CN112430632A - Preparation method of 2- ((trans) -4-aminocyclohexyl) isopropanol - Google Patents
Preparation method of 2- ((trans) -4-aminocyclohexyl) isopropanol Download PDFInfo
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Abstract
The invention discloses a preparation method of 2- ((trans) -4-aminocyclohexyl) isopropanol, which mainly solves the problems of complex reaction, low chiral purity and long reaction period of the existing synthetic method. The preparation method comprises the following steps: taking 1, 4-dioxaspiro [4.5] decane-8-carboxylic acid ethyl ester as a raw material, carrying out methylation reaction in the presence of a Grignard reagent, namely methyl magnesium bromide, and then removing protection to obtain 4- (2-hydroxy isopropyl) cyclohexanone; finally, in a dipotassium hydrogen phosphate-potassium dihydrogen phosphate buffer solution, isopropylamine is used as an amino donor, and 4- (2-hydroxyisopropyl) cyclohexanone is catalyzed by transaminase and coenzyme to convert carbonyl into amino to obtain 2- ((trans) -4-aminocyclohexyl) isopropanol; the transaminase is derived from Vibrio Fluvialis JS17, having the amino acid sequence of SEQ ID No.: 1; the coenzyme is pyridoxal phosphate; the reaction temperature is 25-30 ℃, and the reaction time is 20-60 h. By adopting the method, the conversion rate in the enzymatic step is more than 87 percent, and the chiral purity of the product is 100 percent.
Description
Technical Field
The invention relates to the field of chemical synthesis, and in particular relates to a preparation method of 2- ((trans) -4-aminocyclohexyl) isopropanol.
Background
Prostaglandins (PGs) are a class of physiologically active, oxidized lipid compounds. Derivatives thereof (e.g., prostaglandin D (PGD)) are closely related to the occurrence of asthma, allergic rhinitis, Krabbe's disease, Duchenne muscular dystrophy and systemic lupus erythematosus. One of the key enzymes of prostaglandin D synthesis is prostaglandin D synthase (PGDS), and the study of inhibitors thereof will provide a new approach for treating related diseases.
2- ((trans) -4-aminocyclohexyl) isopropanol is a commonly used drug synthesis intermediate for the synthesis of hematopoietic prostaglandin D synthase (PGDS) inhibitors. At present, the synthesis method and the main process route reported in literature for preparing 2- ((trans) -4-aminocyclohexyl) isopropanol are as follows:
trans-4- (tert-butoxycarbonylamino) cyclohexanecarboxylic acid is used as a raw material, and is subjected to four-step reaction in the presence of reagents such as hydrochloric acid, benzyl bromide, methyl magnesium bromide and lead hydroxide to obtain 2- ((trans) -4-aminocyclohexyl) isopropanol (for example, references WO2013/13188,2013, A1; WO2016/210036,2016 and A1). The method has complex reaction steps, takes long time, has the product yield of only 47.5 percent, and is difficult to obtain the product with high chiral purity. In addition, the reaction reagents and catalysts are expensive and the cost investment is large. The following synthetic route is a product synthetic route of the process.
The synthesis method of the 2- ((trans) -4-aminocyclohexyl) isopropanol mainly has the defects of complex synthesis process, long time consumption, low chiral purity and the like, explores a synthesis route which has simple reaction conditions, is environment-friendly and is easy to amplify, and is an important direction of current research.
Disclosure of Invention
The technical problem to be solved by the invention is that the existing preparation process of 2- ((trans) -4-aminocyclohexyl) isopropanol generally has the defects of complex synthesis process, long time consumption, low chiral purity and the like, so that the invention provides a novel preparation method of 2- ((trans) -4-aminocyclohexyl) isopropanol, and the method has the advantages of few reaction steps and high chiral purity of the product.
In order to solve the technical problems, the invention provides the following technical scheme:
a process for the preparation of 2- ((trans) -4-aminocyclohexyl) isopropanol comprising the steps of:
in a dipotassium hydrogen phosphate-potassium dihydrogen phosphate buffer solution, using isopropylamine as an amino donor, converting a carbonyl into an amino by catalyzing carbonyl through transaminase and coenzyme to obtain 2- ((trans) -4-aminocyclohexyl) isopropanol (formula D);
the transaminase is derived from Vibrio Fluvialis JS17, having the amino acid sequence of SEQ ID No.: 1; in particular the transaminase may be selected from at least one of S138, transaminase S140, transaminase S141 and transaminase S142. Among them, transaminase S138, transaminase S140, transaminase S141, and transaminase S142 are commercially available from seoul han enzyme biotechnology limited.
The amount of said transaminase to be used may be that conventionally used in such catalytic reactions in the art, and in the present invention may specifically be in the range of 0.1 to 3.5g/g, wherein said amount is the mass ratio of said transaminase to said substrate 4- (2-hydroxyisopropyl) cyclohexanone.
The coenzyme can be pyridoxal phosphate.
The coenzyme can be used in the conventional catalytic reaction in the field, and can be specifically 0.01-0.4g/g in the invention, wherein the dosage is the mass ratio of the coenzyme to the substrate 4- (2-hydroxyisopropyl) cyclohexanone.
Specifically, the reaction temperature of the transaminase and the coenzyme can be 25-30 ℃, and the reaction time can be 20-60 h.
The conversion rate of the product after the catalysis in the invention can reach 87.51-93.90%.
The preparation method of the invention specifically comprises the following steps: adding transaminase and coenzyme into dipotassium hydrogen phosphate-potassium dihydrogen phosphate buffer solution containing amino donor, and adjusting pH of the reaction system to 6.5-8.0; 4- (2-hydroxy isopropyl) cyclohexanone (C) is dissolved in dimethyl sulfoxide, and is added into a buffer solution system containing transaminase and coenzyme to carry out transaminase reaction.
Further, the preparation method of the 2- ((trans) -4-aminocyclohexyl) isopropanol provided by the invention also comprises the following steps:
under the action of hydrochloric acid, removing glycol protection from 4- (1, 4-dioxaspiro [4,5] decyl-8) isopropanol (formula B) to obtain 4- (2-hydroxyisopropyl) cyclohexanone (formula C);
the concentration of the hydrochloric acid may be that conventionally used in such reactions in the art, and in the present invention may be specifically 1 to 3M.
The amount of said hydrochloric acid may be conventionally used in such reactions in the art, and in the present invention may specifically be 5 to 10 molar equivalents, wherein said molar equivalents are the molar ratio of said hydrochloric acid to said substrate, 4- (1, 4-dioxaspiro [4,5] decyl-8) isopropanol.
Specifically, the reaction temperature for removing the ethylene glycol protection is 20-35 ℃.
The preparation method provided by the invention can also specifically comprise the following post-treatment steps after the reaction for removing the ethylene glycol protection is finished: adjusting the pH value of the reaction system to 7-7.5 by using a saturated sodium bicarbonate aqueous solution; then extracted with methyltetrahydrofuran, the organic phase was separated and concentrated to dryness to give 4- (2-hydroxyisopropyl) cyclohexanone.
Further, the preparation method of the 2- ((trans) -4-aminocyclohexyl) isopropanol provided by the invention also comprises the following steps:
methylating 1, 4-dioxaspiro [4,5] decane-8-carboxylic acid ethyl ester (A) in the presence of a Grignard reagent to obtain 4- (1, 4-dioxaspiro [4,5] decyl-8) isopropanol (B);
the solvent for the methylation reaction may be one conventionally used in the art for such methylation reactions, and in particular the solvent for the methylation reaction in the present invention may be selected from tetrahydrofuran and/or methyltetrahydrofuran, for example methyltetrahydrofuran.
