CN101348463B - Synthetic method of argatroban and intermediate thereof - Google Patents
Synthetic method of argatroban and intermediate thereof Download PDFInfo
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- CN101348463B CN101348463B CN2008100841497A CN200810084149A CN101348463B CN 101348463 B CN101348463 B CN 101348463B CN 2008100841497 A CN2008100841497 A CN 2008100841497A CN 200810084149 A CN200810084149 A CN 200810084149A CN 101348463 B CN101348463 B CN 101348463B
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Abstract
The invention relates to a method for preparing N<2>-(3-methyl-8-quinoline sulfonyl)- N<G>-nitryl-L-arginine as the intermediate of argatroban. The method comprises the following steps that the reaction of N<G>-nitryl-L-arginine and a 3-methyl-8-quinoline sulfonyl chloride-THF solution is carried out in an aqueous solution of sodium carbonate ; after the reaction ends, THP is collected through evaporation, and the water layer is extracted with an organic solvent, then THF is added with pH adjusted to 2-3, and then a solid saturated water layer of inorganic salt is added; THF is separated and adesiccant is added and stirred for 10-24 hours, with water content of THF measured to be less than 1 percent, then a molecular sift is added for drying, with the water content of THF controlled within 0.2 percent, and then THF reacts with (2R, 4R) 4MPE directly. The invention solves well the control on the water content of N<2>-(3-methyl-8 quinoline sulfonyl)-N N<G>-nitryl-L-arginine, ensures thesuccessful implementation of amide acylation, and satisfies the requirement of the large-scale industrial production.
Description
Technical field
The present invention relates to technical field of medicine synthesis, say so more specifically, argatroban intermediate N
2-(3-methyl-8 quinoline alkylsulfonyl)-N
GThe arginic preparation method of-nitro-L-.
Background technology
Acute, cerebral infarction is the world's five big common diseases, and the palsy mortality ratio accounts for the 10-12% of whole death toll.The survival patient accounts for apoplexy patient 75% and mostly leaves sequela after the palsy, leave over language, sensation or dyskinesia as the common patient that causes, need long-term be in hospital and the household looks after, give social and family brings serious economic problems, but even more serious patient threat to life then.Palsy takes place in annual nearly 3,000,000 people in China, and is also in rising trend in recent years, and lacks the acute stages treated medicine.
Argatroban (Argatroban) is the unique synthetic drugs of ratifying in the world so far that is used for the acute ischemic cerebral apoplexy treatment, have following advantage: (1) is thrombin inhibitors directly, the affinity that zymoplasm is had height, selective inhibition of coagulation enzyme (2) molecular weight is little, the zymoplasm of free state in the deactivation blood not only, and can also enter into thrombus inside, directly deactivation is very fast with scleroproein bonded blood coagulation bolt (3) and zymoplasm bonded speed, and is a kind of process of completely reversibility.Rapid-action, even if the characteristics of very fast recovery make the effect of the excessive also very fast recovery coagulation function (4) naturally of argatroban not rely on intravital antithrombin after the drug withdrawal, can suppress during extremely low concentration to form and platelet aggregation by the scleroproein due to the zymoplasm.Therefore it has better anti-freezing and anti thrombotic action than heparin, can treat efficient height at 48 hours innerlich anwendens of morbidity, and rate of side effects is low.
Its chemical name of argatroban is: (2R, 4R)-4-methyl isophthalic acid-[N
2-((R, S)-the 3-methyl isophthalic acid, 2,3,4-tetrahydrochysene-8-quinoline alkylsulfonyl)-the L-arginyl]-the 2 piperidine carboxylic acid monohydrate.
Chemical structural formula is:
Argatroban is at first synthetic by Mitsubishi chemistry institute (Mitsubishi Pharmaceutical Corp) in 1970.Earlier by Japan's approval treatment periphery thrombus disease and acute apoplexy.Permission, thrombopenia and the thrombus syndromes that brought out in order to heparin by drugs approved by FDA this year are bought by drugmaker of a few family of the U.S., France and Britain in the back.Argatroban is maintaining the leading position in antithrombotic aspect doing well,improving and the total effective rate, and its security and high efficiency are that vast patients with cerebral apoplexy has brought hope.The appearance of argatroban provides a new departure for the treatment of acute ischemic cerebral apoplexy.
About the preparation method of argatroban (Argatroban), the synthetic route of reported in literature has 2, article one route [EP8746 at present; US4258192; US4201863; JP8115267].It is with the 4-methyl piperidine be starting raw material earlier the preparation intermediate (2R, 4R)-4-methyl-Pipecolic Acid ethyl ester.Protect amino L-arginine condensation earlier with nitro and t-BOC then, obtain argatroban through hydrolysis, hydrogenation, hydration again with after 3-methyl-8-quinoline sulfuryl chloride condensation.This route synthesis technique complexity, operating process need to carry out under nitrogen protection, and hypertoxic gas phosgene is arranged in the raw material, and operation easier is bigger, is not suitable for suitability for industrialized production.
