WO2011127794A1 - Dérivés cycliques chiraux d'acide bêta-aminoarylbutyrique, leurs procédés de préparation et procédés pour la préparation de dérivés chiraux d'acide bêta-aminoarylbutyrique par leur intermédiaire - Google Patents

Dérivés cycliques chiraux d'acide bêta-aminoarylbutyrique, leurs procédés de préparation et procédés pour la préparation de dérivés chiraux d'acide bêta-aminoarylbutyrique par leur intermédiaire Download PDF

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Publication number
WO2011127794A1
WO2011127794A1 PCT/CN2011/072498 CN2011072498W WO2011127794A1 WO 2011127794 A1 WO2011127794 A1 WO 2011127794A1 CN 2011072498 W CN2011072498 W CN 2011072498W WO 2011127794 A1 WO2011127794 A1 WO 2011127794A1
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WIPO (PCT)
Prior art keywords
group
chiral
formula
aminoarylbutyric
acid derivative
Prior art date
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PCT/CN2011/072498
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English (en)
Chinese (zh)
Inventor
张富尧
陶伟峰
孙飘扬
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上海源力生物技术有限公司
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Priority claimed from CN2010101475033A external-priority patent/CN102212015A/zh
Priority claimed from CN2010101475122A external-priority patent/CN102212041A/zh
Application filed by 上海源力生物技术有限公司 filed Critical 上海源力生物技术有限公司
Priority to CN2011800025605A priority Critical patent/CN102471294B/zh
Priority to TW100118439A priority patent/TW201240978A/zh
Publication of WO2011127794A1 publication Critical patent/WO2011127794A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D267/02—Seven-membered rings
    • C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D267/10—Seven-membered rings having the hetero atoms in positions 1 and 4 not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to an important intermediate monocyclic ⁇ -aminoarylbutyric acid derivative (Structure 11) which can be used for the synthesis of chiral drugs, and a chiral cyclic ⁇ -aminoarylbutyric acid derivative.
  • Structure 11 monocyclic ⁇ -aminoarylbutyric acid derivative
  • Chiral ⁇ -aminoarylbutyric acid derivatives are an important class of chiral pharmaceutical intermediates that can be widely used in the synthesis of drugs, for example, in the synthesis of retagliptin (see CN101468988); Sitagliptin (see J. Med. Chem. 2005, 48, 141 or Bioorg. Med. Chem. Lett. 2007, 17, 49 or WO2009064476).
  • the efficient synthesis of such chiral intermediates has attracted widespread attention in the pharmaceutical industry.
  • the methods for preparing chiral ⁇ -aminoarylbutyric acid derivatives are broadly classified into three categories: homogeneous asymmetric hydrogenation reduction, chiral induced reduction And chiral split method.
  • WO2009064476 reports the preparation of ⁇ -aminoarylbutyric acid with an optical purity of 90% ee by reduction of ⁇ , ⁇ -unsaturated ⁇ -aminotrifluorophenylbutyric acid derivatives using a homogeneous chiral catalyst Ru-(S)-BINAP.
  • Derivatives; WO2006081151 reports that under the action of a transition metal catalyst complexed with an ammonium salt and a chiral ferrocene diphosphine ligand, the asymmetric hydrogenation of the chiral ⁇ -aminoacrylic acid derivative produces an optical purity of 94% ee.
  • EP 1318139 reports the reaction of a chiral arylamine with methyl phenylacetoacetate, followed by asymmetric induction reduction of the resulting chiral ⁇ -aminoacrylic acid derivative to obtain an optical purity of 70% ee.
  • -Aminoarylbutyric acid derivatives WO2004085661 also describes in detail the reaction of chiral phenylalanine amide with 2,4,5-trifluorophenylacetoacetamide derivatives to form chiral ⁇ , ⁇ -unsaturated
  • the ⁇ -aminotrifluorophenylbutyric acid derivative is then subjected to chiral induced reduction by catalytic hydrogenation to give a ⁇ -amino-2,4,5-trifluorophenylbutyric acid derivative having an optical purity of 96% ee.
  • WO2010009630 describes in detail the preparation of R- ⁇ -amino-2,4,5-trifluoro by resolution of di-p-toluoyl-D-tartaric acid and di-p-toluoyl-L-tartaric acid.
  • Phenylbutyric acid derivative >99% ee, 36% yield
  • S- ⁇ -amino-2,4,5-trifluorophenylbutyric acid derivative >98% ee, 27% yield
  • the chiral ligands and the precious metals used are relatively expensive, and most of them cannot be recycled, so that the target product can be prepared by this method.
  • the cost is higher, and the reaction conditions of the homogeneous homogeneous hydrogenation are harsh, most of which need to be carried out under strict anaerobic conditions, the operation is cumbersome, and the repeatability is poor, which brings difficulties to large-scale production.
  • homogeneous The optical purity of asymmetric hydrogenation is greatly affected by the substrate and the chiral ligand, and the product usually needs to be recrystallized several times to achieve the optical purity requirement. Chiral resolution is an effective method for the preparation of optically pure target products.
  • Ar 1 , Ar 2 is a substituted or unsubstituted aryl group selected from phenyl or naphthyl, which is optionally selected from the group consisting of halogen, trifluoromethyl, methoxy, amino, cyano, nitro Substituted with a substituent of a phenyl group or a d- 6 alkyl group; or, Ar Ar 2 is a substituted or unsubstituted heteroaryl group selected from a furan, pyrrole, thiophene, anthracene or quinoline group, It is optionally substituted with a substituent selected from a halogen, a trifluoromethyl group, a methoxy group, an amino group, a cyano group, a nitro group, a phenyl group or a d- 6 alkyl group.
  • Ar 1 is 2,4,5-trifluorophenyl; Ar 2 is phenyl.
  • the present invention provides a method of preparing such a chiral cyclic ⁇ -aminoarylbutyric acid derivative
  • acetoacetate ( ⁇ ) with a chiral amino alcohol to obtain a cyclic intermediate (V) via the intermediate (IV); the aryl or heteroaryl
  • the acetoacetate can be prepared by the method described in U.S. Patent No. 5,928, 648; the chiral amino alcohol is an S or R type arylamino alcohol, preferably - phenylglycine.
  • the cyclic intermediate (V) is subjected to asymmetric induced reduction to obtain a cyclic chiral ⁇ -aminoarylbutyric acid derivative (structural formula ;);
  • the reducing agent is selected from the group consisting of cyano boron Sodium hydride, lithium cyanoborohydride, sodium borohydride monohydrate, sodium borohydride hydride, sodium borohydride triacetate, lithium borohydride, lithium borohydride, lithium borohydride, sodium borohydride, boron
  • One or a combination of lithium hydride, zinc borohydride, lithium aluminum hydride, hydrogen or borane is preferably sodium cyanoborohydride.
  • Ar Ar 2 is a substituted or unsubstituted aryl group selected from phenyl or naphthyl, which is optionally selected from the group consisting of halogen, trifluoromethyl, methoxy, amino, cyano, nitro Substituted with a substituent of a phenyl group or an alkyl group; or, Ar Ar 2 is a substituted or unsubstituted heteroaryl group selected from a furan, pyrrole, thiophene, anthracene or quinoline group, optionally Substituted by a substituent selected from halogen, trifluoromethyl, methoxy, amino, cyano, nitro, phenyl or d- 6 alkyl, Ar 2 is preferably phenyl.
  • R 2 is hydrogen, d 6 alkyl or a substituted or unsubstituted phenyl group, preferably a methyl group.
  • Ar 1 is 2,4,5-trifluorophenyl
  • Ar 2 is a phenyl group
  • R 2 in the formula III and formula IV is a methyl group.
  • the chiral amino alcohol is an S or R type arylamino alcohol, preferably - phenylglycinol.
  • an R-type ⁇ -aminoarylbutyric acid derivative is prepared by using an arylamino alcohol, and an S-type ⁇ -aminoaryl group is produced by using an R-type arylamino alcohol. Butyric acid derivatives.
  • the ⁇ -aminoarylbutyric acid derivative is in the R form.
  • the reducing agent is selected from the group consisting of sodium cyanoborohydride, lithium cyanoborohydride, sodium borohydride monohydride, sodium borohydride hydride, Sodium triacetate hydride, lithium borohydride, lithium borohydride, lithium borohydride, sodium borohydride, lithium borohydride, zinc borohydride, lithium aluminum hydride, hydrogen or borane or In combination, sodium cyanoborohydride is preferred.
  • the present invention provides a process for the preparation of a chiral ⁇ -aminoarylbutyric acid derivative of the formula I, which comprises preparing an intermediate of the formula ⁇ and then preparing a chiral ⁇ -amino group of the formula I.
  • Aryl butyric acid derivatives, X)R 1 Aryl butyric acid derivatives, X)R 1
  • Ar 1 is a substituted or unsubstituted aryl group selected from phenyl or naphthyl, which is optionally selected from the group consisting of halogen, trifluoromethyl, methoxy, amino, cyano, nitro, phenyl or d_ 6 alkyl substituents; or, Ar 1 is a substituted or unsubstituted heteroaryl, said heteroaryl selected from furan, pyrrole, thiophene, indole or quinoline group optionally substituted selected from Substituted from a substituent of a halogen, a trifluoromethyl group, a methoxy group, an amino group, a cyano group, a nitro group, a phenyl group or a d- 6 alkyl group;
  • R 1 is hydrogen, d 6 alkyl or substituted or unsubstituted phenyl
  • the cyclic intermediate (V) is subjected to asymmetric induced reduction to obtain a cyclic chiral ⁇ -aminoarylbutyric acid derivative (structural formula ;);
  • the reducing agent is selected from the group consisting of cyano boron Sodium hydride, lithium cyanoborohydride, sodium borohydride, sodium borohydride, sodium borohydride triacetate, lithium borohydride, lithium borohydride, lithium triacetate, sodium borohydride, boron
  • the reducing agent is preferably sodium cyanoborohydride.
  • a cyclic chiral ⁇ -aminoarylbutyric acid derivative ( ⁇ ) is obtained by hydrogenation in an alcohol solvent in the presence of a catalyst to obtain a chiral ⁇ -aminoarylbutyric acid derivative (Structure 1).
  • the catalyst is selected from one or a combination of Pd(OH) 2 /C, Pd/C, Pt/C, Rh/C, Ru/C, Pt0 2 , or Raney Ni.
  • the catalyst is preferably Pd(OH) 2 /C;
  • the alcohol solvent is a lower alcohol of 1 to 6 carbons or a substituted or unsubstituted phenol, preferably Methanol.
  • Ar 1 , R 1 are as defined in formula I;
  • R 2 is hydrogen, d 6 alkyl or substituted or unsubstituted phenyl, preferably methyl;
  • Ar 2 is substituted or unsubstituted aryl, said aryl Selected from phenyl or naphthyl, which is substituted by a substituent of halogen, trifluoromethyl, methoxy, amino, cyano, nitro, phenyl or d- 6 alkyl; or, Ar 2 is substituted or unsubstituted a heteroaryl group, the heteroaryl group being selected from the group consisting of a furan, pyrrole, thiophene, anthracene or quinoline group, optionally selected from the group consisting of halogen, trifluoromethyl, methoxy, amino, cyano, nitro Substituted with a substituent of a phenyl or C ⁇ alkyl group;
  • Ar 2 is preferably a
  • Ar 1 is 2,4,5-trifluorophenyl, R 1 is methyl;
  • Formula II, Formula IV and Formula V 2 is a phenyl group; and
  • R 2 in the formula III and formula IV is a methyl group.
  • the chiral amino alcohol is an S or R type arylamino alcohol, preferably phenylglycine.
  • an R-type ⁇ -aminoarylbutyric acid derivative is prepared by using an S-type arylamino alcohol, and an S-type ⁇ -aminoaryl group is produced by using an R-type arylamino alcohol. Butyric acid derivatives.
  • the ⁇ -aminoarylbutyric acid derivative is in the R form.
  • the reducing agent is selected from the group consisting of sodium cyanoborohydride, lithium cyanoborohydride, sodium borohydride monohydride, sodium borohydride diacetate, sodium borohydride triacetate, Lithium borohydride, lithium borohydride, lithium borohydride, sodium borohydride, lithium borohydride, zinc borohydride, lithium aluminum hydride, hydrogen or borane, or a combination thereof, preferably cyano Sodium borohydride.
  • the catalyst in the step 3), is selected from the group consisting of Pd(OH) 2 /C, Pd/C, Pt/C, R/C, Ru/C, Pt0. 2 or one or a combination of Raney Ni, preferably Pd(OH) 2 /C.
  • the alcohol solvent is a lower alcohol of 1 to 6 carbon atoms or a substituted or unsubstituted phenol, preferably methanol.
  • the method of the invention has the characteristics of simple operation, high optical purity of the product, low cost and suitable for industrial production, and has significant social and economic benefits. detailed description
  • reaction mixture IVaC 60g), anhydrous THFC 280ml was added to a 500 ml three-necked flask, and the mixture was stirred and dissolved. The ice bath was cooled at 0 ° C, and NaH (60% content: 14.5 g) was added portionwise. After the addition, the mixture was stirred at room temperature for 20 hours. The reaction was quenched with a saturated aqueous solution of EtOAc. EtOAc (EtOAc)EtOAc. 38g, 70% yield in two steps.
  • a reactant IIa (2 g), ethanol (60 ml) and concentrated hydrochloric acid (1.25 ml) were added to a 200 ml hydrogenation flask, and Pd/C (400 mg) was added thereto, and hydrogen gas was added thereto, and the mixture was reacted at 50 ° C for 80 hours. After the reaction was removed by filtration diluted with Pd / C, the filtrate was concentrated, the residue was extracted with ethyl acetate, washed with saturated NaHC0 3. The organic phase was dried over anhydrous sodium sulfate and concentrated to give almost colorless oil Ic l. Lg, 99.7 %ee, yield 70%.
  • the analog lid was synthesized by the same method as the synthesis of the compound Ila.
  • the analog IIg was synthesized by the same method as the synthesis of the compound Ila.
  • the analog IIh was synthesized by the same method as the synthesis of the compound Ila.
  • the analog m was synthesized by the same method as the synthesis of the compound Ila.
  • the analog IIk was synthesized by the same method as the synthesis of the compound Ila.
  • Analog III was synthesized in the same manner as in the synthesis of compound Ila.
  • the analog IIm was synthesized by the same method as the synthesis of the compound Ila.
  • the analog ⁇ was synthesized by the same method as the synthesis of the compound Ila.
  • the analog Id was synthesized by the same method as the synthesis of the compound la.
  • the analog Ie was synthesized by the same method as the synthesis of the compound la.
  • the analog Ig was synthesized by the same method as the synthesis of the compound la.
  • the analog Ih was synthesized by the same method as the synthesis of the compound la.
  • the analog Ii was synthesized by the same method as the synthesis of the compound la.
  • the analog 3 ⁇ 4 was synthesized by the same method as the synthesis of the compound la.
  • the analog Ik was synthesized by the same method as the synthesis of the compound la.
  • the analog II was synthesized by the same method as the synthesis of the compound la.

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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 porte sur des dérivés cycliques chiraux d'acide bêta-aminoarylbutyrique (formule II) qui peuvent être utilisés comme intermédiaires pour la préparation de médicaments chiraux, sur les procédés de préparation de tels dérivés cycliques chiraux d'acide bêta-aminoarylbutyrique et sur les procédés pour la préparation de dérivés chiraux d'acide bêta-aminoarylbutyrique (formule I) par hydrogénation de dérivés cycliques chiraux d'acide bêta-aminé représentés par la formule II.
PCT/CN2011/072498 2010-04-12 2011-04-07 Dérivés cycliques chiraux d'acide bêta-aminoarylbutyrique, leurs procédés de préparation et procédés pour la préparation de dérivés chiraux d'acide bêta-aminoarylbutyrique par leur intermédiaire WO2011127794A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN2011800025605A CN102471294B (zh) 2010-04-12 2011-04-07 手性环状β-氨基芳基丁酸衍生物、其制备方法及通过其制备手性β-氨基芳基丁酸衍生物的方法
TW100118439A TW201240978A (en) 2011-04-07 2011-05-26 Chiral cyclic beta-amino acid derivatives, their preparation method and the method for preparation of chiral beta-amino acid derivatives via them

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN2010101475033A CN102212015A (zh) 2010-04-12 2010-04-12 制备手性β-氨基芳基丁酸衍生物的方法
CN2010101475122A CN102212041A (zh) 2010-04-12 2010-04-12 手性环状β-氨基芳基丁酸衍生物及其制备方法
CN201010147512.2 2010-04-12
CN201010147503.3 2010-04-12

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EP2674432A1 (fr) 2012-06-14 2013-12-18 LEK Pharmaceuticals d.d. Nouvelle voie de synthèse pour la préparation de composés à substitution ß-aminobutyryle 5,6,7,8-tétrahydro[1,4]diazolo[4,3-alpha]pyrazines-7-yl

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CN105008324B (zh) * 2012-12-21 2017-04-05 斯洛文尼亚莱柯制药股份有限公司 用于制备手性γ‑芳基‑β‑氨基丁酸衍生物的酶途径

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WO2004085661A2 (fr) * 2003-03-24 2004-10-07 Merck & Co., Inc Procede de synthese de derives d'acides amines beta chiraux
CN101468988A (zh) * 2007-12-26 2009-07-01 上海恒瑞医药有限公司 哌嗪类衍生物,其制备方法及其在医药上的应用
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KIM DOOSEOP ET AL.: "(2R)-4-Oxo-4-[3-(Trifluoromethyl)-5,6-dihydro [1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine: A Potent, Orally Active Dipeptidyl Peptidase IV Inhibitor for the Treatment of Type 2 Diabetes", J. MED. CHEM., vol. 48, 13 December 2004 (2004-12-13), pages 141 - 151, XP002529729, DOI: doi:10.1021/jm0493156 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2674432A1 (fr) 2012-06-14 2013-12-18 LEK Pharmaceuticals d.d. Nouvelle voie de synthèse pour la préparation de composés à substitution ß-aminobutyryle 5,6,7,8-tétrahydro[1,4]diazolo[4,3-alpha]pyrazines-7-yl
WO2013186326A1 (fr) 2012-06-14 2013-12-19 Lek Pharmaceuticals D.D. Nouvelle voie de synthèse pour la préparation de composés de 5,6,7,8-tétrahydro[1,4]diazolo [4,3-alpha]pyrazin-7-yle substitués par ss-aminobutyryle
US9388188B2 (en) 2012-06-14 2016-07-12 Lek Pharmaceuticals D.D. Synthetic route for the preparation of β-aminobutyryl substituted 5,6,7,8-tetrahydro[1,4]diazolo[4,3-alpha ]pyrazin-7-yl compounds

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