CN101665458B - Preparation method of N-methoxyl-N-methyl-1-tosylpiperidine-4-amide - Google Patents
Preparation method of N-methoxyl-N-methyl-1-tosylpiperidine-4-amide Download PDFInfo
- Publication number
- CN101665458B CN101665458B CN2009101175002A CN200910117500A CN101665458B CN 101665458 B CN101665458 B CN 101665458B CN 2009101175002 A CN2009101175002 A CN 2009101175002A CN 200910117500 A CN200910117500 A CN 200910117500A CN 101665458 B CN101665458 B CN 101665458B
- Authority
- CN
- China
- Prior art keywords
- phenylpiperidines
- carboxylic acid
- acid
- preparation
- tolysulfonyl
- 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
Abstract
The invention discloses a preparation method of N-methoxyl-N-methyl-1-tosylpiperidine-4-amide used as the intermediate of drug MDL-100907. The method comprises the following steps: firstly using TsCl as protective reagent to ensure piperidine-4-carboxylic acid to react with toluenesulfonyl chloride in alkaline condition, obtaining 1-tosylpiperidine-4-carboxylate, acidifying to obtain 1-tosylpiperidine-4-carboxylic acid, and then amidating 1-tosylpiperidine-4-carboxylic acid in the presence of acylating agent to obtain the target product. The preparation method of the invention firstly utilizes two kinds of acylation systems, namely NBS/PPh3/NH(OMe)Me and P(NMeOMe)3 to directly react with 1-tosylpiperidine-4-carboxylic acid and prepare N-methoxyl-N-methyl-1-tosylpiperidine-4-amide; in addition, the raw materials are cheap and accessible, the reaction time is short, the conditions are mild, the operation is simple, the post-treatment is easy, the yield is high, and the preparation method of the invention provides good conditions for the industrial scale production and commercialization of the product.
Description
Technical field
The invention belongs to chemosynthesis technical field, relate to a kind of intermediate for preparing medicine MDL-100907---the preparation method of N-methoxyl group-N-methyl isophthalic acid-tolysulfonyl phenylpiperidines-4-acid amides.
Background technology
MDL-100907 chemical name: (+)-(R)-1-[1-[2-(4-fluorophenyl) ethyl] piperidin-4-yl]-1-(2, the 3-Dimethoxyphenyl) methyl alcohol, it is a kind of anti-agent of 5-HT2A acceptor of highly selective, can treat multiple disease, as: the vasospasm of schizophrenia, dysthymia disorders, various angina pectoris, anorexia nervosa, Raynaud ' s phenomenon, intermittent claudication syndromes, coronal or periphery, fibromyoma, arrhythmia, thrombus (property) vasculitis etc., and, can assist neural lax treatment aspect the control extrapyramidal system.Therefore, in neurochemistry, electric physiology is similar to atypical anti-neuropathy medicine with the behavior effect aspect, belongs to anti-off one's dot medicine.At present, in synthetic MDL-100907 route, mainly contain four routes, as follows:
Wherein, intermediate 4 and 6 is all by Weinreb acid amides and the preparation of Grignard reagent react.The method of the intermediate of the preparation medicine MDL-100907 of bibliographical information---Weinreb acid amides all is earlier carboxylic acid to be made acyl chlorides, then in the presence of alkali, generate the Weinreb acid amides with N-methyl-N-methoxy amine hydrochlorate effect, there is following weak point in this method: the carboxylic acid that (1) has is not easy to change into acyl chlorides, need to add catalyzer (as DMF), and acyl chlorides is comparatively active, makes troubles to operation; (2) acyl chlorides and N-methyl-N-methoxy amine hydrochlorate long reaction time is mostly at 3 to 15 hours.
Summary of the invention
The purpose of this invention is to provide a kind of intermediate of producing medicine MDL-100907---the preparation method of N-methoxyl group-N-methyl isophthalic acid-tolysulfonyl phenylpiperidines-4-acid amides.
The preparation method of N-methoxyl group of the present invention-N-methyl isophthalic acid-tolysulfonyl phenylpiperidines-4-acid amides, be to be earlier protection reagent with TsCl, piperidines-4-carboxylic acid is reacted with Tosyl chloride under alkaline condition, generate 1-tolylsulfonyl phenylpiperidines-4-carboxylate salt, through acidifying, obtain 1-tolylsulfonyl phenylpiperidines-4-carboxylic acid again; And then make 1-tolylsulfonyl phenylpiperidines-4-carboxylic acid amidation under the acylating reagent effect, obtain N-methoxyl group-N-methyl isophthalic acid-tolysulfonyl phenylpiperidines-4-acid amides.Synthesis step is shown below:
Wherein the preparation technology of 1-tolylsulfonyl phenylpiperidines-4-carboxylic acid is: piperidines-4-carboxylic acid is dissolved in sodium hydroxide or the potassium hydroxide aqueous solution; be cooled to 0～-5 ℃; the diethyl ether solution that slowly adds Tosyl chloride; stir 3～4h; steam solvent ether; be acidified to pH=2～3 with concentrated hydrochloric acid then, separate out white solid, vacuum-drying promptly.The molar weight of described Tosyl chloride is 1～1.1 times of piperidines-4-carboxylic acid; The molar weight of sodium hydroxide or potassium hydroxide is 1.5～2.5 times of piperidines-4-carboxylic acid.
The acylating reagent that the present invention adopts is NBS/PPh
3/ NH (OMe) Me or phosphoramidite P (NMeOMe)
3
When adopting NBS/PPh
3When/NH (OMe) Me was acylating reagent, the acylation process of 1-tolylsulfonyl phenylpiperidines-4-carboxylic acid was: 1-tolylsulfonyl phenylpiperidines-4-carboxylic acid is dissolved in the methylene dichloride, is alkali with pyridine or triethylamine, at acylating reagent NBS/PPh
3Under the effect of/NH (OMe) Me (N-bromo succinic diamide/triphenyl phosphorus/N-methyl-N-methoxyl group amine), under 0～25 ℃, stirring reaction 30～60 minutes, extraction, separation obtain N-methoxyl group-N-methyl isophthalic acid-tolysulfonyl phenylpiperidines-4-acid amides.
Acylating reagent NBS/PPh wherein
3Among/NH (OMe) Me, three's mol ratio is 1: 1: 1～1.1: 1: 1.7, preferred 1.1: 1: 1.Acylating reagent NBS/PPh
3The consumption of/NH (OMe) Me is 3～3.8 times of 1-tolylsulfonyl phenylpiperidines-4-carboxylic acid molar weight; The consumption of pyridine or triethylamine is 1～1.1 times of 1-tolylsulfonyl phenylpiperidines-4-carboxylic acid molar weight.
When adopting phosphoramidite P (NMeOMe)
3During for acylating reagent; the acylation process of 1-tolylsulfonyl phenylpiperidines-4-carboxylic acid is: 1-tolylsulfonyl phenylpiperidines-4-carboxylic acid is dissolved in toluene, ether or the methylene dichloride; under nitrogen protection; with the phosphoramidite is acylating reagent; reacted 30～60 minutes down in 25～80 ℃, extraction, separation obtain N-methoxyl group-N-methyl isophthalic acid-tolysulfonyl phenylpiperidines-4-acid amides.Wherein the consumption of phosphoramidite is 0.3～0.5 times of 1-tolylsulfonyl phenylpiperidines-4-carboxylic acid molar weight.
The present invention compared with prior art has the following advantages:
1, the present invention is a raw material with piperidines-4-carboxylic acid, Tosyl chloride be protecting group, 1-tolylsulfonyl phenylpiperidines-4-carboxylic acid; And then make 1-tolylsulfonyl phenylpiperidines-4-carboxylic acid amidation under the acylating reagent effect, obtain N-methoxyl group-N-methyl isophthalic acid-tolysulfonyl phenylpiperidines-4-acid amides, raw material and all ingredients are all cheap and easy to get, and cost is low, for the commercial scale production and the commercialization of product creates good conditions;
2, preparation technology of the present invention is simple, and is easy to operate, and reaction time is short, and aftertreatment is simple, and efficient is higher.
3, product yield height can reach more than 96%, and compared with prior art, productive rate will exceed more than ten percentage point.
4, the advantages of nontoxic raw materials of the present invention's employing, production process is pollution-free, and is environmentally friendly, meets the industry policy of country.
Embodiment
The preparation of embodiment 1, N-methoxyl group-N-methyl isophthalic acid-tolysulfonyl phenylpiperidines-4-acid amides
(1) 1-tolylsulfonyl phenylpiperidines-4-carboxylic acid is synthetic
With piperidines-4-carboxylic acid (5g, 38.8mmol) and aqueous sodium hydroxide solution (3.1gNaOH, the 46mlH of 1.67mol/L
2O) join in the 100ml reactor, be cooled to 0 ℃, slowly drip diethyl ether solution (7.4gTsCl, 38.8mmol, the 40ml Et of TsCl
2O), stir 4h, steam ether, be acidified to pH=2 with concentrated hydrochloric acid then, separate out a large amount of white solids immediately, vacuum-drying gets 1-tolylsulfonyl phenylpiperidines-4-carboxylic acid 4.5g.Yield 90%.
Fusing point: 165-167 ℃.
1H?NMR(400MHz，CDCl
3)：δ：2.46(s，3H)，1.81-1.87(m，2H)，1.99(d，J＝3.9Hz，1H)2.01(d，J＝3.2Hz，1H)2.26-2.30(m，1H)，2.45-2.48(m，1H)，7.33(d，J＝7.6Hz，2H)，7.63(d，J＝8.0Hz，2H)。
(2) the NBS legal system is equipped with N-methoxyl group-N-methyl isophthalic acid-tolysulfonyl phenylpiperidines-4-acid amides
With 1-tolylsulfonyl phenylpiperidines-4-carboxylic acid (0.566g, 2mmol) and triphenylphosphine (0.52g 2mmol) joins in the 50ml two neck bottles, adds the 10ml methylene dichloride again, is cooled to 0 ℃, add in batches NBS (0.375g, 2.1mmol), stirring reaction 30min.With N-methyl-N-methoxyl group amine (0.12g, 2mmol), pyridine (0.158g, 2mmol) and the 10ml methylene dichloride join in the another one reactor and stir, and it is joined in the reactor of front reaction 1h, solution becomes au bleu; The cancellation of adding saturated sodium bicarbonate solution, separatory, (3 * 3ml), the extraction liquid anhydrous sodium sulfate drying filters dichloromethane extraction, gets colourless liquid after concentrating, and leaves standstill to become white solid, with getting straight product behind ethyl acetate and the sherwood oil recrystallization.Reaction equation is as follows:
Yield 81%.mp：133-135℃。
1H?NMR(400MHz，CDCl
3)：δ：2.39(s，3H)，3.09(s，3H)，3.62(s，3H)，1.78-1.89(m，4H)，2.41-2.61(m，2H)，3.77(t，J＝8.0Hz，2H)，7.32(d，J＝8.4Hz，2H)，7.65(d，J＝8.4Hz，2H)。
The preparation of embodiment 2, N-methoxyl group-N-methyl isophthalic acid-tolysulfonyl phenylpiperidines-4-acid amides
(1) 1-tolylsulfonyl phenylpiperidines-4-carboxylic acid is synthetic
With embodiment 1.
(2) phosphoramidite method prepares N-methoxyl group-N-methyl isophthalic acid-tolysulfonyl phenylpiperidines-4-acid amides
30ml exsiccant toluene is added in the single port bottle of 100ml, add rapidly phosphoramidite (2g, 9.5mmol); add again 1-tolylsulfonyl phenylpiperidines-4-carboxylic acid (3g, 5.3mmol), under nitrogen protection; in 60 ℃ of oil baths, react 30min; cooling, saturated sodium bicarbonate solution cancellation, separatory; ethyl acetate extraction (3 * 10ml); the extraction liquid anhydrous sodium sulfate drying filters, and gets white solid 3.4g after concentrating.
Reaction equation is as follows:
Yield 96%.mp：133-135℃。
1H?NMR(400MHz，CDCl
3)：δ：2.39(s，3H)，3.09(s，3H)，3.62(s，3H)，1.78-1.89(m，4H)，2.41-2.61(m，2H)，3.77(t，J＝8.0Hz，2H)，7.32(d，J＝8.4Hz，2H)，7.65(d，J＝8.4Hz，2H)。
Claims (10)
1.N-the preparation method of methoxyl group-N-methyl isophthalic acid-tolysulfonyl phenylpiperidines-4-acid amides, it is characterized in that: be earlier protection reagent with TsCl, piperidines-4-carboxylic acid is reacted with Tosyl chloride under alkaline condition, generate 1-tolylsulfonyl phenylpiperidines-4-carboxylate salt, through acidifying, obtain 1-tolylsulfonyl phenylpiperidines-4-carboxylic acid again; And then make 1-tolylsulfonyl phenylpiperidines-4-carboxylic acid amidation under the acylating reagent effect, obtain N-methoxyl group-N-methyl isophthalic acid-tolysulfonyl phenylpiperidines-4-acid amides.
2. the preparation method of N-methoxyl group-N-methyl isophthalic acid-tolysulfonyl phenylpiperidines-4-acid amides according to claim 1; it is characterized in that: the preparation technology of described 1-tolylsulfonyl phenylpiperidines-4-carboxylic acid is: piperidines-4-carboxylic acid is dissolved in sodium hydroxide or the potassium hydroxide aqueous solution; be cooled to 0～-5 ℃; the diethyl ether solution that slowly adds Tosyl chloride; stir 3～4h, steam solvent ether, be acidified to pH=2～3 with concentrated hydrochloric acid then; separate out white solid, vacuum-drying promptly.
3. as the preparation method of N-methoxyl group-N-methyl isophthalic acid-tolysulfonyl phenylpiperidines-4-acid amides as described in the claim 2, it is characterized in that: the molar weight of described Tosyl chloride is 1～1.1 times of piperidines-4-carboxylic acid; The molar weight of sodium hydroxide or potassium hydroxide is 1.5～2.5 times of piperidines-4-carboxylic acid.
4. the preparation method of N-methoxyl group-N-methyl isophthalic acid-tolysulfonyl phenylpiperidines-4-acid amides according to claim 1, it is characterized in that: described acylating reagent is NBS/PPh
3/ NH (OMe) Me, wherein three's mol ratio is 1: 1: 1～1.1: 1: 1.7.
5. as the preparation method of N-methoxyl group-N-methyl isophthalic acid-tolysulfonyl phenylpiperidines-4-acid amides as described in the claim 4; it is characterized in that: the acylation process of described 1-tolylsulfonyl phenylpiperidines-4-carboxylic acid is: 1-tolylsulfonyl phenylpiperidines-4-carboxylic acid is dissolved in the methylene dichloride; with pyridine or triethylamine is alkali, at acylating reagent NBS/PPh
3Under the effect of/NH (OMe) Me, under 0～25 ℃, stirring reaction 30～60 minutes, extraction, separation obtain N-methoxyl group-N-methyl isophthalic acid-tolysulfonyl phenylpiperidines-4-acid amides.
6. as the preparation method of N-methoxyl group-N-methyl isophthalic acid-tolysulfonyl phenylpiperidines-4-acid amides as described in the claim 5, it is characterized in that: described acylating reagent NBS/PPh
3The consumption of/NH (OMe) Me is 3～3.8 times of 1-tolylsulfonyl phenylpiperidines-4-carboxylic acid molar weight.
7. as the preparation method of N-methoxyl group-N-methyl isophthalic acid-tolysulfonyl phenylpiperidines-4-acid amides as described in the claim 5, it is characterized in that: the consumption of described pyridine or triethylamine is 1～1.1 times of 1-tolylsulfonyl phenylpiperidines-4-carboxylic acid molar weight.
8. the preparation method of N-methoxyl group-N-methyl isophthalic acid-tolysulfonyl phenylpiperidines-4-acid amides according to claim 1, it is characterized in that: described acylating reagent is phosphoramidite P (NMeOMe)
3
9. as the preparation method of N-methoxyl group-N-methyl isophthalic acid-tolysulfonyl phenylpiperidines-4-acid amides as described in the claim 8; it is characterized in that: the acylation process of described 1-tolylsulfonyl phenylpiperidines-4-carboxylic acid is: 1-tolylsulfonyl phenylpiperidines-4-carboxylic acid is dissolved in toluene, ether or the methylene dichloride; under nitrogen protection; with the phosphoramidite is acylating reagent; reacted 30～60 minutes down in 25～80 ℃, extraction, separation obtain N-methoxyl group-N-methyl isophthalic acid-tolysulfonyl phenylpiperidines-4-acid amides.
10. as the preparation method of N-methoxyl group-N-methyl isophthalic acid-tolysulfonyl phenylpiperidines-4-acid amides as described in the claim 8, it is characterized in that: the consumption of described phosphoramidite is 0.3～0.5 times of 1-tolylsulfonyl phenylpiperidines-4-carboxylic acid molar weight.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009101175002A CN101665458B (en) | 2009-09-30 | 2009-09-30 | Preparation method of N-methoxyl-N-methyl-1-tosylpiperidine-4-amide |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009101175002A CN101665458B (en) | 2009-09-30 | 2009-09-30 | Preparation method of N-methoxyl-N-methyl-1-tosylpiperidine-4-amide |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101665458A CN101665458A (en) | 2010-03-10 |
| CN101665458B true CN101665458B (en) | 2011-07-27 |
Family
ID=41802262
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2009101175002A Expired - Fee Related CN101665458B (en) | 2009-09-30 | 2009-09-30 | Preparation method of N-methoxyl-N-methyl-1-tosylpiperidine-4-amide |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101665458B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102491941B (en) * | 2011-11-25 | 2014-01-22 | 西北师范大学 | Preparation method of N-methoxy-N-methyl-1-p-toluenesulfonyl piperidine-4-amide |
-
2009
- 2009-09-30 CN CN2009101175002A patent/CN101665458B/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN101665458A (en) | 2010-03-10 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103374038B (en) | A kind of preparation method of antiviral | |
| CN106928214A (en) | The preparation method of Yi Zhong oxazolidinone compounds and its intermediate | |
| CN104761474A (en) | Synthetic method of apremilast chiral amine intermediate | |
| CN107176955A (en) | A kind of Ba Rui replaces the preparation method of Buddhist nun | |
| CN106117216B (en) | A kind of method of atmospheric synthesis 6H- iso-indoles [2,1-a] indoles -6- ketone compounds | |
| CN105330581A (en) | Preparation method for (S)-oxiracetam | |
| CN106187901B (en) | A kind of preparation method of Dexmedetomidine and its intermediate | |
| CN101665458B (en) | Preparation method of N-methoxyl-N-methyl-1-tosylpiperidine-4-amide | |
| CN102491974A (en) | Method for synthesizing 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-formamidine hydrochloride | |
| CN103896858B (en) | The preparation technology of cytosine | |
| CN104193643B (en) | For the synthesis of the intermediate of anti-AIDS drug toughener cobicistat | |
| CN104987325B (en) | A kind of preparation method of voriconazole | |
| CN104557877A (en) | Avanafil intermediate as well as preparation method and application thereof | |
| CN104744537A (en) | Synthetic method of capecitabine | |
| CN101531634B (en) | High-purity blonanserin and preparation method thereof | |
| CN109020977B (en) | Preparation method of Acaraburtinib | |
| CN104447511A (en) | Synthetic method of N-t-butyloxycarboryl-3-piperidone | |
| CN103709030A (en) | Environmentally-friendly preparation method of ciprofibrate | |
| CN106380469A (en) | Synthesis method of 1-aromatic carbonyl-2-aryl-3-ester imidazolone compounds | |
| CN101723879B (en) | Method for synthesizing (R)-3-ethyl piperidine hydrochloride | |
| CN102241666A (en) | Method for producing hydrochloride of dopamine D4 receptor agonist A-412997 | |
| CN102491941B (en) | Preparation method of N-methoxy-N-methyl-1-p-toluenesulfonyl piperidine-4-amide | |
| CN111138350A (en) | Asymmetric synthesis method of dexchlorpheniramine and dexbrompheniramine | |
| CN103880729A (en) | New synthetic process of vilazodone intermediate 5-cyano-3(4-chlorobutyl)-indole | |
| CN104610129B (en) | A kind of synthetic method of the chiral carboxylic acid tert-butyl ester of 2 substituent, 4 piperidones 1 |
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 | ||
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20110727 Termination date: 20120930 |