The Grignard reagent may be conventionally used in such methylation reactions in the art, and in particular in the present invention the Grignard reagent is selected from one or more of methyl magnesium chloride, methyl magnesium bromide and methyl magnesium iodide, for example methyl magnesium bromide.
The Grignard reagent may be used in an amount conventionally used in such methylation reactions in the art, and in the present invention specifically the Grignard reagent is 2.0 to 5.0 molar equivalents or 3.0 to 4.0 molar equivalents of the starting ethyl 1, 4-dioxaspiro [4,5] decane-8-carboxylate.
In the invention, when the Grignard reagent is dripped in the methylation reaction, the temperature can be controlled at 0-5 ℃; after the end of the dropwise addition, the reaction temperature can be controlled at 15-30 ℃.
The preparation method provided by the invention can also specifically comprise the following post-treatment steps after the methylation reaction is finished: the metal reagent was quenched with saturated ammonium chloride, and the product was extracted with methyltetrahydrofuran, the organic phase was separated and concentrated to dryness to give 4- (1, 4-dioxaspiro [4,5] decyl-8) isopropanol.
In one embodiment of the present invention, the preparation method of 2- ((trans) -4-aminocyclohexyl) isopropanol comprises the following reaction steps:
wherein each reaction step and each reaction parameter are as described above.
The technical scheme of the invention has the following beneficial effects:
the synthesis process of the invention has simple flow and low requirement on production equipment;
the preparation method adopts an enzyme catalysis conversion method, has high conversion rate (more than 87 percent) and high chiral purity (chiral purity of 100 percent), has mild reaction conditions, and avoids the use of a large amount of organic reagents;
the preparation method has high product conversion rate, ensures the feasibility of industrial amplification, and provides a new way for the large-scale production of the 2- ((trans) -4-aminocyclohexyl) isopropanol.
Drawings
FIG. 1 is a gas detection chromatogram of example 1.
FIG. 2 is a gas detection chromatogram of example 2.
FIG. 3 is a gas detection chromatogram of example 3.
FIG. 4 is a gas detection chromatogram of example 4.
Detailed Description
The technical solutions of the present invention will be described clearly and completely below, and it should be apparent that the described embodiments are some, but not all, embodiments of the present invention. All other embodiments, which can be obtained by a person skilled in the art without any inventive step based on the embodiments of the present invention, are within the scope of the present invention.
Example 1
Transaminase S138 (from Vibrio Fluvialis JS17, having the amino acid sequence of SEQ ID NO: 1, from Han enzymes, Suzhou) catalyzed the synthesis of 2- ((trans) -4-aminocyclohexyl) isopropanol
Potassium dihydrogen phosphate (5.3g), dipotassium hydrogen phosphate (106g), 85mL of isopropylamine, and 35mL of 85% phosphoric acid were dissolved in 900mL of deionized water to prepare a buffer (pH 7.5) containing an amino donor. The obtained 4- (2-hydroxyisopropyl) cyclohexanone (3mg) was dissolved in dimethyl sulfoxide (6 uL). 500uL of buffer, 1mg of pyridoxal phosphate, and 10mg of transaminase were added in this order. The mixed reaction system is placed in a shaker at 30 ℃ and 250rpm for reaction for 48 h. After the reaction was completed, the pH was adjusted to 8-9 using a saturated aqueous sodium bicarbonate solution. 2mL of methyltetrahydrofuran was added and extracted with shaking. After standing, 100uL of the organic phase was dissolved in 900uL of methanol. After filtration, gas chromatography detection was carried out. The result shows that the conversion rate of the 4- (2-hydroxyisopropyl) cyclohexanone in the enzyme catalysis step is 93.90%, and the chiral purity of the product is 100%. The gas detection chromatography column was Rtx-1701(30.0m 0.32mm, ID 0.25uM), FID detector, nitrogen-air mixture flow rate 30mL/min, detector temperature 280 ℃, injector temperature 200 ℃. The temperature rising procedure is as follows: maintaining at 80 deg.C for 3min, heating at 10 deg.C/min to 250 deg.C for 5 min.
