CN105237463B - Preparation methods of one kind (3R, 4R) (base of 1 benzyl, 4 methyl piperidine 3) methylamine L bis- to toluoyltartrates - Google Patents
Preparation methods of one kind (3R, 4R) (base of 1 benzyl, 4 methyl piperidine 3) methylamine L bis- to toluoyltartrates Download PDFInfo
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- 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
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Abstract
The present invention discloses one kind (3R, 4R) (base of 1 benzyl, 4 methyl piperidine 3) methylamine L bis- and, to the preparation method of toluoyltartrates, is made by following reactions steps：
Description
Technical field
The invention belongs to the technical field of organic chemistry, it is related to a kind of preparation technology of medicine intermediate, and in particular to one
Kind treatment medicine for treating rheumatoid arthritis-tropsch imatinib intermediate-(3R, 4R)-(1- benzyl -4- methyl piperidine -3- bases) methylamine -
Preparation methods of the L- bis- to toluoyltartrates.
Background technology
Tropsch imatinib is that the oral JAK of resisting rheumatoid arthritis that Pfizer pharmacy (Pfizer) company researches and develops suppresses
Agent；It is first generation oral medication medicine for treating rheumatoid arthritis, is the kind of first listing in such medicine.FDA is in 2012
Approval listing on November 6, for therapeutic response is not enough or does not tolerate moderate to severe Active rheumatoid arthritis.
Tropsch imatinib is a kind of kinases (JAK) inhibitor.JAKs is one kind of endocellular enzyme, and it is that transmission comes from cell that it, which is acted on,
The signal of cell factor or growth factor receptors on film, so as to adjust hematopoiesis and the immunologic function of cell.It is logical in this signal transduction
Lu Zhong, JAKs phosphorylation and activation signal transduction and transcription activator (STATs), so as to participate in the propagation of cell, differentiation, apoptosis
And many important biological processes such as immunological regulation.Tropsch imatinib adjusts this signal transduction pathway by JAKs, prevents
STATs phosphorylation and activation.Tropsch imatinib is as JAK3 potent inhibitor, and its is rapid-action, and bioavilability is high, to MTX
Therapeutic response is not good or the moderate that does not tolerate is to the determined curative effect of severe activity RA adult patients, and security is also confirmed.
At present, secured permission listing in many countries.
(3R, 4R)-(1- benzyl -4- methyl piperidine -3- bases) preparations of the methylamine-L- two to toluoyltartrates at present
A variety of methods are had been developed that, wherein, representative synthetic route mainly has following two：
One is being disclosed in Organic Process Research＆Development, 2005,9:51-56 and
WO2008029237:
The second is being disclosed in Organic Process Research＆Development, 2014,18:1714–1720:
The shortcoming of first route is：1) starting material is expensive, is reacted by several steps, causes (3R, 4R)-(1- benzyls
Base -4- methyl piperidine -3- bases) methylamine-L- two is very high to the cost of toluoyltartrates；2) second step reaction is used very high
Expensive catalyst Rh/C, and yield is general；3) substantial amounts of borane reagent is used in three-step reaction, post processing is troublesome and can produce
Raw substantial amounts of industrial wastewater；4) the 4th step uses Lithium Aluminium Hydride, and the use of the reagent is needed to carry out in anhydrous condition, and operation is required
It is very harsh, misoperation, it is easy to explode.
The shortcoming of Article 2 route is：1) starting material is expensive, gets off by six-step process, causes (3R, 4R)-(1- benzyls
Base -4- methyl piperidine -3- bases) methylamine-L- two is very high to the cost of toluoyltartrates；2) the 3rd step and the reaction of the 5th step
Middle to use substantial amounts of borane reagent, these all cause very big difficulty for production control, and environmental Kuznets Curves, and potential risk is huge.
The content of the invention
The technical problems to be solved by the invention are to overcome the deficiencies in the prior art, for the initiation material of existing process
The shortcomings of expensive, yield is low, catalyst cost is high, reaction condition is not easily controlled and is difficult to industrial production there is provided it is a kind of (3R,
4R)-(1- benzyl -4- methyl piperidine -3- bases) methylamine-L- two is to the brand-new preparation method of toluoyltartrates, whole piece road
Line is novel, and using technique is collapsed, total recovery is high, in addition, starting material is cheap and easily-available, cost is low, workable, it is easy to industry
Change.
