WO2008072773A1 - Procédé destiné à produire (1r,2r)-2-amino-1-cyclopentanol - Google Patents

Procédé destiné à produire (1r,2r)-2-amino-1-cyclopentanol Download PDF

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Publication number
WO2008072773A1
WO2008072773A1 PCT/JP2007/074355 JP2007074355W WO2008072773A1 WO 2008072773 A1 WO2008072773 A1 WO 2008072773A1 JP 2007074355 W JP2007074355 W JP 2007074355W WO 2008072773 A1 WO2008072773 A1 WO 2008072773A1
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WIPO (PCT)
Prior art keywords
cyclopentanol
benzylamino
reaction
racemic
amino
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PCT/JP2007/074355
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English (en)
Japanese (ja)
Inventor
Kiyoshi Sugi
Erina Honda
Masahide Tanaka
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Sumitomo Chemical Company, Limited
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Publication date
Application filed by Sumitomo Chemical Company, Limited filed Critical Sumitomo Chemical Company, Limited
Publication of WO2008072773A1 publication Critical patent/WO2008072773A1/fr

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    • 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
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/42—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/44—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton bound to carbon atoms of the same ring or condensed ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Definitions

  • the present invention relates to a method for producing (1 R, 2 R) —2-amino-1-cyclopentanol useful as a pharmaceutical intermediate.
  • N-bromosuccinimide N-bromosuccinimide
  • Cyclopentene oxide can be produced by oxidizing cyclopentene with m-chloroperbenzoic acid or sulfolane.
  • a method of oxidizing with a polybasic carboxylic acid anhydride and high-concentration hydrogen peroxide of 50% or more in a high boiling polar solvent such as N_methylpyrrolidone (US Pat. No. 4,590,286) is known. Since expensive reagents or high-concentration hydrogen peroxide water is used, this is not an industrial method and there are concerns about safety and disaster prevention. For this reason, a method for producing (1 R, 2 R) -2-amino-1-cyclopentanol and its hydrochloride on an industrial scale and safely is desired. Disclosure of the invention
  • the present invention provides a process by which (1 R, 2R) -2-amino-1-cyclopentanol can be produced safely on an industrial scale.
  • the present invention includes the following inventions.
  • Racemic 2_ (N-benzylamino) 1 1-cyclopentanol was optically resolved with R- (—) monomandelic acid in 2-propanol solvent (1 R, 2R) 1 2— ( N-benzylamino) 1 1-cyclopentanol, and (1 R, 2R) -2- (N-benzylamino) 1 1-cyclopentanol is debenzylated.
  • Racemic 2- (N-benzylamino) _ 1-cyclopentanol is reacted with R- (1) monomandelic acid in 2-propanol solvent (1 R, 2 R)-2-(N —Benzylamino) _ 1-Cyclopentanol R— (—) — Process for obtaining mandelate, (1 R, 2 R) — 2— (N-Benzylamino) 1 1-cyclopentanol R 1 (1) 1 Mandel (1 R, 2 R) _2— (N-Benzinoleamino) mono 1-cyclopentanol by reacting alkali with acid salt, and (1 R, 2 R) -2- (N-benzylamino) i
  • the production method according to (1) above which comprises a step of debenzylating 1-cyclopentanol to obtain (1 R, 2 R) 1-2-amino-1-cyclopentanol.
  • R- (-) The amount of mandelic acid used is 0.5 to 0.7 moles per mole of racemic 2- (N-benzylamino) — 1-cyclopentanol (2 ) Or the production method described in (3).
  • the production method of the present invention includes Step (I) and Step ( ⁇ ) described below, and more specifically includes Step (A) to Step (E) described below.
  • (R) MA represents R _ (-)-mandelic acid.
  • Process (I) optical resolution process corresponds to process (C) and process (D)
  • process (I I) debenzylation process corresponds to process (E).
  • Cyclopentene oxide S can be obtained by oxidizing pentene pentene with phthalic anhydride and hydrogen peroxide.
  • the peroxide peroxycarboxylic acid
  • hydrogen peroxide solution in a solvent containing phthalic anhydride and phthalic anhydride.
  • Commercially available products can be used for the raw materials cyclopentene, phthalic anhydride and hydrogen peroxide.
  • the amount of phthalic anhydride used is usually in the ratio of 1.:!
  • the amount of hydrogen peroxide used is less than 1.05 times (mole)
  • the yield will decrease, and if it exceeds 2.0 times (mole), a large amount of hydrogen peroxide will remain in the reaction system, resulting in safety and disaster prevention.
  • This oxidation reaction is usually carried out in an inert solvent, and examples of the solvent include o-dichroic benzene, monochrome benzene, toluene, ethyl acetate, methyl acetate, and mixed solvents thereof.
  • the amount of the solvent to be used is usually 5 2 2 mL, preferably 7 1 2 mL, per 1 g of penguin pentene.
  • the above oxidation reaction is preferably carried out in the presence of carbonic acid, from the viewpoint of suppressing the by-production of 1,2-cyclopentanediol.
  • the amount of carbonic acid rium used is usually in a ratio of 0.1 mol, preferably 0.05 mol, per mol of cyclopentene. If the amount of potassium carbonate used is less than 0.1 times (mole), the reaction slows down, and more 1,2-cyclopentanediol is produced as a by-product.
  • the reaction temperature is usually within the range of 20 38 ° C., preferably 25 53 5 ° C. If the reaction temperature is less than 20 ° C, the reaction will be slow, and if it exceeds 38 ° C, there are concerns regarding safety and disaster prevention.
  • the reaction time is usually 2 12 hours, although it depends on the amount of reaction substrate and solvent used, the reaction temperature, and the like. The progress of the reaction can be confirmed by gas chromatography.
  • the post-treatment of the reaction is, for example, as follows. First, the peroxide remaining in the reaction system is decomposed by adding a reducing agent such as sulfite. This peroxide decomposition is usually carried out at 0 1 ° C. Decomposition of peroxide can be confirmed with pod starch paper. Next, the reaction solution containing the target product, cyclopentenoxide, is washed with alkali. Examples of the Al strength include sodium hydroxide and lithium hydroxide.
  • the solution containing cyclopentene oxide thus obtained can be directly used for the subsequent reaction with benzylamine, but cyclopentene oxide can be easily isolated by distillation.
  • distilling the fraction containing the raw material is distilled first, then the cyclopentene oxide is distilled, and finally the solvent remains.
  • the distillation may be either simple distillation or rectification.
  • Racemic 2- (N-benzylamino) 1 1-cyclopentanol is obtained by reacting cyclopentenoxide with benzylamine. This reaction is Usually carried out in an inert solvent.
  • the solvent water is usually used, but a mixed solvent of water and O-dichlorobenzene (weight ratio of about 1: 1) may be used.
  • the amount of the solvent used is usually 2 to 1 OmL per 1 g of cyclopentene oxide.
  • the amount of benzilamine used is usually 0.9 to 1.05 monole, preferably 1.0 to 1.01 mol / mol of cyclopentene oxide. If the amount of Benzene / Amine used is less than 0.9 times (mole), the reaction may be delayed.
  • the reaction temperature is usually 90 to 110 ° C, preferably 95 to 110 ° C.
  • the reaction time is usually 2 to 24 hours, although it depends on the amount of reaction substrate and solvent used, the reaction temperature, and the like. The progress of the reaction can be confirmed by HPLC.
  • the post-treatment of the reaction is, for example, as follows. After completion of the reaction, the reaction solution is cooled to 40-50 ° C and the organic layer is separated. The aqueous layer is extracted with an organic solvent such as o-dichlorobenzene or toluene. The obtained extract is combined with the previous organic layer and concentrated under reduced pressure to obtain crude racemic 2- (N-benzylamino) 1 1-cyclopentanol. The obtained crude racemic 2- (N-benzylamino) 1-cyclopentanol may be directly subjected to optical resolution, but may be purified by recrystallization or distillation.
  • the content of unreacted benzylamine is double with respect to racemic 2- (N-benzylamino) 1-cyclopentanol. If it exceeds 50%, it is preferable to purify by recrystallization or distillation so that the content of benzylamine is 2% by weight or less.
  • Racemic 2- (N-benzylamino) 1 1-cyclopentanol is reacted with R- (1) monomandelic acid in 2_propanol solvent to give (1 R, 2R) 1 2— (N— Benzylamino) 1 1-cyclopentanol R- (-) — Mandelic acid salt is obtained.
  • the solvent is mainly composed of 2-propanol, and usually contains 80% by weight or more of 2-propanol.
  • 2-propanol alone or a mixed solvent of 2_propanol and o-dichlorobenzene (weight ratio of about 9: 1) is used as the solvent.
  • the amount of the solvent used is usually 4 to 6 mL, preferably 4.5 to 5.5 mL, per 1 g of racemic 2- (N-benzylamino) 1-cyclopentanol. If the amount of solvent used is less than 4 mL / lg, stirring the reaction solution May not be sufficiently performed, and the optical purity may be lowered. If it exceeds 6 mLZlg, the yield may be lowered.
  • (—) The amount of mandelic acid used is usually 0.5 to 0.7 moles, preferably 0.5 to 0.65 moles per mole of racemic 2_ (N-benzylamino) 1-cyclopentanol. Is the ratio. If the amount of R— (-) — Mandelic acid used is less than 0.5 times (mole), the yield may decrease, and if it exceeds 0.7 times (mole), the optical purity may decrease. There is.
  • the above reaction may be performed, for example, by dissolving R-(-) monomande ⁇ / acid in a solvent and then adding racemic 2- (N-benzylamino) 1-cyclopentanol, and vice versa. You may carry out by the addition method, or may add both simultaneously.
  • the above reaction is usually carried out with heating. Usually 20-80, depending on the amount and purity of the reaction substrate, the amount of solvent, etc.
  • Dissolve R— (-) Mandelic acid in C, then incubate at 60-65 ° C. If insolubles are present, they may be filtered.
  • the produced (1 R, 2R)-2-(N-benzylamino) mono 1-cyclopentanol R- (-) -mandelate usually crystallizes at 50-60 ° C, but crystal precipitation is observed. If not, seed crystals may be added.
  • the formed slurry is usually stirred at 50 to 53 ° C for 1 to 3 hours, then slowly cooled and aged at a temperature of 10 to 12 ° C. The aging time is usually 2 to 20 hours. After aging, the crystals are filtered and washed with 2-propanol cooled to 5-10 ° C.
  • the obtained (1 R, 2 R)-2-(N-benzylamino) 1-cyclopentanol R- (1) monomandelate may be used in the next step (D) in a wet state, Or it may be used after drying.
  • crystallization usually begins at 70-73 ° C. Stir for 1-2 hours at the temperature at which crystallization started, then cool. Usually, cool to 10 ° C over 3-8 hours, and stir for 2-16 hours at 10-12 ° C. After aging, the crystals are collected by filtration, 5 ⁇ : 15. 2-Propanol ((1 R, 2 R) 1 2-— (N-Benzene) cooled to C (Luamino) 1 1-cyclopentanol R— (—) — Wash with 1 to 3 mL of mandelate.
  • organic solvent examples include hydrocarbons such as toluene, ethers such as tetrahydrofuran, and halogenated hydrocarbons such as benzene benzene. Toluene is preferred.
  • the amount of organic solvent used is (1 R, 2 R) — 2— (N —benzylamino) 1 1-cyclopentanol R— (—) — Mandelate 1 to 0.8 mL
  • the ratio is 0.9 to 5 mL.
  • alkaline examples include hydroxylated lithium, carbonated potassium, sodium hydroxide, etc., and hydroxylated lithium is preferred from the viewpoint of operability. It is preferable to use Al force as an aqueous solution.
  • the concentration of the aqueous solution is usually in the range of 10 to 20%.
  • the amount of alkali used is (1 R, 2 R) — 2 _ (N-benzylamino) 1 1-cyclopentanol R 1 (1) — the amount of mandelate that can be completely dissolved in an organic solvent to form a solution Usually, (1 R, 2 R) 1 2- (N-benzylamino) 1 1-cyclopentanol R— (-) 1 mandelate 1.0 mol or more, preferably 1 0 The ratio is 5 moles or more.
  • the above reaction is usually performed within a range of 20 to 30 ° C.
  • the post-treatment of the reaction is, for example, as follows. After completion of the reaction, the temperature of the reaction solution was raised to 30 to 40 ° C, and the organic layer containing (1 R, 2 R) — 2-(N-benzylamino) 1 1-cyclopentanol was separated, Wash with. By concentrating the obtained organic layer, (1 R, 2 R) 1 2- (N-benzylamino) 1 1-cyclopentanol is obtained as crystals. In addition, the obtained organic layer may be directly subjected to debenzylation without concentrating.
  • racemic 2- (N-benzylamino) 1 1-cyclopentanol was optically resolved to (1 R, 2 R) —2— (N-benzylamino). 1) 1-sucral pentanol can be obtained.
  • This debenzylation reaction is usually performed in the presence of a catalyst in an inert solvent under hydrogen pressure.
  • the solvent include alcohols such as methanol and 2_propanol, hydrocarbons such as toluene, ethers such as tetrahydrofuran, and mixed solvents thereof.
  • the amount of the solvent to be used is usually 2 to 5 mL, preferably 3 to 4 mL, with respect to 1 g of (1 R, 2R) -2- (N-benzylamino) 1-cyclopentanol.
  • the catalyst include Pd carbon, Pt carbon, sponge nickel, etc., and Pd carbon is preferred from an economic viewpoint.
  • Pd carbon include 5% Pd carbon and 10% Pd carbon.
  • the amount of catalyst used is usually 0. 1 part by weight of (1 R, 2R) -2- (N-benzylamino) 1-cyclopentanol as metal equivalents.
  • the hydrogen pressure is usually from normal pressure to IMP a, preferably from normal pressure to 0.5 MPa.
  • the reaction temperature is usually in the range of room temperature to 70 ° C, preferably 50 to 60 ° C.
  • the reaction time is usually 1 to 24 hours, although it depends on the reaction substrate, the amount of solvent and catalyst used, the reaction temperature, the hydrogen pressure, and the like. Completion of the reaction can be confirmed by hydrogen absorption and HP LC.
  • the post-treatment of the reaction is usually performed by filtering the catalyst. By concentrating the obtained filtrate, (1R, 2R) _2-amino_1-cyclopentanol can be obtained.
  • the (1 R, 2R) -2-amino-1-cyclopentanol obtained by the production method of the present invention can be converted into a hydrochloride by reacting with hydrogen chloride.
  • the process will be described in more detail below as step (F).
  • the amount of the solvent used is usually 3 to 8 mL, preferably 4 to 5 mL, per 1 g of (1 R, 2 R) -2-amino-1-cyclopentanol.
  • Hydrogen chloride may be introduced directly into the reaction solution as a gas, or may be added dropwise to the reaction solution as a solution, for example a 2-propanol solution.
  • the amount of the solvent may be an amount that allows the formed hydrochloride to crystallize and precipitate in the reaction solution.
  • the amount of hydrogen chloride used is usually 1.0 to 1.1 moles, preferably 1.01 to 1.07 moles per mole of (1 R, 2R) —2-amino-1-cyclopentanol. It is.
  • the reaction temperature is usually in the range of 0 to 30 ° C, preferably 15 to 25 ° C.
  • the reaction time is usually 10 to 120 minutes, although it depends on the amount of reaction substrate and solvent used, the reaction temperature, and the like.
  • the hydrochloride formed by the above reaction crystallizes and precipitates in the reaction solution to form a slurry.
  • the formed slurry is usually aged for 1-2 hours at a temperature of about 20 ° C and then cooled to 15-10 ° C. After cooling, the crystals are collected by filtration to give the desired (1 R, 2R) -2-amino-1-pentanol hydrochloride.
  • sucral pentene oxide was 93.3%, and the rate of by-product 1,2-cyclopentanediol was 3.5%.
  • the reaction solution was cooled to 5 ° C., and 15% aqueous sodium sulfite solution (12.6 g, 0.015 mo 1) was added dropwise to decompose excess peroxide.
  • a 15% aqueous sodium hydroxide solution (87.91 g, 0.235 mo 1) was added to adjust the pH of the reaction solution to 9-10. After adding tap water (30 mL) and stirring, the organic layer was separated by liquid separation.
  • the present invention can provide a method for producing (1 R, 2R) -2-amino-1-cyclopentanol and its hydrochloride on an industrial scale and safely. can get

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

Abstract

L'invention concerne un procédé de production comprenant les étapes (A) à (E) ci-dessous, qui permet de produire commercialement et de manière sûre (1R,2R)-2-amino-1-cyclopentanol ou un chlorhydrate de celui-ci.
PCT/JP2007/074355 2006-12-15 2007-12-12 Procédé destiné à produire (1r,2r)-2-amino-1-cyclopentanol WO2008072773A1 (fr)

Applications Claiming Priority (2)

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JP2006-339153 2006-12-15
JP2006339153 2006-12-15

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104177230A (zh) * 2014-08-01 2014-12-03 浙江阿尔法化工科技有限公司 一种1,2-环戊二醇的制备方法

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11739050B2 (en) * 2021-09-07 2023-08-29 Sci Pharmtech Inc. Method for purification of terpenoid amino alcohol derivatives

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5626848A (en) * 1979-08-13 1981-03-16 Yamakawa Yakuhin Kogyo Kk Optical resolution of (+-)-1-phenylethylamine
JPH1160543A (ja) * 1997-08-19 1999-03-02 Ichikawa Gosei Kagaku Kk １−アミノテトラリン−２−オールの光学分割方法と分割の過程で生じるジアステレオマー塩
JP2003252836A (ja) * 2002-02-28 2003-09-10 Daicel Chem Ind Ltd 光学活性なトランス−２−アミノシクロアルカノール又はその塩の製造方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5626848A (en) * 1979-08-13 1981-03-16 Yamakawa Yakuhin Kogyo Kk Optical resolution of (+-)-1-phenylethylamine
JPH1160543A (ja) * 1997-08-19 1999-03-02 Ichikawa Gosei Kagaku Kk １−アミノテトラリン−２−オールの光学分割方法と分割の過程で生じるジアステレオマー塩
JP2003252836A (ja) * 2002-02-28 2003-09-10 Daicel Chem Ind Ltd 光学活性なトランス−２−アミノシクロアルカノール又はその塩の製造方法

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104177230A (zh) * 2014-08-01 2014-12-03 浙江阿尔法化工科技有限公司 一种1,2-环戊二醇的制备方法

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