CN105237463A - Preparation method of (3R,4R)-(1-benzyl-4-methylpiperidine-3-yl)methylamine-L-di-p-toluoyltartaric acid salt - Google Patents
Preparation method of (3R,4R)-(1-benzyl-4-methylpiperidine-3-yl)methylamine-L-di-p-toluoyltartaric acid salt Download PDFInfo
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Abstract
The invention discloses a preparation method of (3R,4R)-(1-benzyl-4-methylpiperidine-3-yl)methylamine-L-di-p-toluoyltartaric acid salt prepared from the following reaction steps shown in the description. The preparation method of (3R,4R)-(1-benzyl-4-methylpiperidine-3-yl)methylamine-L-di-p-toluoyltartaric acid salt has the following advantages that the process is novel in design, extremely dangerous chemicals (such as lithium aluminum hydride) are not required to be used, a folding condensation process is adopted, and the total yield is high; more importantly, the starting materials are cheap and easy to obtain, and the cost is low; and the maneuverability is high, and industrialization is easy.
Description
Technical field
The invention belongs to vitochemical technical field, relate to a kind of preparation technology of medicine intermediate, be specifically related to one and treat the preparation method of medicine for treating rheumatoid arthritis-Tuo Fa for Buddhist nun's intermediate-(3R, 4R)-(1-benzyl-4-methyl piperidine-3-base) methylamine-L-two pairs of toluoyltartrates.
Background technology
Holder method is the oral JAK inhibitor of resisting rheumatoid arthritis of Pfizer pharmacy (Pfizer) company research and development for Buddhist nun; Being first-generation oral administration medicine for treating rheumatoid arthritis, is the kind of first listing in such medicine.FDA, in approval listing on November 6th, 2012, is used for the treatment of underaction or the moderate that do not tolerate to severe Active rheumatoid arthritis.
Holder method is a kind of kinases (JAK) inhibitor for Buddhist nun.JAKs is the one of intracellular enzyme, and its effect is the signal transmitted from cytokine on cytolemma or growth factor receptors, thus regulates hematopoiesis and the immunologic function of cell.In this signal transduction pathway, JAKs phosphorylation activation signal transduction and transcription activator (STATs), thus many important biological procedureses such as the participation propagation of cell, differentiation, apoptosis and immunomodulatory.Holder method regulates this signal transduction pathway for Buddhist nun by JAKs, stops phosphorylation and the activation of STATs.Holder method is for Buddhist nun as the potent inhibitor of JAK3, and it is rapid-action, and bioavailability is high, or the moderate that do not tolerate not good to MTX therapeutic response is to the determined curative effect of severe reactivity RA adult patient, and security is also confirmed.At present, to secure permission listing in a lot of country.
The preparation of (3R, 4R)-(1-benzyl-4-methyl piperidine-3-base) methylamine-L-two pairs of toluoyltartrates at present has developed multiple method, and wherein, representative synthetic route mainly contains following two:
The first is disclosed in OrganicProcessResearch & Development, 2005,9:51 – 56 and WO2008029237:
It two is be disclosed in OrganicProcessResearch & Development, 2014,18:1714 – 1720:
Article 1, the shortcoming of route is: 1) starting material is very expensive, reacts through a few step, cause (3R, 4R)-cost of (1-benzyl-4-methyl piperidine-3-base) methylamine-L-two pairs of toluoyltartrates is very high; 2) very expensive catalyzer Rh/C is used in second step reaction, and yield is general; 3) in three-step reaction, use a large amount of borane reagents, aftertreatment bothers and can produce a large amount of trade effluents; 4) the 4th step uses Lithium Aluminium Hydride, and the use of this reagent needs to carry out at anhydrous condition, and operational requirement is very harsh, misoperation, is easy to blast.
The shortcoming of Article 2 route is: 1) starting material is very expensive, gets off through six-step process, cause (3R, 4R)-cost of (1-benzyl-4-methyl piperidine-3-base) methylamine-L-two pairs of toluoyltartrates is very high; 2) use a large amount of borane reagents in the 3rd step and the reaction of the 5th step, these are all production control, and environmental Kuznets Curves causes very large difficulty, and potential risk is huge.
Summary of the invention
Technical problem to be solved by this invention overcomes the deficiencies in the prior art, starting raw material for existing technique is expensive, yield is low, catalyzer cost is high, reaction conditions is not easy control and be difficult to the shortcomings such as industrial production, a kind of (3R is provided, 4R)-(1-benzyl-4-methyl piperidine-3-base) the brand-new preparation method of methylamine-L-two pairs of toluoyltartrates, whole piece route is novel, employing collapses technique, total recovery is high, in addition, starting material is cheaply easy to get, cost is low, workable, is easy to industrialization.
The present invention, for achieving the above object, provides following technical scheme:
A kind of preparation method of (3R, 4R)-(1-benzyl-4-methyl piperidine-3-base) methylamine-L-two pairs of toluoyltartrates, it is obtained by following six-step process step:
The structure (L-DTTA is wherein: L-bis-pairs of toluoyltartaric) of the final product (3R, 4R) obtained by preparation method of the present invention-(1-benzyl-4-methyl piperidine-3-base) methylamine-L-two pairs of toluoyltartrates (VII):
The temperature of reaction of described the first step reaction is 0 ~ 70 DEG C, and preferred temperature is 10 ~ 60 DEG C, and optimum temps is 30 ~ 40 DEG C, and the reaction times is 5 ~ 72 hours, and the preferred reaction time is 16 ~ 30 hours.Wherein the mol ratio of type I compound N-benzyl-4-carbonyl-ethyl nipecotate and ammonia (aqueous solution of 25%) is 1: 1 ~ 1: 10, and preferred molar ratio is 1: 2 ~ 1: 5.Described the first step reaction solvent is ethanol, reacts complete, and concentrating under reduced pressure falls most ethanol, uses methyl tertiary butyl ether extracted products, separates organic phase, then uses dried over sodium sulfate organic phase; After drying, filter sodium sulfate, obtain the t-butyl methyl ether solution of formula II compound.
The t-butyl methyl ether solution that the first step is reacted gained formula II compound by described second step reaction reduces temperature, and the temperature controlling this solution is-80 ~ 0 DEG C, and preferred temperature is-70 ~-20 DEG C, and optimum temps is-60 ~-40 DEG C.Drip the tetrahydrofuran solution of methyl Grignard.The mol ratio of wherein said formula II compound and methyl Grignard is 1: 0.8 ~ 1: 3.0, and preferred molar ratio is 1: 0.9 ~ 1: 2.0, and more excellent mol ratio is 1: 1.1 ~ 1: 1.5.Dropwise, temperature of reaction is-70 ~ 0 DEG C, and preferred temperature is-60 ~-10 DEG C, and optimum temps is-30 ~-20 DEG C.Reaction times is 2 ~ 10 hours, and the preferred reaction time is 4 ~ 7 hours.React complete, slowly drip the ammonium chloride solution termination reaction of 10%, separate organic phase, and then with the product in methyl tertiary butyl ether aqueous phase extracted; The pure saturated sodium-chloride of the organic phase separated washs once, separates organic phase, then uses dried over sodium sulfate organic phase; After drying, filter sodium sulfate, concentrating under reduced pressure falls organic solvent; In above-mentioned concentrated solution, add toluene, and use division box, back flow reaction 4 ~ 10 hours, then concentrates toluene, obtains formula III compound.
Second step is reacted gained III compound and adds in methyl alcohol by described three-step reaction, adds RaneyNi, and wherein the weight ratio of III compound and RaneyNi is 100: 1 ~ 5: 1, weight ratio preferably 30: 1 ~ 10: 1.After described three-step reaction first uses nitrogen replacement three times, pour hydrogen, pressure is 4atm, and temperature of reaction is 10 ~ 80 DEG C, and preferred temperature is 20 ~ 80 DEG C, and optimum temps is 30 ~ 70 DEG C, and the reaction times is 2 ~ 60 hours, and the preferred reaction time is 10 ~ 30 hours.React complete, filter RaneyNi, after concentrating most of methyl alcohol, add water, separate out formula IV compound, filter out product, dry under hot air circulation at 50 DEG C, obtain IV compound.
Three-step reaction gained IV compound is directly dissolved in methyl alcohol by described four-step reaction, adds chlorine bleach liquor, and chlorine bleach liquor's concentration is 2% ~ 30%, is preferably 5 ~ 10%.Temperature of reaction is-10 ~ 65 DEG C, and temperature of reaction preferably 20 ~ 55 DEG C, more excellent temperature of reaction is 40 ~ 50 DEG C.Reaction times is 5 ~ 24 hours, preferably 7 ~ 12 hours reaction times.React complete, decompression evaporates methyl alcohol, recovery.Then use ethyl formate extraction product three times, merge organic phase, obtain formula V compound carboxylate solution.
Four-step reaction gained IV compound carboxylate solution is added tosic acid by described 5th step reaction, the mol ratio of wherein said IV compound and tosic acid is 1: 0.01 ~ 1: 10, mol ratio preferably 1: 0.05 ~ 1: 5, more excellent mol ratio is 1: 0.1 ~ 1: 0.5.Temperature of reaction is 0 ~ 65 DEG C, and preferred temperature is 45 ~ 60 DEG C, and the reaction times is 2 ~ 40 hours, and the preferred reaction time is 6 ~ 24 hours.React complete, decompression evaporates ethyl formate, adds tetrahydrofuran (THF), hierarchy of control temperature, at about 0 DEG C, adds sodium borohydride, and the mol ratio of described IV compound and sodium borohydride is 1: 0.5 ~ 1: 10, mol ratio preferably 1: 1 ~ 1: 6, more excellent mol ratio is 1: 2 ~ 1: 4; Below 10 DEG C, drip the tetrahydrofuran solution of trifluoroacetic acid, the mol ratio of described IV compound and trifluoroacetic acid is 1: 0.5 ~ 1: 10, mol ratio preferably 1: 1 ~ 1: 6, and more excellent mol ratio is 1: 2 ~ 1: 4; React at 20 DEG C after 6 hours, reaction also slowly joined in the HCl solution of 10% of zero degree, then separate organic phase, aqueous phase adjusts pH to 9-10 with the NaOH of 2N again, by methyl tertiary butyl ether aqueous phase extracted twice, and the organic phase use dried over sodium sulfate of merging; After drying, filter sodium sulfate, will the solution of formula VI compounds methyl tertbutyl ether be obtained.Above-mentioned solution is concentrated into supersaturation, slow crystallization under room temperature, then is cooled to-10 ~ 5 DEG C, then filter, wash with the methyl tertiary butyl ether of ice, at 30 ~ 40 DEG C, vacuum-drying obtains light yellow solid formula VI compound.
5th step reaction gained formula VI compound is dissolved in methanol-water (v/v=1/1) by described six-step process, and add L-DTTA, the mol ratio of described formula VI compound and L-DTTA is 1: 0.2 ~ 1: 2, and preferred mol ratio is 1: 0.4 ~ 1: 1.Temperature of reaction is 10 ~ 70 DEG C, and preferred temperature is 20 ~ 60 DEG C, and optimum temps is 35 ~ 50 DEG C, and the reaction times is 2 ~ 60 hours, and the preferred reaction time is 10 ~ 30 hours.Along with the carrying out of reaction, product constantly separates out, after precipitation completely, system is allowed naturally to be down to room temperature, then filter, by the methanol wash of ice, at 50 ~ 60 DEG C, vacuum-drying obtains finished product formula VII compound (3R, 4R)-(1-benzyl-4-methyl piperidine-3-base) methylamine-L-two pairs of toluoyltartrates of off-white color.
(3R provided by the invention, 4R)-(1-benzyl-4-methyl piperidine-3-base) preparation method of methylamine-L-two pairs of toluoyltartrates, there is following advantage: present invention process is novel in design, do not need the chemical (as: Lithium Aluminium Hydride) using danger close, employing collapses technique, and total recovery is high; The more important thing is, starting material is cheaply easy to get, and cost is low; Workable, be easy to industrialization.
Embodiment
In order to make object of the present invention, technical scheme and beneficial effect better clear, will be described in detail the preferred embodiments of the present invention below, but the invention is not restricted to following examples.
Embodiment 1
Add in the ethanol of 7kg in the formula I N-benzyl-4-carbonyl-ethyl nipecotate of 1kg, add the ammoniacal liquor of 25% of 0.9kg again, temperature of reaction is 33 DEG C, react after 22 hours, concentrating under reduced pressure falls the ethanol of the overwhelming majority, and the methyl tertiary butyl ether adding 7kg extracts, and the organic phase with sodium sulfate separated is after dry 3 hours, filter sodium sulfate, obtain the t-butyl methyl ether solution of formula II compound.
The t-butyl methyl ether solution of the formula II compound of upper step gained is cooled to-55 DEG C, under nitrogen protection, drip the tetrahydrofuran solution of the methyl Grignard of 2.5L2mol/L, within 1 hour, dropwise, hierarchy of control temperature, at-27 DEG C, is reacted after 5 hours, slowly drips the ammonium chloride solution termination reaction of 3.5 liter 10%, separate organic phase, and then with the product in the methyl tertiary butyl ether aqueous phase extracted of 3L; The pure saturated sodium-chloride of the organic phase separated washs once, then uses dried over sodium sulfate organic phase; After drying, filter sodium sulfate, concentrating under reduced pressure falls organic solvent; In above-mentioned concentrated solution, add the toluene of 6L, and use division box, back flow reaction 10 hours, then concentrates toluene, obtains the formula III compound of 0.8kg.
The formula III compound of 0.8kg is added in the methyl alcohol of 5L, adds the RaneyNi of 120g.After nitrogen replacement three times, pour hydrogen, pressure is 4atm, and temperature of reaction controls at 40 DEG C, after 6 hours reaction times.Filter RaneyNi, after concentrating most of methyl alcohol, add the water of 3kg, separate out formula IV compound, filter out product, dry under hot air circulation at 50 DEG C, obtain the formula IV compound of 0.75kg.
Be dissolved in the methyl alcohol of 3L by the formula IV compound of 0.75kg, add 5% chlorine bleach liquor of 3L, controlling temperature of reaction is 48 DEG C.After 8 hours reaction times, decompression evaporates methyl alcohol, recovery.Then use 3L ethyl formate extraction product, extract three times, merge organic phase, obtain formula V compound carboxylate solution.
To in the formula V compound carboxylate solution of above-mentioned gained, add the tosic acid of 50g, temperature of reaction is 55 DEG C, reacts after 12 hours, and decompression evaporates ethyl formate; Add the tetrahydrofuran (THF) of 3.5L, hierarchy of control temperature, about zero degree, adds the sodium borohydride of 270g; At 10 DEG C, drip the tetrahydrofuran solution (mass concentration is 50%) of the trifluoroacetic acid of 1.6kg; React at 20 DEG C after 7 hours, reaction also slowly joined in the hydrochloric acid of 5L10% of zero degree, then separate organic phase, aqueous phase adjusts pH to 9-10 with the NaOH of 2N again, with the product in the methyl tertiary butyl ether aqueous phase extracted of 2.6L, the organic phase use dried over sodium sulfate of merging; After drying, filter sodium sulfate, will the solution of the methyl tertiary butyl ether of formula VI compound be obtained.The solution of the methyl tertiary butyl ether of above-mentioned formula VI compound is concentrated into supersaturation, slow crystallization under room temperature, then be cooled to-10 ~ 5 DEG C, then filter, wash with the methyl tertiary butyl ether of ice, at 30 ~ 40 DEG C, vacuum-drying obtains 0.5kg light yellow solid formula VI compound.
The formula VI compound of 0.5kg is dissolved in the methanol-water (v/v=1/1) of 3.2L, adds the L-DTTA of 442g.At 45 DEG C, react after 12 hours, system is allowed naturally to be down to room temperature, then filter, by the methanol wash of ice, at 50 ~ 60 DEG C, vacuum-drying obtains finished product formula VII compound (3R, 4R)-(1-benzyl-4-methyl piperidine-3-base) methylamine-L-two pairs of toluoyltartrates of 550g off-white color.The total recovery of the preparation method of the present embodiment is 23.8%.
Embodiment 2
Add in the ethanol of 20kg in the formula I N-benzyl-4-carbonyl-ethyl nipecotate of 3kg, add the ammoniacal liquor of 25% of 3.9kg again, temperature of reaction is 30 DEG C, react after 30 hours, concentrating under reduced pressure falls the ethanol of the overwhelming majority, and the methyl tertiary butyl ether adding 20kg extracts, and the organic phase with sodium sulfate separated is after dry 5 hours, filter sodium sulfate, obtain the t-butyl methyl ether solution of formula II compound.
The t-butyl methyl ether solution of the formula II compound of upper step gained is cooled to-60 DEG C, under nitrogen protection, drip the tetrahydrofuran solution of the methyl Grignard of 8.6L2mol/L, within 1.5 hours, drip and finish, hierarchy of control temperature, at-30 DEG C, is reacted after 7 hours, slowly drips the ammonium chloride solution termination reaction of 10 liter 10%, separate organic phase, and then with the product in the methyl tertiary butyl ether aqueous phase extracted of 6L; The pure saturated sodium-chloride of the organic phase separated washs once, then uses dried over sodium sulfate organic phase; After drying, filter sodium sulfate, concentrating under reduced pressure falls organic solvent; In above-mentioned concentrated solution, add the toluene of 20L, and use division box, back flow reaction 10 hours, then concentrates toluene, obtains the formula compound of 2.42kg.
The formula III compound of 2.42kg is added in the methyl alcohol of 17L, adds the RaneyNi of 240g.After nitrogen replacement three times, pour hydrogen, pressure is 4atm, and temperature of reaction controls at 30 DEG C, after 30 hours reaction times.Filter RaneyNi, after concentrating most of methyl alcohol, add the water of 10kg, formula IV compound is separated out, and filters out product, dries at 50 DEG C under hot air circulation, obtain the formula IV compound of 2.3kg.
Be dissolved in the methyl alcohol of 9L by the formula IV compound of 2.3kg, add 4L10% chlorine bleach liquor, controlling temperature of reaction is 50 DEG C.After 7 hours reaction times, decompression evaporates methyl alcohol, recovery.Then use 6L ethyl formate extraction product, extract three times, merge organic phase, obtain the carboxylate solution of formula V compound.
To in the carboxylate solution of the formula V compound of above-mentioned gained, add the tosic acid of 0.8kg, temperature of reaction is 60 DEG C, reacts after 6 hours, and decompression evaporates ethyl formate; Add the tetrahydrofuran (THF) of 10L, hierarchy of control temperature, about zero degree, adds the sodium borohydride of 1.4kg; At 10 DEG C, drip the tetrahydrofuran solution (mass concentration is 50%) of the trifluoroacetic acid of 8.4kg; React at 20 DEG C after 6 hours, reaction also slowly joined in the hydrochloric acid of 20L10% of zero degree, then separate organic phase, aqueous phase adjusts pH to 9-10 with the NaOH of 2N again, with the product in the methyl tertiary butyl ether aqueous phase extracted of 8L, the organic phase use dried over sodium sulfate of merging; After drying, filter sodium sulfate, will the solution of the methyl tertiary butyl ether of formula VI compound be obtained.The solution of the methyl tertiary butyl ether of above-mentioned formula VI compound is concentrated into supersaturation, slow crystallization under room temperature, then be cooled to-10 ~ 5 DEG C, then filter, wash with the methyl tertiary butyl ether of ice, at 30 ~ 40 DEG C, vacuum-drying obtains 1.53kg light yellow solid formula VI compound.
The formula VI compound of 1.53kg is dissolved in the methanol-water (v/v=1/1) of 10L, adds the L-DTTA of 1.08kg.At 50 DEG C, react after 10 hours, system is allowed naturally to be down to room temperature, then filter, by the methanol wash of ice, at 50 ~ 60 DEG C, vacuum-drying obtains finished product formula VII compound (3R, 4R)-(1-benzyl-4-methyl piperidine-3-base) methylamine-L-two pairs of toluoyltartrates of 1.53kg off-white color.Preparation method's total recovery of the present embodiment is 22.0%.
Embodiment 3
Add in the ethanol of 35kg in the formula I N-benzyl-4-carbonyl-ethyl nipecotate of 5kg, add the ammoniacal liquor of 25% of 2.6kg again, temperature of reaction is 40 DEG C, react after 16 hours, concentrating under reduced pressure falls the ethanol of the overwhelming majority, and the methyl tertiary butyl ether adding 35kg extracts, and the organic phase with sodium sulfate separated is after dry 5 hours, filter sodium sulfate, obtain the t-butyl methyl ether solution of formula II compound.
The t-butyl methyl ether solution of the formula II compound of upper step gained is cooled to-40 DEG C, under nitrogen protection, drip the tetrahydrofuran solution of the methyl Grignard of 10.5L2mol/L, within 2 hours, drip and finish, hierarchy of control temperature, at-20 DEG C, is reacted after 4 hours, slowly drips the ammonium chloride solution termination reaction of 17 liter 10%, separate organic phase, and then with the product in the methyl tertiary butyl ether aqueous phase extracted of 10L; The pure saturated sodium-chloride of the organic phase separated washs once, then uses dried over sodium sulfate organic phase; After drying, filter sodium sulfate, concentrating under reduced pressure falls organic solvent; In above-mentioned concentrated solution, add the toluene of 35L, and use division box, back flow reaction 12 hours, then concentrates toluene, obtains the formula compound of 3.99kg.
The formula III compound of 3.99kg is added in the methyl alcohol of 27L, adds the RaneyNi of 134g.After nitrogen replacement three times, pour hydrogen, pressure is 4atm, and temperature of reaction controls at 70 DEG C, after 10 hours reaction times.Filter RaneyNi, after concentrating most of methyl alcohol, add the water of 18kg, separate out formula compound, filter out product, dry under hot air circulation at 50 DEG C, obtain the formula IV compound of 3.7kg.
Be dissolved in the methyl alcohol of 15L by the formula IV compound of 3.7kg, add 5% chlorine bleach liquor of 10L, controlling temperature of reaction is 40 DEG C.After 12 hours reaction times, decompression evaporates methyl alcohol, recovery.Then use 11L ethyl formate extraction product, extract three times, merge organic phase, obtain the carboxylate solution of formula V compound.
To in the carboxylate solution of the formula V compound of above-mentioned gained, add the tosic acid of 257g, temperature of reaction is 45 DEG C, reacts after 24 hours, and decompression evaporates ethyl formate; Add the tetrahydrofuran (THF) of 17L, hierarchy of control temperature, about zero degree, adds the sodium borohydride of 1.2kg; At 10 DEG C, drip the tetrahydrofuran solution (mass concentration is 50%) of the trifluoroacetic acid of 7.0kg; React at 20 DEG C after 10 hours, reaction also slowly joined in the hydrochloric acid of 26L10% of zero degree, then separate organic phase, aqueous phase adjusts pH to 9-10 with the NaOH of 2N again, with the product in the methyl tertiary butyl ether aqueous phase extracted of 14L, the organic phase use dried over sodium sulfate of merging; After drying, filter sodium sulfate, will the solution of the methyl tertiary butyl ether of formula VI compound be obtained.The solution of the methyl tertiary butyl ether of above-mentioned formula VI compound is concentrated into supersaturation, slow crystallization under room temperature, then be cooled to-10 ~ 5 DEG C, then filter, wash with the methyl tertiary butyl ether of ice, at 30 ~ 40 DEG C, vacuum-drying obtains 2.45kg light yellow solid formula VI compound.
The formula VI compound of 2.45kg is dissolved in the methanol-water (v/v=1/1) of 16L, adds the L-DTTA of 4.34kg.At 35 DEG C, react after 30 hours, system is allowed naturally to be down to room temperature, then filter, by the methanol wash of ice, at 50 ~ 60 DEG C, vacuum-drying obtains finished product formula VII compound (3R, 4R)-(1-benzyl-4-methyl piperidine-3-base) methylamine-L-two pairs of toluoyltartrates of 2.71kg off-white color.Preparation method's total recovery of the present embodiment is 23.4%.
Embodiment 4
Add in the ethanol of 42kg in the formula I N-benzyl-4-carbonyl-ethyl nipecotate of 6kg, add the ammoniacal liquor of 25% of 5.5kg again, temperature of reaction is 35 DEG C, react after 25 hours, concentrating under reduced pressure falls the ethanol of the overwhelming majority, and the methyl tertiary butyl ether adding 42kg extracts, and the organic phase with sodium sulfate separated is after dry 6 hours, filter sodium sulfate, obtain the t-butyl methyl ether solution of formula II compound.
The t-butyl methyl ether solution of the formula II compound of upper step gained is cooled to-50 DEG C, under nitrogen protection, drip the tetrahydrofuran solution of the methyl Grignard of 14.9L2mol/L, within 2.5 hours, drip and finish, hierarchy of control temperature, at-25 DEG C, is reacted after 6 hours, slowly drips the ammonium chloride solution termination reaction of 20 liter 10%, separate organic phase, and then with the product in the methyl tertiary butyl ether aqueous phase extracted of 14L; The pure saturated sodium-chloride of the organic phase separated washs once, then uses dried over sodium sulfate organic phase; After drying, filter sodium sulfate, concentrating under reduced pressure falls organic solvent; In above-mentioned concentrated solution, add the toluene of 40L, and use division box, back flow reaction 12 hours, then concentrates toluene, obtains the formula III compound of 4.8kg.
The formula III compound of 4.8kg is added in the methyl alcohol of 30L, adds the RaneyNi of 900g.After nitrogen replacement three times, pour hydrogen, pressure is 4atm, and temperature of reaction controls at 50 DEG C, after 8 hours reaction times.Filter RaneyNi, after concentrating most of methyl alcohol, add the water of 22kg, formula IV compound is separated out, and filters out product, dries at 50 DEG C under hot air circulation, obtain the formula IV compound of 4.5kg.
Be dissolved in the methyl alcohol of 18L by the formula IV compound of 4.5kg, add 5% chlorine bleach liquor of 16L, controlling temperature of reaction is 45 DEG C.After 10 hours reaction times, decompression evaporates methyl alcohol, recovery.Then use 14L ethyl formate extraction product, extract three times, merge organic phase, obtain the carboxylate solution of formula V compound.
To in the carboxylate solution of the formula V compound of above-mentioned gained, add the tosic acid of 330g, temperature of reaction is 50 DEG C, reacts after 18 hours, and decompression evaporates ethyl formate; Add the tetrahydrofuran (THF) of 21L, hierarchy of control temperature, about zero degree, adds the sodium borohydride of 1.6kg; At 10 DEG C, drip the tetrahydrofuran solution (mass concentration is 50%) of the trifluoroacetic acid of 9.4kg; React at 20 DEG C after 10 hours, reaction also slowly joined in the hydrochloric acid of 32L10% of zero degree, then separate organic phase, aqueous phase adjusts pH to 9-10 with the NaOH of 2N again, with the product in the methyl tertiary butyl ether aqueous phase extracted of 18L, the organic phase use dried over sodium sulfate of merging; After drying, filter sodium sulfate, will the solution of the methyl tertiary butyl ether of formula compound be obtained.Above-mentioned solution is concentrated into supersaturation, slow crystallization under room temperature, then is cooled to-10 ~ 5 DEG C, then filter, wash with the methyl tertiary butyl ether of ice, at 30 ~ 40 DEG C, vacuum-drying obtains 2.96kg light yellow solid formula VI compound.
The formula VI compound of 2.96kg is dissolved in the methanol-water (v/v=1/1) of 19L, adds the L-DTTA of 3.14kg.At 40 DEG C, react after 18 hours, system is allowed naturally to be down to room temperature, then filter, by the methanol wash of ice, at 50 ~ 60 DEG C, vacuum-drying obtains finished product formula VII compound (3R, 4R)-(1-benzyl-4-methyl piperidine-3-base) methylamine-L-two pairs of toluoyltartrates of 3.24kg off-white color.Preparation method's total recovery of the present embodiment is 23.3%.
In addition, and reported two synthetic route yields compare, and comparing result is as follows:
Route of the present invention is adopted to go to synthesize (3R, 4R)-(1-benzyl-4-methyl piperidine-3-base) yield of methylamine-L-two pairs of toluoyltartrates is higher than Org.Process.Res & Dev2005, the yield reported in 9:51 – 56 and WO2008029237; Meanwhile, with Org.Process.Res & Dev, in 2014,18:1714 – 1720, the yield of report is compared, also very close.
Above preferred embodiment is only in order to illustrate technical scheme of the present invention and unrestricted, although by above preferred embodiment to invention has been detailed description, but those skilled in the art are to be understood that, various change can be made to it in the form and details, and not depart from claims of the present invention limited range.
Claims (10)
1. a preparation method for (3R, 4R)-(1-benzyl-4-methyl piperidine-3-base) methylamine-L-two pairs of toluoyltartrates, is obtained by following reactions steps:
2. preparation method according to claim 1, it is characterized in that, described the first step reaction solvent is ethanol, and temperature of reaction is 0 ~ 70 DEG C, reaction times is 5 ~ 72 hours, and the mol ratio of type I compound N-benzyl-4-carbonyl-ethyl nipecotate and ammoniacal liquor is 1: 1 ~ 1: 10;
The t-butyl methyl ether solution temperature of described second step reaction compound of formula H is-80 ~ 0 DEG C, the methyl Grignard dripped is tetrahydrofuran solution, the mol ratio of formula II compound and tetrahydrofuran solution is 1: 0.8 ~ 1: 3.0, temperature of reaction is-70 ~ 0 DEG C, and the reaction times is 2 ~ 10 hours;
The weight ratio of described three-step reaction Chinese style III compound and RaneyNi is 100: 1 ~ 5: 1, and temperature of reaction is 10 ~ 80 DEG C, and the reaction times is 2 ~ 60 hours;
Described four-step reaction compound of formula IV is dissolved in methyl alcohol, and the chlorine bleach liquor's concentration added is 2% ~ 30%, and temperature of reaction is-10 ~ 65 DEG C, and the reaction times is 5 ~ 24 hours;
The mol ratio of described 5th step reaction compound of formula V and tosic acid is 1: 0.01 ~ 1: 10, and temperature of reaction is 0 ~ 65 DEG C, and the reaction times is 2 ~ 40 hours;
Be dissolved in by formula VI compound in methanol-water (v/v=1/1) in described six-step process, the mol ratio of formula VI compound and L-DTTA is 1: 0.2 ~ 1: 2, and temperature of reaction is 10 ~ 70 DEG C, and the reaction times is 2 ~ 60 hours.
3. preparation method according to claim 1, it is characterized in that, described the first step reaction solvent is ethanol, and temperature of reaction is 10 ~ 60 DEG C, reaction times is 16 ~ 30 hours, and the mol ratio of type I compound N-benzyl-4-carbonyl-ethyl nipecotate and ammoniacal liquor is 1: 2 ~ 1: 5;
The t-butyl methyl ether solution temperature of described second step reaction compound of formula H is-70 ~-20 DEG C, the methyl Grignard dripped is tetrahydrofuran solution, the mol ratio of formula II compound and tetrahydrofuran solution is 1: 0.9 ~ 1: 2.0, temperature of reaction is-60 ~-10 DEG C, and the reaction times is 4 ~ 7 hours;
The weight ratio of described three-step reaction Chinese style III compound and RaneyNi is 30: 1 ~ 10: 1, and temperature of reaction is 20 ~ 80 DEG C, and the reaction times is 10 ~ 30 hours;
Described four-step reaction compound of formula IV is dissolved in methyl alcohol, and the chlorine bleach liquor's concentration added is 5% ~ 10%, and temperature of reaction is 20 ~ 55 DEG C, and the reaction times is 7 ~ 12 hours;
The mol ratio of described 5th step reaction compound of formula V and tosic acid is 1: 0.05 ~ 1: 5, and temperature of reaction is 45 ~ 60 DEG C, and the reaction times is 6 ~ 24 hours;
Be dissolved in by formula VI compound in methanol-water (v/v=1/1) in described six-step process, the mol ratio of formula VI compound and L-DTTA is 1: 0.4 ~ 1: 1, and temperature of reaction is 20 ~ 60 DEG C, and the reaction times is 10 ~ 30 hours.
4. want the preparation method described in 3 according to right, it is characterized in that: described the first step temperature of reaction is 30 ~ 40 DEG C;
The t-butyl methyl ether solution temperature of described second step reaction compound of formula H is-60 ~-40 DEG C, and the mol ratio of formula II compound and tetrahydrofuran solution is 1: 1.1 ~ 1: 1.5, and temperature of reaction is-30 ~-20 DEG C;
Described three-step reaction temperature is 30 ~ 70 DEG C;
Described four-step reaction temperature is 40 ~ 50 DEG C;
The mol ratio of described 5th step reaction compound of formula V and tosic acid is 1: 0.1 ~ 1: 0.5;
Described six-step process temperature is 35 ~ 50 DEG C.
5. want the preparation method described in 3 according to right, it is characterized in that: described the first step reaction solvent is ethanol, temperature of reaction is 33 DEG C, and the reaction times is 22 hours;
The t-butyl methyl ether solution temperature of described second step reaction compound of formula H is-55 DEG C, and temperature of reaction is-27 DEG C, and the reaction times is 5 hours;
Described three-step reaction temperature is 40 DEG C, and the reaction times is 6 hours;
Described four-step reaction compound of formula IV is dissolved in methyl alcohol, and the chlorine bleach liquor's concentration added is 5%, and temperature of reaction is 48 DEG C, and the reaction times is 8 hours;
Described 5th step temperature of reaction is 55 DEG C, and the reaction times is 12 hours;
Described six-step process temperature is 45 DEG C, and the reaction times is 12 hours.
6. preparation method according to claim 2, is characterized in that: the described the first step after completion of the reaction concentrating under reduced pressure falls ethanol, uses methyl tertiary butyl ether extracted products, separate organic phase, then use dried over sodium sulfate, filter sodium sulfate, obtain the t-butyl methyl ether solution of formula II compound;
Described second step after completion of the reaction, slowly drips the ammonium chloride solution termination reaction of 10%, separates organic phase, with the product in methyl tertiary butyl ether aqueous phase extracted; The pure saturated sodium-chloride of the organic phase separated washs, and separates organic phase, and use dried over sodium sulfate organic phase, filter sodium sulfate, concentrating under reduced pressure falls organic solvent, adds toluene, and back flow reaction 4 ~ 10 hours, then concentrates toluene, obtains formula III compound;
In described three-step reaction, after nitrogen replacement three times, pour hydrogen, pressure is 4atm, react complete, filter RaneyNi, after concentrating most of methyl alcohol, add water, formula IV compound is separated out, and filters out product, dries, obtain formula IV compound under 50 degree of lower hot air circulation;
Described four-step reaction is complete, and decompression evaporates methyl alcohol, then uses ethyl formate extraction product three times, merges organic phase, obtains the carboxylate solution of formula V compound.
7. preparation method according to claim 6, it is characterized in that: described 5th step reaction is complete, decompression evaporates ethyl formate, add tetrahydrofuran (THF), hierarchy of control temperature is at about 0 DEG C, add sodium borohydride, the mol ratio of formula V compound and sodium borohydride is 1: 0.5 ~ 1: 10, at 10 DEG C, drip the tetrahydrofuran solution of trifluoroacetic acid, the mol ratio of formula V compound and trifluoroacetic acid is 1: 0.5 ~ 1: 10, react under 20 degree after 6 hours, reaction solution is joined in the HCl solution of 10% of 0 DEG C of degree, then organic phase is separated, aqueous phase adjusts pH to 9-10 with the NaOH of 2N again, by methyl tertiary butyl ether aqueous phase extracted twice, the organic phase with sodium sulfate merged is dry, after drying, filter sodium sulfate, the solution of the methyl tertiary butyl ether obtaining formula VI compound is concentrated into supersaturation, slow crystallization under room temperature, then be cooled to-10 ~ 5 DEG C, then filter, wash with the methyl tertiary butyl ether of ice, at 30 ~ 40 DEG C, vacuum-drying obtains light yellow solid formula VI compound.
8. preparation method according to claim 7, is characterized in that: the mol ratio of described formula V compound and sodium borohydride is the mol ratio of 1: 1 ~ 1: 6, formula V compounds and trifluoroacetic acid is 1: 1 ~ 1: 6.
9. preparation method according to claim 7, is characterized in that: the mol ratio of described formula V compound and sodium borohydride is the mol ratio of 1: 2 ~ 1: 4, formula V compounds and trifluoroacetic acid is 1: 2 ~ 1: 4.
10. preparation method according to claim 6, it is characterized in that: near room temperature after described six-step process, filter, by the methanol wash of ice, at 50 ~ 60 DEG C, vacuum-drying obtains finished product formula VII compound (3R, 4R)-(1-benzyl-4-methyl piperidine-3-base) methylamine-L-two pairs of toluoyltartrates of off-white color.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW200823216A (en) * | 2006-09-05 | 2008-06-01 | Pfizer Prod Inc | Combination therapies for rheumatoid arthritis |
| JP2011236157A (en) * | 2010-05-11 | 2011-11-24 | Toray Fine Chemicals Co Ltd | Method for producing optically active nipecotic acid derivative |
| CN103896826A (en) * | 2012-12-26 | 2014-07-02 | 上海朴颐化学科技有限公司 | Asymmetric synthesis method of nitrogen protected (3R,4R)-3-methylamino-4-methylpiperidine, and relevant intermediate and raw material preparation method |
| WO2015087201A1 (en) * | 2013-12-09 | 2015-06-18 | Unichem Laboratories Limited | An improved process for the preparation of (3r,4r)-(1-benzyl-4-methylpiperidin-3-yl)-methylamine |
| CN104837817A (en) * | 2012-07-25 | 2015-08-12 | 力奇制药公司 | New synthetic route for preparation of 3-amino-piperidine compounds |
| CN104860872A (en) * | 2015-03-27 | 2015-08-26 | 天津药物研究院有限公司 | Bis-(3R,4R)-1-benzyl-N,4-dimethyl piperidin-3-amine L-di-p-toluyl tartrate synthesis method |
-
2015
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Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW200823216A (en) * | 2006-09-05 | 2008-06-01 | Pfizer Prod Inc | Combination therapies for rheumatoid arthritis |
| JP2011236157A (en) * | 2010-05-11 | 2011-11-24 | Toray Fine Chemicals Co Ltd | Method for producing optically active nipecotic acid derivative |
| CN104837817A (en) * | 2012-07-25 | 2015-08-12 | 力奇制药公司 | New synthetic route for preparation of 3-amino-piperidine compounds |
| CN103896826A (en) * | 2012-12-26 | 2014-07-02 | 上海朴颐化学科技有限公司 | Asymmetric synthesis method of nitrogen protected (3R,4R)-3-methylamino-4-methylpiperidine, and relevant intermediate and raw material preparation method |
| WO2015087201A1 (en) * | 2013-12-09 | 2015-06-18 | Unichem Laboratories Limited | An improved process for the preparation of (3r,4r)-(1-benzyl-4-methylpiperidin-3-yl)-methylamine |
| CN104860872A (en) * | 2015-03-27 | 2015-08-26 | 天津药物研究院有限公司 | Bis-(3R,4R)-1-benzyl-N,4-dimethyl piperidin-3-amine L-di-p-toluyl tartrate synthesis method |
Non-Patent Citations (3)
| Title |
|---|
| BRIAN R. DE COSTA等: "Synthesis and Biological Evaluation of Conformationally Restricted 2-(l -Pyrrolidinyl)-N-[2-(3 ,4-dichlorophenyl)ethyl]-N-mehty lethylenediamines as a Receptor Ligands. 1. Pyrrolidine, Piperidine, Homopiperidine, and Tetrahydroisoquinoline Classes", 《JOURNAL OF THE MEDICINAL CHEMISTRY》 * |
| DAVID H. BROWN RIPIN等: "Development of a Scaleable Route for the Production of cis-N-Benzyl-3-methylamino-4-methylpiperidine", 《ORGANIC PROCESS RESEARCH & DEVELOPMENT》 * |
| 张从海，等: "伯胺的单烷基化反应研究进展", 《化学研究与应用》 * |
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