CN105037250A - Synthesis method of anileridine - Google Patents
Synthesis method of anileridine Download PDFInfo
- Publication number
- CN105037250A CN105037250A CN201510317736.6A CN201510317736A CN105037250A CN 105037250 A CN105037250 A CN 105037250A CN 201510317736 A CN201510317736 A CN 201510317736A CN 105037250 A CN105037250 A CN 105037250A
- Authority
- CN
- China
- Prior art keywords
- ether
- reaction
- anileridine
- ethyl
- propionate
- 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.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
- C07D211/64—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4 having an aryl radical as the second substituent in position 4
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
The invention relates to a synthesis method of anileridine. By using sulfonate (1) as the raw material, the consumption of p-aminophenylethylamine (2), reaction temperature and reaction time are controlled to reduce the generation of the byproduct, so that the yield of the intermediate compound (3) is greater than 90%. The intermediate compound (3) is subjected to alcoholysis reaction in an ethanol solution of concentrated sulfuric acid to obtain the target compound anileridine (4) at high yield. Compared with the processes reported in the documents, the synthesis method provided by the invention has the advantages of high yield and low cost.
Description
Technical field
The present invention relates to a kind of synthetic method of anileridine.Belong to the field of chemical synthesis.
Background technology
Anileridine (anileridine) is the one of piperidines anodyne, for opioid receptor agonist, act on similar to Pethidine (pethidine), but analgesic activity is stronger, is now mainly used in oral pain alleviating or intravenous drip Supplementary Anesthesia.
(the ElpernB such as Elpern; GardnerLN, GrumbachL.J.A.C.S.1957,1951-1954.) with 4-ethoxy acyl-4-phenyl piperidine hydrochlorate 5 for raw material; synthesized anileridine by replacement and catalytic hydrogenation two-step reaction, synthetic route is as figure below.
There are two shortcomings in this synthetic route: one is that raw materials used 4-ethoxy acyl-4-phenyl piperidine hydrochlorate 5 need be prepared through polystep reaction, expensive; Two is synthesized in the reaction of anileridine 4 by intermediate 6 that to employ with noble metal platinum be the high-pressure catalytic hydrogenation of catalyzer, and conversion unit requires high, and reaction used catalyst is expensive, improves production cost.Therefore explore a synthetic method of efficiently synthesizing anileridine and there is important using value.
Summary of the invention
The technical problem that object of the present invention will solve is by changing synthetic method, improves reaction yield, reduces production cost, efficiently synthesize anileridine.
The technical solution adopted for the present invention to solve the technical problems is: the synthetic method of anileridine synthesizes anileridine (4) by two-step reaction, and reaction formula is as follows:
Concrete reactions steps is as follows:
Be dissolved in solvent by sulphonate 1, concentration controls at 0.01 ~ 1M, adds the alkali of 2 ~ 5eq and the p-aminophenyl ethamine 2 of 3 ~ 5eq, is warming up to 120 ~ 140 DEG C of reaction 12 ~ 24h in closed reactor; Stopped reaction, is down to room temperature, and steaming desolventizes, and adds the ethyl acetate of reaction product volume 1 ~ 5 times, methylene dichloride or chloroform extraction 2 times; Combining extraction liquid, saturated common salt washing, anhydrous sodium sulfate drying, filtration, concentrated, concentrated solution obtains 4-cyano group-4-Phenylpiperidine 3 through chromatographic separation or recrystallization purifying.
Be dissolved in dehydrated alcohol by described 4-cyano group-4-Phenylpiperidine 3, concentration controls at 0.1 ~ 1M, is cooled to 0 DEG C, the vitriol oil of instillation 5.0 ~ 10.0eq, stirring reaction 0.5h; Be warming up to backflow, reaction 10 ~ 20h; Be down to room temperature, reaction solution poured into cold K
2cO
3in the aqueous solution, regulate pH to 10, add the ethyl acetate of reaction volume 2 ~ 5 times, methylene dichloride or chloroform extraction 2 times; Combining extraction liquid, saturated common salt washing, anhydrous sodium sulfate drying, filtration, concentrated, concentrated solution obtains anileridine 4 through chromatographic separation or recrystallization purifying.
Alkali is tertiary amine, pyridine, DMAP, 1,8-diazabicylo 11 carbon-7-alkene, sodium carbonate, sodium bicarbonate, salt of wormwood or saleratus.
Solvent is ether, propyl ether, isopropyl ether, butyl ether, isoamyl oxide, hexyl ether, ethyl vinyl ether, butyl vinyl ether, methyl-phenoxide, phenyl ethyl ether, butyl phenylate, amyl group phenyl ether, ethyl benzyl ether, dibenzyl ether, diox, trioxane, tetrahydrofuran (THF), glycol dimethyl ether, ethylene glycol diethyl ether, ethylene glycol dibutyl ether, N, dinethylformamide, N, N-diethylformamide, N, N-N,N-DIMETHYLACETAMIDE, dimethyl sulfoxide (DMSO), acetonitrile, methyl-formiate, ethyl formate, propyl formate, butyl formate, tetryl formate, pentyl formate, methyl acetate, ethyl acetate, propyl acetate, butylacetate, isobutyl acetate, pentyl acetate, methyl propionate, ethyl propionate, propyl propionate, butyl propionate, isobutyl propionate, amyl propionate, methylene dichloride, chloroform, tetracol phenixin, monochloroethane or 1, 2-ethylene dichloride.
Containing two amino in the molecule of the raw materials used p-aminophenyl ethamine 2 of the present invention, all with sulphonate 1, ring-closure reaction occurs, be shown below, reaction product comprises: the target product 3 that the alkylamine on p-aminophenyl ethamine 2 and sulphonate 1 react; The by product 7 that aromatic amine on p-aminophenyl ethamine 2 and sulphonate 1 react; The by product 8 that alkylamine on p-aminophenyl ethamine 2 and aromatic amine all react with sulphonate 1.
The present invention is investigated the temperature of reaction of above-mentioned ring-closure reaction, reaction times, the consumption of p-aminophenyl ethamine 2 and the consumption of alkali by conditional filtering experiment, avoids the generation of by product 7 and 8 largely.Found by conditional filtering experiment: the temperature of reaction of above-mentioned ring-closure reaction should between 120 DEG C ~ 140 DEG C, when temperature of reaction is 100 DEG C, not exclusively, the productive rate of target compound 3 is lower in reaction, (is greater than 140 DEG C) and causes the increase of by product 8 when temperature of reaction is higher; The consumption of p-aminophenyl ethamine 2 should between 3 ~ 5 times of sulphonate 1 consumption, and the consumption of p-aminophenyl ethamine 2 obviously declines lower than the reaction yield of target compound during 3eq 3, and the consumption of p-aminophenyl ethamine 2 can not significantly improve productive rate more than 5eq.
In the present invention, raw materials used sulphonate 1 is that raw material obtains through one kettle way by benzyl cyanide, and reaction formula is as follows:
Gained intermediate 4-cyano group-4-Phenylpiperidine 3 of the present invention, high yield can obtain target compound anileridine 4 by alcoholysis reaction in the ethanolic soln of the vitriol oil.
Beneficial effect of the present invention:
(1) the present invention is in the annulation taking p-aminophenyl ethamine 2 as raw material and sulphonate 1 generation, screened by reaction conditions, decrease the generation of by product 7 and 8, the productive rate of target compound 3 is made to be greater than 90%, synthetic route two step total recovery reaches 70 ~ 80%, compares literature method combined coefficient high;
(2) in two-step reaction involved in the present invention, reaction raw materials is cheaply easy to get, and does not use expensive catalyst, and without hypertoxic intermediate, synthesis cost is low.
Embodiment
Embodiment 1
The preparation of methylsulfonic acid-3-cyano group-3-phenyl penta diester
Be dissolved in by diisopropylamine (3.30mL, 24mmol) in 20mL anhydrous tetrahydro furan, argon shield borehole cooling is to-30 DEG C, and instillation 2.4mol/L n-Butyl Lithium (10mL, 24mmol), reacts 0.5h; Add benzyl cyanide (1.17g, 10mmol), continue stirring reaction 0.5h; Instillation oxyethane (1.06g, 24mmol), reaction 0.5h; Instillation methylsulfonyl chloride (2.74g, 24mmol), continues stirring reaction 0.5h; Slowly rise to 0 DEG C of reaction 1h, add 1mL water termination reaction; Steam except tetrahydrofuran (THF), add 50mL methylene dichloride and 20mL water extracts, aqueous phase 50mL methylene dichloride extracts again; Merge organic phase, saturated common salt is washed, anhydrous sodium sulfate drying, filters, and is separated to obtain white solid, yield 65% after concentrated through silica gel column chromatography.
1HNMR(400MHz，CDCl
3)：δ7.56～7.36(m，5H)，4.20(m，4H)，2.94(s，6H)，2.59(dt，J＝14.1，7.0Hz，2H)，2.46(ddd，J＝14.4，6.8，6.0Hz，2H)；
13CNMR(100MHz，CDCl
3)：δ135.0，129.6，129.0，125.7，120.3，64.7，43.3，39.7，37.4；
MS(ESI，m/z)：379.1[M+NH
4]
+.
Embodiment 2
The preparation of intermediate piperidine 3 and by product piperidines 8
Sulphonate 1 (10.6g, 29.4mmol) is dissolved in 100mLTHF, adds Et
3n (17.6mL, 145mmol) and p-aminophenyl ethamine 2 (12.0g, 88.2mmol), be warming up to 120 DEG C of reaction 20h in closed reactor; Stopped reaction, is down to room temperature, and steaming desolventizes, and adds 200mL methylene dichloride and 100mL water extracts, and aqueous phase 100mL methylene dichloride extracts again; Merge organic phase, saturated common salt is washed, anhydrous sodium sulfate drying, filters, and is separated to obtain piperidines 38.20g, yield 91.5% after concentrated through silica gel column chromatography; Another by product piperidines 80.42g.
The spectral data of intermediate piperidine 3:
1HNMR(600MHz，CDCl
3)δ7.52～7.45(m，2H)，7.38(dd，J＝10.5，4.9Hz，2H)，7.30(t，J＝7.3Hz，1H)，6.98(d，J＝8.3Hz，2H)，6.61(d，J＝8.3Hz，2H)，3.55(s，2H)，3.08(d，J＝12.4Hz，2H)，2.71(dd，J＝10.2，5.4Hz，2H)，2.64(dd，J＝10.3，5.2Hz，2H)，2.54(td，J＝12.1，3.9Hz，2H)，2.17～2.07(m，4H).
13CNMR(150MHz，CDCl
3)δ144.5，140.2，130.0，129.4，129.0，128.1，125.6，122.0，115.3，60.7，50.8，42.8，36.6，32.8.
HRMScalcdfor[M+H]
+306.1970，found306.1974.
The spectral data of by product piperidines 8:
1HNMR(600MHz，CDCl
3)δ7.56(dd，J＝11.3，4.2Hz，4H)，7.48～7.41(m，4H)，7.40～7.33(m，2H)，7.19(d，J＝8.5Hz，2H)，6.98(d，J＝8.6Hz，2H)，3.77(d，J＝13.1Hz，2H)，3.29～3.22(m，2H)，3.14(d，J＝12.3Hz，2H)，2.82(dd，J＝10.1，5.8Hz，2H)，2.73(dd，J＝10.2，5.7Hz，2H)，2.61(td，J＝11.8，3.9Hz，2H)，2.26(dd，J＝10.2，3.6Hz，4H)，2.22～2.13(m，5H).
13CNMR(150MHz，CDCl
3)δ149.4，140.2，140.0，132.0，129.4，129.1(129.11)，129.1(129.07)，129.0，128.3，128.1，125.6，122.1，121.7，117.2，60.4，50.8，47.8，42.8，42.7，36.6，36.4，32.8.
HRMScalcdfor[M+H]
+475.2862，found475.2863.
Embodiment 3
The preparation of intermediate piperidine 3 and by product piperidines 8
Sulphonate 1 (10.6g, 29.4mmol) is dissolved in 100mLTHF, adds Et
3n (17.6mL, 145mmol) and p-aminophenyl ethamine 2 (12.0g, 88.2mmol), be warming up to 140 DEG C of reaction 12h in closed reactor; Stopped reaction, is down to room temperature, and steaming desolventizes, and adds 200mL methylene dichloride and 100mL water extracts, and aqueous phase 100mL methylene dichloride extracts again; Merge organic phase, saturated common salt is washed, anhydrous sodium sulfate drying, filters, and is separated to obtain piperidines 38.12g, yield 90.3% after concentrated through silica gel column chromatography; Another by product piperidines 80.56g.
The spectral data of intermediate piperidine 3 and by product piperidines 8 is shown in embodiment 2
Embodiment 4
The preparation of anileridine 4
Piperidines 3 (1.98g, 6.5mmol) is dissolved in 10mL ethanol, is cooled to 0 DEG C, the instillation 3mL vitriol oil, stirring reaction 0.5h; Be warming up to backflow, reaction 10h; Be down to room temperature, reaction solution poured into cold K
2cO
3in the aqueous solution, regulate PH to 10, add 100mL extraction into ethyl acetate, aqueous phase 50mL ethyl acetate extracts again; Merge organic phase, saturated common salt is washed, anhydrous sodium sulfate drying, filters, and is separated to obtain anileridine 41.85g, yield 80.6% after concentrated through silica gel column chromatography
1HNMR(600MHz，CDCl
3)δ7.36(d，J＝7.7Hz，2H)，7.30(t，J＝7.7Hz，2H)，7.22(dd，J＝13.0，5.5Hz，1H)，6.96(d，J＝8.2Hz，2H)，6.59(d，J＝8.2Hz，2H)，4.10(q，J＝7.1Hz，2H)，3.53(s，2H)，2.92(s，2H)，2.72～2.64(m，2H)，2.57(d，J＝13.0Hz，2H)，2.54～2.46(m，2H)，2.20(d，J＝11.0Hz，2H)，1.99(s，2H)，1.15(t，J＝7.1Hz，3H).
13CNMR(150MHz，CDCl
3)δ174.4，144.5，142.8，130.0，129.5，128.5，126.9，125.8，115.3，61.0，60.8，51.5，49.3，33.8，32.8，14.1.
HRMScalcdfor[M+H]
+353.2229，found353.2233。
Claims (1)
1. a synthetic method for anileridine, it is characterized in that this synthetic method synthesizes anileridine (4) by two-step reaction, reaction formula is as follows:
Concrete reactions steps is as follows:
Be dissolved in solvent by sulphonate (1), concentration controls at 0.01 ~ 1M, adds the alkali of 2 ~ 5eq and the p-aminophenyl ethamine (2) of 3 ~ 5eq, is warming up to 120 ~ 140 DEG C of reaction 12 ~ 24h in closed reactor; Stopped reaction, is down to room temperature, and steaming desolventizes, and adds the ethyl acetate of reaction product volume 1 ~ 5 times, methylene dichloride or chloroform extraction 2 times; Combining extraction liquid, saturated common salt washing, anhydrous sodium sulfate drying, filtration, concentrated, concentrated solution obtains 4-cyano group-4-Phenylpiperidine (3) through chromatographic separation or recrystallization purifying;
Be dissolved in dehydrated alcohol by described 4-cyano group-4-Phenylpiperidine (3), concentration controls at 0.1 ~ 1M, is cooled to 0 DEG C, the vitriol oil of instillation 5.0 ~ 10.0eq, stirring reaction 0.5h; Be warming up to backflow, reaction 10 ~ 20h; Be down to room temperature, be poured into cold K
2cO
3in the aqueous solution, regulate pH to 10, add the ethyl acetate of reaction volume 2 ~ 5 times, methylene dichloride or chloroform extraction 2 times; Combining extraction liquid, saturated common salt washing, anhydrous sodium sulfate drying, filtration, concentrated, concentrated solution obtains anileridine (4) through chromatographic separation or recrystallization purifying;
Described alkali is tertiary amine, pyridine, DMAP, 1,8-diazabicylo 11 carbon-7-alkene, sodium carbonate, sodium bicarbonate, salt of wormwood or saleratus;
Described solvent is ether, propyl ether, isopropyl ether, butyl ether, isoamyl oxide, hexyl ether, ethyl vinyl ether, butyl vinyl ether, methyl-phenoxide, phenyl ethyl ether, butyl phenylate, amyl group phenyl ether, ethyl benzyl ether, dibenzyl ether, diox, trioxane, tetrahydrofuran (THF), glycol dimethyl ether, ethylene glycol diethyl ether, ethylene glycol dibutyl ether, N, dinethylformamide, N, N-diethylformamide, N, N-N,N-DIMETHYLACETAMIDE, dimethyl sulfoxide (DMSO), acetonitrile, methyl-formiate, ethyl formate, propyl formate, butyl formate, tetryl formate, pentyl formate, methyl acetate, ethyl acetate, propyl acetate, butylacetate, isobutyl acetate, pentyl acetate, methyl propionate, ethyl propionate, propyl propionate, butyl propionate, isobutyl propionate, amyl propionate, methylene dichloride, chloroform, tetracol phenixin, monochloroethane or 1, 2-ethylene dichloride.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510317736.6A CN105037250B (en) | 2015-06-11 | 2015-06-11 | A kind of synthetic method of anileridine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510317736.6A CN105037250B (en) | 2015-06-11 | 2015-06-11 | A kind of synthetic method of anileridine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105037250A true CN105037250A (en) | 2015-11-11 |
| CN105037250B CN105037250B (en) | 2017-12-12 |
Family
ID=54444291
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510317736.6A Active CN105037250B (en) | 2015-06-11 | 2015-06-11 | A kind of synthetic method of anileridine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105037250B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB840006A (en) * | 1956-08-08 | 1960-07-06 | Merck & Co Inc | Synthesis of substituted piperidines |
| US2966490A (en) * | 1955-05-26 | 1960-12-27 | Merck & Co Inc | Nu-[beta-(p-aminophenyl) ethyl]-4-phenyl-4-carboethoxypiperidine salts thereof and processes of preparing the same |
| CN103980186A (en) * | 2013-02-07 | 2014-08-13 | 上海威智医药科技有限公司 | Preparation method of amino protection (R)-3-amino piperidine |
-
2015
- 2015-06-11 CN CN201510317736.6A patent/CN105037250B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2966490A (en) * | 1955-05-26 | 1960-12-27 | Merck & Co Inc | Nu-[beta-(p-aminophenyl) ethyl]-4-phenyl-4-carboethoxypiperidine salts thereof and processes of preparing the same |
| GB840006A (en) * | 1956-08-08 | 1960-07-06 | Merck & Co Inc | Synthesis of substituted piperidines |
| CN103980186A (en) * | 2013-02-07 | 2014-08-13 | 上海威智医药科技有限公司 | Preparation method of amino protection (R)-3-amino piperidine |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105037250B (en) | 2017-12-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104447445B (en) | A kind of preparation method synthesizing Apremilast intermediate | |
| WO2012100722A1 (en) | Process for preparing racemic nicotine | |
| EP3828170A1 (en) | Method for safely preparing pimavanserin and tartrate salt thereof using triphosgene | |
| CN103435538B (en) | (R) preparation method of-3-amido piperidine hydrochlorate | |
| CN102127005B (en) | Intermediate of alvimopan and synthesis method thereof | |
| CN103664776A (en) | Preparation method for tyrosine kinase inhibitor and midbody thereof | |
| CN110028433B (en) | Preparation method of deuterium-labeled doxapram and metabolite thereof | |
| CN106366022A (en) | Intermediate used for AZD9291 preparation, and preparation method and application thereof | |
| CN103087019B (en) | Preparation method of tasimelteon | |
| CN103254122B (en) | Preparation method of cardiovascular drug nilvadipine | |
| CN101186607A (en) | Method for synthesizing palonosetron hydrochloride | |
| CN105037250A (en) | Synthesis method of anileridine | |
| CN102936216B (en) | Preparation method of 7,9-dioxo-2,6-aza-spiro[3.5]nona-2-tert-butyl formate and intermediate thereof | |
| CN102070513B (en) | Synthesis method of 1-teriary butoxy carbonyl-4-piperidone | |
| CN102898356A (en) | Method for preparing 1-( 3-methoxy propyl )- 4-piperidine amine and salt thereof | |
| CN104177301B (en) | A kind of preparation method of dexrazoxane | |
| CN105111155A (en) | Synthesis method of tert-butyl 4,7-diazaspiro[2.5]octyl-7-formate | |
| CN104447355A (en) | Novel method for preparing bromhexine hydrochloride | |
| CN104693090A (en) | Silodosin and preparation methods for intermediates thereof | |
| CN102731368A (en) | Preparation method of 5,5-difluoro-3-substituted piperidine derivative | |
| CN103896826A (en) | Asymmetric synthesis method of nitrogen protected (3R,4R)-3-methylamino-4-methylpiperidine, and relevant intermediate and raw material preparation method | |
| CN105968103A (en) | Synthesis method of anti-tumor medicine afatinib | |
| CN104262301A (en) | Method for synthesizing S-(+)-tetrahydrofuran-3-methanol | |
| CN101723879B (en) | Method for synthesizing (R)-3-ethyl piperidine hydrochloride | |
| CN103570781B (en) | A kind of industrialized process for preparing of capecitabine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |