CN104003929B - A kind of synthetic method of α, α-diphenyl-4-piperidine carbinols - Google Patents
A kind of synthetic method of α, α-diphenyl-4-piperidine carbinols Download PDFInfo
- Publication number
- CN104003929B CN104003929B CN201410176820.6A CN201410176820A CN104003929B CN 104003929 B CN104003929 B CN 104003929B CN 201410176820 A CN201410176820 A CN 201410176820A CN 104003929 B CN104003929 B CN 104003929B
- Authority
- CN
- China
- Prior art keywords
- piperidine
- gained
- chloride
- diphenyl
- acetyl group
- 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
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
- C07D211/08—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
Abstract
The synthetic method of open a kind of α, α diphenyl 4 piperidine carbinols of the present invention, i.e. with 4 piperidine carboxylic acids as raw material, reacts with acetylation reagent and obtains N Acetylpiperidin formic acid；The N Acetylpiperidin formic acid obtained first generates N Acetylpiperidin formyl chloride, generates N acetyl 4 benzoyl piperidine with benzene generation friedel-crafts acylation again；Gained N acetyl 4 benzoyl piperidine and phenyl-magnesiumhalide generation grignard reaction obtain N acetyl group α, α diphenyl 4 piperidine carbinols；Gained N acetyl group α, α diphenyl 4 piperidine carbinols deacetylate i.e. obtains α, α diphenyl 4 piperidine carbinols.This synthetic method has that raw material is cheap and easy to get, processing step is simple, reaction yield is high, low raw-material cost, be suitable for the features such as industrialized production.
Description
Technical field
The present invention relates to the synthetic method of a kind of α, α-diphenyl-4-piperidine carbinols.Specifically with 4-piperidine carboxylic acid as raw material, through N-acetylation, friedel-crafts acylation and grignard reagent benzene base magnesium halide addition, hydrolyze deacetylate again and obtain α, α-diphenyl-4-piperidine carbinols.Belong to organic chemical industry and synthesize field.
Background technology
α, α-diphenyl-4-piperidine carbinols another name azacyclonol (Azacyclonol), is the key intermediate of the Loratadines such as synthetic hydrochloric acid fexofenadine (Fexofenadine).The most traditional synthetic method of α, α-diphenyl-4-piperidine carbinols mainly has three routes: Article 1 is raw material with α, α-diphenyl-4-piconol, through Pt/C, the route of hydrogen high pressure reduction；Article 2 is with 4-cyanopyridine as raw material, through generating sodium salt with metallic sodium, then with benzophenone through free radical coupling and the route of catalytic hydrogenation；Article 3 with γ pyridine carboxylic acid ethyl ester as initiation material, hydrogenated reduction, N-benzyloxy phosphinylidyne epoxide fourth lactim protects, then becomes the tertiary alcohol with form reagent reacting, and after prepare the route of target product through catalytic hydrogenolysis deprotection.Above method is respectively present the shortcomings such as source chemicals is rare, reactions steps is more, need reaction under high pressure, yield relatively low.
Presently preferred synthetic route, is with 4-piperidine ethyl formate hydrochlorate as raw material, goes benzyl protection to obtain the route of α, α-diphenyl-4-piperidine carbinols through N-benzyl protection and grignard reagent benzene base magnesium halide addition, again catalytic hydrogenolysis.This route raw materials technology is cheap and easily-available, easy and simple to handle, often step reaction yield the highest, be a synthetic route with industrial applications prospect.But the subject matter of this route is in grignard reaction step, expensive phenyl-magnesiumhalide, and 4 times more than that the consumption of phenyl-magnesiumhalide is substrate to be used.Final step debenzylation uses noble metal catalyst so that the production cost of α, α-diphenyl-4-piperidine carbinols is higher.
Summary of the invention
The purpose of the present invention is in order to solve above-mentioned α, the technical problem that the production cost of α-diphenyl-4-piperidine carbinols is high, and the α that a kind of production cost is low is provided, the synthetic method of α-diphenyl-4-piperidine carbinols, the method has feature easy and simple to handle, to be suitable to industrialization synthesis α, α-diphenyl-4-piperidine carbinols simultaneously.
Technical scheme
A kind of α; the synthetic method of α-diphenyl-4-piperidine carbinols; i.e. with 4-piperidine carboxylic acid as raw material; through N-acetylation, friedel-crafts acylation and grignard reagent benzene base magnesium halide addition, again hydrolyze deacetylate protection synthesis α; α-diphenyl-4-piperidine carbinols, its concrete synthetic route is as follows:
The synthetic method of above-mentioned a kind of α, α-diphenyl-4-piperidine carbinols, specifically comprising the following steps that of its building-up process
(1), 4-piperidine carboxylic acid and acetylation reagent under being heated to reflux, carry out N-acetylization reaction 4-6h, obtain N-Acetylpiperidin formic acid；
Described acetylation reagent is chloroacetic chloride, acetic anhydride or acetic acid；
The above-mentioned 4-piperidine carboxylic acid used by N-acetylization reaction and the amount of acetylation reagent, calculate, i.e. 4-piperidine carboxylic acid: acetylation reagent is 1:1.5-2 in molar ratio；
(2), the N-Acetylpiperidin formic acid of step (1) gained and chloride reagent, at temperature is 20-40 DEG C, react 6-8h, the reactant liquor of gained, successively through vacuum rotary steam, petroleum ether, obtains N-Acetylpiperidin formyl chloride；
Described chloride reagent is butter or organic acyl chlorides；Described butter is thionyl chloride or Phosphorous chloride.；Described organic acyl chlorides is chloroacetic chloride, Benzenecarbonyl chloride. or oxalyl chloride；
N-Acetylpiperidin formic acid used by above-mentioned course of reaction and the amount of chloride reagent, calculate, i.e. N-Acetylpiperidin formic acid: chloride reagent is 1:2 in molar ratio；
The N-Acetylpiperidin formyl chloride of gained, controlling temperature with benzene under aluminum chloride effect is 70 DEG C, carries out the friedel-crafts acylation reaction 10h that refluxes, the reactant liquor of gained successively through hydrolysis, separatory, wash, revolve steaming, obtain N-acetyl group-4-benzoyl piperidine；
N-Acetylpiperidin formyl chloride used by above-mentioned course of reaction, aluminum chloride, the amount of benzene, calculate in molar ratio, i.e. N-Acetylpiperidin formyl chloride: aluminum chloride: benzene is 1:2.5-2.7:5；
(3), in ether solvent the N-acetyl group-4-benzoyl piperidine of step (2) gained and grignard reagent benzene base magnesium halide control under nitrogen protection temperature be 25-30 DEG C carry out grignard reaction 24h after; the reactant liquor of gained is successively through hydrolyzing, extract, be dried, concentrating; obtain N-acetyl group-α, α-diphenyl-4-piperidine carbinols；
Described Grignard reagent phenyl-magnesiumhalide is phenyl-magnesium-bromide or phenyl-magnesium-chloride；
Described ether solvent is ether, oxolane, diisopropyl ether or methyl tertiary butyl ether(MTBE)；
N-acetyl group-4-benzoyl piperidine used by above-mentioned grignard reaction and the amount of grignard reagent benzene base magnesium halide, calculate, N-acetyl group-4-benzoyl piperidine: Grignard reagent phenyl-magnesiumhalide is 1:1.2-1.5 in molar ratio；
(4), in alcohols solvent; N-acetyl group-the α of step (3) gained; α-diphenyl-4-piperidine carbinols is at hydrochloric acid; preferably under the effect of the aqueous hydrochloric acid solution that mass percent concentration is 15-18%; control temperature 65-97 DEG C and be hydrolyzed reaction 8-12h with the acetyl group sloughing on nitrogen; the reactant liquor of gained is neutralized, extract, be dried and concentrate, final α, α-diphenyl-4-piperidine carbinols；
Described alcohols solvent is methanol, ethanol, normal propyl alcohol or isopropanol, its consumption, by N-acetyl group-α, α-diphenyl-4-piperidine carbinols: alcohols solvent is that the ratio of 0.5mol:1L calculates；
The usage amount of described aqueous hydrochloric acid solution, by N-acetyl group-α, α-diphenyl-4-piperidine carbinols: aqueous hydrochloric acid solution is that the ratio of 0.25mol:1L calculates.
The Advantageous Effects of the present invention
A kind of α of the present invention, the synthetic method of α-diphenyl-4-piperidine carbinols, due in used technology path, relate to is popular response, the raw material used is cheap and easy to get, need not the specific conditions such as High Temperature High Pressure, it is to avoid use expensive noble metal catalyst, therefore this synthetic method have easy and simple to handle, production cost is low, be suitable to the features such as industrialization.
Detailed description of the invention
Below by specific embodiment, the present invention is expanded on further, but is not limiting as the present invention.
In various embodiments of the present invention, nuclear magnetic resonance analyser used is Brucker
AM500 (500MHz) nuclear magnetic resonance analyser, TMS is internal standard；Melting point apparatus is WRS-1C melting point apparatus (Shanghai Physics Optics Instrument Factory).
Shanghai Hai Qu chemical company of 4-piperidine carboxylic acid manufacturer, the specification of remaining raw material is chemical pure, Shanghai traditional Chinese medicines provide.
Embodiment 1
A kind of synthetic method of α, α-diphenyl-4-piperidine carbinols, specifically comprising the following steps that of its building-up process
(1), the synthesis of N-acetyl group-4-piperidine carboxylic acid
250 mL four-hole bottles of the condensing tube being furnished with drying tube to the mouth of pipe add 4-piperidine carboxylic acid (38.8g, 0.30mol), 58mL acetic anhydride, continuing 6h, TLC detection reaction after being slowly ramped to backflow complete, the reactant liquor of gained is cooled to room temperature, a large amount of Light brown solid is had to separate out, sucking filtration goes out solid, solid sucking filtration after the washing of appropriate methyl tertiary butyl ether(MTBE), obtains Light brown solid, carry out recrystallization with methanol and obtain off-white color solid 46.3g, yield 90.1 %；
The above-mentioned 4-piperidine carboxylic acid used by N-acetylization reaction and the amount of acetylation reagent, calculate, i.e. 4-piperidine carboxylic acid: acetylation reagent is 1:2 in molar ratio；
The white solid industry nuclear magnetic resoance spectrum of above-mentioned gained detects, and its nuclear magnetic resonance, NMR modal data is as follows:1H NMR (CDCl3, 500 MHz): δ: 1.72 (m, 4H), 2.04 (s, 3H), 2.41 (m, 1H), 3.36 (t, 4H), 10.6 (s,
1H).Result shows, the white solid product of preparation method gained of the present invention is N-acetyl group-4-piperidine carboxylic acid；
(2), the synthesis of N-acetyl group-4-benzoyl piperidine
It is furnished with in the condensing tube of drying tube, thermometer and mechanical agitator 100 mL four-hole bottle to the mouth of pipe; add N-acetyl group-4-piperidine carboxylic acid (17.2 g of step (1) gained; 0.10mol) with 50mL toluene; it is heated to solid and dissolves to obtain homogeneous phase solution; add 15mL chloride reagent i.e. thionyl chloride, be heated to 40 DEG C and keep 6h in this temperature, by reactant liquor vacuum rotary steam to dry; obtain residual liquid petroleum ether and obtain white or faint yellow solid 18.3g, yield 96.7%；
N-Acetylpiperidin formic acid used by above-mentioned course of reaction and the amount of chloride reagent thionyl chloride, calculate, i.e. N-Acetylpiperidin formic acid: chloride reagent thionyl chloride is 1:2 in molar ratio；
It is furnished with to the mouth of pipe in the condensing tube of drying tube and the 250mL four-hole bottle of thermometer, add above-mentioned prepared N-acetyl group-4-piperidine formyl chlorine (18.3g, 0.097mol) with 50mL benzene, heating for dissolving makes reactant liquor become homogeneous, add 35g aluminum trichloride (anhydrous), it is warming up to 70 DEG C, back flow reaction 10h, the reactant liquor of gained is poured into after being cooled to room temperature in the frozen water by 30mL ice cube and 50mL concentrated hydrochloric acid and is hydrolyzed, after being fully hydrolyzed, upper strata oil reservoir is separated with separatory funnel, water layer 50mL toluene extracts 3 times, oil reservoir merges, wash 3 times with saturated sodium-chloride water, solution rotation is steamed to dry, stand overnight, obtain faint yellow solid N-acetyl group-4-benzoyl piperidine 17.5g, yield 78.5%；
N-Acetylpiperidin formyl chloride used by above-mentioned course of reaction, aluminum chloride, the amount of benzene, calculate in molar ratio, i.e. N-Acetylpiperidin formyl chloride: aluminum chloride: benzene is 1:2.5:5；
The nuclear magnetic resonance, NMR modal data of the faint yellow solid product of above-mentioned gained is as follows:1H NMR (CDCl3, 500 MHz): δ: 1.62 (m, 4H), 2.02 (s, 3H), 3.1 (m, 1H), 3.35 (t, 4H), 7.66 (m,
5H).The faint yellow solid product of preparation method gained of the present invention is N-acetyl group-4-benzoyl piperidine；
(3), the synthesis of N-acetyl group-α, α-diphenyl-4-piperidine carbinols
Stirring is being installed, Dropping funnel, airway, on the four-hole bottle of condensing tube, under nitrogen protection, add magnesium (3.25g, 0.13mol), oxolane (20mL), with iodine (0.1g), after the mixture of gained is heated to reflux causing to reaction, slowly drip chlorobenzene (14.6g, 0.13mol) with oxolane (15mL), reactant is made to maintain the reflux for, dripping complete continuation backflow makes magnesium react completely, obtain phenyl-magnesium-chloride, then 10 DEG C it are cooled to, N-acetyl group-4-benzoyl piperidine (the 23.1g of dropping step (2) gained, 0.10mol) with oxolane (25mL), after dripping off control temperature be 25-30 DEG C overnight, about 60 are dripped under ice bath
ML saturated aqueous ammonium chloride, a large amount of white solid is had to generate, it is stirred at room temperature to solid and all dissolves, separating organic layer, water layer dichloromethane extracts, and merges organic layer, successively with saturated brine, saturated sodium carbonate, saturated brine washing, anhydrous sodium sulfate is dried, filters, and concentrating under reduced pressure obtains white solid 26.3g, yield 85.1%；
N-acetyl group-4-benzoyl piperidine used by above-mentioned grignard reaction and the amount of Grignard reagent, calculate, N-acetyl group-4-benzoyl piperidine: Grignard reagent is 1:1.2 in molar ratio；
The nuclear magnetic resonance, NMR modal data of the white solid product of above-mentioned gained is as follows:1H NMR (CDCl3, 500 MHz): δ: 1.54 (m, 4H), 2.01 (s, 1H), 2.02 (s, 3H), 2.31
( m, 1H) ,3.32 ( t, 4H) ,7.09 ( m, 10H)。
Nuclear magnetic resoance spectrum data result shows, the white solid product of preparation method gained of the present invention is N-acetyl group-α, α-diphenyl-4-piperidine carbinols；
(4), the synthesis of α, α-diphenyl-4-piperidine carbinols
In 100ml alcohol solvent, N-acetyl group-the α of step (3) gained, α-diphenyl-4-piperidine carbinols (15.5g, 0.05mol) with mass percent concentration be 18% aqueous hydrochloric acid solution (200mL) control temperature 65-97 DEG C be hydrolyzed reaction 12h, TLC detection reaction is complete, reactant liquor is cooled to room temperature, extract with dichloromethane (2*50mL), the residual liquid that water layer is concentrated under reduced pressure to give, it is neutralized to pH for neutrality with 0.1N sodium hydroxide (100mL), dichloromethane (3*60mL) extracts, organic layer merges, anhydrous sodium sulfate is dried, filter, concentrating under reduced pressure obtains white solid 12.7g, yield 95.0%；Fusing point 160-161 DEG C.
Nuclear magnetic resonance, NMR modal data is as follows:1H NMR (CDCl3, 500 MHz): δ: 1.49 (m, 4H), 2.01 (s, 1H), 2.60 (m, 1H), 3.02 (t, 4H), 7.21 (m,
10H).Result shows, the white solid product of preparation method gained of the present invention is α, α-diphenyl-4-piperidine carbinols.
Embodiment 2
A kind of synthetic method of α, α-diphenyl-4-piperidine carbinols, specifically comprising the following steps that of its building-up process
(1) 250 mL four-hole bottles of the condensing tube, being furnished with drying tube to the mouth of pipe add 4-piperidine carboxylic acid (38.8g, 0.30mol), 32 mL chloroacetic chloride, continuing 4h, TLC detection reaction after being slowly ramped to backflow complete, the reactant liquor of gained is cooled to room temperature, a large amount of Light brown solid is had to separate out, sucking filtration goes out solid, solid sucking filtration after the washing of appropriate methyl tertiary butyl ether(MTBE), obtains Light brown solid, carry out recrystallization with methanol and obtain off-white color solid 46.3g, yield 90.1 %；
The above-mentioned 4-piperidine carboxylic acid used by N-acetylization reaction and the amount of acetylation reagent, calculate, i.e. 4-piperidine carboxylic acid: acetylation reagent is 1:1.5 in molar ratio；
Nuclear magnetic resoance spectrum data consistent with Example 1.
(2), it is furnished with in the condensing tube of drying tube, thermometer and mechanical agitator 100 mL four-hole bottle to the mouth of pipe; add N-acetyl group-4-piperidine carboxylic acid (17.2 g of step (1) gained; 0.10mol) He 50 mL toluene; it is heated to solid and dissolves to obtain homogeneous phase solution; add 19g chloride reagent, be heated to 20 DEG C and keep 8h in this temperature, by reactant liquor vacuum rotary steam to dry; obtain residual liquid petroleum ether and obtain white or faint yellow solid 16.8g, yield 88.6%；
Described chloride reagent is organic acyl chlorides；Described organic acyl chlorides is oxalyl chloride；
N-Acetylpiperidin formic acid used by above-mentioned course of reaction and the amount of chloride reagent, calculate, i.e. N-Acetylpiperidin formic acid: chloride reagent is 1:2 in molar ratio；
The N-Acetylpiperidin formyl chloride of gained, under aluminum chloride effect again with benzene generation friedel-crafts acylation reaction, generate N-acetyl group-4-benzoyl piperidine；
It is furnished with to the mouth of pipe in the condensing tube of drying tube and the 250mL four-hole bottle of thermometer, add the N-acetyl group-4-piperidine formyl chlorine (16.8g of step (1) gained, 0.089mol) with 50mL anhydrous benzene, heating for dissolving makes reactant liquor become homogeneous, add 35g aluminum trichloride (anhydrous), it is warming up to 70 DEG C, back flow reaction 10h, the reactant liquor of gained is poured into after being cooled to room temperature after being fully hydrolyzed in the frozen water by 30mL ice cube and 50mL concentrated hydrochloric acid, upper strata oil reservoir is separated with separatory funnel, water layer 80mL toluene extracts 3 times, oil reservoir merges, wash 3 times with saturated sodium-chloride water, solution rotation is steamed to dry, stand overnight, obtain faint yellow solid N-acetyl group-4-benzoyl piperidine 15.8g, yield 78.2%,
N-Acetylpiperidin formyl chloride used by above-mentioned course of reaction, aluminum chloride, the amount of benzene, calculate in molar ratio, i.e. N-Acetylpiperidin formyl chloride: aluminum chloride: benzene is 1:2.7:5；
The faint yellow solid product nuclear magnetic resoance spectrum data consistent with Example 1 of above-mentioned gained；
(3), stirring is being installed, Dropping funnel, airway, on the four-hole bottle of condensing tube, add magnesium (3.25g under nitrogen protection, 0.13mol), oxolane (20mL), with iodine (0.1g), after the mixture of gained is heated to reflux causing to reaction, slowly drip bromobenzene (20.4g, 0.13mol) with oxolane (15mL), reactant is made to maintain the reflux for, dripping complete continuation backflow makes magnesium react completely, obtain phenyl-magnesium-bromide, then 10 DEG C it are cooled to, N-acetyl group-4-benzoyl piperidine (the 23.1g of dropping step (2) gained, 0.10mol) with oxolane (25mL), in 25-30 DEG C of incubated overnight after dripping off, about 60 are dripped under ice bath
ML saturated aqueous ammonium chloride, a large amount of white solid is had to generate, it is stirred at room temperature to solid and all dissolves, separating organic layer, water layer dichloromethane extracts, and merges organic layer, successively with saturated brine, saturated sodium carbonate, saturated brine washing, anhydrous sodium sulfate is dried, filters, and concentrating under reduced pressure obtains white solid 27.3g, yield 88.5%；
Described Grignard reagent is phenyl-magnesium-bromide；
Described ether solvent is oxolane；
N-acetyl group-4-benzoyl piperidine used by above-mentioned grignard reaction and the amount of Grignard reagent, calculate, N-acetyl group-4-benzoyl piperidine: Grignard reagent is 1:1.5 in molar ratio；Nuclear magnetic resoance spectrum data consistent with Example 1；
(4), in 100ml alcoholic solvent, N-acetyl group-the α of step (3) gained, α-diphenyl-4-piperidine carbinols (15.5g, 0.05mol) with mass percent concentration be 15% aqueous hydrochloric acid solution (200mL) control temperature 65-97 DEG C be hydrolyzed reaction 12h, TLC detection reaction is complete, the reactant liquor of gained is cooled to room temperature, extract with dichloromethane (2*50mL), the residual liquid that water layer is concentrated under reduced pressure to give, it is neutralized to pH for neutrality with 0.1N sodium hydroxide (100mL), dichloromethane (3*60mL) extracts, organic layer merges, anhydrous sodium sulfate is dried, filter, concentrating under reduced pressure obtains white solid 12.3g, yield 92.0%；
Nuclear magnetic resoance spectrum data consistent with Example 1.
The above is only the citing of embodiments of the present invention; it should be pointed out that, for those skilled in the art, on the premise of without departing from the technology of the present invention principle; can also make some improvement and modification, these improve and modification also should be regarded as protection scope of the present invention.
Claims (2)
1. the synthetic method of a α, α-diphenyl-4-piperidine carbinols, it is characterised in that specifically include following steps:
(1), 4-piperidine carboxylic acid and acetylation reagent be heated to reflux carrying out N-acetylization reaction 4-6h, the reactant liquor of gained is the most cooled, sucking filtration, washing, again sucking filtration, recrystallization, obtain N-Acetylpiperidin formic acid；
Described acetylation reagent is chloroacetic chloride, acetic anhydride or acetic acid；
The above-mentioned 4-piperidine carboxylic acid used by N-acetylization reaction and the amount of acetylation reagent, calculate, i.e. 4-piperidine carboxylic acid: acetylation reagent is 1:1.5-2.0 in molar ratio；
The reactant liquor of described gained is the most cooled, sucking filtration, washing, again sucking filtration, recrystallization, being that the reactant liquor of gained is cooled to room temperature, solid separates out, and sucking filtration washs with methyl tertiary butyl ether(MTBE) after going out solid, then sucking filtration, the Light brown solid methanol obtained carries out recrystallization；
(2), the N-Acetylpiperidin formic acid of step (1) gained and chloride reagent, control to react 6-8h at temperature is 20-40 DEG C, the reactant liquor of gained, successively through vacuum rotary steam, petroleum ether, obtains N-Acetylpiperidin formyl chloride；
Described chloride reagent is butter or organic acyl chlorides；Wherein butter is thionyl chloride or Phosphorous chloride., and organic acyl chlorides is chloroacetic chloride, Benzenecarbonyl chloride. or oxalyl chloride；
N-Acetylpiperidin formic acid used by above-mentioned course of reaction and the amount of chloride reagent, calculate, i.e. N-Acetylpiperidin formic acid: chloride reagent is 1:2 in molar ratio；
The N-Acetylpiperidin formyl chloride of above-mentioned gained, controlling temperature with benzene under aluminum chloride effect is 70 DEG C, carries out the friedel-crafts acylation reaction 10h that refluxes, the reactant liquor of gained successively through hydrolysis, separatory, wash, revolve steaming, obtain N-acetyl group-4-benzoyl piperidine；
N-Acetylpiperidin formyl chloride used by above-mentioned course of reaction, aluminum chloride, the amount of benzene, calculate in molar ratio, i.e. N-Acetylpiperidin formyl chloride: aluminum chloride: benzene is 1:2.5-2.7:5；
The reactant liquor of described gained successively through hydrolysis, separatory, wash, revolve steaming; obtain N-acetyl group-4-benzoyl piperidine, be that the reactant liquor of gained is cooled to room temperature, reactant liquor poured in the frozen water by ice cube and concentrated hydrochloric acid and be hydrolyzed; after being fully hydrolyzed; separating upper strata oil reservoir with separatory funnel, water layer toluene extracts 3 times, and oil reservoir merges; wash 3 times with saturated sodium-chloride water; rotation is steamed to dry, stands overnight, obtains N-acetyl group-4-benzoyl piperidine；
(3), in ether solvent; N-acetyl group-4-the benzoyl piperidine of step (2) gained and grignard reagent benzene base magnesium halide control under nitrogen protection temperature be 25-30 DEG C carry out grignard reaction 24h after; the reactant liquor of gained is successively through hydrolyzing, extract, be dried, concentrating; obtain N-acetyl group-α, α-diphenyl-4-piperidine carbinols；
Described ether solvent is ether, oxolane, diisopropyl ether or methyl tertiary butyl ether(MTBE)；
Described Grignard reagent phenyl-magnesiumhalide is phenyl-magnesium-bromide or phenyl-magnesium-chloride；
N-acetyl group-4-benzoyl piperidine used by above-mentioned grignard reaction and the amount of grignard reagent benzene base magnesium halide, calculate, N-acetyl group-4-benzoyl piperidine: Grignard reagent phenyl-magnesiumhalide is 1:1.2-1.5 in molar ratio；
The reactant liquor of described gained is successively through hydrolyzing, extract, be dried, concentrating; obtain N-acetyl group-α; α-diphenyl-4-piperidine carbinols; it is that the reactant liquor of gained is dripped under ice bath saturated aqueous ammonium chloride; a large amount of white solid is had to generate; it is stirred at room temperature to solid and all dissolves; separate organic layer; water layer dichloromethane extracts, and merges organic layer, successively with saturated brine, saturated sodium carbonate, saturated brine washing; anhydrous sodium sulfate is dried, filters; concentrating under reduced pressure, obtains N-acetyl group-α, α-diphenyl-4-piperidine carbinols；
(4), in alcohols solvent; N-acetyl group-the α of step (3) gained; α-diphenyl-4-piperidine carbinols is under the effect of hydrochloric acid; control temperature 65-97 DEG C is hydrolyzed and reacts 8-12h; the reactant liquor of gained is neutralized, extract, be dried, concentrate; final α, α-diphenyl-4-piperidine carbinols；
Described alcohols solvent is methanol, ethanol, normal propyl alcohol or isopropanol；
Described under the effect of hydrochloric acid, i.e. under the effect of the aqueous hydrochloric acid solution that mass percent concentration is 15-18%；
The usage amount of described aqueous hydrochloric acid solution, by N-acetyl group-α, α-diphenyl-4-piperidine carbinols: aqueous hydrochloric acid solution is that the ratio of 0.25mol:1L calculates；
The reactant liquor of described gained is neutralized, extract, be dried concentration, final α, α-diphenyl-4-piperidine carbinols, is that the reactant liquor of gained is cooled to room temperature, extract with dichloromethane, the residual liquid that water layer is concentrated under reduced pressure to give, it is neutral for being neutralized to pH with 0.1N sodium hydroxide, and dichloromethane extracts, organic layer merges, anhydrous sodium sulfate is dried, filters, concentrating under reduced pressure, obtains α, α-diphenyl-4-piperidine carbinols.
2. α as claimed in claim 1; the synthetic method of α-diphenyl-4-piperidine carbinols; it is characterized in that the consumption of the alcohols solvent described in step (4), by N-acetyl group-α, α-diphenyl-4-piperidine carbinols: alcohols solvent is that the ratio of 0.5mol:1L calculates.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410176820.6A CN104003929B (en) | 2014-04-30 | 2014-04-30 | A kind of synthetic method of α, α-diphenyl-4-piperidine carbinols |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410176820.6A CN104003929B (en) | 2014-04-30 | 2014-04-30 | A kind of synthetic method of α, α-diphenyl-4-piperidine carbinols |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104003929A CN104003929A (en) | 2014-08-27 |
| CN104003929B true CN104003929B (en) | 2016-07-20 |
Family
ID=51364864
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410176820.6A Expired - Fee Related CN104003929B (en) | 2014-04-30 | 2014-04-30 | A kind of synthetic method of α, α-diphenyl-4-piperidine carbinols |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104003929B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108069956B (en) * | 2016-11-18 | 2021-03-16 | 扬州奥锐特药业有限公司 | 1-azabicyclo [2,2,2] oct-4-yl phenyl ketone compound, preparation method and application thereof |
| CN112724070B (en) * | 2021-01-08 | 2022-11-25 | 南京方生和医药科技有限公司 | Preparation method of alpha, alpha-diphenyl-4-piperidinemethanol |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2898339A (en) * | 1957-07-29 | 1959-08-04 | Wm S Merrell Co | N-substituted benzhydrol, benzhydryl, and benzhydrylidene piperidine |
| US4032642A (en) * | 1974-12-11 | 1977-06-28 | A. H. Robins Company, Incorporated | 1-Substituted-4-benzylpiperidines |
| US4810713A (en) * | 1985-12-20 | 1989-03-07 | A. H. Robins Company, Incorporated | Arylalkyl-heterocyclic amines, n-substituted by aryloxyalkyl groups used in a method for allergy treatment |
| US4886794A (en) * | 1987-05-07 | 1989-12-12 | A. H. Robins Company, Incorporated | 4-[(α,α-diaryl)-hydroxymethyl]-1-piperidinylalkyl-cyclic carbamate derivatives as allergic response inhibitors |
| US5070087A (en) * | 1989-05-08 | 1991-12-03 | A. H. Robins Company, Incorporated | Aryl(alkyland alkylene)-N-((phenoxy and phenylthio)alkyl) aminoheterocyclics as cardiovascular, anthihistaminic, antisecretory and antiallergy agents |
| WO1992019596A2 (en) * | 1991-04-30 | 1992-11-12 | Reilly Industries, Inc. | PROCESSES FOR PRODUCING α-PYRIDYL CARBINOLS |
| CN1793138A (en) * | 2005-12-23 | 2006-06-28 | 上海博速医药科技有限公司 | Process for prepering aspetllinone |
-
2014
- 2014-04-30 CN CN201410176820.6A patent/CN104003929B/en not_active Expired - Fee Related
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2898339A (en) * | 1957-07-29 | 1959-08-04 | Wm S Merrell Co | N-substituted benzhydrol, benzhydryl, and benzhydrylidene piperidine |
| US4032642A (en) * | 1974-12-11 | 1977-06-28 | A. H. Robins Company, Incorporated | 1-Substituted-4-benzylpiperidines |
| US4810713A (en) * | 1985-12-20 | 1989-03-07 | A. H. Robins Company, Incorporated | Arylalkyl-heterocyclic amines, n-substituted by aryloxyalkyl groups used in a method for allergy treatment |
| US4886794A (en) * | 1987-05-07 | 1989-12-12 | A. H. Robins Company, Incorporated | 4-[(α,α-diaryl)-hydroxymethyl]-1-piperidinylalkyl-cyclic carbamate derivatives as allergic response inhibitors |
| US5070087A (en) * | 1989-05-08 | 1991-12-03 | A. H. Robins Company, Incorporated | Aryl(alkyland alkylene)-N-((phenoxy and phenylthio)alkyl) aminoheterocyclics as cardiovascular, anthihistaminic, antisecretory and antiallergy agents |
| WO1992019596A2 (en) * | 1991-04-30 | 1992-11-12 | Reilly Industries, Inc. | PROCESSES FOR PRODUCING α-PYRIDYL CARBINOLS |
| CN1793138A (en) * | 2005-12-23 | 2006-06-28 | 上海博速医药科技有限公司 | Process for prepering aspetllinone |
Non-Patent Citations (5)
| Title |
|---|
| Synthesis and Antiallergy Activity of 4-( Diarylhydroxymet hy1)- 1-[ 3-(aryloxy)propyl]piperidines and Structurally Related Compounds;David A.Walsh,等;《Journal of Medicinal Chemistry》;19890101;第32卷(第1期);第105-118页 * |
| α,α-二苯基-4-吡啶甲醇催化加氢工艺研究;聂伟安,等;《湖南城市学院学报(自然科学版)》;20060930;第15卷(第03期);第64-65页 * |
| α,α-二苯基-4-哌啶甲醇催化氢化合成工艺研究;蒋崇文,等;《精细化工中间体》;20050630;第35卷(第03期);第22-23页 * |
| α,α-二苯基-4-哌啶甲醇的合成及质谱裂解研究;章鹏飞,等;《杭州师范学院学报(自然科学版)》;20060731;第5卷(第04期);第315-317页 * |
| α,α-二苯基-4-哌啶甲醇的合成研究;刘恺,等;《精细化工中间体》;20110831;第41卷(第04期);第43-45页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104003929A (en) | 2014-08-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104370755B (en) | Preparation method for optical activity active 3-amino butanol and optical activity 3-amino butyric acid | |
| CN104557945A (en) | Synthesis method of ibrutinib | |
| CN104003929B (en) | A kind of synthetic method of α, α-diphenyl-4-piperidine carbinols | |
| CN105037139B (en) | A kind of 2 phenylpropionic acid preparation methods | |
| CN104961640A (en) | Preparation method of optically pure 3-amino-1-butanol | |
| CN108623455B (en) | Intermediate of anti-heart failure medicine | |
| CN105777584B (en) | The preparation method of alanine derivatives | |
| CN104744266A (en) | Preparation method of ticagrelor intermediate | |
| CN105418620B (en) | A kind of synthetic method of 4- (tertbutyloxycarbonyl) octahydros furans simultaneously [3,2-b] pyridine -6- carboxylic acids | |
| CN110357774A (en) | A method of 2,5- dimethyl phenyl acetic acid is prepared by raw material of 2,5- dimethyl halobenzene | |
| CN108727200B (en) | Method for synthesizing nonane diamine | |
| CN113024479B (en) | Preparation method of clomazone | |
| CN107021886A (en) | One class quaternary amines chiral ionic liquid and preparation method thereof | |
| CN106748966A (en) | A kind of synthetic method of Ramipril key intermediate | |
| CN103483366B (en) | Preparation method of methoxy diethyl borane | |
| CN102924201B (en) | Method for preparing perfluoroalkyl alkyl ketone compound | |
| CN103755748A (en) | Preparation process for chiral (R)-1-ferrocenyl ethyl dimethylamine | |
| CN104151232A (en) | Method for preparing etocoxib | |
| CN103980139A (en) | Naphthoic acid compound and preparation method thereof | |
| CN104892380B (en) | A kind of method producing cyclamen aldehyde | |
| CN108250008A (en) | 3,3,3`, 3`- tetramethyl -1,1`- spiro indan -6,6`- diol, derivatives chiral separation methods | |
| CN108358776A (en) | The preparation method of 4- chloromethyl benzoic acid chlorides | |
| CN112159347B (en) | Preparation method of picolitamide | |
| CN102557941B (en) | Preparation method for intermediate compound of derivative of spiro-propyl formyl | |
| CN107573212A (en) | The synthetic method of trans 4 alkyl-cyclohexyl benzene structure liquid crystal intermediates and monomer |
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 | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20160720 Termination date: 20190430 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |