CN101712645B - Preparation method for (2R, 4R)-4-substituted-2-piperidine carboxylic acid compound and intermediate thereof - Google Patents
Preparation method for (2R, 4R)-4-substituted-2-piperidine carboxylic acid compound and intermediate thereof Download PDFInfo
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Abstract
The invention relates to a synthesis method for preparing a (2R,4R)-4-methyl-2 -piperidine carboxylic acid compound taking diethyl oxalate as starting materials and an intermediate thereof, and belongs to the field of organic synthesis. The synthesis method comprises the following steps of: taking the diethyl oxalate and 1-bromo-substituted-propylene as the starting materials, performing a Grignard reaction and an addition reaction on the diethyl oxalate and 1-bromo-3-substituted-propylene to obtain intermediate 2-carbonyl-4-substituted-5 cyan ethyl valerate; and then performing a cyclization reaction, a benzyl ester protection reaction and a deprotection reaction on the intermediate 2-carbonyl-4-substituted-5 cyan ethyl valerate to obtain trans-4-substituted-2-piperidine ethyl formate; and finally, splitting the trans-4-substituted-2-piperidine carboxylic acid ethyl ester to obtain a chiral target product (2R,4R)-4-methyl-2-piperidine formic acid compound. The preparation method has the advantages of readily available raw materials, simple process, and mild reaction condition.
Description
Technical field
The present invention relates to a kind of is that (2R 4R)-synthetic method and the intermediate thereof of 4-methyl-2-formic acid, belongs to the organic synthesis field for starting raw material preparation with the oxalic acid diethyl ester.
Background technology
(2R, 4R)-4-replacement-Pipecolic Acid is the nitrogen-containing heterocycle compound of a class good biological activity, this compound was the key intermediate of argatroban when particularly 4-was substituted by methyl.Argatroban is the direct thrombin inhibitors of monovalence, directly be combined with the catalytic activity site of zymoplasm, not only deactivation liquid phase zymoplasm, the zymoplasm of can also deactivation being combined with fibrinous thrombus, approved is used for thrombotic diseases such as heparin-induced thrombopenia and thrombosis, percutaneous coronary intervention (pci), cerebral apoplexy thrombolysis at present.The inside and outside studies show that, it goes back other effects of Trombin inhibiting, as the restenosis that can suppress metastases, inflammatory process and postangioplasty etc.Argatroban went on the market in the U.S. in 2000, be used for prevention and treat heparin-induced thrombocytopenia or thromboembolism (HIT/HITTS), and be approved in 2002 and take place or have pass through skin percutaneous coronary intervention patient's a anticoagulant therapy of HIT/HITTS danger.Good market prospects.
Known (2R, 4R)-synthetic method of 4-replacement-Pipecolic Acid mainly contains:
1) with the synthetic 4-methyl of 4-methyl piperidine and sodium cyanide-2-cyano group piperidine compounds, hydrolysis again, split obtain target compound (S.Okamoto, et al.US4072757,1978, Mitsubishi Chemical Industries, Japan[1]; S.Okamoto, et al.US4258192,1981, Mitsubishi Chemical Industries, Japan[2]), this technology cis-trans-isomer selectivity is low, need in the process to use a large amount of soda acids, reactant is sneaked into a large amount of inorganic salt before causing splitting, and must carry out desalting treatment with resin, complicated operation, yield is low.
2) document C.Agami, etal.Eur.J.Org.Chem.2001,2385-2389[3] and document C.Alegret, F.Santacana, A.Riera, J.Org.Chem.2007,72,7688-7692[4] method because initiator can't buy from the market, and its complex synthetic route, so this technology is difficult to industrialization.
3) document K.Tibaudeau, et al.US6440417,2002, ConjuChem Inc.Canada[4] method, though operational path is short, need not split, but need trifluoroacetic acid in the operational path, the chemical reagent that chiral catalyst etc. are expensive is so this technology is difficult to industrialization.
4) document J.Cossy, D.Belotti, Bioorg.Med.Chem.Lett.11,1989-1992,2001[5] method need with the isobutyl-lithium that is difficult on the industrial production use, its processing condition are also restive.
Prior art (2R, 4R)-synthetic method of 4-replacement-Pipecolic Acid in, perhaps yield is low, and is perhaps raw materials used expensive, perhaps complicated operation, these deficiencies are synthetic for they, particularly industrial production is all very inconvenient.
Summary of the invention
The objective of the invention is provides a kind of cheap raw material that adopts for the deficiency that solves above-mentioned technology, provide an operational path advantages of simple, cost low, simple to operate (2R, 4R)-new synthetic method of 4-replacement-Pipecolic Acid heterogeneous ring compound.
For achieving the above object; a kind of (2R provided by the present invention; 4R)-new synthetic method of 4-replacement-Pipecolic Acid heterogeneous ring compound; be to be starting raw material with oxalic acid diethyl ester and 1-bromo-propylene; get trans 4-replacement-Pipecolic Acid ethyl ester through grignard reaction, addition, cyclization, the protection of benzyl ester, five step of deprotection popular response, obtain the chirality target product through fractionation again.Reaction expression is:
Step 4, the protective reaction of benzyl ester, 4-replacement-Pipecolic Acid ethyl ester is dissolved in organic solvent obtains solution, stir and the adding chloroformic acid benzyl ester, slowly drip with organic bases then, dropwise the back and continue reaction 3 hours, filter and collect filtrate, with a small amount of organic solvent washing filter cake and collect filtrate, merge gained filtrate twice again, concentrate and obtain N-benzyloxy carbonyl acyl group-4-replacement-Pipecolic Acid ethyl ester;
Step 5, take off the protective reaction of benzyl ester, N-benzyloxy carbonyl acyl group-4-replacement-Pipecolic Acid ethyl ester is dissolved in organic solvent and adds a small amount of palladium carbon, heated mixt and logical hydrogen reaction, complete reaction is filtered and is also collected filtrate to not absorbing till the hydrogen, again with the organic solvent washing filter cake and collect filtrate, merge gained filtrate twice, concentrate and obtain trans 4-replacement-Pipecolic Acid ethyl ester;
Step 6, split process, trans 4-replacement-Pipecolic Acid ethyl ester is dissolved in organic solvent, stir and heating, add L-tartrate then, be incubated molten clear back and continue to stir 5-15min, the crystallization of lowering the temperature then filters and collects filter cake, with a little organic solvent washing filter cake, then filter cake is put into water, add alkaline matter and transfer pH value is transferred to 11, to keep pH value be 11 and stir 0.5-1h, transfer to neutrality with mineral acid again, with organic solvent extraction 2 times, the extracting solution drying, filter last concentrate obtain (2R, 4R)-4-replacement-Pipecolic Acid.
Wherein in step 1 grignard reaction, the mass ratio of solute and anhydrous tetrahydro furan is 1: 2-20, solvent also can be methyltetrahydrofuran or ether; Reactant 1-bromo-propylene: magnesium: the mol ratio of oxalic acid diethyl ester is 1: 1-2: 1-2.
In step 2 addition reaction, the mass ratio of solute and anhydrous tetrahydro furan is 1: 2-20, solvent also can be methyltetrahydrofuran or ether; Reactant 2-carbonyl-3-allyl acetic acid ethyl ester: methyl-cyanacetate: the mol ratio of sodium hydride is 1: 1-2: 1-2.
In step 3 ring-closure reaction, organic solvent is ethanol; Catalyzer is Raney's nickel, and reactant 2-carbonyl-4-replaces-5 cyanopentanoic acid ethyl esters: the mol ratio of hydrogen is 1: 1.5-10.
In the protective reaction of step 4 benzyl ester, organic solvent is methylene dichloride; Organic bases is triethylamine, and reactant 4-replacement-Pipecolic Acid ethyl ester: chloroformic acid benzyl ester: the mol ratio of triethylamine is 1: 1-2: 1-2.
Step 5 is taken off in the protective reaction of benzyl ester, and organic solvent is ethanol; Catalyzer is palladium carbon; Reactant N-benzyloxy carbonyl acyl group-4-replacement-Pipecolic Acid ethyl ester: the mol ratio of hydrogen is 1: 1-4.
In step 6 resolution reaction, organic solvent is ethanol, and reactant 4-replacement-Pipecolic Acid ethyl ester: the tartaric mol ratio of L-is 1: 1-2.
(2R, 4R)-intermediate of 4-replacement-Pipecolic Acid is that 2-carbonyl-4-replaces-5 cyanopentanoic acid ethyl esters, has the structure suc as formula II,
Wherein R represent methylidene alkyl or C
6-12Aryl.
The invention has the advantages that: raw material is easy to get, and technology is simple, and the reaction conditions gentleness has wide range of applications, can be used for different substrates synthetic multiple (2R, 4R)-4-methyl-Pipecolic Acid.
