CN109704981B - Method for substituting and synthesizing (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate - Google Patents
Method for substituting and synthesizing (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate Download PDFInfo
- Publication number
- CN109704981B CN109704981B CN201910118478.7A CN201910118478A CN109704981B CN 109704981 B CN109704981 B CN 109704981B CN 201910118478 A CN201910118478 A CN 201910118478A CN 109704981 B CN109704981 B CN 109704981B
- Authority
- CN
- China
- Prior art keywords
- methoxyphenyl
- fluoro
- ethyl
- amino
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Disclosure of the inventionThe method for synthesizing the (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate by substitution comprises the following steps: (1) carrying out substitution reaction on 2- (2-fluoro-3-methoxyphenyl) -2-ethyl glycolate shown as a formula II and methanesulfonyl chloride to obtain 2-chloro (2-fluoro-3-methoxyphenyl) ethyl acetate shown as a formula V;
(2) carrying out Blaise reaction on ethyl 2-chloro (2-fluoro-3-methoxyphenyl) acetate shown in a formula V to obtain (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoic acid ethyl ester shown in a formula I;
Description
Technical Field
The invention belongs to the technical field of organic synthesis and medical intermediates, and particularly relates to a method for synthesizing (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate by substitution.
Background
elagolix is an oral GnRH antagonist that has received approval from the U.S. food and drug administration for the treatment of pain due to endometriosis. The intermediate (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate used in the synthesis has the following structural formula:
according to the description of us patent WO2009062087, the intermediate can be synthesized via the following route:
from the above synthetic route, the route of the prior art is synthesized by a four-step method, and has the disadvantages of long synthetic route, complex process, high equipment cost investment, difficult control of reaction process and low yield.
Disclosure of Invention
The technical problem to be solved by the invention is as follows: the conventional route for synthesizing the target intermediate is long.
The invention adopts the following technical scheme to solve the technical problems:
a method for substituting and synthesizing (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate comprises the following steps:
(1) carrying out substitution reaction on 2- (2-fluoro-3-methoxyphenyl) -2-ethyl glycolate shown as a formula II and methanesulfonyl chloride to obtain 2-chloro (2-fluoro-3-methoxyphenyl) ethyl acetate shown as a formula V;
(2) carrying out Blaise reaction on ethyl 2-chloro (2-fluoro-3-methoxyphenyl) acetate shown in a formula V to obtain (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoic acid ethyl ester shown in a formula I;
preferably, in the method for synthesizing (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoic acid ethyl ester by substitution, the specific operation of the step (1) is as follows: dissolving 2- (2-fluoro-3-methoxyphenyl) -2-ethyl glycolate shown as a formula II in a solvent, and adding methane sulfonyl chloride and alkali to the solvent to perform substitution reaction; after the reaction is finished, the mixture is concentrated to be dry, and the concentrate is washed and dried to obtain the 2-chloro (2-fluoro-3-methoxyphenyl) ethyl acetate shown in the formula V.
Preferably, in the method for synthesizing (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoic acid ethyl ester by substitution, the specific operation of the step (2) is as follows: dissolving ethyl 2-chloro (2-fluoro-3-methoxyphenyl) acetate shown as a formula V in an organic solvent, and adding zinc powder into the organic solvent to perform Blaise reaction; after the reaction is finished, concentrating the mixture to be dry, washing, drying and purifying to obtain the (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate shown in the formula I.
Preferably, in the method for synthesizing (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoic acid ethyl ester by substitution, the reactant in the step (2) further comprises a catalyst.
Preferably, in the method for synthesizing ethyl (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoate by substitution, the solvent in the step (1) is any one selected from dichloromethane, 1, 2-dichloroethane, chloroform, THF, DMF and diethylene glycol dimethyl ether; and/or
The base in the step (1) is selected from triethylamine, DIPEA, pyridine, DMAP or a mixture of triethylamine and pyridine.
Preferably, in the method for synthesizing (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoic acid ethyl ester by substitution, the washing operation in the step (1) is as follows: washing the concentrate by using a mixture of dichloromethane and hydrochloric acid aqueous solution as a detergent, separating an organic phase, and washing the organic phase by using saturated sodium bicarbonate aqueous solution and saturated salt solution in sequence.
