CN101337906B - Method for preparing 4-methyl-3-oxo-N-phenyl-pentanamide - Google Patents
Method for preparing 4-methyl-3-oxo-N-phenyl-pentanamide Download PDFInfo
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- CN101337906B CN101337906B CN2008101410402A CN200810141040A CN101337906B CN 101337906 B CN101337906 B CN 101337906B CN 2008101410402 A CN2008101410402 A CN 2008101410402A CN 200810141040 A CN200810141040 A CN 200810141040A CN 101337906 B CN101337906 B CN 101337906B
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- methyl
- oxo
- preparation
- aniline
- phenyl
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- 238000000034 method Methods 0.000 title claims abstract description 11
- ADHRFDCBLJVNFO-UHFFFAOYSA-N 4-methyl-3-oxo-n-phenylpentanamide Chemical compound CC(C)C(=O)CC(=O)NC1=CC=CC=C1 ADHRFDCBLJVNFO-UHFFFAOYSA-N 0.000 title 1
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims abstract description 46
- 238000002360 preparation method Methods 0.000 claims abstract description 17
- LJFYRBGCOBFNBW-UHFFFAOYSA-N propanoyl 2-methylpropanoate Chemical compound CCC(=O)OC(=O)C(C)C LJFYRBGCOBFNBW-UHFFFAOYSA-N 0.000 claims abstract description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 16
- 238000006243 chemical reaction Methods 0.000 claims description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- 229940059260 amidate Drugs 0.000 claims description 7
- 238000004821 distillation Methods 0.000 claims description 7
- NPUKDXXFDDZOKR-LLVKDONJSA-N etomidate Chemical compound CCOC(=O)C1=CN=CN1[C@H](C)C1=CC=CC=C1 NPUKDXXFDDZOKR-LLVKDONJSA-N 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 6
- 239000002994 raw material Substances 0.000 claims description 5
- NSOXQYCFHDMMGV-UHFFFAOYSA-N Tetrakis(2-hydroxypropyl)ethylenediamine Chemical group CC(O)CN(CC(C)O)CCN(CC(C)O)CC(C)O NSOXQYCFHDMMGV-UHFFFAOYSA-N 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- 230000006837 decompression Effects 0.000 claims description 3
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 3
- 239000013078 crystal Substances 0.000 claims description 2
- 230000000694 effects Effects 0.000 claims description 2
- 239000012535 impurity Substances 0.000 abstract description 4
- 230000035484 reaction time Effects 0.000 abstract description 2
- 238000007112 amidation reaction Methods 0.000 abstract 1
- 238000007670 refining Methods 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 9
- 238000010438 heat treatment Methods 0.000 description 5
- 238000009413 insulation Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000001816 cooling Methods 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 238000005292 vacuum distillation Methods 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 description 1
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 229960005370 atorvastatin Drugs 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000001698 pyrogenic effect Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to the preparation of a medical intermediate, particularly a method for preparing 4-methyl-3-oxo-N-phenyl valeramide. Amidation reaction is performed between isobutyryl methyl acetate and aniline, and then 4-methyl-3-oxo-N-phenyl valeramide is obtained after being processed; the charge molar ratio between isobutyryl methyl acetate and aniline is 1:0.5 to 10. The method has simple and convenient operation and high yield which is not less than 96 percent; the obtained product has fewer impurities, and the content is more than 98 percent. In addition, aniline is recycled and reused easily, residual aniline can be removed during the refining process, and the reaction time is shortened.
Description
(1) technical field
The present invention relates to the preparation of medicine intermediate, the preparation method of particularly a kind of 4-methyl-3-oxo-N-phenyl valeramide.
(2) background technology
4-methyl-3-oxo-N-phenyl valeramide is preparation atorvastatin main ring 4-fluoro-α-(2-methyl isophthalic acid-oxygen propyl group)-γ-oxo-N, the key intermediate of β-diphenyl benzene yulocrotine.
Patent US5,097,04 5 discloses the synthetic of 4-methyl-3-oxo-N-phenyl valeramide: with toluene is reaction solvent; Quadrol is a catalyzer, isobutyryl methyl acetate and the aniline reaction that in batches adds, and constantly reflux steams the methyl alcohol that reaction generates in reaction process; After reaction finished, first air distillation went out a part of solvent, reduces to room temperature 85mmHg vacuum distillation recovered solvent and reaches 16h; Cooling, extracting in water organic layer; Reheat, Jia Shui, 20mmHg vacuum distillation recovered solvent, centrifugal, hexanaphthene rinsing, vacuum-drying gets product.
Research US 5,097,045 can find, for the methyl alcohol that makes generation in time steams, need improve constantly temperature of reaction in the process, and starting material and product can decompose under the situation of being heated for a long time, causes that impurity increases in the product, of poor quality, and content is 94-95%; Yield is low, has only 70-80%; Production process is unstable, and cost is high; The removal process complicacy of solvent toluene is loaded down with trivial details; And after need being distilled to premium grads again, to use the toluene that reclaims; Need to handle and can leave a large amount of height waste liquid that boils when distilling again, this all is unfavorable for the industriallization operation and produces, and has also brought certain environmental protection pressure.
(3) summary of the invention
The object of the present invention is to provide the preparation method of a kind of 4-methyl-3-oxo-N-phenyl valeramide, yield is high, and impurity in products is few, and cost is low, pollutes less and be convenient to suitability for industrialized production.
The technical scheme that the present invention adopts is following:
The preparation method of a kind of 4-methyl-3-oxo-N-phenyl valeramide, promptly isobutyryl methyl acetate and aniline carry out amidate action, and aftertreatment gets 4-methyl-3-oxo-N-phenyl valeramide; The isobutyryl methyl acetate is 1 with the amount of substance ratio that feeds intake of aniline: 0.5-10.
The present invention has saved special solvent; Excessive reaction raw materials to add is a solvent; Excessive raw material can also impel reaction to carry out to product generation direction simultaneously, also can further the methyl alcohol that generates be distilled in the reaction process, more helps reacting to the direction that generates product carrying out to improve yield; Overcome shortcomings such as the raw material that only depends on pyrogenic distillation to go out methyl alcohol and bring and reaction product decomposes, the impurity in products that obtains is few, content is high.Isobutyryl methyl acetate and aniline are easy to recovery of applied simultaneously, have overcome the many shortcoming of toluene as solvent recuperation, have shortened the reaction times.
Preferably, from practicing thrift the cost recovery aspect of the intact raw material of cost and unreacted, consider simultaneously to improve yield to greatest extent, the isobutyryl methyl acetate is 1 with the amount of substance ratio of aniline: 1.3-3.
Amidate action preferably carries out under the effect of organic amine catalyzer, and described organic amine catalyzer is preferably quadrol, triethylamine, diethylamine or 4-dimethylamino pyridine, is the best with the 4-dimethylamino pyridine again wherein.Catalyzer is 0.005-20 with the amount of substance ratio of isobutyryl methyl acetate: 100.
Temperature of reaction is 20-150 ℃, is preferably 80-120 ℃, takes into account the carrying out and methyl alcohol the steaming from reactive system of amidate action.
Atmospheric pressure reflux or distill out methyl alcohol in the amidate action process.
Described aftertreatment is reclaimed aniline for reaction finishes the back in 20-150 ℃ of preferred 50-118 ℃ of vacuum decompression distillation, and the residuum purified crystals promptly gets 4-methyl-3-oxo-N-phenyl valeramide.The 4-methyl that obtains-3-oxo-N-phenyl valeramide content is more than 98%, and yield is not less than 96%.
(4) embodiment:
Below with specific embodiment technical scheme of the present invention is described, but protection scope of the present invention is not limited thereto:
Embodiment 1
Start stirring after in the four-hole bottle of 1000ml dried and clean, dropping into aniline 380g; Drop into isobutyryl methyl acetate 250g, 4-dimethylamino pyridine (DMAP) 0.25g more successively; Stir and slowly be heated to 80 ℃ of insulations of interior temperature 1 hour after 10 minutes; Be warming up to 120 ℃ of insulations 1 hour then, the methyl alcohol that insulation fractionation reaction generates.Stop heating and be cooled to naturally slowly heating concentrating under reduced pressure recovery aniline and the intact isobutyryl methyl acetate of unreacted about 50 ℃ again; Vacuum pressure gauge shows that gauge pressure is-0.097Mpa; Temperature stops heating in the time of 40 ℃ to the distillation top, reclaims aniline with circulating water cooling in the still-process; In temperature drip sherwood oil 400g, 200g water and 25g hydrochloric acid (36wt%) mixed solution successively 60 ℃ the time, be cooled to 10 ℃, stirred crystallization is more than 2 hours, filter give money as a gift product 350g, HPLC analyzes content 98.4%, yield 97.8%.
Embodiment 2-6
The charging capacity of aniline changes 209g, 265g, 530g, 884g, 1414g respectively into, and other are with embodiment 1.
Embodiment 7-9
Catalyzer adopts quadrol, triethylamine, diethylamine respectively, and other are with embodiment 1.
Embodiment 10
Start stirring after in the four-hole bottle of 1000ml dried and clean, dropping into aniline 450g; Drop into isobutyryl methyl acetate 250g, 4-dimethylamino pyridine (DMAP) 0.30g more successively; Stir and slowly be heated to 90 ℃ of insulations of interior temperature 1 hour after 10 minutes; Be warming up to 120 ℃ of insulations 1 hour then, atmospheric pressure reflux reclaims the methyl alcohol that reaction generates.Stop heating and also be cooled to naturally about 60 ℃, the reheat concentrating under reduced pressure reclaims aniline and isobutyryl methyl acetate, and vacuum pressure gauge shows that gauge pressure is-0.099Mpa, pushes up temperature to distillation and in the time of 50 ℃, stops heating, reclaims aniline with circulating water cooling in the still-process; In temperature drip sherwood oil 400g, 200g water and 25g hydrochloric acid (36wt%) mixed solution successively 70 ℃ the time, be cooled to 20 ℃, stirred crystallization is more than 2 hours, filter give money as a gift product 346g, HPLC analyzes content 99.0%, yield 96.7%.
Embodiment 11-13
4-dimethylamino pyridine charging capacity changes 0.2g, 2.12g, 21.21g respectively into, and other is with embodiment 10.
Claims (10)
1. the preparation method of 4-methyl-3-oxo-N-phenyl valeramide, isobutyryl methyl acetate and aniline carry out amidate action, and aftertreatment promptly gets 4-methyl-3-oxo-N-phenyl valeramide; The isobutyryl methyl acetate is 1 with the amount of substance ratio that feeds intake of aniline: 1.3-10, it is characterized in that method has been saved special solvent, and be solvent with the excessive reaction raw materials aniline that adds.
2. the preparation method of 4-methyl as claimed in claim 1-3-oxo-N-phenyl valeramide is characterized in that the isobutyryl methyl acetate and the amount of substance ratio of aniline are 1: 1.3-3.
3. according to claim 1 or claim 2 the preparation method of 4-methyl-3-oxo-N-phenyl valeramide is characterized in that amidate action carries out under the effect of organic amine catalyzer.
4. the preparation method of 4-methyl as claimed in claim 3-3-oxo-N-phenyl valeramide is characterized in that described organic amine catalyzer is quadrol, triethylamine, diethylamine or 4-dimethylamino pyridine.
5. the preparation method of 4-methyl as claimed in claim 4-3-oxo-N-phenyl valeramide is characterized in that the catalyzer and the amount of substance ratio of isobutyryl methyl acetate are 0.005-20: 100.
6. like the preparation method of claim 1 or 2 or 5 described 4-methyl-3-oxo-N-phenyl valeramides, it is characterized in that temperature of reaction is 20-150 ℃.
7. the preparation method of 4-methyl as claimed in claim 6-3-oxo-N-phenyl valeramide is characterized in that temperature of reaction is 80-120 ℃.
8. the preparation method of 4-methyl as claimed in claim 7-3-oxo-N-phenyl valeramide is characterized in that in the amidate action process atmospheric pressure reflux or distills out methyl alcohol.
9. the preparation method of 4-methyl as claimed in claim 7-3-oxo-N-phenyl valeramide; It is characterized in that reclaiming aniline in 20-150 ℃ of vacuum decompression distillation after described aftertreatment is for the reaction end, the residuum purified crystals promptly gets 4-methyl-3-oxo-N-phenyl valeramide.
10. the preparation method of 4-methyl as claimed in claim 9-3-oxo-N-phenyl valeramide is characterized in that reclaiming aniline in 50-118 ℃ of vacuum decompression distillation.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008101410402A CN101337906B (en) | 2008-08-15 | 2008-08-15 | Method for preparing 4-methyl-3-oxo-N-phenyl-pentanamide |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008101410402A CN101337906B (en) | 2008-08-15 | 2008-08-15 | Method for preparing 4-methyl-3-oxo-N-phenyl-pentanamide |
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| CN101337906A CN101337906A (en) | 2009-01-07 |
| CN101337906B true CN101337906B (en) | 2012-06-27 |
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| CN2008101410402A Expired - Fee Related CN101337906B (en) | 2008-08-15 | 2008-08-15 | Method for preparing 4-methyl-3-oxo-N-phenyl-pentanamide |
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Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106397241A (en) * | 2016-08-23 | 2017-02-15 | 杨锋 | Eco-friendly aftertreatment method of 4-methyl-3-oxo-N-phenylvaleramide |
| CN113896646B (en) * | 2020-07-06 | 2023-06-02 | 浙江海森药业股份有限公司 | Efficient green preparation method of 4-methyl-3-oxo-N-phenyl valeramide |
| CN112457210A (en) * | 2020-11-06 | 2021-03-09 | 上海应用技术大学 | Preparation method of 3-oxo-N- (4-trifluoromethylphenyl) butanamide |
| CN114213269B (en) * | 2021-12-10 | 2024-04-05 | 江苏阿尔法药业股份有限公司 | Preparation method of atorvastatin calcium intermediate |
| CN114213270B (en) * | 2021-12-17 | 2024-05-28 | 江苏阿尔法药业股份有限公司 | Method for synthesizing atorvastatin calcium intermediate by using continuous flow micro-channel reactor |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1223647A (en) * | 1996-07-29 | 1999-07-21 | 沃尼尔·朗伯公司 | Improved process for the synthesis of protected esters of (S)-3,4-dihydroxytubyric acid |
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- 2008-08-15 CN CN2008101410402A patent/CN101337906B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1223647A (en) * | 1996-07-29 | 1999-07-21 | 沃尼尔·朗伯公司 | Improved process for the synthesis of protected esters of (S)-3,4-dihydroxytubyric acid |
Non-Patent Citations (1)
| Title |
|---|
| rajeshwar reddy sagyam et al..an efficient synthesis of highly substituted pyrrole and bis pyrrole derivatives.《journal of heterocyclic chemistry》.2007,第44卷(第4期),923-926. * |
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| CN101337906A (en) | 2009-01-07 |
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Owner name: HENAN YUCHEN PHARMACEUTICAL CO., LTD. Free format text: FORMER NAME: HEBEI YUCHEN FINE CHEMICAL CO., LTD. |
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Address after: Zhang pan town of Xuchang city of Henan Province in 461100 before Wang Village Patentee after: HENAN YUCHEN PHARMACEUTICAL Co.,Ltd. Address before: Zhang pan town of Xuchang city of Henan Province in 461100 before Wang Village Patentee before: Henan Yuchen Fine Chemical Co.,Ltd. |
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Granted publication date: 20120627 |