CN100412065C - 4-(p-fluorophenyl)-6-isopropyl-2-methylaminopyrimidine-5-methyl formate synthesis method - Google Patents
4-(p-fluorophenyl)-6-isopropyl-2-methylaminopyrimidine-5-methyl formate synthesis method Download PDFInfo
- Publication number
- CN100412065C CN100412065C CNB2004100203144A CN200410020314A CN100412065C CN 100412065 C CN100412065 C CN 100412065C CN B2004100203144 A CNB2004100203144 A CN B2004100203144A CN 200410020314 A CN200410020314 A CN 200410020314A CN 100412065 C CN100412065 C CN 100412065C
- Authority
- CN
- China
- Prior art keywords
- reaction
- methyl
- isobutyryl
- fluorophenyl
- described method
- 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.)
- Expired - Fee Related
Links
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to the field of chemistry, particularly to a synthesis method for 4-(p-fluorophenyl)-6-isoproylethyl-2-methylaminopyrimidin-5-methyl formate. The present invention introduces new hydrochloric acid methylguanidine used as raw materials. Thereby, reaction procedures are reduced greatly, pollution is reduced, and the controllability of reaction is enhanced.
Description
Technical field
The present invention relates to chemical field, be specifically related to the synthetic of 4-(to fluorophenyl)-6-sec.-propyl-2-methylamino pyrimidine-5-methyl-formiate.
Background technology
(Rosuvastatin is the blood lipid-lowering medicine of the wild adopted company of Japanese salt exploitation superstatin), has the effect that reduces cholesterol levels in the blood, is used for the prevention and the treatment of cardiovascular and cerebrovascular diseases clinically in super his spit of fland.Compare with the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor that other have gone on the market, when its maximum characteristics are reducing cholesterol, have lower rhabdomyolysis effect.Good market prospects.
With regard to it is synthetic, more existing at present reports.Though some difference is seen on the whole between each method, the step that relates to of reaction and intermediate still have a lot of similarities.4-(to fluorophenyl)-6-sec.-propyl-2-methylamino pyrimidine-5-methyl-formiate is exactly one of numerous important intermediates.
It is that raw material carries out condensation reaction earlier, encircles dehydrogenation, separates through sulphur oxidation and ammonia with the cyclization of sulfuric acid methyl-isothiourea, process again that European patent EP 0521471 discloses with 4-fluorobenzaldehyde and isobutyryl ethyl acetate, obtains the synthetic method of 4-(to fluorophenyl)-6-sec.-propyl-2-methylamino pyrimidine-5-ethyl formate through five steps.Synthetic route is as follows:
As can be seen, this method steps is longer, just can obtain 4-(to fluorophenyl)-6-sec.-propyl-2-methylamino pyrimidine-5-ethyl formate through five steps.
The inventor finds through test of long duration, utilizes the hydrochloride methyl guanidine to replace the sulfuric acid methyl-isothiourea to carry out cyclization, only needs for two steps just can obtain this intermediate 4-(to fluorophenyl)-6-sec.-propyl-2-methylamino pyrimidine-5-methyl-formiate (ethyl ester).
Summary of the invention
The object of the invention is to overcome and generates the long shortcoming of 4-(to fluorophenyl)-6-sec.-propyl-2-methylamino pyrimidine-5-ethyl formate (methyl esters) reactions steps in the existing method, and the new synthetic method of relevant this intermediate is provided.
Synthetic method concrete steps of the present invention are as follows:
Step 1, (E/Z)-2-isobutyryl-to the preparation of fluorobenzene methyl acrylate
4-fluorobenzaldehyde, isobutyryl methyl acetate, acetate, piperidines are dissolved in the benzene, and reflux is told moisture, and reaction finishes, and cooling is with saturated brine washing, anhydrous magnesium sulfate drying.Filter, concentrate, cut is collected in underpressure distillation, (E/Z)-2-isobutyryl-to the fluorobenzene methyl acrylate.
The preparation of step 2,4-(to fluorophenyl)-6-sec.-propyl-2-methylamino pyrimidine-5-methyl-formiate
In reaction flask, add the product that obtains in the above-mentioned steps---(E/Z)-the 2-isobutyryl-to fluorobenzene methyl acrylate, hydrochloride methyl guanidine, dimethyl formamide, heating is reacted, reaction is finished, add potassium permanganate, proceed reaction again, reaction is finished, and adds ethyl acetate and less water, filters, tell ethyl acetate layer, the water layer ethyl acetate extraction, washing, anhydrous magnesium sulfate drying, filter, concentrate, silica gel column chromatography gets 4-(to fluorophenyl)-6-sec.-propyl-2-methylamino pyrimidine-5-methyl-formiate.
Wherein concrete reaction conditions is: the 4-fluorobenzaldehyde in the step 1 and the mol ratio of isobutyryl methyl acetate are 1: 0.8-1.4 is preferably 1: 1.2; The cut of 125--127 ℃/0.5mmHg is collected in underpressure distillation; (E/Z)-2-isobutyryl in the step 2-to the mol ratio of fluorobenzene methyl acrylate and hydrochloride methyl guanidine is 1: 0.8-2 is preferably 1: 1.4; Temperature of reaction is controlled between 80 ℃-140 ℃, preferred 115 ℃.
Method synthetic route synoptic diagram of the present invention is as follows:
Synthetic method of the present invention is compared with European patent EP 0521471, has following advantage:
● reactions steps shortens: the bright target compound of the synthetic this law of existing European patent (EP 0521471) method needed for five steps, new raw material---the hydrochloride methyl guanidine replaces the ring and the reaction of original isothiourea and present method is owing to having introduced, and makes whole steps shorten greatly.Meanwhile, reaction yield is compared with original method, almost without any variation.
● pollute little, controllability enhancing: the present invention has introduced the guanidine compound that has amido, the ring and the reaction of the isothiourea of sulphur atom have been replaced containing in the prior art, owing to directly carried out aminating reaction, saved the process of desulfurization in the prior art, thereby avoided pollution to environment.Simultaneously, reactions steps shortens, and controlling unit reduces, and controllability strengthens.
Embodiment
Embodiment 1
Step 1, (E/Z)-2-isobutyryl-to the preparation of fluorobenzene methyl acrylate
4-fluorobenzaldehyde 124.1g (1.0mol), isobutyryl methyl acetate 172.9g (1.2mol), acetate 60g (1.0mol), piperidines 85.1g (1.0mol) are dissolved in the 600ml benzene; reflux is told moisture; reaction in about 10 hours finishes; cooling; with saturated brine washing, anhydrous magnesium sulfate drying.Filter, concentrate, 125--127 ℃/0.5mmHg cut is collected in underpressure distillation, gets product, yield 83.2%.
The preparation of step 2,4-(to fluorophenyl)-6-sec.-propyl-2-methylamino pyrimidine-5-methyl-formiate
In reaction flask, add and go up step product 2.5g (0.01mol), hydrochloride methyl guanidine 1.53g (0.014mol), dimethyl formamide 15ml.In 115 ℃ of reactions 20 hours, add potassium permanganate 4g, reacted 3 hours, reaction is finished, and adds ethyl acetate and less water, filters, tell ethyl acetate layer, water layer ethyl acetate extraction, washing, anhydrous magnesium sulfate drying, filter, concentrate silica gel column chromatography (eluent: trichloromethane), get product, yield 28.4%.
Appraising datum: mp:88.5-90 ℃
1HNMR (trichloromethane) δ: 1.20 (d, 6H); 2.99 (d, 3H); 3.09 (m, 1H); 3.56 (s, 3H); 5.30 (s, 1H); 7.03 (m, 2H); 7.51 (m, 2H)
Embodiment 2
Step 1, (E/Z)-2-isobutyryl-to the preparation of fluorobenzene methyl acrylate
4-fluorobenzaldehyde 124.1g (1.0mol), isobutyryl methyl acetate 115.3g (0.8mol), acetate 60g (1.0mol) piperidines 85.1g (1.0mol) are dissolved in the 600ml benzene; reflux is told moisture; reaction in about 10 hours finishes; cooling; with saturated brine washing, anhydrous magnesium sulfate drying.Filter, concentrate, 125--127 ℃/0.5mmHg cut is collected in underpressure distillation, gets product, yield 77.3%.
The preparation of step 2,4-(to fluorophenyl)-6-sec.-propyl-2-methylamino pyrimidine-5-methyl-formiate
In reaction flask, add and go up step product 2.5g (0.01mol), hydrochloride methyl guanidine 0.88g (0.008mol), dimethyl formamide 15ml.In 115 ℃ of reactions 20 hours, add potassium permanganate 4g, reacted 3 hours, reaction is finished, and adds ethyl acetate and less water, filters, tell ethyl acetate layer, water layer ethyl acetate extraction, washing, anhydrous magnesium sulfate drying, filter, concentrate silica gel column chromatography (eluent: trichloromethane), get product, yield 23.1%.
Appraising datum: mp:88.5-90 ℃
1HNMR (trichloromethane) δ: 1.20 (d, 6H); 2.99 (d, 3H); 3.09 (m, 1H); 3.56 (s, 3H); 5.30 (s, 1H); 7.03 (m, 2H); 7.51 (m, 2H)
Embodiment 3
Step 1, (E/Z)-2-isobutyryl-to the preparation of fluorobenzene methyl acrylate
4-fluorobenzaldehyde 124.1g (1.0mol), isobutyryl methyl acetate 144.1g (1.0mol), acetate 60g (1.0mol) piperidines 85.1g (1.0mol) are dissolved in the 600ml benzene; reflux is told moisture; reaction in about 10 hours finishes; cooling; with saturated brine washing, anhydrous magnesium sulfate drying.Filter, concentrate, 125--127 ℃/0.5mmHg cut is collected in underpressure distillation, gets product, yield 80.5%.
The preparation of step 2,4-(to fluorophenyl)-6-sec.-propyl-2-methylamino pyrimidine-5-methyl-formiate
In reaction flask, add and go up step product 2.5g (0.01mol), hydrochloride methyl guanidine 1.31g (0.012mol), dimethyl formamide 15ml.In 80 ℃ of reactions 20 hours, add potassium permanganate 4g, reacted 3 hours, reaction is finished, and adds ethyl acetate and less water, filters, tell ethyl acetate layer, water layer ethyl acetate extraction, washing, anhydrous magnesium sulfate drying, filter, concentrate silica gel column chromatography (eluent: trichloromethane), get product, yield 26.3%.
Appraising datum: mp:88.5-90 ℃
1HNMR (trichloromethane) δ: 1.20 (d, 6H); 2.99 (d, 3H); 3.09 (m, 1H); 3.56 (s, 3H); 5.30 (s, 1H); 7.03 (m, 2H); 7.51 (m, 2H)
Embodiment 4
Step 1, (E/Z)-2-isobutyryl-to the preparation of fluorobenzene methyl acrylate
4-fluorobenzaldehyde 124.1g (1.0mol), isobutyryl methyl acetate 158.5g (1.1mol), acetate 60g (1.0mol) piperidines 85.1g (1.0mol) are dissolved in the 600ml benzene; reflux is told moisture; reaction in about 10 hours finishes; cooling; with saturated brine washing, anhydrous magnesium sulfate drying.Filter, concentrate, 125--127 ℃/0.5mmHg cut is collected in underpressure distillation, gets product, yield 81.1%.
The preparation of step 2,4-(to fluorophenyl)-6-sec.-propyl-2-methylamino pyrimidine-5-methyl-formiate
In reaction flask, add and go up step product 2.5g (0.01mol), hydrochloride methyl guanidine 1.75g (0.016mol), dimethyl formamide 15ml.In 140 ℃ of reactions 20 hours, add potassium permanganate 4g, reacted 3 hours, reaction is finished, and adds ethyl acetate and less water, filters, tell ethyl acetate layer, water layer ethyl acetate extraction, washing, anhydrous magnesium sulfate drying, filter, concentrate silica gel column chromatography (eluent: trichloromethane), get product, yield 27.2%.
Appraising datum: mp:88.5-90 ℃
1HNMR (trichloromethane) δ: 1.20 (d, 6H); 2.99 (d, 3H); 3.09 (m, 1H); 3.56 (s, 3H); 5.30 (s, 1H); 7.03 (m, 2H); 7.51 (m, 2H)
Embodiment 5
Step 1, (E/Z)-2-isobutyryl-to the preparation of fluorobenzene methyl acrylate
4-fluorobenzaldehyde 124.1g (1.0mol), isobutyryl methyl acetate 201.7g (1.4mol), acetate 60g (1.0mol) piperidines 85.1g (1.0mol) are dissolved in the 600ml benzene; reflux is told moisture; reaction in about 10 hours finishes; cooling; with saturated brine washing, anhydrous magnesium sulfate drying.Filter, concentrate, 125--127 ℃/0.5mmHg cut is collected in underpressure distillation, gets product, yield 83.0%.
The preparation of step 2,4-(to fluorophenyl)-6-sec.-propyl-2-methylamino pyrimidine-5-methyl-formiate
In reaction flask, add and go up step product 2.5g (0.01mol), hydrochloride methyl guanidine 2.19g (0.02mol), dimethyl formamide 15ml.In 115 ℃ of reactions 20 hours, add potassium permanganate 4g, to react 3 hours, reaction is finished, and adds ethyl acetate and less water, filter, the water layer ethyl acetate extraction, washing, anhydrous magnesium sulfate drying filters, concentrate silica gel column chromatography (eluent: trichloromethane), get product, yield 28.1%.
