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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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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