WO2004043905A1 - Procede servant a preparer un derive d'acide 2-amino-3-hydroxypropanoique - Google Patents

Procede servant a preparer un derive d'acide 2-amino-3-hydroxypropanoique Download PDF

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WO2004043905A1
WO2004043905A1 PCT/JP2003/014199 JP0314199W WO2004043905A1 WO 2004043905 A1 WO2004043905 A1 WO 2004043905A1 JP 0314199 W JP0314199 W JP 0314199W WO 2004043905 A1 WO2004043905 A1 WO 2004043905A1
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group
formula
salt
reaction
acid
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PCT/JP2003/014199
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Hiroyuki Kousaka
Hideki Musashi
Kenji Suzuki
Masami Kozawa
Kenichi Seki
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Ono Pharmaceutical Co., Ltd.
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Publication of WO2004043905A1 publication Critical patent/WO2004043905A1/fr

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    • 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
    • C07C271/22—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 carboxyl groups
    • 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 method for producing a 2- (optionally protected amino) -3-hydroxypropanoic acid derivative, which is an important intermediate for pharmaceuticals, agricultural chemicals, and the like, and a derivative of oxysilanecarboxylic acid as a raw material thereof.
  • 2- (Amino-protected amino) -3-hydroxypropanoic acid derivatives are used as intermediates for pharmaceuticals, agricultural chemicals, etc., and are important intermediates for various fine chemical derivatives.
  • the oxysilane carboxylic acid derivative as a raw material thereof is also an important intermediate for pharmaceuticals and the like.
  • optically active 2- (optionally protected amino) -13-hydroxypropanoic acid derivatives derived from optically active oxysilane carboxylic acid derivatives are used as intermediates of various pharmaceuticals. I have.
  • a process for producing (2R *, 3R *) — 2— (optionally protected amino) 13-hydroxypropanoic acid derivative includes: (1) Cyclohexylaldehyde and glycine derivative (2) Oxysilane carboxylic acid ester or carboxylic acid amide (see, for example, Tetrahedron Lett., 1999, 40, 3843, J. Chem. Soc., Chem. Commun., 1995, 487). (For example, see Tetrahedron Lett., 1991, 32, 667, J. Org. Chem., 1985, 50, 1560) and the like.
  • the product is a mixture of the (2R *, 3R *) form and the (2R *, 3S *) form, and the main product is (2R *, 3S *).
  • the method (2) requires a processing operation for converting the resulting azide form or alkylamine form into an amino group.
  • the methods (3) and (4) are particularly aimed at in the present invention. (2R *, 3R *)-2- (optionally protected amino) -1,3-hydroxypropanoic acid Even when applied directly to the synthesis of derivatives, there were problems such as low yield.
  • the present inventors have proposed a method for producing a 2- (optionally protected amino) -13-hydroxypropanoic acid derivative and a method for producing an optically active oxolanic acid ruponic acid derivative in high yield and high purity. After intensive studies, the present invention has been completed.
  • R 1 contains a C 1-8 alkyl group, a C 3-8 monocyclic carbocyclic ring, or one or two hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom 3
  • R 1 is a 3- to 8-membered monocyclic heterocyclic ring containing 1-2 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom
  • the atom bonded to the oxysilane ring is a carbon atom.
  • the racemic or optically active oxysilane carboxylic acid derivative represented by the formula is subjected to a ring-opening reaction with ammonia, and then, if desired, protected.
  • Formula (I) characterized by being subjected to a reaction
  • R 2 represents a hydrogen atom or a protecting group for an amino group, and R 1 has the same meaning as the above symbol.
  • SJR 1 is a 1-methylethyl group, a 1-ethylpropyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a 1-cyclopentene-4-yl group or a tetrahydropyran-14-yl group.
  • optically active 2_ (optionally protected amino) 1-3-hydroxypropanoic acid derivative is a (2R, 3R) form.
  • R 1 has the same meaning as the above symbol.
  • Formula (II) obtained by subjecting a 2,3-trans-13-substituted 1-2-propenoic acid represented by the following to an epoxidation reaction or an asymmetric epoxidation reaction
  • racemic or optically active oxysilane carboxylic acid derivative represented by the formula (I) is subjected to a ring-opening reaction with ammonia and, if desired, to a protection reaction.
  • Cl-6 alkyl group The alkyl group is (1) an aryl group (The aryl group is (a) a halogen atom, (b) a C1-6 alkyl group, or (c) C:! ⁇ (2) a C 1-6 alkoxy group (the alkoxy group may be an aryl group (the aryl group may be (i) a halogen atom, (Ii) optionally substituted with a C1-6 alkyl group, or (iii) optionally substituted with a C1-6 alkoxy group), or (3) C1-6 6 alkylthio group (the alkyl
  • the ruthio group is optionally an aryl group (the aryl group may be optionally substituted with (i) a halogen atom, (ii) a Cl-6alkyl group, or (iii) a C1-6alkoxy group). May be optionally substituted)) or may be optionally substituted) or may be optionally substituted) or
  • aryl group (the aryl group may be optionally substituted with (1) a halogen atom, (2) a C1-6 alkyl group, or (3) a C1-6 alkoxy group) Represents
  • X and Y represent (1) X is OR 4 and Y is NHR 5 , or (2) X is NHR 5 and Y is OR 4 ,
  • R 4 and R 5 are each independently
  • C 1-6 alkyl group (the alkyl group is an aryl group (the aryl group is (a) a halogen atom, (b) a C 1-6 alkyl group, or (c) a C 1-6 alkoxy group May be optionally substituted), may be optionally substituted), or
  • aryl group (the aryl group may be optionally substituted with (1) a halogen atom, (2) a C1-6 alkyl group, or (3) C:!-6 alkoxy group)
  • R 1 has the same meaning as described above.
  • R 1 has the same meaning as the above symbol.
  • R 1 has the same meaning as the above symbol.
  • R 1 has the same meaning as the above symbol.
  • R 1 has the same meaning as the above symbol.
  • R 1 has the same meaning as the above symbol.
  • R 1 is 1-methylethyl group, 1-ethylpropyl group, cyclopentyl A salt of the above-mentioned [11], which is a cyclohexyl group, a cyclohexyl group, a cycloheptyl group, a 1-cyclopentene-14r group or a tetrahydropyran-4-yl group; [15] (1) (2S, 3R ) —3-cyclohexyl-2-oxo carboxylic acid and (R) — 2-amino-1-phenylethanol salt,
  • R 1 has the same meaning as the above symbol.
  • R 1 has the same meaning as the above symbol.
  • R 1 has the same meaning as the above symbol.
  • C 1-6 alkyl group (the alkyl group is an aryl group (the aryl group is (a) a halogen atom, (b) a C 1-6 alkyl group, or (c) a C 1-6 alkoxy group May be optionally substituted) or may be optionally substituted) or
  • aryl group (the aryl group may be optionally substituted with (1) a halogen atom, (2) a C1-6 alkyl group, or (3) a C1-6 alkoxy group).
  • R 1A and R 2A are each independently
  • C 1-6 alkyl group (the alkyl group is an aryl group (the aryl group is (a) a halogen atom, (b) a C 1-6 alkyl group, or (c) a C 1-6 alkoxy group May be optionally substituted), may be optionally substituted), or
  • aryl group (the aryl group may be optionally substituted with (1) a halogen atom, (2) a C1-6 alkyl group, or (3) a C1-6 alkoxy group).
  • a C 1-6 alkyl group (the alkyl group is (1) an aryl group (the aryl group is (a) a halogen atom, (b) a C 1-6 alkyl group, or (c) C (2) C 1-6 alkoxy group (the alkoxy group is an aryl group (the aryl group is (i) a halogen atom, (ii) C 1-6 alkyl group, or (iii) optionally substituted with C 1-6 alkoxy group) or (3) C 1-6 alkylthio group ( The alkylthio group may be an aryl group (the aryl group may be optionally substituted with (i) a halogen atom, (ii) a C 1-6 alkyl group, or (iii) a C 1-6 alkoxy group. ) May be optionally substituted)) may be optionally substituted)) or
  • the aryl group may be optionally substituted with (1) a halogen atom, (2) a C1-6 alkyl group, or (3) a C1-6 alkoxy group).
  • R 3A and R 4A each independently
  • C 1-6 alkyl group (the alkyl group is an aryl group (the aryl group is (a) a halogen atom, (b) a C 1-6 alkyl group, or (c) a C 1-6 Optionally substituted with an alkoxy group), optionally substituted with), or
  • aryl group (the aryl group may be optionally substituted with (1) a halogen atom, (2) a C1-6 alkyl group, or (3) a C1-6 alkoxy group)
  • the present invention relates to a method for producing an optically active oxysilane carboxylic acid derivative, comprising optically resolving an optically active amino alcohol derivative represented by the formula (1) as a resolving agent.
  • 2- (optionally protected amino) -13-hydroxypropanoic acid derivative refers to racemic 2- (optionally protected amino) -1,3-hydroxypropane It refers to acid derivatives and / or optically active 2- (optionally protected amino) _3-hydroxypropanoic acid derivatives.
  • the “optically active” compound refers to a compound having an optical rotation, and preferably an optical isomer having an optical purity of 50 ee or more. More preferably, it represents an optical isomer having 90% ee or more, and most preferably, represents a substantially pure optical isomer.
  • substantially pure means that the optical purity is 95% ee or more.
  • a diastereomer salt refers to a salt in which one or both of the salts are an optically active compound, and preferably contains a compound having an optical purity of 50% ee or more. Represents a salt. More preferably, it refers to a salt containing a compound having 90% ee or more, and most preferably, a salt containing a substantially pure optically active compound.
  • the “optically active salt” refers to a salt in which both of the compounds forming the salt are optically active compounds, and preferably have an optical purity of 50% ee or more. Represents a salt composed of compounds. More preferably, it represents a salt composed of compounds having 90 ee or more, and most preferably a salt composed of substantially pure optically active compounds.
  • optically active reagents, raw materials and / or compounds denoted by R or S can be applied to optically active reagents, raw materials and / or compounds replaced with S or R, respectively.
  • the symbol- ⁇ ' indicates that the symbol is connected to the other side of the paper (that is, a single arrangement). Configuration), and represents a mixture of ⁇ -configuration and 5-configuration.
  • the C 1 to 8 alkyl group represented by R 1 is methyl, E chill, propyl, butyl, pentyl, hexyl, heptyl, Okuchiru group and their different biological.
  • the C 3-8 monocyclic carbocyclic ring represented by R 1 includes a C 3-8 monocyclic carbocyclic aryl, a partially or wholly saturated carbocyclic ring. It is.
  • a 3- to 8-membered monocyclic heterocycle containing 1 to 2 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom represented by R 1 is an oxygen atom, a nitrogen atom And an unsaturated heterocyclic ring containing 1 to 2 heteroatoms selected from sulfur atoms, or a partially or fully saturated heterocyclic ring.
