WO2009133778A1 - Procédé pour la fabrication de 3-aminopipéridine-1-carboxylate de tert-butyle et intermédiaires de celui-ci - Google Patents

Procédé pour la fabrication de 3-aminopipéridine-1-carboxylate de tert-butyle et intermédiaires de celui-ci Download PDF

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Publication number
WO2009133778A1
WO2009133778A1 PCT/JP2009/057811 JP2009057811W WO2009133778A1 WO 2009133778 A1 WO2009133778 A1 WO 2009133778A1 JP 2009057811 W JP2009057811 W JP 2009057811W WO 2009133778 A1 WO2009133778 A1 WO 2009133778A1
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Prior art keywords
tert
butyl
formula
piperidine
carboxylate
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PCT/JP2009/057811
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English (en)
Japanese (ja)
Inventor
安岡順一
池本哲哉
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住友化学株式会社
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Publication of WO2009133778A1 publication Critical patent/WO2009133778A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms

Definitions

  • the present invention relates to a method for producing t tert -butyl 3-aminobiperidine monocarboxylate and an intermediate thereof.
  • Patent Document 1 International Publication No. 2000 00 No. 0 0 0 3 0 5 Disclosure of Invention
  • the present inventors have studied a production method of industrially advantageous tert-butyl 3-aminopiperidine 1-1-carboxylene, and the alkoxy moiety is primary or 2 Tert-butyl 3- (alkoxycarbonylamino) piperidine 1-carboxylate, which is a primary alkoxy group, reacts with a base to form a carbamate protecting group on the nitrogen atom at position 1; Among the carbamate protecting groups on the amino group bonded to the position, the carbamate protecting group on the amino group bonded to the 3-position is selectively removed, and tert-butyl 3-aminobiperidine 1-carboxylate It was found that a good yield was obtained. That is, the present invention provides the inventions described in the following [1] to [10].
  • R 1 and R 2 each independently represent a hydrogen atom or an alkyl group having 1 to 8 carbon atoms.
  • R 1 and R 2 each have the same meaning as above, and * represents that the carbon atom is an optically active center.
  • R 1 and R 2 each have the same meaning as above, and * represents that the carbon atom is an optically active center.
  • tert-Butylcarboxylation is a 3- (alkoxycarbonylamino) piperidine represented by the formula (1) or an optically active 3- (alkoxycarbonyl) represented by the formula (1 ').
  • [Amino] The production method according to [5] or [6], wherein the reaction is performed by reacting piperidine with ditert-butyl dicarbonate.
  • tert-butyl 3- (alkoxycarbonylamino) piperidine mono 1-carboxylate represented by the above formula (2) (hereinafter tert-butyl 3- (alkoxycarbonylamino) piperidine mono 1-carboxylate (2 ) And a manufacturing method thereof will be described.
  • examples of the alkyl group having 1 to 8 carbon atoms represented by R 1 and R 2 include a methyl group, an ethyl group, a pill group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, Examples thereof include tert-butynole group, pentyl group, isopentyl group, neopentyl group, hexyl group, isohexyl group, heptyl group, isoheptyl group, octyl group, isooctyl group and the like.
  • R 1 and R 2 are independently preferably a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, or a butyl group, and more preferably a methyl group for both R 1 and R 2 forces.
  • tert-Butyl 3- (alkoxycarbonylamino) piperidine mono 1-carboxylate (2) is, for example, tert-butyl 3- (ethoxycarbonylamino) piperidine mono-monocarboxylate, tert-butyl 3 — (Propoxycarbonylamino) piperidine _ 1 _carboxylate, tert butyl 3— (isobutoxycarbonylamino) piperidine 1-force ruboxylate, tert-butyl 3 _ (isopropoxycarbonylamino) pi
  • Examples include peridine monocarboxylate.
  • tert-butyl 3 — (alkoxycarbonylamino) piperidine mono 1-carboxylate (2) is not particularly limited, and can be produced by any known method and used in the present invention.
  • 3- (alkoxycarbonylamino) piperidine hereinafter, 3 ⁇ 4- (alkoxycarbonylamino) piperidine (1) represented by the above formula (1) is abbreviated.
  • di-tert-butyl dicarbonate hereinafter abbreviated as Bocation reaction).
  • 3- (alkoxycarbonylamino) piperidine (1) examples include ethyl piperidine-3-ylcarbamate, propylpiperidine-3-yl Carbamate, 3-butyl piperidine 3-ylcarbamate, isopropyl piperidine 3-ylcarbamate, isobutyl piperidine 3-ylcarbamate, 2-ethylhexyl piperidine 3-ylcarbamate, etc. Can be mentioned. These compounds may be any acid addition salt.
  • 3- (Alkoxycarbonylamino) piperidine (1) can be obtained, for example, by catalytic hydrogen reduction of 3- (alkoxycarbonylamino) pyridine. Further, 3- (alkoxycarbonylamino) piperidine (1) is used, for example, optically active acid such as optically active tartaric acid, optically active mandelic acid, optically active camphorsulfonic acid, optically active lactic acid or the like.
  • optically active 3- (alkoxycarbonylamino) piperidine represented by the above formula (1 ') hereinafter optically active 3- (alkoxycarbonylamino) piperidine (1') This is abbreviated as).
  • optically active tartaric acid when both R 1 and R 2 are methyl groups, and optically active mandelic acid when R 1 is a methyl group and R 2 is a hydrogen atom.
  • the amount of ditert-butyl dicarbonate used is usually 0.9 to 3 moles, preferably 1 to 2 moles, relative to 3- (alkoxycarbonylamino) piperidine (1).
  • the B o cation reaction is usually carried out in the presence of a solvent.
  • a solvent examples include water; ether solvents such as tetrahydrofuran and tert-butyl methyl ether; nitrile solvents such as acetonitrile; ester solvents such as ethyl acetate; aromatic solvents such as toluene; Examples include alcohol solvents such as 1-butanol, 2-propanol, and 2-methyl_2-propanol. These solvents may be used alone or in combination of two or more.
  • the amount of the solvent to be used is generally 1 to 50 L, preferably 2 to 20 L, relative to 1 kg of 3-(alkoxycarbonylamino) piperidine (1).
  • Such B ocification reaction may be carried out in the presence of a base.
  • the base include alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; alkali metal hydrogen carbonates such as sodium carbonate and carbonic acid lithium; sodium hydroxide and hydroxide Alkali metal hydroxides such as potassium; organic bases such as triethylamine, disobutylethylamine, pyridine; and the like. These bases may be used alone or in combination of two or more.
  • the amount of the base used is usually 1 to 5 mol times, preferably 1 to 2 mol times with respect to diter t-ptyl dicarbonate.
  • the amount of the base used is determined in consideration of the amount necessary to neutralize the acid contained in the salt. Just decide.
  • the reaction temperature for the B o cation reaction is usually 10 to 80 ° C, preferably 0 to 50 ° C.
  • the reaction time is usually 15 minutes to 12 hours, preferably 30 minutes to 5 hours, although it depends on the reaction temperature and the amount of reaction reagent used.
  • the progress of the reaction can be confirmed by usual means such as gas chromatography and high performance liquid chromatography.
  • Te is, for example, 3- (alkoxycarbonyl - Ruamino) and aspects will in addition to the piperidine (1) a base and di-te r t _ butyl concurrently, 3- (alkoxides aryloxycarbonyl ⁇ Mino)
  • ditert-butyl dicarbonate is added to a mixture of piperidine (1) and a base.
  • the mixture after completion of the B ocification reaction contains tert-butyl 3- (alkoxycarbonylamino) piperidine _ 1 _carboxylate (2) or its acid-added salt.
  • the mixture may be subjected to a reaction, but usually the mixture is subjected to a usual post-treatment such as filtration, neutralization, extraction, washing and the like, and then subjected to the next reaction.
  • the mixture after the above-mentioned post-treatment may be subjected to the following reaction after subjecting it to a normal isolation treatment such as distillation or crystallization.
  • optically active 3- (alkoxycarbonylamino) piperidine (1 ') is used in the Bocation reaction
  • optically active tert-butyl 3- (alkoxycarbonyl) represented by the above formula (2') is usually used.
  • (Amino) piperidine monocarboxylate hereinafter abbreviated as optically active tert-butyl 3- (alkoxycarbonylamino) piperidine monocarboxylate (2 ′)
  • optically active tert-butyl 3- (alkoxycarbonylamino) piperidine monocarboxylate (2 ′) is usually used.
  • the above formula (3) according to the reaction of tert-butyl 3- (alkoxycarbonylamino) piperidine_1-carboxylate (2) with a base (hereinafter also referred to as the present deprotection reaction).
  • tert-butyl 3-aminopiperidine — 1 —carboxylate (hereinafter abbreviated as tert-butyl 3-aminobiperidine 1-carboxylate (3)) will be described.
  • metal hydroxide, metal alkoxide, metal amide, metal carbonate, etc. are used as the base used in this deprotection reaction.
  • metal hydroxides include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, and alkaline earth metal hydroxides such as calcium hydroxide and barium hydroxide. Is mentioned.
  • metal alkoxide for example, an alkyl group metal alkoxide having 1 to 4 carbon atoms such as sodium methoxide, strong tert-butoxide and the like can be mentioned.
  • the metal amide include alkali metal amides such as sodium amide and lithium amide.
  • the metal carbonate include alkali metal carbonates such as cesium carbonate and potassium carbonate. From the viewpoint of reactivity, metal hydroxides and metal alkoxides are preferable, alkali metal hydroxides, alkaline earth metal hydroxides, and Al 1-4 metal alkoxides having 1 to 4 carbon atoms are more preferable, alkaline metal water. More preferred are oxides. These bases may be used alone or in combination of two or more.
  • the amount of the base used is usually 1 to 10 moles, preferably 2 to 5 moles per tert-butyl 3- (alkoxycarbonylamino) piperidine 1-carboxylate (2). is there.
  • Solvents include, for example, water; tetrahydrofuran, etherol solvent such as tert-butylmethylol ether Medium: Aromatic solvents such as toluene, xylene, monochrome benzene, 1,2-dichloro benzene, etc .; 1-butanol, 2-propanol, 2-methyl-2-propanol, 4-methyl-2-pentanol, etc.
  • Alcohol solvent dimethyl sulfoxide, sulfolane, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone, 1,3-dimethyl-1 3 , 4, 5, 6—Tetrahydrol 2 (1 H) 1-pyridinone and other non-proton polar solvents; Water, ether solvent and alcohol solvent are preferred. These solvents may be used alone or in combination of two or more. The amount of the solvent to be used is usually 1 to 50 L, preferably 2 to 20 L with respect to 1 kg of tert_butyl 3- (alkoxycarbonylamino) piperidine mono 1 -carboxylate (2).
  • the reaction temperature of this deprotection reaction is usually 0 to 160 ° C, preferably 50 to 120 ° C.
  • the reaction time is usually 15 minutes to 12 hours, preferably 30 minutes to 5 hours, although it depends on the reaction temperature and the amount of reaction reagent used.
  • the progress of the reaction can be confirmed by usual means such as gas chromatography and high performance liquid chromatography.
  • the mixing order in this deprotection reaction is not particularly limited. Preferred embodiments include, for example, an embodiment in which a base is added to tert-butyl 3- (alkoxycarbonylamino) piperidine-1-carboxylate (2), and tert-butyl 3- (alkoxycarbonyl) to the base.
  • Amino) Piperidin 1 1 Carboxylate (2) is added.
  • the mixture after completion of the deprotection reaction contains tert-butyl 3_aminobiperidine-1-carboxylate (3) or an acid addition salt thereof, and the mixture is filtered, if necessary.
  • Tert-butyl 3 _ aminobiperidine _ 1-carboxylate (3) or its acid addition by subjecting to normal post-treatment such as summation, extraction, washing, etc., followed by usual isolation treatment such as distillation and crystallization
  • the salt can be isolated.
  • the isolated tert-butyl 3-aminobiperidine 1-carboxylate (3) is further recrystallized; extraction and purification; rectification; adsorption treatment of activated carbon, silica force, alumina, etc .; It may be purified by a conventional purification process such as a chromatographic method; -When optically active tert-butyl 3- (alkoxycarbonylamino) piperidine 1_carboxylate (2,) is used in this deprotection reaction, the optical activity represented by the above formula (3 ') is usually used. Tert-butyl 3-aminobiveridine 1-carboxylate is obtained. According to the present invention, tert-butyl 3-aminobiperidine monocarboxylate can be obtained safely and with high yield, which is industrially advantageous.
  • tert-Butyl 3-aminopiperidine monocarboxylate is useful, for example, as an optically active compound as a synthetic intermediate for Alzheimer's therapeutics (see International Publication No. WO 2000 00 0 0 3 0 5) It is an important compound.
  • the present invention is industrially applicable as a method for producing such a compound and its intermediate.

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

Abstract

L'invention porte sur un procédé pour la fabrication de 3-aminopipéridine-1-carboxylate de tert-butyle dans lequel une base est mise à réagir avec du 3-(alcoxycarbonylamino)-pipéridine-1-carboxylate de tert-butyle.
PCT/JP2009/057811 2008-04-30 2009-04-14 Procédé pour la fabrication de 3-aminopipéridine-1-carboxylate de tert-butyle et intermédiaires de celui-ci WO2009133778A1 (fr)

Applications Claiming Priority (2)

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JP2008-118121 2008-04-30
JP2008118121 2008-04-30

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WO2009133778A1 true WO2009133778A1 (fr) 2009-11-05

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0248578A (ja) * 1988-06-28 1990-02-19 Ferrosan:As 複素環式化合物、その製造方法並びにその使用
JPH1059909A (ja) * 1996-08-16 1998-03-03 Kanegafuchi Chem Ind Co Ltd β−アミノ−α−ヒドロキシ酸誘導体の製造方法
JP2002047256A (ja) * 2000-07-26 2002-02-12 Kanegafuchi Chem Ind Co Ltd α−アミノ−α´，α´，α´−トリハロケトン誘導体、α−アミノ−α´，α´，α´−トリハロアルコ−ル誘導体、及び、α−ヒドロキシ−β−アミノカルボン酸誘導体の製造法
WO2005000305A1 (fr) * 2003-06-20 2005-01-06 Eli Lilly And Company 3-aminopiperidines et 3-aminoquinuclidines utilises comme inhibiteurs de l'absorption de monoamines
JP2007513945A (ja) * 2003-12-12 2007-05-31 イーライ リリー アンド カンパニー 体熱感、衝動調節障害および一般的な病状による人格変化の治療
WO2007122103A1 (fr) * 2006-04-20 2007-11-01 F. Hoffmann-La Roche Ag Dérivés du diazépan modulateurs des récepteurs de la chimiokine

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0248578A (ja) * 1988-06-28 1990-02-19 Ferrosan:As 複素環式化合物、その製造方法並びにその使用
JPH1059909A (ja) * 1996-08-16 1998-03-03 Kanegafuchi Chem Ind Co Ltd β−アミノ−α−ヒドロキシ酸誘導体の製造方法
JP2002047256A (ja) * 2000-07-26 2002-02-12 Kanegafuchi Chem Ind Co Ltd α−アミノ−α´，α´，α´−トリハロケトン誘導体、α−アミノ−α´，α´，α´−トリハロアルコ−ル誘導体、及び、α−ヒドロキシ−β−アミノカルボン酸誘導体の製造法
WO2005000305A1 (fr) * 2003-06-20 2005-01-06 Eli Lilly And Company 3-aminopiperidines et 3-aminoquinuclidines utilises comme inhibiteurs de l'absorption de monoamines
JP2007513945A (ja) * 2003-12-12 2007-05-31 イーライ リリー アンド カンパニー 体熱感、衝動調節障害および一般的な病状による人格変化の治療
WO2007122103A1 (fr) * 2006-04-20 2007-11-01 F. Hoffmann-La Roche Ag Dérivés du diazépan modulateurs des récepteurs de la chimiokine

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
COLLOT, V. ET AL.: "Heck cross-coupling reaction of 3-iodoindazoles with methyl acrylate: a mild and flexible strategy to design 2-azatryptamines", TETRAHEDRON LETTERS, vol. 41, 2000, pages 4363 - 4366 *
XU, Q. ET AL.: "trans-(lS, 2S)-1-Substituted-2-(N, N-dialkylamino)-l-indanol derivatives as chiral ligands in the catalytic enantioselective addition of diethylzinc to aldehydes", TETRAHEDRON:ASYMMETRY, vol. 13, 2002, pages 945 - 951 *

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