WO2003066578A1 - Methode de production d'un derive d'acide beta-hydroxyamino et d'un intermediaire dudit derive - Google Patents

Methode de production d'un derive d'acide beta-hydroxyamino et d'un intermediaire dudit derive Download PDF

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Publication number
WO2003066578A1
WO2003066578A1 PCT/JP2003/001239 JP0301239W WO03066578A1 WO 2003066578 A1 WO2003066578 A1 WO 2003066578A1 JP 0301239 W JP0301239 W JP 0301239W WO 03066578 A1 WO03066578 A1 WO 03066578A1
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Prior art keywords
group
tetrahydropyran
formula
general formula
salt
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PCT/JP2003/001239
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English (en)
Japanese (ja)
Inventor
Naoki Matsunaga
Katsuya Hisaichi
Yoshikazu Takaoka
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Ono Pharmaceutical Co., Ltd.
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Priority to AU2003211488A priority Critical patent/AU2003211488A1/en
Publication of WO2003066578A1 publication Critical patent/WO2003066578A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D339/00—Heterocyclic compounds containing rings having two sulfur atoms as the only ring hetero atoms
    • C07D339/08—Six-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/02—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups
    • C07C251/20—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups being part of rings other than six-membered aromatic rings
    • 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 method for producing a hydroxy-3-amino acid derivative and an intermediate thereof.
  • the present invention relates to novel pinene derivatives and salts thereof, methods for producing them, and methods for producing optically active i3-hydroxyamino acid derivatives and salts thereof using the same.
  • the present invention relates to a method for producing an optically active 1-hydroxyamino acid, particularly a 2- (t-butoxycalponyl) amino- 3 -hydroxypropanoic acid derivative represented by the formula:
  • j3-Hydroxyamino acid derivatives are generally important compounds as intermediates for pharmaceuticals, and many synthetic methods have been developed.
  • Synthesis, 34-36, (1990) describes a method represented by Reaction Scheme 1.
  • the method represented by the reaction scheme 1 is a method for synthesizing (2S, 3S) -2-amino-13-hydroxy-4-methylpentanoic acid using 4-methyl-2-penten-1-ol as a starting material.
  • the present inventors have found that (2R, 3R) —2-amino-3-hydroxyl-3 can be obtained by using a formylcyclohexane as a starting material and by a method similar to the method shown in the reaction scheme 1.
  • DI BALH represents hydrogenated diisobutylaluminum
  • THF represents tetrahydrofuran
  • S0 3 ⁇ P y represents a sulfur trioxide 'pyridine complex
  • DMSO represents dimethyl sulfoxide
  • B oc 2 ⁇ is di - t one Puchinore dicarbonate (di-t-butyl carbonate) Express.
  • Step 4 is not suitable for mass synthesis due to the reaction at low temperature
  • step 5 The oxidation reaction in step 5 has the danger of explosion in mass synthesis.
  • a binene derivative represented by the general formula (II) and an aldehyde derivative represented by the general formula ( ⁇ ) are subjected to an asymmetric aldol reaction at 0 ° C. in dichloromethane in the presence of titanium chloride triethoxide and triethylamine.
  • (I) To produce a binene derivative and a salt thereof (Step 1), and subjecting the pinene derivative represented by the general formula (I) and a salt thereof to a hydrolysis reaction in tetrahydrobrane in the presence of 1.2 N hydrochloric acid at room temperature, Producing an optically active hydroxyamino acid derivative represented by the general formula (IV) and a salt thereof (Step 2);
  • An optically active hydroxyamino acid derivative represented by the general formula (IV) and a salt thereof are subjected to a hydrolysis reaction in ethanol in the presence of a 1 N aqueous lithium hydroxide solution at room temperature, and further, di-t-butyl dicarbonate is present. Thereafter, the compound is subjected to a protection reaction to produce an optically active 2- (t-butoxycarbonyl) amino-3-hydroxypropanoic acid derivative represented by the general formula (V) and a salt thereof (Step 3).
  • the protection reaction may be performed after the hydrolysis, or the hydrolysis reaction may be performed after the protection reaction.
  • step 2 (1R, 2R, 5R)-(+) — 2-hydroxy-13-pinanone is recovered, and the recovered compound is reacted again with a glycine derivative to obtain a compound of the general formula (II) ) Can be resynthesized. That is, (1 R, 2R, 5R) one (+) — 2-—hid Mouth xie 3-pinanone can be recovered and reused.
  • the production method of the present invention is more advantageous for mass synthesis than the conventional method.
  • pinene derivative represented by the general formula (I) is a novel compound that has not been known so far, and is a useful intermediate of the production method of the present invention.
  • R 1 represents a C 1-8 alkyl group
  • Cy cl is a 3- to 15-membered C3 to C15 monocyclic, bicyclic or tricyclic carbocycle or 1 to 5 heteroatoms selected from oxygen, nitrogen or sulfur atoms Represents a monocyclic, bicyclic or tricyclic heterocyclic ring, wherein Cy cl is 1 to 5 R 3 May be replaced by
  • R 3 represents a C 1-8 alkyl group, a C 1-8 alkoxy group, a hydroxyl group, a C 1-8 alkoxy group or a oxo group substituted by a C 1-8 alkoxy group.
  • the present invention relates to a method for producing an optically active 2-(-tert-butoxycarbonyl) amino-3-hydroxypropanoic acid derivative represented by the formula: or a salt thereof.
  • the Cl8 alkyl group refers to a methyl, ethyl, propyl, butanol, pentyl, hexyl, heptyl, octyl group and isomers thereof.
  • a C 28 alkenyl group means a C 28 alkenyl group having 12 double bonds, and specifically, ether, propenyl, butyr, butageninole, penteninole, Pentageninole, hexeninole, hexageninole, heptenyl, heptaenyl, octenyl, octagenyl group and isomers thereof.
  • a C 28 alkynyl group means a C 28 alkynyl group having 12 triple bonds, and specifically, ethel, propynyl, butyral, butadininole, pentininole, pentadyninole. Hexidinole, hexadininole, heptinyl, heptadinyl, otatur, octadininole group and isomers thereof.
  • a C 18 alkoxy group refers to methoxy, ethoxy, Si, butoxy, pentinoleoxy, hexinoleoxy, heptinoleoxy, octyloxy, and isomers thereof.
  • a C 3-15 monocyclic, bicyclic or tricyclic carbocycle includes a C 3-15 monocyclic, bicyclic or tricyclic carbocyclic aryl, a part or all thereof.
  • Carbocycles, spiro-bonded bicyclic carbocycles and bridged bicyclic carbocycles are examples of monocyclic, bicyclic or tricyclic carbocycles.
  • a 3- to 15-membered monocyclic, bicyclic or tricyclic heterocycle containing 1 to 5 heteroatoms selected from an oxygen atom, a nitrogen atom or a sulfur atom includes: 3- to 15-membered monocyclic, bicyclic or tricyclic heterocyclic aryl containing 1 to 5 heteroatoms selected from oxygen, nitrogen or sulfur, partially or wholly saturated And heterocycles.
  • oxygen atom nitrogen source 3- to 15-membered monocyclic, bicyclic or tricyclic heteroaryls containing 1 to 5 heteroatoms selected from the group consisting of pyrrole, imidazole, triazole and tetrazole , Pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepin, thiophene, thiopyran, chepin, genkixazo / re, isisoxazole, thiazole, isotizazole, franzane, oxazine, oxazine, oxazine.
  • allyl include aziridine, azetidine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, virazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, and tetrahydride.
  • -Hydrobenzon fen Dihydroisobenzothiophene, perhydroisobenzothiophene, dihydric indazonole, perhydroindazonole, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydrosoquinoline, perhydroisoquinoline, dihydrotetralophthalazine Dro phthalazine, c.
  • -Hydrophthalazine Dihydronaphthyridine, Tetrahydronaphthyridine, Perhydronaphthyridine, Dihydroquinoxaline, Tetrahydroquinoxaline, Perhydroquinoxalin, Dihydroquinazoline, Tetrahydroquinazoline, Perhydroquinazoline, Dihydrocinnoline, Tetrahydranoline , Benzoxathian, dihydrobenzozoxazine, dihydrobenzozothiazine, virazinomorpholine, dihydrobenzoxazonole, ⁇ .
  • the C3-8 cycloalkylidene group represents a cyclopropylidene, cyclobutylidene, cyclopentylidene, cyclohexylidene, cycloheptylidene or cyclootatilidene group.
  • one of the carbon atoms constituting the ring of the C 3-8 cycloalkylidene group ( ⁇ Excludes carbon atoms having a alkylidene bond.
  • a heterocyclic group in which is replaced by an oxygen atom, a nitrogen atom or a sulfur atom is a divalent group formed by losing two hydrogen atoms from one of the ring-constituting carbon atoms on the heterocyclic ring.
  • the hetero ring include oxetane, oxolan, perhydropyran, réellen, thiolan, thiane, azetidine, pyrrolidine, and piperidine ring.
  • R 1 is preferably a C 1-4 alkyl group, particularly preferably a methyl and ethyl group.
  • R 2 is preferably substituted with a Cl-8 alkyl group, a C1-8 alkyl group substituted by Cycl, Cyc1, or a C3-8 cycloalkylidene group or the heterocyclic group.
  • C 1-8 alkyl group particularly preferably 2-methylpropyl group, 1-ethylpropyl group, cyclopropynole group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptinol group, cyclopentene_ 4-Inole group, Cyclohexene-1-yl group, 4-Methyl / Recyclohexyl group, 4-Hydroxycyclohexyl group, 4-Methoxymethyloxy hexyl group, 4-Methoxy methoxy group Xyl group, 4-ethoxycyclohexyl group, cyclohexylmethynole group, adamantane-11-yl group
  • cyclopentyl cyclohexyl, cycloheptyl, tetrahydropyran-41-yl, 4-methoxymethyloxycyclohexyl or 4-hydroxycyclohexyl. is there.
  • the alkyl group, alkoxy group and alkylene group include straight-chain and branched-chain ones.
  • isomers in double bonds, rings and condensed rings ⁇ , ⁇ , cis, trans
  • isomers due to the presence of asymmetric carbon R, S, ⁇ , ⁇ , enantiomer, diastereomer
  • optical rotation Optically active isomers D, L, d, 1)
  • polar compounds high polar, low polar
  • the compound of the present invention represented by the general formula (I) can be produced by the following methods or the methods described in Examples.
  • This asymmetric aldol reaction is known.
  • an organic metal reagent titanium chloride triethoxide, titanium chloride triisopropoxide, titanium dichloride diisopropoxide, dimethyl alcohol
  • an organic solvent diichloromethane, chlorophonolem, tetrahydrofuran, etc.
  • Aluminum chloride, etc. bases
  • triethylamine, lithium disopropion / reamine, t_butylmagnesium chloride, 1,8,1 diazabisic [5.4.0] In the presence, at a temperature of 0 to 20 ° C.
  • optically active 2_ (t-butoxycarbonyl) amino-3-hydroxypropanoic acid derivative represented by the general formula (V) can be prepared from the pinene derivative represented by the formula (I) and a salt thereof by the following method or It can be produced by the method described in the examples.
  • This hydrolysis reaction is known and is carried out under acidic conditions.
  • an organic solvent tetrahydrofuran, dioxane, ethanol, methanol, etc.
  • an acid acetic acid, trifluoroacetic acid, methanesulfonic acid, hydrochloric acid, sulfuric acid, boric acid, citric acid, ammonium acetate, etc.
  • It is performed at a temperature of 100 ° C.
  • optically active 2_ (t-butoxycarbonyl) amino-3-hydroxypropanoic acid derivative represented by the general formula (IV) ),
  • the carboxylic acid ester moiety of the optically active hydroxyamino acid derivative or a salt thereof is hydrolyzed, and the amino group is further protected with a t-butoxycarbyl group.
  • the protection reaction is performed even if the protection reaction is performed after hydrolysis. After that, a hydrolysis reaction may be performed.
  • This hydrolysis reaction is known and is carried out under alkaline conditions.
  • organic solvents methanol, ethanol, tetrahydrofuran, dioxane, 1,2-dimethoxetane, etc.
  • alkali metal hydroxides sodium hydroxide, hydroxide hydroxide, lithium hydroxide, etc.
  • alkaline hydroxides Use an earth metal hydroxide (barium hydroxide, canoleum hydroxide, etc.) or carbonate (sodium carbonate, potassium carbonate, etc.) or an aqueous solution or a mixture thereof at a temperature of 0 to 40 ° C. Done.
