CN102234241A - Chemical synthesis method of chiral D-phenylalanine - Google Patents
Chemical synthesis method of chiral D-phenylalanine Download PDFInfo
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- CN102234241A CN102234241A CN2010101656378A CN201010165637A CN102234241A CN 102234241 A CN102234241 A CN 102234241A CN 2010101656378 A CN2010101656378 A CN 2010101656378A CN 201010165637 A CN201010165637 A CN 201010165637A CN 102234241 A CN102234241 A CN 102234241A
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Abstract
The invention relates to a chemical synthesis method for preparing chiral D-phenylalanine. The chemical synthesis method comprises the following reaction steps: (a) carrying out hydrogenation reduction on acetamidocinnamic acid and derivatives thereof (I) in the presence of a chiral catalyst to obtain acetamido-D-phenylalanine (II), and (b) carrying out hydrolysis reaction on the acetamido-D-phenylalanine to remove acetyl, thus obtaining D-phenylalanine (III).
Description
Technical field
The present invention relates to a kind of chemical synthesis process of non-natural chiral D-phenylalanine.
Background technology
The D-phenylalanine is the important source material of synthesizing polypeptide antibioticses such as Gramicidin S as a kind of important chipal compounds.It can be used as the intermediate of multiple medicines such as heterocycle polypeptide drug, anodyne, tranquilizer, antitumour drug, anti-acquired immunodeficiency syndrome drug, hypoglycemic and cardiovascular drug, diet pill, dietary supplements.
The D-phenylalanine is as important medicine and pesticide intermediate, have been widely used in fields such as medicine, agricultural chemicals, food, feeds, its market demand constantly increases, so it is simple to seek technology, the preparation method of lower-cost D-phenylalanine is necessary.The method for preparing at present the D-phenylalanine mainly contains enantiomorph Split Method, asymmetric chemical synthesis process, and biological process, wherein biological process using hydantoinase particularly.But, also there are not a large amount of industrialization at present because enzyme activity is low.Concrete production technique has following several: 1, enantiomorph Split Method, and utilize chemical synthesis process to produce the DL-phenylalanine, carry out chemistry then and split.This method does not need racemization, by special method racemic modification is separated into single-optically active form, mainly adopt chromatogram Split Method, enzyme Split Method; 2, asymmetric chemical synthesis, directly by chemical synthesis process D-phenylalanine, main method has the a-ketone acid to change methods such as ammonification, asymmetric alkylation, asymmetry catalysis hydrogenation.3, biological process mainly comprises fermentation method and using hydantoinase.Fermentation method and using hydantoinase also are limited to laboratory study at present all owing to the SA reason that is subjected to employed enzyme.
Because produce the complex process of D-phenylalanine at present, the cost height is not suitable for suitability for industrialized production, and the optical purity of product (ee%) is low, can not satisfy medicine synthetic demand.At existing deficiency, adopt the chiral catalyst of novel organophosphorus phosphine part to carry out the D-phenylalanine that asymmetric synthesis prepares high optical activity.
Summary of the invention
The chemical synthesis process that the purpose of this invention is to provide a kind of D-phenylalanine of synthetic high optical activity.
Specifically, method of the present invention comprises following reactions steps:
(a) with kharophen styracin and derivative (I) thereof under the situation that the chiral catalyst of transition metal-organophosphorus coordination system exists; hydro-reduction obtains acetylaminohydroxyphenylarsonic acid D-phenylalanine (II); (b) the acetylaminohydroxyphenylarsonic acid D-phenylalanine that obtains is hydrolyzed reaction; remove ethanoyl, obtain D-phenylalanine (III).
R in the said structure formula
1, R
2, R
3, R
4And R
5Be same to each other or different to each other; and can represent hydrogen atom; alkyl with 1-6 carbon atom; cycloalkyl with 3-6 carbon atom; halogen atom; alkoxyl group with 1-6 carbon atom; haloalkyl with 1-6 carbon atom; halogenated alkoxy with 1-6 carbon atom; alkylthio with 1-6 carbon atom; alkyl sulfinyl with 1-6 carbon atom; alkyl sulphonyl with 1-6 carbon atom; nitro; cyano group; phenyl; phenoxy group; amino; hydroxyl; have the alkylamino of 1-6 carbon atom or the dialkyl amido that each moieties all has 1-6 carbon atom, or R
1, R
2, R
3, R
4And R
5Any two adjacent substituting groups of expression can form the saturated or unsaturated ring of 5-or 6-unit that can contain 1-4 oxygen and/or nitrogen and/or sulfur heteroatom.Specifically, R
1～R
5Can be hydrogen atom, alkyl, halogen atom, alkoxyl group, haloalkyl, nitro, cyano group, halogenated alkoxy, be preferably hydrogen atom, alkyl, halogen atom, haloalkyl, nitro, cyano group, more preferably hydrogen atom, halogen atom, haloalkyl, nitro, cyano group most preferably are hydrogen atom, halogen atom, haloalkyl, nitro, cyano group.
Preparation method's provided by the present invention concrete steps:
A): in kharophen styracin and derivative (I) and methyl alcohol adding autoclave.Reactor is installed, charge into nitrogen then.Nitrogen pressure maintains 100psi (0.7Mpa).Reactor stirred 30 minutes, and purpose is that solvent is outgased fully, then venting.The chiral catalyst and the small amount of methanol solution of transition metal-organophosphor ligand system are added.Reactor fills hydrogen, replaces 3 times, fills hydrogen then, and pressure is kept 0.7-4MPa.20-80 ℃ of reactor internal temperature reacted 2-10 hour, and in reaction process, hydrogen pressure is lower than under the situation of required pressure, continued to add hydrogen.Venting charges into nitrogen more then, stirs 30 minutes, emits nitrogen, and reaction soln is poured out, and filters, and the solvent evaporate to dryness obtains acetylaminohydroxyphenylarsonic acid D-phenylalanine (II).
B): acetylaminohydroxyphenylarsonic acid D-phenylalanine (II), hydrochloric acid, methyl alcohol are added in the reactor, heating reflux reaction 5-9 hour, cooling, solvent evaporated with about 80 ℃ dissolvings of 30ml water, is transferred pH value 5.5 with strong aqua then, there is solid to separate out, obtains product D-phenylalanine (III).
Described transition metal comprises ruthenium, rhodium, palladium, preferred transition metal rhodium; Described organophosphor ligand comprises (1R, 2R)-two [(2-p-methoxy-phenyl) phenyl phosphorus] ethane, (1R, 2R)-two [(2-aminomethyl phenyl) phenyl phosphorus] ethane, (1R, 2R)-two [(2-isopropyl phenyl) phenyl phosphorus] ethane, (1R, 2R)-two [naphthyl phenyl phosphorus] ethane, preferred (1R, 2R)-two [(2-p-methoxy-phenyl) phenyl phosphorus] ethane.The purity of described chiral catalyst is greater than 99.5%.
Preparation method of the present invention is applied widely, and simple in production process operation, and preparation cost is low, and the optical purity of products advantages of higher is suitable for suitability for industrialized production.
Embodiment
Embodiment 1
A): kharophen styracin ((Z)-2-acetylaminohydroxyphenylarsonic acid 3-phenyl-vinylformic acid) 8.2g and methyl alcohol 200ml are added in the autoclave.Reactor is installed, charge into nitrogen then.Nitrogen pressure maintains 0.7Mpa, and reactor stirred 30 minutes, and purpose is that solvent is outgased fully.Venting then.Chiral catalyst ([Rh (1, the 5-cyclooctadiene) ((1R, 2R)-two [(2-p-methoxy-phenyl) phenyl phosphorus] ethane)] BF4) and small amount of methanol solution are added.Reactor fills hydrogen, replaces 3 times, fills hydrogen then, and pressure is kept 1MPa, and 30 ℃ of reactor internal temperatures reacted 8 hours, in the reaction process, when hydrogen pressure is lower than 1MPa, continues to add hydrogen.Venting charges into nitrogen more then, stirs 30 minutes, emits nitrogen, and reaction soln is poured out, and filters, and the solvent evaporate to dryness obtains acetylaminohydroxyphenylarsonic acid D-phenylalanine (II), yield 98.3%.
1H-NMR(DMSO-d6)，δ12.58ppm(1H，COOH)，9.39ppm(1H，NH)，7.61ppm(2H，C
6H
5)，7.39ppm(2H，C
6H
5)，7.32ppm(1H，C
6H
5)，7.21ppm(1H，CH)，1.97ppm(3H，CH
3)。
B): with acetylaminohydroxyphenylarsonic acid D-phenylalanine (II) 8.03g, 6M hydrochloric acid 100ml, methyl alcohol 50ml add in the reactor, heating reflux reaction 9 hours, cooling, solvent evaporated is then with about 80 ℃ dissolvings of 30ml water, transfer pH value 5.5 with strong aqua, there is solid to separate out, obtains product D-phenylalanine (III), yield 76%.
1H-NMR(D
2O)，δ2.93-3.03ppm(2H，CH
2)，3.95ppm(1H，CH)，7.18ppm(2H，C
6H
5)，7.29ppm(2H，C
6H
5)，7.33ppm(H，C
6H
5)。
Product D-phenylalanine chemical purity: (HPLC): 〉=99.95%
Optical purity: (HPLC, e.e%): 〉=99.5%
Embodiment 2
A): kharophen styracin ((Z)-2-acetylaminohydroxyphenylarsonic acid 3-phenyl-vinylformic acid) 8.2g and methyl alcohol 200ml are added in the autoclave.Reactor is installed, charge into nitrogen then.Nitrogen pressure maintains 0.7Mpa, and reactor stirred 30 minutes, and purpose is that solvent is outgased fully.Venting then.With chiral catalyst ([Rh (1, the 5-cyclooctadiene) ((1R, 2R)-two [(2-p-methoxy-phenyl) phenyl phosphorus] ethane)] BF
4) and the adding of small amount of methanol solution.Reactor fills hydrogen, replaces 3 times, fills hydrogen then, and pressure is kept 3MPa, and 30 ℃ of reactor internal temperatures reacted 5 hours, in the reaction process, and when hydrogen pressure is lower than 3MPa,, continue to add hydrogen.Venting charges into nitrogen more then, stirs 30 minutes, emits nitrogen, and reaction soln is poured out, and filters, and the solvent evaporate to dryness obtains acetylaminohydroxyphenylarsonic acid D-phenylalanine (II), yield 99.1%.
1H-NMR(DMSO-d6，400MHz)，δ12.42ppm(1H，COOH)，9.35ppm(1H，s，NH)，7.58ppm(2H，C
6H
5)，7.35ppm(2H，C
6H
5)，7.31ppm(1H，C
6H
5)，7.19ppm(1H，CH)，2.01ppm(3H，CH
3)。
B): with acetylaminohydroxyphenylarsonic acid D-phenylalanine (II) 8.03g, 10% sodium hydroxide 100ml, methyl alcohol 50ml add in the reactor, heating reflux reaction 6 hours, cooling, solvent evaporated is then with about 80 ℃ dissolvings of 30ml water, transfer pH value 5.5 with strong aqua, there is solid to separate out, obtains product D-phenylalanine (III), yield 83%.
1H-NMR(D
2O)，
1H-NMR(D
2O)，δ2.87-2.96ppm(2H，CH
2)，3.85ppm(1H，CH)，7.16ppm(2H，C
6H
5)，7.27ppm(2H，C
6H
5)，7.31ppm(H，C
6H
5)。
Product D-phenylalanine chemical purity: (HPLC): 〉=99.95%
Optical purity: (HPLC, e.e%): 〉=99.5%
Embodiment 3
According to the mode identical with embodiment 1, adopt (Z)-2-acetylaminohydroxyphenylarsonic acid 3-(4-chloro-phenyl-)-vinylformic acid raw material, prepared 4-chloro-D-phenylalanine.
1H-NMR(D
2O)，δ2.86-2.97ppm(2H，CH
2)，3.91ppm(1H，CH)，7.17ppm(2H，C
6H
5)，7.20ppm(2H，C
6H
5)。Yield 81%.
Product 4-chloro-D-phenylalanine chemical purity: (HPLC): 〉=98.95%
Optical purity: (HPLC, e.e%): 〉=99%
Embodiment 4
According to the mode identical with embodiment 1, adopt (Z)-2-acetylaminohydroxyphenylarsonic acid 3-(4-aminomethyl phenyl)-vinylformic acid raw material, prepared 4-methyl D-phenylalanine,
1H-NMR (D
2O), δ 2.84-2.90ppm (2H, CH
2), 3.79ppm (1H, CH), 7.08ppm (2H, C
6H
5), 7.35ppm (2H, C
6H
5).Yield 77%.
Product 4-methyl D-phenylalanine chemical purity: (HPLC): 〉=98%
Optical purity: (HPLC, e.e%): 〉=99%
Embodiment 5
According to the mode identical with embodiment 1, adopt (Z)-2-acetylaminohydroxyphenylarsonic acid 3-(4-p-methoxy-phenyl)-vinylformic acid raw material, prepared 4-methoxyl group-D-phenylalanine,
1H-NMR (D
2O), δ 2.83-2.88ppm (2H, CH
2), 3.82ppm (1H, CH), 6.95ppm (2H, C
6H
5), 7.02ppm (2H, C
6H
5), 3.91ppm (3H, CH
3).Yield 70%.
Product 4-methoxyl group-D-phenylalanine chemical purity: (HPLC): 〉=98%
Optical purity: (HPLC, e.e%): 〉=99%
Embodiment 6
According to the mode identical with embodiment 1, adopt (Z)-2-acetylaminohydroxyphenylarsonic acid 3-(4-nitrophenyl)-vinylformic acid raw material, prepared 4-nitro-D-phenylalanine,
1H-NMR (D
2O), δ 2.81-2.86ppm (2H, CH
2), 3.69ppm (1H, CH), 7.17ppm (2H, C
6H
5), 8.07ppm (2H, C
6H
5).Yield 71%.
Product 4-nitro-D-phenylalanine chemical purity: (HPLC): 〉=98%
Optical purity: (HPLC, e.e%): 〉=99%
Embodiment 7
According to the mode identical with embodiment 1, adopt (Z)-2-acetylaminohydroxyphenylarsonic acid 3-(4-aminophenyl)-vinylformic acid raw material, prepared 4-amino-D-phenylalanine,
1H-NMR (D
2O), δ 2.69-2.72ppm (2H, CH
2), 3.75ppm (1H, CH), 6.56ppm (2H, C
6H
5), 7.07ppm (2H, C
6H
5).Yield 76%.
Product 4-amino-D-phenylalanine chemical purity: (HPLC): 〉=98%
Optical purity: (HPLC, e.e%): 〉=99%
Embodiment 8
According to the mode identical with embodiment 1, adopt (Z)-2-acetylaminohydroxyphenylarsonic acid 3-(4-trifluoromethyl)-vinylformic acid raw material, prepared 4-trifluoromethyl-D-phenylalanine,
1H-NMR (D
2O), δ 2.79-2.82ppm (2H, CH
2), 3.81ppm (1H, CH), 7.34ppm (2H, C
6H
5), 7.77ppm (2H, C
6H
5).Yield 80%.
Product 4-trifluoromethyl-D-phenylalanine chemical purity: (HPLC): 〉=98%
Optical purity: (HPLC, e.e%): 〉=99%
Embodiment 9
According to the mode identical with embodiment 1, adopt (Z)-2-acetylaminohydroxyphenylarsonic acid 3-(4-cyano-phenyl)-vinylformic acid raw material, prepared 4-cyano group-D-phenylalanine,
1H-NMR (D
2O), δ 2.67-2.76ppm (2H, CH
2), 3.65ppm (1H, CH), 7.32ppm (2H, C
6H
5), 7.80ppm (2H, C
6H
5).Yield 72%.
Product 4-cyano group-D-phenylalanine chemical purity: (HPLC): 〉=98%
Optical purity: (HPLC, e.e%): 〉=99%
Embodiment 10
According to the mode identical with embodiment 1, adopt (Z)-2-acetylaminohydroxyphenylarsonic acid 3-(xenyl)-vinylformic acid raw material, prepared D-4, the 4-biphenyl alanine,
1H-NMR (D
2O), δ 2.77-2.84ppm (2H, CH
2), 3.83ppm (1H, CH), 7.31ppm (2H, C
6H
5), 7.69ppm (2H, C
6H
5), 7.56ppm (2H, C
6H
5), 7.28ppm (2H, C
6H
5), 7.30ppm (H, C
6H
5).Yield 69%.
Product D-4,4-biphenyl alanine chemical purity: (HPLC): 〉=98%
Optical purity: (HPLC, e.e%): 〉=99%
Embodiment 11
According to the mode identical with embodiment 1, adopt (Z)-2-acetylaminohydroxyphenylarsonic acid 3-(3-chloro-4-hydroxy phenyl)-vinylformic acid raw material, prepared 3-chloro-4-hydroxyl-D-phenylalanine,
1H-NMR (D
2O), δ 2.73-2.82ppm (2H, CH
2), 3.80ppm (1H, CH), 7.16ppm (1H, C
6H
5), 7.02ppm (1H, C
6H
5), 6.87ppm (H, C
6H
5).Yield 65%.
Product 3-chloro-4-hydroxyl-D-phenylalanine chemical purity: (HPLC): 〉=98%
Optical purity: (HPLC, e.e%): 〉=99%
Embodiment 12
According to the mode identical with embodiment 1, adopt (Z)-2-acetylaminohydroxyphenylarsonic acid 3-(4-benzoyl phenyl)-vinylformic acid raw material, prepared 4-benzoyloxy-D-phenylalanine,
1H-NMR (D
2O), δ 2.83-2.87ppm (2H, CH
2), 3.69ppm (1H, CH), 7.02ppm (2H, C
6H
5), 6.95ppm (2H, C
6H
5), 7.19ppm (2H, C
6H
5), 8.01ppm (2H, C
6H
5), 7.30ppm (H, C
6H
5).Yield 75%.
Product 4-benzoyloxy-D-phenylalanine chemical purity: (HPLC): 〉=98%
Optical purity: (HPLC, e.e%): 〉=99%
Claims (9)
1. chemical synthesis process for preparing chiral D-phenylalanine, it is characterized in that: this method comprises the steps:
(a) with kharophen styracin and derivative (I) thereof under the situation that chiral catalyst exists, hydro-reduction obtains acetylaminohydroxyphenylarsonic acid D-phenylalanine (II),
(b) compound acetylaminohydroxyphenylarsonic acid D-phenylalanine is hydrolyzed reaction removes ethanoyl, obtains D-phenylalanine (III);
R wherein
1, R
2, R
3, R
4And R
5Be same to each other or different to each other; the expression hydrogen atom; alkyl with 1-6 carbon atom; cycloalkyl with 3-6 carbon atom; halogen atom; alkoxyl group with 1-6 carbon atom; haloalkyl with 1-6 carbon atom; halogenated alkoxy with 1-6 carbon atom; alkylthio with 1-6 carbon atom; alkyl sulfinyl with 1-6 carbon atom; alkyl sulphonyl with 1-6 carbon atom; nitro; cyano group; phenyl; phenoxy group; amino; hydroxyl; have the alkylamino of 1-6 carbon atom or the dialkyl amido that each moieties all has 1-6 carbon atom, or R
1, R
2, R
3, R
4And R
5Any two adjacent substituting groups of expression can form the saturated or unsaturated ring of 5-or 6-unit that can contain 1-4 oxygen and/or nitrogen and/or sulfur heteroatom.
2. method according to claim 1, wherein R
1, R
2, R
3, R
4And R
5Be same to each other or different to each other and all represent hydrogen atom, have the alkyl of 1-6 carbon atom, cycloalkyl, halogen atom, alkoxyl group, nitro, cyano group, sulfonic group with 1-6 carbon atom with 3-6 carbon atom.
3. method according to claim 2, wherein R
1, R
2, R
3, R
4And R
5All represent hydrogen atom.
4. method according to claim 1, its feature exists: the chiral catalyst (a) is a kind of transition metal-organophosphous ligand complex catalyst.
5. according to claim 1 and 4 described methods, its feature exists: the organophosphor ligand that the chiral catalyst (a) is mentioned comprises (1R, 2R)-two [(2-p-methoxy-phenyl) phenyl phosphorus] ethane, (1R, 2R)-two [(2-aminomethyl phenyl) phenyl phosphorus] ethane, (1R, 2R)-two [(2-isopropyl phenyl) phenyl phosphorus] ethane, (1R, 2R)-two [naphthyl phenyl phosphorus] ethane, preferably (1R, 2R)-two [(2-p-methoxy-phenyl) phenyl phosphorus] ethane.
6. according to claim 1 and 4 described methods, it is characterized in that: the purity of the chiral catalyst (a) is greater than 99.5%.
7. method according to claim 1 is characterized in that: 20～80 ℃ of the hydro-reduction temperature of reaction (a).
8. method according to claim 1 is characterized in that: the hydro-reduction hydrogen pressure 0.7～4MPa (a).
9. method according to claim 1 is characterized in that: hydrolysis reaction (b) is sodium hydroxide hydrolysis or hydrochloric acid hydrolysis.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106399412A (en) * | 2016-06-03 | 2017-02-15 | 南京红杉生物科技有限公司 | Method for synthesizing D-biphenyl alanine |
Citations (4)
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|---|---|---|---|---|
| DD253995A1 (en) * | 1986-11-28 | 1988-02-10 | Akad Wissenschaften Ddr | PROCESS FOR THE PREPARATION OF (R) - AND (S) -PHENYL-ALLANINE AND THEIR DERIVATIVES |
| CN1321636A (en) * | 1997-02-14 | 2001-11-14 | 钟渊化学工业株式会社 | Process for preparing homophenylalanin derivs |
| JP2003261522A (en) * | 2002-03-08 | 2003-09-19 | Daiichi Fine Chemical Co Ltd | Method for producing optically active phenylalanine derivative |
| CN101671716A (en) * | 2009-10-15 | 2010-03-17 | 淮北新旗氨基酸有限公司 | Method for manufacturing D-phenylalanine by bio-enzyme asymmetric transformation |
-
2010
- 2010-05-07 CN CN2010101656378A patent/CN102234241A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DD253995A1 (en) * | 1986-11-28 | 1988-02-10 | Akad Wissenschaften Ddr | PROCESS FOR THE PREPARATION OF (R) - AND (S) -PHENYL-ALLANINE AND THEIR DERIVATIVES |
| CN1321636A (en) * | 1997-02-14 | 2001-11-14 | 钟渊化学工业株式会社 | Process for preparing homophenylalanin derivs |
| JP2003261522A (en) * | 2002-03-08 | 2003-09-19 | Daiichi Fine Chemical Co Ltd | Method for producing optically active phenylalanine derivative |
| CN101671716A (en) * | 2009-10-15 | 2010-03-17 | 淮北新旗氨基酸有限公司 | Method for manufacturing D-phenylalanine by bio-enzyme asymmetric transformation |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106399412A (en) * | 2016-06-03 | 2017-02-15 | 南京红杉生物科技有限公司 | Method for synthesizing D-biphenyl alanine |
| CN106399412B (en) * | 2016-06-03 | 2019-12-10 | 南京红杉生物科技有限公司 | Method for synthesizing D-biphenylalanine |
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Application publication date: 20111109 |