Appraising datum: mp:88.5-90 ℃
1HNMR (trichloromethane) δ: 1.20 (d, 6H); 2.99 (d, 3H); 3.09 (m, 1H); 3.56 (s, 3H); 5.30 (s, 1H); 7.03 (m, 2H); 7.51 (m, 2H)
Claims (8)
1. the synthetic method of a 4-(to fluorophenyl)-6-sec.-propyl-2-methylamino pyrimidine-5-methyl-formiate is made up of the following step;
A. 4-fluorobenzaldehyde, isobutyryl methyl acetate, acetate, piperidines are dissolved in the benzene, reflux is told moisture, and reaction finishes, cooling; with the saturated brine washing, anhydrous magnesium sulfate drying filters, and concentrates; cut is collected in underpressure distillation, (E/Z)-2-isobutyryl-to the fluorobenzene methyl acrylate
B. in reaction flask, add the product that obtains among the above-mentioned steps a---(E/Z)-the 2-isobutyryl-to fluorobenzene methyl acrylate, hydrochloride methyl guanidine, dimethyl formamide, heating is reacted, and reaction is finished, add potassium permanganate, proceed reaction again, reaction is finished, add ethyl acetate and less water, filter the water layer ethyl acetate extraction, washing, anhydrous magnesium sulfate drying filters, and concentrates, silica gel column chromatography gets 4-(to fluorophenyl)-6-sec.-propyl-2-methylamino pyrimidine-5-methyl-formiate.
2. the described method of claim 1, wherein the mol ratio of 4-fluorobenzaldehyde among the step a and isobutyryl methyl acetate is 1: 0.8-1.4,
3. the described method of claim 2, mol ratio wherein is 1: 1.2.
4. claim 1,2 or 3 described methods, wherein the cut of 125-127 ℃/0.5mmHg is collected in underpressure distillation.
5. the described method of claim 1, wherein (the E/Z)-2-isobutyryl among the step b-to the mol ratio of fluorobenzene methyl acrylate and hydrochloride methyl guanidine is 1: 0.8-2.
6. the described method of claim 5, mol ratio wherein is 1: 1.4.
7. the described method of claim 1, wherein the temperature of reaction among the step b is controlled between 80 ℃-140 ℃.
8. the described method of claim 7, temperature of reaction wherein is 115 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100203144A CN100412065C (en) | 2004-08-13 | 2004-08-13 | 4-(p-fluorophenyl)-6-isopropyl-2-methylaminopyrimidine-5-methyl formate synthesis method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100203144A CN100412065C (en) | 2004-08-13 | 2004-08-13 | 4-(p-fluorophenyl)-6-isopropyl-2-methylaminopyrimidine-5-methyl formate synthesis method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1733734A CN1733734A (en) | 2006-02-15 |
| CN100412065C true CN100412065C (en) | 2008-08-20 |
Family
ID=36076380
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2004100203144A Expired - Fee Related CN100412065C (en) | 2004-08-13 | 2004-08-13 | 4-(p-fluorophenyl)-6-isopropyl-2-methylaminopyrimidine-5-methyl formate synthesis method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100412065C (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109796414B (en) * | 2019-02-26 | 2022-05-20 | 中国药科大学 | Method for continuously preparing rosuvastatin intermediate by adopting micro-channel modular reaction device |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4822798A (en) * | 1982-09-18 | 1989-04-18 | Bayer Aktiengesellschaft | Circulation-active 4-phenyl-6-substituted dihydropyrimidines |
| US5260440A (en) * | 1991-07-01 | 1993-11-09 | Shionogi Seiyaku Kabushiki Kaisha | Pyrimidine derivatives |
| JPH06256318A (en) * | 1993-03-01 | 1994-09-13 | Shionogi & Co Ltd | Method for synthesizing 5-carboalkoxypyrimidine derivative |
-
2004
- 2004-08-13 CN CNB2004100203144A patent/CN100412065C/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4822798A (en) * | 1982-09-18 | 1989-04-18 | Bayer Aktiengesellschaft | Circulation-active 4-phenyl-6-substituted dihydropyrimidines |
| US5260440A (en) * | 1991-07-01 | 1993-11-09 | Shionogi Seiyaku Kabushiki Kaisha | Pyrimidine derivatives |
| JPH06256318A (en) * | 1993-03-01 | 1994-09-13 | Shionogi & Co Ltd | Method for synthesizing 5-carboalkoxypyrimidine derivative |
Non-Patent Citations (1)
| Title |
|---|
