酸钠中的一种或其混合物，碱与化合物V的摩尔比为(1.0-2.0)；1；
根据本发明优选的，步骤(3.1)中，所述苄氧胺盐酸盐和化合物V的摩尔比为0.9-1.5:1；优选反应温度为10-80℃，反应时间为2-5小时。
根据本发明优选的，步骤(3.2)中，所述化合物XI在浓硫酸存在下，于乙酸乙酯中，经还原剂还原、添加草酸进行反应并进行手性拆分得到化合物XII，N-保护基-5R-苄氧氨基哌啶-2S-甲酸酯(XII)；
根据本发明优选的，步骤(3.2)中，所述浓硫酸为质量分数95-98％的硫酸，该浓硫酸与化合物XI的摩尔比为(3.0-6.0)：1，最优选所述浓硫酸为质量分数98％的硫酸。
根据本发明优选的，步骤(3.2)中，乙酸乙酯与化合物XI的质量比为5-20:1；进一步优选乙酸乙酯与化合物XI的质量比为10-14:1。
根据本发明优选的，步骤(3.2)中，所述还原剂为硼氢化钠、三氰基硼氢化钠、三乙酰 氧基硼氢化钠、三丙酰氧基硼氢化钠、硼氢化钾、三氰基硼氢化钾、三乙酰氧基硼氢化钾或三丙酰氧基硼氢化钾。所述还原剂与化合物XI的摩尔比为(2.0-4.0)：1。
根据本发明优选的，步骤(3.3)中所得化合物XII经过脱N-保护剂、中和得到5R-苄氧氨基哌啶-2S-甲酸酯(II a)；
根据本发明优选的，步骤(3.3)中所述化合物XII经过脱N-保护基、中和得到化合物IIa，根据N-保护基的不同，可以选择以下方式脱N-保护基；当N-保护基为苄基时，采用催化氢解脱苄基；当N-保护基为苯甲酰基或烷氧羰基时，采用碱性条件下水解脱相应N-保护基；优选的，步骤(3.3)中所述催化氢解所用催化剂为钯炭或兰尼镍，优选的钯炭催化剂用量为化合物XII质量的0.5％-5％，进一步优选的催化剂用量为1％-3％质量比；优选的兰尼镍催化剂用量为化合物XII质量的1％-20％，进一步优选的催化剂用量为5％-10％质量比。优选的，步骤(3.3)所述的溶剂为甲醇、乙醇、丙醇、丁醇、乙酸乙酯、四氢呋喃、乙腈中的一种或其混合溶剂，进一步优选的所述溶剂与化合物XII的质量比为4:1至15:1；优选的步骤(3.3)中氢气压力为0.1-1.0MPa，反应温度为20-85℃，脱保护、中和反应时间共3-10小时。当N-保护基为苯甲酰基或烷氧羰基时，采用碱性条件下水解脱相应N-保护基；优选的，步骤(3.3)中所述碱为氢氧化钾、氢氧化钠、氢氧化锂；碱和化合物XII摩尔比(2.0-3.0):1；优选的，步骤(3.3)所述的溶剂为水、甲醇、乙醇、丙醇、丁醇、乙酸乙酯、四氢呋喃、乙腈中的一种或其混合溶剂，进一步优选的所述溶剂与化合物XII的质量比为3:1至15:1；优选的步骤(1.1)中水解反应温度为10-100℃，反应2-10小时。
根据本发明优选的，步骤(3.4)利用所得5R-苄氧氨基哌啶-2S-甲酸酯(II a)于溶剂中经过水解、酸化得到5R-苄氧氨基哌啶-2S-甲酸(II b)；
根据本发明优选的，步骤(3.4)中所述溶剂为水、乙酸乙酯、二氯甲烷、氯仿、1,2-二氯乙烷、苯、甲苯或其混合物；优选所述溶剂与化合物IIa的质量比为4:1至12:1。
根据本发明优选的，步骤(3.4)中所述碱为氢氧化钠、氢氧化钾、氢氧化锂、碳酸钾、碳酸钠、碳酸钙、碳酸氢钾、碳酸氢钠之一或组合；优选所述碱和化合物IIa的摩尔比为(1.5-3.0):1。
根据本发明优选的，步骤(3.4)中，所述水解反应温度为10-80℃，反应时间为2-5小时。
根据目的产物以及保护基的不同，可以选择不同途径制备所需目的产物。
由本发明制备的5R-苄氧氨基哌啶-2S-甲酸酯草酸盐(II c)、5R-苄氧氨基哌啶-2S-甲酸酯(II a)或5R-苄氧氨基哌啶-2S-甲酸(II b)为原料，可按照已知方法制备阿维巴坦(I a)和瑞利巴坦(I b)。以5R-苄氧氨基哌啶-2S-甲酸酯为例，反应式通式如下(反应路线4)：
Figure PCTCN2018078072-appb-000006
本发明的技术特点和优良效果：
1、本发明涉及一种5R-苄氧氨基哌啶-2S-甲酸酯(II a)、5R-苄氧氨基哌啶-2S-甲酸酯草酸盐(II c)、5R-苄氧氨基哌啶-2S-甲酸(II b)的绿色制备方法。本发明开发设计了一种新的制备5R-苄氧氨基哌啶-2S-甲酸及其衍生物的制备方法，以L-谷氨酸为初始原料，价廉易得，所涉及各步反应类型经典，反应条件易于控制，可操作性强，工艺简洁，原子经济性高，总收率可达60.0％以上，相对于现有技术提高了0.5倍-3倍，所得产品纯度高，成本低。
2、本发明的方法和现有技术相比，所用溶剂易于回收，减少了废液排放，工艺绿色环保。
3、利用本发明所得5R-苄氧氨基哌啶-2S-甲酸酯(II a)、5R-苄氧氨基哌啶-2S-甲酸酯草酸盐(II c)、5R-苄氧氨基哌啶-2S-甲酸(II b)可制备阿维巴坦(Ia)和瑞利巴坦(I b)。
附图说明
图1为本发明实施例18所得产品的核磁氢谱图。
图2为本发明实施例18所得产品的核磁碳谱图。
具体实施方式
以下所述的实施例对本发明的技术方案进行了详细完整的说明，但是本发明不仅限于以下实施例。基于本发明的实施例，任何本领域技术人员结合本技术方案衍生出的任何不具备 创造性的方案或实施例，或基于本发明方案的任何不具备创造性的实施顺序的变化，均属于本发明的保护范围。
实施例中的％均为质量百分比，有特别说明的除外。
利用气相或液相色谱仪监控反应过程和产品纯度，利用配有手性柱(ES-OVS，150mm×4.6mm，安捷伦公司)的液相色谱仪检测光学纯度(面积比％)，并计算收率和e.e％值。
实施例1：N-苄基-N-甲氧羰基甲基-L-谷氨酸二甲酯(IV 1)的制备
向装有搅拌、温度计和回流冷凝管(连接30％氢氧化钠水溶液吸收装置)的500毫升四口烧瓶中加入300克甲醇，14.7克(0.10摩尔)L-谷氨酸，30.0克(0.25摩尔)氯化亚砜，加热，60～63℃反应7小时，冷却至20～25℃，氮气置换体系中的氯化氢气体，置换30分钟后，蒸馏回收过量的氯化亚砜和甲醇，然后向剩余物中加入300克新鲜甲醇。再加入41.5克(0.30摩尔)碳酸钾，11.0克(0.10摩尔)2-氯乙酸甲酯，40～45℃搅拌反应4小时后，再加入13.0克(0.10摩尔)氯苄，40～45℃搅拌反应4小时，反应完毕，趁热过滤，滤饼用甲醇洗涤两次，每次50克，合并滤液，常压蒸馏回收甲醇后，减压蒸馏得到31.2克无色透明液体N-苄基-N-甲氧羰基甲基-L-谷氨酸二甲酯，GC纯度99.6％,收率为92.6％。
实施例2：N-苄基-N-乙氧羰基甲基-L-谷氨酸二乙酯(IV 2)的制备
向装有搅拌、温度计和回流冷凝管(连接30％氢氧化钠水溶液吸收装置)的500毫升四口烧瓶中加入300克乙醇，14.7克(0.10摩尔)L-谷氨酸，25.0克(0.08摩尔)固体光气，加热，70～75℃反应5小时，冷却至20～25℃，氮气置换体系中的氯化氢气体，置换30分钟后。蒸馏回收过量的三光气和乙醇，然后向剩余物中加入300克新鲜乙醇。再加入41.5克(0.30摩尔)碳酸钾，17.5克(0.10摩尔)溴苄，30～35℃搅拌反应4小时后，再加入18.5克(0.11摩尔)2-溴乙酸乙酯，40～45℃搅拌反应4小时，反应完毕，趁热过滤，滤饼用乙醇洗涤两次，每次50克，合并滤液，常压蒸馏回收乙醇后，减压蒸馏得到36.0克无色透明液体N-苄基-N-乙氧羰基甲基-L-谷氨酸二乙酯，GC纯度99.8％,收率为95.0％。
实施例3：N-苄基-N-苄氧羰基甲基-L-谷氨酸二苄酯(IV 3)的制备
向装有搅拌、温度计和回流冷凝管(连接30％氢氧化钠水溶液吸收装置)的500毫升四口烧瓶中加入280克苄醇，14.7克(0.10摩尔)L-谷氨酸，36.0克(0.30摩尔)氯化亚砜，加热，80～85℃反应5小时，冷却至20～25℃，氮气置换体系中的氯化氢气体，置换30分钟后。蒸馏回收过量的氯化亚砜和苄醇，然后向剩余物中加入280克新鲜苄醇。再加入41.5克(0.30摩尔)碳酸钾，19.5克(0.11摩尔)2-氯乙酸苄酯，50～55℃搅拌反应4小时后，再加入17.5克(0.10摩尔)溴苄，40～45℃搅拌反应4小时，反应完毕，趁热过滤，滤饼用苄醇洗涤两次，每次80克，合并滤液，常压蒸馏回收苄醇后，减压蒸馏得到53.5克淡黄色透明液体N-苄基-N-苄氧羰基甲基-L-谷氨酸二苄酯，GC纯度99.5％,收率为94.7％。
实施例4：N-苯甲酰基-N-甲氧羰基甲基-L-谷氨酸二甲酯(IV 4)的制备
向装有搅拌、温度计和回流冷凝管(连接30％氢氧化钠水溶液吸收装置)的500毫升四口烧瓶中加入300克甲醇，14.7克(0.10摩尔)L-谷氨酸，35.0克(0.23摩尔)氯化亚砜，加热，60～63℃反应7小时，冷却至20～25℃，氮气置换体系中的氯化氢气体，置换30分钟后，蒸馏回收过量的氯化亚砜和甲醇，然后向剩余物中加入300克新鲜甲醇。再加入41.5克(0.30摩尔)碳酸钾，11.0克(0.10摩尔)2-氯乙酸甲酯，40～45℃搅拌反应4小时后，再加入15.0克(0.10摩尔)苯甲酰氯，40～45℃搅拌反应5小时，反应完毕，趁热过滤，滤饼用甲醇洗涤两次，每次50克，合并滤液，常压蒸馏回收甲醇后，减压蒸馏得到32.1克淡黄色透明液体N-苯甲酰基-N-甲氧羰基甲基-L-谷氨酸二甲酯，GC纯度99.5％,收率为91.5％。
实施例5：N-苄基哌啶-5-酮-2S-甲酸甲酯(V 1)的制备
向装有搅拌、温度计的500毫升四口烧瓶中加入200克四氢呋喃，6.0克(0.11摩尔)甲醇钠，冷却至-5～0℃，并于该温度下滴加33.7克(0.10摩尔)N-苄基-N-甲氧羰基甲基-L-谷氨酸二甲酯(由实施例1制备)，滴毕，20～25℃搅拌反应4小时，过滤，滤饼用四氢呋喃洗涤两次，每次50克，合并滤液，常压蒸馏回收四氢呋喃后，向所得固体中加入100克水，15克30％盐酸，200克1,2-二氯乙烷，20～25℃搅拌反应2小时，分层，水层用1,2-二氯乙烷萃取，每次50克，合并有机层，常压蒸馏回收溶剂后，减压蒸馏得到22.5克无色透明液体N-苄基哌啶-5-酮-2S-甲酸甲酯，GC纯度99.8％,收率为91.1％。
实施例6：N-苄基哌啶-5-酮-2S-甲酸乙酯(V 2)的制备
向装有搅拌、温度计的500毫升四口烧瓶中加入200克四氢呋喃，7.5克(0.11摩尔)乙醇钠，冷却至-5～0℃，并于该温度下滴加38.0克(0.10摩尔)N-苄基-N-乙氧羰基甲基-L-谷氨酸二乙酯(由实施例2制备)，滴毕，20～25℃搅拌反应4小时，过滤，滤饼用四氢呋喃洗涤两次，每次50克，合并滤液，常压蒸馏回收四氢呋喃后，向所得固体中加入100克水，15克30％盐酸，200克1,2-二氯乙烷，20～25℃搅拌反应2小时，分层，水层用1,2-二氯乙烷萃取，每次50克，合并有机层，常压蒸馏回收溶剂后，减压蒸馏得到24.4克无色透明液体N-苄基哌啶-5-酮-2S-甲酸乙酯，GC纯度99.7％,收率为93.5％。
实施例7：N-苄基哌啶-5-酮-2S-甲酸苄酯(V 3)的制备
向装有搅拌、温度计的500毫升四口烧瓶中加入250克四氢呋喃，4.1克(0.1摩尔)60％氢化钠，冷却至-5～0℃，并于该温度下滴加56.5克(0.10摩尔)N-苄基-N-苄氧羰基甲基-L-谷氨酸二苄酯(由实施例3所述方法制备)，滴毕，20～25℃搅拌反应5小时，过滤，滤饼用四氢呋喃洗涤两次，每次50克，合并滤液，常压蒸馏回收四氢呋喃后，向所得固体中加入100克水，15克30％盐酸，200克1,2-二氯乙烷，20～25℃搅拌反应3小时，分层，水层用1,2-二氯乙烷萃取，每次50克，合并有机层，常压蒸馏回收1,2-二氯乙烷和苄醇后，减压蒸馏得到30.6克淡黄色透明液体N-苄基哌啶-5-酮-2S-甲酸苄酯，GC纯度99.6％,收率为93.5％。
实施例8：哌啶-5-酮-2S-甲酸甲酯(VI 1)的制备
向500毫升不锈钢压力釜中，加入24.7克(0.10摩尔)N-苄基哌啶-5-酮-2S-甲酸甲酯(由实施例5制得)，200克甲醇，0.3克5％钯碳催化剂，氮气置换三次后，通入氢气，保持氢气压力为0.2-0.3MPa，40-45℃反应5小时。冷却至20-25℃，氮气置换三次后，过滤除去钯碳，滤液浓缩回收甲醇、甲苯后，减压蒸馏得到15.1克淡黄色液体哌啶-5-酮-2S-甲酸甲酯，气相纯度99.8％，产品收率96.2％。
实施例9：哌啶-5-酮-2S-甲酸乙酯(VI 2)的制备
向500毫升不锈钢压力釜中，加入26.1克(0.10摩尔)N-苄基哌啶-5-酮-2S-甲酸乙酯(由实施例6制得)，160克乙醇，1.5克50％兰尼镍催化剂，氮气置换三次后，通入氢气，保持氢气压力为0.1-0.3MPa，50-55℃反应5小时。冷却至20-25℃，氮气置换三次后，过滤除去催化剂，滤液浓缩回收乙醇、甲苯后，减压蒸馏得到16.5克淡黄色液体哌啶-5-酮-2S-甲酸乙酯，气相纯度99.9％，产品收率96.5％。
实施例10：哌啶-5-酮-2S-甲酸(IX)的制备
向500毫升不锈钢压力釜中，加入32.3克(0.10摩尔)N-苄基哌啶-5-酮-2S-甲酸苄酯(由实施例7制得)，200克甲醇，0.4克5％钯碳催化剂，氮气置换三次后，通入氢气，保持氢气压力为0.2-0.3MPa，40-45℃反应6小时。冷却至20-25℃，氮气置换三次后，过滤除去钯碳，滤液浓缩回收甲醇、甲苯后，得到14.0克淡黄色液体哌啶-5-酮-2S-甲酸，液相纯度99.9％，产品收率97.9％。
实施例11：5-苄氧亚氨基哌啶-2S-甲酸甲酯(VII 1)的制备
向装有搅拌、温度计以及回流冷凝管的500毫升四口烧瓶中分别加入220克乙酸乙酯，25.0克(0.16摩尔)哌啶-5-酮-2S-甲酸甲酯(由实施例8所述方法制得)，27.0克(0.17摩尔)苄氧胺盐酸盐，18.2克(0.18摩尔)三乙胺。50-55℃搅拌反应4小时，冷却，加入100克水，分层，有机层用饱和食盐水洗涤两次，每次25克。有机相回收溶剂后，减压蒸馏得到41.3克淡黄色透明液体5-苄氧亚氨基哌啶-2S-甲酸甲酯，GC纯度98.9％,收率为98.5％。
实施例12：5-苄氧亚氨基哌啶-2S-甲酸乙酯(VII 2)的制备
向装有搅拌、温度计以及回流冷凝管的500毫升四口烧瓶中分别加入250克1,2-二氯乙烷，26.0克(0.15摩尔)哌啶-5-酮-2S-甲酸乙酯(由实施例9制得)，26.0克(0.16摩尔)苄氧胺盐酸盐，17.2克(0.17摩尔)三乙胺。50-55℃搅拌反应4小时，冷却，加入100克水，分层，有机层用饱和食盐水洗涤两次，每次25克。有机相回收溶剂后，减压蒸馏得到40.8克淡黄色透明液体5-苄氧亚氨基哌啶-2S-甲酸乙酯，GC纯度98.8％,收率为98.5％。
实施例13：5-苄氧亚氨基哌啶-2S-甲酸(Ⅹ)的制备
向装有搅拌、温度计以及回流冷凝管的500毫升四口烧瓶中分别加入150克乙酸乙酯，14.3克(0.10摩尔)哌啶-5-酮-2S-甲酸(由实施例10方法制得)，19.0克(0.12摩尔)苄氧胺盐酸盐，15.5克(0.15摩尔)三乙胺。60-65℃搅拌反应4小时，冷却，加入100克水，分层， 有机层用饱和食盐水洗涤两次，每次25克。有机相回收溶剂后，得到24.7克淡黄色固体粉末5-苄氧亚氨基哌啶-2S-甲酸，HPLC纯度99.6％,收率为99.5％。
实施例14：5R-苄氧氨基哌啶-2S-甲酸甲酯(II a1)的制备
向装有搅拌、温度计的500毫升四口烧瓶中加入200克乙酸乙酯，加入21.0g(0.08摩尔)5-苄氧亚氨基哌啶-2S-甲酸甲酯(VII 1，由实施例11所述方法制得)。在-20℃下，滴加40.3克浓硫酸(0.40摩尔)，滴毕，搅拌1小时。
于-20℃下，加入38.0克(0.18摩尔)三乙酰氧基硼氢化钠，-20℃至-15℃搅拌反应5小时。保持温度10℃以下，加入100克水淬灭反应；用氨水中和。分层，饱和食盐水洗涤有机层两次，每次25克。有机相浓缩回收溶剂，然后向所得剩余物中加入80克乙酸乙酯，40克甲醇，10.4克(0.08摩尔)草酸二水合物，加热至45℃，搅拌1小时后，冷却，过滤。先用60克乙酸乙酯/甲醇(2:1)混合液洗涤滤饼，再以50克乙酸乙酯洗涤。真空干燥，得到18.0克单一异构体5R-苄氧氨基哌啶-2S-甲酸甲酯，手性HPLC纯度99.5％,收率为63.5％，以L-谷氨酸计总收率为50.0％。
实施例15：5R-苄氧氨基哌啶-2S-甲酸乙酯(II a2)的制备
