CN100488961C - Argatroban byproduct and its synthesis, separation and identification method - Google Patents

Argatroban byproduct and its synthesis, separation and identification method Download PDF

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CN100488961C
CN100488961C CNB2007100569173A CN200710056917A CN100488961C CN 100488961 C CN100488961 C CN 100488961C CN B2007100569173 A CNB2007100569173 A CN B2007100569173A CN 200710056917 A CN200710056917 A CN 200710056917A CN 100488961 C CN100488961 C CN 100488961C
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宋洪海
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Tianjin Weijie Technology Co Ltd
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Abstract

This invention relates to an outgrowth of argatroban and a method for synthesization and separation and authentication, in which, when preparing argatroban by catalysis and hydrogenation, it makes an outgrowth with difficult separation to determine that said outgrowth is a compound by separation, authentication and synthesization, which is hydrolyzed further to get argatroban, and when testifying the hydrolyzed intermediate, it first of all recovers nitro delinking, then hydrolyzes quinoline 1, 2, 3 and 4 to get 1, and the content of compound 3 can be reduced to the allowance sphere by following the hydrogenation reactin of the intermediate.

Description

Argatroban byproduct and synthetic and isolation and identification method
Technical field
The present invention relates to a kind of argatroban byproduct and synthetic and isolation and identification method.
Technical background
The Japanese Mitsubishi S.Okamoto of chemical company in 1978 etc. have reported argatroban (Argatroban, 1) hydrate antithrombin activity [US 4 101 653] first.During more than 20 year subsequently, numerous investigators further investigate to the biological activity of Argatroban and as the value of medicine.1981, S.Okamoto compared [Okamoto, S.et al., Biochem.Biophys.Res.Commun.101,440 (1981)] in animal body with heparin; T.Kumoto etc. have carried out reporting [Kumada, T.et al., Thromb.Res.24,285 (1981)] to its three-dimensional activity of selecting; 1984, R.Kumato carried out the clinical blood dialysis and has estimated [Biochemistry 23,85 (1984) for Kikumoto, R.et al.]; This author in 1986 has reported Argatroban and has suppressed the Mammals thrombin activity, can be used as treatment and pre-preventing thrombosis medicament and platelet aggregation inhibitor.The Argatroban monohydrate can be used as [JP 61-48829] such as selectivity antithrombotic agent, the obstruction of treatment chronic arterial and cerebral thrombosiss.1992 and 1993, Taparelli and J.A.Jakubowski successively reported reversibility [Taparelli, C., Trends Pharmacol.Sci., 1993 of Argatroban antithrombin, 14,366, Jakubowski, J.A.et al, Rep.Med.Chem., 1992,27,99]; The nineties, multidigit investigator such as L.R.Buch reported correlative study [Buch, L.R., Cadiosvasc.Drug Rev., 1991,9,247, Strupcnewski, J.D.et al., Academic:San Diego, 1991; Vol.26, p299, Brundish, D.et al., J.Med.Chem.1999; 42,4584, Shebuski, R.J., Academic:San Diego, 1999; Vol.26, p98].Japan's approval in 1992 is used antithrombin medicament [Hijikata-Okunomiya, A., et al, Thromb.Hemostasis, 1992,18,135] as non-enteron aisle.
Argatroban [(2R, 4R)-and 1-{ (2S)-5-[(amino imino methyl) amino]-1-oxo-2-{[(1,2,3,4-tetrahydrochysene-3-methyl-8-quinolyl) sulphonyl] amino } amyl group }-4-methyl-Pipecolic Acid] its chemical ingredients is the mixture of 21 (R) and 21 (S), normally 64-65:36-35[US 6 440 417, Bioorganic ﹠amp; Medicine Chemistry Letters, 11 (2001), 1989-1992, Journal of Pharmaceutical Sciences, Vol.82, No.6,672 (1993)], chemical formula:
Figure C200710056917D00041
Figure C200710056917D00051
Now Bao Dao Argatroban synthetic route all is to be starting raw material with nitro-L-arginine, with piperidine carboxylic acid ester or quinoline sulfuryl chloride condensation precedence difference, constitutes two main routes:
The arginic amino of amido protecting method: nitro-L-is protected with t-Boc, with the piperidine carboxylic acid ester condensation, go the t-Boc protecting group again, go nitro must not have crystal water Argatroban (Fig. 1 with quinoline sulfuryl chloride condensation, ester hydrolysis, hydrogenation, 2) [EP8746, US 4 258 192, and US 4 201 863, JP 81-15,267, US 6 440 417, the flat 2-31055 of special permission communique, Bioorganic﹠amp; Medicine Chemistry Letters, 11 (2001), 1989-1992].
Non-protection method: remove nitro with piperidine carboxylic acid ester condensation, ester hydrolysis, hydrogenation again after nitro-L-arginine and the quinoline sulfuryl chloride condensation, also must not have crystal water target product (Fig. 3) [the flat 1-35000 of special permission communique, EP 823 430].
Above-mentioned any route must be through intermediate 2[(2R, 4R)-and 1-[N G-nitro-N 2-(3-methyl-8-quinoline alkylsulfonyl)-L-arginyl]-4-methyl-Pipecolic Acid]; hydro-reduction gets Argatroban; simultaneously; all generate an identical main by product; because the character and the Argatroban of this main by product are close; not easily separated, the purification difficulty is big, and it is up to standard that product A rgatroban impurity level is difficult to.Therefore study the character of this by product and synthesized, separation and evaluation have important practical value.
Summary of the invention
The purpose of this invention is to provide a kind of argatroban byproduct and synthetic and isolation and identification method.The present invention is on the basis of the various synthetic routes of research, and the main by product of argatroban has been carried out synthetic and isolation identification, makes product A rgatroban impurity level up to standard.This method steps is reasonable in design, simple to operate, mild condition, yield height.
The invention provides a kind of argatroban byproduct and be (2R, 4R)-1-[N 2-(3-methyl-8-quinoline alkylsulfonyl)-L-arginyl]-4-methyl-Pipecolic Acid (compound 3), its structure is:
Figure C200710056917D00052
Synthetic and the isolation and identification method step of described argatroban byproduct compound 3 comprise:
1) is raw material, protects with the piperidine carboxylic acid ester condensation, goes the t-Boc protecting group, gets intermediate 2 with nitro-L-arginine with quinoline sulfuryl chloride condensation and ester hydrolysis through uncle's fourth oxygen acyl group (t-Boc).
2) intermediate 2 through the reduction of palladium carbon catalytic hydrogenation or with the tin protochloride reduction, gets primary product compound 3 again.
Said palladium carbon catalytic hydrogenation reduction step:
(1) adds compound 2, triphenylphosphine, 5% palladium carbon and dehydrated alcohol and glacial acetic acid mixed solvent in the reactor successively.Compound 2: triphenylphosphine: the weight ratio of 5% palladium carbon: 1:0.01～0.03:0.1～0.3; The volume ratio of dehydrated alcohol and glacial acetic acid: 3～4:1.
(2) heat up 65-70 ℃, feed hydrogen, the 10MPa that keep-ups pressure reacted 20～24 hours, and HPLC follows the tracks of reaction, and disappearing to reactant is reaction end, stopped reaction.
(3) remove by filter palladium carbon, the distillation precipitation, with the methylene dichloride dissolving, saturated sodium bicarbonate is regulated pH=7.Tell organic layer, with the saturated sodium-chloride washing, leave standstill, tell organic layer, anhydrous magnesium sulfate drying filters.
(4) distillation removes methylene dichloride, gets product compound 3; Perhaps
The said tin protochloride reduction step of using:
(1) adds compound 2, tin protochloride and anhydrous ethanol solvent in the reactor successively.Compound 2: tin protochloride: the weight ratio of anhydrous ethanol solvent: 1:2～3:30～40.
(2) 20-25 ℃ of stirring reactions 24 hours, HPLC follows the tracks of reaction, and compound 2 content no longer descend stopped reaction.
(3) ethanol is taken off in vacuum distilling, water and methylene dichloride dissolving, and water layer is used dichloromethane extraction again, merges organic layer, and washing, saturated sodium-chloride are washed, are washed, anhydrous magnesium sulfate drying, filtration.
(4) methylene dichloride is taken off in vacuum distilling, gets product compound 3.
The present invention learns mixture that one component is Argatroban through the LC-MS analysis, molecular ion peak 507,509, and another component quasi-molecular ions is 503,505.Preliminary judgement, the latter is the unhydrided product of quinoline ring.With common means, Argatroban and this by product are difficult to separate, in order to obtain the by product sample, further to identify structure, attempt two kinds of methods and control reducing compounds 2, reduce the denitration base and the not hydrogenation of quinoline ring gets compound 3.A kind of method is to make of tin protochloride that room temperature reaction spends the night in reductive agent, the dehydrated alcohol, and reaction is only reduced the denitration base and got the unhydrided compound 3 of quinoline ring, yield about 65%.Other method still adopts palladium carbon catalytic hydrogenation, and other condition is consistent with the hydrogenation conditions of preparation Argatroban, adds a little triphenylphosphine, the palladium-carbon catalyst appropriateness is poisoned reduce catalysis intensity.Experimental result proves, obtains compound 3 equally, yield 〉=80%.
The present invention is through catalytic hydrogenation system argatroban with compound 2.By separating, identify and synthesizing, confirm that by product wherein is a compound 3.Compound 3 further hydrogenations get 1, when proving hydrogenation 2, at first reduce the denitration base, and 1,2,3,4 hydrogenations of quinoline get 1 then.Follow the tracks of 2 hydrogenation, can make 3 content drop to allowed band, successful solution separate the problem of difficulty.
Synthetic and the isolation and identification method of argatroban byproduct provided by the invention is on the basis of the various synthetic routes of research, argatroban byproduct synthetic and isolation identification have been carried out, this method steps is reasonable in design, and simple to operate, mild condition, yield height, product quality are good.
Description of drawings
Fig. 1 nitro arginine t-Boc protection back and (2R, 4R) piperidine carboxylic acid ester condensation reaction route diagram.
Fig. 2 nitro arginine t-Boc protection back with trans piperidine carboxylic acid ester condensation, separate, split, illustrate with quinoline sulfuryl chloride condensation reaction route again.
The non-protection method reaction scheme diagram of Fig. 3.
Embodiment
Example 1.
The preparation example of intermediate 2 (compound 2) is seen (US 4 258 192), and reaction formula is seen accompanying drawing 1.
Example 2, palladium carbon catalytic hydrogenation method:
Add palladium carbon, 13ml dehydrated alcohol and the 4ml glacial acetic acid of 1g in the 100ml autoclave successively by the compound 2 of example 1 preparation, 0.02g triphenylphosphine, 0.2g 5%.65-70 ℃ of the outer temperature of control autoclave feed hydrogen, the 10MPa that keep-ups pressure, and HPLC (high performance liquid chromatography) follows the tracks of reaction, reacts stopped reaction 24 hours.Remove by filter palladium carbon, precipitation, with the dissolving of 20ml methylene dichloride, saturated sodium bicarbonate is regulated pH=7.Tell organic layer, with the washing of 10ml saturated sodium-chloride, leave standstill, tell organic layer, anhydrous magnesium sulfate drying filters, and removes methylene dichloride, gets white solid 0.75g, is compound 3, yield 82%.
Compound 3 structures are identified:
Mass spectrum: molecular ion peak 503,505
Nuclear-magnetism: 1HNMR (300MHz, DMSO); δ: 0.69 (d, 3H, piperidine-CH 3), 2.53 (s, 3H, ArCH 3), 7.6 (m, 3H,
Figure C200710056917D00071
), 7.7 (t, 1H, ArH), 8.2 (d, 2H, ArH), 8.3 (s, 1H, ArH), 8.9 (s, 1H, ArH).
1HNMR (300MHz, D 2O); δ: 7.6 (m, 3H,
Figure C200710056917D00072
), be close to disappearance.
The HPLC trace analysis:
(1) condition: chromatographic column: Agilent (Anjelen Sci. ﹠ Tech. Inc) Extend C18
250×4.6mm，5μm
Moving phase: methyl alcohol: water=45:55 (volume, ml)
Detect wavelength: 216nm
Flow velocity: 1.2ml/min
Column temperature: 40 ℃
(2) retention time is respectively:
R-Argatroban 59.2 minutes
S-Argatroban 64.3 minutes
Compound 3 8.5 minutes
The unknown impuritie of synthetic Argatroban, retention time is 8.5 minutes.
Identify and the HPLC contrast by mass spectrum, nuclear-magnetism, prove that unknown impuritie is exactly a compound 3 among the Argatroban.When synthetic compound 3 further palladium hydrocarbonizes, follow the tracks of reaction, when 3 completely dissolves stop hydrogenation, get final product Argatroban.Experimental results show that: the high reason of compound 3 content is that hydrogenation is not thorough when synthesizing Argatroban.Follow the tracks of reaction, strengthen hydrogenation, can make intermediate 3 content drop to allowed band, solved compound 3 and separated difficulty, i.e. Argatroban purifying difficulty key issue.
Example 3. tin protochloride methods:
Add compound 2,2.4g tin protochloride and the 40ml dehydrated alcohol of 1g in the 100ml four-hole bottle by example 1 preparation, 20-25 ℃ of stirring reactions 24 hours, HPLC follows the tracks of reaction, and compound 2 content no longer descend stopped reaction.Vacuum removal ethanol adds water and methylene dichloride, and water layer is used dichloromethane extraction again, merges organic layer, and washing, saturated sodium-chloride are washed, washed, and anhydrous magnesium sulfate drying, filtration, precipitation get 0.6g compound 3.Yield 65%.The HPLC retention time is 8.5 minutes.
The preparation of example 4.Argatroban:
The palladium carbon, 13ml dehydrated alcohol and the 4ml glacial acetic acid that add 1g compound 2,0.2g 5% in the 100ml autoclave, 65-70 ℃ of the outer temperature of control, logical hydrogen pressure 10MPa, HPLC follows the tracks of reaction, reacts 24 hours.Method of purification is with example 2.The HPLC normalization method is analyzed:
Retention time is respectively:
59.2 minutes content of R-Argatroban: 48.8%
64.3 minutes content of S-Argatroban: 44.9%
3 8.5 minutes content of compound: 6.3%.

Claims (5)

1, a kind of argatroban byproduct is characterized in that it is compound 3:(2R, 4R)-and 1-[N2-(3-methyl-8-quinoline alkylsulfonyl)-L-arginyl]-4-methyl-Pipecolic Acid, its structure is:
Figure C200710056917C00021
2, the synthetic isolation and identification method of the described argatroban byproduct compound 3 of claim 1 is characterized in that comprising the steps:
1) be raw material, protect with the piperidine carboxylic acid ester condensation, go the t-Boc protecting group, get intermediate 2:(2R with nitro-L-arginine with quinoline sulfuryl chloride condensation and ester hydrolysis through uncle's fourth oxygen acyl group, 4R)-1-[N G-nitro N 2-(3-methyl-8-quinoline alkylsulfonyl)-L-arginyl]-4-methyl-Pipecolic Acid;
2) intermediate 2 through the reduction of palladium carbon catalytic hydrogenation or with the tin protochloride reduction, gets primary product compound 3 again;
Said palladium carbon catalytic hydrogenation reduction step:
(1) adds compound 2, triphenylphosphine, 5% palladium carbon and dehydrated alcohol and glacial acetic acid mixed solvent in the reactor successively;
(2) heat up 65-70 ℃, feed hydrogen, the 10MPa that keep-ups pressure reacted 20～24 hours, the HPLC monitoring, and disappearing to reactant is reaction end, stopped reaction;
(3) remove by filter palladium carbon, the distillation precipitation, with the methylene dichloride dissolving, saturated sodium bicarbonate is regulated pH=7, tells organic layer, with the saturated sodium-chloride washing, leaves standstill again, tells organic layer, and anhydrous magnesium sulfate drying filters;
(4) distillation removes methylene dichloride, gets product compound 3; Perhaps
The said tin protochloride reduction step of using:
(1) adds compound 2, tin protochloride and anhydrous ethanol solvent in the reactor successively;
(2) 20-25 ℃ of stirring reactions 24 hours, high performance liquid chromatography is followed the tracks of reaction, and compound 2 content no longer descend stopped reaction;
(3) ethanol is taken off in vacuum distilling, water and methylene dichloride dissolving, and water layer is used dichloromethane extraction again, merges organic layer, and washing, saturated sodium-chloride are washed, are washed, anhydrous magnesium sulfate drying, filtration;
(4) methylene dichloride is taken off in vacuum distilling, gets product compound 3.
3, method according to claim 2 is characterized in that: described compound 2: triphenylphosphine: the weight ratio of 5% palladium carbon: 1:0.01～0.03:0.1～0.3; The volume ratio of dehydrated alcohol and glacial acetic acid: 3～4:1.
4, method according to claim 2 is characterized in that: described compound 2: tin protochloride: the weight ratio of anhydrous ethanol solvent: 1:2～3:30～40.
5, method according to claim 2 is characterized in that: described high performance liquid chromatography is followed the tracks of reaction:
(1) condition:
Chromatographic column: Agilent Extend C 18
250×4.6mm，5μm
Moving phase: methyl alcohol: water=45:55, volume, ml,
Detect wavelength: 216nm
Flow velocity: 1.2ml/min
Column temperature: 40 ℃
(2) retention time is respectively:
R-Argatroban 59.2 minutes
S-Argatroban 64.3 minutes
Compound 38.5 minutes.
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CN104730155B (en) * 2013-12-23 2017-02-15 四川科瑞德制药股份有限公司 Detection method of argatroban intermediate
CN105273045A (en) * 2014-06-10 2016-01-27 重庆圣华曦药业股份有限公司 Synthesis and separation identification method for aragatroban related substances
CN110818688A (en) * 2019-10-30 2020-02-21 北京沃邦医药科技有限公司 Argatroban degradation impurity and preparation method thereof
CN110981934B (en) * 2019-11-12 2021-05-25 鲁南制药集团股份有限公司 Synthetic method of argatroban hydrate

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
A Short Synthesis of Argatroban: A Potent Selective ThrombinInhibitor. Janine Cossy et al.Bioorganic & Medicinal Chemistry Letters,No.11. 2001
A Short Synthesis of Argatroban: A Potent Selective ThrombinInhibitor. Janine Cossy et al.Bioorganic &amp *
Medicinal Chemistry Letters,No.11. 2001 *

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