CN116063179A - Synthesis method of 4-methoxy methyl acetoacetate - Google Patents
Synthesis method of 4-methoxy methyl acetoacetate Download PDFInfo
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- CN116063179A CN116063179A CN202310133509.2A CN202310133509A CN116063179A CN 116063179 A CN116063179 A CN 116063179A CN 202310133509 A CN202310133509 A CN 202310133509A CN 116063179 A CN116063179 A CN 116063179A
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- methoxy methyl
- methyl acetoacetate
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- 238000001308 synthesis method Methods 0.000 title description 7
- 238000000034 method Methods 0.000 claims abstract description 26
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims abstract description 15
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims abstract description 13
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 13
- ICPWFHKNYYRBSZ-UHFFFAOYSA-M 2-methoxypropanoate Chemical compound COC(C)C([O-])=O ICPWFHKNYYRBSZ-UHFFFAOYSA-M 0.000 claims abstract description 10
- 239000003960 organic solvent Substances 0.000 claims abstract description 10
- 239000003513 alkali Substances 0.000 claims abstract description 9
- 238000010438 heat treatment Methods 0.000 claims abstract description 5
- 239000002904 solvent Substances 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 37
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 33
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 20
- 239000000243 solution Substances 0.000 claims description 15
- 238000010791 quenching Methods 0.000 claims description 13
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 12
- 230000000171 quenching effect Effects 0.000 claims description 11
- 239000012295 chemical reaction liquid Substances 0.000 claims description 9
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 7
- 239000012043 crude product Substances 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- -1 methoxyl methyl Chemical group 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 238000004321 preservation Methods 0.000 claims description 2
- 230000001105 regulatory effect Effects 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 14
- 238000003786 synthesis reaction Methods 0.000 abstract description 8
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 3
- MDEDOIDXVJXDBW-UHFFFAOYSA-N methoxymethyl acetate Chemical compound COCOC(C)=O MDEDOIDXVJXDBW-UHFFFAOYSA-N 0.000 abstract description 2
- 238000005580 one pot reaction Methods 0.000 abstract description 2
- 238000004064 recycling Methods 0.000 abstract description 2
- 239000002351 wastewater Substances 0.000 abstract description 2
- 239000007788 liquid Substances 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 230000002378 acidificating effect Effects 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- RHWKPHLQXYSBKR-BMIGLBTASA-N dolutegravir Chemical compound C([C@@H]1OCC[C@H](N1C(=O)C1=C(O)C2=O)C)N1C=C2C(=O)NCC1=CC=C(F)C=C1F RHWKPHLQXYSBKR-BMIGLBTASA-N 0.000 description 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 3
- 229960002542 dolutegravir Drugs 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 239000002253 acid Substances 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- HFLMYYLFSNEOOT-UHFFFAOYSA-N methyl 4-chloro-3-oxobutanoate Chemical compound COC(=O)CC(=O)CCl HFLMYYLFSNEOOT-UHFFFAOYSA-N 0.000 description 2
- QGBPKJFJAVDUNC-UHFFFAOYSA-N methyl 4-methoxy-3-oxobutanoate Chemical compound COCC(=O)CC(=O)OC QGBPKJFJAVDUNC-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 229960004742 raltegravir Drugs 0.000 description 2
- CZFFBEXEKNGXKS-UHFFFAOYSA-N raltegravir Chemical compound O1C(C)=NN=C1C(=O)NC(C)(C)C1=NC(C(=O)NCC=2C=CC(F)=CC=2)=C(O)C(=O)N1C CZFFBEXEKNGXKS-UHFFFAOYSA-N 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 1
- 229940124321 AIDS medicine Drugs 0.000 description 1
- 229940099797 HIV integrase inhibitor Drugs 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000003084 hiv integrase inhibitor Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 229940124524 integrase inhibitor Drugs 0.000 description 1
- 239000002850 integrase inhibitor Substances 0.000 description 1
- YDCHPLOFQATIDS-UHFFFAOYSA-N methyl 2-bromoacetate Chemical compound COC(=O)CBr YDCHPLOFQATIDS-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000002910 solid waste Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229940014075 tivicay Drugs 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/48—Separation; Purification; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/48—Separation; Purification; Stabilisation; Use of additives
- C07C67/52—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation
- C07C67/54—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation by distillation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/48—Separation; Purification; Stabilisation; Use of additives
- C07C67/58—Separation; Purification; Stabilisation; Use of additives by liquid-liquid treatment
Abstract
The invention relates to the technical field of organic synthesis, in particular to a method for synthesizing 4-methoxy methyl acetoacetate; the method comprises the following steps: in the presence of a solvent, methyl methoxyacetate and methyl acetate react under the action of alkali by heating to generate 4-methoxy methyl acetoacetate. The raw materials of methoxy methyl acetate and methyl acetate used in the first step of the invention have low price, and the raw materials are supplied in a large quantity in the market, so that the raw material supply is ensured. The first step of the invention has less waste water, convenient treatment and recycling of the organic solvent, thereby effectively reducing the cost. The invention only relates to one-step reaction, and has lower production cost. The purity of the obtained product is more than 99 percent, and the yield is more than 70 percent; and the raw materials and the reagents are cheap, and the method is suitable for industrial mass production.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a method for synthesizing 4-methoxy methyl acetoacetate.
Background
4-methoxy methyl acetoacetate is an important medical intermediate compound, and is mainly used for synthesizing a novel anti-AIDS drug Dolutegravir at present, wherein Dolutegravir is an anti-AIDS integrase inhibitor approved by the FDA in the United states in 2013 by GSK company, and the product is named as Tivicay. Dolutegravir is the 4 th new drug marketed in 2013 by GSK company as an FDA priority rating drug. Compared with the existing HIV integrase inhibitors of raltegraVir (raltegraVir) and etiquevir (slvitegravir), the drug has higher safety. The quality and price of the 4-methoxy methyl acetoacetate serving as a starting material for synthesizing the dolutegradvir have great influence on further synthesis of the dolutegradvir. Therefore, the method has a certain significance in researching the synthesis of the 4-methoxy methyl acetoacetate. EP3480201, CN105418420, CN104478719, US4564696, US6403804, US4892966 and the like report preparation methods using methyl 4-chloroacetoacetate as raw materials, and the method has the advantages of mild reaction, simple operation and good yield and purity. But the raw material methyl 4-chloroacetoacetate is expensive, resulting in high production cost and less suppliers, resulting in unstable raw material supply. Journal of the American Chemical Society,1954 report that methyl 4-methoxyacetoacetate was obtained by reacting methyl methoxyacetate and methyl bromoacetate as starting materials with zinc powder to form a zinc reagent. Although the raw materials of the method are cheap, a large amount of zinc powder is used in the method, a large amount of solid waste is generated, and the treatment is difficult. CN111004121,2020, a reports a preparation method using methyl haloacetate as a raw material, the raw material of the method is cheap and easy to obtain, the yield and purity are better, but two steps of reaction are needed, the production cost is increased, and a large amount of acid is needed for the second step of hydrolysis, so that more waste acid is caused, the treatment is difficult, and meanwhile, the reaction temperature is higher, so that the corrosion to equipment is serious.
Disclosure of Invention
The purpose of the invention is that: overcomes the defects in the prior art, and provides a synthesis method of the 4-methoxy methyl acetoacetate which is convenient to operate and lower in cost and is suitable for industrial production.
In order to achieve the above object, the present invention adopts the following technical scheme:
a method for synthesizing methyl 4-methoxy acetoacetate, the method comprising: in the presence of a solvent, methyl methoxyacetate and methyl acetate react under the action of alkali by heating to generate 4-methoxy methyl acetoacetate.
Further, the method specifically comprises the following steps: sequentially adding methyl methoxyacetate and an organic solvent into a reaction container, adding alkali in batches under stirring, dropwise adding methyl acetate at a proper temperature after the addition, continuously preserving heat for reaction after the addition is finished, heating to a proper temperature, continuously reacting to completion, cooling the reaction liquid to room temperature, slowly adding into a hydrochloric acid aqueous solution for quenching reaction, and performing post-treatment to obtain the 4-methoxy methyl acetoacetate.
