CN106636246B - Biological method for preparing (S) -1- (5-phenyl-1H-imidazole-2-yl) ethylamine - Google Patents
Biological method for preparing (S) -1- (5-phenyl-1H-imidazole-2-yl) ethylamine Download PDFInfo
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- XQFMQMXJXWTGON-QMMMGPOBSA-N (1s)-1-(5-phenyl-1h-imidazol-2-yl)ethanamine Chemical compound N1C([C@@H](N)C)=NC=C1C1=CC=CC=C1 XQFMQMXJXWTGON-QMMMGPOBSA-N 0.000 title claims abstract description 13
- 238000010170 biological method Methods 0.000 title abstract description 7
- 238000000034 method Methods 0.000 claims abstract description 29
- 150000001875 compounds Chemical class 0.000 claims description 50
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 30
- 238000002360 preparation method Methods 0.000 claims description 28
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 27
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 27
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical group CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 claims description 15
- 102000003929 Transaminases Human genes 0.000 claims description 14
- 108090000340 Transaminases Proteins 0.000 claims description 14
- NGVDGCNFYWLIFO-UHFFFAOYSA-N pyridoxal 5'-phosphate Chemical compound CC1=NC=C(COP(O)(O)=O)C(C=O)=C1O NGVDGCNFYWLIFO-UHFFFAOYSA-N 0.000 claims description 12
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 10
- 239000005695 Ammonium acetate Substances 0.000 claims description 10
- 235000019257 ammonium acetate Nutrition 0.000 claims description 10
- 229940043376 ammonium acetate Drugs 0.000 claims description 10
- 239000005515 coenzyme Substances 0.000 claims description 10
- 235000007682 pyridoxal 5'-phosphate Nutrition 0.000 claims description 9
- 239000011589 pyridoxal 5'-phosphate Substances 0.000 claims description 9
- 238000007363 ring formation reaction Methods 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 238000006911 enzymatic reaction Methods 0.000 claims description 5
- 239000008055 phosphate buffer solution Substances 0.000 claims description 5
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Inorganic materials O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 claims description 4
- 239000007800 oxidant agent Substances 0.000 claims description 4
- 230000001590 oxidative effect Effects 0.000 claims description 4
- 239000008096 xylene Substances 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- 102000004190 Enzymes Human genes 0.000 claims description 3
- 108090000790 Enzymes Proteins 0.000 claims description 3
- 229960001327 pyridoxal phosphate Drugs 0.000 claims description 3
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 3
- 125000003944 tolyl group Chemical group 0.000 claims description 3
- 239000003810 Jones reagent Substances 0.000 claims description 2
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 2
- 235000004279 alanine Nutrition 0.000 claims description 2
- 239000007853 buffer solution Substances 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 238000006243 chemical reaction Methods 0.000 description 65
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 239000000243 solution Substances 0.000 description 20
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 17
- 239000012074 organic phase Substances 0.000 description 16
- 238000003756 stirring Methods 0.000 description 16
- 239000000203 mixture Substances 0.000 description 13
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 12
- 235000018102 proteins Nutrition 0.000 description 12
- 102000004169 proteins and genes Human genes 0.000 description 12
- 108090000623 proteins and genes Proteins 0.000 description 12
- 239000000843 powder Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 238000010992 reflux Methods 0.000 description 7
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- -1 1, 1-dimethylethoxy Chemical group 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 description 4
- HEQOJEGTZCTHCF-UHFFFAOYSA-N 2-amino-1-phenylethanone Chemical compound NCC(=O)C1=CC=CC=C1 HEQOJEGTZCTHCF-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- OXKRFEWMSWPKKV-GHTZIAJQSA-N n-[(2s,3r)-2-(pyridin-3-ylmethyl)-1-azabicyclo[2.2.2]octan-3-yl]-1-benzofuran-2-carboxamide Chemical compound C([C@@H]1N2CCC(CC2)[C@H]1NC(=O)C=1OC2=CC=CC=C2C=1)C1=CC=CN=C1 OXKRFEWMSWPKKV-GHTZIAJQSA-N 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 239000008363 phosphate buffer Substances 0.000 description 3
- 238000002390 rotary evaporation Methods 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- GOPYZMJAIPBUGX-UHFFFAOYSA-N [O-2].[O-2].[Mn+4] Chemical class [O-2].[O-2].[Mn+4] GOPYZMJAIPBUGX-UHFFFAOYSA-N 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 208000002551 irritable bowel syndrome Diseases 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- LIGACIXOYTUXAW-UHFFFAOYSA-N phenacyl bromide Chemical compound BrCC(=O)C1=CC=CC=C1 LIGACIXOYTUXAW-UHFFFAOYSA-N 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 229940107700 pyruvic acid Drugs 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229960003767 alanine Drugs 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- QFNHIDANIVGXPE-FNZWTVRRSA-N eluxadoline Chemical compound C1=C(C(O)=O)C(OC)=CC=C1CN(C(=O)[C@@H](N)CC=1C(=CC(=CC=1C)C(N)=O)C)[C@@H](C)C1=NC(C=2C=CC=CC=2)=CN1 QFNHIDANIVGXPE-FNZWTVRRSA-N 0.000 description 1
- 229960002658 eluxadoline Drugs 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- TYRGLVWXHJRKMT-QMMMGPOBSA-N n-benzyloxycarbonyl-l-serine-betalactone Chemical compound OC(=O)[C@H](C)NC(=O)OCC1=CC=CC=C1 TYRGLVWXHJRKMT-QMMMGPOBSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- JKVUQLWTIZFTMF-UHFFFAOYSA-M potassium;2-oxopropanoate Chemical compound [K+].CC(=O)C([O-])=O JKVUQLWTIZFTMF-UHFFFAOYSA-M 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/10—Nitrogen as only ring hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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- Engineering & Computer Science (AREA)
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- Biotechnology (AREA)
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- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
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- Bioinformatics & Cheminformatics (AREA)
- General Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
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Abstract
The invention relates to a novel method for preparing (S) -1- (5-phenyl-1H-imidazole-2-yl) ethylamine by a protected biological method, and compared with the chemical synthesis method in the prior art, the invention provides a green technical scheme for preparing (S) -1- (5-phenyl-1H-imidazole-2-yl) ethylamine.
Description
Technical Field
The invention belongs to the field of biological pharmacy, and particularly relates to a method for preparing (S) -1- (5-phenyl-1H-imidazole-2-yl) ethylamine by a biological method.
Background
(S) -1- (5-phenyl-1H-imidazol-2-yl) ethylamine is a key intermediate for the treatment of diarrhea-predominant irritable bowel syndrome irudoline (Eluxadoline). Irudoline is known under the chemical name 4- (aminocarbonyl) -N- [ (1, 1-dimethylethoxy) carbonyl ] -2, 6-dimethyl-L-phenylalanine under the trade name vibenzi, approved by the FDA for marketing 5/27/2015. According to the statistics of an authority, the diarrhea irritable bowel syndrome patients have a high 2800 ten thousand in Europe and the United states, and the market prospect is wide. The structural formula of irudoline is shown as follows
The preparation methods of (S) -1- (5-phenyl-1H-imidazole-2-yl) ethylamine reported in the prior literature are all prepared by chemical methods, and have the problems of low optical purity of the product, unsafe process, serious environmental pollution, high production cost and the like, so that the industrial production is greatly hindered. Breslin et al discloses a method for preparing (S) -1- (5-phenyl-1H-imidazol-2-yl) ethylamine (Bioorganic & Medicinal Chemistry Letters,2012,22, 4869-4872), the synthetic route of which is shown below,
according to the method, N-Cbz-L-alanine is used as a raw material and is subjected to three steps of condensation, imidazole cyclization and Cbz protecting group removal to obtain a target compound (S) -1- (5-phenyl-1H-imidazole-2-yl) ethylamine, wherein chiral inversion is easy to occur at a higher reaction temperature in the imidazole cyclization step to cause lower optical purity of a product, explosive hydrogen and an expensive palladium catalyst are required to be used for removing the Cbz protecting group, the risk coefficient is higher in industrial production, and the production cost is greatly increased.