Example 2
Transaminase S140 (available from Biotechnology Ltd of Han Suzhou enzymes, Vibrio Fluvialis JS17, having the amino acid sequence of SEQ ID NO: 1) catalyzes the synthesis of 2- ((trans) -4-aminocyclohexyl) isopropanol
Potassium dihydrogen phosphate (5.3g), dipotassium hydrogen phosphate (106g), 85mL of isopropylamine, and 35mL of 85% phosphoric acid were dissolved in 900mL of deionized water to prepare a buffer (pH 7.5) containing an amino donor. The obtained 4- (2-hydroxyisopropyl) cyclohexanone (3mg) was dissolved in dimethyl sulfoxide (6 uL). 500uL of buffer, 0.1mg of pyridoxal phosphate, and 10mg of transaminase were added in this order. The mixed reaction system is placed in a shaker at 30 ℃ and 250rpm for reaction for 48 h. After the reaction was completed, the pH was adjusted to 8-9 using a saturated aqueous sodium bicarbonate solution. 2mL of methyltetrahydrofuran was added and extracted with shaking. After standing, 100uL of the organic phase was dissolved in 900uL of methanol. After filtration, gas chromatography detection was carried out. The result shows that the conversion rate of the 4- (2-hydroxyisopropyl) cyclohexanone in the enzyme catalysis step is 93.59%, and the chiral purity of the product is 100%. The gas detection chromatography column was Rtx-1701(30.0m 0.32mm, ID 0.25uM), FID detector, nitrogen-air mixture flow rate 30mL/min, detector temperature 280 ℃, injector temperature 200 ℃. The temperature rising procedure is as follows: maintaining at 80 deg.C for 3min, heating at 10 deg.C/min to 250 deg.C for 5 min.
Example 3
Transaminase S141 (from Vibrio Fluvialis JS17, having the amino acid sequence of SEQ ID NO: 1, from Han enzymes, Suzhou) catalyzed the synthesis of 2- ((trans) -4-aminocyclohexyl) isopropanol
Potassium dihydrogen phosphate (5.3g), dipotassium hydrogen phosphate (106g), 85mL of isopropylamine, and 35mL of 85% phosphoric acid were dissolved in 900mL of deionized water to prepare a buffer (pH 7.5) containing an amino donor. The obtained 4- (2-hydroxyisopropyl) cyclohexanone (3mg) was dissolved in dimethyl sulfoxide (6 uL). 500uL of buffer, 0.1mg of pyridoxal phosphate, and 2mg of transaminase were added in this order. The mixed reaction system is placed in a shaker at 30 ℃ and 250rpm for reaction for 48 h. After the reaction was completed, the pH was adjusted to 8-9 using a saturated aqueous sodium bicarbonate solution. 2mL of methyltetrahydrofuran was added and extracted with shaking. After standing, 100uL of the organic phase was dissolved in 900uL of methanol. After filtration, gas chromatography detection was carried out. The result shows that the conversion rate of the 4- (2-hydroxyisopropyl) cyclohexanone in the enzyme catalysis step is 89.24%, and the chiral purity of the product is 100%. The gas detection chromatography column was Rtx-1701(30.0m 0.32mm, ID 0.25uM), FID detector, nitrogen-air mixture flow rate 30mL/min, detector temperature 280 ℃, injector temperature 200 ℃. The temperature rising procedure is as follows: maintaining at 80 deg.C for 3min, heating at 10 deg.C/min to 250 deg.C for 5 min.
Example 4
Transaminase S142 (from Vibrio Fluvialis JS17, having the amino acid sequence of SEQ ID NO: 1, available from Han enzymes Biotech, Suzhou) catalyzed synthesis of 2- ((trans) -4-aminocyclohexyl) isopropanol
Potassium dihydrogen phosphate (5.3g), dipotassium hydrogen phosphate (106g), 85mL of isopropylamine, and 35mL of 85% phosphoric acid were dissolved in 900mL of deionized water to prepare a buffer (pH 7.5) containing an amino donor, and the obtained 4- (2-hydroxyisopropyl) cyclohexanone (3mg) was dissolved in dimethyl sulfoxide (6 uL). 500uL of buffer, 1mg of pyridoxal phosphate, 10mg of transaminase (R142) were added in this order. The mixed reaction system is placed in a shaker at 30 ℃ and 250rpm for reaction for 48 h. After the reaction was completed, the pH was adjusted to 8-9 using a saturated aqueous sodium bicarbonate solution. 2mL of methyltetrahydrofuran was added and extracted with shaking. After standing, 100uL of the organic phase was dissolved in 900uL of methanol. After filtration, gas chromatography detection was carried out. The result shows that the conversion rate of the substrate 4- (2-hydroxyisopropyl) cyclohexanone in the enzyme catalysis step is 87.51%, and the chiral purity of the product is 100%.
In summary, the above embodiments are merely preferred embodiments of the present invention, and are not intended to limit the scope of the present invention, and any modifications, equivalents, improvements, etc. made within the spirit and principle of the present invention should be included in the scope of the present invention.
Sequence listing
<110> Shanghai Hequan drug development Co Ltd
Preparation method of <120> 2- ((trans) -4-aminocyclohexyl) isopropanol
<130> CPC-NP-20-101839
<160> 1
<170> SIPOSequenceListing 1.0
<210> 1
<211> 453
<212> PRT
<213> transaminase ()
<400> 1
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Val Thr His Gly Glu Gly Pro Tyr Ile Val Asp Val Asn Gly Arg Arg
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Tyr Leu Asp Ala Asn Ser Gly Leu Trp Asn Met Val Ala Gly Phe Asp
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Val Met Gly Ala Gly Gly Val Ile Pro Pro Ala Lys Gly Tyr Phe Gln
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Glu Val Ile Cys Gly Phe Gly Arg Thr Gly Asn Thr Trp Gly Cys Val
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Claims (10)
1. A process for the preparation of 2- ((trans) -4-aminocyclohexyl) isopropanol (D), characterized in that it comprises the following steps:
catalyzing 4- (2-hydroxyisopropyl) cyclohexanone (C) by transaminase and coenzyme in dipotassium hydrogen phosphate-potassium dihydrogen phosphate buffer solution by taking isopropylamine as an amino donor;
wherein the transaminase is derived from Vibrio Fluvialis JS17 having the amino acid sequence of SEQ ID No.: 1.
2. The method according to claim 1, wherein the reaction mixture,
the transaminase is selected from at least one of transaminase S138, transaminase S140, transaminase S141, and transaminase S142;
and/or the coenzyme is pyridoxal phosphate;
and/or the reaction temperature is 25-30 ℃;
and/or the reaction time is 20-60 h;
and/or the reaction pH is 6.5-8.0.
3. The method according to claim 1, wherein the reaction mixture,
the dosage of the transaminase is 0.1-3.5 g/g;
and/or the dosage of the coenzyme is 0.01-0.4 g/g.
4. The method according to claim 1, wherein the method comprises the steps of:
adding transaminase and coenzyme into dipotassium hydrogen phosphate-potassium dihydrogen phosphate buffer solution containing amino donor, and adjusting pH of the reaction system to 6.5-8.0; 4- (2-hydroxy isopropyl) cyclohexanone (C) is dissolved in dimethyl sulfoxide, and is added into a buffer solution system containing transaminase and coenzyme to carry out transaminase reaction.
6. the method according to claim 5,
the concentration of the hydrochloric acid is 1-3M;
and/or the dosage of the hydrochloric acid is 5-10 molar equivalents;
and/or the reaction temperature for removing the ethylene glycol protection is 20-35 ℃.
