CN114044759A - Application of novel Effevirgren reaction process technology - Google Patents
Application of novel Effevirgren reaction process technology Download PDFInfo
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- CN114044759A CN114044759A CN202111373657.9A CN202111373657A CN114044759A CN 114044759 A CN114044759 A CN 114044759A CN 202111373657 A CN202111373657 A CN 202111373657A CN 114044759 A CN114044759 A CN 114044759A
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- reaction process
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- 238000006243 chemical reaction Methods 0.000 title claims abstract description 14
- 238000005516 engineering process Methods 0.000 title claims abstract description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000002904 solvent Substances 0.000 claims abstract description 15
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims abstract description 14
- XPOQHMRABVBWPR-UHFFFAOYSA-N Efavirenz Natural products O1C(=O)NC2=CC=C(Cl)C=C2C1(C(F)(F)F)C#CC1CC1 XPOQHMRABVBWPR-UHFFFAOYSA-N 0.000 claims abstract description 11
- XPOQHMRABVBWPR-ZDUSSCGKSA-N efavirenz Chemical compound C([C@]1(C2=CC(Cl)=CC=C2NC(=O)O1)C(F)(F)F)#CC1CC1 XPOQHMRABVBWPR-ZDUSSCGKSA-N 0.000 claims abstract description 11
- 229960003804 efavirenz Drugs 0.000 claims abstract description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000000034 method Methods 0.000 claims abstract description 8
- 238000003747 Grignard reaction Methods 0.000 claims abstract description 5
- 238000012216 screening Methods 0.000 abstract description 4
- 238000007086 side reaction Methods 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 239000012046 mixed solvent Substances 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 150000004795 grignard reagents Chemical class 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 239000007818 Grignard reagent Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 241000725303 Human immunodeficiency virus Species 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 208000031886 HIV Infections Diseases 0.000 description 1
- 208000037357 HIV infectious disease Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229940122313 Nucleoside reverse transcriptase inhibitor Drugs 0.000 description 1
- 150000001345 alkine derivatives Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- -1 cyclopropylethynyl Chemical group 0.000 description 1
- 150000005171 halobenzenes Chemical class 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000012433 hydrogen halide Substances 0.000 description 1
- 229910000039 hydrogen halide Inorganic materials 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229940042402 non-nucleoside reverse transcriptase inhibitor Drugs 0.000 description 1
- 239000002726 nonnucleoside reverse transcriptase inhibitor Substances 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
- C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
- C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D265/18—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in position 2
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
Abstract
The invention discloses an application of a new efavirenz reaction process technology, belonging to the technical field of drug synthesis. The process of the present invention employs tetrahydrofuran and methyl tert-butyl ether as solvents for the grignard reaction. The invention realizes the solvent replacement of the reaction system by screening different solvent combinations and proportions, ensures no side reaction, has stable product quality and realizes the cost reduction.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to application of a novel Efavirenz reaction process technology.
Background
Efavirenz is chemically (S) -6-chloro-4- (cyclopropylethynyl) -1, 4-dihydro-4- (trifluoromethyl) -2H-3, 1-oxazaprinin-2-one and has the following structural formula:
efavirenz was approved by the U.S. FDA for use against Human Immunodeficiency Virus (HIV) infection in 1998 and is the first choice of non-nucleoside reverse transcriptase inhibitors (NNRTIs) recommended by current international guidelines for aids therapy. Efavirenz in combination with 2 nuclear-oxib reverse transcriptase inhibitor (NRTI) drugs can be used as a first-line treatment regimen against HIV infection.
In the preparation of efavirenz, the synthesis of key intermediates thereof relies on grignard reagents. Grignard reagents are generally prepared by reacting a halogenated hydrocarbon with magnesium powder in anhydrous diethyl ether or tetrahydrofuran (halobenzenes must be reacted in THF). The Grignard reagent can form a complex with oxygen atoms in ether or tetrahydrofuran, and active hydrogen-containing substances (such as water, alcohol, ammonia NH) such as absolute anhydrous carbon dioxide and ethanol are required in the preparation process3Hydrogen halide, terminal alkyne, etc.). For large-scale production, the solvent recovery rate is low and the cost is high.
Disclosure of Invention
Aiming at the technical problems, the invention aims to provide the application of the novel Effvirgren reaction process technology, realize the solvent replacement of a reaction system by screening different solvent combinations and proportions, ensure no side reaction, stabilize the product quality and reduce the cost.
In order to achieve the above purpose, the solution of the invention is:
the application of a new efavirenz Grignard reaction process technology adopts tetrahydrofuran and methyl tert-butyl ether as solvents of the Grignard reaction.
Further, the weight ratio of tetrahydrofuran to methyl t-butyl ether was 80%: 20% and 70%: 30% or 60%: 40 percent.
Further, the weight ratio of tetrahydrofuran to methyl t-butyl ether was 70%: 30 percent.
After the scheme is adopted, the method is simple in process and strong in operability, reaction phenomena are not abnormal through the mixed solvent in a certain proportion, the concentration of the Grignard reagent is well controlled, and the product quality standard is met. The invention reduces the production cost by using the mixed solvent, and is suitable for commercial application.
Drawings
FIG. 1 shows the results of different solvent ratios as a function of concentration in the present invention.
Detailed Description
The technical solution and the advantages of the present invention will be described in detail with reference to the accompanying drawings.
The invention aims to realize solvent replacement of a reaction system by screening different solvent combinations and proportions, ensure no side reaction, stabilize product quality and reduce cost.
The invention mainly considers the behavior of two mixed solvents possibly showing good solvent to the performance of a single solvent, the invention selects the components and the proportion of the mixed solvents to be only suitable for preparing the Grignard reagent by the key intermediate of the efavirenz produced by the applicant, can ensure that the original synthetic route is not changed, the raw materials are simple and easy to obtain, the raw materials can be recycled, the reaction condition is controllable, the side reaction is not caused by the replacement of the reagent, the synthetic yield is reduced, the synthetic cost is reduced, and the invention is suitable for industrial production and application.
The following examples are illustrative of the present invention. These examples are intended to illustrate the invention but are not to be construed as limiting the scope of the invention.
Example 1
Grignard reaction THF: screening of MTBE mixing ratio
As can be seen from the above table and FIG. 1, THF was selected: MTBE mixed solution, its mixing ratio is 70%: 30 percent (weight ratio), and the system has better fluidity, and the proportion is selected as the reaction solvent, so the production cost is reduced. Meanwhile, the quality is ensured, and the method is suitable for commercial application.
The method has the advantages of simple process and strong operability, no abnormal reaction phenomenon exists through the mixed solvent with a certain proportion, the concentration of the format reagent is well controlled, and the product quality standard is met. The invention reduces the production cost by using the mixed solvent, and is suitable for commercial application.
The above embodiments are only for illustrating the technical idea of the present invention, and the protection scope of the present invention is not limited thereby, and any modifications made on the basis of the technical scheme according to the technical idea of the present invention fall within the protection scope of the present invention.
Claims (3)
1. The application of the novel Efavirenz reaction process technology is characterized in that: the method adopts tetrahydrofuran and methyl tert-butyl ether as solvents for the Grignard reaction.
2. The use of the novel efavirenz reaction process technology of claim 1, characterized in that: the weight ratio of tetrahydrofuran to methyl tert-butyl ether in the solvent is 80%: 20% and 70%: 30% or 60%: 40 percent.
3. The use of the novel efavirenz reaction process technology of claim 2, characterized in that: the weight ratio of tetrahydrofuran to methyl tert-butyl ether in the solvent is 70%: 30 percent.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111373657.9A CN114044759A (en) | 2021-11-18 | 2021-11-18 | Application of novel Effevirgren reaction process technology |
| CN202210791841.3A CN115181072A (en) | 2021-11-18 | 2022-07-06 | Application of novel Effevirgren reaction process technology |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111373657.9A CN114044759A (en) | 2021-11-18 | 2021-11-18 | Application of novel Effevirgren reaction process technology |
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| CN114044759A true CN114044759A (en) | 2022-02-15 |
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| CN202111373657.9A Pending CN114044759A (en) | 2021-11-18 | 2021-11-18 | Application of novel Effevirgren reaction process technology |
| CN202210791841.3A Pending CN115181072A (en) | 2021-11-18 | 2022-07-06 | Application of novel Effevirgren reaction process technology |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115181072A (en) * | 2021-11-18 | 2022-10-14 | 盐城迪赛诺制药有限公司 | Application of novel Effevirgren reaction process technology |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106946718A (en) * | 2017-04-27 | 2017-07-14 | 武汉工程大学 | A kind of method for synthesizing efavirenz intermediate |
| CN109761829A (en) * | 2019-02-19 | 2019-05-17 | 盐城迪赛诺制药有限公司 | A kind of preparation method of high chiral purity efavirenz intermediate |
| CN111548317A (en) * | 2020-04-28 | 2020-08-18 | 苏州纪元康生物科技有限公司 | Efavirenz synthesis method and method for preparing intermediate thereof |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BR9916750A (en) * | 1998-11-19 | 2001-11-06 | Du Pont Pharm Co | Reverse transcriptase inhibiting compounds, pharmaceutical compositions, methods of treating infections by human immunodeficiency virus, processes for preparing the compound and its crystalline form |
| CN101928219B (en) * | 2010-06-08 | 2013-01-09 | 太仓浦源医药原料有限公司 | Method for preparing ethyl 2-oxo-4-phenylbutyrate |
| CN103880596B (en) * | 2012-12-21 | 2015-12-23 | 凌沛学 | A kind of preparation method of Nitric acid butoconazole intermediate of applicable suitability for industrialized production |
| CN108947855B (en) * | 2018-08-10 | 2021-10-22 | 江苏沙星化工有限公司 | Synthesis method of efavirenz key intermediate |
| CN111807968B (en) * | 2020-07-01 | 2022-05-20 | 复旦大学 | A kind of synthetic method of 2-(1-cyclohexenyl) ethylamine |
| CN114044759A (en) * | 2021-11-18 | 2022-02-15 | 盐城迪赛诺制药有限公司 | Application of novel Effevirgren reaction process technology |
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- 2021-11-18 CN CN202111373657.9A patent/CN114044759A/en active Pending
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- 2022-07-06 CN CN202210791841.3A patent/CN115181072A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106946718A (en) * | 2017-04-27 | 2017-07-14 | 武汉工程大学 | A kind of method for synthesizing efavirenz intermediate |
| CN109761829A (en) * | 2019-02-19 | 2019-05-17 | 盐城迪赛诺制药有限公司 | A kind of preparation method of high chiral purity efavirenz intermediate |
| CN111548317A (en) * | 2020-04-28 | 2020-08-18 | 苏州纪元康生物科技有限公司 | Efavirenz synthesis method and method for preparing intermediate thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115181072A (en) * | 2021-11-18 | 2022-10-14 | 盐城迪赛诺制药有限公司 | Application of novel Effevirgren reaction process technology |
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| CN115181072A (en) | 2022-10-14 |
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Application publication date: 20220215 |
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