| 4_4_氟苯基_6_异丙基_2_N_甲基_N_甲磺酰胺基嘧啶_5_羧酸甲酯的合成. 王道林等.中国药物化学杂志，第14卷第3期. 2004 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1733734A (en) | 2006-02-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104672238B (en) | A kind of Li Gelieting preparation method | |
| CN109563066A (en) | The method for preparing the cyclic keto-enols of Spiroketals substitution | |
| JP3491506B2 (en) | Method for producing dihydropyridine derivative | |
| CN100412065C (en) | 4-(p-fluorophenyl)-6-isopropyl-2-methylaminopyrimidine-5-methyl formate synthesis method | |
| CN114213327A (en) | Synthesis method of (-) -huperzine A | |
| CA2614138A1 (en) | Method for producing 4(3h)-quinazolinone derivative | |
| CN104803908A (en) | Hydrate of 2-isopropoxy-5-methyl-4-(4-piperidyl) aniline dihydrochloride as well as preparation method and application of hydrate | |
| CN112679416A (en) | Preparation method of benidipine hydrochloride | |
| KR20080027885A (en) | Process for producing 1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-ylidene]methylpiperidine | |
| CN106496099A (en) | The synthetic method of 2 [(2R, 6S) 6 [(2S) 2 hydroxyl, 2 phenethyl] 1 methyl piperidine] 1 1-Phenylethanone. | |
| CN103755715B (en) | Cumarone is [2,3-c] pyridine compounds and synthetic method thereof also | |
| CN102976949B (en) | Preparation method of methyl 2-nitrobenzal acetoacetate | |
| JP5463051B2 (en) | Method for producing 1,4-dihydropyridine derivative | |
| CN109956899B (en) | Preparation method of vitamin B6 | |
| CN101372477B (en) | Method for synthesizing diaza-onium salt | |
| CN103408483A (en) | Calcium ion channels antagonist manidipine preparation method | |
| CN108689926A (en) | The preparation method of Pitavastatin Calcium 5- oxo impurity | |
| CN108409639B (en) | Preparation and structure confirmation method of (S) -3-Boc-aminomethyl piperidine | |
| CN110498808B (en) | Intermediate for synthesizing (2S,3R) -3-substituted phenyl pyrrolidine-2-carboxylic acid and preparation method and application thereof | |
| CN110372677B (en) | Method for preparing atorvastatin key intermediate L1 by solvent-free method | |
| CN105017132A (en) | 1,4-dihydropyridine compound and preparation method thereof | |
| CN1296367C (en) | Process for preparation of ethyl 2,3-dihydrobenzo [1,4] dioxins -2-carboxylate | |
| KR20060104761A (en) | Process for preparing lercanidipine hydrochloride | |
| WO2004002958A1 (en) | Industrial process for the synthesis of isobutyl methyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridine dicarboxylate (nisoldipine) | |
| Igarashi et al. | Partial Asymmetric Synthesis of⊿ ¹¸ ⁹-2-Octalone with Chiral Enamine (Commemoration Issue Dedicated to Professor Minoru Ohno On the Occasion of his Retirement) |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C56 | Change in the name or address of the patentee |
Owner name: TASLY HOLDING GROUP CO., LTD. Free format text: FORMER NAME: TIANJIN TASLY GROUP CO., LTD. |
|
| CP01 | Change in the name or title of a patent holder |
Address after: 300402, No. 1, Liaohe East Road, Beichen Science Park, Beichen District, Tianjin Patentee after: TASLY HOLDING GROUP CO., LTD. Address before: 300402, No. 1, Liaohe East Road, Beichen Science Park, Beichen District, Tianjin Patentee before: Tianjin Tasly Group Co., Ltd. |
|
| EE01 | Entry into force of recordation of patent licensing contract |
Application publication date: 20060215 Assignee: Tianshili Diyi Pharmaceutical Ind Co., Ltd., Jiangsu Assignor: TASLY HOLDING GROUP CO., LTD. Contract record no.: 2015320000357 Denomination of invention: Synthesis method of 4- (fluoro phenyl) -6- isopropyl -2- methylamine pyrimidine -5- formic acid methyl ester Granted publication date: 20080820 License type: Exclusive License Record date: 20150521 |
|
| LICC | Enforcement, change and cancellation of record of contracts on the licence for exploitation of a patent or utility model | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20080820 Termination date: 20170813 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |