CN106636246A - Preparation of (S)-1-(5-phenyl-1H-imidazol-2-yl)ethylamine through biological method - Google Patents
Preparation of (S)-1-(5-phenyl-1H-imidazol-2-yl)ethylamine through biological method Download PDFInfo
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Abstract
The invention relates to a novel method for preparing (S)-1-(5-phenyl-1H-imidazol-2-yl)ethylamine through a biological method. Compared with the conventional chemical synthesis method in the prior art, an environment-friendly technical scheme for preparing the (S)-1-(5-phenyl-1H-imidazol-2-yl)ethylamine has the advantages of mild reaction conditions, high optical purity of a product, lowered production cost, environmental friendliness and high industrial application value.
Description
Technical field
The invention belongs to field of biological pharmacy, and in particular to a kind of bioanalysis prepares (S) -1- (5- phenyl -1H- imidazoles -2-
Base) ethamine method.
Background technology
(S) -1- (5- phenyl -1H- imidazoles -2- bases) ethamine is for treating diarrhoeal intestinal irritable syndrome Yi Luduo quinolines
(Eluxadoline) key intermediate.The chemical name of Yi Luduo quinolines is 4- (amino carbonyl)-N- [(1,1- dimethylethoxies
Base) carbonyl] -2,6- dimethyl-L-phenylalanine, trade name Viberzi, on May 27th, 2015 obtain FDA approval listing.According to
Authoritative institution counts, and the patient of diarrhoeal intestinal irritable syndrome is up to 28,000,000 in Europe and the U.S., wide market.Yi Lu
Many quinoline structural formulas are as follows
The preparation method of (S) -1- (5- phenyl -1H- imidazoles -2- bases) ethamine of existing document report is chemical legal system
It is standby, there are problems that product optical purity is relatively low, technique is dangerous, environmental pollution is serious, production cost, industrialized production is received
To greatly obstruction.The method that Henry J.Breslin et al. disclose preparation (S) -1- (5- phenyl -1H- imidazoles -2- bases) ethamine
(Bioorganic＆Medicinal Chemistry Letters, 2012,22,4869-4872), synthetic route is as follows,
The document obtains mesh by raw material Jing condensations, imidazoles cyclization, de- Cbz protection group three-step reactions of N-Cbz-L- alanine
Mark compound (S) -1- (5- phenyl -1H- imidazoles -2- bases) ethamine, wherein reaction temperature is higher easy in imidazoles ring-forming sequence
The upset of green hand's property causes product optical purity relatively low, needs to use explosive substance hydrogen and expensive palladium during de- Cbz protection groups
Catalyst, danger coefficient is higher in industrial production, and production cost is greatly improved.
Compared with chemical synthesis, biological synthesis process has the advantages that reaction condition is gentle, high conversion rate is subject in recent years
Extensive concern, has no that at present bioanalysis prepares the open source literature of (S) -1- (5- phenyl -1H- imidazoles -2- bases) ethamine.
The content of the invention
In order to overcome the drawbacks described above existing for prior art, the invention discloses a kind of bioanalysis prepares (S) -1- (5-
Phenyl -1H- imidazoles -2- bases) ethamine method.
Concrete technology route is as follows：
Compound II carries out enzyme process reaction under the collective effect of transaminase, coenzyme, amino group donor and phosphate buffer
Generate compound I.Wherein coenzyme is phosphopyridoxal pyridoxal phosphate, and amino group donor is isopropylamine or alanine, preferably isopropylamine.
Furtherly, transaminase is commercially available ATA101～ATA148 on market, from still section's biological medicine (on
Sea) Co., Ltd.
Furtherly, in the enzyme process reaction compound II concentration be 25-70g/L, the concentration of transaminase be 5-12g/L, auxiliary
The concentration of enzyme is 0.1-1mM, amino group donor concentration is 60-100g/L and the concentration of buffer solution is 10-100mM.
Furtherly, the enzyme process reaction temperature is 30 DEG C～40 DEG C, pH=5～8.
Furtherly, transaminase is added in the form of enzyme powder form, the clasmatosis liquid containing transaminase or full cell, preferably
With the addition of enzyme powder form.
A kind of method for preparing following formula: compound II,
Methods described includes
Wherein Y is selected from N or O, and compound II-A carries out in organic solvent imidazoles annulation and obtains compound II.