向装有搅拌、温度计的500毫升四口烧瓶中加入200克乙酸乙酯，加入22.0g(0.08摩尔)5-苄氧亚氨基哌啶-2S-甲酸乙酯(VII 2，由实施例12所述方法制得)，在-20℃下，滴加40.3克浓硫酸(0.40摩尔)，滴毕，搅拌1小时。
于-20℃下，加入38.0克(0.18摩尔)三乙酰氧基硼氢化钠，-20℃至-15℃搅拌反应5小时。保持温度10℃以下，加入100克水淬灭反应；用氨水中和。分层，饱和食盐水洗涤有机层两次，每次25克。有机相浓缩回收溶剂，然后向所得剩余物中加入80克乙酸乙酯，40克甲醇，10.4克(0.08摩尔)草酸二水合物，加热至45℃，搅拌1小时后，冷却，过滤。先用60克乙酸乙酯/甲醇(2:1)混合液洗涤滤饼，再以50克乙酸乙酯洗涤。真空干燥，得到19.3克单一异构体5R-苄氧氨基哌啶-2S-甲酸乙酯，手性HPLC纯度99.6％,收率为65.4％，以L-谷氨酸计总收率为54.7％。
实施例16：5R-苄氧氨基哌啶-2S-甲酸甲酯(II a1)的制备
向装有搅拌、温度计的500毫升四口烧瓶中加入300克乙酸乙酯，42.5g(0.12摩尔)5R-苄氧氨基哌啶-2S-甲酸甲酯(由实施例14所述方法制得)，100克(0.24摩尔)20％的碳酸氢钠溶液，30-35℃搅拌反应2小时。分层，水层以乙酸乙酯萃取两次，每次60克。合并有机层，饱和氯化钠溶液洗涤两次，每次50克。所得有机相回收溶剂后，减压蒸馏得到30.8克浅黄色的黏性油状物5R-苄氧氨基哌啶-2S-甲酸甲酯，GC纯度99.8％,收率为97.3％。
实施例17：5R-苄氧氨基哌啶-2S-甲酸乙酯(II a2)的制备
向装有搅拌、温度计的500毫升四口烧瓶中加入300克乙酸乙酯，44.0g(0.12摩尔)5R-苄氧氨基哌啶-2S-甲酸乙酯(由实施例15所述方法制得)，100克(0.24摩尔)20％的碳酸氢 钠溶液，20-25℃搅拌反应2小时。分层，水层以乙酸乙酯萃取两次，每次60克。合并有机层，饱和氯化钠溶液洗涤两次，每次50克。所得有机相回收溶剂后，减压蒸馏得到32.3克浅黄色的黏性油状物5R-苄氧氨基哌啶-2S-甲酸乙酯，GC纯度99.5％,收率为96.8％。
实施例18：5R-苄氧氨基哌啶-2S-甲酸(II b)的制备
向装有搅拌、温度计的500毫升四口烧瓶中加入100克水，100克甲醇，31.7克(0.12摩尔)5R-苄氧氨基哌啶-2S-甲酸甲酯(由实施例16所述方法制得)，30克(0.15摩尔)20％的氢氧化钠水溶液，30-35℃搅拌反应3小时，水解反应完成后，用30％盐酸酸化pH值为6.0-7.0，过滤，干燥得到29.3克白色粉末固体5R-苄氧氨基哌啶-2S-甲酸，HPLC纯度99.8％,收率为97.5％。
所得产品核磁数据如下： 1HNMR(400MHz，DMSO-d 6)δ：1.26(m，1H)，1.45(q，1H)，1.80(m，1H)，2.11(m,1H)，3.03(m，2H)，3.20(d，1H)，4.58(s，2H)，6.77(d,1H)，7.29-7.37(m,5H)。
13C-NMR(400MHz，DMSO-d 6)δ：25.96，26.94，46.11，54.40，59.37，76.36，127.99，128.54，128.63，138.54，169.36。
实施例19：5R-苄氧氨基哌啶-2S-甲酸(II b)的制备
向装有搅拌、温度计的500毫升四口烧瓶中加入100克水，50克乙醇，27.8克(0.10摩尔)5R-苄氧氨基哌啶-2S-甲酸乙酯(由实施例17所述方法制得)，24克(0.12摩尔)20％的氢氧化钠水溶液，40-45℃搅拌反应3小时，水解反应完成后，用30％盐酸酸化pH值为2.5-3.0，过滤，干燥得到24.5克浅黄色粉末固体5R-苄氧氨基哌啶-2S-甲酸，HPLC纯度99.9％,收率为98.0％。
实施例20：5R-苄氧氨基哌啶-2S-甲酸(II b)的制备
向装有搅拌、温度计的500毫升四口烧瓶中加入100克水，100克甲醇，35.5克(0.10摩尔)5R-苄氧氨基哌啶-2S-甲酸甲酯(由实施例14所述方法制得)，80克(0.40摩尔)20％的氢氧化钠水溶液，30-35℃搅拌反应4小时，水解反应完成后，用30％盐酸酸化pH值为2.5-3.0，过滤，干燥得到24.3克浅黄色粉末固体5R-苄氧氨基哌啶-2S-甲酸，HPLC纯度99.8％,收率为97.2％。
实施例21：N-苄基哌啶-5-酮-2S-甲酸(Ⅷ 1)的制备
向装有搅拌、温度计的500毫升四口烧瓶中加入100克水，100克甲醇，24.7克(0.10摩尔)N-苄基哌啶-5-酮-2S-甲酸甲酯(由实施例5所述方法制得)，24克(0.12摩尔)20％的氢氧化钠水溶液，40-45℃搅拌反应4小时，水解反应完成后，用30％盐酸酸化pH值为2.5-3.0，过滤，干燥得到22.9克浅黄色粉末固体N-苄基哌啶-5-酮-2S-甲酸，HPLC纯度99.7％,收率为98.3％。
实施例22：哌啶-5-酮-2S-甲酸(IX)的制备
向500毫升不锈钢压力釜中，加入23.3克(0.10摩尔)N-苄基哌啶-5-酮-2S-甲酸(由 实施例21方法制得)，120克甲醇，0.3克5％钯碳催化剂，氮气置换三次后，通入氢气，保持氢气压力为0.1-0.3MPa，40-45℃反应5小时。冷却至20-25℃，氮气置换三次后，过滤除去钯碳，滤液浓缩回收甲醇、甲苯后，得到14.1克淡黄色液体哌啶-5-酮-2S-甲酸，液相纯度99.9％，产品收率98.6％。