Further, the organic solvent is selected from one of toluene or xylene.
Further, the base is sodium methoxide.
Further, the proper temperature is 60-65 ℃ when methyl acetate is added dropwise, the reaction is continued for 4 hours at 60-65 ℃, the temperature is raised to 85-90 ℃ after the heat preservation reaction is finished, and the reaction is continued until the reaction is complete.
Further, the mol ratio of the dosage of the methoxyl methyl acetate to the dosage of the methoxyl alkali is 1 (1.2-2.4) to the dosage of the methoxyl alkali is 2.0-4.0.
Further, the reaction is quenched by slowly adding the mixture into an aqueous hydrochloric acid solution, and the method comprises the following steps: and (3) regulating the pH value of the solution to 3-4 by adopting a cold hydrochloric acid solution, wherein the temperature of the reaction solution is controlled to be less than 30 ℃ in the quenching process.
Further, the post-processing includes the steps of: separating, extracting the water phase with organic solvent, mixing the organic solvents, desolventizing to obtain crude product, rectifying and purifying to obtain pure 4-methoxy methyl acetoacetate.
The technical scheme adopted by the invention has the following beneficial effects:
the raw materials of methoxy methyl acetate and methyl acetate used in the first step of the invention have low price, and the raw materials are supplied in a large quantity in the market, so that the raw material supply is ensured.
The first step of the invention has less waste water, convenient treatment and recycling of the organic solvent, thereby effectively reducing the cost.
The invention only relates to one-step reaction, and has lower production cost. The purity of the obtained product is more than 99 percent, and the yield is more than 70 percent; and the raw materials and the reagents are cheap, and the method is suitable for industrial mass production.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
Example 1
The synthesis method of the 4-methoxy methyl acetoacetate comprises the following steps:
synthesis of Compound (I)
Into a 500ml four-necked flask, 250ml of toluene and 52g (0.5 mol) of methyl methoxyacetate were charged, and the solution was stirred. 81.0g (1.5 mol) of sodium methoxide are added in portions at 15 to 25 ℃. After the temperature is raised to 60 ℃ at the inner temperature, 44.5g (0.6 mol) of methyl acetate is dripped, the reaction is carried out for 4 hours after the temperature is raised to 85-90 ℃ at the inner temperature, the reaction is carried out for 24 hours after the GC detection reaction is completed, the reaction liquid is cooled to the room temperature, the reaction liquid is stirred and added into a cold aqueous hydrochloric acid solution to quench the reaction, the system is kept to be acidic, the PH is controlled to be 3-4 again, the inner temperature is controlled to be lower than 30 ℃, after the quenching is completed, the liquid is separated, the aqueous phase is extracted for three times by toluene, the organic phases are combined, the saturated brine is washed for one time, the toluene is recovered after the dissolution, 68.3g of a brownish black crude product is obtained, 50.8g of colorless liquid is obtained after rectification and purification, the yield is 69.5%, and the GC purity is 99.1%.
Example 2
The synthesis method of the 4-methoxy methyl acetoacetate comprises the following steps:
synthesis of Compound (I)
250ml of xylene and 52g (0.5 mol) of methyl methoxyacetate were placed in a 500ml four-necked flask, and the solution was stirred. 108.0g (2.0 mol) of sodium methoxide are added in portions at 15 to 25 ℃. Adding dropwise 74.08g (1.0 mol) of methyl acetate to the mixture, reacting for 4 hours at a temperature of between 85 and 90 ℃ after the mixture is heated to the internal temperature of 60 ℃, cooling the reaction liquid to the room temperature after the GC detection reaction is completed, stirring the reaction liquid, adding the reaction liquid into a cold aqueous hydrochloric acid solution to quench the reaction, keeping the system to be acidic, controlling the pH value to be 3 to 4 again, controlling the internal temperature to be lower than 30 ℃, separating the liquid after the quenching is completed, extracting the aqueous phase with dimethylbenzene for three times, merging the organic phases, washing the organic phases with saturated brine once, desolventizing and recovering the dimethylbenzene to obtain 70.3g of brown-black crude product, rectifying and purifying to obtain 51.8g of colorless liquid, wherein the yield is 70.9% and the GC purity is 98.9%.
Example 3
The synthesis method of the 4-methoxy methyl acetoacetate comprises the following steps:
synthesis of Compound (I)
866g of toluene and 208g (2.0 mol) of methyl methoxyacetate were placed in a 5000ml four-necked flask, and the solution was stirred. 259.3g (4.8 mol) of sodium methoxide were added in portions at 15 to 25 ℃. After the temperature is raised to 60 ℃ at the inner temperature, 355.6g (4.8 mol) of methyl acetate is dripped, the reaction is carried out for 4 hours after the addition, then the temperature is raised to 85-90 ℃ for reaction for 24 hours, after the GC detection reaction is basically complete, the reaction liquid is cooled to room temperature, stirred and added into cold aqueous hydrochloric acid solution for quenching reaction, the system is kept to be acidic, the PH is controlled to be 3-4 again, the inner temperature is controlled to be lower than 30 ℃, after the quenching is completed, the liquid is separated, the aqueous phase is extracted for three times by toluene, the organic phases are combined, saturated brine is used for washing once, the toluene is recovered after the precipitation, 263.3g of a brown-black crude product is obtained, 211.4g of colorless liquid is obtained after rectification and purification, the yield is 72.3%, and the GC purity is 99.3%.
Example 4
The synthesis method of the 4-methoxy methyl acetoacetate comprises the following steps:
synthesis of Compound (I)
1530kg of toluene and 350kg of methyl methoxyacetate are added into a 3000L reaction kettle, and the solution is stirred. 362.5kg of sodium methoxide are added in portions at 15-25 ℃. After the reaction is completed and heated to the internal temperature of 60 ℃, 500kg of methyl acetate is dripped, the reaction is completed and kept for 4 hours, then the temperature is raised to the internal temperature of 85-90 ℃ for reaction for 24 hours, after the GC detection reaction is basically complete, the reaction liquid is cooled to room temperature, stirred and added into cold aqueous hydrochloric acid solution for quenching reaction, the system is kept to be acidic, the PH is controlled to be 3-4 again, the internal temperature is controlled to be lower than 30 ℃, after the quenching is completed, the liquid is separated, the aqueous phase is extracted with toluene for three times, the organic phase is combined, the toluene is removed and recovered, 437.4kg of brown-black crude product is obtained, 346.7kg of colorless liquid is obtained through rectification and purification, the yield is 74.2%, and the GC purity is 99.2%.
The above examples illustrate only a few embodiments of the invention, which are described in detail and are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of the invention should be assessed as that of the appended claims.
Claims (8)
1. A method for synthesizing 4-methoxy methyl acetoacetate is characterized in that: the method comprises the following steps: in the presence of a solvent, methyl methoxyacetate and methyl acetate react under the action of alkali by heating to generate 4-methoxy methyl acetoacetate.
2. The method for synthesizing 4-methoxy methyl acetoacetate according to claim 1, wherein: the method specifically comprises the following steps: sequentially adding methyl methoxyacetate and an organic solvent into a reaction container, adding alkali in batches under stirring, dropwise adding methyl acetate at a proper temperature after the addition, continuously preserving heat for reaction after the addition is finished, heating to a proper temperature, continuously reacting to completion, cooling the reaction liquid to room temperature, slowly adding into a hydrochloric acid aqueous solution for quenching reaction, and performing post-treatment to obtain the 4-methoxy methyl acetoacetate.
3. The method for synthesizing 4-methoxy methyl acetoacetate according to claim 2, wherein: the organic solvent is selected from one of toluene or xylene.
4. The method for synthesizing 4-methoxy methyl acetoacetate according to claim 2, wherein: the alkali is sodium methoxide.
5. The method for synthesizing 4-methoxy methyl acetoacetate according to claim 2, wherein: the proper temperature is 60-65 ℃ when methyl acetate is added dropwise, the reaction is continued for 4 hours at 60-65 ℃, the temperature is raised to 85-90 ℃ after the heat preservation reaction is finished, and the reaction is continued until the reaction is complete.
6. The method for synthesizing 4-methoxy methyl acetoacetate according to claim 2, wherein: the mol ratio of the dosage of the methoxyl methyl acetate to the dosage of the methoxyl alkali is 1 (1.2-2.4) (2.0-4.0).
7. The method for synthesizing 4-methoxy methyl acetoacetate according to claim 2, wherein: the quenching reaction is carried out by slowly adding into hydrochloric acid aqueous solution: and (3) regulating the pH value of the solution to 3-4 by adopting a cold hydrochloric acid solution, wherein the temperature of the reaction solution is controlled to be less than 30 ℃ in the quenching process.
8. The method for synthesizing 4-methoxy methyl acetoacetate according to claim 2, wherein: the post-treatment comprises the following steps: separating, extracting the water phase with organic solvent, mixing the organic solvents, desolventizing to obtain crude product, rectifying and purifying to obtain pure 4-methoxy methyl acetoacetate.
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| CN202310133509.2A CN116063179A (en) | 2023-02-20 | 2023-02-20 | Synthesis method of 4-methoxy methyl acetoacetate |
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| CN202310133509.2A CN116063179A (en) | 2023-02-20 | 2023-02-20 | Synthesis method of 4-methoxy methyl acetoacetate |
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101175730A (en) * | 2005-05-16 | 2008-05-07 | 杜邦公司 | Method for preparing substituted pyrimidines |
| WO2010106016A1 (en) * | 2009-03-17 | 2010-09-23 | Glaxo Group Limited | Pyrimidine derivatives used as itk inhibitors |
| CN109456186A (en) * | 2018-12-25 | 2019-03-12 | 南京莱克施德药业有限公司 | A kind of preparation process of 4- methoxyl group methyl acetoacetate |
| CN109503380A (en) * | 2018-10-29 | 2019-03-22 | 南京杰运医药科技有限公司 | The synthetic method of 4- alkoxy acetoacetates |
| CN111004121A (en) * | 2019-12-09 | 2020-04-14 | 南京杰运医药科技有限公司 | Preparation method of 4-alkoxy acetoacetic ester compound |
| CN114702425A (en) * | 2022-03-28 | 2022-07-05 | 苏州汉酶生物技术有限公司 | Preparation method of (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivative and intermediate |
| CN114728975A (en) * | 2019-09-16 | 2022-07-08 | 武田药品工业株式会社 | Azole-fused pyridazin-3 (2H) -one derivatives |
-
2023
- 2023-02-20 CN CN202310133509.2A patent/CN116063179A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101175730A (en) * | 2005-05-16 | 2008-05-07 | 杜邦公司 | Method for preparing substituted pyrimidines |
| WO2010106016A1 (en) * | 2009-03-17 | 2010-09-23 | Glaxo Group Limited | Pyrimidine derivatives used as itk inhibitors |
| CN109503380A (en) * | 2018-10-29 | 2019-03-22 | 南京杰运医药科技有限公司 | The synthetic method of 4- alkoxy acetoacetates |
| CN109456186A (en) * | 2018-12-25 | 2019-03-12 | 南京莱克施德药业有限公司 | A kind of preparation process of 4- methoxyl group methyl acetoacetate |
| CN114728975A (en) * | 2019-09-16 | 2022-07-08 | 武田药品工业株式会社 | Azole-fused pyridazin-3 (2H) -one derivatives |
| CN111004121A (en) * | 2019-12-09 | 2020-04-14 | 南京杰运医药科技有限公司 | Preparation method of 4-alkoxy acetoacetic ester compound |
| CN114702425A (en) * | 2022-03-28 | 2022-07-05 | 苏州汉酶生物技术有限公司 | Preparation method of (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivative and intermediate |
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