Second route [US4,117,127; JP 02-212473; BP0,823,430; EP0,008,746; JCS Perk Trans 1 1981 (5); JP 02-212473].It is earlier with (2R 4R)-4-methyl-Pipecolic Acid ethyl ester condensation, obtains argatroban through hydrolysis, hydrogenation, hydration then with intermediate again after 3-methyl-8-quinoline sulfuryl chloride condensation with nitro L-arginine.With respect to first kind of synthetic method, this synthetic route processing method is simple relatively, and raw material is easy to get, but finds in large-scale industrial production: the N of preparation
2-(3-methyl-8 quinoline alkylsulfonyl)-N
G-nitro-L-arginine is a syrup, itself and (2R, 4R) the reaction needed anhydrous condition of 4MPE.Method for this step reaction bibliographical information, be to be that the dried molassed pulpous state is anhydrous to guarantee until substrate with vacuum distilling, then with (2R, 4R)-4-methyl-Pipecolic Acid ethyl ester condensation, this requires the vacuum tightness of vacuum pump to want high in industrial production, and the material heated time is long, and intermediate is easy to generate decomposition, of paramount importancely is: the moisture of trace is difficult to remove by distillation fully.In case the moisture content of intermediate exceeds standard, directly have influence on the carrying out of amidate action.
Summary of the invention
The objective of the invention is to, a kind of argatroban intermediates preparation is provided, it is that post-treating method to the nitro L-arginine in the second route and 3-methyl-8-quinoline sulfuryl chloride condensation has carried out important improvement.Adopt drying means twice, control moisture reaches 1%, preferably can reach below 0.2%.Directly feed intake and carry out next step reaction, thereby well solved the thorny problem that the moisture difficulty that runs in producing is removed, satisfied the needs of large-scale industrial production.Prove that through big production test this method is economically viable.
Technical scheme of the present invention is as follows:
Argatroban intermediate N
2-(3-methyl-8 quinoline alkylsulfonyl)-N
GThe arginic preparation method of-nitro-L-, this method follow these steps to carry out:
(1) in aqueous sodium carbonate, makes compound (II) and compound (III) reaction; Wherein compound (II) is 1 with the mol ratio of compound (III): 1-1.2;
(2) reaction finishes, and steams THF, and the water layer organic solvent extraction adds THF then, and accent PH is 2-3, adds the inorganic salt saturated aqueous solution again, leaves standstill;
(3) tell THF, add siccative, stirred 10-24 hour, the moisture content that is dried to THF is less than 1%;
(4) add molecular sieve again and carry out drying, leave standstill, the moisture content of measuring THF is less than 0.2%; Directly with (2R, 4R) 4MPE reacts.
Compound (II) compound (III)
Argatroban intermediate preferred manufacturing procedure of the present invention is yellow soda ash to be added water-soluble clear, adds compound (II) again, is heated to 60-70 ℃, is stirred to molten clear.Slowly drip compound (III)-THF solution at 15-25 ℃ then, reacted 3-8 hour.Water layer adopts organic solvent extraction, for example tetrahydrofuran (THF), methylene dichloride, chloroform or ethyl acetate, preferably methylene dichloride or chloroform extraction.Add THF then, accent PH is 2-3, adds the inorganic salt saturated aqueous solution again, leaves standstill.
Siccative of the present invention is anhydrous magnesium sulfate or anhydrous sodium sulphate.Molecular sieve is 3A-5A molecular sieve or silica gel.Preferred 3A-5A molecule, preferred especially 4A molecular sieve.Wherein molecular sieve needs according to the method for routine drying treatment in addition, and sealing is preserved.
Preparation method of the present invention, wherein employed inorganic salt are sodium-chlor or ammonia chloride.After the first time of the present invention THF solution being carried out siccative, the moisture determination of THF is less than 1%; Just can filter, and then add molecular sieve drying, leave standstill, the moisture content of measuring THF should be less than 0.2%.
Embodiment
The invention will be further described below in conjunction with specific embodiment.Following each embodiment only is used to the present invention is described and is not limitation of the present invention.N of the present invention
G-nitro-L-arginine compounds (II) can be with reference to following method preparation with the synthetic of compound (III) 3-methyl-8-quinoline sulfuryl chloride.
Of the present invention as follows: (reference: EP 823430A1) with reference to synthetic route
One, nitro arginine
The nitro arginine
Two, N
2-(3-methyl-8-quinoline sulphonyl)-N
GThe arginic preparation of-nitro-L-
Side chain C-V
Embodiment 1
Anhydrous sodium carbonate 27g is added in the reaction flask, add water-soluble clearly, add 47g N
G-nitro-L-arginine 0.214mol), it is molten clear to be heated with stirring to 60 ℃ of left and right sides, be cooled to 25 ℃, the tetrahydrofuran solution of Dropwise 5 0g (0.206mol) 3-methyl-8-quinoline sulfuryl chloride, added in 15 minutes, room temperature reaction 5 hours, the complete tetrahydrofuran (THF) that boils off of reaction, the cooling water washs with chloroform 100ml * 2, after water adds the 300ml tetrahydrofuran (THF), transfer to about PH2.5 with 10% hydrochloric acid, add the saturated water layer of solid sodium chloride, tell the tetrahydrofuran (THF) layer, water layer extracts with tetrahydrofuran (THF) 400ml * 3 and merges, anhydrous sodium sulfate drying spends the night.Filter and remove siccative, add 120g 4A molecular sieve in the filtrate and carry out dried overnight, place to be detected, use.
Intermediate quality examination result:
Content is 87.35%, HPLC normalization method, post: C18; Moving phase is methyl alcohol: water=3.5: 1, λ=271nm.Water content is 0.11%.Concentration is 97.12mg/ml, and yield is 51%.
Embodiment 2
With anhydrous sodium carbonate 1.62kg, join in the 300L reactor, it is molten clear to add the water stirring, adds N
G-nitro-L-arginase 12 .72kg (12.4mol) is heated with stirring to about 60 ℃, the solution clarification.Be cooled to 25 ℃, with the tetrahydrofuran solution 3.0kg (12.4mol) of 3-methyl-8-quinoline sulfuryl chloride, tetrahydrofuran (THF) 31.8kg is sucked into 20L and drips in the bottle, slowly splashes in the reactor, adds in about 40 minutes.25 ℃ of reactions of temperature control 5 hours.Reaction is finished, pressure reducing and steaming tetrahydrofuran (THF) (temperature in the control＜50 ℃).Below the cooling reaction solution to 30 ℃, with chloroform 6L * 2 washings, add the 16kg tetrahydrofuran (THF) afterwards in the water liquid, transfer to about PH2.5 with 10% hydrochloric acid under stirring, add sodium-chlor 7.5kg and stir, standing demix, tell the tetrahydrofuran (THF) layer, water layer is used tetrahydrofuran (THF) 21.3kg * 3 extractions again, merges the tetrahydrofuran (THF) layer, carry out drying with anhydrous magnesium sulfate 5kg, spend the night.Filter and remove siccative, add 7.2kg 4A molecular sieve in the filtrate and carry out dried overnight, place to be detected, use.Intermediate quality examination result:
Content is 83.86%, HPLC normalization method, post: C18; Moving phase is methyl alcohol: water=3.5: 1, λ=271nm.Water content is 0.09%.Concentration is 95.33mg/ml, and product is pure to be 2.665kg, and yield is 46%.
Embodiment 3
With anhydrous sodium carbonate 1.62kg, join in the 300L reactor, it is molten clear to add the water stirring, adds N
G-nitro-L-arginine 3.5kg (15.9mol) is heated with stirring to about 60 ℃, the solution clarification.Be cooled to 25 ℃, with the tetrahydrofuran solution 3.6kg of 3-methyl-8-quinoline sulfuryl chloride (14.9mol), tetrahydrofuran (THF) 98kg is sucked into 20L and drips in the bottle, slowly splashes in the reactor, adds in about 40 minutes.25 ℃ of reactions of temperature control 5 hours.Reaction is finished, pressure reducing and steaming tetrahydrofuran (THF) (temperature in the control＜50 ℃).Below the cooling reaction solution to 30 ℃, with chloroform 12L * 2 washings, add the 32kg tetrahydrofuran (THF) afterwards in the water liquid, transfer to about PH2.5 with 10% hydrochloric acid under stirring, add ammonium chloride 10kg and stir, standing demix, tell the tetrahydrofuran (THF) layer, water layer is used tetrahydrofuran (THF) 30kg * 3 extractions again, merges the tetrahydrofuran (THF) layer, carry out drying with anhydrous magnesium sulfate 5kg, spend the night.Filter and remove siccative, add 7.2kg 5A molecular sieve in the filtrate and carry out dried overnight, place to be detected, use.Intermediate quality examination result:
Content is 85.82%, HPLC normalization method, post: C18; Moving phase is methyl alcohol: water=3.5: 1, λ=271nm.Water content is 0.05%.Concentration is 97.37mg/ml, and yield is 55%.