There is provided following technical scheme to reach above-mentioned purpose by the present invention：
A kind of (3R, 4R)-(1- benzyl -4- methyl piperidine -3- bases) preparations of the methylamine-L- two to toluoyltartrates
Method, it is made by following six-step process step：
The present invention preparation method obtained by final product (3R, 4R)-(1- benzyl -4- methyl piperidine -3- bases) methylamine -
To toluoyltartrates (VII) structure, (L-DTTA therein is L- bis-：L- bis- is to toluoyltartaric)：
The reaction temperature of the first step reaction is 0~70 DEG C, and preferred temperature is 10~60 DEG C, and optimum temperature is 30~40
DEG C, the reaction time is 5~72 hours, and preferred reaction time is 16~30 hours.Wherein type I compound N- benzyls -4- carbonyls -3-
The mol ratio of piperidine ethyl formate and ammonia (25% aqueous solution) is 1: 1~1: 10, and preferred molar ratio is 1: 2~1: 5.Described
Single step reaction solvent is ethanol, and reaction is finished, and be concentrated under reduced pressure most ethanol, uses methyl tertiary butyl ether(MTBE) extracted products, point
Go out organic phase, then dry organic phase with sodium sulphate；After drying, sodium sulphate is filtered, the methyl tertbutyl of Formula II compound is obtained
Ethereal solution.
The t-butyl methyl ether solution that the first step reacts gained Formula II compound is reduced temperature, control by the second step reaction
The temperature for making the solution is -80~0 DEG C, and preferred temperature is -70~-20 DEG C, and optimum temperature is -60~-40 DEG C.Methyl lattice are added dropwise
The tetrahydrofuran solution of family name's reagent.Wherein described Formula II compound and the mol ratio of methyl Grignard are 1: 0.8~1: 3.0,
Preferred molar ratio is 1: 0.9~1: 2.0, and more excellent mol ratio is 1: 1.1~1: 1.5.Completion of dropping, reaction temperature is -70~0
DEG C, preferred temperature is -60~-10 DEG C, and optimum temperature is -30~-20 DEG C.Reaction time is 2~10 hours, preferred reaction time
For 4~7 hours.Reaction is finished, and 10% ammonium chloride solution terminating reaction is slowly added dropwise, separates organic phase, methyl is then used again
Product in tertbutyl ether aqueous phase extracted；The organic phase separated washed once with pure saturated sodium-chloride, separate organic phase, Ran Houyong
Sodium sulphate dries organic phase；After drying, sodium sulphate is filtered, be concentrated under reduced pressure organic solvent；Toluene is added into above-mentioned concentrate,
And division box is used, back flow reaction 4~10 hours, then concentration falls toluene, obtains formula III compound.
Second step is reacted gained III compounds and added in methanol by the three-step reaction, adds Raney Ni, wherein
III compounds and Raney Ni weight ratio are 100: 1~5: 1, weight ratio preferably 30: 1~10: 1.The three-step reaction is first
After nitrogen displacement three times, hydrogen is poured, pressure is 4atm, and reaction temperature is 10~80 DEG C, and preferred temperature is 20~80 DEG C, most
Good temperature is 30~70 DEG C, and the reaction time is 2~60 hours, and preferred reaction time is 10~30 hours.Reaction is finished, and is filtered
Raney Ni, concentration is fallen after most of methanol, adds water, separates out formula IV compound, product is filtered out, in hot air circulation at 50 DEG C
Lower drying, obtains IV compounds.
IV compounds obtained by three-step reaction are directly dissolved in methanol by the four-step reaction, add sodium hypochlorite molten
Liquid, liquor natrii hypochloritis's concentration is 2%~30%, preferably 5~10%.Reaction temperature is -10~65 DEG C, and reaction temperature is preferred
20~55 DEG C, more excellent reaction temperature is 40~50 DEG C.Reaction time is 5~24 hours, preferably 7~12 hours reaction time.Instead
It should finish, decompression evaporates methanol, recovery.Then extract product three times with Ethyl formate, merge organic phase, obtain Formula V
Compound carboxylate solution.
IV compounds carboxylate solution obtained by four-step reaction is added p-methyl benzenesulfonic acid by the 5th step reaction, wherein
The IV compounds and the mol ratio of p-methyl benzenesulfonic acid are 1: 0.01~1: 10, mol ratio preferably 1: 0.05~1: 5, more excellent mole
Than for 1: 0.1~1: 0.5.Reaction temperature is 0~65 DEG C, and preferred temperature is 45~60 DEG C, and the reaction time is 2~40 hours, excellent
It is 6~24 hours to select the reaction time.Reaction is finished, and decompression evaporates Ethyl formate, adds tetrahydrofuran, control system temperature is 0
DEG C or so, sodium borohydride is added, the mol ratio of the IV compounds 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, the tetrahydrofuran solution of trifluoroacetic acid, the IV compounds is added dropwise
Mol ratio with 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；20
Reacted at DEG C after 6 hours, reaction is also slowly added into 10% HCl solution of zero degree, organic phase, aqueous phase is then separated
PH to 9-10 is adjusted with 2N NaOH again, with methyl tertiary butyl ether(MTBE) aqueous phase extracted twice, the organic phase of merging is dried with sodium sulphate；
After drying, sodium sulphate is filtered, the solution of Formula IV compounds methyl tertbutyl ether will be obtained.Above-mentioned solution is concentrated into supersaturation,
Slow crystallization at room temperature, then it is cooled to -10~5 DEG C, then filter, washed with the methyl tertiary butyl ether(MTBE) of ice, at 30~40 DEG C
Vacuum drying obtains light yellow solid Formula IV compound.
5th step is reacted gained Formula IV compound and is dissolved in methanol-water (v/v=1/1) by the six-step process, adds
L-DTTA, the Formula IV compound and L-DTTA mol ratio are 1: 0.2~1: 2, and mol ratio preferably is 1: 0.4~1: 1.Instead
It is 10~70 DEG C to answer temperature, and preferred temperature is 20~60 DEG C, and optimum temperature is 35~50 DEG C, and the reaction time is 2~60 hours, excellent
It is 10~30 hours to select the reaction time.With the progress of reaction, product is constantly separated out, and is waited after precipitation completely, makes system natural
Room temperature is down to, is then filtered, is washed with the methanol of ice, the finished product Formula VII of off-white color is obtained in vacuum drying at 50~60 DEG C
Compound (3R, 4R)-(1- benzyl -4- methyl piperidine -3- bases) methylamine-L- two is to toluoyltartrates.
(3R, the 4R) that the present invention is provided-(1- benzyl -4- methyl piperidine -3- bases) methylamine-L- two is to toluoyltartaric
The preparation method of salt, with following advantage：Present invention process is novel in design, it is not necessary to use the chemicals of danger close (such as：Tetrahydrochysene
Aluminium lithium), using technique is collapsed, total recovery is high；Importantly, starting material is cheap and easily-available, cost is low；It is workable, easily
In industrialization.
Embodiment
In order that the purpose of the present invention, technical scheme and beneficial effect are more preferably clear, below by the preferred reality of the present invention
Example is applied to be described in detail, but the invention is not restricted to following examples.
Embodiment 1
Add in 7kg ethanol, add in 1kg compound of formula I N- benzyls -4- carbonyls-ethyl nipecotate
0.9kg 25% ammoniacal liquor, reaction temperature is 33 DEG C, after reacting 22 hours, the ethanol for the overwhelming majority that is concentrated under reduced pressure, and is added
7kg methyl tertiary butyl ether(MTBE) is extracted, and after the organic phase separated is dried 3 hours with sodium sulphate, is filtered sodium sulphate, is obtained Formula II
The t-butyl methyl ether solution of compound.
The t-butyl methyl ether solution of Formula II compound obtained by upper step is cooled to -55 DEG C, under nitrogen protection, is added dropwise
The tetrahydrofuran solution of 2.5L 2mol/L methyl Grignard, 1 hour completion of dropping, control system temperature is at -27 DEG C
Under, after 5 hours of reaction, 3.5 liter 10% of ammonium chloride solution terminating reaction is slowly added dropwise, separates organic phase, 3L is then used again
Methyl tertiary butyl ether(MTBE) aqueous phase extracted in product；The organic phase separated washed once with pure saturated sodium-chloride, then use sulfuric acid
Sodium dries organic phase；After drying, sodium sulphate is filtered, be concentrated under reduced pressure organic solvent；6L toluene is added into above-mentioned concentrate,
And division box is used, back flow reaction 10 hours, then concentration falls toluene, obtains 0.8kg formula III compound.
In the methanol that 0.8kg formula III compound is added to 5L, 120g Raney Ni are added.With nitrogen displacement three times
Afterwards, hydrogen is poured, pressure is 4atm, and reaction temperature is controlled after 40 DEG C, 6 hours of reaction time.Raney Ni are filtered, are concentrated
Fall after most of methanol, add 3kg water, separate out formula IV compound, filter out product, in drying under hot air circulation at 50 DEG C,
Obtain 0.75kg formula IV compound.
0.75kg formula IV compound is dissolved in 3L methanol, 3L 5% liquor natrii hypochloritis, control reaction temperature is added
Spend for 48 DEG C.After 8 hours reaction time, decompression evaporates methanol, recovery.Then with 3L Ethyl formates extraction product, extraction
Three times, merge organic phase, obtain Formula V compound carboxylate solution.
Into the Formula V compound carboxylate solution of above-mentioned gained, 50g p-methyl benzenesulfonic acid is added, reaction temperature is 55
DEG C, after 12 hours of reaction, decompression evaporates Ethyl formate；Add 3.5L tetrahydrofuran, control system temperature in zero degree or so,
Add 270g sodium borohydride；At 10 DEG C, the tetrahydrofuran solution of 1.6kg trifluoroacetic acid is added dropwise, and (mass concentration is
50%)；Reacted at 20 DEG C after 7 hours, reaction is also slowly added into 5L 10% hydrochloric acid of zero degree, then separated
Organic phase, aqueous phase adjusts pH to 9-10 with 2N NaOH again, with the product in 2.6L methyl tertiary butyl ether(MTBE) aqueous phase extracted, merging
Organic phase is dried with sodium sulphate；After drying, sodium sulphate is filtered, the solution of the methyl tertiary butyl ether(MTBE) of Formula IV compound will be obtained.
The solution of the methyl tertiary butyl ether(MTBE) of above-mentioned Formula IV compound is concentrated into supersaturation, slow crystallization, then be cooled to -10 at room temperature
~5 DEG C, then filter, washed with the methyl tertiary butyl ether(MTBE) of ice, in being dried in vacuo to obtain 0.5kg light yellow solid formulas at 30~40 DEG C
VI compounds.
0.5kg Formula IV compound is dissolved in 3.2L methanol-water (v/v=1/1), 442g L-DTTA is added.
At 45 DEG C, after reacting 12 hours, allow system to be down to room temperature naturally, then filter, washed with the methanol of ice, in true at 50~60 DEG C
Sky be dried to obtain finished product Formula VII compound (3R, 4R)-(1- benzyl -4- methyl piperidine -3- bases) methylamines of 550g off-white colors -
L- bis- is to toluoyltartrates.The total recovery of the preparation method of the present embodiment is 23.8%.
Embodiment 2
Add in 20kg ethanol, add in 3kg compound of formula I N- benzyls -4- carbonyls-ethyl nipecotate
3.9kg 25% ammoniacal liquor, reaction temperature is 30 DEG C, after reacting 30 hours, the ethanol for the overwhelming majority that is concentrated under reduced pressure, and is added
20kg methyl tertiary butyl ether(MTBE) is extracted, and after the organic phase separated is dried 5 hours with sodium sulphate, is filtered sodium sulphate, is obtained Formula II
The t-butyl methyl ether solution of compound.
The t-butyl methyl ether solution of Formula II compound obtained by upper step is cooled to -60 DEG C, under nitrogen protection, is added dropwise
The tetrahydrofuran solution of 8.6L 2mol/L methyl Grignard, 1.5 hours, which are added dropwise, finishes, and control system temperature is at -30 DEG C
Under, after 7 hours of reaction, 10 liter 10% of ammonium chloride solution terminating reaction is slowly added dropwise, organic phase is separated, then again with 6L's
Product in methyl tertiary butyl ether(MTBE) aqueous phase extracted；The organic phase separated washed once with pure saturated sodium-chloride, then use sodium sulphate
Dry organic phase；After drying, sodium sulphate is filtered, be concentrated under reduced pressure organic solvent；20L toluene is added into above-mentioned concentrate,
And division box is used, back flow reaction 10 hours, then concentration falls toluene, obtains 2.42kg formula compound.
In the methanol that 2.42kg formula III compound is added to 17L, 240g Raney Ni are added.With nitrogen displacement three
After secondary, hydrogen is poured, pressure is 4atm, and reaction temperature is controlled after 30 DEG C, 30 hours of reaction time.Raney Ni are filtered,
Concentration is fallen after most of methanol, adds 10kg water, and formula IV compound is separated out, and product is filtered out, under hot air circulation at 50 DEG C
Drying, obtains 2.3kg formula IV compound.
2.3kg formula IV compound is dissolved in 9L methanol, 4L10% liquor natrii hypochloritises, controlling reaction temperature is added
For 50 DEG C.After 7 hours reaction time, decompression evaporates methanol, recovery.Then with 6L Ethyl formates extraction product, extraction three
It is secondary, merge organic phase, obtain the carboxylate solution of Formula V compound.
Into the carboxylate solution of the Formula V compound of above-mentioned gained, 0.8kg p-methyl benzenesulfonic acid, reaction temperature are added
For 60 DEG C, after 6 hours of reaction, decompression evaporates Ethyl formate；10L tetrahydrofuran is added, control system temperature is left in zero degree
The right side, adds 1.4kg sodium borohydride；At 10 DEG C, the tetrahydrofuran solution of 8.4kg trifluoroacetic acid is added dropwise, and (mass concentration is
50%)；Reacted at 20 DEG C after 6 hours, reaction is also slowly added into 20L 10% hydrochloric acid of zero degree, then separated
Organic phase, aqueous phase adjusts pH to 9-10 with 2N NaOH again, with the product in 8L methyl tertiary butyl ether(MTBE) aqueous phase extracted, and merging has
Machine is dried with sodium sulphate；After drying, sodium sulphate is filtered, the solution of the methyl tertiary butyl ether(MTBE) of Formula IV compound will be obtained.Will
The solution of the methyl tertiary butyl ether(MTBE) of above-mentioned Formula IV compound is concentrated into supersaturation, slow crystallization, then be cooled to -10~5 at room temperature
DEG C, then filter, washed with the methyl tertiary butyl ether(MTBE) of ice, in being dried in vacuo to obtain 1.53kg light yellow solid Formula IV at 30~40 DEG C
Compound.
1.53kg Formula IV compound is dissolved in 10L methanol-water (v/v=1/1), 1.08kg L-DTTA is added.
At 50 DEG C, after reacting 10 hours, allow system to be down to room temperature naturally, then filter, washed with the methanol of ice, at 50~60 DEG C
Vacuum drying obtains finished product Formula VII compound (3R, 4R)-(1- benzyl -4- methyl piperidine -3- bases) first of 1.53kg off-white colors
Amine-L- two is to toluoyltartrates.The preparation method total recovery of the present embodiment is 22.0%.
Embodiment 3
Add in 35kg ethanol, add in 5kg compound of formula I N- benzyls -4- carbonyls-ethyl nipecotate
2.6kg 25% ammoniacal liquor, reaction temperature is 40 DEG C, after reacting 16 hours, the ethanol for the overwhelming majority that is concentrated under reduced pressure, and is added
35kg methyl tertiary butyl ether(MTBE) is extracted, and after the organic phase separated is dried 5 hours with sodium sulphate, is filtered sodium sulphate, is obtained Formula II
The t-butyl methyl ether solution of compound.
The t-butyl methyl ether solution of Formula II compound obtained by upper step is cooled to -40 DEG C, under nitrogen protection, is added dropwise
The tetrahydrofuran solution of 10.5L 2mol/L methyl Grignard, 2 hours, which are added dropwise, finishes, control system temperature at -20 DEG C,
React after 4 hours, 17 liter 10% of ammonium chloride solution terminating reaction is slowly added dropwise, organic phase is separated, 10L first is then used again
Product in base tertbutyl ether aqueous phase extracted；The organic phase separated washed once with pure saturated sodium-chloride, then dry with sodium sulphate
Dry organic phase；After drying, sodium sulphate is filtered, be concentrated under reduced pressure organic solvent；35L toluene is added into above-mentioned concentrate, and
Using division box, back flow reaction 12 hours, toluene is fallen in then concentration, obtains 3.99kg formula compound.
In the methanol that 3.99kg formula III compound is added to 27L, 134g Raney Ni are added.With nitrogen displacement three
After secondary, hydrogen is poured, pressure is 4atm, and reaction temperature is controlled after 70 DEG C, 10 hours of reaction time.Raney Ni are filtered,
Concentration is fallen after most of methanol, adds 18kg water, separates out formula compound, filters out product, in baking under hot air circulation at 50 DEG C
It is dry, obtain 3.7kg formula IV compound.
3.7kg formula IV compound is dissolved in 15L methanol, 10L 5% liquor natrii hypochloritis, control reaction is added
Temperature is 40 DEG C.After 12 hours reaction time, decompression evaporates methanol, recovery.Then with 11L Ethyl formates extraction product,
Extraction three times, merges organic phase, obtains the carboxylate solution of Formula V compound.
Into the carboxylate solution of the Formula V compound of above-mentioned gained, 257g p-methyl benzenesulfonic acid is added, reaction temperature is
45 DEG C, react after 24 hours, decompression evaporates Ethyl formate；17L tetrahydrofuran is added, control system temperature is left in zero degree
The right side, adds 1.2kg sodium borohydride；At 10 DEG C, the tetrahydrofuran solution of 7.0kg trifluoroacetic acid is added dropwise, and (mass concentration is
50%)；React after 10 hours, reaction is also slowly added into 26L 10% hydrochloric acid of zero degree, Ran Houfen at 20 DEG C
Go out organic phase, aqueous phase is adjusted pH to 9-10 with 2N NaOH again, with the product in 14L methyl tertiary butyl ether(MTBE) aqueous phase extracted, merged
Organic phase dried with sodium sulphate；After drying, filter sodium sulphate, will obtain Formula IV compound methyl tertiary butyl ether(MTBE) it is molten
Liquid.The solution of the methyl tertiary butyl ether(MTBE) of above-mentioned Formula IV compound is concentrated into supersaturation, at room temperature slow crystallization, then be cooled to-
10~5 DEG C, then filter, washed with the methyl tertiary butyl ether(MTBE) of ice, in be dried in vacuo at 30~40 DEG C 2.45kg is light yellow solid
Body Formula IV compound.
2.45kg Formula IV compound is dissolved in 16L methanol-water (v/v=1/1), 4.34kg L-DTTA is added.
At 35 DEG C, after reacting 30 hours, allow system to be down to room temperature naturally, then filter, washed with the methanol of ice, at 50~60 DEG C
Vacuum drying obtains finished product Formula VII compound (3R, 4R)-(1- benzyl -4- methyl piperidine -3- bases) first of 2.71kg off-white colors
Amine-L- two is to toluoyltartrates.The preparation method total recovery of the present embodiment is 23.4%.
Embodiment 4
Add in 42kg ethanol, add in 6kg compound of formula I N- benzyls -4- carbonyls-ethyl nipecotate
5.5kg 25% ammoniacal liquor, reaction temperature is 35 DEG C, after reacting 25 hours, the ethanol for the overwhelming majority that is concentrated under reduced pressure, and is added
42kg methyl tertiary butyl ether(MTBE) is extracted, and after the organic phase separated is dried 6 hours with sodium sulphate, is filtered sodium sulphate, is obtained Formula II
The t-butyl methyl ether solution of compound.
The t-butyl methyl ether solution of Formula II compound obtained by upper step is cooled to -50 DEG C, under nitrogen protection, is added dropwise
The tetrahydrofuran solution of 14.9L 2mol/L methyl Grignard, 2.5 hours, which are added dropwise, finishes, and control system temperature is at -25 DEG C
Under, after 6 hours of reaction, 20 liter 10% of ammonium chloride solution terminating reaction is slowly added dropwise, separates organic phase, 14L is then used again
Methyl tertiary butyl ether(MTBE) aqueous phase extracted in product；The organic phase separated washed once with pure saturated sodium-chloride, then use sulfuric acid
Sodium dries organic phase；After drying, sodium sulphate is filtered, be concentrated under reduced pressure organic solvent；40L first is added into above-mentioned concentrate
Benzene, and division box is used, back flow reaction 12 hours, then concentration falls toluene, obtains 4.8kg formula III compound.
In the methanol that 4.8kg formula III compound is added to 30L, 900g Raney Ni are added.With nitrogen displacement three times
Afterwards, hydrogen is poured, pressure is 4atm, and reaction temperature is controlled after 50 DEG C, 8 hours of reaction time.Raney Ni are filtered, are concentrated
Fall after most of methanol, add 22kg water, formula IV compound is separated out, and filters out product, in drying under hot air circulation at 50 DEG C,
Obtain 4.5kg formula IV compound.
4.5kg formula IV compound is dissolved in 18L methanol, 16L 5% liquor natrii hypochloritis, control reaction is added
Temperature is 45 DEG C.After 10 hours reaction time, decompression evaporates methanol, recovery.Then with 14L Ethyl formates extraction product,
Extraction three times, merges organic phase, obtains the carboxylate solution of Formula V compound.
Into the carboxylate solution of the Formula V compound of above-mentioned gained, 330g p-methyl benzenesulfonic acid is added, reaction temperature is
50 DEG C, react after 18 hours, decompression evaporates Ethyl formate；21L tetrahydrofuran is added, control system temperature is left in zero degree
The right side, adds 1.6kg sodium borohydride；At 10 DEG C, the tetrahydrofuran solution of 9.4kg trifluoroacetic acid is added dropwise, and (mass concentration is
50%)；React after 10 hours, reaction is also slowly added into 32L 10% hydrochloric acid of zero degree, Ran Houfen at 20 DEG C
Go out organic phase, aqueous phase is adjusted pH to 9-10 with 2N NaOH again, with the product in 18L methyl tertiary butyl ether(MTBE) aqueous phase extracted, merged
Organic phase dried with sodium sulphate；After drying, sodium sulphate is filtered, the solution of the methyl tertiary butyl ether(MTBE) of formula compound will be obtained.
Above-mentioned solution is concentrated into supersaturation, at room temperature slow crystallization, then is cooled to -10~5 DEG C, then filtered, with the methyl- tert of ice
Butyl ether is washed, in being dried in vacuo to obtain 2.96kg light yellow solid Formula IV compounds at 30~40 DEG C.
2.96kg Formula IV compound is dissolved in 19L methanol-water (v/v=1/1), 3.14kg L-DTTA is added.
At 40 DEG C, after reacting 18 hours, allow system to be down to room temperature naturally, then filter, washed with the methanol of ice, at 50~60 DEG C
Vacuum drying obtains finished product Formula VII compound (3R, 4R)-(1- benzyl -4- methyl piperidine -3- bases) first of 3.24kg off-white colors
Amine-L- two is to toluoyltartrates.The preparation method total recovery of the present embodiment is 23.3%.
In addition, comparing with the two synthetic route yields reported, comparing result is as follows：
Synthesis (3R, 4R)-(1- benzyl -4- methyl piperidine -3- bases) methylamine-L- two is gone to toluene using the route of the present invention
The yield of formyl tartrate is higher than Org.Process.Res＆Dev 2005,9:Reported in 51-56 and WO2008029237
Yield；Meanwhile, with Org.Process.Res＆Dev, 2014,18:The yield reported in 1714-1720 is compared, also very close to.
Preferred embodiment above is merely illustrative of the technical solution of the present invention and unrestricted, although being preferable to carry out by above-mentioned
The present invention is described in detail for example, it is to be understood by those skilled in the art that can be in the form and details
Various changes are made to it, without departing from claims of the present invention limited range.
Claims (9)
1. one kind (3R, 4R)-(1- benzyl -4- methyl piperidine -3- bases) methylamine-L- two is to the preparation side of toluoyltartrates
Method, is made by following reactions steps：
Characterized in that,
The first step reaction dissolvent is ethanol, and reaction temperature is 0~70 DEG C, and the reaction time is 5~72 hours, type I compound N- benzyls
The mol ratio of base -4- carbonyls-ethyl nipecotate and ammoniacal liquor is 1: 1~1: 10；
The t-butyl methyl ether solution temperature of the second step reaction compound of formula H is -80~0 DEG C, the RMgBr of dropwise addition
For tetrahydrofuran solution, the mol ratio of Formula II compound and tetrahydrofuran solution is 1: 0.8~1: 3.0, reaction temperature is -70~
0 DEG C, the reaction time is 2~10 hours；
The compound of three-step reaction Chinese style III and Raney Ni weight ratio are 100: 1~5: 1, and reaction temperature is 10~80
DEG C, the reaction time is 2~60 hours；
The four-step reaction compound of formula IV is dissolved in methanol, and liquor natrii hypochloritis's concentration of addition is 2%~30%, instead
It is -10~65 DEG C to answer temperature, and the reaction time is 5~24 hours；
The mol ratio of 5th step reaction compound of formula V and p-methyl benzenesulfonic acid is 1: 0.01~1: 10, reaction temperature is 0~
65 DEG C, the reaction time is 2~40 hours；
Formula IV compound is dissolved in methanol-water solution in the six-step process, Formula IV compound and L-DTTA mol ratio
For 1: 0.2~1: 2, reaction temperature is 10~70 DEG C, and the reaction time is 2~60 hours.
2. preparation method according to claim 1, it is characterised in that the first step reaction dissolvent is ethanol, reaction temperature
Spend for 10~60 DEG C, the reaction time is 16~30 hours, type I compound N- benzyls -4- carbonyls-ethyl nipecotate and ammoniacal liquor
Mol ratio be 1: 2~1: 5；
The t-butyl methyl ether solution temperature of the second step reaction compound of formula H is -70~-20 DEG C, and the grignard of dropwise addition is tried
Agent is tetrahydrofuran solution, and the mol ratio of Formula II compound and tetrahydrofuran solution is 1: 0.9~1: 2.0, and reaction temperature is -60
~-10 DEG C, the reaction time is 4~7 hours；
The compound of three-step reaction Chinese style III and Raney Ni weight ratio are 30: 1~10: 1, and reaction temperature is 20~80
DEG C, the reaction time is 10~30 hours；
The four-step reaction compound of formula IV is dissolved in methanol, and liquor natrii hypochloritis's concentration of addition is 5%~10%, instead
It is 20~55 DEG C to answer temperature, and the reaction time is 7~12 hours；
The mol ratio of 5th step reaction compound of formula V and p-methyl benzenesulfonic acid is 1: 0.05~1: 5, reaction temperature is 45~
60 DEG C, the reaction time is 6~24 hours；
Formula IV compound is dissolved in methanol-water solution in the six-step process, Formula IV compound and L-DTTA mol ratio
For 1: 0.4~1: 1, reaction temperature is 20~60 DEG C, and the reaction time is 10~30 hours.
3. the preparation method according to right wants 2, it is characterised in that：The first step reaction temperature is 30~40 DEG C；
The t-butyl methyl ether solution temperature of second step reaction compound of formula H is -60~-40 DEG C, Formula II compound with
The mol ratio of tetrahydrofuran solution is 1: 1.1~1: 1.5, and reaction temperature is -30~-20 DEG C；
The three-step reaction temperature is 30~70 DEG C；
The four-step reaction temperature is 40~50 DEG C；
The mol ratio of the 5th step reaction compound of formula V and p-methyl benzenesulfonic acid is 1: 0.1~1: 0.5；
The six-step process temperature is 35~50 DEG C.
4. the preparation method according to right wants 2, it is characterised in that：The first step reaction dissolvent is ethanol, reaction temperature
For 33 DEG C, the reaction time is 22 hours；
The t-butyl methyl ether solution temperature of the second step reaction compound of formula H is -55 DEG C, and reaction temperature is -27 DEG C,
Reaction time is 5 hours；
The three-step reaction temperature is 40 DEG C, and the reaction time is 6 hours；
The four-step reaction compound of formula IV is dissolved in methanol, and liquor natrii hypochloritis's concentration of addition is 5%, reaction temperature
For 48 DEG C, the reaction time is 8 hours；
The 5th step reaction temperature is 55 DEG C, and the reaction time is 12 hours；
The six-step process temperature is 45 DEG C, and the reaction time is 12 hours.
5. preparation method according to claim 1, it is characterised in that：The first step is concentrated under reduced pressure second after completion of the reaction
Alcohol, uses methyl tertiary butyl ether(MTBE) extracted products, separates organic phase, is then dried with sodium sulphate, filters sodium sulphate, obtains Formula II chemical combination
The t-butyl methyl ether solution of thing；
The second step after completion of the reaction, is slowly added dropwise 10% ammonium chloride solution terminating reaction, separates organic phase, use methyl- tert
Product in butyl ether aqueous phase extracted；The organic phase separated is washed with pure saturated sodium-chloride, separates organic phase, is dried with sodium sulphate
Organic phase, filters sodium sulphate, and be concentrated under reduced pressure organic solvent, adds toluene, and first is fallen in back flow reaction 4~10 hours, then concentration
Benzene, obtains formula III compound；
In the three-step reaction, after nitrogen displacement three times, hydrogen is poured, pressure is 4atm, and reaction is finished, and filters Raney
Ni, concentration is fallen after most of methanol, adds water, and formula IV compound is separated out, and filters out product, is dried under 50 degree of lower hot air circulations
It is dry, obtain formula IV compound；
The four-step reaction is finished, and decompression evaporates methanol, then extracts product three times with Ethyl formate, is merged organic phase, is obtained
To the carboxylate solution of Formula V compound.
6. preparation method according to claim 5, it is characterised in that：The 5th step reaction is finished, and decompression evaporates formic acid
Ethyl ester, adds tetrahydrofuran, control system temperature adds sodium borohydride at 0 DEG C or so, and Formula V compound and sodium borohydride rub
You are than being 1: 0.5~1: 10, at 10 DEG C, be added dropwise the tetrahydrofuran solution of trifluoroacetic acid, and Formula V compound and trifluoroacetic acid rub
You are reacted after 6 hours than being 1: 0.5~1: 10 under 20 degree, and 10% HCl that reaction solution is slowly added into 0 DEG C of degree is molten
In liquid, organic phase is then separated, aqueous phase is adjusted pH to 9-10 with 2N NaOH again, with methyl tertiary butyl ether(MTBE) aqueous phase extracted twice, closed
And organic phase dried with sodium sulphate；After drying, sodium sulphate is filtered, the solution of the methyl tertiary butyl ether(MTBE) of Formula IV compound will be obtained
Supersaturation is concentrated into, at room temperature slow crystallization, then is cooled to -10~5 DEG C, then filtered, washed with the methyl tertiary butyl ether(MTBE) of ice,
Light yellow solid Formula IV compound is obtained in vacuum drying at 30~40 DEG C.
7. preparation method according to claim 6, it is characterised in that：The mol ratio of the Formula V compound and sodium borohydride
For 1: 1~1: 6, the mol ratio of Formula V compound and trifluoroacetic acid is 1: 1~1: 6.
8. preparation method according to claim 6, it is characterised in that：The mol ratio of the Formula V compound and sodium borohydride
For 1: 2~1: 4, the mol ratio of Formula V compound and trifluoroacetic acid is 1: 2~1: 4.
9. preparation method according to claim 5, it is characterised in that：The six-step process finishes rear near room temperature, mistake
Filter, wash with the methanol of ice, in be dried in vacuo at 50~60 DEG C obtain the finished product Formula VII compound (3R, 4R) of off-white color-
(1- benzyl -4- methyl piperidine -3- bases) methylamine-L- two is to toluoyltartrates.
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