Preferably, in the method for synthesizing (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoic acid ethyl ester by substitution, the organic solvent in the step (2) is a mixed solvent, and the mixed solvent is formed by mixing acetonitrile and any one of toluene, xylene, 1, 2-dichloroethane, THF and DMF; and/or
The catalyst is TBAB, TBACl, TBAOTf or TBAI.
Preferably, in the method for the substituted synthesis of ethyl (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoate, the washing operation in the step (2) is as follows: washing the concentrate with a mixture of dichloromethane and saturated aqueous ammonium chloride solution as a detergent, separating the organic phase, and washing the organic phase with saturated aqueous sodium bicarbonate solution and saturated brine in this order.
Preferably, according to the method for synthesizing (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoic acid ethyl ester by substitution, every 1.0g of ethyl 2- (2-fluoro-3-methoxyphenyl) -2-hydroxyacetate shown in the formula II reacts with 0.9-2.4equiv of methylsulfonyl chloride and 1-4equiv of alkali; and/or
The process of the substitution reaction in the step (1) is heating to 50 ℃ for reacting for 18 h; or heating to reflux for 4-32 h.
Preferably, according to the method for synthesizing (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate by substitution, every 1.0g of 1.0equiv of ethyl 2-chloro (2-fluoro-3-methoxyphenyl) acetate shown as the formula V reacts with 1-5equiv of zinc powder and 0.1-0.2equiv of catalyst; and/or
The Blaise reaction process in the step (2) is heating to 50 ℃ for 10h, or heating to reflux for 6-32 h.
The invention has the following beneficial effects: according to the technical scheme, the target product can be obtained only through two steps of reaction, the synthetic route is short, and the operation is simple; reasonable reagents, solvents and reaction conditions are selected to obtain higher yield, so that economic benefits are improved; in the second step of reaction, the catalyst is added to promote the main reaction, reduce side reaction and avoid introducing unnecessary impurities, so that the reactants are easy to purify and the product with higher purity is obtained.
Detailed Description
In order to facilitate the understanding of the technical solutions of the present invention for those skilled in the art, the technical solutions of the present invention will now be further described with reference to specific embodiments.
In the embodiment of the invention, (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate shown as a formula I is synthesized through the following route:
example 1
(1) The synthetic route of the ethyl 2-chloro (2-fluoro-3-methoxyphenyl) acetate shown as the formula V:
the method comprises the following specific operations: dissolving 1.0g, 1.0equiv. of ethyl 2- (2-fluoro-3-methoxyphenyl) -2-hydroxyacetate shown as the formula II in 10mL of dichloromethane in a reactor, adding 1.2equiv. of methanesulfonyl chloride (MsCl) and 2.0equiv. of DMAP, and heating to reflux for 18 h; after the reaction is finished, the mixture is concentrated to be dry, the mixture of dichloromethane and 1N hydrochloric acid aqueous solution is used as a detergent to wash the concentrate, an organic phase is separated, then the saturated sodium bicarbonate aqueous solution and saturated saline solution are used to wash the organic phase, then sodium sulfate is used to dry and spin-dry the organic phase, and finally the 2-chloro (2-fluoro-3-methoxyphenyl) ethyl acetate shown in the formula V is obtained by column chromatography, wherein the yield is 86%. Detecting by using a high resolution mass spectrum (ESI +), wherein the detection value is 247.0539; m + H+The calculated high resolution mass spectrum of 247.0532 was compared to confirm the structure of the product.
(2) The synthetic route of (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate shown as the formula I:
the method comprises the following specific operations: in a reactor, 1.0g, 1.0equiv. of ethyl (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoate represented by the formula V is dissolved in a mixed solvent composed of 10mL of acetonitrile and 10mL of toluene, and 2.0equiv. zinc powder and 0.1equiv. TB are added theretoAI, heating the system to reflux, and reacting for 18h under stirring; after the reaction is finished, concentrating the mixture to be dry; washing the concentrate with a mixture of dichloromethane and saturated aqueous ammonium chloride solution as a detergent, and separating the organic phase; the organic phase was washed with saturated sodium bicarbonate and saturated brine in this order, and then dried over sodium sulfate and spin-dried to give 0.52equiv. colorless oil, i.e., (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoic acid ethyl ester, as shown in formula I, with a yield of 52%. Detecting by using a high resolution mass spectrum (ESI +), wherein the detection value is 254.1195; m + H+The calculated high resolution mass spectrum of 254.1187 was compared to confirm the structure of the product.