Wherein organic solvent be toluene, dimethylbenzene, THF or Isosorbide-5-Nitrae-dioxane, preferred toluene；Imidazoles annulation is in vinegar
Carry out under the conditions of sour ammonium, compound II-A is 1 with the reaction mol ratio of ammonium acetate:1～10, preferably 1:2～3.
Furtherly, the preparation method of compound II is as follows：
Wherein R is selected from N or O,
Step a)：Compound II-B carries out in organic solvent imidazoles annulation and obtains compound II-C；
Step b)：Compound II-C prepare compounds II in the presence of oxidant.
Wherein organic solvent be toluene, dimethylbenzene, THF or Isosorbide-5-Nitrae-dioxane, preferred toluene；Imidazoles annulation is in vinegar
Carry out under the conditions of sour ammonium, compound II-B is 1 with the reaction mol ratio of ammonium acetate:1～10, preferably 1:2～3；Oxidant is optional
From MnO2, PCC, PDC or Jones reagent, preferably MnO2。
II-A and II-B are cheap and easy to get for compound, are available commercially or voluntarily prepare.
Compared with existing chemical synthesis process, the invention provides a kind of bioanalysis prepares (S) -1- (5- phenyl -1H- miaows
Azoles -2- bases) ethamine green technology scheme, program reaction condition is gentle, product optical purity is high, production cost is reduced, right
Environmental friendliness, with good industrial application value.
Specific embodiment
The technology contents of the present invention are further elaborated with reference to specific embodiment, be its purpose is to preferably
Understand present disclosure, but protection scope of the present invention not limited to this.
Embodiment 1
The preparation of compound II-A (Y is N atoms)
Pyruvic acid (1.0g), dichloromethane (10ml), DMF (0.05ml) are added in 100ml there-necked flasks.By oxalyl chloride
(1.8g) reactant liquor is slowly added at 0 DEG C, process is added dropwise and is kept 0～5 DEG C of reacting liquid temperature.Completion of dropping is slowly increased to room temperature,
Stirring 2 hours.Reaction system ice bath is cooled to into 0 DEG C, 2- aminoacetophenones (1.5g) are added in there-necked flask, N is added dropwise, N- bis- is different
Propylethylamine (2.8g), is added dropwise below 5 DEG C of process keeping temperature.Completion of dropping is slowly returned and warmed to room temperature, and is stirred 1 hour.Will be anti-
Liquid is answered to pour in 100mL frozen water, dichloromethane is extracted three times, and organic phase uses successively 1N watery hydrochloric acid, saturated nacl aqueous solution to wash
Wash, point liquid, anhydrous sodium sulfate drying, revolving is evaporated, and crude product silica gel chromatography obtains compound II-A (1.98g, yield
87%).
The preparation of compound II
By compound II-A (1.98g), ammonium acetate (2.23g) and toluene (20ml) are sequentially added in 50ml there-necked flasks, point
Hydrophone point water, is heated to reflux 6 hours.System is returned to after room temperature, is poured into water, and dichloromethane is extracted three times, and organic phase is used successively
5% sodium acid carbonate, saturated nacl aqueous solution, washing, anhydrous sodium sulfate drying, revolving, post purifying excessively obtain compound II
(1.7g, yield 95%)
The preparation of compound I
The phosphate buffer (40mL, pH=7.0) and isopropylamine (3.0g) of 10mM are added in 100mL reaction vessels,
With phosphorus acid for adjusting pH to 7.0, compound II (1.7g) is added, be stirring evenly and then adding into transaminase enzyme powder ATA101 (0.3g) and auxiliary
Enzyme PLP (1.325mg), is settled to 50mL, the open reaction of magnetic agitation at 30 DEG C, anti-with isopropylamine (4M) control in course of reaction
PH is answered to detect reaction process in 7.0 or so, TLC.80 DEG C of insulation 2h make protein denaturation in reactant liquor after reaction terminates, and cross and filter off
Isolating protein, plus NaOH (10M) regulation pH=13, equal-volume ethyl acetate is extracted three times, merges organic phase, and anhydrous sodium sulfate is done
Dry, vacuum distillation obtains compound I (1.63g, yield 95%), and product ee values are 99.6%.
The preparation of the compound II-A of embodiment 2 (Y is N atoms)
The preparation of compound II-A：It is identical with the experimental procedure of compound II-A in embodiment 1.
The preparation of compound II：It is identical with the experimental procedure of compound II in embodiment 1.
The preparation of compound I
The phosphate buffer (15mL, pH=7.0) and isopropylamine (2.5g) of 10mM are added in 50mL reaction vessels, is used
Phosphorus acid for adjusting pH adds compound II (1.7g) to 7.0, is stirring evenly and then adding into transaminase enzyme powder ATA101 (0.3g) and coenzyme
PLP (1.325mg), is settled to 25mL, the open reaction of magnetic agitation at 30 DEG C, with isopropylamine (4M) control reaction in course of reaction
PH detects reaction process in 7.0 or so, TLC.80 DEG C of insulation 2h make protein denaturation in reactant liquor after reaction terminates, and filter and remove
Protein, plus NaOH (10M) regulation pH=13, equal-volume ethyl acetate is extracted three times, merges organic phase, and anhydrous sodium sulfate is done
Dry, vacuum distillation obtains compound I (1.61g, yield 94%), and product ee values are 99.7%.
Embodiment 3
The preparation of compound II-A (Y is O atom)
Potassium pyruvate (1.3g), 2- bromoacetophenones (2g) and DMSO (10ml), agitating heating are added in 250ml there-necked flasks
To 60 DEG C overnight.HPLC shows that reaction terminates, and adds water (30ml), ethyl acetate (20ml*2) extraction to merge in reaction bulb
Organic phase, anhydrous sodium sulfate drying, filtration, filtrate is concentrated to dryness to obtain compound II-A (1.8g, yield 86%).
The preparation of compound II
By compound II-A (1.8g), ammonium acetate (1.35g) and toluene (18ml) are sequentially added in 50ml there-necked flasks, point water
Device point water, is heated to reflux 6 hours.System is returned to after room temperature, is poured into water, and dichloromethane is extracted three times, and organic phase is successively with 5%
Sodium acid carbonate, saturated nacl aqueous solution, washing, anhydrous sodium sulfate drying, revolving, cross post purifying obtain compound II (1.5g, receive
Rate 92%)
The preparation of compound I
The phosphate buffer (40mL, pH=7.0) and isopropylamine (3.0g) of 10mM are added in 100mL reaction vessels,
With phosphorus acid for adjusting pH to 7.0, compound II (1.5g) is added, be stirring evenly and then adding into transaminase enzyme powder ATA115 (0.3g) and auxiliary
Enzyme PLP (1.325mg), is settled to 50mL, the open reaction of magnetic agitation at 30 DEG C, anti-with isopropylamine (4M) control in course of reaction
PH is answered to detect reaction process in 7.0 or so, TLC.80 DEG C of insulation 2h make protein denaturation in reactant liquor after reaction terminates, and cross and filter off
Isolating protein, plus NaOH (10M) regulation pH=13, equal-volume ethyl acetate is extracted three times, merges organic phase, and anhydrous sodium sulfate is done
Dry, vacuum distillation obtains compound I (1.45g, yield 96%), and product ee values are 99.7%.
Embodiment 4
The preparation of compound II-A (Y is N atoms)
Pyruvic acid (1.0g), dichloromethane (10ml), DMF (0.05ml) are added in 100ml there-necked flasks.By thionyl chloride
(1.63g) reactant liquor is slowly added at 0 DEG C, process is added dropwise and is kept 0～5 DEG C of reacting liquid temperature.Completion of dropping is slowly increased to room temperature,
Stirring 2 hours.Reaction system ice bath is cooled to into 0 DEG C, 2- aminoacetophenones (1.5g) are added in there-necked flask, N is added dropwise, N- bis- is different
Propylethylamine (2.8g), is added dropwise below 5 DEG C of process keeping temperature.Completion of dropping is slowly returned and warmed to room temperature, and is stirred 1 hour.Will be anti-
Liquid is answered to pour in 100mL frozen water, dichloromethane is extracted three times, and organic phase uses successively 1N watery hydrochloric acid, saturated nacl aqueous solution to wash
Wash, point liquid, anhydrous sodium sulfate drying, revolving is evaporated, and crude product silica gel chromatography obtains compound II-A (2.1g, yield
90%).
The preparation of compound II
By compound II-A (2.1g), ammonium acetate (2.33g) and dimethylbenzene (20ml) are sequentially added in 50ml there-necked flasks, point
Hydrophone point water, is heated to reflux 6 hours.System is returned to after room temperature, is poured into water, and dichloromethane is extracted three times, and organic phase is used successively
5% sodium acid carbonate, saturated nacl aqueous solution, washing, anhydrous sodium sulfate drying, revolving, post purifying excessively obtain compound II
(1.85g, yield 97%)
The preparation of compound I
The phosphate buffer (25mL, pH=7.0) and isopropylamine (3.2g) of 10mM are added in 100mL reaction vessels,
With phosphorus acid for adjusting pH to 7.0, add compound II (1.85g), be stirring evenly and then adding into transaminase enzyme powder ATA115 (0.4g) and
Coenzyme PLP (1.35mg), is settled to 35mL, the open reaction of magnetic agitation at 30 DEG C, is controlled with isopropylamine (4M) in course of reaction
Reaction pH detects reaction process in 7.0 or so, TLC.80 DEG C of insulation 2h make protein denaturation in reactant liquor after reaction terminates, and filter
Isolating protein, plus NaOH (10M) is gone to adjust pH=13, equal-volume ethyl acetate is extracted three times, merges organic phase, anhydrous sodium sulfate
It is dried, vacuum distillation obtains compound I (1.78g, yield 96%), product ee values are 99.7%.
Embodiment 5
The preparation of compound II-B (Y is O atom)
2- bromoacetophenones (2g), lactic acid (1g), toluene (10ml) are added in 25ml there-necked flasks, stirring is lower to add bicarbonate
Sodium (1g), is heated to 60 DEG C overnight.HPLC shows that reaction terminates, and adds the water of 30ml, toluene (10ml*2) to carry in reaction bulb
Take, merge organic phase, anhydrous sodium sulfate drying, filtration, filtrate is concentrated to dryness to obtain compound II-B (1.91g, yield 92%).
The preparation of compound II-C
By compound II-B (1.87g), ammonium acetate (2.1g) and toluene (20ml) are sequentially added in 50ml there-necked flasks, point water
Device point water, is heated to reflux 6 hours.System is returned to during room temperature falls back, dichloromethane extraction (20ml*3), and organic phase is used successively
5% sodium acid carbonate, saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, revolving, crude product chromatography obtains compound
II-C (1.6g, yield 95%).
The preparation of compound II
Compound II-C (1.6g) and dichloromethane (20ml) are added in 50ml there-necked flasks.Stirring is lower to add active dioxy
Change manganese (6.5g), be heated to back flow reaction 24 hours.HPLC shows that reaction is finished, and filters, and filtrate is concentrated to dryness, pure with chromatographic column
Change to obtain compound II (1.5g, yield 95%).
The preparation of compound I
The phosphate buffer (25mL, pH=7.0) and isopropylamine (2.8g) of 10mM are added in 100mL reaction vessels,
With phosphorus acid for adjusting pH to 7.0, add compound II (1.5g), be stirring evenly and then adding into transaminase enzyme powder ATA110 (0.32g) and
Coenzyme PLP (1.25mg), is settled to 35mL, the open reaction of magnetic agitation at 30 DEG C, is controlled with isopropylamine (4M) in course of reaction
Reaction pH detects reaction process in 7.0 or so, TLC.80 DEG C of insulation 2h make protein denaturation in reactant liquor after reaction terminates, and filter
Isolating protein, plus NaOH (10M) is gone to adjust pH=13, equal-volume ethyl acetate is extracted three times, merges organic phase, anhydrous sodium sulfate
It is dried, vacuum distillation obtains compound I (1.45g, yield 96%), product ee values are 99.8%.
Embodiment 6
The preparation of compound II-B (Y is N atoms)
2- aminoacetophenones (2.7g), lactic acid (1.8g), dichloromethane (20ml) are added in 50ml there-necked flasks, to reaction
HATU (8.4g) and triethylamine (3g) are added in liquid, is stirred overnight under room temperature.HPLC shows that reaction terminates, and adds in reaction bulb
Water (40ml), is extracted twice with dichloromethane (20ml*2), merges organic phase, and anhydrous sodium sulfate drying, filtration, filtrate is concentrated into
Dry, crude product silica gel chromatography obtains compound II-B (3.97g, yield 96%).
The preparation of compound II-C
By compound II-B (3.97g), ammonium acetate (4.43g) and toluene (40ml) are sequentially added in 100ml there-necked flasks, point
Hydrophone point water, is heated to reflux 6 hours.System is returned to during room temperature falls back, and dichloromethane is extracted three times, and organic phase is used successively
5% sodium acid carbonate, saturated nacl aqueous solution, washing, anhydrous sodium sulfate drying, revolving is evaporated, and crude product chromatography must be changed
Compound II-C (3.43g, yield 95%).
The preparation of compound II
Compound II-C (3.2g) and dichloromethane (40ml) are added in 100ml there-necked flasks.Stirring is lower to add activity two
Manganese oxide (13g), is heated to back flow reaction 24 hours.HPLC shows that reaction is finished, and filters, and filtrate is concentrated to dryness, and uses chromatographic column
Purify to obtain compound II (3g, yield 95%).
The preparation of compound I
The phosphate buffer (25mL, pH=7.0) and isopropylamine (5.6g) of 10mM are added in 100mL reaction vessels,
With phosphorus acid for adjusting pH to 7.0, compound II (3g) is added, be stirring evenly and then adding into transaminase enzyme powder ATA110 (0.64g) and auxiliary
Enzyme PLP (2.5mg), is settled to 60mL, the open reaction of magnetic agitation at 30 DEG C, with isopropylamine (4M) control reaction in course of reaction
PH detects reaction process in 7.0 or so, TLC.80 DEG C of insulation 2h make protein denaturation in reactant liquor after reaction terminates, and filter and remove
Protein, plus NaOH (10M) regulation pH=13, equal-volume ethyl acetate is extracted three times, merges organic phase, and anhydrous sodium sulfate is done
Dry, vacuum distillation obtains compound I (2.9g, yield 96%), and product ee values are 99.7%.
Claims (10)
1. a kind of method that bioanalysis prepares (S) -1- (5- phenyl -1H- imidazoles -2- bases) ethamine, methods described is as follows：
Compound II carries out enzyme process reaction under the collective effect of transaminase, coenzyme, amino group donor and phosphate buffer and generates
Compound I.
2. the method for claim 1, it is characterised in that:The transaminase is selected from the still limited public affairs of section's biological medicine (Shanghai)
The own enzyme storehouse ATA101～ATA148 of department.
3. the method for claim 1, it is characterised in that:The coenzyme is phosphopyridoxal pyridoxal phosphate (PLP).
4. the method for claim 1, it is characterised in that：The amino group donor is isopropylamine or alanine.
5. the method for claim 1, it is characterised in that：In the enzyme process reaction compound II concentration be 25-70g/L,
The concentration of transaminase is 5-12g/L, the concentration of coenzyme is 0.1-1mM, amino group donor concentration is 60-100g/L and buffer solution
Concentration is 10-100mM.
6. a kind of method for preparing following formula: compound II,
Methods described includes
Wherein Y is selected from N or O, and compound II-A carries out in organic solvent imidazoles annulation and obtains compound II.
7. a kind of method for preparing following formula: compound II,
Methods described includes
Wherein R is selected from N or O,
Step a)：Compound II-B carries out in organic solvent imidazoles annulation and obtains compound II-C；
Step b)：Compound II-C prepare compounds II in the presence of oxidant.
8. such as the method for claim 6 or 7, it is characterised in that：The organic solvent is selected from toluene, dimethylbenzene, THF or 1,4- bis-
The ring of oxygen six.
9. method as claimed in claims 6 or 7, it is characterised in that：The imidazoles annulation is carried out under ammonium acetate catalysis.
10. method as claimed in claim 7, it is characterised in that：Oxidant described in step b) is MnO2, PCC, PDC or
Jones reagents.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115594613A (en) * | 2022-10-31 | 2023-01-13 | 上海柏狮生物科技有限公司（Cn） | Edoxaban intermediate and preparation method 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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2016
- 2016-12-28 CN CN201611236622.XA patent/CN106636246B/en active Active
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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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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115594613A (en) * | 2022-10-31 | 2023-01-13 | 上海柏狮生物科技有限公司（Cn） | Edoxaban intermediate and preparation method thereof |
| CN115594613B (en) * | 2022-10-31 | 2024-04-19 | 上海柏狮生物科技有限公司 | Edison intermediate and preparation method thereof |
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