  • This protection reaction is well known, and includes a base (sodium hydroxide, potassium hydroxide, lithium hydroxide, triethynoleamine, dimethylamino) in a water-miscible organic solvent (dioxane, acetate, etc.) and a mixture with water.
  • a base sodium hydroxide, potassium hydroxide, lithium hydroxide, triethynoleamine, dimethylamino
  • a water-miscible organic solvent dioxane, acetate, etc.
  • a protecting reagent such as pyridine and di-t-butyl dicarbonate.
  • the alkaline hydrolysis reaction and the protection reaction can be performed in one pot. That is, for example, in an organic solvent (methanol, ethanol, tetrahydrofuran, dioxane, etc.), an alkali metal hydroxide (sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), an alkaline earth metal hydroxide
  • the reaction is carried out at a temperature of 0 to 40 ° C. using sodium hydroxide (potassium hydroxide, calcium calcium hydroxide, etc.) or a carbonate (sodium carbonate, potassium carbonate, etc.) or an aqueous solution thereof or a mixture thereof. Thereafter, the reaction mixture is treated with ge-butyl dicarbonate at a temperature of 0 to 40 ° C.
  • the protection reaction with di-t-butoxycarbon group is not limited to the reaction using di-t-butyl dicarbonate.
  • the one described in T. W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1991 can be used.
  • R 1 The compound that is tyl is known and has a CAS Registry Number of 90473-01-1.
  • the aldehyde derivative represented by the general formula (III) is a known compound or can be produced by a known method.
  • the CAS registration number for formylcyclohexane where R 2 is a cyclohexyl group is 2043-61-0.
  • the product of each reaction may be isolated, washed, dried and purified for each step and used in the next reaction, or the procedure may not be performed at all or may be stopped at an appropriate stage. The process may proceed.
  • reaction product in each reaction is purified by 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, column chromatography, washing, and recrystallization. Can be purified.
  • 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, column chromatography, washing, and recrystallization.
  • the solvent in the column indicated by the chromatographic separation and the force in the TLC indicates the elution solvent or developing solvent used, and the ratio indicates the volume ratio.
  • Example 1 The same operation as in Example 1 was carried out using the corresponding aldehyde derivative instead of formyl hexane, to obtain the present compound shown below.
  • Example 1 (1) The same operation as in Example 1 was carried out using the corresponding aldehyde derivative instead of formyl hexane, to obtain the present compound shown below.
  • Example 1 (1) The same operation as in Example 1 was carried out using the corresponding aldehyde derivative instead of formyl hexane, to obtain the present compound shown below.
  • Echinole (3 R) 3- (1,4-trans-1-4-methynolecyclohexane) -N- [(1 R, 2 R, 5 R) 1-2-hydroxy-1 2,6,6-trimethinolebi cyclo [3 . 1. 1] Heptot 3_ylidene] —D—Selynate
  • Example 2 To a solution of the compound produced in Example 2 (190 mg) in ethanol (8 ml) was added a 1N aqueous solution of lithium hydroxide (1.8 ml). The reaction mixture was stirred at room temperature for 3.5 hours. Di-tert-butyl dicarbonate (0.24 m 1) was added to the reaction mixture. The reaction mixture was stirred overnight at room temperature. The reaction mixture was poured into water and washed with t-butyl methyl ether. To the aqueous layer was added a 5% aqueous hydrogen sulfate aqueous solution until the pH reached 3. The aqueous layer was extracted with ethyl acetate.
  • the extract was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated to give the compound of the present invention (175 mg, 81 ° / 0 , 97.3% ee) having the following physical data. .
  • Example 3 Using the compounds produced in Examples 1 (1) to 1 (25), the same operation as in Example 2 ⁇ Example 3 was performed to obtain the present invention compound shown below.
  • Example 4 (1)

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un dérivé de pinène de la formule générale (I), ou un sel dudit dérivé; et une méthode de production dudit dérivé ou sel, ou une méthode de production, à partir dudit dérivé ou sel, d'un dérivé d'acide 2-(t-butoxycarbonyl)amino-3-hydropropanoïque éventuellement actif de la formule générale (V). Dans ladite formule, R1 est alkyle et R2 est alkyle, alcényle, alkynyle, un groupe cyclique, etc. Le dérivé d'acide 2-(t-butoxycarbonyl)amino-3-hydropropanoïque, qui est utile en tant qu'intermédiaire important entrant dans la composition de médicaments, peut être synthétisé efficacement à partir du nouvel intermédiaire de la formule générale (I).
PCT/JP2003/001239 2002-02-07 2003-02-06 Methode de production d'un derive d'acide beta-hydroxyamino et d'un intermediaire dudit derive WO2003066578A1 (fr)

Priority Applications (1)

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AU2003211488A AU2003211488A1 (en) 2002-02-07 2003-02-06 PROCESS FOR PRODUCING ss-HYDROXYAMINO ACID DERIVATIVE AND INTERMEDIATE THEREFOR

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JP2002030669A JP2005298337A (ja) 2002-02-07 2002-02-07 β−ヒドロキシアミノ酸誘導体の製造方法およびその中間体
JP2002-30669 2002-02-07

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004043905A1 (fr) * 2002-11-08 2004-05-27 Ono Pharmaceutical Co., Ltd. Procede servant a preparer un derive d'acide 2-amino-3-hydroxypropanoique

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP5099932B2 (ja) * 2009-03-12 2012-12-19 独立行政法人科学技術振興機構 フルオレノンイミンを用いた炭素−炭素結合生成反応

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
SOLLADIE-CAVALLO ARLETTE ET AL.: "A four-step synthesis of erythro-m-chloro-3-hydroxytyrosine ethyl ester enantiomerically pure", TETRAHEDRON LETTERS, vol. 39, no. 15, 1998, pages 2191 - 2194, XP004110666 *
SOLLADIE-CAVALLO ARLETTE ET AL.: "Erythro-selective aldol condensation using directly generated Ti-enolates", GAZZETTA CHIMICA ITALIANA, vol. 126, no. 3, 1996, pages 173 - 178, XP002968872 *
SOLLADIE-CAVALLO ARLETTE ET AL.: "Full conversion in diastereoselective aldol additions using "naked" enolates under catalytic amount of phosphazene base", SYNLETT., no. 3, 2000, pages 327 - 330, XP002968871 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004043905A1 (fr) * 2002-11-08 2004-05-27 Ono Pharmaceutical Co., Ltd. Procede servant a preparer un derive d'acide 2-amino-3-hydroxypropanoique

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