  • Examples of the 3- to 8-membered monocyclic unsaturated heterocyclic ring containing 1 to 2 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom include pyrrol, imidazole, pyrazole, pyridine, Pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepin, thiophene, thiopyran, chepin, oxazole, isoxazole, thiazole, isothiazole, othiazole, othiazole, oxazine, oxazine, thiazine, thiazine, thiazine, thiazine No.
  • Partially or fully saturated 3- to 8-membered monocyclic unsaturated heterocyclic ring containing 1 to 2 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom include aziridines, azetidines, pyrrolines, Pyrrolidine, imidazoline, imidazolidinine, pyrazoline, virazolidine, dihydropyridine, tetrahydropyridin, piperidine, dihydrovirazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, parahydropyrimidine, dihydropyridazine, tetrahydropyridazine , Perhydropyridazine, dihydroazepine, tetrahydroazepine, parahydroazepine, dihydrodiazepine, tetrahydrodiazepine, parahydrodiazepine, oxolan, ox
  • R 1 is preferably a 1-methylethyl group, a 1-ethylpropyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a 1-cyclopentene-14-yl group, a tetrahydropyran-14-yl group, or the like. And more preferred is a cyclohexyl group.
  • examples of the protecting group for the amino group represented by R 2 include a benzyloxycarbonyl (Cb z) group, a t-butoxycarbonyl (Bo c) group, and an aryloxycarbonyl (Al 1 oc) group.
  • R 2 is preferably a hydrogen atom, a benzyloxycarbonyl (Cb z) group or a t-butoxycarbonyl (Bo c) group, and more preferably a t-butoxycarbonyl (Bo c) group.
  • the C 1-6 alkyl group represented by R 3 , R 4 , R 5 , R A R A2 , R 1A , R 2A , R 3A , or R 4A is linear or branched.
  • cyclic for example, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, 1, Examples thereof include 1-dimethylpropyl, cyclopentyl, hexyl, 1,1-dimethylbutyl and cyclohexyl.
  • the aryl group represented by R 3 , R 4 , R 5 , R A R A2 , R 1A , R 2A , R 3A , or R 4A includes phenyl, o_methylphenyl, m_methylphenyl, p —Methylphenyl, o-trifluoromethylphenyl, m-trifluoromethylphenyl, p-trifluoromethylphenyl, p-t-butylphenyl, o-chlorophenyl, m-chlorophenyl, p — Clophenyl, o-Promophenyl, ⁇ -Bromophenyl, ⁇ -Bromophenyl, ⁇ -Methoxyphenyl, ⁇ -Methoxyphenyl, ⁇ -Trifluoromethoxyphenyl, ⁇ -Trifluoromethoxyphenyl, 3, 5 —Dimethylphenyl, 3,5-bistrifluoro
  • examples of the halogen atom include fluorine, chlorine, bromine and iodine.
  • the C 1-6 alkoxy group may be linear, branched or cyclic, for example, methoxy, ethoxy, propoxy, isopropoxy, cyclopropoxy, butoxy, isobutoxy, s-butoxy , T-butoxy, pentyloxy, 1,1-dimethylpropoxy, cyclopentyloxy, hexyloxy, 1,1-dimethylbutoxy, cyclohexyloxy and the like.
  • the C1-6 alkylthio group may be linear, branched or cyclic, and may be, for example, methylthio, ethylthio, propylthio, isopropylthio, cyclopropylthio, butylthio, isobutylthio, s —Butylthio, t-butylthio, pentylthio, 1,1-dimethylpropylthio, cyclopentylthio, hexylthio, 1,1-dimethylbutylthio, cyclohexylthio and the like.
  • R ⁇ R A 1 and R A 2 phenyl group, m- black port-phenylene group, a benzyl group, include benzylthiomethyl group or trityl O carboxymethyl group, as more preferable, Fuweniru group Benzyl group or benzylthiomethyl group.
  • R 1 A and R 3 A preferably include a hydrogen atom, a methyl group or an ethyl group, and more preferably a hydrogen atom.
  • R 5 , R 2 A and R 4 A are preferably a hydrogen atom, a methyl group, an ethyl group, an isopropyl group or a benzyl group, and more preferably a hydrogen atom.
  • the reaction product is purified by a conventional purification means, for example, distillation under normal pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, ion exchange resin. It can be purified by a method such as scavenger resin or column chromatography or washing and recrystallization. Purification may be performed for each reaction or may be performed after several reactions are completed.
  • a conventional purification means for example, distillation under normal pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, ion exchange resin. It can be purified by a method such as scavenger resin or column chromatography or washing and recrystallization. Purification may be performed for each reaction or may be performed after several reactions are completed.
  • R 1 has the same meaning as the above symbol.
  • R 1 ⁇ C00H (HI) (wherein, R 1 has the same meaning as the above symbol.)
  • This epoxidation reaction is known, and is carried out by reacting with an oxidizing agent in a reaction solvent in the presence or absence of a catalyst.
  • the solvent used in the reaction is slightly different depending on the oxidizing agent used, but is not particularly limited as long as it does not participate in the reaction.
  • water acetic acid, lower fatty acids such as propionic acid, methanol, ethanol, propanol Alcohols such as butanol, cellosolps such as methoxyethanol and ethoxyethanol, aromatic hydrocarbons such as benzene, toluene, xylene, mesitylene, benzene, and benzene, hexane, cyclohexane, Aliphatic hydrocarbons such as octane and decane, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride; ethers such as tetrahydrofuran, getyl ether, t-butyl methyl ether, and dimethoxyethane , Ethyl acetate, butyl acetate
  • the oxidizing agent is not particularly restricted but includes, for example, peracids such as peracetic acid, perbenzoic acid, m-chloroperbenzoic acid and the like, and oxidizing agents such as t-butyl hydroperoxide, cumene hydroperoxide and the like.
  • peracids such as peracetic acid, perbenzoic acid, m-chloroperbenzoic acid and the like
  • oxidizing agents such as t-butyl hydroperoxide, cumene hydroperoxide and the like.
  • Oxides aqueous hydrogen peroxide, sodium peroxymonosulfate (Oxone; trade name), oxygen and the like.
  • Preferred are peracetic acid, m-chloroperbenzoic acid, aqueous hydrogen peroxide, t — Butyl hydroperoxide, cumene hydroperoxide, and poxium peroxy monosulfate (Oxone; trade name).
  • a more preferable one is hydrogen
  • the amount of the oxidizing agent is usually in the range of 0.5 to 10 molar equivalents, preferably 0.8 to 3 molar equivalents, based on the substrate. In consideration of operability and economic efficiency, around 1 molar equivalent is most preferable.
  • tungstic acid or a salt thereof or a hydrate thereof or phosphotungstic acid or a salt thereof or a hydrate thereof as a catalyst.
  • the reaction proceeds efficiently by using a catalyst.
  • Tungstates include lithium tungstate, sodium tungstate, potassium tungstate, cesium tungstate, magnesium tandastate, calcium tungstate, barium tungstate, zinc tungstate, cobalt tungstate, copper tungstate, evening Examples include gallium stenoate, ammonium tungstate, and hydrates thereof, with sodium tungstate dihydrate being preferred.
  • Examples of the phosphotungstate include sodium phosphotungstate, calcium phosphotungstate, and barium phosphotungstate.
  • the amount of tungstic acid catalyst used is usually 0 ::! 1100 mol%, preferably 1-50 mol%. Further, in the present invention, when hydrogen peroxide solution is used as the oxidizing agent, by controlling the pH in the reaction system, decomposition of the product can be suppressed, and the desired product can be obtained in high yield.
  • the range of pH is preferably pH 7 or less, more preferably pH 4.5-6.5, and most preferably pH 5.0-6.0.
  • the reaction temperature is usually in the range of 0 to 150 ° C, preferably in the range of 20 to 100 ° C, more preferably in the range of 50 to 80 ° C.
  • the reaction time is usually 0.1 to: 1000 hours.
  • the desired oxosilanecarboxylic acid derivative can be isolated by extracting with an appropriate solvent and concentrating the solvent.
  • optically active oxysilane carboxylic acid can be obtained, for example, by subjecting an aryl alcohol described in J. Org. Chem., 1985, 50, 1563 or Tetrahedron Lett., 1991, 32, 667 to an asymmetric epoxidation reaction. It can also be produced by oxidizing the produced optically active epoxy alcohol.
  • R 1 has the same meaning as the above symbol.
  • the 2,3-trans-13-substituted-12-propenoic acid represented by the formula (IV) is obtained by a general method known as Devna reaction according to the formula (IV)
  • R 1 has the same meaning as the above symbol.
  • R 1 has the same meaning as the above symbol.
  • ammonia used for the ring opening reaction examples include liquid ammonia, ammonia gas and aqueous ammonia, all of which are preferred.
  • the amount of ammonia used is preferably in excess with respect to the substrate, preferably in the range of 1 to 200 molar equivalents, particularly preferably in the range of 1 to 100 molar equivalents.
  • This reaction is preferably performed in a sealed reaction vessel in order to suppress the loss of ammonia to be used, and may be pressurized depending on the reaction temperature. This reaction is more preferably performed under closed pressure.
  • This reaction does not require the use of any solvent, but can be carried out in a solvent if necessary.
  • the reaction solvent is not particularly limited as long as it does not participate in the reaction.
  • examples include water, alcohols such as methanol, ethanol, propanol, and butanol, cellosolves such as methoxyethanol and ethoxyethanol, and benzene.
  • the reaction temperature is usually in the range of 0 to L80 ° C, preferably in the range of 50 to L50 ° C, more preferably in the range of 70 to 120 ° C.
  • the reaction time is generally 0.1 to 1000 hours.
  • the pH is adjusted by adding an acidic aqueous solution, followed by extraction with an appropriate solvent and concentration of the solvent to obtain the desired (2R *, 3R *)-2-amino-3-hydroxy.
  • the propanoic acid derivative can be isolated.
  • isolation is facilitated by subjecting the amino group to a protection reaction according to a conventional method. Become.
  • the protection reaction of an amino group is known and can be performed, for example, by the method described in T. W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1999.
  • the present invention further provides an optically active (2R, 3R) -2-amino-3-hydroxypropanoic acid derivative, an optically active (2 S, 3S) -1-amino-3-hydroxypropanoic acid derivative, optically active (2R, 3R) -2- (protected amino) -13-hydroxypropanoic acid derivative and optically active (2S, 3 S) -2- (Protected amino) 1-3-hydroxypropanoic acid derivative can be produced.
  • optically active 2- (optionally protected amino) -1-hydroxypropanoic acid derivative can also be produced by the following methods (1) to (4). That is,
  • racemic 2- (optionally protected amino) 1-3-hydroxypropanoic acid derivative and an optically resolving agent such as optically active amino alcohol or optically active sulfonic acid are represented by the following formula: Reaction, fractional recrystallization, and filtration of the precipitated diastereomer salt.If necessary, further recrystallization with an appropriate solvent.Decomposition of the diastereomer salt with an acidic aqueous solution or basic aqueous solution by a conventional method. After that, extraction with an appropriate organic solvent can provide the desired optically active 2- (optionally protected amino) -13-hydroxypropanoic acid derivative.
  • the solvent used for the reaction is not particularly limited as long as the generated salt precipitates.
  • water, alcohols (methanol, ethanol, propanol, etc.) examples include acetonitrile, tetrahydrofuran, chloroform, acetone, hexane, heptane, benzene, and toluene.
  • the reaction temperature is not particularly limited as long as the generated salt precipitates.
  • the time required for the reaction depends on the rate of precipitation of the salt formed, but is often less than one day.
  • Examples of the acidic aqueous solution for decomposing the diastereomer salt include aqueous solutions of hydrochloric acid, sulfuric acid, phosphoric acid, sodium dihydrogen phosphate, potassium dihydrogen phosphate, sodium hydrogen sulfate, potassium hydrogen sulfate and the like.
  • Examples of the basic aqueous solution for decomposing the diastereomer salt include aqueous solutions of sodium hydroxide, hydroxylated water, sodium carbonate and the like.
  • Organic solvents for extracting the optically active 2- (optionally protected amino) 1-3-hydroxypropanoic acid derivative include getyl ether, ethyl acetate, benzene, toluene, chloroform, dichloroethane and the like. .
  • a racemic 2- (optionally protected amino) -13-hydroxypropanoic acid derivative represented by the formula (I) is first subjected to an esterification reaction or an amidation reaction, and then subjected to an enzyme.
  • an optically active 2- (optionally protected amino) -13-hydroxypropanoic acid derivative can be obtained.
  • This esterification reaction is known.
  • a carboxylic acid is dissolved in an organic solvent (chloroform, dichloromethane, geethylether, tetrahydrofuran, etc. alone, or a mixed solvent composed of an arbitrary ratio of a plurality of solvents among them).
  • an acid halide agent oxalyl chloride, thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, etc.
  • the amidation reaction is well-known.
  • a carboxylic acid is converted into an organic solvent (chloroform, dichloromethane, getyl ether, tetrahydrofuran, or the like alone, or a mixed solvent composed of an arbitrary ratio of a plurality of these solvents).
  • an acid halide agent oxalyl chloride, thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, etc.
  • a medium or no solvent at 120 ° C to reflux temperature
  • esterification or amidation can also be performed by the method described in Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition (Richard C. Larock, John, Wiley & Sons Inc, 1999). A reaction can take place.
  • Methods for obtaining an optically active substance by stereoselective hydrolysis using an enzyme or the like include the following (A) and (B). That is, (A) a method for selectively hydrolyzing an ester derivative or an amide derivative of a carboxylic acid, which is a desired stereoisomer, to obtain a desired stereoisomer, kyruponic acid; and
  • a racemic carboxylic acid derivative serving as a substrate is added to an appropriate solvent (for example, water, a buffer, etc.), and an enzyme or the like is added as a catalyst to carry out the reaction.
  • the reaction temperature and pH in the system are set in consideration of the optimal range of the enzyme.
  • the inside of the system is made basic, and the remaining ester derivative or amide derivative is extracted and removed with a suitable solvent.
  • the aqueous layer is made acidic, and the desired carboxylic acid is extracted with a suitable solvent. By concentrating the compound, the desired optically active 2- (optionally protected amino) -13-hydroxypropanoic acid can be isolated.
  • a racemic carboxylic acid derivative serving as a substrate is added to an appropriate solvent (eg, water, buffer, etc.), and an enzyme or the like is added as a catalyst for the reaction.
  • the reaction temperature and pH in the system are set in consideration of the optimal range of the enzyme.
  • the reaction system is made basic, and the remaining target ester derivative or amide derivative is extracted with an appropriate solvent, and the solvent is concentrated to give 2- (protected amino) 13.
  • 2- (protected amino) 13 can be isolated.
  • the desired optically active 2- (optionally protected amino) -13-hydroxypropanoic acid can be isolated by hydrolyzing this ester derivative or amide derivative.
  • the enzyme used in this reaction is not particularly limited as long as it gives optically active 2- (optionally protected amino) -13-hydroxypropanoic acid or a derivative thereof. Not determined.
  • a commercially available hydrolase such as lipase
  • a commercially available hydrolase such as lipase
  • a compound having a hydroxyl group can be prepared by mixing an organic solvent (e.g., chloroform, dichloromethane, dimethyl ether, tetrahydrofuran, or the like alone, or a mixture of any of a plurality of solvents in any ratio).
  • organic solvent e.g., chloroform, dichloromethane, dimethyl ether, tetrahydrofuran, or the like alone, or a mixture of any of a plurality of solvents in any ratio.
  • Optically active carboxylic acid halides eg, Mandel
  • a base pyridine, triethylamine, N, N-dimethylaniline, N, N-dimethylaminopyridine, diisopropylethylamine, etc.
  • Acid chloride etc.
  • Optical resolution can be performed by a method such as fractional recrystallization of the target optically active substance according to the above-mentioned method.
  • the deprotection reaction of a hydroxyl group is known, for example, in an organic solvent (methanol, tetrahydrofuran, 1,4-dioxane, etc.), an alkali metal hydroxide (sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), Use alkaline earth metal hydroxides (barium hydroxide, calcium hydroxide, etc.) or carbonates (sodium carbonate, potassium carbonate, etc.) or their aqueous solutions or mixtures thereof at a temperature of 0 to 40 ° C. Done.
  • an organic solvent methanol, tetrahydrofuran, 1,4-dioxane, etc.
  • an alkali metal hydroxide sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.
  • Use alkaline earth metal hydroxides barium hydroxide, calcium hydroxide, etc.
  • carbonates sodium carbonate, potassium carbonate, etc.
  • the deprotection reaction can also be performed by the method described in Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition (Richard C. Larock, John, Wiley & Sons Inc, 1999). Can be performed.
  • the hydroxyl group of 3-hydroxypropanoic acid derivative is protected with an appropriate acyl group, and then subjected to stereoselective hydrolysis using an enzyme or the like to give an optically active 2-(optionally protected amino).
  • a 1-hydroxypropanoic acid derivative can be obtained.
  • This acylation reaction is known and can be carried out according to the method described above.
  • a method for obtaining an optically active substance by stereoselective hydrolysis using an enzyme or the like is known, and can be carried out according to the method described above.
  • the salt represented by the formula (IV) is prepared by equimolar amount of the salt represented by the formula ( ⁇ )
  • R 1 has the same meaning as the above symbol.
  • the solvent used in the reaction is not particularly limited as long as it does not participate in the reaction.
  • water alcohols (methanol, ethanol, propanol, etc.), acetonitrile, tetrahydrofuran, chloroform, acetone, hexane, heptane , Benzene, toluene and the like.
  • Particularly preferred reaction solvents include water, methanol, ethanol or toluene.
  • the solvent used for recrystallization is not particularly limited as long as the generated salt precipitates, and examples thereof include water, alcohols (methanol, ethanol, propanol, etc.), acetonitrile, tetrahydrofuran, chloroform, acetone, hexane, Heptane, benzene, toluene and the like can be mentioned.
  • Particularly preferred reaction solvents include water, methanol, ethanol or toluene.
  • the temperature at which the recrystallization is performed is not particularly limited as long as the generated salt precipitates, but is preferably in the range of 12 to 100 ° C. in terms of operation. Particularly preferably, it is 0 to 70 ° C.
  • the time required for recrystallization depends on the rate of precipitation of the salt formed, but is often less than one day. Preferably it is in the range of 10 minutes to 10 hours.
  • the present invention further provides a salt of a diastereomer or an optically active salt represented by the formula (IV) by subjecting the same to the above-mentioned operation using the optically active amino alcohol derivative represented by the formula (A). be able to.
  • optically active amino alcohol derivative represented by the formula (A) As the optically active amino alcohol derivative represented by the formula (A), (R) -12-amino-11-phenylethanol, (R) -2-amino-3-phenyl-2-propanol (also known as D—) Or (S) —2-amino-13- (benzylthio) -11-propanol (also known as S-benzylil-D-cystinol) and the like.
  • the optically active salt represented by the formula (IV) is composed of an equimolar amount of an oxysilanecarboxylic acid derivative represented by the formula (II) and an optically active amino alcohol represented by the formula (A).
  • the derivative can be produced by mixing the derivative in the presence of an appropriate solvent, fractionally recrystallizing, collecting the precipitate by filtration, and, if necessary, further recrystallizing with an appropriate solvent.
  • the solvent used for the recrystallization is not particularly limited as long as the generated salt precipitates.
  • reaction solvents include water, methanol, ethanol or toluene.
  • the temperature at which the recrystallization is performed is not particularly limited as long as the generated salt precipitates, but is preferably in the range of 120 to 100 ° C. for the operation. Particularly preferably, it is 0 to 7 ° C.
  • the time required for recrystallization depends on the rate of salt formation, but in most cases
  • optically active amino alcohol derivative represented by the formula (A) used herein (R) -2-amino-1-phenylethanol, (R) -2-amino-3-phenyl-2-propanol are preferable. (Also known as: D-phenylalaninol) or (S) -2-amino-3- (benzylthio) -11-propanol (Also known as S-benzyl-D-cystinol) and the like. .
  • the oxysilanecarboxylic acid derivative represented by the formula (II) can be produced by decomposing a salt represented by the formula (IV) or a diastereomer salt with an acidic aqueous solution and extracting the resulting mixture with an appropriate organic solvent.
  • acidic aqueous solutions for decomposing salts include hydrochloric acid, sulfuric acid, phosphoric acid, sodium dihydrogen phosphate, dihydrogen phosphate lime, sodium hydrogen sulfate, hydrogen sulfate An aqueous solution of lithium or the like can be mentioned, and an aqueous solution of hydrochloric acid, sulfuric acid or potassium hydrogen sulfate is particularly preferable.
  • organic solvent for extracting the oxysilane carboxylic acid derivative examples include getyl ether, ethyl acetate, benzene, toluene, chloroform, dichloroethane, and the like, and particularly preferred is ethyl acetate, toluene, or dichloroethane.
  • optically active salt represented by the formula (IV) can be further subjected to the same operation as described above to produce an optically active oxysilanecarboxylic acid derivative represented by the formula ( ⁇ ). .
  • Examples of the acidic aqueous solution for decomposing the salt include those described above, and an aqueous solution of hydrochloric acid, sulfuric acid or hydrogen sulfate is particularly preferable.
  • organic solvent for extracting the ethoxylan ruponic acid derivative examples include those described above, and particularly preferred are ethyl acetate, toluene and dichloroethane.
  • the acidic aqueous solution after extracting the oxysilane carboxylic acid derivative was made alkaline with sodium hydroxide, potassium hydroxide, sodium carbonate, carbonated lime, or the like. Thereafter, by extracting with an appropriate organic solvent, the used amino alcohol derivative can be recovered without racemization, and the recovered amino alcohol derivative can be reused as it is.
  • a high-purity amino alcohol derivative can be obtained by performing purification such as recrystallization if necessary.
  • the extraction solvent examples include getyl ether, ethyl acetate, benzene, toluene, chloroform, dichloroethane, and the like, and particularly preferably ethyl acetate, chloroform, or dichloroethane.
  • the temperature was raised to 60 ° C., and the mixture was stirred for 30 minutes, and then heated to 75 ° C. and stirred for 4 hours.
  • the reaction solution was cooled to 40 ° C, and about 340 g of pyridine was distilled off under reduced pressure.
  • the reaction residue was heated to 60 ° C, toluene (420 g) and 20% hydrochloric acid (511) were added, and the mixture was stirred at 60 ° C for 30 minutes.
  • a 10% aqueous sodium hydroxide solution (899 g) was added to the organic layer, and the mixture was stirred at 60 ° C for 30 minutes. The organic layer was separated and extracted to the aqueous layer side.
  • reaction solution was cooled to 40 ° C, and about 69 g of pyridine was distilled off under reduced pressure.
  • the reaction residue was heated to 60 ° C, toluene (75 g) and 20% hydrochloric acid (99 g) were added, and the mixture was stirred at 60 ° C for 30 minutes.
  • a 10% aqueous sodium hydroxide solution (174 g) was added to the organic layer, and the mixture was stirred at 60 ° C for 30 minutes.
  • the organic layer was separated and extracted to the aqueous layer side.
  • Example 1 Synthesis of racemic (2R *, 3S *)-3-cyclohexyl-2-oxylancarboxylic acid
  • a reaction flask equipped with a cooling pipe, a thermometer, a pH meter, a hydrogen peroxide dropping pipe, and an alkaline aqueous dropping pipe add water (20 g), 2,3-trans-1,3-cyclohexyl-2-propenoic acid (2 , 00g, 13mmo 1) and tungstic acid Sodium 'dihydrate (0.64 g, 1.95 mmo 1) was added, and the temperature was raised to 60 ° C., and then the pH of the reaction solution was adjusted to 5.3 by adding lmo 1 / L sulfuric acid.
  • a 35% hydrogen peroxide solution (1.26 g, 15.6 mmo1) was added dropwise over 3 hours.
  • the pH of the reaction solution was adjusted to 5.25 to 535 while dropping an lmo 1 / L aqueous solution of potassium hydroxide in order to decrease the pH of the reaction solution with the dropwise addition.
  • Example 2 Synthesis of racemic (2R *, 3S *)-3-cyclohexyl-2-oxylancarboxylic acid In a reaction flask equipped with a cooling tube, thermometer, pH meter, hydrogen peroxide solution dropping tube, and alkaline solution dropping tube, the toluene of 2,3-trans-13-cyclohexyl-2-propenoic acid obtained in Reference Example 1 was added.
  • a solution (purity 36.2%, 693 g, 1.63 mol) was charged, the temperature was raised to 60 ° C, and about 400 g of toluene was distilled off under reduced pressure. The residue was charged with water (2510 g) and sodium ungustenate 'dihydrate (82.5, 0.24 mmol), and the pH of the reaction mixture was found to be 5.78 at 60 ° C. The pH of the reaction solution was adjusted to 5.3 by adding 70% sulfuric acid (about 21.8 g). A 35% aqueous hydrogen peroxide solution (194 g, 1.96 mol) was added dropwise over about 4 hours.
  • the pH in the reaction system was adjusted to 5.25 to 5.30 while dropping a 35% aqueous sodium hydroxide solution.
  • the 35% sodium hydroxide aqueous solution was dropped using a pH controller in conjunction with a pH meter.
  • the mixture was stirred at 60 ° C for 2 hours.
  • 35% aqueous hydrogen peroxide (40.9 g, 0.42 mO 1) was added while adjusting the pH in the reaction system to 5.25 to 5.30, and the mixture was stirred at 60 ° C for 2 hours.
  • aqueous hydrogen peroxide (19.4 g, 0.20 mol 1) was added while adjusting the pH in the reaction system to 5.25 to 5.30, and the mixture was stirred at 60 ° C for 2 hours.
  • the reaction solution was cooled to 5 ° C, toluene (1004 g) was added, 70% sulfuric acid (126 g) was added dropwise at 5 ° C, and the mixture was stirred for 30 minutes.
  • a 3% aqueous solution of sodium sulfite (78 g) was added to the organic layer, and the mixture was stirred at 5 ° C for 30 minutes, and then the aqueous layer was separated.
  • Example? -8 Synthesis of racemic (2R *, 3S *)-13-cyclohexyl-12-oxysilanecarboxylic acid Table 2 shows the results obtained by performing the reaction in the same manner as in Example 1 except that the reaction temperature in Example 1 was changed as described below.
  • Example 9 Synthesis of racemic (2R *, 3S *)-3-cyclohexyl-2-oxylancarboxylic acid In a reaction flask, 2,3-trans-13-cyclohexyl-1-propenoic acid (0.48 g, 3.1 mmo 1), 1,2-dichlorobenzene (9.5 g) and peracetic acid
  • aqueous ammonia (10 g, 165 mmo 1) was placed in a 10 OmL autoclave, and the temperature was raised to 100 ° C. with stirring.
  • a 2 L autoclave was charged with 28% aqueous ammonia (367 g, 6.04 mol) and heated to 95 ° C. with stirring.
  • a solution of (2S, 3R) -3-cyclohexyl-1-oxysilanecarboxylic acid (35.4g, 0.208mo 1) in toluene (147g) was pumped into a autoclave under pressure for 2 hours. It was dropped. After washing the pump with toluene (20 g), the mixture was stirred for 4 hours.
  • Racemic (2R *, 3 S *) _ 3-cyclohexyl-1-oxysilanecarbonic acid (0.49 g, 2.9 mmo 1) is dissolved in ethanol (1.2 g) and (R) -2 amino-1 After adding phenylethanol (0.24 g, 1.59 mmo 1), the mixture was heated and dissolved at 50 ° C, and cooled to 20 ° C over 2 hours. The precipitated crystals are collected by filtration and dried, and the salt of (2S, 3R) -3-cyclohexyl-1-oxosilane is converted to white crystals from the salt of rubonic acid and (R) -2-amino-1-phenylethanol. Thus, 0.23 g (yield 26%) was obtained.
  • Example 15 Optical resolution of 3-cyclohexyl-2-oxosilanecarboxylic acid
  • A (2S, 3R) —3-cyclohexyl-12-oxosilanecarboxylic acid and
  • the salt prepared in (A) was subjected to liquid chromatography in the same manner as in Example 14.
  • Comparative Example 1 Optical resolution of 3-cyclohexyloxy-2-carboxylic acid Racemic (2R *, 3S *)-13-cyclohexyl-2-oxolanecarboxylic acid (2.1 g, 12.3 mmo 1) It was dissolved in ethanol (20 mL), brucine (4.2 g, 10.8 mmo 1) was added, and the mixture was dissolved by heating at 60 ° C. Then, heptane was added and the mixture was cooled to room temperature. The precipitated crystals were collected by filtration and dried to give O.lg (yield 2%) as a white solid.
  • Comparative Example 2 Optical Resolution of 3-Cyclohexyl-2-oxysilanecarboxylic Acid The reaction was carried out in the same manner as in Comparative Example 1 except that brucine in Comparative Example 1 was changed to cinchonine or (R) -phenylethylamine. When the solid obtained was confirmed, the yield was 4% for cinchonine, l% ee optical purity, and 2% for (R) -phenylethylamine, l% ee optical purity. . Industrial applicability
  • a 2-, 3-trans-3-substituted-l- 2-propene penic acid which is an easily available 2- (amino-protected amino) -3-hydroxypropanoic acid derivative, is used as a starting material.
  • 2- (amino-protected amino) -3-hydroxypropanoic acid derivative is used as a starting material.

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Abstract

Procédé servant à préparer un composé représenté par la formule (I), dans laquelle R2 représente hydrogène ou un groupe de protection amino. Ce procédé consiste à soumettre un composé représenté par la formule (II), dans laquelle R1 représente alkyle ou un composé carbocyclique monocyclique ou hétérocyclique, à une réaction d'ouverture de noyau avec ammoniaque, puis éventuellement une réaction de protection. Composé représenté par la formule (IV), dans laquelle R3 représente alkyle substitué ou aryle substitué, X et Y représentent respectivement OR4 et NHR5 ou respectivement NHR5 et OR4, R4 et R5 représentant indépendamment chacun hydrogène, alkyle substitué ou aryle substitué. Procédé servant à préparer ce composé. Ces composés représentés par la formule (I), (II) et (IV) sont utiles en tant qu'intermédiaires importants pour des produits médicaux ou, par exemple, chimiques agricoles.
PCT/JP2003/014199 2002-11-08 2003-11-07 Procede servant a preparer un derive d'acide 2-amino-3-hydroxypropanoique WO2004043905A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0048953A2 (fr) * 1980-09-29 1982-04-07 E.R. Squibb & Sons, Inc. Antibiotiques de bêta-lactame
JPS61189264A (ja) * 1985-02-15 1986-08-22 Suntory Ltd プロリン誘導体の製造方法
JP2003055358A (ja) * 2001-08-09 2003-02-26 Ono Pharmaceut Co Ltd β−ヒドロキシアミノ酸誘導体の製造方法
WO2003066578A1 (fr) * 2002-02-07 2003-08-14 Ono Pharmaceutical Co., Ltd. Methode de production d'un derive d'acide beta-hydroxyamino et d'un intermediaire dudit derive

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0048953A2 (fr) * 1980-09-29 1982-04-07 E.R. Squibb & Sons, Inc. Antibiotiques de bêta-lactame
JPS61189264A (ja) * 1985-02-15 1986-08-22 Suntory Ltd プロリン誘導体の製造方法
JP2003055358A (ja) * 2001-08-09 2003-02-26 Ono Pharmaceut Co Ltd β−ヒドロキシアミノ酸誘導体の製造方法
WO2003066578A1 (fr) * 2002-02-07 2003-08-14 Ono Pharmaceutical Co., Ltd. Methode de production d'un derive d'acide beta-hydroxyamino et d'un intermediaire dudit derive

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Title
CARDANI ET AL: "Asymmetric Synthesis of Functionalized alpha-Amino-beta-Hydroxi Acids via Chiral Norephedrine-Derived Oxazolidines", TETRAHEDRON, vol. 44, no. 17, 1988, pages 5563 - 5572, XP002977610 *
KUROKAWA ET AL.: "Synthetic Studies on Antifungal Cyclic Peptides, Echinocandins. Stereoselective Total Synthesis of Echinocandin D via a Novel Peptide Coupling", TETRAHEDRON, vol. 49, no. 28, 1993, pages 6195 - 6222, XP000571478 *
KUROKAWA ET AL.: "Total Synthesis of Echinocandins. 1. Stereocontrolled Syntheses of the Constituent Amino Acids", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 108, no. 19, 1986, pages 6041 - 6043, XP002977612 *
MURAKAMI ET AL.: "A Stereoselective Synthesis of 2-Amino-2-Deoxy-D-Ribose", CHEMISTRY LETTERS, no. 8, 1982, pages 1271 - 1274, XP002977611 *
PONS ET AL.: "Efficient Synthesis of Enantiometrically Pure L and D-Allothreonines and (S) and (R) Isoserines", TETRAHEDRON LETTERS, vol. 31, no. 35, 1990, pages 5023 - 5026, XP002977609 *

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