WO2007105729A1 - Procédé de synthèse d'un cyclopropylamide - Google Patents

Procédé de synthèse d'un cyclopropylamide Download PDF

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Publication number
WO2007105729A1
WO2007105729A1 PCT/JP2007/054969 JP2007054969W WO2007105729A1 WO 2007105729 A1 WO2007105729 A1 WO 2007105729A1 JP 2007054969 W JP2007054969 W JP 2007054969W WO 2007105729 A1 WO2007105729 A1 WO 2007105729A1
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Prior art keywords
acid
represented
propyloxysilanecarboxylic
cyclopropylamide
chemical
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PCT/JP2007/054969
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English (en)
Japanese (ja)
Inventor
Tomoyuki Onishi
Takayoshi Torii
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Ajinomoto Co., Inc.
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Publication of WO2007105729A1 publication Critical patent/WO2007105729A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C247/00—Compounds containing azido groups
    • C07C247/02—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C247/12—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D301/00—Preparation of oxiranes
    • C07D301/32—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/48—Compounds containing oxirane rings 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, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • the present invention relates to a cyclopropylamide compound, specifically, the following formula (3):
  • the present invention relates to a method for producing 3-amino-2-hydroxyhexanoic acid cyclopropylamide represented by the formula, a novel compound useful for the production of the cyclopropylamide, and a method for producing the novel compound.
  • the present invention also relates to a process for producing (2S, 3R) -3-propyloxysilanecarboxylic acid, which is useful for producing a specific optically active form of 3-amino-2-hydroxyhexanoic acid cyclopropylamide.
  • 3-Amino_2-hydroxyhexanoic acid cyclopropylamide is a useful compound as an intermediate of a pharmaceutical compound.
  • its optically active compound (2S, 3S) -3-amino-2-hydroxyl Xanthic acid cyclopropylamide is known as hepatitis C drug (6):
  • the method for producing 3-amino-2-hydroxyhexanoic acid cyclopropylamide includes protecting the amino group of 3-amino-2-hydroxyhexanoic acid, amidating the carboxylic acid moiety, and then protecting the group. There is known a method for removing (see Patent Document 2).
  • 3-amino_2-hydroxyhexanoic acid is produced by, for example, using power levalin as a starting material and reducing the carboxylic acid site to an aldehyde, hydrocyano hydride, and hydrolysis (Patent Document) Preparations are not always easy because they require many steps.
  • Patent Document 1 Pamphlet of International Publication No. 98/17679
  • Patent Document 2 International Publication No. 2002/18369 Pamphlet
  • Patent Document 3 US Patent Application Publication 2005/197301
  • Non-Patent Document 1 S.-H. Chen et al., Letters in Drug Design & Discovery 2005, 2, 118
  • the present invention relates to an efficient method for producing 3-amino-1-hydroxyhexanoic acid cyclopropylamide suitable for industrial production, an intermediate compound useful for the production method, and an intermediate compound.
  • An object is to provide a manufacturing method.
  • 3-propyloxysilane carboxylic acid cyclopropylamide is useful for the production of 3-amino-2-hydroxyhexanoic acid cyclopropyl amide.
  • 3-propylaminosilane cyclopropylamide is reacted with a metal azide to form an azide, which can be easily reduced to obtain 3-amino-2-hydroxyhexanoic acid cyclopropylamide. I found it.
  • 3_propyloxysilanecarboxylic acid cyclopropylamide is a novel compound, the present inventors have found that the compound can be easily produced by reacting 3_propyloxysilanecarboxylic acid with cyclopropylamine. .
  • the inventors of the present invention are (2S, 3S) _3-amino-1-hydroxyhexanoic acid, which is an optically active form of 3-amino-1-hydroxyhexanoic acid cycloamide by these methods.
  • Shi The present inventors have found a method for easily obtaining (2S, 3R) -3-propyloxysilanecarboxylic acid as a starting material by diastereomer method in producing chloropropylamide.
  • a method for producing (2S, 3R) 3 propyl oxysilane carboxylic acid a method of oxidizing oxysilane carbinol obtained by sharp pressing asymmetric epoxidation of 2 hexene 1-ol was known (L.
  • the present inventors have completed the present invention based on the above findings. That is, the present invention includes the following contents.