Embodiment
Embodiment 1
Be starting raw material with oxalic acid diethyl ester and 1-bromo-propylene, and preparation (2R, 4R)-4-methyl-Pipecolic Acid.
(1) in 100ml dry reaction bottle, add magnesium chips 0.05mol and anhydrous tetrahydro furan 30ml, add the anhydrous tetrahydrofuran solution 20ml of 1-bromo-propylene 0.05mol in the addition funnel.Drip a little 1-bromo-propylene solution earlier and enter reaction flask, add a granule iodine, little color that is heated to disappears, this moment, reaction caused, withdrew heating, began to drip the tetrahydrofuran solution of 1-bromo-propylene, dropwise, it is complete, standby to the magnesium chips dissolving to continue stirring reaction.In the 250ml reaction flask of drying, add oxalic acid diethyl ester 0.05mol and anhydrous tetrahydro furan 80ml; cooling, the standby tetrahydrofuran solution above slowly dripping is stirred in nitrogen protection; dropwise; reacted 2 hours, and added the aqueous solution of ammonium chloride, ethyl acetate extraction; anhydrous sodium sulfate drying; filter, evaporate to dryness obtains 2-carbonyl-3-allyl acetic acid ethyl ester, and this step productive rate is about 85%.
(2) set by step it is standby that (1) produces the 2-carbonyl-3-allyl acetic acid ethyl ester of capacity, in 100ml dry reaction bottle, add anhydrous tetrahydro furan 50ml and methyl-cyanacetate 0.05mol, stir, gradation adds the 0.05mol sodium hydride, add and stir half an hour, slowly drip the anhydrous tetrahydrofuran solution 30ml of 0.05mol2-carbonyl-3-alkene-Valeric acid ethylester, dropwise stirring reaction 2 hours.Concentrate tetrahydrofuran solution, in enriched material, add ethyl acetate 50ml, wash with salt solution, anhydrous sodium sulfate drying, filtering and concentrating obtains 2-carbonyl-4-methyl-5 cyanopentanoic acid ethyl ester, 2-carbonyl-4-methyl-5 cyanopentanoic acid ethyl ester is reaction intermediate, and this step productive rate is about 82%.
(3) set by step it is standby that (2) produce the 2-carbonyl-4-methyl-5 cyanopentanoic acid ethyl ester of capacity, in the reaction vessel of 100ml clean dried, adds ethanol 60ml, 2-carbonyl-4-methyl-5 cyanopentanoic acid ethyl ester 0.05mol, Raney's nickel Ni 0.3g, the logical hydrogen reaction of heating, reaction does not react completely when extremely not absorbing hydrogen, stopped reaction filters, and uses the washing with alcohol filter cake, merge ethanol, concentrate, obtain 4-methyl-Pipecolic Acid ethyl ester, this step productive rate is about 90%.
(4) set by step it is standby that (3) produce the 4-methyl-Pipecolic Acid ethyl ester of capacity; in 100ml dry reaction bottle, add the 60ml methylene dichloride; 4-methyl-Pipecolic Acid ethyl ester 0.05mol stirs adding chloroformic acid benzyl ester 0.05mol, slowly drips triethylamine 0.05mol; dropwise reaction 3 hours; filter, with a small amount of washed with dichloromethane filter cake, combined dichloromethane solution; concentrate and obtain N-benzyloxy carbonyl acyl group-4-methyl-Pipecolic Acid ethyl ester, this step productive rate is about 92%.
(5) set by step it is standby that (4) produce the N-benzyloxy carbonyl acyl group-4-methyl-Pipecolic Acid ethyl ester of capacity, in the reaction vessel of 100ml clean dried, adds ethanol 50ml; N-benzyloxy carbonyl acyl group-4-methyl-Pipecolic Acid ethyl ester 0.05mol, palladium carbon 0.2g, hydrogen reaction is led in airtight heating; reaction does not react completely when extremely not absorbing hydrogen; stopped reaction filters, and uses the washing with alcohol filter cake; merge ethanolic soln; concentrate, obtain trans 4-methyl-Pipecolic Acid ethyl ester, this step productive rate is about 95%.
(6) set by step (5) produce trans 4-methyl-Pipecolic Acid ethyl ester standby of capacity, add 60ml ethanol, trans 4-methyl-Pipecolic Acid ethyl ester 0.05mol, stirring heating to the clean reaction flask of 100ml, add L-tartrate 0.05mol, be incubated molten clear back and stir continuation 10min.Slowly the cooling crystallization filters, with a little washing with alcohol filter cake.Filter cake is added in the 30ml water, transfer pH value 11 with sodium hydroxide, keep pH value 11 to stir half an hour, transfer to neutrality with hydrochloric acid again, extract 2 times anhydrous sodium sulfate drying with methylene dichloride 30ml, obtain after concentrating (2R, 4R)-4-methyl-Pipecolic Acid, this step productive rate is about 45%.
This method preparation (2R, 4R)-4-methyl-Pipecolic Acid, overall yield is about 24%.
Embodiment 2
Be starting raw material with oxalic acid diethyl ester and 1-bromo-propylene, and preparation (2R, 4R)-4-methyl-Pipecolic Acid.
(1) in 100ml dry reaction bottle, add magnesium chips 0.05mol and ether 30ml, add the diethyl ether solution 20ml of 1-bromo-propylene 0.05mol in the addition funnel.A little 1-bromo-propylene solution of dropping enters reaction flask earlier, adds a little ethylene dibromide, and little being heated to caused reflection, withdraws heating, begins to drip the tetrahydrofuran solution of 1-bromo-propylene, dropwises, and it is complete, standby to the magnesium chips dissolving to continue stirring reaction.In the 250ml reaction flask of drying, add oxalic acid diethyl ester 0.05mol and ether 80ml; cooling, the standby diethyl ether solution above slowly dripping is stirred in nitrogen protection; dropwise; reacted 2 hours, and added the aqueous solution of ammonium chloride, ethyl acetate extraction; anhydrous sodium sulfate drying; filter, evaporate to dryness obtains 2-carbonyl-3-allyl acetic acid ethyl ester, and this step productive rate is about 83%.
Preparation method's step (2), (3), (4), (5), (6) are with embodiment 1.
Embodiment 3
Be starting raw material with oxalic acid diethyl ester and 1-bromo-propylene, and preparation (2R, 4R)-4-methyl-Pipecolic Acid.
Preparation method's step (1), (2), (3), (4), (5), (6) just are changed to methyltetrahydrofuran at step (1) solvent by anhydrous tetrahydro furan with embodiment 1
Embodiment 4
Be starting raw material with oxalic acid diethyl ester and 1-bromo-propylene, and preparation (2R, 4R)-4-methyl-Pipecolic Acid.
Preparation method's step (1), (2), (3), (4), (5), (6) just are changed to methyltetrahydrofuran at step (2) solvent by anhydrous tetrahydro furan with embodiment 1.
Embodiment 5
Be starting raw material with oxalic acid diethyl ester and 1-bromo-propylene, and preparation (2R, 4R)-4-methyl-Pipecolic Acid.
Claims (3)
1. one kind (2R, 4R)-preparation method of 4-methyl-Pipecolic Acid,
It is characterized in that may further comprise the steps:
1) grignard reaction, at first 1-bromo-propylene is dissolved in anhydrous tetrahydro furan and obtains solution, get a little solution and magnesium chips and place reaction vessel, add a small amount of iodine or ethylene dibromide, little heated solution to reaction causes, and stops heating, continue in reaction vessel, to drip the tetrahydrofuran solution of 1-bromo-propylene then, after dropwising, be stirred to magnesium chips and dissolve fully, obtain tetrahydrofuran solution; Oxalic acid diethyl ester is dissolved in anhydrous tetrahydro furan obtains solution, oxalic acid diethyl ester solution is lowered the temperature, stir and slowly drip the grignard reaction solution for preparing previously, dropwised afterreaction 1-3 hour, add saturated subacidity salts solution again, through extraction, drying, last concentrated extract obtains 2-carbonyl-3-allyl acetic acid ethyl ester then;
2) drying receptacle is got in addition reaction, methyl-cyanacetate is dissolved in anhydrous tetrahydro furan obtains solution, add sodium hydride then and stirred 0.5-1 hour, use again 2-carbonyl-3-allyl acetic acid ethyl ester is dissolved in the solution that anhydrous tetrahydro furan obtains slowly drips, dropwise stirring reaction 1-3 hour; Concentrate crude reaction, use the organic extractant solution resultant, after the salt solution washing, carry out drying, concentrated again, obtain 2-carbonyl-4-methyl-5 cyanopentanoic acid ethyl ester at last;
3) ring-closure reaction, 2-carbonyl-4-methyl-5 cyanopentanoic acid ethyl ester is dissolved in organic solvent, adding Raney's nickel then mixes, heating and logical hydrogen reaction, fully reaction is filtered and is also collected filtrate to no longer absorbing till the hydrogen, with organic solvent washing gained filter cake and collect filtrate, merge gained filtrate and concentrated twice, obtain 4-methyl-Pipecolic Acid ethyl ester;
4) benzyl ester protective reaction, 4-methyl-Pipecolic Acid ethyl ester is dissolved in organic solvent obtains solution, stir and the adding chloroformic acid benzyl ester, slowly drip with organic bases then, dropwise the back and continue reaction 3 hours, filter and also collect filtrate, again with a small amount of organic solvent washing filter cake and collect filtrate, merge gained filtrate twice, concentrate and obtain N-benzyloxy carbonyl acyl group-4-methyl-Pipecolic Acid ethyl ester;
5) take off the protective reaction of benzyl ester, N-benzyloxy carbonyl acyl group-4-methyl-Pipecolic Acid ethyl ester is dissolved in organic solvent and adds a small amount of palladium carbon, heated mixt and logical hydrogen reaction, complete reaction is to not absorbing till the hydrogen, filter and collect filtrate, with the organic solvent washing filter cake and collect filtrate, merge gained filtrate twice again, concentrate and obtain trans 4-methyl-Pipecolic Acid ethyl ester;
6) split process, trans 4-methyl-Pipecolic Acid ethyl ester is dissolved in organic solvent, stir and heating, add L-tartrate then, be incubated molten clear back and continue to stir 5-15min, the crystallization of lowering the temperature then, filter and the collection filter cake, with a little organic solvent washing filter cake, then filter cake is put into water, add the alkaline matter accent pH value is transferred to 11, keep the pH value to be 11 and to stir 0.5-1h, transfer to neutrality with mineral acid again, use organic solvent extraction 2 times, the extracting solution drying, filter last concentrate obtain (2R, 4R)-4-methyl-Pipecolic Acid.
2. a kind of (2R according to claim 1,4R)-preparation method of 4-methyl-Pipecolic Acid, it is characterized in that: in described step 1 grignard reaction, the mass ratio of solute and anhydrous tetrahydro furan is 1: 2-20, solvent also can be methyltetrahydrofuran or ether; Reactant 1-bromo-propylene: magnesium: the mol ratio of oxalic acid diethyl ester is 1: 1-2: 1-2.
3. a kind of (2R according to claim 1,4R)-preparation method of 4-methyl-Pipecolic Acid, it is characterized in that: in described step 2 addition reaction, the mass ratio of solute and anhydrous tetrahydro furan is 1: 2-20, solvent also can be methyltetrahydrofuran or ether; Reactant 2-carbonyl-3-allyl acetic acid ethyl ester: methyl-cyanacetate: the mol ratio of sodium hydride is 1: 1-2: 1-2.
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| CN102952065A (en) * | 2011-08-24 | 2013-03-06 | 重庆华邦胜凯制药有限公司 | Resolution method for cis-2,3-pyridine diformate |
| CN103524401B (en) * | 2013-10-31 | 2016-01-20 | 江苏宝众宝达药业有限公司 | A kind of synthetic method of (2R, 4R)-4-methyl-2 piperidine carboxylic acid |
| CN106699638B (en) * | 2016-12-30 | 2019-06-25 | 天津药物研究院药业有限责任公司 | A kind of preparation method of argatroban intermediate |
| CN106831540B (en) * | 2017-03-09 | 2019-06-11 | 爱斯特（成都）生物制药股份有限公司 | A kind of preparation method of (S)-nipecotic acid |
| CN108047125A (en) * | 2017-12-28 | 2018-05-18 | 北京沃邦医药科技有限公司 | The preparation method of one kind (2R, 4R) -4- methyl piperidine -2- Ethyl formate compounds |
| CN109761885B (en) * | 2019-02-21 | 2020-06-26 | 北京悦康科创医药科技股份有限公司 | Resolution method of argatroban isomer impurities |
| CN109761886B (en) * | 2019-02-21 | 2020-09-11 | 北京悦康科创医药科技股份有限公司 | Resolution method of argatroban starting material isomer impurities |
| CN109734653B (en) * | 2019-02-21 | 2020-07-14 | 北京悦康科创医药科技股份有限公司 | Resolution method of argatroban starting material isomer impurities |
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