CN101175714A - Process to chiral beta amino acid derivatives by asymmetric hydrogenation - Google Patents
Process to chiral beta amino acid derivatives by asymmetric hydrogenation Download PDFInfo
- Publication number
- CN101175714A CN101175714A CNA2006800028725A CN200680002872A CN101175714A CN 101175714 A CN101175714 A CN 101175714A CN A2006800028725 A CNA2006800028725 A CN A2006800028725A CN 200680002872 A CN200680002872 A CN 200680002872A CN 101175714 A CN101175714 A CN 101175714A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- unsubstituted
- ammonium
- structural formula
- aryl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The present invention relates to a process for the efficient preparation of enantiomerically enriched beta amino acid derivatives which are useful in the asymmetric synthesis of biologically active molecules. The process comprises an enantioselective hydrogenation of a prochiral beta amino acrylic acid derivative substrate in the presence of an ammonium salt and a transition metal precursor complexed with a chiral ferrocenyl diphosphine ligand.
Description
Invention field
The present invention relates to effective preparation method of the beta amino acids derivative of enantiomorph enrichment, this derivative can be used for the asymmetric synthesis of bioactive molecules.This method be included in ammonium salt and with the existence of the transition metal precursors of chiral ferrocene diphosphine ligand complexing under, the enantiomorph of prochirality beta-amino acrylic acid derivative substrate is selected hydrogenation.
Background of invention
The invention provides effective preparation method of beta amino acids derivative of the structural formula I of enantiomorph enrichment:
In formula I, indicate
*Stereocenter have (R)-or (S)-configuration; Wherein
Z is OR
2, SR
2Or NR
2R
3
R
1Be C
1-8Alkyl, aryl, heteroaryl, aryl-C
1-2Alkyl or heteroaryl-C
1-2Alkyl;
R
2And R
3Each independently is hydrogen, C
1-8Alkyl, aryl or aryl-C
1-2Alkyl; Or R
2And R
3Form optional containing with the nitrogen-atoms that they connected and be selected from O, S and NC
1-4The heteroatomic 4-to 7-of other of alkyl unit heterocyclic ring system, described heterocyclic ring system optional with 5-to 6-unit saturated or aromatic carbocyclic system or contain and be selected from O, S and NC
1-4Saturated or aromatic heterocycle system of the heteroatomic 5-to 6-of the 1-2 of alkyl unit condenses, and described condensed ring system is unsubstituted or independently is selected from hydroxyl, amino, fluoro base, C
1-4Alkyl, C
1-4The 1-2 of alkoxyl group and trifluoromethyl substituting group replaces.
The inventive method relates to, in ammonium salt and complexing to the transition metal precursors of chiral ferrocene diphosphine ligand, through the asymmetric hydrogenation structural formula II prochirality enamine of transition metal catalytic:
Amino is not wherein protected, and selects mode with effective enantiomorph, the method for the chirality beta amino acids derivative of preparation structural formula I.
Adopt the chiral ferrocene diphosphine as the part of complexing to rhodium or iridium precursor, the method of enamine carbon-to-carbon double bond (C=C-N) of reducing has been described in the patent documentation (U.S. Patent number of on October 8th, 1996 submitting to referring to Ciba-Geigy Corp 5 asymmetricly, 563,309 with relevant patent families and patent application).The methods involving that adopts rhodium Me-DuPHOS catalytic complexes to obtain N-acylations beta amino acids is announced (U.S.2002/0128509 that is issued to the announcement in 12 days September in 2002 of Degussa AG).Following publication is also described with the rhodium metal precursor asymmetric hydrogenation N-acylations beta-amino vinylformic acid that is complexed to chiral phosphine ligand: (1) T.Hayashi, etc.,
Bull.Chem.Soc.Japan, 53:1136-1151 (1980); (2) G.Zhu etc.,
J.Org. Chem., 64:6907-6910 (1999); (3) W.D.Lubell, etc.,
Tetrahedron: Asymmetry, 2:543-554 (1991).In these publications, all embodiment that provided have amino in the β amino-acrylic acid derivatives substrate as the acetamide derivative protection.The amine protection needs in two extra chemical steps (promptly protect and go and protect) introducing program, thereby synthetic protected substrate also may be difficult.The protection that the inventive method centers on the primary amino in the substrate of asymmetric hydrogenation needs, and sets about from good reactivity and enantio-selectivity.
Summary of the invention
The present invention relates to the preparation method of beta amino acids derivative of the enantiomorph enrichment of structural formula I.This method adopts, ammonium salt and with the transition metal precursors of chiral ferrocene diphosphine ligand complexing in the presence of, the asymmetric hydrogenation of prochirality β amino-acrylic acid derivatives, wherein primary amino is not protected.The inventive method can be applicable to the preparation of pilot plant's scale or plant-scale beta amino acids derivative.Beta amino acids is used to prepare multiple bioactive molecules.
Detailed Description Of The Invention
The invention provides effective preparation method of beta amino acids derivative of the structural formula I of enantiomorph enrichment:
In formula I, indicate
*Stereocenter have (R)-or (S)-configuration;
Compare with relative enantiomorph, at least 70% enantiomeric excess, wherein
Z is OR
2, SR
2Or NR
2R
3
R
1Be C
1-8Alkyl, aryl, heteroaryl, aryl-C
1-2Alkyl or heteroaryl-C
1-2Alkyl;
R
2And R
3Each independently is hydrogen, C
1-8Alkyl, aryl or aryl-C
1-2Alkyl; Or R
2And R
3Form optional containing with the nitrogen-atoms that they connected and be selected from O, S, NH and NC
1-4The heteroatomic 4-to 7-of other of alkyl unit heterocyclic ring system, described heterocycle is unsubstituted or independently is selected from oxo base, hydroxyl, halogen, C
1-4Alkoxyl group and C
1-4The 1-3 of alkyl substituting group replaces, and wherein alkyl and alkoxyl group do not replace or replaced by 1-5 fluorine; And described heterocycle ring system optional with 5-to 6-unit saturated or aromatic carbocyclic ring system or contain and be selected from O, S and NC
0-4Saturated or the aromatic heterocycle ring system of the heteroatomic 5-to 6-of the 1-2 of alkyl unit condenses, and described condensed ring system is unsubstituted or is selected from hydroxyl, amino, fluorine, C
1-4Alkyl, C
1-4The 1-2 of alkoxyl group and trifluoromethyl substituting group replaces.
The inventive method comprises, in appropriate organic solvent, ammonium salt and be complexed to structural formula II I the chiral ferrocene diphosphine ligand transition metal precursors in the presence of:
R wherein
4Be C
1-4Alkyl or aryl;
R
5And R
6Each independently is C
1-6Alkyl, C
5-12Cycloalkyl or aryl; With
R
7Be C
1-4Alkyl or unsubstituted phenyl,
The step of the prochirality enamine of hydrogenation structural formula II:
The inventive method design, the catalytic complexes of transition metal precursors and chiral ferrocene diphosphine ligand both can (a) generates by add kinds of transition metals and chiral ferrocene diphosphine ligand original position in succession or simultaneously to reaction mixture, also can (b) through or add in the reaction mixture without separating to make again in advance.Ready-made catalytic complexes is expressed from the next:
Wherein X represents non-coordination anion, and for example trifluoromethanesulfonic acid root, tetrafluoroborate and hexafluoro-phosphate radical and L are for example alkene (or chelating two-alkene for example 1,5-cyclooctadiene or norbornadiene) or solvent molecules (for example MeOH and TFE) of neutral ligand.At alkene is that complex compound is expressed from the next under the situation of aromatic hydrocarbons:
Represent at X under the situation of halogen, ready-made catalytic complexes is expressed from the next:
Structural formula II I part is called as the Josiphos part in the art, can obtain by the Solvias AG of commercial sources from Switzerland Basel.
An embodiment at the formula III part that is used for the inventive method indicates
*The carbon stereocenter have (the R)-configuration described in the formula IV:
At another embodiment of the formula III part that is used for the inventive method, R
4Be C
1-2Alkyl, R
5And R
6Be C
1-4Alkyl, R
7It is unsubstituted phenyl.In this embodiment of a class, R
4Be methyl, R
5And R
6Be the tertiary butyl, R
7It is unsubstituted phenyl.Back one part is called tertiary butyl Josiphos in the art.The form of the tertiary butyl Josiphos part that can obtain by commercial sources is S, R and R, S enantiomeric form.R, S-tertiary butyl Josiphos are { (R)-1-[(S)-(diphenylphosphino) the ferrocenyl] } ethyls-two-tertiary butyl phosphine with following formula V:
The Ferrocenediphosphines part of formula III has two asymmetric centers, and method plan of the present invention comprises single enantiomer, each diastereomer and their the non-enantiomer mixture purposes in asymmetric hydrogenation formula II compound.This invention is intended to comprise the purposes of all these class isomeric form of structural formula II I part.The face formula enantio-selectivity of hydrogenation can depend on the particular stereoisomer of the part that is used for this reaction.The chirality of the Ferrocenediphosphines part by selecting formula III advisably can indicate in the control type I compound
*The configuration of stereocenter of new formation.
At an embodiment of the substrate that is used for the inventive method, R
1Be benzyl, wherein the phenyl of benzyl is not substituted or is selected from 1-3 substituting group replacement of fluorine, trifluoromethyl and trifluoromethoxy.In another embodiment of the inventive method, Z is OR
2Or NR
2R
3In such embodiment, NR
2R
3Be heterocycle with structural formula VI:
R wherein
8Be hydrogen or do not replace or by the C of 1-5 fluorine replacement
1-4Alkyl.In another kind of embodiment, Z is OR
2
At another embodiment of the substrate that is used for the inventive method, R
1Be that 6-methoxyl group-pyridin-3-yl and Z are C
1-4Alkoxyl group.In such embodiment, Z is a methoxy or ethoxy.
Asymmetric hydrogenation of the present invention carries out in appropriate organic solvent.The organic solvent that is suitable for comprises low-grade alkane alcohol, for example methyl alcohol, ethanol, Virahol, hexafluoroisopropanol, phenol, 2,2,2 tfifluoroethyl alcohol (TFE) and their mixture; Tetrahydrofuran (THF); Methyl tertiary butyl ether; With their mixture.
Also can in the presence of the ammonium salt of the about 10mol% of about 0.01-(with respect to the prochirality enamine substrate of formula II), carry out asymmetric hydrogenation.In one embodiment, ammonium salt is the ammonium halide salt that is selected from ammonium chloride, brometo de amonio and ammonium iodide.In this embodiment of a class, ammonium halide salt is an ammonium chloride.In another embodiment, ammonium salt is for example ammonium acetate and an ammonium formiate of ammonium carboxylate salt.In another embodiment, ammonium salt is the about 5mol% of about 0.05-to the ratio of prochirality enamine substrate.
The temperature of reaction of this reaction can be between about 10 ℃-Yue 90 ℃ scope.The preferred range of this reaction is about 45 ℃-Yue 65 ℃.
Can carry out this hydrogenation in the hydrogen pressure scope of the about 1500psig of about 20psig-.Preferred hydrogen pressure scope is the about 200psig of about 80psig-.
Transition metal precursors is [M (monoolefine)
2Cl]
2, [M (diolefine) Cl]
2, [M (monoolefine)
2Acetyl pyruvate (acetonate)], [M (diolefine) acetyl pyruvate], [M (monoolefine)
4] X or [M (diolefine)
2] X, wherein X is selected from methanesulfonate, trifluoromethanesulfonic acid root (Tf), tetrafluoroborate (BF
4), hexafluoro-phosphate radical (PF
6) and hexafluoroantimonic anion (SbF
6) non-coordination anion and M be rhodium (Rh) or iridium (Ir).Wherein M is that the transition metal precursors of ruthenium (Ru) is [M (aromatic hydrocarbons) Cl
2]
2, [M (diolefine) Cl
2]
nOr [M (diolefine) (3-2-methyl isophthalic acid-propenyl)
2].In one embodiment, transition metal precursors is [Rh (cod) Cl]
2, [Rh (norbornadiene) Cl]
2, [Rh (cod)
2] X or [Rh (norbornadiene)
2] X.In such embodiment, transition metal precursors is [Rh (cod) Cl]
2
Transition metal precursors is the about 10mol% of about 0.01-to the ratio of substrate.Transition metal precursors is the about 0.4mol% of about 0.05mol%-to the preferred ratio of substrate.
The β amino-acrylic acid derivatives substrate of the formula II of asymmetric hydrogenation contains olefinic double bonds, except as otherwise noted, and is intended to comprise E and two kinds of geometrical isomers of Z or their mixture as initial feed.Wave line in the structural formula II substrate (squiggly) key table shows Z or E geometrical isomer or their mixture.
In one embodiment of the invention, the geometric configuration that is used for the two keys of β amino-acrylic acid derivatives substrate of asymmetric hydrogenation is the Z-configuration of being explained among the formula VII:
By in appropriate organic solvent, for example in methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF) and their aqueous mixture, with the reaction of ammonia source, can be used for the formula II (Z=OR of asymmetric hydrogenation of the present invention with high yield preparation by the beta-keto esters of structural formula VI
2Or SR
2) the β amino acrylates.
Ammonia source " NH
3" comprise ammonium acetate, ammonium hydroxide, ammonium formiate, DL-Lactic acid ammonium salt, two generation ammonium citrate, volatile salt, ammonium carbamate and ammonium benzoate.In one embodiment, the ammonia source is an ammonium acetate.Can be as D.W.Brooks etc.,
Angew.Chem.Int.Ed.Engl., prepare beta-keto esters as 18:72 (1979) is described.
Can as
Org.Syn.Collect., Vol.3, p.108 described in, through acid amides exchange, prepare the β amino acryl amides by corresponding ester.
Can need not isolating construction formula II intermediate, implement the inventive method.
Another embodiment of the present invention relates to the preparation method of structural formula 1 compound:
In formula 1, indicate
* *Stereocenter have (R)-configuration;
Compare with enantiomorph with relative (S)-configuration, at least 70% enantiomeric excess, wherein Ar is 1-5 the phenyl that substituting group replaces that does not replace or independently be selected from fluorine, trifluoromethyl and trifluoromethoxy; With
R
8Be hydrogen or C unsubstituted or that replaced by 1-5 fluorine
1-4Alkyl;
This method comprises the following steps:
(a), use ammonia source Processing Structure formula 3 compounds by in appropriate organic solvent:
Preparation structural formula 2 compounds:
(b) in appropriate organic solvent, in the presence of the rhodium metal precursor of ammonium salt and the Ferrocenediphosphines that is complexed to chiral structure formula IV:
R wherein
4Be C
1-4Alkyl or aryl;
R
5And R
6Each independently is C
1-6Alkyl, C
5-12Cycloalkyl or aryl; With
R
7Be C
1-4Alkyl or unsubstituted phenyl,
Hydrogenation structural formula 2 compounds:
In the such embodiment of a class, Ar is 2,5-difluorophenyl or 2,4,5-trifluorophenyl.In such subclass, R
8It is trifluoromethyl.
In another kind of such embodiment, rhodium metal precursor is chlorination (1, the 5-cyclooctadiene) rhodium (I) dimer { [Rh (cod) Cl]
2.
In another kind of such embodiment, R
4Be methyl, R
5And R
6Be the tertiary butyl, R
7It is unsubstituted phenyl.In such subclass, rhodium metal precursor is chlorination (1, the 5-cyclooctadiene) rhodium (I) dimer.
In the such embodiment of another class, R
4Be methyl, R
5And R
6Be the tertiary butyl, R
7Be unsubstituted phenyl, Ar is 2,5-difluorophenyl or 2,4,5-trifluorophenyl, R
8Be trifluoromethyl, rhodium metal precursor is chlorination (1, the 5-cyclooctadiene) rhodium (I) dimer.In such subclass, ammonium salt is an ammonium chloride.
Can need not each step that isolating construction formula (2) intermediate carries out this method.In one embodiment, in the presence of ammonium salt, two kinds of chemical conversions are all carried out in same reaction vessel.In the such embodiment of a class, ammonium salt be selected from ammonium acetate, ammonium hydroxide, ammonium formiate, DL-Lactic acid ammonium salt, two generation ammonium citrate, volatile salt, ammonium carbamate and ammonium benzoate.In such subclass, ammonium salt is an ammonium formiate.
In another embodiment, obtain structural formula 1 compound greater than 90% enantiomeric excess.In this class embodiment, obtain structural formula 1 compound greater than 95% enantiomeric excess.
Structural formula 1 compound as the inhibitor of dipeptidyl peptidase-IV is disclosed in WO03/004498 (announcement on January 16th, 2003), and it can be used for treating diabetes B.
The following term that the application uses in full has specified meaning:
Term " % enantiomeric excess " (being abbreviated as " ee ") is meant the main enantiomorph of the % that deducts the less important enantiomorph of %.Therefore, 70% enantiomeric excess is exactly that the another kind of enantiomorph of a kind of enantiomorph of 85% and 15% forms.Term " enantiomeric excess " and term " optical purity " synonym.
The inventive method provides the structural formula I compound of high-optical-purity, general excessive 70%ee.In one embodiment, obtain the formula I compound of the optical purity of excessive 80%ee.In the such embodiment of a class, obtain the formula I compound of the optical purity of excessive 90%ee.In such subclass, obtain the formula I compound of the optical purity of excessive 95%ee.
Term " enantio-selectivity " refers to that wherein a kind of enantiomorph generates (or disappearance) than other enantiomorph and gets reaction more rapidly, and required enantiomorph is occupied an leading position in product mixtures.
Abovementioned alkyl is intended to comprise those alkyl of the straight or branched configuration of designated length.The example of this class alkyl has methyl, ethyl, propyl group, sec.-propyl, butyl, sec-butyl, the tertiary butyl, amyl group, isopentyl, hexyl, isohexyl etc.Alkyl is unsubstituted or independently is selected from halogen, hydroxyl, carboxyl, aminocarbonyl, amino, C
1-4Alkoxyl group and C
1-4The 1-3 of alkylthio group replaces.
Term " cycloalkyl " means the alkane ring (that is, cyclopentyl, cyclohexyl, suberyl etc.) of any amount carbon atom in 5-12 total carbon atom or this scope.
Term " halogen " is intended to comprise halogen atom fluorine, chlorine, bromine and iodine.
Abbreviation " cod " refers to " 1, the 5-cyclooctadiene ".
Term " aryl " comprises phenyl and naphthyl." aryl " independently is selected from fluoro base, hydroxyl, trifluoromethyl, amino, C for unsubstituted or quilt
1-4Alkyl and C
1-4The 1-5 of alkoxyl group substituting group replaces.
Term " aromatic hydrocarbons " refers to benzene, naphthalene and o-, m-or p-(adjacent, or to) isopropyl toluene (o, m or p-cymene).
The cyclic hydrocarbon that term " alkene " refers to contain the acyclic of one or more pairs of keys or comprises the aromatic ring hydrocarbon.This term includes, but not limited to 1,5-cyclooctadiene and norbornadiene (" nbd ").
Term " heteroaryl " refers to 5-or 6-unit aromatic heterocycle, and it contains at least one ring hetero atom that is selected from O, S and N.Heteroaryl also comprises and is fused to other kind ring for example aryl, cycloalkyl and be not heteroaryl on the heterocycle of aromatics.The example of heteroaryl comprises, but be not limited to, pyrryl isoxazolyl, isothiazolyl, pyrazolyl, pyridyl oxazolyl, 1,2,4-oxadiazole base, 1,3,4-oxadiazole base, thiadiazolyl group, thiazolyl, imidazolyl, triazolyl, tetrazyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, benzoisoxazole base benzoxazolyl, benzothiazolyl, the diazosulfide base, dihydro benzo furyl, indolinyl, pyridazinyl, indazolyl, pseudoindoyl, the dihydrobenzo thienyl, the indolizine base, the cinnolines base, 2, the 3-phthalazinyl, quinazolyl, the naphthyridine base, carbazyl, the benzo dioxolyl, quinoxalinyl, purine radicals, the furazan base, different benzyl furyl, benzimidazolyl-, benzofuryl, benzothienyl, quinolyl, indyl, isoquinolyl and dibenzofuran group." heteroaryl " independently is selected from fluoro base, hydroxyl, trifluoromethyl, amino, C for unsubstituted or quilt
1-4Alkyl and C
1-4The 1-5 of alkoxyl group substituting group replaces.
Details are as follows for the representative experimental arrangement of employing novel method.The following example only is used for explanation, does not plan the inventive method is limited to the specified conditions that prepare these particular compound.
Embodiment 1
(2R)-and 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro [1,2,4] triazolo [4,3-α] pyrazine-7 (8H)-
Base]-1-(2,4, the 5-trifluorophenyl) fourth-2-amine (2-5)
3-(trifluoromethyl)-5,6,7,8-tetrahydrochysene [1,2,4] triazolo [4,3-α] pyrazine, hydrochloride
Preparation (1-4)
Flow process 1
Steps A: the preparation of bishydrazide (1-1)
Make hydrazine (20.1g,, 35% weight in the water 0.22mol) is mixed with the 310mL acetonitrile.Add 31.5g Trifluoroacetic Acid Ethyl Ester (0.22mol) through 60min.Internal temperature is increased to 14 ℃ by 25 ℃.In the 22-25 ℃ of aging solution 60min that is generated.Cooling solution to 7 ℃.Be lower than under 16 ℃ of temperature, adding the 17.9g 50% weight NaOH aqueous solution (0.22mol) and 25.3g chloroacetyl chloride (0.22mol) simultaneously through 130min.Reaction is when finishing, and under 27～30 ℃ and 26～27Hg vacuum, the vacuum distilling mixture is with except that anhydrating and ethanol.During the distillation, slowly ` adds the 720mL acetonitrile, to keep constancy of volume (about 500mL).Filter soup compound, remove sodium-chlor.With about 100mL acetonitrile rinsing filter cake.Removing desolvates obtains bishydrazide
1-1
1H-NMR (400MHz, DMSO-d
6): δ 4.2 (s, 2H), 10.7 (s, 1H) and 11.6 (s, 1H) ppm.
13C-NMR (100MHz, DMSO-d
6): δ 41.0,116.1 (q, J=362Hz), 155.8 (q, J=50Hz), and 165.4ppm.
Step B:5-(trifluoromethyl)-2-(chloro methyl)-1,3, the preparation of 4-oxadiazole (1-2)
Make the bishydrazide in ACN (82mL) from steps A
1-1(43.2g 0.21mol) is cooled to 5 ℃.(32.2g, 0.21mol), temperature keeps below 10 ℃ to add phosphoryl chloride.Heated mixt to 80 ℃ and under this temperature aging 24h show up to HPLC and be less than 2% area
1-1In an independent container, mix 260mL IPAc and 250mL water and be cooled to 0 ℃.Add the quencher of reaction soup compound, keep internal temperature to be lower than 10 ℃.After the adding, this mixture of vigorous stirring 30min improves temperature to room temperature, and removes the waterbearing stratum.Use 215mL water, 215mL 5% weight sodium bicarbonate aqueous solution then, at last with 215mL 20% weight salt brine solution washing organic layer.75-80mm Hg, 55 ℃ down distillation remove volatile matter, obtain need not purifying and the oil that is directly used in step C.In addition, this product can obtain through distillation purifying
1-2
1H-NMR(400MHz，CDCl
3)：δ4.8(s，2H)ppm.
13C-NMR (100MHz, CDCl
3): δ 32.1,115.8 (q, J=337Hz), 156.2 (q, J=50Hz), and 164.4ppm.
Step C:N-[(2Z)-and piperazine-2-subunit] preparation of trifluoroacetyl hydrazine (1-3)
To-20 ℃ of following refrigerative quadrols (33.1g, add in methyl alcohol 0.55mol) (150mL) solution from step B through Zheng Liu De oxadiazole
1-2(29.8g 0.16mol), keeps internal temperature at-20 ℃ simultaneously.After finishing adding, in-20 ℃ of aging soup compound 1h that generated.Add ethanol (225mL) then, slowly heat soup compound to-5 ℃.Behind the 60min, in-5 ℃, filter soup compound, and wash with ethanol (60mL) in-5 ℃.Obtain the amidine of white solid
1-3
1H-NMR (400MHz, DMSO-d
6): δ 2.9 (t, 2H), 3.2 (t, 2H), 3.6 (s, 2H) and 8.3 (b, 1H) ppm.
13C-NMR (100MHz, DMSO-d
6): δ 40.8,42.0,43.3,119.3 (q, J=350Hz), 154.2 and 156.2 (q, J=38Hz) ppm.
Step D:3-(trifluoromethyl)-5,6,7,8-tetrahydrochysene [1,2,4] triazolo [4,3-α] pyrazine, hydrochloric acid
The preparation of salt (1-4)
With amidine
1-3(27.3g, 0.13mol) suspension in 110mL methyl alcohol is heated to 55 ℃.Under this temperature, through 15min add 37% hydrochloric acid (11.2mL, 0.14mol).During the adding, all solids dissolving generates settled solution.Aging reaction 30min.Make solution be cooled to 20 ℃, and aging under this temperature, form (10min to 1h) up to seed bed.Add 300mL MTBE in 20 ℃ through 1h.The soup compound to 2 that generated of cooling ℃, aging 30min also filters.Use 50mL ethanol: MTBE (1: 3) washing solid, and in 45 ℃ of vacuum-dryings.
1H-NMR (400MHz, DMSO-d
6): δ 3.6 (t, 2H), 4.4 (t, 2H), 4.6 (s, 2H) and 10.6 (b, 2H) ppm;
13C-NMR (100MHz, DMSO-d
6): δ 39.4,39.6,41.0,118.6 (q, J=325Hz), 142.9 (q, J=50Hz), and 148.8ppm.
Flow process 2
Steps A: 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro [1,2,4] triazolo [4,3-α] pyrazine-
7 (8H)-yl]-preparation of 1-(2,4, the 5-trifluorophenyl) fourth-2-ketone (2-3)
With 2,4,5-trifluorophenyl acetate (
2-1) (150g, 0.789mol), meldrum's acid (125g, 0.868mol) and 4-(dimethylamino) pyridine (DMAP) (7.7g 0063mol) adds in the 5L three-necked flask.Under the room temperature, disposable adding N,N-dimethylacetamide (DMAc) is (525mL) to dissolve this solid.Under the room temperature, disposable adding N, (282mL 1.62mol), keeps temperature to be lower than 40 ℃ to the N-diisopropylethylamine simultaneously.(107mL 0.868mol), keeps temperature between 0-5 ℃ simultaneously dropwise to add pivalyl chloride through 1-2h.In 5 ℃ of aging reaction mixture 1h.In 40-50 ℃, disposable adding triazolium salt hydrochlorate
1-4(180g, 0.789mol).In 70 ℃ of aging reaction solution several hours.In 20-45 ℃, dropwise add 5% sodium bicarbonate aqueous solution (625mL) again.In 20-30 ℃ to this batch cloth crystal seed and aging 1-2h.Add other 525mL 5% sodium bicarbonate aqueous solution through 2-3h again.Aging after several hours under the room temperature, cross filter solid before, the cooling soup compound is to 0-5 ℃ and aging 1h.With the 20%DMAc aqueous solution (300mL), then add two batches of 20%DMAc aqueous solution (400mL), last water (400mL) washing displacement wet cake.Suction dried filter cake under the room temperature.
Step B:(2Z)-and 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro [1,2,4] triazolo [4,3-α] pyrrole
Piperazine-7 (8H)-yl]-preparation of 1-(2,4, the 5-trifluorophenyl) but-2-ene-2-amine (2-4)
In the 5L round-bottomed flask, pack into methyl alcohol (100mL), keto-amide
2-3(200g) and ammonium acetate (110.4g).Add methyl alcohol (180mL) and 28% ammonium hydroxide aqueous solution (58.6mL) then, keep temperature to be lower than 30 ℃ during the adding.Add extra methyl alcohol (100mL) to reaction mixture.Heated mixt and aging 2h under reflux temperature.The cooling reactant is cooled to about 5 ℃ then to room temperature in ice bath.Behind the 30min, cross filter solid and dry, obtain solid
2-4M.p.271.2 ℃.
Step C:(2R)-and 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro [1,2,4] triazolo [4,3-α] pyrrole
Piperazine-7 (8H)-yl]-preparation of 1-(2,4, the 5-trifluorophenyl) fourth-2-amine (2-5)
Under nitrogen atmosphere, in the 250ml flask, add chlorination (1, the 5-cyclooctadiene) rhodium (I) dimer { [Rh (cod) Cl]
2(46mg, 0.093mmol) and (R, S) tertiary butyl Josiphos (106mg, 0.196mmol), ammonium chloride (12.5mg, 0.234mmol) and the enamine acid amides (25g, 61.8mmol).Add degassing MeOH (225mL) again, and the 1h that under room temperature, stirs the mixture.Under nitrogen, the soup compound transfer is entered hydrogenator.Outgas after three times, in 50 ℃, under the 100psi hydrogen, hydrogenation enamine acid amides 18h.The test yield of determining through HPLC be 97% and optical purity be 94%ee.
Further improve optical purity with following method.To concentrate also from the methanol solution (18g is among the 180mL MeOH) of hydrogenation and be changed into methyl tertiary butyl ether (MTBE) (45mL).In this solution, add moisture H
3PO
4Solution (0.5M, 95mL).After separating each layer, add 3NNaOH (35mL), use MTBE (180mL+100mL) aqueous layer extracted again to water layer.Concentrate MTBE solution, change solvent into hot toluene (180mL, about 75 ℃).Make hot toluene solution slowly cool to 0 ℃ (5-10h) again.Filtering separation crystal (98-99%ee); M.p.114.1-115.7 ℃.
1H?NMR(300MHz，CD
3CN)：δ7.26(m)，7.08(m)，4.90(s)，4.89(s)，4.14(m)，3.95(m)，3.40(m)，2.68(m)，2.49(m)，1.40(bs).
Compound
2-5Exist with the amido linkage rotational isomer.Unless explanation is arranged, because carbon-13 signal is not split fully, main and minor rotamer flocks together:
13C NMR (CD
3CN): δ 171.8,157.4 (ddd, J
CF=242.4,9.2,2.5Hz), 152.2 (mainly), 151.8 (less important), 149.3 (ddd; J
CF=246.7,14.2,12.9Hz), 147.4 (ddd, J
CF=241.2,12.3,3.7Hz), 144.2 (q, J
CF=38.8Hz), 124.6 (ddd, J
CF=18.5,5.9,4.0Hz), 120.4 (dd, J
CF=19.1,6.2Hz), 119.8 (q, J
CF=268.9Hz), 106.2 (dd, J
CF=29.5,20.9Hz), 50.1,44.8,44.3 (less important), 43.2 (less important), 42.4,41.6 (less important), 41.4,39.6,38.5 (less important), 36.9.
Embodiment 2
(2R)-and 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro [1,2,4] triazolo [4,3-α] pyrazine-7 (8H)-
Base]-preparation of 1-(2,4, the 5-trifluorophenyl) fourth-2-amine (2-5)
Under nitrogen atmosphere, with chloro (1, the 5-cyclooctadiene) rhodium (I) dimer { [Rh (cod) Cl]
2(0.074mg, 0.15 μ mol) and (R, S) tertiary butyl Josiphos (0.179mg, 0.033 μ mol), ammonium formiate (6.6mg, 0.15mmol) and keto-amide
2-3(6.1mg, 15 μ mol) add the 1-mL reactor.Add degassing MeOH (200 μ L) again, under nitrogen, in pressurized vessel, in the time of 55 ℃, 5h stirs the mixture.In the time of 55 ℃, under 250psi hydrogen, hydrogenated mixture 20h.Through HPLC determine the experiment yield be 91% and optical purity be 95%ee.
Following high performance liquid chromatography (HPLC) condition is used for determining the percentage transformation efficiency of product:
Post: Agilent Extend C18,150mm * 4.6mm
Elutriant: solvent orange 2 A: 80/20% volume water/methyl alcohol 10mM TRIS pH 9
Solvent B:20/80% volume water/methyl alcohol 10mM TRIS pH 9
Gradient: 0min 55%A:45%B
8min?24％A：76％B
15min?24％A：76％B
Flow velocity: 2mL/min
Inject volume: 5 μ L
Ultraviolet detection: 215nm
Column temperature: 23 ℃
Retention time: compound
2.4: 5.9min
Compound
2.5: 4.2min.
Following high performance liquid chromatography (HPLC) condition is used to measure optical purity:
Post: Chirapak, AD-H, 250mm * 4.6mm
Elutriant: 60/40/0.1/0.1 volume/volume ethanol/hexane/diethylamine/water Isochratic Run Time:24min
Flow velocity: 0.8mL/min
Inject volume: 10 μ L
Ultraviolet detection: 268nm
Column temperature: 35 ℃
Retention time: (R)-amine
2-5: 7.5min
(S)-amine: 14.5min
Claims (21)
1. method for preparing structural formula I compound:
In formula I, indicate
*Stereocenter have (R)-or (S)-configuration;
With the enantiomeric excess of corresponding enantiomorph more at least 70%, wherein Z is OR
2, SR
2Or NR
2R
3
R
1Be C
1-8Alkyl, aryl, heteroaryl, aryl-C
1-2Alkyl or heteroaryl-C
1-2Alkyl;
R
2And R
3Each independently is hydrogen, C
1-8Alkyl, aryl or aryl-C
1-2Alkyl; Or R
2And R
3Form optional containing with the nitrogen-atoms that they connected and be selected from O, S, NH and NC
1-4The heteroatomic 4-to 7-of other of alkyl unit heterocyclic ring system, described heterocycle is unsubstituted or independently is selected from oxo base, hydroxyl, halogen, C
1-4Alkoxyl group and C
1-4The 1-3 of alkyl substituting group replaces, and wherein alkyl and alkoxyl group are unsubstituted or by 1-5 fluorine replacement; And described heterocyclic ring system optional with 5-to 6-unit saturated or aromatic carbocyclic system or contain and be selected from O, S and NC
0-4Saturated or aromatic heterocycle system of the heteroatomic 5-to 6-of the 1-2 of alkyl unit condenses, and described condensed ring system is unsubstituted or is selected from hydroxyl, amino, fluorine, C
1-4Alkyl, C
1-4The 1-2 of alkoxyl group and trifluoromethyl substituting group replaces;
This method is included in the appropriate organic solvent, ammonium salt and be complexed to structural formula II I the chiral ferrocene diphosphine ligand transition metal precursors in the presence of:
R wherein
4Be C
1-4Alkyl or aryl;
R
5And R
6Each independently is C
1-6Alkyl, C
5-12Cycloalkyl or aryl; With
R
7Be C
1-4Alkyl or unsubstituted phenyl,
The step of the prochirality enamine of hydrogenation structural formula II:
2. the process of claim 1 wherein that described Ferrocenediphosphines part has structural formula IV:
Wherein indicate
*Stereocenter have (R)-configuration.
3. the method for claim 2, wherein R
4Be C
1-2Alkyl, R
5And R
6Be C
1-4Alkyl, and R
7It is unsubstituted phenyl.
4. the method for claim 3, wherein R
4Be methyl, R
5And R
6Be the tertiary butyl, and R
7It is unsubstituted phenyl.
5. the process of claim 1 wherein that described ammonium salt is an ammonium chloride.
6. the process of claim 1 wherein R
1Be benzyl, wherein the phenyl of benzyl is unsubstituted or 1-3 substituting group being selected from fluorine, trifluoromethyl and trifluoromethoxy replaces.
7. the process of claim 1 wherein that Z is OR
2Or NR
2R
3
8. the method for claim 7, wherein NR
2R
3Be heterocycle with structural formula VI:
R wherein
8Be hydrogen or C unsubstituted or that replaced by 1-5 fluorine
1-4Alkyl.
9. the process of claim 1 wherein that described transition metal precursors is [M (cod) Cl]
2, [M (norbornadiene) Cl]
2, [M (cod)
2] X or [M (norbornadiene)
2] X, wherein X is that methanesulfonates, triflate, Tetrafluoroboric acid ester, phosphofluoric acid ester or hexafluoro-antimonic acid ester and M are rhodium or iridium.
10. the method for claim 9, wherein said transition metal precursors is [Rh (cod) Cl]
2
11. method for preparing the compound of structural formula 1:
In formula 1, indicate
* *Stereocenter have (R)-configuration;
Enantiomeric excess with enantiomorph more at least 70% with corresponding (S)-configuration; Wherein
Ar is unsubstituted or independently is selected from 1-5 the phenyl that substituting group replaces of fluorine, trifluoromethyl and trifluoromethoxy; With
R
8Be hydrogen or C unsubstituted or that replaced by 1-5 fluorine
1-4Alkyl;
This method comprises the following steps:
In appropriate organic solvent, ammonium salt and be complexed to structural formula IV the chiral ferrocene diphosphine rhodium metal precursor in the presence of:
R wherein
4Be C
1-4Alkyl or aryl;
R
5And R
6Each independently is C
1-6Alkyl, C
5-12Cycloalkyl or aryl; With
R
7Be C
1-4Alkyl or unsubstituted phenyl,
The compound of hydrogenation structural formula 2:
12. the method for claim 11, it also is included in the appropriate organic solvent, by using the compound of ammonia source Processing Structure formula 3:
The step of the compound of preparation structural formula 2:
13. the method for claim 11, wherein Ar is 2,5-difluorophenyl or 2,4,5-trifluorophenyl and R
8It is trifluoromethyl.
14. the method for claim 11, wherein said rhodium metal precursor are [Rh (cod) Cl]
2
15. the method for claim 11, wherein R
4Be methyl, R
5And R
6Be the tertiary butyl, and R
7It is unsubstituted phenyl.
16. the method for claim 15, wherein said rhodium metal precursor are [Rh (cod) Cl]
2
17. the method for claim 11, wherein R
4Be methyl, R
5And R
6Be the tertiary butyl, R
7Be unsubstituted phenyl, Ar is 2,5-difluorophenyl or 2,4,5-trifluorophenyl, R
8Be that trifluoromethyl and rhodium metal precursor are chloro (1, the 5-cyclooctadiene) rhodium (I) dimers.
18. the method for claim 17, wherein said ammonium salt is an ammonium chloride.
19. the method for claim 12, wherein said ammonia source is an ammonium acetate.
20. method for preparing the compound of structural formula 1:
In formula 1, indicate
* *Stereocenter have (R)-configuration;
Enantiomeric excess with enantiomorph more at least 70% with corresponding (S)-configuration;
Wherein
Ar is unsubstituted or independently is selected from 1-5 the phenyl that substituting group replaces of fluorine, trifluoromethyl and trifluoromethoxy; With
R
8Be hydrogen or C unsubstituted or that replaced by 1-5 fluorine
1-4Alkyl;
This method is included in the appropriate organic solvent, under nitrogen atmosphere, in the presence of the rhodium metal precursor of the chiral ferrocene diphosphine that is complexed to structural formula IV:
R wherein
4Be C
1-4Alkyl or aryl;
R
5And R
6Each independently is C
1-6Alkyl, C
5-12Cycloalkyl or aryl; With
R
7Be C
1-4Alkyl or unsubstituted phenyl,
Step with the compound of ammonium salt Processing Structure formula 3:
21. the method for claim 20, wherein said ammonium salt be selected from ammonium acetate, ammonium hydroxide, ammonium formiate, DL-Lactic acid ammonium salt, two generation ammonium citrate, volatile salt, ammonium carbamate and ammonium benzoate.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US64669705P | 2005-01-24 | 2005-01-24 | |
| US60/646,697 | 2005-01-24 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101175714A true CN101175714A (en) | 2008-05-07 |
Family
ID=36587261
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006800028725A Pending CN101175714A (en) | 2005-01-24 | 2006-01-20 | Process to chiral beta amino acid derivatives by asymmetric hydrogenation |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP1856028A1 (en) |
| JP (1) | JP2008528503A (en) |
| CN (1) | CN101175714A (en) |
| AR (1) | AR052879A1 (en) |
| AU (1) | AU2006208297A1 (en) |
| CA (1) | CA2594494A1 (en) |
| TW (1) | TW200637805A (en) |
| WO (1) | WO2006081151A1 (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102898387A (en) * | 2012-09-26 | 2013-01-30 | 浙江工业大学 | Channelized method for continuously producing N-[(2Z)-piperazine-2-subunit]-2, 2, 2-trifluoroacetyl hydrazine |
| CN105254519A (en) * | 2015-11-25 | 2016-01-20 | 常州吉恩药业有限公司 | Synthesizing method of sitagliptin key intermediate |
| CN105315286A (en) * | 2014-07-30 | 2016-02-10 | 连云港润众制药有限公司 | Preparation of Sitagliptin |
| CN106243025A (en) * | 2015-06-05 | 2016-12-21 | 株式会社爱茉莉太平洋 | The manufacture method of pyridine intermediate |
| CN110831944A (en) * | 2017-07-04 | 2020-02-21 | 意大利合成制造有限公司 | Efficient process for the preparation of sitagliptin by very efficient preparation of intermediate 2,4, 5-trifluorophenylacetic acid |
| CN113636950A (en) * | 2020-05-11 | 2021-11-12 | 浙江医药股份有限公司新昌制药厂 | Preparation method of chiral 4-aryl-beta-amino acid derivative |
Families Citing this family (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8334385B2 (en) | 2007-11-02 | 2012-12-18 | Glenmark Generics Limited | Process for the preparation of R-sitagliptin and its pharmaceutically acceptable salts thereof |
| WO2010078440A1 (en) | 2008-12-31 | 2010-07-08 | Chiral Quest, Inc. | Process and intermediates for the preparation of n-acylated-4-aryl beta-amino acid derivatives |
| EP2223923A1 (en) | 2009-02-25 | 2010-09-01 | Esteve Química, S.A. | Process for the preparation of a chiral beta aminoacid derivative and intermediates thereof |
| IT1395596B1 (en) * | 2009-06-30 | 2012-10-16 | Dipharma Francis Srl | PROCEDURE FOR THE PREPARATION OF SITAGLIPTIN |
| CZ303113B6 (en) | 2010-03-16 | 2012-04-11 | Zentiva, K.S. | Process for preparing sitagliptin |
| CA2800507A1 (en) | 2010-03-31 | 2011-10-06 | Teva Pharmaceuticals Industries Ltd. | Solid state forms of sitagliptin salts |
| EP2392575A1 (en) | 2010-06-04 | 2011-12-07 | LEK Pharmaceuticals d.d. | A novel synthetic approach to ß-aminobutyryl substituted compounds |
| CN103038236B (en) | 2010-06-04 | 2015-09-30 | 力奇制药公司 | The novel synthesis of the compound that beta-amino butyryl radicals replaces |
| EP2397141A1 (en) | 2010-06-16 | 2011-12-21 | LEK Pharmaceuticals d.d. | Process for the synthesis of beta-amino acids and derivatives thereof |
| EP2609099A2 (en) | 2010-08-27 | 2013-07-03 | USV Limited | Sitagliptin, salts and polymorphs thereof |
| WO2012035549A2 (en) | 2010-09-13 | 2012-03-22 | Panacea Biotec Ltd | An improved process for the synthesis of beta amino acid derivatives |
| EP2508506A1 (en) | 2011-04-08 | 2012-10-10 | LEK Pharmaceuticals d.d. | Preparation of sitagliptin intermediates |
| EP2527320A1 (en) | 2011-05-27 | 2012-11-28 | LEK Pharmaceuticals d.d. | Preparation of Sitagliptin Intermediates |
| SI2736909T1 (en) | 2011-07-27 | 2017-08-31 | Farma Grs, D.O.O. | Process for the preparation of sitagliptin and its pharmaceutically acceptable salts |
| WO2013065066A1 (en) | 2011-11-02 | 2013-05-10 | Cadila Healthcare Limited | Processes for preparing 4-oxo-4-[3-(trifluoromethyl)-5,6- dihydro [l,2,41-triazolo[43-a]pyrazin-7(8h)-yl]-l-(2,4,5- trifluorophenyl)butan-2-amine |
| EP2615080A1 (en) | 2012-01-12 | 2013-07-17 | LEK Pharmaceuticals d.d. | Preparation of Optically Pure ß-Amino Acid Type Active Pharmaceutical Ingredients and Intermediates thereof |
| EP2674432A1 (en) | 2012-06-14 | 2013-12-18 | LEK Pharmaceuticals d.d. | New synthetic route for the preparation of ß aminobutyryl substituted 5,6,7,8-tetrahydro[1,4]diazolo[4,3-alpha]pyrazin-7-yl compounds |
| US9227901B2 (en) * | 2012-07-05 | 2016-01-05 | Abbvie Inc. | Process for preparing bicyclic amine derivatives |
| CN107325025B (en) * | 2017-07-17 | 2019-04-09 | 中国科学院化学研究所 | A kind of chiral alpha-amino acid derivatives and preparation method thereof |
| WO2024121301A1 (en) | 2022-12-09 | 2024-06-13 | Krka, D.D., Novo Mesto | Process for the preparation of sitagliptin |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0646590B1 (en) * | 1993-10-01 | 1999-08-25 | Novartis AG | Ferrocenyldiphosphines substituted with fluoroalkyl groups as ligands for homogeneous catalysts |
| AR043515A1 (en) * | 2003-03-19 | 2005-08-03 | Merck & Co Inc | PROCEDURE TO PREPARE CHIRAL DERIVATIVES BETA AMINO ACIDS BY ASYMMETRIC HYDROGENATION |
| TW200602293A (en) * | 2004-04-05 | 2006-01-16 | Merck & Co Inc | Process for the preparation of enantiomerically enriched beta amino acid derivatives |
-
2006
- 2006-01-17 AR ARP060100175 patent/AR052879A1/en unknown
- 2006-01-20 WO PCT/US2006/002147 patent/WO2006081151A1/en active Application Filing
- 2006-01-20 AU AU2006208297A patent/AU2006208297A1/en not_active Abandoned
- 2006-01-20 CA CA002594494A patent/CA2594494A1/en not_active Abandoned
- 2006-01-20 EP EP06719111A patent/EP1856028A1/en not_active Withdrawn
- 2006-01-20 JP JP2007552303A patent/JP2008528503A/en not_active Withdrawn
- 2006-01-20 CN CNA2006800028725A patent/CN101175714A/en active Pending
- 2006-01-23 TW TW095102476A patent/TW200637805A/en unknown
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102898387A (en) * | 2012-09-26 | 2013-01-30 | 浙江工业大学 | Channelized method for continuously producing N-[(2Z)-piperazine-2-subunit]-2, 2, 2-trifluoroacetyl hydrazine |
| CN102898387B (en) * | 2012-09-26 | 2015-01-07 | 浙江工业大学 | Channelized method for continuously producing N-[(2Z)-piperazine-2-subunit]-2, 2, 2-trifluoroacetyl hydrazine |
| CN105315286A (en) * | 2014-07-30 | 2016-02-10 | 连云港润众制药有限公司 | Preparation of Sitagliptin |
| CN105315286B (en) * | 2014-07-30 | 2018-08-17 | 连云港润众制药有限公司 | The preparation of Xi Gelieting |
| CN106243025A (en) * | 2015-06-05 | 2016-12-21 | 株式会社爱茉莉太平洋 | The manufacture method of pyridine intermediate |
| CN105254519A (en) * | 2015-11-25 | 2016-01-20 | 常州吉恩药业有限公司 | Synthesizing method of sitagliptin key intermediate |
| CN105254519B (en) * | 2015-11-25 | 2017-05-17 | 常州吉恩药业有限公司 | Synthesizing method of sitagliptin key intermediate |
| CN110831944A (en) * | 2017-07-04 | 2020-02-21 | 意大利合成制造有限公司 | Efficient process for the preparation of sitagliptin by very efficient preparation of intermediate 2,4, 5-trifluorophenylacetic acid |
| CN110831944B (en) * | 2017-07-04 | 2022-05-27 | 意大利合成制造有限公司 | Method for preparing sitagliptin by preparing intermediate 2,4, 5-trifluoro-phenylacetic acid |
| CN113636950A (en) * | 2020-05-11 | 2021-11-12 | 浙江医药股份有限公司新昌制药厂 | Preparation method of chiral 4-aryl-beta-amino acid derivative |
| CN113636950B (en) * | 2020-05-11 | 2023-01-17 | 浙江医药股份有限公司新昌制药厂 | Preparation method of chiral 4-aryl-beta-amino acid derivative |
Also Published As
| Publication number | Publication date |
|---|---|
| TW200637805A (en) | 2006-11-01 |
| WO2006081151A1 (en) | 2006-08-03 |
| AR052879A1 (en) | 2007-04-11 |
| AU2006208297A1 (en) | 2006-08-03 |
| EP1856028A1 (en) | 2007-11-21 |
| CA2594494A1 (en) | 2006-08-03 |
| JP2008528503A (en) | 2008-07-31 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101175714A (en) | Process to chiral beta amino acid derivatives by asymmetric hydrogenation | |
| CN100339354C (en) | Process for the preparation of chiral beta amino acid derivatives by asymmetric hydrogenation | |
| US7495123B2 (en) | Process for the preparation of enantiomerically enriched beta amino acid derivatives | |
| JPH0641171A (en) | Ferrocenyldiphosphine as ligand of homogeneous catalyst | |
| EP2029541B1 (en) | Process for preparation of enantiomerically enriched cyclic beta-aryl or heteroaryl carboxylic acids | |
| US6258979B1 (en) | Chiral ferrocene phosphines active in asymmetric catalysis | |
| US9796678B2 (en) | Method for manufacturing optically active compound | |
| CN1972898A (en) | Process for the preparation of enantiomerically enriched beta amino acid derivatives | |
| JP2012521385A (en) | Method for preparing propionic acid derivatives | |
| AU2007292167B2 (en) | Process for production of optically active aminophosphinylbutanoic acid | |
| CN102316862A (en) | The method for preparing S1P receptor stimulating agent or antagonist | |
| JP2004010555A (en) | Method for producing optically active fluorine compound | |
| WO2011113399A1 (en) | Method of preparing sitagliptin | |
| WO2016119758A1 (en) | Method for preparing chiral 2-[1-cyclopropylethyl]-6-isopropyl-phenol | |
| WO2006057904A1 (en) | Stereoselective preparation of 4-aryl piperidine amides by asymmetric hydrogenation of a prochiral enamide and intermediates of this process |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Open date: 20080507 |