Compared with chemical synthesis methods, biological synthesis methods have the advantages of mild reaction conditions, high conversion rate and the like, and have attracted much attention in recent years, and no published literature for preparing (S) -1- (5-phenyl-1H-imidazol-2-yl) ethylamine by biological methods is available at present.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention discloses a method for preparing (S) -1- (5-phenyl-1H-imidazole-2-yl) ethylamine by a biological method.
The specific process route is as follows:
and carrying out an enzymatic reaction on the compound II under the combined action of transaminase, coenzyme, an amino donor and a phosphate buffer solution to generate the compound I. Wherein the coenzyme is pyridoxal phosphate, and the amino donor is isopropylamine or alanine, preferably isopropylamine.
Further, transaminases are commercially available from ATA101 to ATA119, available from Otsugae biomedicine (Shanghai) Co., Ltd.
Furthermore, the concentration of the compound II in the enzymatic reaction is 25-70g/L, the concentration of transaminase is 5-12g/L, the concentration of coenzyme is 0.1-1mM, the concentration of amino donor is 60-100g/L, and the concentration of buffer solution is 10-100 mM.
Further, the temperature of the enzymatic reaction is 30-40 ℃, and the pH value is 5-8.
Further, the transaminase is added in the form of enzyme powder, a cell suspension containing the transaminase, or whole cells, preferably in the form of enzyme powder.
A process for the preparation of a compound of formula II,
the method comprises the following steps
Wherein Y is selected from N or O, and the compound II-A is subjected to imidazole cyclization reaction in an organic solvent to obtain a compound II.
Wherein the organic solvent is toluene, xylene, THF or 1, 4-dioxane, preferably toluene; the imidazole cyclization reaction is carried out under the condition of ammonium acetate, and the reaction molar ratio of the compound II-A to the ammonium acetate is 1: 1-10, preferably 1: 2-3.
Further, the preparation of compound II is as follows:
wherein R is selected from the group consisting of N or O,
step a): performing imidazole cyclization reaction on the compound II-B in an organic solvent to obtain a compound II-C;
step b): and preparing the compound II from the compound II-C under the action of an oxidant.
Wherein the organic solvent is toluene, xylene, THF or 1, 4-dioxane, preferably toluene; the imidazole cyclization reaction is carried out under the condition of ammonium acetate, and the reaction molar ratio of the compound II-B to the ammonium acetate is 1: 1-10, preferably 1: 2-3; the oxidant is selected from MnO2PCC, PDC or Jones reagent, preferably MnO2。
The compounds II-A and II-B are cheap and easily available, and can be obtained commercially or prepared by self.
Compared with the existing chemical synthesis method, the invention provides a green technical scheme for preparing (S) -1- (5-phenyl-1H-imidazole-2-yl) ethylamine by a biological method, and the scheme has the advantages of mild reaction conditions, high optical purity of the product, low production cost, environmental friendliness and good industrial application value.
Detailed Description
The technical content of the present invention is further described below with reference to specific examples for better understanding of the content of the present invention, but the scope of the present invention is not limited thereto.
Example 1
Preparation of Compound II-A (Y is an N atom)
Pyruvic acid (1.0g), dichloromethane (10ml), DMF (0.05ml) was added to a 100ml three-necked flask. Oxalyl chloride (1.8g) is slowly added into the reaction solution at 0 ℃, and the temperature of the reaction solution is kept between 0 and 5 ℃ in the dropping process. After the dropwise addition, the temperature was slowly raised to room temperature and stirred for 2 hours. The reaction system is cooled to 0 ℃ in an ice bath, 2-aminoacetophenone (1.5g) is added into a three-necked bottle, N-diisopropylethylamine (2.8g) is added dropwise, and the temperature is kept below 5 ℃ in the dropwise adding process. After the dropwise addition, the temperature was slowly raised to room temperature, and the mixture was stirred for 1 hour. The reaction solution was poured into 100mL of ice water, dichloromethane was extracted three times, the organic phase was washed with 1N dilute hydrochloric acid, saturated sodium chloride solution, liquid separation, dried over anhydrous sodium sulfate, evaporated to dryness by rotary evaporation, and the crude product was purified by silica gel chromatography to obtain compound II-a (1.98g, yield 87%).
Preparation of Compound II
Compound II-A (1.98g), ammonium acetate (2.23g) and toluene (20ml) were sequentially added to a 50ml three-necked flask, and water was separated from the water separator and heated under reflux for 6 hours. After the system was returned to room temperature, the mixture was poured into water, extracted with dichloromethane three times, the organic phase was washed with 5% sodium bicarbonate, saturated sodium chloride solution, dried over anhydrous sodium sulfate, rotary evaporated, and purified by column chromatography to obtain Compound II (1.7g, yield 95%)
Preparation of Compound I
Adding 10mM phosphate buffer (40mL, pH 7.0) and isopropylamine (3.0g) into a 100mL reaction vessel, adjusting the pH to 7.0 by using phosphoric acid, adding a compound II (1.7g), uniformly stirring, adding transaminase powder ATA101(0.3g) and coenzyme PLP (1.325mg), fixing the volume to 50mL, magnetically stirring at 30 ℃ for open reaction, controlling the reaction pH to be about 7.0 by using isopropylamine (4M) in the reaction process, and detecting the reaction process by TLC. After the reaction, the temperature is kept at 80 ℃ for 2h to denature proteins in the reaction solution, the proteins are removed by filtration, NaOH (10M) is added to adjust the pH value to 13, the mixture is extracted for three times by using ethyl acetate with the same volume, organic phases are combined, dried by anhydrous sodium sulfate and distilled under reduced pressure to obtain the compound I (1.63g, the yield is 95%) and the ee value of the product is 99.6%.
EXAMPLE 2 preparation of Compound II-A (Y is an N atom)
Preparation of Compound II-A: the same procedure was used as in example 1 for the preparation of compound II-A.
Preparation of compound II: the same procedure was used as for the experiment of Compound II in example 1.
Preparation of Compound I
Adding 10mM phosphate buffer (15mL, pH 7.0) and isopropylamine (2.5g) into a 50mL reaction vessel, adjusting the pH to 7.0 by using phosphoric acid, adding a compound II (1.7g), uniformly stirring, adding transaminase powder ATA101(0.3g) and coenzyme PLP (1.325mg), fixing the volume to 25mL, magnetically stirring at 30 ℃ for an open reaction, controlling the reaction pH to be about 7.0 by using isopropylamine (4M) in the reaction process, and detecting the reaction progress by TLC. After the reaction, the reaction solution was incubated at 80 ℃ for 2 hours to denature proteins in the reaction solution, the proteins were removed by filtration, NaOH (10M) was added to adjust the pH to 13, the mixture was extracted three times with ethyl acetate of equal volume, the organic phases were combined, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain compound I (1.61g, yield 94%) whose ee value was 99.7%.
Example 3
Preparation of Compound II-A (Y is an O atom)
To a 250ml three-necked flask, potassium pyruvate (1.3g), 2-bromoacetophenone (2g) and DMSO (10ml) were added, and the mixture was heated to 60 ℃ overnight with stirring. After completion of the reaction by HPLC, water (30ml) was added to the reaction flask, ethyl acetate (20 ml. times.2) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain Compound II-A (1.8g, yield 86%).
Preparation of Compound II
Compound II-A (1.8g), ammonium acetate (1.35g) and toluene (18ml) were sequentially added to a 50ml three-necked flask, and water was separated from the water separator and heated under reflux for 6 hours. After the system was returned to room temperature, the mixture was poured into water, extracted with dichloromethane three times, the organic phase was washed with 5% sodium bicarbonate, saturated sodium chloride solution, dried over anhydrous sodium sulfate, rotary evaporated, and purified by column chromatography to obtain Compound II (1.5g, yield 92%)
Preparation of Compound I
Adding 10mM phosphate buffer solution (40mL, pH 7.0) and isopropylamine (3.0g) into a 100mL reaction vessel, adjusting the pH to 7.0 by using phosphoric acid, adding a compound II (1.5g), uniformly stirring, adding transaminase powder ATA115(0.3g) and coenzyme PLP (1.325mg), fixing the volume to 50mL, magnetically stirring at 30 ℃ for open reaction, controlling the reaction pH to be about 7.0 by using isopropylamine (4M) in the reaction process, and detecting the reaction process by TLC. After the reaction, the temperature is kept at 80 ℃ for 2h to denature proteins in the reaction solution, the proteins are removed by filtration, NaOH (10M) is added to adjust the pH value to 13, the mixture is extracted for three times by using ethyl acetate with the same volume, organic phases are combined, dried by anhydrous sodium sulfate and distilled under reduced pressure to obtain the compound I (1.45g, the yield is 96%) and the ee value of the product is 99.7%.
Example 4
Preparation of Compound II-A (Y is an N atom)
Pyruvic acid (1.0g), dichloromethane (10ml), DMF (0.05ml) was added to a 100ml three-necked flask. Thionyl chloride (1.63g) was slowly added to the reaction solution at 0 ℃ and the temperature of the reaction solution was maintained at 0-5 ℃ during the dropwise addition. After the dropwise addition, the temperature was slowly raised to room temperature and stirred for 2 hours. The reaction system is cooled to 0 ℃ in an ice bath, 2-aminoacetophenone (1.5g) is added into a three-necked bottle, N-diisopropylethylamine (2.8g) is added dropwise, and the temperature is kept below 5 ℃ in the dropwise adding process. After the dropwise addition, the temperature was slowly raised to room temperature, and the mixture was stirred for 1 hour. The reaction solution was poured into 100mL of ice water, dichloromethane was extracted three times, the organic phase was washed with 1N dilute hydrochloric acid, saturated sodium chloride solution, liquid separation, dried over anhydrous sodium sulfate, evaporated to dryness by rotary evaporation, and the crude product was purified by silica gel chromatography to obtain compound II-a (2.1g, yield 90%).
Preparation of Compound II
Compound II-A (2.1g), ammonium acetate (2.33g) and xylene (20ml) were sequentially added to a 50ml three-necked flask, and water was separated from the water separator and heated under reflux for 6 hours. After the system was returned to room temperature, the mixture was poured into water, extracted with dichloromethane three times, the organic phase was washed with 5% sodium bicarbonate, saturated sodium chloride solution, dried over anhydrous sodium sulfate, rotary evaporated, and purified by column chromatography to obtain Compound II (1.85g, yield 97%)
Preparation of Compound I
Adding 10mM phosphate buffer solution (25mL, pH 7.0) and isopropylamine (3.2g) into a 100mL reaction vessel, adjusting the pH to 7.0 by using phosphoric acid, adding a compound II (1.85g), uniformly stirring, adding transaminase powder ATA115(0.4g) and coenzyme PLP (1.35mg), fixing the volume to 35mL, magnetically stirring at 30 ℃ for open reaction, controlling the reaction pH to be about 7.0 by using isopropylamine (4M) in the reaction process, and detecting the reaction process by TLC. After the reaction, the temperature is kept at 80 ℃ for 2h to denature proteins in the reaction solution, the proteins are removed by filtration, NaOH (10M) is added to adjust the pH value to 13, the mixture is extracted for three times by using ethyl acetate with the same volume, organic phases are combined, dried by anhydrous sodium sulfate and distilled under reduced pressure to obtain the compound I (1.78g, the yield is 96%) and the ee value of the product is 99.7%.
Example 5
Preparation of Compound II-B (Y is an O atom)
2-bromoacetophenone (2g), lactic acid (1g) and toluene (10ml) were put in a 25ml three-necked flask, and sodium hydrogencarbonate (1g) was added thereto with stirring and the mixture was heated to 60 ℃ overnight. After completion of the reaction by HPLC, 30ml of water was added to the reaction flask, extracted with toluene (10 ml. times.2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain Compound II-B (1.91g, 92% yield).
Preparation of Compound II-C
Compound II-B (1.87g), ammonium acetate (2.1g) and toluene (20ml) were sequentially added to a 50ml three-necked flask, and water was separated from the water separator and heated under reflux for 6 hours. The system was returned to room temperature and poured into water, extracted with dichloromethane (20ml x 3), the organic phase was washed successively with 5% sodium bicarbonate, saturated sodium chloride solution, dried over anhydrous sodium sulfate, rotary evaporated and the crude product was purified by column chromatography to give compound II-C (1.6g, 95% yield).
Preparation of Compound II
Compound II-C (1.6g) and methylene chloride (20ml) were charged into a 50ml three-necked flask. Activated manganese dioxide (6.5g) was added with stirring and heated to reflux for 24 hours. HPLC showed the reaction was complete, filtered, the filtrate was concentrated to dryness and purified by column chromatography to give compound II (1.5g, 95% yield).
Preparation of Compound I
Adding 10mM phosphate buffer solution (25mL, pH 7.0) and isopropylamine (2.8g) into a 100mL reaction vessel, adjusting the pH to 7.0 by using phosphoric acid, adding a compound II (1.5g), uniformly stirring, adding transaminase powder ATA110(0.32g) and coenzyme PLP (1.25mg), fixing the volume to 35mL, magnetically stirring at 30 ℃ for an open reaction, controlling the reaction pH to be about 7.0 by using isopropylamine (4M) in the reaction process, and detecting the reaction progress by TLC. After the reaction, the temperature is kept at 80 ℃ for 2h to denature proteins in the reaction solution, the proteins are removed by filtration, NaOH (10M) is added to adjust the pH value to 13, the mixture is extracted for three times by using ethyl acetate with the same volume, organic phases are combined, dried by anhydrous sodium sulfate and distilled under reduced pressure to obtain the compound I (1.45g, the yield is 96%) and the ee value of the product is 99.8%.
Example 6
Preparation of Compound II-B (Y is an N atom)
2-Aminoacetophenone (2.7g), lactic acid (1.8g) and methylene chloride (20ml) were put in a 50ml three-necked flask, and HATU (8.4g) and triethylamine (3g) were added to the reaction mixture, followed by stirring at room temperature overnight. After HPLC indicated the reaction was complete, water (40ml) was added to the reaction flask, extracted twice with dichloromethane (20ml x 2), the organic phases were combined, dried over anhydrous sodium sulphate, filtered, the filtrate concentrated to dryness and the crude product was purified by silica gel chromatography to give compound II-B (3.97g, 96% yield).
Preparation of Compound II-C
Compound II-B (3.97g), ammonium acetate (4.43g) and toluene (40ml) were added to a 100ml three-necked flask in this order, and water was separated from the water separator and heated under reflux for 6 hours. The system is returned to room temperature and poured into water, dichloromethane is used for extraction for three times, 5% sodium bicarbonate and saturated sodium chloride solution are used for organic phase in turn, washing is carried out, anhydrous sodium sulfate is used for drying, rotary evaporation and evaporation are carried out, and a crude product is purified by a chromatographic column to obtain a compound II-C (3.43g, the yield is 95%).
Preparation of Compound II
Compound II-C (3.2g) and methylene chloride (40ml) were charged into a 100ml three-necked flask. Activated manganese dioxide (13g) was added with stirring and heated to reflux for 24 hours. HPLC showed the reaction was complete, filtered, the filtrate was concentrated to dryness and purified by column chromatography to give compound II (3g, 95% yield).
Preparation of Compound I
10mM phosphate buffer (25mL, pH 7.0) and isopropylamine (5.6g) are added into a 100mL reaction vessel, the pH is adjusted to 7.0 by phosphoric acid, a compound II (3g) is added, transaminase powder ATA110(0.64g) and coenzyme PLP (2.5mg) are added after uniform stirring, the volume is increased to 60mL, the reaction is opened under magnetic stirring at 30 ℃, the reaction pH is controlled to be about 7.0 by isopropylamine (4M) in the reaction process, and the reaction progress is detected by TLC. After the reaction, the temperature is kept at 80 ℃ for 2h to denature proteins in the reaction solution, the proteins are removed by filtration, NaOH (10M) is added to adjust the pH value to 13, the mixture is extracted for three times by using ethyl acetate with the same volume, organic phases are combined, dried by anhydrous sodium sulfate and distilled under reduced pressure to obtain the compound I (2.9g, the yield is 96%) and the ee value of the product is 99.7%.
Claims (9)
1. A method for the biological preparation of (S) -1- (5-phenyl-1H-imidazol-2-yl) ethylamine which is as follows:
and carrying out an enzymatic reaction on the compound II under the combined action of transaminase, pyridoxal phosphate (PLP), an amino donor and a phosphate buffer solution to generate the compound I.
2. The method of claim 1, wherein: the transaminase is selected from the available enzyme libraries ATA 101-ATA 119 of biological medicine (Shanghai) Co., Ltd.
3. The method of claim 1, wherein: the amino donor is isopropylamine or alanine.
4. The method of claim 1, wherein: in the enzymatic reaction, the concentration of a compound II is 25-70g/L, the concentration of transaminase is 5-12g/L, the concentration of coenzyme is 0.1-1mM, the concentration of an amino donor is 60-100g/L, and the concentration of a buffer solution is 10-100 mM.
5. A process for the preparation of a compound of formula II,
the method comprises the following steps
Wherein Y is selected from N or O, and the compound II-A is subjected to imidazole cyclization reaction in an organic solvent to obtain a compound II.
6. A process for the preparation of a compound of formula II,
the method comprises the following steps
Wherein R is selected from the group consisting of N or O,
step a): performing imidazole cyclization reaction on the compound II-B in an organic solvent to obtain a compound II-C;
step b): and preparing the compound II from the compound II-C under the action of an oxidant.
7. The method of claim 5 or 6, characterized by: the organic solvent is selected from toluene, xylene, THF or 1, 4-dioxane.
8. The method of claim 5 or 6, wherein: the imidazole cyclization reaction is carried out under the catalysis of ammonium acetate.
9. The method of claim 6, wherein: in step b) the oxidant is MnO2PCC, PDC or Jones reagents.
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| WO2010062590A2 (en) * | 2008-10-27 | 2010-06-03 | Janssen Pharmaceutica Nv | Process for the preparation of protected l-alanine derivatives |
| CN105177071A (en) * | 2015-10-22 | 2015-12-23 | 苏州汉酶生物技术有限公司 | Method for preparing (S)-2-amino-1-butanol by biological method |
| CN105693554A (en) * | 2016-04-06 | 2016-06-22 | 成都伊诺达博医药科技有限公司 | Preparation method of alanine derivatives |
| CN105906610A (en) * | 2016-05-24 | 2016-08-31 | 绍兴文理学院 | 3-(4-phenyl-1H-imidazolyl-5-yl)-1H-indole derivatives, and preparation method and application thereof |
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| WO2010062590A2 (en) * | 2008-10-27 | 2010-06-03 | Janssen Pharmaceutica Nv | Process for the preparation of protected l-alanine derivatives |
| CN105177071A (en) * | 2015-10-22 | 2015-12-23 | 苏州汉酶生物技术有限公司 | Method for preparing (S)-2-amino-1-butanol by biological method |
| CN105693554A (en) * | 2016-04-06 | 2016-06-22 | 成都伊诺达博医药科技有限公司 | Preparation method of alanine derivatives |
| CN105906610A (en) * | 2016-05-24 | 2016-08-31 | 绍兴文理学院 | 3-(4-phenyl-1H-imidazolyl-5-yl)-1H-indole derivatives, and preparation method and application thereof |
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