Embodiment 4
The preparation of amidate action:
To contain 35gN
2-(3-methyl-8-quinoline alkylsulfonyl)-N
GThe arginic tetrahydrofuran solution of-nitro-L-, be cooled to-10 ℃ of solution (keeping-10 ℃) that are added dropwise to 19.5g phosphorus oxychloride and 90ml tetrahydrofuran (THF), finish, drip 20g (2R in-10 ℃, 4R)-solution of 4-methyl-2 piperidine carboxylic acid ethyl ester and 90ml tetrahydrofuran (THF), in-10 ℃ of dropping 24g triethylamines, dropwise then, be warming up to-5 ℃ of stirring reactions 1 hour, adding 330ml saturated aqueous common salt is finished in reaction, tell organic layer after the stirring, obtain (2R, 4R)-1-[N
G-nitro-N
2-(3-methyl-8-quinoline alkylsulfonyl)-L-arginyl]-4-methyl-2 piperidine carboxylic acid ethyl ester.Yield 66.3%.
Can be by reference literature US4,117,127; JP 02-212473; EP0,823,430; EP0,008,746; JCS Perk Trans 1 1981 (5); JP 02-212473 method makes argatroban with embodiment 4 products.
The argatroban monohydrate is white or off-white powder shape solid.
1H?NMR(200MHz?CD
3OD)：δppm?0.85(d，3H)，1.05(d，3H)，1.30～1.80(m，6H)，2.13(m，1H)，2.45(m，1H)，2.60～3.20(m，6H)，3.29(s，1H)，3.35(m，2H)，3.98(m，1H)，4.11(m，2H)，6.54(t，1H)，7.07(d，1H)，7.42(d，1H)。
After the preferred embodiment that describes in detail, being familiar with this technology personage can be well understood to, can carry out various variations and modification not breaking away under above-mentioned claim and the spirit, all foundations technical spirit of the present invention all belongs to the scope of technical solution of the present invention to any simple modification, equivalent variations and modification that above embodiment did.And the embodiment that the present invention also is not subject in the specification sheets to be given an actual example.
Claims (7)
1. argatroban intermediate N
2-(3-methyl-8-quinoline alkylsulfonyl)-N
GThe arginic preparation method of-nitro-L-, this method follow these steps to carry out:
(1) in aqueous sodium carbonate, makes compound (II) and compound (III)-THF solution reaction; Wherein compound (II) is 1 with the mol ratio of compound (III): 1-1.2;
(2) reaction finishes, and steams THF, and the water layer organic solvent extraction adds THF then, and accent pH is 2-3, adds the saturated water layer of inorganic salt solid again, leaves standstill;
(3) tell THF and add siccative, stirred 10-24 hour, the moisture content of measuring THF is less than 1%;
(4) add molecular sieve drying again, leave standstill, the moisture content of measuring THF is less than 0.2%;
Compound (II) compound (III).
2. preparation method as claimed in claim 1, step wherein (1) add yellow soda ash water-soluble clear, add compound (II) again, are heated to 60-70 ℃, are stirred to molten clear.
3. preparation method as claimed in claim 1, compound wherein (III)-THF solution slowly drips at 15-25 ℃, reacts then 3-8 hour.
4. preparation method as claimed in claim 1, siccative wherein is anhydrous magnesium sulfate or anhydrous sodium sulphate.
5. preparation method as claimed in claim 1, wherein the exsiccant molecular sieve is the 3A-5A molecular sieve.
6. preparation method as claimed in claim 1, wherein the employed organic solvent of step (2) is tetrahydrofuran (THF), methylene dichloride, chloroform or ethyl acetate.
7. preparation method as claimed in claim 1, wherein the employed inorganic salt of step (2) are sodium-chlor or ammonium chloride.
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| CN101519429B (en) * | 2009-03-31 | 2012-07-25 | 深圳翰宇药业股份有限公司 | Solid phase method for synchronizing Argatroban |
| CN101560244B (en) * | 2009-04-21 | 2011-05-25 | 深圳翰宇药业股份有限公司 | New method for synthesizing argatroban by combining solid phase method and liquid phase method |
| CN102558047B (en) * | 2011-12-14 | 2013-10-30 | 天津药物研究院药业有限责任公司 | Method for preparing 3-methylquinoline |
| CN103936821B (en) * | 2013-01-18 | 2016-04-13 | 江苏奥赛康药业股份有限公司 | A kind of preparation method of optical purity argatroban |
| CN104059125A (en) * | 2014-06-20 | 2014-09-24 | 天津市亨必达化学合成物有限公司 | Method for preparing argatroban intermediate amidate |
| CN105218627A (en) * | 2015-11-19 | 2016-01-06 | 天津市亨必达化学合成物有限公司 | A kind of purification process of argatroban chiral intermediate hydrolyzate |
| CN111793022A (en) * | 2020-04-27 | 2020-10-20 | 滁州拜奥生物科技有限公司 | Preparation method of 3-methylquinoline |
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