实施例23：5R-苄氧氨基哌啶-2S-甲酸(II b)的制备
向装有搅拌、温度计的500毫升四口烧瓶中加入150克乙酸乙酯，加入20.0g(0.08摩尔)5-苄氧亚氨基哌啶-2S-甲酸(由实施例13方法制得)，在-20℃下，滴加40.3克浓硫酸(0.40摩尔)，滴毕，搅拌1小时。
于-20℃下，加入38.0克(0.18摩尔)三乙酰氧基硼氢化钠，-20℃至-15℃搅拌反应5小时。保持温度10℃以下，加入100克水淬灭反应；用氨水中和。分层，饱和食盐水洗涤有机层两次，每次25克。有机相浓缩回收溶剂，然后向所得剩余物中加入80克乙酸乙酯，40克甲醇，10.4克(0.08摩尔)草酸二水合物，加热至45℃，搅拌1小时后，冷却，过滤。先用60克乙酸乙酯/甲醇(2:1)混合液洗涤滤饼，再以50克乙酸乙酯洗涤。将所得滤饼加入至另一500毫升四口烧瓶中，加入100克水，100克甲醇，80克(0.4摩尔)20％的氢氧化钠水溶液，30-35℃搅拌反应4小时，水解反应完成后，用30％盐酸酸化pH值为2.5-3.0，过滤，干燥得到13.5克浅黄色粉末固体5R-苄氧氨基哌啶-2S-甲酸，HPLC纯度99.6％,收率为67.5％。
实施例24：N-苄基-5-苄氧亚氨基哌啶-2S-甲酸甲酯(XI 1)的制备
向装有搅拌、温度计以及回流冷凝管的500毫升四口烧瓶中分别加入180克乙酸乙酯，24.7克(0.10摩尔)N-苄基哌啶-5-酮-2S-甲酸甲酯(由实施例5方法制得)，19.0克(0.12摩尔)苄氧胺盐酸盐，15.5克(0.15摩尔)三乙胺。60-65℃搅拌反应4小时，冷却，加入100克水，分层，有机层用饱和食盐水洗涤两次，每次25克。有机相回收溶剂后，得到35.0克淡黄色固体粉末N-苄基-5-苄氧亚氨基哌啶-2S-甲酸甲酯，HPLC纯度99.5％,收率为99.5％。
实施例25：N-苄基-5R-苄氧氨基哌啶-2S-甲酸甲酯(XII 1)的制备
向装有搅拌、温度计的500毫升四口烧瓶中加入220克乙酸乙酯，加入28.2克(0.08摩尔)N-苄基-5-苄氧亚氨基哌啶-2S-甲酸甲酯(由实施例24方法制得)，在-20℃下，滴加40.3克浓硫酸(0.4摩尔)，滴毕，搅拌1小时。
于-20℃下，加入38.0克(0.18摩尔)三乙酰氧基硼氢化钠，-20℃至-15℃搅拌反应5小时。保持温度10℃以下，加入100克水淬灭反应；用氨水中和。分层，饱和食盐水洗涤有机层两次，每次25克。有机相浓缩回收溶剂，然后向所得剩余物中加入80克乙酸乙酯，40克甲醇，10.4克(0.08摩尔)草酸二水合物，加热至45℃，搅拌1小时后，冷却，过滤。先用60克乙酸乙酯/甲醇(2:1)混合液洗涤滤饼，再以50克乙酸乙酯洗涤，干燥，得到23.2克浅黄色粉末固体N-苄基-5R-苄氧氨基哌啶-2S-甲酸甲酯，HPLC纯度99.7％,收率为65.3％。
实施例26：5R-苄氧氨基哌啶-2S-甲酸甲酯(II a1)的制备
向500毫升不锈钢压力釜中，加入50克甲醇，100克乙酸乙酯，22.2克(0.05摩尔)N-苄基-5R-苄氧氨基哌啶-2S-甲酸甲酯(由实施例25制得)，0.3克5％钯碳催化剂，氮气置换三次后，通入氢气，保持氢气压力为0.2-0.3MPa，40-45℃反应5小时。冷却至20-25℃，氮气置换三次后，过滤除去钯碳，将滤液转移至另一四口烧瓶中，加入50克(0.12摩尔)20％的碳酸氢钠水溶液，30-35℃搅拌反应3小时。分层，水层以乙酸乙酯萃取三次，每次60克。合并有机层，饱和氯化钠溶液洗涤两次，每次50克。所得有机相回收溶剂后，减压蒸馏得到12.8克浅黄色的黏性油状物5R-苄氧氨基哌啶-2S-甲酸甲酯，GC纯度99.8％,收率为97.0％。

Claims (10)

  1. 一种N-保护基哌啶-5-酮-2S-甲酸酯的制备方法，其特征在于，包括步骤：
    (1)于酸性试剂存在下，L-谷氨酸和醇经酯化反应制备化合物III，即L-谷氨酸二酯盐酸盐；
    (2)步骤(1)反应完成后，蒸馏回收过量的酸性试剂和醇，再向剩余物中加入与步骤(1)相同的醇，依次然后加入碱、2-卤代乙酸酯、N-保护试剂或碱、N-保护试剂、2-卤代乙酸酯，经两次取代反应得到化合物IV；
    (3)化合物IV在溶剂和强碱作用下，经分子内缩合成环得到化合物V，即N-保护基哌啶-5-酮-2S-甲酸酯；
    Figure PCTCN2018078072-appb-100001
  2. 一种5R-苄氧氨基哌啶-2S-甲酸或其衍生物的制备方法，5R-苄氧氨基哌啶-2S-甲酸(II b)或其衍生物为5R-苄氧氨基哌啶-2S-甲酸酯(II a)或5R-苄氧氨基哌啶-2S-甲酸酯草酸盐(II c)，其特征在于，包括步骤：
    (1)于酸性试剂存在下，L-谷氨酸和醇经酯化反应制备化合物III，即L-谷氨酸二酯盐酸盐；
    (2)步骤(1)反应完成后，蒸馏回收过量的酸性试剂和醇，再向剩余物中加入与步骤(1)相同的醇，依次然后加入碱、2-卤代乙酸酯、N-保护试剂或碱、N-保护试剂、2-卤代乙酸酯，经两次取代反应得到化合物IV；
    (3)化合物IV在溶剂和强碱作用下，经分子内缩合成环得到化合物V，即N-保护基哌啶-5-酮-2S-甲酸酯；