Example 2
(1) The synthetic route of the ethyl 2-chloro (2-fluoro-3-methoxyphenyl) acetate shown as the formula V:
the method comprises the following specific operations: dissolving 1.0g, 1.0equiv. of ethyl 2- (2-fluoro-3-methoxyphenyl) -2-hydroxyacetate shown as the formula II in 15mL of 1, 2-dichloroethane in a reactor, adding 0.9equiv. of methanesulfonyl chloride (MsCl) and 1.0equiv. of triethylamine, and heating to reflux for 4 hours; after the reaction is finished, the mixture is concentrated to be dry, the mixture of dichloromethane and 1N hydrochloric acid aqueous solution is used as a detergent to wash the concentrate, an organic phase is separated, then the saturated sodium bicarbonate aqueous solution and saturated saline solution are used to wash the organic phase, then sodium sulfate is used to dry and spin-dry the organic phase, and finally the 2-chloro (2-fluoro-3-methoxyphenyl) ethyl acetate shown in the formula V is obtained by column chromatography, wherein the yield is 77%. Detection was performed by high resolution mass spectrometry (ESI +) and found to be 247.0534.
(2) The synthetic route of (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate shown as the formula I:
the method comprises the following specific operations: dissolving 1.0g, 1.0equiv. (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoic acid ethyl ester shown as the formula V in a mixed solvent consisting of 3mL of acetonitrile and 15mL of 1, 2-dichloroethane, adding 1.0equiv zinc powder and 0.2equiv TBAB into the mixed solvent, heating the system to reflux, and reacting for 18 hours under stirring; after the reaction is finished, concentrating the mixture to be dry; washing the concentrate with a mixture of dichloromethane and saturated aqueous ammonium chloride solution as a detergent, and separating the organic phase; the organic phase was washed with saturated sodium bicarbonate and saturated brine in this order, and then dried over sodium sulfate and spin-dried to give 0.45equiv. colorless oil, i.e., (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoic acid ethyl ester, as shown in formula I, with a yield of 45%. Detection was carried out by high resolution mass spectrometry (ESI +) and found to be 254.1192.
Example 3
(1) The synthetic route of the ethyl 2-chloro (2-fluoro-3-methoxyphenyl) acetate shown as the formula V:
the method comprises the following specific operations: dissolving 1.0g, 1.0equiv. of ethyl 2- (2-fluoro-3-methoxyphenyl) -2-hydroxyacetate shown as the formula II in 12mL of DMF in a reactor, adding 2.4equiv. of methanesulfonyl chloride (MsCl) and 2.0equiv. of pyridine, and heating to reflux for 18 h; after the reaction is finished, the mixture is concentrated to be dry, the mixture of dichloromethane and 1N hydrochloric acid aqueous solution is used as a detergent to wash the concentrate, an organic phase is separated, then the saturated sodium bicarbonate aqueous solution and saturated saline solution are used to wash the organic phase, then sodium sulfate is used to dry and spin-dry the organic phase, and finally the 2-chloro (2-fluoro-3-methoxyphenyl) ethyl acetate shown in the formula V is obtained by column chromatography, wherein the yield is 90%. Detection was performed by high resolution mass spectrometry (ESI +) and found to be 247.0536.
(2) The synthetic route of (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate shown as the formula I:
the method comprises the following specific operations: dissolving 1.0g, 1.0equiv. (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoic acid ethyl ester shown as the formula V in a mixed solvent consisting of 15mL of acetonitrile and 3mL of xylene in a reactor, adding 2.0equiv zinc powder and 0.1equiv TBAI, heating the system to reflux, and reacting for 32 hours under stirring; after the reaction is finished, concentrating the mixture to be dry; washing the concentrate with a mixture of dichloromethane and saturated aqueous ammonium chloride solution as a detergent, and separating the organic phase; the organic phase was washed with saturated sodium bicarbonate and saturated brine in this order, and then dried over sodium sulfate and spin-dried to give 0.41equiv. colorless oil, i.e., (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoic acid ethyl ester, as shown in formula I, with a yield of 41%. Detection was carried out by high resolution mass spectrometry (ESI +) and found to be 254.1194.