7. The preparation method according to claim 5, further comprising the following post-treatment steps: after the reaction for removing the glycol protection is finished, adjusting the pH value of the reaction system to 7-7.5 by using a saturated sodium bicarbonate aqueous solution; then extracted with methyltetrahydrofuran, the organic phase was separated and concentrated to dryness to give 4- (2-hydroxyisopropyl) cyclohexanone.
9. the method according to claim 8,
the solvent of the methylation reaction is selected from tetrahydrofuran and/or methyltetrahydrofuran;
and/or, the Grignard reagent is selected from one or more of methyl magnesium chloride, methyl magnesium bromide and methyl magnesium iodide;
and/or the Grignard reagent is 2.0-5.0 molar equivalents or 3.0-4.0 molar equivalents of ethyl 1, 4-dioxaspiro [4,5] decane-8-carboxylate.
10. The method according to claim 8,
when the Grignard reagent is dripped in the methylation reaction, the temperature is 0-5 ℃;
and/or, after the end of the dropwise addition, the reaction temperature is 15-30 ℃.
And/or after the methylation reaction is finished, quenching the metal reagent by using saturated ammonium chloride, extracting the product by using methyl tetrahydrofuran, separating an organic phase, and concentrating to be dry to obtain the 4- (1, 4-dioxaspiro [4,5] decyl-8) isopropanol.
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Citations (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060287344A1 (en) * | 2005-01-13 | 2006-12-21 | Albers Ronald J | Haloaryl substituted aminopurines, compositions thereof, and methods of treatment therewith |
CN102341494A (en) * | 2009-01-08 | 2012-02-01 | 科德克希思公司 | Transaminase polypeptides |
WO2013013188A1 (en) * | 2011-07-21 | 2013-01-24 | Tolero Pharmaceuticals, Inc. | Heterocyclic protein kinase inhibitors |
CN103097375A (en) * | 2010-06-17 | 2013-05-08 | 詹森药业有限公司 | Cyclohexyl-azetidinyl antagonists of CCR2 |
US20130149751A1 (en) * | 2010-08-16 | 2013-06-13 | John Limanto | Process for preparing aminocyclohexyl ether compounds |
CN104098563A (en) * | 2013-04-02 | 2014-10-15 | 山东亨利医药科技有限责任公司 | JNK (stress-activated kinases,SAPK) inhibitor compound |
US20150368682A1 (en) * | 2013-02-28 | 2015-12-24 | Merck Sharp & Dohme Corp. | Immobilized transaminases and process for making and using immobilized transaminase |
CN105324125A (en) * | 2013-03-15 | 2016-02-10 | 印第安纳大学研究及科技有限公司 | Prodrugs with prolonged action |
CN106232587A (en) * | 2014-04-24 | 2016-12-14 | 田边三菱制药株式会社 | Novel two replacement 1,2,4 triaizine compounds |
CN107604019A (en) * | 2017-09-27 | 2018-01-19 | 上海合全药物研发有限公司 | The method that living things catalysis prepares the amino piperidine of (R) 1 N benzene methoxycarbonyl group 3 |
CN109321509A (en) * | 2018-11-13 | 2019-02-12 | 江南大学 | A method of 1,2- alkamine compound is produced using resting cell |
CN109641906A (en) * | 2015-06-24 | 2019-04-16 | 百时美施贵宝公司 | The aminopyridine compounds that heteroaryl replaces |
CN111032682A (en) * | 2017-06-14 | 2020-04-17 | 科德克希思公司 | Engineered transaminase polypeptides for industrial biocatalysis |
US20200123152A1 (en) * | 2017-06-13 | 2020-04-23 | Glaxosmithkline Intellectual Property Development Limited | Chemical Compounds as H-PGDS Inhibitors |
US20200239437A1 (en) * | 2017-08-04 | 2020-07-30 | Bristol-Myers Squibb Company | Substituted indole compounds useful as inhibitors of tlr7/8/9 |
US20200338076A1 (en) * | 2019-02-12 | 2020-10-29 | Tolero Pharmaceuticals, Inc. | Formulations comprising heterocyclic protein kinase inhibitors |
US20210087174A1 (en) * | 2017-12-20 | 2021-03-25 | Bristol-Myers Squibb Company | Aryl and heteroaryl substituted indole compounds |
-
2020
- 2020-11-18 CN CN202011295681.0A patent/CN112430632B/en active Active
Patent Citations (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060287344A1 (en) * | 2005-01-13 | 2006-12-21 | Albers Ronald J | Haloaryl substituted aminopurines, compositions thereof, and methods of treatment therewith |
CN102341494A (en) * | 2009-01-08 | 2012-02-01 | 科德克希思公司 | Transaminase polypeptides |
CN103097375A (en) * | 2010-06-17 | 2013-05-08 | 詹森药业有限公司 | Cyclohexyl-azetidinyl antagonists of CCR2 |
US20130149751A1 (en) * | 2010-08-16 | 2013-06-13 | John Limanto | Process for preparing aminocyclohexyl ether compounds |
WO2013013188A1 (en) * | 2011-07-21 | 2013-01-24 | Tolero Pharmaceuticals, Inc. | Heterocyclic protein kinase inhibitors |
US20150368682A1 (en) * | 2013-02-28 | 2015-12-24 | Merck Sharp & Dohme Corp. | Immobilized transaminases and process for making and using immobilized transaminase |
CN105324125A (en) * | 2013-03-15 | 2016-02-10 | 印第安纳大学研究及科技有限公司 | Prodrugs with prolonged action |
CN104098563A (en) * | 2013-04-02 | 2014-10-15 | 山东亨利医药科技有限责任公司 | JNK (stress-activated kinases,SAPK) inhibitor compound |
CN106232587A (en) * | 2014-04-24 | 2016-12-14 | 田边三菱制药株式会社 | Novel two replacement 1,2,4 triaizine compounds |
CN109641906A (en) * | 2015-06-24 | 2019-04-16 | 百时美施贵宝公司 | The aminopyridine compounds that heteroaryl replaces |
US20200123152A1 (en) * | 2017-06-13 | 2020-04-23 | Glaxosmithkline Intellectual Property Development Limited | Chemical Compounds as H-PGDS Inhibitors |
CN111032682A (en) * | 2017-06-14 | 2020-04-17 | 科德克希思公司 | Engineered transaminase polypeptides for industrial biocatalysis |
US20200239437A1 (en) * | 2017-08-04 | 2020-07-30 | Bristol-Myers Squibb Company | Substituted indole compounds useful as inhibitors of tlr7/8/9 |
CN107604019A (en) * | 2017-09-27 | 2018-01-19 | 上海合全药物研发有限公司 | The method that living things catalysis prepares the amino piperidine of (R) 1 N benzene methoxycarbonyl group 3 |
US20210087174A1 (en) * | 2017-12-20 | 2021-03-25 | Bristol-Myers Squibb Company | Aryl and heteroaryl substituted indole compounds |
CN109321509A (en) * | 2018-11-13 | 2019-02-12 | 江南大学 | A method of 1,2- alkamine compound is produced using resting cell |
US20200338076A1 (en) * | 2019-02-12 | 2020-10-29 | Tolero Pharmaceuticals, Inc. | Formulations comprising heterocyclic protein kinase inhibitors |
Non-Patent Citations (2)
Title |
---|
JUSTIN R. HARRISON等: "Discovery and Optimization of a Compound Series Active against Trypanosoma cruzi, the Causative Agent of Chagas Disease", 《J. MED. CHEM.》 * |
李伟翔等: "酶促不对称催化手性合成系统研究进展", 《分子催化》 * |
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