  • a 3-propyloxysilane carboxylic acid represented by the following formula (1) is reacted with cyclopropylamine:
  • a process for producing 3-propylbenzoic acid cyclopropylamide represented by:
  • 3-amino-1-hydroxyhexanoic acid represented by the above formula (3) which is useful as an intermediate for producing a hepatitis C drug represented by the above formula (6)
  • Cycloguchi propinoreamide and its production intermediate (3-propyloxysilanecarboxylic acid cyclopropenoleamide represented by the above formula (1), 3-azido 2-hydroxyhexanoic acid cyclopropyl amide represented by the above formula (2) )
  • the above formula (3 ′) useful as an intermediate for producing a hepatitis C drug represented by the formula (6).
  • (2S, 3S) -3-amino-2-hydroxyhexanoic acid cyclopropylamide and its production intermediate ((2S, 3R) -3-propyloxysilane represented by the formula (1 ′))
  • Carbonic acid cyclopropylamide, (2S, 3S) —3-azido-2-hydroxyhexanoic acid cyclopropylamide, represented by the above formula (2,) is efficiently produced by a method suitable for industrial production The power to do S.
  • (2S, 3R) represented by the above formula (4 ′) that can be used as a starting material for the production of the compounds represented by the above formulas (1 ′) to (3 ′).
  • _ 3 _Propyloxysilanecarboxylic acid can be efficiently produced by a method suitable for industrial production.
  • a 3-propyloxysilanecarboxylic acid cyclopropylamide represented by the formula (1) is reacted with a metal azide to produce a 3-azido 2-hydroxyhexanoic acid cycla represented by the formula (2).
  • a method for producing oral propylamide will be described. Note that 3-propyloxysilane strength rubonic acid cyclopropylamide and 3-azido 2-hydroxyhexanoic acid cyclopropylamide are novel compounds.
  • metal azide examples include potassium azide, strontium azide, cesium azide, sodium azide, lead azide, barium azide, lithium azide, rubidium azide and the like. In particular, sodium azide and lithium azide are preferable.
  • the amount of metal azide to be used is usually 1 to 5 monoequivalents, preferably 1 to 2 molar equivalents per mol of 3_propyloxysilanecarboxylic acid cyclopropylamide.
  • the salt examples include aluminum chloride, indium chloride, cobalt (II) chloride, dinoleconium chloride, zinc nitrate, copper nitrate (II), nickel nitrate (II) nitrate, cobalt sulfate (II), magnesium sulfate and the like. . Particularly preferred is copper (II) nitrate.
  • the amount of salt used is usually from 0.001 to 1 per 1 mol of 3-propyloxysilanecarboxylic acid cyclopropylamide. Molar equivalent, preferably 0 ⁇ 01 to 0.2 molar equivalent.
  • reaction solvent examples include water, methanol, ethanol, acetonitrile, tetrahydrofuran, ⁇ , ⁇ ⁇ ⁇ ⁇ -dimethylformamide, and any mixed solvent thereof.
  • a mixed solvent containing water and water are preferable.
  • the reaction temperature is preferably 10 to 70 ° C.
  • the reaction time is usually about 50 hours at 10 minutes.
  • purify by a treatment such as extraction with an appropriate organic solvent.
  • the obtained 3_azido_2-hydroxyhexanoic acid cyclopropylamide can be isolated as a solid by methods known to those skilled in the art, such as crystallization and chromatography. Can be used for
  • the 3_azido_2-hydroxyhexanoic acid cyclopropylamide represented by the formula (2) is reduced to the 3-amino_2-hydroxy represented by the formula (3).
  • a method for producing xanthic acid cyclopropylamide will be described. The reduction can be carried out by catalytic reduction or using a suitable reducing agent.
  • Catalytic reduction can be carried out according to methods known to those skilled in the art.
  • the catalyst used for the catalytic reduction include palladium, rhodium, ruthenium, platinum and nickel. These are usually used by being supported on a carrier such as activated carbon, silica, alumina, barium sulfate or calcium carbonate.
  • the catalyst may contain water.
  • palladium is preferably used by being supported on a support, such as palladium carbon, which is particularly preferred.
  • the amount of the catalyst to be used is usually 0.:! To 50% by mass, preferably 0.:! To 25% by mass, based on 3-azido 2-hydroxyhexanoic acid cyclopropylamide.
  • Examples of the solvent used for the catalytic reduction include water, methanol, ethanol, ethyl acetate, tetrahydrofuran, and any mixed solvent thereof.
  • the hydrogen pressure at the time of contact reduction is preferably 1 to 10 atm.
  • the reaction temperature is usually 0 ° C to 60 ° C, preferably 10 ° C to 40 ° C.
  • the reaction time is usually about 10 minutes to 50 hours. After completion of the reaction, the catalyst can be separated from the system by filtration or the like.
  • reaction solvent examples include water, methanol, ethanol, tert-butanol, ether, tetrahydrofuran, and the like. And an arbitrary mixed solvent thereof.
  • the reaction temperature is preferably ⁇ 10 to 30 ° C.
  • the reaction time is usually about 10 minutes to 50 hours.
  • the obtained 3-amino-2-hydroxyhexanoic acid cyclopropylamide can be purified and isolated by methods known to those skilled in the art, such as crystallization and chromatography.
  • 3_propyloxysilanecarboxylic acid cyclopentoleamide represented by the above formula (1) 3_azido_2-hydroxyhexanoic acid cyclopropylamide represented by the above formula (2), and the above
  • the 3-amino-1-hydroxyhexanoic acid cyclopropylamide represented by the formula (3) may be racemic or optically active, respectively.
  • 3_propyloxysilane carboxylic acid cyclopropylamide can be produced by reacting 3_propyloxysilanecarboxylic acid represented by the above formula (4) with cyclopropylamine.
  • the reaction can be carried out in the presence of a suitable condensing agent and a base.
  • 3-propyloxysilane carboxylic acid can be converted to a mixed acid anhydride with an acylating reagent in the presence of a base and then reacted with cyclopropylamine.
  • the 3-propyloxysilanecarboxylic acid represented by the formula (4) may be a racemate or an optically active substance.
  • condensing agents used in peptide synthesis can be widely used.
  • the amount of the condensing agent to be used is usually 1 to 3 mole equivalents, preferably 1 to 1.5 mole equivalents per mole of 3-propyloxysilanecarboxylic acid.
  • Examples of the base include triethylamine, diisopropylethylamine, dicyclohexenoremethinoleamine, N-methylmorpholine, N-ethylmorpholine, pyridine, 2,6-lutidine, 2,4,6- Organic bases such as collidine, 4_picoline, N-ethylpiperidine, N, N-dimethylaminopyridine and the like can be mentioned.
  • the amount of the base used is usually 1 to 3 molar equivalents, preferably 1 to 1.5 molar equivalents per mol of 3_propyloxysilane force rubonic acid.
  • the amount of cyclopropylamine used is usually:! To 3 molar equivalents, preferably:! To 1.5 molar equivalents per mole of 3_propyloxysilanecarboxylic acid.
  • reaction solvent examples include ethyl acetate, isopropyl acetate, toluene, jetyl ether, t-butyl methyl ether, tetrahydrofuran, dichloromethane, chlorophenol, N, N dimethylformamide, 1-methyl-2-pyrrolidone, and any mixture thereof.
  • solvents examples include solvents.
  • the reaction temperature is preferably ⁇ 10 to 30 ° C.
  • the reaction time is usually about 10 minutes to 50 hours.
  • the acylation reagent is:
  • the amount of the acylating reagent to be used is generally 1 to 3 molar equivalents, preferably:! To 1.5 molar equivalents per 1 mol of 3-propyloxysilanecarboxylic acid.
  • Examples of the base include triethylamine, diisopropylethylamine, dicyclohexenoremethinoleamine, N-methylmorpholine, N-ethylmorpholine, pyridine, 2,6-lutidine, 2,4,6- Organic bases such as collidine, 4_picoline, N-ethylpiperidine, N, N-dimethylaminopyridine and the like can be mentioned.
  • the amount of the base used is usually 1 to 3 molar equivalents, preferably 1 to 1.5 molar equivalents per mol of 3_propyloxysilane force rubonic acid.
  • the amount of cyclopropylamine used is 1 mol of 3_propyloxysilanecarboxylic acid. , Usually 1 to 3 molar equivalents, preferably 1 to: ⁇ ⁇ 5 moles.
  • the reaction solvent include ethyl acetate, isopropyl acetate, toluene, jetyl ether, t-butyl methyl ether, tetrahydrofuran, dichloromethane, chloroform, N, N dimethylformamide, 1_methyl_2_pyrrolidone, and any of these. And the like.
  • the mixed acid anhydride is relatively unstable, it is preferably prepared at -30 to 10 ° C.
  • 3_propyloxysilanecarboxylic acid cyclopropylamide is obtained by adding cyclopropylamine to the reaction mixture and reacting.
  • the reaction temperature is preferably -30 to 30 ° C.
  • the reaction time is usually about 10 minutes to 50 hours.
  • it is preferable to purify by a treatment such as adding an acid such as hydrochloric acid or sulfuric acid to the reaction solution and extracting with an appropriate organic solvent.
  • the obtained 3_propyloxysilanecarboxylic acid cyclopropylamide can be isolated by methods known to those skilled in the art, such as distillation and chromatography, but may be used in the next reaction without isolation.
  • 3_propyloxysilanecarboxylic acid is produced by oxidizing trans_2-hexenoic acid.
  • trans_2-hexenoic acid See, for example, PF Corey et al., Journal 'Ob'Organic' Chemistry, 51 ⁇ , 1925, 1986 (see J. Org. Chem. 1986, 51, 1925).
  • Examples of the oxidizing agent include hydrogen peroxide, m-peroxybenzoic acid, oxone TM persulfate compound, and the like. Oxone TM persulfate compounds are particularly preferred.
  • the amount of the oxidizing agent used is usually 1 to 3 molar equivalents, preferably:! To 2 molar equivalents, per 1 mol of trans 2-hexenoic acid.
  • Examples of the reaction solvent include acetone, ethyl methyl ketone, isobutyl methyl ketone, water, and any mixed solvent thereof. A mixed solvent of acetone and water is particularly preferable. It is preferable to control the pH to 6 or higher during the reaction.
  • hexenoic acid For each mole of tran s _ 2—hexenoic acid, 2 to 5 molar equivalents of sodium bicarbonate are present and the pH is controlled to 6 or higher. It is particularly preferred.
  • the reaction temperature is preferably 0 to 70 ° C.
  • the reaction time is usually about 10 minutes to 50 hours.
  • an acid such as hydrochloric acid or sulfuric acid
  • the obtained 3-propyloxysilanecarboxylic acid can be isolated as a solid by methods known to those skilled in the art such as crystallization and chromatography, but may be used for the next reaction without isolation.
  • the 3 propyl oxysilane carboxylic acid obtained by the above method is usually a racemate containing (2R, 3S) 3 propyl oxysilane carboxylic acid and (2S, 3R) 3 propyl oxysilane carboxylic acid.
  • the racemate can be optically resolved by a diastereomer method using an optically active amine compound, and an optically active 3-propyloxysilanecarboxylic acid can be obtained.
  • (2S, 3R) _3-propyloxysilanecarboxylic acid force S containing (2R, 3S) _3_propyloxysilanecarboxylic acid as an impurity is used for the optical resolution of the present invention.
  • (2R, 3S) _ 3 _propyloxysilane carboxylic acid is included as an impurity (2S, 3R) _ 3
  • (2S, 3R) _ 3 propyloxysilanecarboxylic acid with high optical purity
  • the reaction is usually carried out in a solvent.
  • a solvent water and alcohol-based organic solvents are preferably used. Water is particularly preferable.
  • the alcohol-based organic solvent include methanol, ethanol, 1_propanol, 2_propanol, tert-butanol, and any mixed solvent thereof.
  • a mixture of water and an alcohol-based organic solvent may be used. These solvents and non-alcohol organic solvents may be mixed and used.
  • Non-alcohol solvents include, for example, ethyl acetate, isopropyl acetate, toluene, xylene, cyclohexane, methylcyclohexane, tert butyl methyl ether, isobutyl methyl ketone, butyl acetate, black benzene, tetrahydrofuran, N, N dimethyl Nolehonolemamide, N, N-dimethylacetamide, dimethyl sulfoxide, N methinole_2 pyrrolidone, N ethyl pyrrolidone, acetone, ethyl methyl ketone, acetonitrile, and any mixed solvent thereof may be mentioned.
  • the usage-amount of a solvent is 4-200 times mass normally with respect to 3-propyl oxysilane carboxylic acid, Preferably it is 8-100 times mass, More preferably, it is 8-50 times mass.
  • the amount of the optically active amine compound to be used is usually 0.5 to 1.5 molar equivalents, preferably 0.8 to 1.2 molar equivalents with respect to 1 mol of 3 propyloxysilanecarboxylic acid. is there.
  • the reaction temperature is generally 0 to: 120 ° C, preferably. 20 to: 100 ° C, more preferably 40: a 100 o C.
  • the reaction time is usually about 0.:! To 2 hours, preferably about 0.5 to :! hours.
  • the diastereomeric salt formed is usually separated by separating the salt, neutralizing the salt, and isolating (2S, 3R) _3_propyloxysilanecarboxylic acid.
  • the crystallization solvent the same solvent as the reaction solvent can be used. Crystallization can be performed, for example, under the following conditions. After completion of the reaction, the reaction solution is first cooled. The cooling is usually:! ⁇ 10 hours, preferably 2 ⁇ 5 hours gradually. The temperature reached by cooling is 0 to 40 ° C, preferably 0 to 25 ° C. The reaction solution is stirred at the cooling reached temperature, and crystallization is performed. The crystallization time is usually about 0.5 to 24 hours, preferably about 1 to 5 hours.
  • the precipitated diastereomeric salt crystals can be separated from the reaction solution by operations such as filtration and centrifugation. [0075] After the diastereomeric salt is obtained as crystals, the salt is neutralized and (2S, 3R) -3 propyl oxysilane carboxylic acid is isolated. Neutralization and isolation can be performed by extracting diastereomeric salts with an aprotic organic solvent under acidic conditions.
  • the extraction can be performed by a known method.
  • an organic solvent such as ether, ethyl acetate, isopropyl acetate, or toluene is used as the organic phase
  • an acidic aqueous solution such as aqueous hydrochloric acid or sulfuric acid is used as the aqueous phase, and the diastereomeric salt is extracted to the organic layer side.
  • the pH of the acidic water solution is usually pHO.5-3, preferably 1-2.
  • racemic 3_propyloxysilanecarboxylic acid when racemic 3_propyloxysilanecarboxylic acid is used, according to the present invention, an optically active (2S, 3R) -3-propyloxysilanecarboxylic acid having an optical purity of 80% ee or more is obtained. be able to.
  • Preferred optically active amine compounds in the present invention include (1R, 2S)-(+)-cis-1-amino-2-indanol, (IS, 2R)-(—) mono-cis-1-amino- 2-Indanol, (1R, 2S) — (1) 2-Amino-1, 2-diphenylethanol, (IS, 2R) — (+) — 2-Amino-1,2,2-diphenylethanol, (1R, 2R ) - (-) - 2-Amino one 1- (4-Nitorofue sulfonyl) one 1, 3 - propanediol, (1 S, 2S) - (+) - 2- amino-1- (4 - Nitorofue sulfonyl) 1 1,3-propanediol, (1R, 2R) — (—) — 2-amino 1-phenyl 1, 3-propanediol, (IS, 2S) — (+) — 2-amino 1-pheny
  • a particularly preferred optically active amine compound is brucine.
  • (2S, 3R) _3_propyde represented by the formula (5) obtained by the production method of the present invention
  • the brucine salt of luxiylcarboxylic acid is a novel compound.
  • the brucine salt of (2S, 3R) 3-propyloxysilanecarboxylic acid represented by the formula (5) is useful as an intermediate for producing the hepatitis C drug represented by the formula (6).
  • optical purity of (2S *, 3R *)-2,3-epoxyhexanoic acid is determined by CP after derivatization to (2S *, 3R *) _ 2,3_epoxyhexanoate with trimethylsilyldiazomethane.
  • the absolute configuration of (2S *, 3R *) _ 2,3-epoxyhexanoic acid was determined from literature values by measuring the optical rotation after conversion to the methyl ester (Chem. Ber. 1986, 119, 2178).
  • (+)-(2S, 3R) _Epoxyhexanoic acid brucine salt (105 mg, 0.200 mmol) prepared in Example 1 was mixed with ether (4.0 ml) and 1M hydrochloric acid (1 ml) and stirred. The layers were separated. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and (+)-(2S, 3R) _epoxyhexanoic acid ( 22.5 mg, 0.173 mmol, 86%) was obtained as a colorless oil. When the optical purity of the product was determined based on the method described in Reference Example 1, it was confirmed to be 84% ee.
  • (+)-(2S, 3R) _Epoxyhexanoic acid brucine salt (1.00 g, 1.91 mmol) prepared in Example 7 was stirred with ether (38 ml) and 1M hydrochloric acid (9.5 ml). The layers were separated. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to obtain (+)-(2S, 3R) _epoxyhexanoic acid (231 mg, 1.77 mmol, 93%) as a colorless oil. . When the optical purity of the product was determined based on the method described in Reference Example 1, it was confirmed to be 100% e.e.
  • (+) _ (2S, 3R) _2,3_epoxyhexanoic acid (170 mg, 1.31 mmol) and triethylamine (201 ⁇ , 1.44 mmol) with optical purity of 100% ee prepared in Example 8 were mixed with dichloromethane (1.3 After cooling to _10 ° C, bivaloyl chloride (177 ⁇ 1, 1.44 mmol) in dichloromethane (0.7 m 1) The solution was added. After stirring at ⁇ 10 ° C. for 30 minutes, a solution of cyclopropylamine (100 ⁇ , 1.44 mmol) in dichloromethane (0.7 ml) was added. After further stirring at ⁇ 10 ° C.
  • (+)-(2S, 3R) -2,3-Epoxyhexanoic acid cyclopropylamide (106 mg, 0.626 mmol) was mixed with water (1.2 ml), then sodium azide (61.0 mg, 0.939 mmol) was added. added. After adding a solution of copper nitrate ( ⁇ ) trihydrate (15.1 mg, 0.063 mmol) in water (0.2 ml) to the mixture, the mixture was stirred at 65 ° C for 16 hours. Ethyl acetate was added and extracted, and the organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure.

Abstract

La présente invention concerne : un procédé de synthèse du cyclopropylamide de l'acide 3-amino-2-hydroxyhexanoïque très efficace, adapté à la production à échelle industrielle ; un composé intermédiaire pouvant être employé dans le procédé ; et un procédé de synthèse du composé intermédiaire. Le cyclopropylamide de l'acide 3-amino-2-hydroxyhexanoïque peut être obtenu par réaction du cyclopropylamide de l'acide 3-propyloxirannecarboxylique avec un azide métallique pour obtenir le cyclopropylamide de l'acide 3-azide-2-hydroxyhexanoïque, avant réduction du produit. Le cyclopropylamide de l'acide 3-propyloxirannecarboxylique peut être obtenu par réaction de l'acide 3-propyloxirannecarboxylique avec la cyclopropylamine. Une forme optiquement active du cyclopropylamide de l'acide 3-amino-2-hydroxyhexanoïque peut être obtenue en utilisant au titre de produit de départ l'acide (2S,3R)-3-propyloxirannecarboxylique optiquement actif qui peut être lui-même obtenu par une méthode faisant intervenir des diastéréoisomères.
PCT/JP2007/054969 2006-03-13 2007-03-13 Procédé de synthèse d'un cyclopropylamide WO2007105729A1 (fr)

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EP2039689A1 (fr) * 2006-05-26 2009-03-25 Kaneka Corporation Procédé de production de dérivés optiquement actifs de cyclopropylamide d'acide 3-amino-2-hydroxypropionique et de leurs sels
WO2009081608A1 (fr) * 2007-12-21 2009-07-02 Kaneka Corporation Procédé de production d'hydrochlorure amide de l'acide n-cyclopropyl-3-amino-2-hydroxyhéxanoïque
JP2009530282A (ja) * 2006-03-16 2009-08-27 バーテックス ファーマシューティカルズ インコーポレイテッド 立体的化合物を製造するための方法および中間体
US7612237B2 (en) 2006-07-04 2009-11-03 Degussa Gmbh Process for preparing β-amino-α-hydroxycarboxamides
CN101691338B (zh) * 2009-08-26 2013-08-14 凯莱英生命科学技术(天津)有限公司 一种手性环氧化合物的合成方法及其中间产物与最终产物
US8993577B2 (en) 2009-02-20 2015-03-31 Astrazeneca Ab Cyclopropyl amide derivatives
US9012452B2 (en) 2010-02-18 2015-04-21 Astrazeneca Ab Processes for making cyclopropyl amide derivatives and intermediates associated therewith
US9029381B2 (en) 2007-08-22 2015-05-12 Astrazeneca Ab Cyclopropyl amide derivatives

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US8993577B2 (en) 2009-02-20 2015-03-31 Astrazeneca Ab Cyclopropyl amide derivatives
CN101691338B (zh) * 2009-08-26 2013-08-14 凯莱英生命科学技术(天津)有限公司 一种手性环氧化合物的合成方法及其中间产物与最终产物
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