    所得化合物V经下列途径之一制备5R-苄氧氨基哌啶-2S-甲酸(IIb)或其衍生物，根据目标产物选择具体途径及相应步骤；途径1：化合物V脱保护基、苄氧基氨盐酸盐缩合、亚胺还原-手性拆分、中和、水解；途径2：化合物V水解、脱保护基、苄氧基氨盐酸盐缩合、亚胺还原-手性拆分、中和；途径3：化合物V和苄氧基氨盐酸盐缩合、亚胺还原-手性拆分、脱保护基、中和、水解；
    Figure PCTCN2018078072-appb-100002
  3. 根据权利要求2所述的5R-苄氧氨基哌啶-2S-甲酸或其衍生物的制备方法，其特征在于，途径1-3包括步骤：
    途径1：
    (1.1)所得化合物V经过脱N-保护基，得到化合物VI，哌啶-5-酮-2S-甲酸酯(VI)；
    (1.2)所得化合物VI于溶剂和碱存在下，和苄氧基氨盐酸盐缩合得到化合物VII；
    (1.3)所得化合物VII在浓硫酸存在下，于乙酸乙酯中，经还原剂还原、添加草酸进行反应并进行手性拆分得到5R-苄氧氨基哌啶-2S-甲酸酯草酸盐(II c)；
    (1.4)所得5R-苄氧氨基哌啶-2S-甲酸酯草酸盐经过中和，得到5R-苄氧氨基哌啶-2S-甲酸酯(II a)；
    (1.5)所得5R-苄氧氨基哌啶-2S-甲酸酯(II a)经过水解、酸化得到5R-苄氧氨基哌啶-2S-甲酸(II b)；
    途径2：
    (2.1)所得化合物V经过酯基水解，得到化合物Ⅷ，N-保护基哌啶-5-酮-2S-甲酸(VIII)；
    (2.2)化合物Ⅷ，即N-保护基哌啶-5-酮-2S-甲酸经过脱N-保护剂，得到哌啶-5-酮-2S-甲酸(IX)；
    (2.3)所得化合物哌啶-5-酮-2S-甲酸(IX)于溶剂和碱存在下，和苄氧基氨盐酸盐缩合得到5-苄氧亚氨基哌啶-2S-甲酸(X)；
    (2.4)所得化合物Ⅹ在浓硫酸存在下，于乙酸乙酯中，经还原剂还原、添加草酸进行反应并进行手性拆分、中和得到5R-苄氧氨基哌啶-2S-甲酸(II b)；
    途径3：
    (3.1)所得化合物V于溶剂和碱存在下，和苄氧基氨盐酸盐缩合得到N-保护基-5-苄氧亚氨基哌啶-2S-甲酸酯(XI)；
    (3.2)所得化合物XI在浓硫酸存在下，于乙酸乙酯中，经还原剂还原、添加草酸进行反应并进行手性拆分得到化合物N-保护基-5R-苄氧氨基哌啶-2S-甲酸酯(XII)；
    (3.3)所得化合物XII经过脱N-保护剂、中和得到5R-苄氧氨基哌啶-2S-甲酸酯(II a)；
    (3.4)所得5R-苄氧氨基哌啶-2S-甲酸酯(II a)经过水解、酸化得到5R-苄氧氨基哌啶-2S-甲酸(II b)；
    Figure PCTCN2018078072-appb-100003
  4. 如权利要求1所述的一种N-保护基哌啶-5-酮-2S-甲酸酯的制备方法或权利要求2-3之一所述的5R-苄氧氨基哌啶-2S-甲酸或其衍生物的制备方法，其特征在于，步骤(1)所用酸性试剂为氯化亚砜、光气、双光气、三光气、草酰氯，使用氯化亚砜或光气为酸性试剂时，氯化亚砜或光气和L-谷氨酸的摩尔比为(2.1-4.5):1，优选酯化反应温度为40-80℃，反应时间为1-8小时；使用双光气或草酰氯为酸性试剂时，双光气或草酰氯和L-谷氨酸的摩尔比为(1.1-2.5):1，优选酯化反应温度为40-80℃，反应时间为1-8小时；使用三光气为酸性试剂时，三光气和L-谷氨酸的摩尔比为(0.7-1.5):1，优选酯化反应温度为60-80℃，反应时间为1-8小时；步骤(1)所述醇与L-谷氨酸的质量比为8:1至30:1；上述C 1-6的饱和脂肪醇选自甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、正戊醇、异戊醇、叔戊醇、己醇；上述取代的C 6-9的芳醇或烷基取代芳醇，选自苄醇、邻甲基苄醇、对甲基苄醇。
  5. 如权利要求1所述的制备方法，其特征在于，步骤(2)所述加入与步骤(1)相同的醇是指醇的种类及质量和步骤(1)相同；步骤(2)所述碱为无机碱或有机碱，无机碱选自碳酸钾、碳酸钠、碳酸钙、碳酸氢钾、碳酸氢钠、碳酸氢钙、醋酸钾、醋酸钠、醋酸钙之一或组合，有机碱选自三甲胺、三乙胺、三正丁胺之一或组合；步骤(2)所述2-卤代乙酸酯 为2-氯乙酸甲酯、2-溴乙酸甲酯、2-碘乙酸甲酯、2-碘乙酸甲酯、2-氯乙酸乙酯、2-溴乙酸乙酯、2-碘乙酸乙酯、2-碘乙酸乙酯、2-氯乙酸苄酯、2-溴乙酸苄酯、2-碘乙酸苄酯、2-碘乙酸苄酯；步骤(2)所述N-保护试剂为氯苄、溴苄、苯甲酰氯、氯甲酸甲酯、氯甲酸乙酯、氯甲酸叔丁酯、氯甲酸苄酯、氯甲酸-9-芴基甲酯、二碳酸二叔丁酯；步骤(2)中，2-卤代乙酸酯、N-保护试剂、碱和L-谷氨酸的摩尔比为(1.0-2.0)：(1.0-2.0)：(2.0-4.0):1；优选反应温度为40-70℃，两次取代反应时间均为1-5小时。
  6. 如权利要求1所述的制备方法，其特征在于，步骤(3)中，所述强碱为氢化钠、甲醇钠、乙醇钠、叔丁醇钠、叔丁醇钾或苄醇钠；进一步优选所述强碱和化合物IV的摩尔比为(1.0-2.0):1。
  7. 如权利要求3所述的制备方法，其特征在于，途径1步骤(1.1)中所述化合物V经过脱N-保护基，得到化合物VI，根据N-保护基的不同，选择以下方式脱N-保护基；当N-保护基为苄基时，采用催化氢解脱苄基；当N-保护基为苯甲酰基或烷氧羰基时，采用碱性条件下水解脱相应N-保护基；优选的，步骤(1.1)中所述催化氢解所用催化剂为钯炭或兰尼镍，优选的钯炭催化剂用量为化合物V质量的0.5％-5％，进一步优选的催化剂用量为1％-3％质量比；优选的兰尼镍催化剂用量为化合物V质量的1％-20％，进一步优选的催化剂用量为5％-10％质量比；优选的，步骤(1.1)所述的溶剂为甲醇、乙醇、丙醇、丁醇、乙酸乙酯、四氢呋喃、乙腈中的一种或其混合溶剂，进一步优选的所述溶剂与化合物V的质量比为4:1至15:1；优选的步骤(1.1)中氢气压力为0.1-1.0MPa，反应温度为20-85℃，反应3-10小时；当N-保护基为苯甲酰基或烷氧羰基时，采用碱性条件下水解脱相应N-保护基；优选的，步骤(1.1)中所述碱为氢氧化钾、氢氧化钠、氢氧化锂；碱和化合物V摩尔比(2.0-3.0):1；优选的，步骤(1.1)所述的溶剂为水、甲醇、乙醇、丙醇、丁醇、乙酸乙酯、四氢呋喃、乙腈中的一种或其混合溶剂，进一步优选的所述溶剂与化合物V的质量比为3:1至15:1；优选的步骤(1.1)中水解反应温度为10-100℃，反应2-10小时；途径1步骤(1.2)中所述溶剂所述的溶剂为甲醇、乙醇、丙醇、丁醇、乙酸乙酯、四氢呋喃、乙腈中的一种或其混合溶剂，进一步优选的所述溶剂与化合物VI的质量比为3:1至15:1；步骤(1.2)中，所述苄氧胺盐酸盐和化合物VI的摩尔比为0.9-1.5:1；优选反应温度为10-80℃，反应时间为2-5小时；步骤(1.3)中，所述浓硫酸为质量分数95-98％的硫酸，该浓硫酸与化合物VII的摩尔比为(3.0-6.0)：1，最优选所述浓硫酸为质量分数98％的硫酸；步骤(1.3)中，乙酸乙酯与化合物VII的质量比为5-20:1；进一步优选乙酸乙酯与化合物VII的质量比为10-14:1；步骤(1.3)中，所述还原剂为硼氢化钠、三氰基硼氢化钠、三乙酰氧基硼氢化钠、三丙酰氧基硼氢化钠、硼氢化钾、三氰基硼氢化钾、三乙酰氧基硼氢化钾或三丙酰氧基硼氢化钾；所述还原剂与化合物VII的摩尔比为(2.0-4.0)：1；步骤(1.4)中，所得5R-苄氧氨基哌啶-2S-甲酸酯草酸盐于溶剂中，经碱中和，得到5R-苄氧氨基哌啶-2S-甲酸酯(II a)；步骤(1.4)中所述溶剂为乙酸乙酯、二氯甲烷、氯仿、1,2-二氯乙烷、苯、甲苯或其混合物；优选所述溶剂与化合 物II b的质量比为4:1至12:1；步骤(1.4)中所述碱为碳酸钾、碳酸钠、碳酸钙、碳酸氢钾、碳酸氢钠、碳酸氢钙、氨水之一或组合；优选所述碱和5R-苄氧氨基哌啶-2S-甲酸酯草酸盐的摩尔比为(1.5-3.0):1；步骤(1.4)中，所述中和反应温度为10-40℃，反应时间为2-5小时；步骤(1.5)中，所得5R-苄氧氨基哌啶-2S-甲酸酯(II a)于溶剂中，经碱水解，得到5R-苄氧氨基哌啶-2S-甲酸(II b)；步骤(1.5)中所述溶剂为水、乙酸乙酯、二氯甲烷、氯仿、1,2-二氯乙烷、苯、甲苯或其混合物；优选所述溶剂与化合物II a的质量比为4:1至12:1；步骤(1.5)中所述碱为氢氧化钠、氢氧化钾、氢氧化锂、碳酸钾、碳酸钠、碳酸钙、碳酸氢钾、碳酸氢钠之一或组合；优选所述碱和5R-苄氧氨基哌啶-2S-甲酸酯(II a)的摩尔比为(1.5-3.0):1；步骤(1.5)中，所述水解反应温度为10-80℃，反应时间为2-5小时。
  8. 如权利要求3所述的制备方法，其特征在于，途径2步骤(2.1)中，所述化合物V于溶剂中，经碱水解，得到化合物VIII，N-保护基哌啶-5-酮-2S-甲酸(VIII)；步骤(2.1)中所述溶剂为水、乙酸乙酯、二氯甲烷、氯仿、1,2-二氯乙烷、苯、甲苯或其混合物；优选所述溶剂与化合物V的质量比为4:1至12:1；步骤(2.1)中所述碱为氢氧化钠、氢氧化钾、氢氧化锂、碳酸钾、碳酸钠、碳酸钙、碳酸氢钾、碳酸氢钠之一或组合；优选所述碱和化合物V的摩尔比为(1.5-3.0):1；步骤(2.1)中，所述水解反应温度为10-80℃，反应时间为2-5小时；步骤(2.2)中所述得到化合物VIII经过脱N-保护基得到化合物IX，即哌啶-5-酮-2S-甲酸(IX)；根据N-保护基的不同，选择以下方式脱N-保护基；当N-保护基为苄基时，采用催化氢解脱苄基；当N-保护基为苯甲酰基或烷氧羰基时，采用碱性条件下水解脱相应N-保护基；优选的，步骤(2.2)中所述催化氢解所用催化剂为钯炭或兰尼镍，优选的钯炭催化剂用量为化合物Ⅷ质量的0.5％-5％，进一步优选的催化剂用量为1％-3％质量比；优选的兰尼镍催化剂用量为化合物Ⅷ质量的1％-20％，进一步优选的催化剂用量为5％-10％质量比；优选的，步骤(1.1)所述的溶剂为甲醇、乙醇、丙醇、丁醇、乙酸乙酯、四氢呋喃、乙腈中的一种或其混合溶剂，进一步优选的所述溶剂与化合物Ⅷ的质量比为4:1至15:1；优选的步骤(1.1)中氢气压力为0.1-1.0MPa，反应温度为20-85℃，反应3-10小时；当N-保护基为苯甲酰基或烷氧羰基时，采用碱性条件下水解脱相应N-保护基；优选的，步骤(1.1)中所述碱为氢氧化钾、氢氧化钠、氢氧化锂；碱和化合物VIII摩尔比(2.0-3.0):1；优选的，步骤(1.1)所述的溶剂为水、甲醇、乙醇、丙醇、丁醇、乙酸乙酯、四氢呋喃、乙腈中的一种或其混合溶剂，进一步优选的所述溶剂与化合物Ⅷ的质量比为3:1至15:1；优选的步骤(1.1)中水解反应温度为10-100℃，反应2-10小时；步骤(2.3)中所述溶剂所述的溶剂为甲醇、乙醇、丙醇、丁醇、乙酸乙酯、四氢呋喃、乙腈中的一种或其混合溶剂，进一步优选的所述溶剂与化合物IX的质量比为3:1至15:1；步骤(2.3)中，所述苄氧胺盐酸盐和化合物IX的摩尔比为0.9-1.5:1；优选反应温度为10-80℃，反应时间为2-5小时；步骤(2.4)中，所述浓硫酸为质量分数95-98％的硫酸，该浓硫酸与化合物Ⅹ的摩尔比为(3.0-6.0)：1，最优选所述浓硫酸为质量分数98％ 的硫酸；步骤(2.4)中，乙酸乙酯与化合物Ⅹ的质量比为5-20:1；进一步优选乙酸乙酯与化合物Ⅹ的质量比为10-14:1；步骤(2.4)中，所述还原剂为硼氢化钠、三氰基硼氢化钠、三乙酰氧基硼氢化钠、三丙酰氧基硼氢化钠、硼氢化钾、三氰基硼氢化钾、三乙酰氧基硼氢化钾或三丙酰氧基硼氢化钾；所述还原剂与化合物X的摩尔比为(2.0-4.0)：1。
  9. 如权利要求1所述的制备方法，其特征在于途径3步骤(3.1)中所述所得化合物V于溶剂和碱存在下，和苄氧基氨盐酸盐缩合得到化合物XI，N-保护基-5-苄氧亚氨基哌啶-2S-甲酸酯(XI)；步骤(3.1)中所述的溶剂为甲醇、乙醇、丙醇、丁醇、乙酸乙酯、四氢呋喃、乙腈、二氯甲烷、氯仿、1,2-二氯乙烷、苯、甲苯中的一种或其混合溶剂，进一步优选的所述溶剂与化合物V的质量比为3:1至15:1；步骤(3.1)中所述碱为有机碱三乙胺、三正丁胺、二异丙基乙胺、吡啶或无机碱碳酸钾、碳酸钠中的一种或其混合物，碱与化合物V的摩尔比为(1.0-2.0)：1；步骤(3.1)中，所述苄氧胺盐酸盐和化合物V的摩尔比为0.9-1.5:1；优选反应温度为10-80℃，反应时间为2-5小时；步骤(3.2)中，所述化合物XI在浓硫酸存在下，于乙酸乙酯中，经还原剂还原、添加草酸进行反应并进行手性拆分得到化合物XII，N-保护基-5R-苄氧氨基哌啶-2S-甲酸酯(XII)；步骤(3.2)中，所述浓硫酸为质量分数95-98％的硫酸，该浓硫酸与化合物XI的摩尔比为(3.0-6.0)：1，最优选所述浓硫酸为质量分数98％的硫酸；步骤(3.2)中，乙酸乙酯与化合物XI的质量比为5-20:1；进一步优选乙酸乙酯与化合物XI的质量比为10-14:1；步骤(3.2)中，所述还原剂为硼氢化钠、三氰基硼氢化钠、三乙酰氧基硼氢化钠、三丙酰氧基硼氢化钠、硼氢化钾、三氰基硼氢化钾、三乙酰氧基硼氢化钾或三丙酰氧基硼氢化钾；所述还原剂与化合物XI的摩尔比为(2.0-4.0)：1；步骤(3.3)中所得化合物XII经过脱N-保护剂、中和得到5R-苄氧氨基哌啶-2S-甲酸酯(II a)；步骤(3.3)中所述化合物XII经过脱N-保护基、中和得到化合物IIa，根据N-保护基的不同，选择以下方式脱N-保护基；当N-保护基为苄基时，采用催化氢解脱苄基；当N-保护基为苯甲酰基或烷氧羰基时，采用碱性条件下水解脱相应N-保护基；优选的，步骤(3.3)中所述催化氢解所用催化剂为钯炭或兰尼镍，优选的钯炭催化剂用量为化合物XII质量的0.5％-5％，进一步优选的催化剂用量为1％-3％质量比；优选的兰尼镍催化剂用量为化合物XII质量的1％-20％，进一步优选的催化剂用量为5％-10％质量比；优选的，步骤(3.3)所述的溶剂为甲醇、乙醇、丙醇、丁醇、乙酸乙酯、四氢呋喃、乙腈中的一种或其混合溶剂，进一步优选的所述溶剂与化合物XII的质量比为4:1至15:1；优选的步骤(3.3)中氢气压力为0.1-1.0MPa，反应温度为20-85℃，脱保护、中和反应时间共3-10小时；当N-保护基为苯甲酰基或烷氧羰基时，采用碱性条件下水解脱相应N-保护基；优选的，步骤(3.3)中所述碱为氢氧化钾、氢氧化钠、氢氧化锂；碱和化合物XII摩尔比(2.0-3.0):1；优选的，步骤(3.3)所述的溶剂为水、甲醇、乙醇、丙醇、丁醇、乙酸乙酯、四氢呋喃、乙腈中的一种或其混合溶剂，进一步优选的所述溶剂与化合物XII的质量比为3:1至15:1；优选的步骤(1.1)中水解反应温度为10-100℃，反应2-10小时；步骤(3.4)利用所得5R-苄氧氨基哌啶-2S-甲酸酯(II a) 于溶剂中经过水解、酸化得到5R-苄氧氨基哌啶-2S-甲酸(II b)；步骤(3.4)中所述溶剂为水、乙酸乙酯、二氯甲烷、氯仿、1,2-二氯乙烷、苯、甲苯或其混合物；优选所述溶剂与化合物II a的质量比为4:1至12:1；步骤(3.4)中所述碱为氢氧化钠、氢氧化钾、氢氧化锂、碳酸钾、碳酸钠、碳酸钙、碳酸氢钾、碳酸氢钠之一或组合；优选所述碱和化合物II a的摩尔比为(1.5-3.0):1；步骤(3.4)中，所述水解反应温度为10-80℃，反应时间为2-5小时。
  10. 如权利要求2或3所述的制备方法，其特征在于根据目的产物以及保护基的不同，选择不同途径制备所需目的产物；利用所得5R-苄氧氨基哌啶-2S-甲酸酯(II a)、5R-苄氧氨基哌啶-2S-甲酸酯草酸盐(II c)、5R-苄氧氨基哌啶-2S-甲酸(II b)能够制备阿维巴坦和瑞利巴坦。
PCT/CN2018/078072 2017-12-28 2018-03-06 一种5r-苄氧氨基哌啶-2s-甲酸或其衍生物的制备方法 WO2019127902A1 (zh)

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AU2018344100B2 (en) 2020-04-30
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AU2018344100A1 (en) 2019-07-18
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