Example 4
(1) The synthetic route of the ethyl 2-chloro (2-fluoro-3-methoxyphenyl) acetate shown as the formula V:
the method comprises the following specific operations: dissolving 1.0g, 1.0equiv. ethyl 2- (2-fluoro-3-methoxyphenyl) -2-hydroxyacetate shown as the formula II in 10mL of chloroform in a reactor, adding 1.2equiv. methylsulfonyl chloride (MsCl) and 4.0equiv. DIPEA, stirring, heating to 50 ℃ and reacting for 18 h; after the reaction is finished, the mixture is concentrated to be dry, the mixture of dichloromethane and 1N hydrochloric acid aqueous solution is used as a detergent to wash the concentrate, an organic phase is separated, then the saturated sodium bicarbonate aqueous solution and saturated saline solution are used to wash the organic phase, then sodium sulfate is used to dry and spin-dry the organic phase, and finally the 2-chloro (2-fluoro-3-methoxyphenyl) ethyl acetate shown in the formula V is obtained by column chromatography, wherein the yield is 85%. Detection was performed by high resolution mass spectrometry (ESI +) and found to be 247.0534.
(2) The synthetic route of (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate shown as the formula I:
the method comprises the following specific operations: dissolving 1.0g, 1.0equiv. of (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoic acid ethyl ester shown as the formula V in a mixed solvent consisting of 10mL of acetonitrile and 10mL of THF in a reactor, adding 2.0equiv. of zinc powder and 0.2equiv. of TBACl, stirring, heating the system to 50 ℃, and reacting for 6 hours under stirring; after the reaction is finished, concentrating the mixture to be dry; washing the concentrate with a mixture of dichloromethane and saturated aqueous ammonium chloride solution as a detergent, and separating the organic phase; the organic phase was washed with saturated sodium bicarbonate and saturated brine in this order, and then dried over sodium sulfate and spin-dried to give 0.31equiv. colorless oil, i.e., (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoic acid ethyl ester, as shown in formula I, with a yield of 31%. Detection was carried out by high resolution mass spectrometry (ESI +) and found to be 254.1194.
Example 5
(1) The synthetic route of the ethyl 2-chloro (2-fluoro-3-methoxyphenyl) acetate shown as the formula V:
the method comprises the following specific operations: dissolving 1.0g, 1.0equiv. of ethyl 2- (2-fluoro-3-methoxyphenyl) -2-glycolate represented by the formula II in 15mL of diethylene glycol dimethyl ether in a reactor, adding 1.2equiv. of methanesulfonyl chloride (MsCl), 1.1equiv. of triethylamine, and 0.1equiv. of pyridine, and heating to reflux for reaction for 32 h; after the reaction is finished, the mixture is concentrated to be dry, the mixture of dichloromethane and 1N hydrochloric acid aqueous solution is used as a detergent to wash the concentrate, an organic phase is separated, then the organic phase is washed by saturated sodium bicarbonate aqueous solution and saturated saline solution in sequence, then sodium sulfate is dried and spin-dried, and finally, the 0.85equiv. ethyl 2-chloro (2-fluoro-3-methoxyphenyl) acetate shown in the formula V is obtained through column chromatography, wherein the yield is 85 percent. Detection was performed by high resolution mass spectrometry (ESI +) and found to be 247.0539.
(2) The synthetic route of (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate shown as the formula I:
the method comprises the following specific operations: in a reactor, 1.0g, 1.0equiv. of (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoic acid ethyl ester shown as the formula V is dissolved in a mixed solvent consisting of 10mL of acetonitrile and 10mL of toluene, 5.0equiv. of zinc powder is added into the mixed solvent, the system is heated to reflux, and the reaction is carried out for 20 hours under stirring; after the reaction is finished, concentrating the mixture to be dry; washing the concentrate with a mixture of dichloromethane and saturated aqueous ammonium chloride solution as a detergent, and separating the organic phase; the organic phase was washed with saturated sodium bicarbonate and saturated brine in this order, and then dried over sodium sulfate and spin-dried to give 0.52equiv. colorless oil, i.e., (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoic acid ethyl ester, as shown in formula I, with a yield of 52%. Detection was carried out by high resolution mass spectrometry (ESI +) and found to be 254.1189.
Technical solution of the present invention, the present invention is described above by way of example with reference to the specific embodiments, and it is obvious that the specific implementation of the present invention is not limited by the above-described manner, and it is within the scope of the present invention to employ various insubstantial modifications of the method concept and technical solution of the present invention, or to directly apply the concept and technical solution of the present invention to other occasions without modification.
Claims (5)
1. A method for substituting and synthesizing (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate is characterized in that,
the method comprises the following steps:
(1) dissolving every 1.0equiv. ethyl 2- (2-fluoro-3-methoxyphenyl) -2-hydroxyacetate shown as the formula II in a solvent, adding 0.9-2.4equiv. methane sulfonyl chloride and 1-4equiv. alkali, heating to 50 ℃ for reacting for 18 hours or heating to reflux for reacting for 4-32 hours to perform substitution reaction; after the reaction is finished, concentrating the mixture to be dry, washing, drying and purifying the concentrate to obtain 2-chloro (2-fluoro-3-methoxyphenyl) ethyl acetate shown in the formula V;
(2) dissolving 2-chloro (2-fluoro-3-methoxyphenyl) ethyl acetate shown in the formula V at each 1.0equiv in an organic solvent, adding 1-5equiv zinc powder and 0.1-0.2equiv catalyst into the organic solvent to perform Blaise reaction, wherein the Blaise reaction is performed by heating to 50 ℃ for 10 hours or heating to reflux for 6-32 hours; after the reaction is finished, concentrating the mixture to be dry, washing and drying to obtain (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate shown as a formula I;
2. the method for the substitution synthesis of ethyl (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoate according to claim 1, wherein the solvent used in the step (1) is selected from any one of dichloromethane, 1, 2-dichloroethane, chloroform, THF, DMF and diethylene glycol dimethyl ether; and/or the base in step (1) is selected from triethylamine, DIPEA, pyridine, DMAP or a mixture of triethylamine and pyridine.
3. The method for the substitution synthesis of ethyl (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoate according to claim 1, wherein the washing in step (1) is specifically performed as follows: washing the concentrate by using a mixture of dichloromethane and hydrochloric acid aqueous solution as a detergent, separating an organic phase, and washing the organic phase by using saturated sodium bicarbonate aqueous solution and saturated salt solution in sequence.
4. The method for the substitution synthesis of ethyl (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoate according to claim 1, wherein the organic solvent used in step (2) is a mixed solvent comprising acetonitrile and any one of toluene, xylene, 1, 2-dichloroethane, THF and DMF; and/or the catalyst is TBAB, TBACl, TBAOTf or TBAI.
5. The method for the substitution synthesis of ethyl (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-butenoate according to claim 1, wherein the washing in the step (2) is specifically performed as follows: washing the concentrate with a mixture of dichloromethane and saturated aqueous ammonium chloride solution as a detergent, separating the organic phase, and washing the organic phase with saturated aqueous sodium bicarbonate solution and saturated brine in this order.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910118478.7A CN109704981B (en) | 2019-02-16 | 2019-02-16 | Method for substituting and synthesizing (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910118478.7A CN109704981B (en) | 2019-02-16 | 2019-02-16 | Method for substituting and synthesizing (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109704981A CN109704981A (en) | 2019-05-03 |
| CN109704981B true CN109704981B (en) | 2022-01-28 |
Family
ID=66263664
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910118478.7A Active CN109704981B (en) | 2019-02-16 | 2019-02-16 | Method for substituting and synthesizing (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109704981B (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007103996A1 (en) * | 2006-03-09 | 2007-09-13 | Bristol-Myers Squibb Company | 2-(aryloxy)acetamide factor viia inhibitors useful as anticoagulants |
| WO2009062087A1 (en) * | 2007-11-07 | 2009-05-14 | Neurocrine Biosciences, Inc. | Processes for the preparation of uracil derivatives |
| CN105218389A (en) * | 2014-06-30 | 2016-01-06 | 山东诚创医药技术开发有限公司 | One prepares the method for 3-amino-2-(the fluoro-3-methoxyphenyl of 2-)-2-butylene acid esters |
| CN107922401A (en) * | 2015-06-03 | 2018-04-17 | 百时美施贵宝公司 | For treating 4 hydroxyl 3 (heteroaryl) pyridine, the 2 ketone APJ activators of cardiovascular disorder |
-
2019
- 2019-02-16 CN CN201910118478.7A patent/CN109704981B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007103996A1 (en) * | 2006-03-09 | 2007-09-13 | Bristol-Myers Squibb Company | 2-(aryloxy)acetamide factor viia inhibitors useful as anticoagulants |
| WO2009062087A1 (en) * | 2007-11-07 | 2009-05-14 | Neurocrine Biosciences, Inc. | Processes for the preparation of uracil derivatives |
| CN105218389A (en) * | 2014-06-30 | 2016-01-06 | 山东诚创医药技术开发有限公司 | One prepares the method for 3-amino-2-(the fluoro-3-methoxyphenyl of 2-)-2-butylene acid esters |
| CN107922401A (en) * | 2015-06-03 | 2018-04-17 | 百时美施贵宝公司 | For treating 4 hydroxyl 3 (heteroaryl) pyridine, the 2 ketone APJ activators of cardiovascular disorder |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109704981A (en) | 2019-05-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110305018A (en) | A kind of preparation method of the bromo- 2- fluoronitrobenzene of 3- | |
| CN110183445A (en) | The synthetic method of Moxifloxacin and its derivative | |
| CN105175346B (en) | A kind of method of synthesizing rosuvastatin spit of fland calcium intermediate | |
| CN109704981B (en) | Method for substituting and synthesizing (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate | |
| CN110790689B (en) | Synthetic method of 1, 1-difluoro-2-isonitrile-ethyl phenyl sulfone compound | |
| CN110551144A (en) | Preparation method of amoxicillin | |
| CN105968040A (en) | Preparation method of ledipasvir intermediate | |
| CN109928933B (en) | 2-chloro-5-aldehyde pyrimidine and preparation method thereof | |
| CN104016954A (en) | Method for preparing and purifying nebivolol intermediate | |
| CN101591328A (en) | The chemical synthesis process of a kind of 2-bromothiophene and derivative thereof | |
| CN104987325B (en) | A kind of preparation method of voriconazole | |
| CN110003133B (en) | Chiral camphor sulfonyl hydrazide bifunctional catalyst and preparation method and application thereof | |
| CN108299466B (en) | Improved dolutegravir synthesis method | |
| CN105017284A (en) | Preparation method for ceftizoxime alapivoxil, intermediates thereof and preparation method for intermediates | |
| CN109666001B (en) | Method for preparing Elagolix intermediate by multi-step method | |
| CN106478518A (en) | A kind of preparation method of heptenoic acid ring pentyl ester derivant | |
| CN111747879A (en) | Large-process synthesis method of erexib | |
| CN109810064B (en) | Method for synthesizing Elagolix intermediate polysubstituted pyrimidine derivative by two-step method | |
| CN113087648B (en) | Synthesis method for improving purity of fludioxonil | |
| CN107629039A (en) | The preparation method and intermediate of deuterated acrylamide | |
| CN110862335B (en) | Preparation method of VEGFR2 selective inhibitor SU1498 | |
| CN108558862B (en) | Synthetic method and intermediate of anti-leukemia cancer cell active molecule | |
| CN109734616B (en) | Method for synthesizing (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate by two-step method | |
| CN114315747A (en) | Preparation method of 5, 5-dimethyl isoxazolidine-3-thioketone | |
| CN102659668B (en) | Method for synthesizing 1-alkyl-piperidine-4-sulfonyl benzylamine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |