WO2010006954A1 - Novel n-substituted beta-amino acid esters - Google Patents
Novel n-substituted beta-amino acid esters Download PDFInfo
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- WO2010006954A1 WO2010006954A1 PCT/EP2009/058567 EP2009058567W WO2010006954A1 WO 2010006954 A1 WO2010006954 A1 WO 2010006954A1 EP 2009058567 W EP2009058567 W EP 2009058567W WO 2010006954 A1 WO2010006954 A1 WO 2010006954A1
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- 0 C[C@](*)C(CCC1)C1c1c(*)cccc1 Chemical compound C[C@](*)C(CCC1)C1c1c(*)cccc1 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
Definitions
- the present invention relates to novel ⁇ -amino acid esters and to a method for the preparation of said ⁇ -amino acid esters by reduction of the corresponding enamines or amination of ⁇ -keto esters followed by condensation with a halogen-substituted benzene derivative.
- Ezetimibe (formula (1 ), also known as (3f?,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4- fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)-2-azetidinone, C 24 H 2I F 2 NO 3 , CAS 163222-33-1 ) is a cholesterol absorption inhibitor.
- Preferred groups are 9-anthrylmethyl, benzyloxymethyl, p-bromobenzyl, p-bromophenacyl, 3-buten-1-yl, f-butyldimethylsilyl, di-f-butylmethylsilyl, f-butyldiphenylsilyl cyclohexyl, carboxamido- methyl, ⁇ — chloroalkyl, cinnamyl, cyclohexyl, cyclopentyl, cyclopropylmethyl, 5-dibenzo- suberyl, 2,6-dichlorobenzyl, 2,2-dichloro-1 ,1-difluoroethyl, 2,6-dimethoxybenzyl, 4-(dimethylaminocarbonyl)benzyl, 2,6-dimethylbenzyl, dimethylthiophosphinyl,
- racemic products of general formula (2) when racemic products of general formula (2) are obtained they are preferably subsequently separated into their optically pure isomers as in general only one of said isomers is suitable for the preparation of biologically active products whereas the other isomer is, at best, inactive. Separation can be conveniently carried out by optical resolution of the product of the reduction reaction.
- the enantiopure compounds may also be obtained by a kinetic resolution using an enzymatic acylation or preferably by a dynamic kinetic resolution using an enzymatic acylation and an amine racemization metal catalyst, preferably based on ruthenium or iridium.
- the enantiopure compounds are prepared by enzyme catalyzed ester hydrolysis with lipases as the preferred enzymes.
- the catalyst may also contain one or more anions, such as a halogen (for instance chloride or bromide), BF 4 , PF 6 , acetate, triflate, tosylate and the like.
- a halogen for instance chloride or bromide
- BF 4 boron
- PF 6 boron triflate
- the catalyst can be conveniently prepared by combining a metal source with the chiral ligand(s) in a solvent.
- Preferred catalysts in this respect have been found to be ferrocene-based ligands in combination with suitable metals such as iridium and rhodium.
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Abstract
The present invention relates to β-amino acid esters of Formula (2), and to a method for the preparation of β-amino acid esters of formula (2) by reduction of the corresponding enamines or amination of a β-keto ester followed by condensation with a halogen-substituted benzene derivative.
Description
NOVEL N-SUBSTITUTED β-AMINO ACID ESTERS
Field of the invention
The present invention relates to novel β-amino acid esters and to a method for the preparation of said β-amino acid esters by reduction of the corresponding enamines or amination of β-keto esters followed by condensation with a halogen-substituted benzene derivative.
Background of the invention
Ezetimibe (formula (1 ), also known as (3f?,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4- fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)-2-azetidinone, C24H2I F2NO3, CAS 163222-33-1 ) is a cholesterol absorption inhibitor.
Several synthetic schemes towards ezetimibe have been disclosed, for example in WO 95/08532 and in Shankar et al. (Tetrahedron Lett. 37, 4095-4098 (1996)). In the last document an approach has been described based on the preparation of a central intermediate for ezetimibe of general formula (3) from a β-amino ester of general formula (2) as outlined below.
(2) (3)
wherein R1 is H or benzyl, R2 is F and R3 is a chiral carboxylic acid protecting group. The rationale behind the need for this rather complex structural requirement for R3 is the fact that β-amino ester (2) of the required stereospecificity could only be obtained by chiral induction from the R3-group in a corresponding bromoacetate ester in a reaction with the required imine. Thus, specific R3 groups reported in this respect in Shankar et al. are derived from the chiral alcohols (-)-menthol, (-)-isopinocampheol, [(1 S)-endo]-(-)-borneol, (+)-isomenthol, (-)-trans-2-phenylcyclohexanol and (-)-δ-phenylmenthol which have as general drawbacks that they are expensive or, since they are not incorporated in the final product, will have a relatively high burden on the environment because of their high atomic weight, or both. In view of the above it is clear that there is room for improvement in the approach for the synthesis of ezetimibe intermediates.
Detailed description of the invention
In a first aspect of the present invention novel compounds (2) are disclosed.
The group Ri is not particularly restricted and may be any that can be introduced and removed with little or no adverse effect on other parts of the molecule. Methods for phenol protection are well known in the art and as examples of general classes of phenol protecting groups, mention can be made of ethers, acetals, esters, silyl groups and carbonates. For the purpose of the present invention, we found the benzyl radical may be conveniently so employed. However, suitable alternatives are acetyl, allyl, 9-anthrylmethyl, benzoyl, benzyl carbonyl, benzyloxymethyl, benzylsulfonyl,
p-bromophenacyl, n-butyl, sec-butyl, f-butyl, f-butyldimethylsilyl, f-butyldiphenylsilyl cyclohexyl, cyclopropylmethyl, 2,6-dichlorobenzyl, 2,2-dichloro-1 ,1-difluoroethyl, 4-(dimethylaminocarbonyl)benzyl, 2,6-dimethylbenzyl, dimethylphosphinyl, dimethylthio- phosphinyl, ethyl, 9-fluorenecarboxyl, 2-formylbenzenesulfonyl, heptafluoro-p-tolyl, hydrogen, isobutyl, isopropyl, levulinyl, methanesulfonyl, p-methoxybenzyl, methoxyethoxymethyl, methoxymethyl, methyl, methyl carbonyl, methylsulfonyl, methylthiomethyl, o-nitrobenzyl, p-nitrobenzyl, phenacyl, phenylthiomethyl, 4-picolyl, pivaloyl, propargyl, propyl, tetrafluoro-4-pyridyl, 2-tetrahydropyranyl, p-toluenesulfonyl, 2,2,2-trichloroethyl carbonyl, triethylsilyl, trifluoromethylsulfonyl, trimethylsilyl, 2-(trimethylsilyl)ethoxymethyl and vinyl carbonyl.
The group R2 can be any group and preferably is alkoxy or halogen. Most preferably the group R2 is fluorine as this atom is also present in ezetimibe or methoxy. The group R2 can be in the ortho position, the meta position or the para position; the latter is shown in (2a).
The group R3 preferably is an easily accessible carboxylic acid protecting group such as an alkenyl or substituted alkenyl, alkyl or substituted alkyl, alkylcarbonyl or substituted alkylcarbonyl, aryl or substituted aryl, arylcarbonyl or substituted arylcarbonyl, silyl or substituted silyl, sulfonyl or substituted sulfonyl, but not a chiral group such as (-)-menthyl, (-)-isopinocampheyl, [(1 S)-endo]-(-)-borneyl, (+)-isomenthyl, (-)-trans-2-phenylcyclohexanyl and (-)-δ-phenylmenthyl. Preferred groups are 9-anthrylmethyl, benzyloxymethyl, p-bromobenzyl, p-bromophenacyl, 3-buten-1-yl, f-butyldimethylsilyl, di-f-butylmethylsilyl, f-butyldiphenylsilyl cyclohexyl, carboxamido- methyl, ω — chloroalkyl, cinnamyl, cyclohexyl, cyclopentyl, cyclopropylmethyl, 5-dibenzo- suberyl, 2,6-dichlorobenzyl, 2,2-dichloro-1 ,1-difluoroethyl, 2,6-dimethoxybenzyl, 4-(dimethylaminocarbonyl)benzyl, 2,6-dimethylbenzyl, dimethylthiophosphinyl,
2-(9,10-dioxo)anthrylmethyl, diphenylmethyl, 2-(diphenylphosphino)ethyl, 1 ,3-dithianyl-2- methyl, 9-fluorenylmethyl, 2-haloethyl, hydrogen, isopropyldimethylsilyl, p-methoxy-
benzyl, methoxyethoxymethyl, methoxymethyl, p-methoxyphenacyl, α-methylcinnamyl, p-(methylmercapto)phenyl, α-methylphenacyl, 1-methyl-1-phenylethyl, 4-(methylsulfinyl)- benzyl, o-nitrobenzyl, p-nitrobenzyl, 6/s(o-nitrophenyl)methyl, 2-(p-nitrophenylsulfenyl)- ethyl), n-pentyl, phenacyl, phenyldimethylsilyl, Λ/-phthalimidomethyl, 4-picolyl, piperonyl, 1-pyrenylmethyl, 2-(2'-pyridyl)ethyl, 4-sulfobenzyl, 2-tetrahydrofuranyl, 2-tetrahydro- pyranyl, 2-(p-toluenesulfonyl)ethyl, 2,2,2-trichloroethyl, triethylsilyl, 2-(trifluoromethyl)- 6-chromylmethyl, 2,4,6-trimethylbenzyl, 4-(trimethylsilyl)-2-buten-1-yl, 2-(trimethylsilyl)- ethyl, 2-(tιϊmethylsilyl)ethoxymethyl and triphenylmethyl. Most preferred groups are those that are relatively cheap and have a relative low molecular weight such as allyl, benzyl, n-butyl, sec-butyl, f-butyl, 1 ,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethyl- propyl, ethyl, isobutyl, isopropyl, methyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, methyl carbonyl, methylthiomethyl, 2-methylthioethyl, phenyl, propyl and trimethylsilyl.
Thus, in contrast with compounds disclosed in Shankar et al. (Tetrahedron Lett. 37, 4095-4098 (1996)), the advantage of the compounds of the present invention is that they do not require expensive chiral protective groups R3 but rather protective groups that are easily accessible and generally much cheaper. If so required, chirality at carbon atom 3 in compound (2) can be effectively introduced using the method as described in the second aspect of the invention without the need for chiral protective groups R3 as described in the prior art. By using the compound (2) as defined in the present invention, further progress in the preparation of valuable medicines, the racemic form as well as the enantiomerically enriched forms and notably ezetimibe, can be realized.
In a second aspect of the invention a method for the preparation of novel compounds (2) is disclosed. In a first embodiment of the second aspect the method comprises reduction of a compound of general formula (4) wherein R1, R2 and R3 have the meaning as outlined in the first aspect above for compounds of general formula (2). For the reduction of enamines, a variety of methods exist such as for example direct electron transfer in a one-electron reduction, hydride transfer in reductions with for example lithium aluminum hydride and the like or a hydride shift as in the Meerwein-Ponndorf-Verley reduction, or hydrogen reductions with a catalyst such as the Lindlar catalyst or the Adkins catalyst. In principle, said methods are suitable for converting enamines of general formula (4) into the novel compounds of general formula (2).
(4) (2)
In a second embodiment, when racemic products of general formula (2) are obtained they are preferably subsequently separated into their optically pure isomers as in general only one of said isomers is suitable for the preparation of biologically active products whereas the other isomer is, at best, inactive. Separation can be conveniently carried out by optical resolution of the product of the reduction reaction. Alternatively, the enantiopure compounds may also be obtained by a kinetic resolution using an enzymatic acylation or preferably by a dynamic kinetic resolution using an enzymatic acylation and an amine racemization metal catalyst, preferably based on ruthenium or iridium. In another alternative, the enantiopure compounds are prepared by enzyme catalyzed ester hydrolysis with lipases as the preferred enzymes.
In a third embodiment, optically pure compounds of formula (2) wherein the configuration of carbon atom 3 is R or S, are produced directly from enamines of general formula (4). EP 1103536 discloses hydrogenation of cyclic enamides by means of a catalyst in the presence of hydrogen. Unfortunately, the substrates of the present invention are acyclic enamines bearing an NH moiety. An enamine is much more difficult to hydrogenate than an enamide. Surprisingly, asymmetric hydrogenation could be achieved by using a chiral homogeneous catalyst complex that contains a metal such as rhodium, ruthenium, iridium, palladium, platinum or copper, of which the first three are preferred. The complex contains at least one chiral ligand which can be monodentate, bidentate or tridentate. Suitable ligands are chiral monodentate phosphines, phosphites, phosphoramidites or phosphonites. If the ligand is monodentate the complex contains from 1-3 monodentate ligands, which may be the same or different. The complex may also contain a non-chiral ligand, such as triphenylphosphine. Suitable bidentate ligands are bisphosphines, bisphosphites, bisphosphonites, phosphine-phosphites, phosphine- phosphoramidites phosphite-oxazolines or phosphiteoxazolidines. The complex usually contains a single bidentate ligand. Many chiral hydrogenation ligands are described in
"The Handbook of Homogeneous Hydrogenation", eds. J. G. de Vries and CJ. Elsevier, Wiley-VCH, Weinheim, 2007. The catalyst may also contain one or more anions, such as a halogen (for instance chloride or bromide), BF4, PF6, acetate, triflate, tosylate and the like. The catalyst can be conveniently prepared by combining a metal source with the chiral ligand(s) in a solvent. Preferred catalysts in this respect have been found to be ferrocene-based ligands in combination with suitable metals such as iridium and rhodium. Examples of suitable ferrocene-based ligands are JosiPhos 2-1 , JosiPhos 9-1 , JosiPhos 11-1 , JosiPhos 404-1 , TaniaPhos 1-1 and WalPhos 3-1 but also structurally related ligands such as Mopf, BoPhos, and Fesulphos are suitable. Other preferred ligands are bidentate phosphine ligands such as TangPhos. Examples of suitable metal sources are rhodium(l) tetrafluoroborate bis-1 ,5-cyclooctadiene complex and iridium chloride-1 ,5-cyclooctadiene complex, RuCI3, RuCI3. nH2O, [RuCI2(η6-benzene)]2, [RuCI2(η6-cymene)]2, [RuCI2(η6-mesitylene)]2, [RuCI2(η6-hexamethylbenzene)]2, [RuCI2(Ti 6-1 ,2,3,4-tetramethylbenzene)]2, [RuBr2(η6-benzene)]2, [Rul2(η6-benzene)]2, trans-[RuCI2(DMSO)4], RuCI2(PPh3)3, Ru(COD)(COT), (in which COD = 1 ,5- cyclooctadiene and COT = 1 ,3,5-cyclooctatriene), Ru(COD)(methylallyl)2, IrCI3, [Ir(COD)CI]2, [Ir(CO)2CI]n, [IrCI(CO)3],,, [lr(Cp*)CI2]2, lr(Acac)(COD), [Ir(NBD)CI]2, [lr(COD)(C6H6)]+BF4 ", [(CF3C(O)CHC(O)CF3)Ir(COE)2], (in which COE is cyclooctene) [lr(CH3CN)4]+BF4-, lrCI(CO)(PPh3)2, [Rh(C6H10)CI]2 (in which C6H10 = hexa-1 ,5-diene), [Rh(COD)CI]2, [Rh(Cp)(CO)2], [Rh(norbornadiene)2]BF4, [Rh(Cp*)CI2]2 (in which Cp* is pentamethylcyclopentadienyl). Suitable solvents for the hydrogenation reaction are: ethyl acetate, 2-propanol, acetone, tetrahydrofuran, dichloroethane, dichloromethane, trifluoroethanol or toluene. Most preferably the solvents are free from oxidizing impurities. Particularly the use of halogenated alcohols such as trifluoroethanol as solvent led to superior results.
The hydrogenation reaction may be carried out at temperatures between 0-12O0C or more preferred between room temperature and 8O0C. The hydrogen pressure may vary between 0.1-200 bar, preferably between 0.5-100 bar, more preferably between 1 and 80 bar, most preferably between 5 and 70 bar. When using the catalysts of the present invention high enantiomeric excess values (e.e.) are achieved and hence preferably the configuration at carbon atom 3 in (2) is 75-100% R or S, more preferably 85-99.99% R or S, still more preferably 95-99.99% R or S, most preferably 97-99.99% R or S and still most preferably 99-99.99% R or S, depending on the stereochemistry of the catalyst used.
In a fourth embodiment of the second aspect the method comprises amination of a compound of general formula (5) wherein R1 and R3 have the meaning as outlined in the first aspect above for compounds of general formula (2). Said amination can, for example, be carried out using ammonium salicylate or a comparable reagent in the presence of a hydrogen source such as hydrogen gas and a catalyst, preferably the same catalyst as mentioned in the third embodiment of the second aspect of the present invention. Using the method of this embodiment, optically pure compounds of formula (6) wherein the configuration is R or S, are obtained with relatively inexpensive and readily available chemicals thus presenting an additional advantage over the embodiments described above. The resulting amine salt of general formula (6) is subsequently reacted with a compound of general formula (7) wherein R2 has the meaning as outlined in the first aspect above for compounds of general formula (2) and X is a leaving group, preferably halogen, more preferably iodine or bromine. The reaction between (6) and (7) is carried out in the presence of a catalyst, preferably a metal catalyst wherein the metal preferably is copper. Optionally, the mixture resulting from the reaction between (6) and (7) is treated with an alcohol R3-OH in the presence of an activating agent such as thionyl chloride or with an activated derivative of the alcohol R3-OH as under some conditions use for the reaction between (6) and (7) part of the ester moiety may be hydrolyzed.
(5) (6)
In a third aspect of the invention the use of novel compounds of general formula (2) in the preparation of a medicament is disclosed. A preferred example of such a medicament is ezetimibe of formula (1). Hence, compounds (2) are used to convert into intermediates of general formula (3), for instance by reaction with Grignard reagents such as ethyl magnesium bromide. Preferably this use is carried out starting from compounds (2) having the R configuration at carbon atom 3 as this results in the required ezetimibe stereochemistry. Further conversion of (3) into ezetimibe is then
carried out by coupling of (3) with an optionally protected 3-hydroxy-4- fluorophenylpropane preferably having the S configuration which is activated at carbon atom 1 such as, for instance, 1-bromo-3-hydroxy-4-fluorophenylpropane, 1 -chloro-3- hydroxy-4-fluorophenylpropane, 1 -iodo-3-hydroxy-4-fluorophenylpropane and the like. Protecting groups are thereafter removed using standard techniques.
EXAMPLES
Example 1 (Z)-Ethyl 3-(4-(benzyloxy)phenyl)-3-(4-fluorophenylamino)acrylate
Ethyl-3-(-4-benzyloxy)phenyl-3-oxopropanoate (2 g, 6.7 mmol) was dissolved in 4-fluoroaniline (6 ml_, 76.5 mmol). p-Toluenesulphonic acid (256 mg, 1.35 mmol) and molecular sieves 5A (4 g) were added and the reaction mixture was reacted at 1000C for roughly 2 hours until the starting material was totally consumed. The reaction mixture was filtered and rinsed with CH2CI2 and washed with a saturated aqueous solution of NaHCOs and dried with Na2SO4. 4-Fluoroaniline was removed by vacuum distillation (3 mm Hg at 67°C) and the residue was crystallized from ethanol to give off white crystals (1 .46 g, 61 % yield). Rf 0.19 (in ethyl acetate/n-heptane, 1/5). 1H-NMR (CDCI3, 300 MHz, ppm): δ 10.12 (br s, 1 H), 7.32-7.14 (m, 5H, arom.), 7.13-7.09 (m, 2H, arom.), 6.78-6.61 (m, 4H, arom.), 6.58-6.52 (m, 2H, arom.), 4.89 (br s, 2H), 4.87 (br s, 1 H), 4.09 (q, J = 7.3 Hz, 2H), 1.19 (dt, J = 7.3 Hz, 3H). 13C-NMR (CDCI3, 75 MHz, ppm) δ 170.2, 160.5, 159.8, 159.0, 157.2, 136.4, 129.7, 128.6, 128.1 , 127.5, 124.0, 123.9, 1 15.5, 1 15.2, 1 14.7, 90.3, 70.0, 59.2, 14.5.
Example 2 (S*)-Ethyl 3-(4-(benzyloxy)phenyl)-3-(4-fluorophenylamino)propanoate
1. Preparation of the catalyst
Rhodium(l) tetrafluoroborate bis-1 ,5-cyclooctadiene complex (CAS 35138-22-8, 104 mg, 0.255 mmol) and JosiPhos 2-1 (R,R)-1-[1-(Di-tert-butylphosphino)ethyl]-2-(diphenyl- phosphino)ferrocene (JosiPhos SL-J002-1 , CAS 155830-69-6, 139 mg, 0.255 mmol) were dissolved in degassed CH2CI2 (10 ml_). The reaction mixture was degassed three times and stirred for 1 h at 400C. After stirring, the solvent was removed in vacuo and
the formed catalyst was kept under nitrogen atmosphere. Next the formed catalyst was dissolved in degassed trifluoroethanol (5 ml_).
Z Asymmetric hvdroqenation
(Z)-Ethyl 3-(4-(benzyloxy)phenyl)-3-(4-fluorophenylamino)acrylate (2 g, 5.1 mmol) was added to an autoclave which was closed firmly and placed under inert atmosphere. Next degassed trifluoroethanol (50 ml.) was added via the injection port. After the system was degassed three times with nitrogen the preformed catalyst (see 1.) was added via the injection port to the reaction mixture. The reaction mixture was allowed to react under
50 bar of hydrogen at 500C overnight. The solvent was removed in vacuo and the crude compound was purified by column chromatography (ethyl acetate/n-heptane, 1/5) to give the product (1.69 g, 84% yield) as a white solid. Rf 0.21 (ethyl acetate /n-heptane, 1/5).
The enantiomeric excess of the title product was determined with chiral HPLC to be 74% under the following conditions:
Column: Chiralpak AD-H from Daicel Technologies (250 x 4.6 mm, 5 μm) Mobile phase: 90/10 v/v% n-heptane/2-propanol
Flow: 1.0 ml/min.
Detection: UV 220nm
Injection: 5 μl_
Column temp.:ambient Retention times: enantiomer #1 : 19.9 min; enantiomer #2: 25.1 min.
Note that the absolute stereochemistry at carbon atom number 3 is not known; the structure could be R or S which is indicated by the symbol S* in the title.
Example 3 (S*)-Ethyl 3-(4-(benzyloxy)phenyl)-3-(4-fluorophenylamino)propanoate
Ferrocene-based ligands
(Z)-Ethyl 3-(4-(benzyloxy)phenyl)-3-(4-fluorophenylamino)acrylate was asymmetrically hydrogenated as described in Example 2 however various conditions such as additives, hydrogen pressure, ligands, solvents and temperature were investigated as summarized in Tables 1 to 4. Six ligands were tested, namely JosiPhos 2-1 (Table 1 ), JosiPhos 9-1 (Table 2), JosiPhos 11-1 (Table 3), JosiPhos 404-1 (Table 4), TaniaPhos 1-1 (Table 5) and WalPhos 3-1 (Table 6). The chemical structures of these ligands are as follows:
JosiPhos 404-1 TaniaPhos 1-1 WalPhos 3-1
Table 1 : Asymmetric hydrogenation using JosiPhos 2-1 and Rh(COD)2BF4 (1 %) at 25 bar of hydrogen at 500C for 18 h; Substrate/catalyst ratio = 25
25 bar of hydrogen at 500C for 18 h; Substrate/catalyst ratio = 25
Table 3: Asymmetric hydrogenation using JosiPhos 11-1 and Rh(COD)2BF4 (1 %) at 25 bar of hydrogen at 500C for 18 h; Substrate/catalyst ratio = 25 (the last entry was carried out at 80°C)
Table 4: Asymmetric hydrogenation using JosiPhos 404-1 and Rh(COD)2BF4 (1 %) in trifluoroethanol for 18 h; Substrate/catalyst ratio = 25
Table 5: Asymmetric hydrogenation using TaniaPhos 1-1 and Rh(COD)2BF4 (1 %) in trifluoroethanol for 18 h; Substrate/catalyst ratio = 25
Example 4
(S*)-Ethyl 3-(4-(benzyloxy)phenyl)-3-(4-fluorophenylamino)propanoate Rhodium TangPhos catalyst
(Z)-Ethyl 3-(4-(benzyloxy)phenyl)-3-(4-fluorophenylamino)acrylate was asymmetrically hydrogenated as described in Example 2 however TangPhos (Tang and Zhang, Angew. Chem., Int. Ed. 41., 1612 (2002)) was used as ligand and various solvents were investigated as summarized in Table 7. The chemical structure of TangPhos is:
25 bar of hydrogen at 500C for 18 h; Substrate/catalyst ratio = 25
Example 5
(S*)-Ethyl 3-(4-(benzyloxy)phenyl)-3-(4-fluorophenylamino)propanoate
Iridium catalyst
(Z)-Ethyl 3-(4-(benzyloxy)phenyl)-3-(4-fluorophenylamino)acrylate was asymmetrically hydrogenated as described in the foregoing examples however with iridium as the catalytic metal. The results are summarized in Table 9. See Example 3 for the chemical structures of the ligands.
Table 9: Asymmetric hydrogenation using various ligands and [Ir(COD)CI]2 (1 %) at
25 bar of hydrogen at 500C for 18 h; Substrate/catalyst ratio = 25
(S*)-Ethyl 3-(4-(benzyloxy)phenyl)-3-(4-fluorophenylamino)propanoate
Iridium Pfaltz catalyst
V Preparation of the iridium Pfaltz catalyst [Ir(COD)CI]2 (83 mg, 0.124 mmol) and (R)-(-)-2-[2-(diphenylphosphino)phenyl]-4-(1- methylethyl)-4,5-dihydrooxazole (CAS 164858-78-0, 99 mg, 0.265 mmol) are placed into a Schlenk tube. The Schlenk tube is placed under vacuum and refilled three times with nitrogen. Dry and degassed dichloromethane (5 ml.) was added and the reaction mixture was stirred for 1.5 h at 500C and subsequently cooled to room temperature. An aqueous solution of NH4PF6 (0.4 M, 5 ml.) was added and the biphasic mixture was vigorously stirred for 15 min. The organic phase was separated and washed with H2O (20 ml.) and dried with Na2SO4. The catalyst was re-crystallized upon addition of diethyl ether from a concentrated solution in dichloromethane. The red solid was isolated and dried under vacuum. 2. Asymmetric hvdroqenation
[lr(COD)(l_igand)]+;PF6- (obtained under 1 , 1.5 mg, 0.0018 mmol) and (Z)-ethyl 3-(4- (benzyloxy)phenyl)-3-(4-fluorophenylamino)acrylate (691 mg, 1.77 mmol) were placed inside the vessel of a hydrogenation autoclave. Trifluoroethanol (5 ml.) was added and the autoclave was closed and placed under nitrogen. The autoclave was subsequently placed under hydrogen at 25 bar and heated at 500C. The reaction mixture was stirred vigorously with a mechanical stirrer. The consumption of hydrogen was monitored indicating full conversion after 5 h (average turnover frequency approx. 200 h"1). HPLC analysis (as described in Example 2) of the reaction mixture after hydrogenation indicated full conversion and an e.e. of 45%.
Example 7 (Z)-ethyl 3-(4-(benzyloxy)phenyl)-3-(2-methoxyphenylamino)acrylate
Ethyl-3-(-4-benzyloxy)phenyl-3-oxopropanoate (2 g, 6.7 mmol) was dissolved in 2- methoxyaniline (6 ml_, 76.5 mmol). p-Toluenesulphonic acid (0.255 g, 1.341 mmol) and molecular sieves 5A (1 g) were added and the reaction mixture was reacted at 1000C for approximately 2 hours until the starting material was totally consumed. The reaction mixture was filtered and rinsed with CH2CI2 and washed with a saturated aqueous solution of NaHCOs and dried with Na2SO4. 2-Methoxyaniline was removed by vacuum distillation and the residue was crystallized from ethanol to give off white crystals (1.3 g,
48% yield). 1H-NMR (CDCI3, 300 MHz, ppm): δ 10.23 (br s, 1 H), 7.51-7.35 (m, 7H, arom.), 6.96-6.70 (m, 4H, arom.), 6.78-6.61 (m, 1 H, arom.), 6.33-6.27 (m, 1 H, arom.),
5.07 (br s, 2H), 5.00 (br s, 1 H), 4.22 (q, 2H), 3.92 (s, 3H), 1.23 (t, 3H). HPLC retention time 13.77 min using the following conditions:
Column: lnertsil ODS-3 (150 x 4.6 mm, 5 μm)
Eluent A: 1O mM H3PO4
Eluent B: Methanol
Flow: 1.0 ml_/min
Temp: 400C
Injection volume: 5 μl_
Example 8 Ethyl 3-(4-(benzyloxy)phenyl)-3-(2-methoxyphenylamino)propanoate
(Z)-Ethyl 3-(4-(benzyloxy)phenyl)-3-(2-methoxyphenylamino)acrylate was asymmetrically hydrogenated as described in the foregoing examples under various conditions using various catalysts as summarized in Table 10. 1H-NMR (CDCI3, 300 MHz, ppm): δ 1 1.00 (br s, 1 NH), 7.51-7.35 (m, 7H, arom.), 6.96-6.70 (m, 4H, arom.), 6.78-6.61 (m, 1 H, arom.), 6.33-6.27 (m, 1 H, arom.), 5.05 (br s, 2H), 4.87 (t, 1 H), 4.14 (q, 2H), 3.90 (t, 3H), 2.85 (m, 2H), 1.23 (t, 3H). HPLC retention time 12.50 min using the same conditions as in Example 7
Table 10: Asymmetric hydrogenation of (Z)-ethyl 3-(4-(benzyloxy)phenyl)-3-(2- methoxyphenylamino)acrylate in trifluoroethanol using various catalysts and substrate/catalyst ratios (S/C) at 25 bar of hydrogen at 500C for 16 h
The chemical structures of Pfaltz-tert-But-PF6 (CAS 148461-16-9) and Pfaltz-tert-But- ToI-PF6 (CAS 2184600-05) are:
Example 9
(S*)-Ethyl 3-amino-3-(4-(benzyloxy)phenyl)propanoate (substrate/catalyst ratio 5000)
In a 100 ml. Hastelloy autoclave was placed 1/2[Me2NH2]{RuCI(R)-dm-segphos)}2(μ-CI)3] (6.2 mg, 0.0033 mmol), ammonium salicylate (10.4 g, 67.0 mmol) and salicylic acid (0.463 g, 3.35 mmol). The atmosphere was replaced with nitrogen (5x) followed by addition of ethyl 3-(4-benzyloxy)phenyl)-3-oxopropanoate (10.00 g, 33.52 mmol) in ethanol (50 ml_). Nitrogen was again introduced followed by hydrogen. The reaction was stirred for 18 h at 85°C, with 50 bar hydrogen pressure. The reaction was cooled to room temperature and filtered. Ethanol was evaporated and the crude reaction mixture was stirred in saturated aqueous NaHCO3 for 30 min. Next the product was extracted with toluene (3x). The toluene phase was washed with a Na2CO3 solution. Evaporation of the toluene yielded the title product (8 g, 80%).
Example 10
(S*)-Ethyl 3-(4-(benzyloxy)phenyl)-3-(4-fluorophenylamino)propanoate
Ullmann coupling
A Schlenck flask was charged with (S*)-ethyl 3-amino-3-(4- (benzyloxy)phenyl)propanoate (150 mg, 0.50 mmol) and copper acetylacetonate (16.6 mg, 63 μmol). The flask was evacuated and flushed with nitrogen (5x). Subsequently, DMF (1.O mL), K2CO3 (141.2 mg, 1.01 mmol), acetylacetone (12.4 μL, 1.98 mmol) and 1-bromo-4-fluorobenzene (160 μL, 0.573 mmol) were added. The reaction mixture was heated at 1200C for 16 h. The reaction progress was monitored by HPLC. After completion the reaction mixture was allowed to reach room temperature and yielded the desired compound in 62% yield. In a comparative experiment with CuCI (5.9 mg, 60 μmol) instead of copper acetylacetonate the desired compound was obtained in 42% yield.
Example 11 (S*)-3-(4-(Benzyloxy)phenyl)-3-(4-fluorophenylamino)propanoate
Ullmann coupling
A round bottom flask was charged with CuCI2 (1.028 g, 10.4 mmol) and crushed KOH (17.O g, 0.31 mol). To this was added a solution of (S*)-ethyl 3-amino-3-(4- (benzyloxy)phenyl)propanoate (20.O g, 66.8 mmol) in DMF (11 O mL). Subsequently acetylacetone (1.65 mL, 16.08 mmol) and 4-fluor-bromobenzene (12 mL, 0.11 mol) were added. The resulting mixture was heated under nitrogen for 20 h. The reaction was allowed to cool to room temperature and water (100 mL) was added. The suspension was filtered over celite and extracted with pentane (4 x 150 mL). The aqueous phase was separated and acidified to pH=2 with HCI (1 M) and extracted with ethyl acetate (4 x 150 mL). The combined organic phases were extracted with water (10 x 175 mL), dried over Na2SO4 and concentrated in vacuo to furnish a brown liquid (25.1 g, 96%) (e.e. 96.6%)
Example 12 (S*)-Ethyl 3-(4-(benzyloxy)phenyl)-3-(4-fluorophenylamino)propanoate from (S*)-3-(4-(Benzyloxy)phenyl)-3-(4-fluorophenylamino)propanoate
A round bottom flask was charged with (S*)-3-(4-(benzyloxy)phenyl)-3-(4- fluorophenylamino)propanoate (25.1 g, 68.6 mmol) and ethanol (150 ml_). The solution was cooled to 00C and stirred for 30 min. Subsequently, thionyl chloride (7.6 ml_, 109.1 mmol) was added carefully. The mixture was heated to 78°C for 2 h and then cooled to room temperature. Concentration in vacuo provided the crude title product which was further purified by column chromatography (heptane/ethyl acetate, 10/1 ) yielding the desired compound as off white foam (18.9 g, 71%).
Claims
1. Compound of the general formula (2)
wherein R1 is acyl or substituted acyl, alkenyl or substituted alkenyl, alkyl or substituted alkyl, alkylcarbonyl or substituted alkylcarbonyl, aryl or substituted aryl, arylcarbonyl or substituted arylcarbonyl, hydrogen, phosphinyl or substituted phosphinyl, silyl or substituted silyl, sulfonyl or substituted sulfonyl and wherein R2 is chosen from the group consisting of alkoxy, bromine, chlorine, fluorine and iodine and wherein R3 is chosen from the group consisting of allyl, 9-anthrylmethyl, benzyl, benzyloxymethyl, p-bromobenzyl, p-bromophenacyl, 3-buten-1-yl, n-butyl, sec-butyl, f-butyl, f-butyldimethylsilyl, di-f-butylmethylsilyl, f-butyldiphenylsilyl cyclohexyl, carboxamidomethyl, co— chloroalkyl, cinnamyl, cyclohexyl, cyclopentyl, cyclopropylmethyl, 5-dibenzosuberyl, 2,6-dichlorobenzyl, 2,2-dichloro-1 ,1-difluoroethyl, 2,6-dimethoxybenzyl, 4-(dimethylaminocarbonyl)benzyl, 2,6-dimethylbenzyl,
1 ,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, dimethylthiophosphinyl, 2-(9,10-dioxo)anthrylmethyl, diphenylmethyl, 2-(diphenylphosphino)ethyl,
1 ,3-dithianyl-2-methyl, ethyl, 9-fluorenylmethyl, 2-haloethyl, hydrogen, isobutyl, isopropyl, isopropyldimethylsilyl, p-methoxybenzyl, methoxyethoxymethyl, methoxymethyl, p-methoxyphenacyl, methyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, methyl carbonyl, α-methylcinnamyl, p-(methylmercapto)phenyl, α-methylphenacyl, 1-methyl-1-phenylethyl, 4-(methylsulfinyl)benzyl, methylthiomethyl, 2-methylthioethyl, o-nitrobenzyl, p-nitrobenzyl, b/s(o-nitrophenyl)methyl, 2-(p-nitrophenylsulfenyl)ethyl), n-pentyl, phenacyl, phenyl, phenyldimethylsilyl, Λ/-phthalimidomethyl, 4-picolyl, piperonyl, propyl, 1-pyrenylmethyl, 2-(2'-pyridyl)ethyl, 4-sulfobenzyl, 2-tetrahydrofuranyl, 2-tetra- hydropyranyl, 2-(p-toluenesulfonyl)ethyl, 2,2,2-trichloroethyl, triethylsilyl, 2-(trifluoro- methyl)-6-chromylmethyl, 2,4,6-trimethylbenzyl, 4-(trimethylsilyl)-2-buten-1-yl, trimethyl- silyl, 2-(tιϊmethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl and triphenylmethyl and can be in the ortho, meta or para position.
2. A compound according to claim 1 wherein R1 is chosen from the group consisting of acetyl, allyl, 9-anthrylmethyl, benzoyl, benzyl, benzyl carbonyl, benzyloxymethyl, benzylsulfonyl, p-bromophenacyl, n-butyl, sec-butyl, f-butyl, f-butyldimethylsilyl, f-butyldiphenylsilyl cyclohexyl, cyclopropylmethyl, 2,6-dichlorobenzyl, 2,2-dichloro-1 ,1- difluoroethyl, 4-(dimethylaminocarbonyl)benzyl, 2,6-dimethylbenzyl, dimethylphosphinyl, dimethylthiophosphinyl, ethyl, 9-fluorenecarboxyl, 2-formylbenzenesulfonyl, heptafluoro- p-tolyl, hydrogen, isobutyl, isopropyl, levulinyl, methanesulfonyl, p-methoxybenzyl, methoxyethoxymethyl, methoxymethyl, methyl, methyl carbonyl, methylsulfonyl, methylthiomethyl, o-nitrobenzyl, p-nitrobenzyl, phenacyl, phenylthiomethyl, 4-picolyl, pivaloyl, propargyl, propyl, tetrafluoro-4-pyridyl, 2-tetrahydropyranyl, p-toluenesulfonyl, 2,2,2-trichloroethyl carbonyl, triethylsilyl, trifluoromethylsulfonyl, trimethylsilyl, 2-(trimethylsilyl)ethoxymethyl and vinyl carbonyl.
3. A compound of the general formula (2a)
according to claim 2 wherein R1 is benzyl, R2 is fluorine and R3 is ethyl.
4. A compound according to any one of claims 1 to 3 wherein the configuration at carbon atom number 3 is from 95% to 100% S or from 95% to 100% R.
5. A compound according to any one of claims 1 to 3 which has an e.e. value of from 50 to 100.
6. Method for the preparation of a compound of general formula (2)
comprising reduction of a compound of general formula (4)
7. Method according to claim 6 further comprising subsequent optical resolution of the product of said reduction.
8. Method according to claim 6 wherein said reduction is carried out by means of asymmetric hydrogenation.
9. Method for the preparation of a compound of general formula (2)
with ammonium salicylate in the presence of a catalyst to give a compound of general formula (6)
wherein R1, R2 and R3 have the meaning as given in any one of claims 1 to 3.
10. Use of a compound according to any one of claims 1 to 5 in the preparation of a medicament.
11. Use according to claim 10 wherein said medicament is ezetimibe.
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Cited By (4)
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JP2015537055A (en) * | 2012-12-18 | 2015-12-24 | ディーエスエム アイピー アセッツ ビー.ブイ. | Use of a mixture of E / Z isomers to obtain specific products quantitatively by combined asymmetric hydrogenation |
JP2016505568A (en) * | 2012-12-18 | 2016-02-25 | ディーエスエム アイピー アセッツ ビー.ブイ. | Use of a mixture of E / Z isomers to obtain specific products quantitatively by combining asymmetric hydrogenation and isomerization |
US9388440B2 (en) | 2009-04-01 | 2016-07-12 | Mylan Laboratories Limited | Enzymatic process for the preparation of (S)-5-(4-fluoro-phenyl)-5-hydroxy-1morpholin-4-yl-pentan-1-one, an intermediate of Ezetimibe and further conversion to Ezetimibe |
KR101764185B1 (en) | 2016-11-25 | 2017-08-02 | 강원대학교산학협력단 | Process for preparing chiral β-amino acid derivative by asymmetric hydrogenation with cinchona-derived organocatalyst |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9388440B2 (en) | 2009-04-01 | 2016-07-12 | Mylan Laboratories Limited | Enzymatic process for the preparation of (S)-5-(4-fluoro-phenyl)-5-hydroxy-1morpholin-4-yl-pentan-1-one, an intermediate of Ezetimibe and further conversion to Ezetimibe |
JP2015537055A (en) * | 2012-12-18 | 2015-12-24 | ディーエスエム アイピー アセッツ ビー.ブイ. | Use of a mixture of E / Z isomers to obtain specific products quantitatively by combined asymmetric hydrogenation |
JP2016505568A (en) * | 2012-12-18 | 2016-02-25 | ディーエスエム アイピー アセッツ ビー.ブイ. | Use of a mixture of E / Z isomers to obtain specific products quantitatively by combining asymmetric hydrogenation and isomerization |
KR101764185B1 (en) | 2016-11-25 | 2017-08-02 | 강원대학교산학협력단 | Process for preparing chiral β-amino acid derivative by asymmetric hydrogenation with cinchona-derived organocatalyst |
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