CN1305849C - Method for preparing 3-methylamino piperidine and its salt - Google Patents
Method for preparing 3-methylamino piperidine and its salt Download PDFInfo
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- CN1305849C CN1305849C CNB200410065966XA CN200410065966A CN1305849C CN 1305849 C CN1305849 C CN 1305849C CN B200410065966X A CNB200410065966X A CN B200410065966XA CN 200410065966 A CN200410065966 A CN 200410065966A CN 1305849 C CN1305849 C CN 1305849C
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Abstract
The present invention relates to 3-methylamino piperidine (I) and a preparation method of salt of the 3-methylamino piperidine. The present invention is characterized in that 3-aminopyridine is used as starting raw material; the 3-aminopyridine has a methylation reaction, and 3-methylaminopyridine is prepared; the 3-methylaminopyridine is reduced in a sodium metal-alcohol system, and the 3-methylamino piperidine is obtained; the 3-methylamino piperidine and various kinds of acid are combined, and the salt of the 3-methylamino piperidine is obtained.
Description
Technical field
The present invention relates to preparation method suc as formula compound 3-methylamino piperidine shown in (I) and salt thereof.
Background technology
Q-35 (Balofloxacin) is the fluoroquinolone antibacterial agent by the common exploitation of Japanese Choongwae Pharmacutical Corp and Korea S Choongwae company, go on the market in Korea S first the year ends 2002, medicinal is dihydrate [pharmacy progress, 2003,27 (3): 190-193].This product obviously is better than Ciprofloxacin (Ciprofloxacin) or Ofloxacine USP 23 (Ofloxacin) to the external activity of G+ bacterium such as methicillin-resistant gold Portugal bacterium, with similar [the Nippon Kagaku Ryoho Gakkai Zasshi of tosufloxacin (Tosufloxacin) and Sparfloxacin (Sparfloxacin), 1995,43 (S-5): 1-9], and low [the AntimicrobAgents Chemother of phototoxicity, 1993,37 (10): 2217-2223], clinical being used for the treatment of by bacterial each system infects.The 3-methylamino piperidine is the key intermediate of synthetic Q-35, synthetic method literature search to the 2004 year November of relevant 3-methylamino piperidine, the researchist who finds the Chinese Academy of Medical Sciences, China Concord Medical Science University Institute of Medicinal Biological Technique has carried out reporting [Chinese Journal of Pharmaceuticals to 3-methylamino piperidine synthetic, 2004,35 (7): 385-388], they are that reaction obtains product to starting raw material through eight steps with the gamma-butyrolactone, total recovery 11.5% has been used noble metal catalyst PtO therebetween
2, cost is very high.
Summary of the invention
The simple synthesis that the purpose of this invention is to provide a kind of 3-of preparation methylamino piperidine and salt thereof.This method synthetic route is short, and raw material is cheap and easy to get, suitability for industrialized production.
Purpose of the present invention can reach by following measure:
The synthetic route of 3-methylamino piperidine is as follows:
Wherein, R
1Be (C
1～C
2) alkyl, R
2Be (C
1～C
3Alkyl, R
3Be (C
2～C
5) alkyl, M is metal Na or metal K.
The concrete operations step is:
(1) is starting raw material and ortho-formiate class reagent react with the 3-aminopyridine, obtains formula II compound
(2) formula II compound obtains the formula III compound with borohydride reduction in alcoholic solution
(3) the formula III compound reduces in sodium Metal 99.5-pure system and makes formula I compound
(4) formula I compound and various acid-respons obtain the various salt of formula I compound.
Obtain in the reaction of formula II compound, ortho-formiate class reagent is trimethyl orthoformate, triethyl orthoformate.Preferred triethyl orthoformate.
Obtain in the reaction of formula II compound, the molar ratio range of 3-aminopyridine and ortho-formiate is 1: 1.5～10.Be preferably 1: 4～7.
Obtain in the reaction of formula II compound, be reflected under the backflow and carry out.
Obtain in the reaction of formula III compound, alcoholic solvent is methyl alcohol, ethanol, Virahol.Be preferably ethanol.
Obtain in the reaction of formula III compound, hydroborate is sodium borohydride, POTASSIUM BOROHYDRIDE.Preferred hydroboration clock.
Obtain in the reaction of formula I compound, alcoholic solvent is ethanol, Virahol, propyl carbinol, isopropylcarbinol, Pentyl alcohol, primary isoamyl alcohol.Preferred propyl carbinol.
Obtain in the reaction of formula I compound, the volume ratio scope of raw material and alcohol is 1: 10～40.Be preferably 1: 20～30.
Obtain in the reaction of formula I compound, employed reductive agent is a sodium Metal 99.5.
In the alcoholic solution of three methylamino piperidines, lead to dry hydrogen chloride or in the three methylamino piperidine aqueous solution, drip 3mol/l aqueous hydrochloric acid, the treated three methylamino piperidine dihydrochlorides that obtain.Three methylamino piperidines and other various acid are in conjunction with obtaining various salt, as dihydrochloride, oxalate, picrate.
Advantage of the present invention is as follows:
In order to reduce the production cost of Q-35 bulk drug, make it become acceptable drug on the price, the applicant studies the synthetic of 3-methylamino piperidine, has proposed new synthetic route.The present invention has shortened reactions steps greatly, and used raw material and reagent is all inexpensive is easy to get in the route has significantly reduced the production cost of 3-methylamino piperidine, has simplified technological operation.
Description of drawings
Fig. 1 is a nmr spectrum of the present invention.
Fig. 2 is a mass spectrum of the present invention.
Embodiment
Embodiment 1
In the 250ml there-necked flask, add 18.8g (0.2mol) 3-aminopyridine, 220ml (2mol) trimethyl orthoformate, stirring and refluxing 10h.Reaction removes solvent under reduced pressure after finishing.The resistates vacuum fractionation is collected 58～60 ℃/100Pa cut, gets formula II compound (R
1Be methyl) colourless liquid 20.4g (0.15mol), yield 75%.The TLC method is followed the tracks of reaction process, and developping agent is an ethyl acetate, observes product spot R under the 254nm luminescent lamp
f=0.8.
Embodiment 2
In the 250ml there-necked flask, add 18.8g (0.2mol) 3-aminopyridine, 160ml (1.22mol) triethyl orthoformate, stirring and refluxing 5h.Reaction removes solvent under reduced pressure after finishing.The resistates vacuum fractionation is collected 60～62 ℃/100Pa cut, gets formula II compound (R
1Be ethyl) colourless liquid 25.5g (0.17mol), yield 85%.The TLC method is followed the tracks of reaction process, and developping agent is an ethyl acetate, observes product spot R under the 254nm luminescent lamp
f=0.8.
Embodiment 3
In the 250ml there-necked flask, add 18.8g (0.2mol) 3-aminopyridine, 40ml (0.3mol) triethyl orthoformate, stirring and refluxing 6h.Reaction removes solvent under reduced pressure after finishing.The resistates vacuum fractionation is collected 60～62 ℃/100Pa cut, gets formula II compound (R
1Be ethyl) colourless liquid 18g, yield 60%.
Embodiment 4
Modus ponens II compound (R
1Being ethyl) 50g (0.33mol) adds in the 500ml there-necked flask, and to wherein adding the 300ml dehydrated alcohol, frozen water is cooled to 0 ℃ again, stirs down that gradation adds the 15g sodium borohydride on a small quantity, slowly rises to room temperature again, slowly is warming up to backflow after half an hour.Continue reaction 3h.Reaction removes solvent under reduced pressure after finishing.Resistates is dissolved in the 300ml water, extracts at twice with the 1000ml ether, merges extraction phase, anhydrous magnesium sulfate drying.Reclaim solvent, the resistates vacuum fractionation is collected 80～82 ℃/100Pa cut, gets 3-methylamino pyridine colourless liquid 28.8g (0.27mol).The TLC method is followed the tracks of reaction process, and developping agent is an ethyl acetate, observes product spot R under the 254nm luminescent lamp
f=0.5.Yield: 80%.
Embodiment 5
Modus ponens II compound (R
1Being ethyl) 50g (0.33mol) adds in the 500ml there-necked flask, again to wherein adding the 300ml dehydrated alcohol, stirs down that gradation adds the 20g POTASSIUM BOROHYDRIDE on a small quantity, is warming up to backflow.Continue reaction 3h.Reaction removes solvent under reduced pressure after finishing.Resistates is dissolved in the 300ml water, extracts at twice with the 1000ml ether, merges extraction phase, anhydrous magnesium sulfate drying.Reclaim solvent, the resistates vacuum fractionation is collected 80～82 ℃/100Pa cut, gets 3-methylamino pyridine colourless liquid 29g (0.27mol).Yield: 80%.
Embodiment 6
Modus ponens II compound (R
1Being ethyl) 50g (0.33mol) adds in the 500ml there-necked flask, again to wherein adding the 300ml Virahol, stirs down that gradation adds the 20g sodium borohydride on a small quantity, is warming up to backflow.Continue reaction 5h.Reaction removes solvent under reduced pressure after finishing.Resistates is dissolved in the 300ml water, extracts at twice with the 1000ml ether, merges extraction phase, anhydrous magnesium sulfate drying.Reclaim solvent, the resistates vacuum fractionation is collected 80～82 ℃/100Pa cut, gets 3-methylamino pyridine colourless liquid 20g (0.185mol).Yield: 55.6%.
Embodiment 7
In the 100ml there-necked flask, add 1g (9.26mmol) 3-methylamino pyridine and 25ml propyl carbinol, stir, be warming up to backflow.Gradation adds 2g (87.0mmol) sodium Metal 99.5 silk on a small quantity.TLC is cooled to room temperature after analyzing the raw material reaction end, adds 2ml water.Evaporated under reduced pressure, 30ml chloroform extraction, anhydrous magnesium sulfate drying.Logical dry hydrogen chloride gas, the solid of separating out get white powdered solid 3-methylamino piperidine dihydrochloride 650mg (3.48mmol), yield 37.6% at the alcohol-ether recrystallization.Fusing point: 191～193 ℃.
1HNMR (methyl alcohol) d:1.74～2.35 (4H, m, 4,5-H), 2.80 (3H, s, CH3), 3.05～3.78 (5H, m, 2,3,6-H), 4.87 (2H, s, NH).MS(m/z)：114(M
+)。Purity 99.7% (GC method).Developping agent: 3ml methyl alcohol adds 3 ammoniacal liquor, product spot R
f=0.3.Nuclear magnetic resonance spectrum and mass spectrum are seen accompanying drawing 1,2.
Embodiment 8
In the 100ml there-necked flask, add 1g (9.26mmol) 3-methylamino pyridine and 40ml primary isoamyl alcohol, stir, be warming up to 120 ℃.Gradation adds 2g (87.0mmol) sodium Metal 99.5 silk on a small quantity.TLC is cooled to room temperature after analyzing the raw material reaction end, adds 2ml water.Evaporated under reduced pressure, 30ml chloroform extraction, anhydrous magnesium sulfate drying.Logical dry hydrogen chloride gas, the solid of separating out get white powdered solid 3-methylamino piperidine dihydrochloride 670mg (3.58mmol), yield 38.7% at the alcohol-ether recrystallization.
Embodiment 9
In the 100ml there-necked flask, add 1g (9.26mmol) 3-methylamino pyridine and 10ml ethanol, stir, be warming up to 120 ℃, gradation adds 2g (87.0mmol) sodium Metal 99.5 silk on a small quantity.TLC is cooled to room temperature after analyzing the raw material reaction end, adds 2ml water.Evaporated under reduced pressure, 30ml chloroform extraction, anhydrous magnesium sulfate drying.Decompression and solvent recovery, gained oily matter recrystallization in alcohol-ether gets white solid 300mg (2.63mmol), yield 28.4%.Fusing point: 188～190 ℃.Developping agent: 3ml methyl alcohol adds 3 ammoniacal liquor, product spot R
f=0.3.
Claims (15)
1, the method for following formula I compound of preparation and salt thereof,
It is characterized in that the preparation method of Formula I may further comprise the steps:
(1) is starting raw material and ortho-formiate class reagent react with the 3-aminopyridine, obtains formula II compound
Wherein, R
1Be (C
1～C
2) alkyl;
(2) formula II compound obtains the formula III compound with borohydride reduction in alcoholic solution;
(3) the formula III compound reduces in sodium Metal 99.5-pure system and makes formula I compound;
(4) formula I compound and acid-respons obtain the salt of formula I compound;
Synthetic route is as follows:
Wherein, R
2Be (C
1～C
3) alkyl, R
3Be (C
2～C
5) alkyl, M is metal Na or metal K.
2, preparation method according to claim 1 is characterized in that obtaining in the reaction of formula II compound, and ortho-formiate class reagent ortho-formiate class reagent is trimethyl orthoformate or triethyl orthoformate.
3, preparation method according to claim 2 is characterized in that obtaining in the reaction of formula II compound, and ortho-formiate class reagent is triethyl orthoformate.
4, preparation method according to claim 1 is characterized in that obtaining in the reaction of formula II compound, and the molar ratio range of 3-aminopyridine and ortho-formiate is 1: 1.5～10.
5, preparation method according to claim 4 is characterized in that obtaining in the reaction of formula II compound, and the molar ratio range of 3-aminopyridine and ortho-formiate is 1: 4～7.
6, preparation method according to claim 1 is characterized in that obtaining in the reaction of formula III compound, and alcoholic solvent is methyl alcohol, ethanol or Virahol.
7, preparation method according to claim 6 is characterized in that obtaining in the reaction of formula III compound, and alcoholic solvent is an ethanol.
8, preparation method according to claim 1 is characterized in that obtaining in the reaction of formula III compound, and hydroborate is sodium borohydride or POTASSIUM BOROHYDRIDE.
9, preparation method according to claim 8 is characterized in that obtaining in the reaction of formula III compound, and hydroborate is a POTASSIUM BOROHYDRIDE.
10, preparation method according to claim 1 is characterized in that obtaining in the reaction of formula I compound, and alcohol reagent is ethanol, Virahol, propyl carbinol, isopropylcarbinol, Pentyl alcohol or primary isoamyl alcohol.
11, preparation method according to claim 10 is characterized in that obtaining in the reaction of formula I compound, and alcohol reagent is a propyl carbinol.
12, preparation method according to claim 1 is characterized in that obtaining in the reaction of formula I compound, and the volume ratio scope of raw material and alcohol is 1: 10～40.
13, preparation method according to claim 12 is characterized in that the volume ratio scope of raw material and alcohol is 1: 20～30.
14, according to the preparation method of claim 1, the salt of described formula I compound is: the dihydrochloride of formula I compound, oxalate, picrate.
15, according to the preparation method of claim 14, the salt of described formula I compound is: the dihydrochloride of formula I compound.
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|---|---|---|---|
| CNB200410065966XA CN1305849C (en) | 2004-12-29 | 2004-12-29 | Method for preparing 3-methylamino piperidine and its salt |
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|---|---|---|---|
| CNB200410065966XA CN1305849C (en) | 2004-12-29 | 2004-12-29 | Method for preparing 3-methylamino piperidine and its salt |
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|---|---|
| CN1660809A CN1660809A (en) | 2005-08-31 |
| CN1305849C true CN1305849C (en) | 2007-03-21 |
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|---|---|---|---|
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| CN109503462B (en) * | 2019-01-21 | 2022-03-25 | 内蒙古京东药业有限公司 | Synthesis method of tofacitinib intermediate (3R, 4R) -N, 4-dimethyl-1-benzyl-3-piperidylamine |
| CN113234012B (en) * | 2021-06-01 | 2023-04-25 | 上海巽田科技股份有限公司 | Preparation method of 3-methylaminopyridine and derivative or salt thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1037335A (en) * | 1988-03-11 | 1989-11-22 | 拜尔公司 | The preparation method of 1-cyclopropyl Quinolone carboxylic acid and derivative thereof |
| WO2001062734A1 (en) * | 2000-02-25 | 2001-08-30 | Daiichi Pharmaceutical Co., Ltd. | Process for producing quinolonecarboxylic acids and intermediates thereof |
-
2004
- 2004-12-29 CN CNB200410065966XA patent/CN1305849C/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1037335A (en) * | 1988-03-11 | 1989-11-22 | 拜尔公司 | The preparation method of 1-cyclopropyl Quinolone carboxylic acid and derivative thereof |
| WO2001062734A1 (en) * | 2000-02-25 | 2001-08-30 | Daiichi Pharmaceutical Co., Ltd. | Process for producing quinolonecarboxylic acids and intermediates thereof |
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Owner name: LIANYUNGANG RUIZHONG PHARMACEUTICAL CO., LTD. Free format text: FORMER OWNER: JIANGSU ZHENGDA TIANQING PHARMACEUTICAL CO., LTD. Effective date: 20110324 |
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Effective date of registration: 20110324 Address after: 222006, Jiangsu Province Economic and Technological Development Zone of Lianyungang Industrial Zone Dapu Road No. 16 Patentee after: Lianyungang Runzhong Pharmaceutical Co.,Ltd. Address before: 222006 Sinpo City, Lianyungang Province, North Road, No. 8, No. Patentee before: Jiangsu Chiatai Tianqing Pharmaceutical Co., Ltd. |