CN103570803A - Preparation method of argatroban intermediate - Google Patents
Preparation method of argatroban intermediate Download PDFInfo
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- CN103570803A CN103570803A CN201210315616.9A CN201210315616A CN103570803A CN 103570803 A CN103570803 A CN 103570803A CN 201210315616 A CN201210315616 A CN 201210315616A CN 103570803 A CN103570803 A CN 103570803A
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Abstract
The invention relates to a preparation method of argatroban intermediate (2R,4R)-ethyl-1-((S)-2-(tert-butoxy amido)-5-(3-nitroguanidine)valery)-4-methylpiperidine-2-ethyl carboxylate. The method comprises the following steps: enabling NG-nitro-N2-t-Boc-L-arginine and (2R,4R)-4-methyl-2-ethyl nipecotate to perform condensation reaction in the presence of a condensing agent selected from 1-ethyl-3-(3-dimethylamine propyl)carbodiimide hydrochloride, N,N-diisopropyl carbodiimide and N,N'-carbonyl diimidazole and an aprotic solvent to generate the argatroban intermediate. The raw material for the method is wide in source, cheap and easily-available; the method is mild in reaction condition, short in step, simple in operation, easy to purify the product, low in production cost and environment-friendly, not only suitable for laboratory synthesis, but also suitable for large-scale industrial production.
Description
Technical field
The invention belongs to field of medicine and chemical technology, relate in particular to a kind of preparation method of argatroban intermediate.
Background technology
Argatroban (Argatroban), chemistry (2R, 4R)-4-methyl isophthalic acid by name-[N-((R, S)-3-methyl isophthalic acid, 2,3,4-tetrahydrochysene-8-quinoline alkylsulfonyl)-L-arginyl]-2 piperidine carboxylic acid, structural formula (I):
Argatroban is the antithrombin medicine of being developed by Mitsubishi, successively by Japan's approval treatment periphery thrombus disease and acute ischemic cerebral apoplexy.Thrombocytopenia and thrombus syndromes that on June 30th, 2000, U.S. FDA approval was brought out for heparin.It is the unique synthetic drugs for acute ischemic cerebral apoplexy treatment of ratifying in the world so far.On 10 1st 5,2004 in the approval listing of European Sweden, the import of state food and drug administration's approval on August 2nd, 2002 Mitsubishi argatroban injection, trade(brand)name MQPA (NOVASTAN), has 2mL/10mg, these two kinds of dosage of 20 mL/10mg.
(2R, 4R)-ethyl-1-((S)-2-(tert.-butoxy amide group)-5-(3-nitroguanidine) pentanoyl)-4-methyl piperidine-2-carboxylic acid, ethyl ester is to prepare argatroban important intermediate, structural formula (II):
The synthetic method of existing argatroban intermediate (II) mainly contains following several:
1. what compound patent EP8746 provided take compd A as raw material, reacts and in triethylamine, carry out the synthetic method of condensation reaction with compd B with isobutyl chlorocarbonate, and its synthetic route is as follows:
The method mainly has the following disadvantages:
A. compd A residue is more, have wastage of material, and isobutyl chlorocarbonate toxicity is large;
B. impurity is more, and purification difficult needs reaction at low temperature-20 ℃;
C. aftertreatment need to be crossed column purification, is difficult to suitability for industrialized production.
Can find out from above 3, due to raw material restriction and consider the factors such as environment, operability, this technique industrialization is restricted.
2. what patent CN1951916 provided take dicyclohexylcarbodiimide as condensing agent, prepares the method for argatroban intermediate (II), and its synthetic route is as follows:
The method is implemented according to the following steps: in dichloromethane solvent, add successively (2R, 4R)-4-methyl-Pipecolic Acid ethyl ester, DC C and NG-nitro-N2-t-Boc-L-arginine, stirring reaction 1-5 hour at-5～35 ℃, reaction finishes, add 50ml water, stir 0.5-1 hour, reaction solution is chilled to 0 ℃, solids removed by filtration, filtrate layering, remove water layer, organic layer is used respectively 5-10% sodium hydroxide solution washed twice, with 5-10% citric acid solution, wash once, use again saturated common salt water washing, anhydrous sodium sulfate drying, steam methylene dichloride, obtain yellow solid product.The method aftertreatment quite bothers, and needs washing 4 times.
In this method there is condensation reaction and obtain argatroban intermediate (II) in compd A and compd B under condensing agent DCC exists, and still, wherein can generate 2.9% formula III compound,
Formula III compound is the product of compd A self condensation, remove this material and bring certain difficulty to subsequent purification, can lose portion of product unavoidably, causes yield to lower.
In addition, CN1951916 is used DCC condensing agent can produce another very large impurity formula IV compound (containing 21.88%).Due to the water-soluble low of formula IV compound and can not remove by recrystallize, aftertreatment is more difficult, can only cross post and remove, and is not suitable for suitability for industrialized production; Its quality standard also difficulty meets the requirements, and reaches the ingredient requirement index of follow-up qualified argatroban, and this makes the use of argatroban increase inapt Hazard Factor.The condition of giving according to embodiment 4 completely in addition operates, can not obtain the said yield of this patent and quality standard (yield: 87.5%, content: 98.7% (HPLC quantitative analysis method)), in fact yield only approximately 70%, HPLC quantitative analysis method content only has 75.0%, HPLC purity 74.6%, wherein impurity formula IV compound account for 21.88% and impurity formula III account for 2.9%.
In sum, the preparation method of existing argatroban intermediate, all have that product is difficult to purifying, cost is higher, production efficiency is lower, unfriendly to environment, be not suitable for the defects such as large suitability for industrialized production.Therefore, this area still needs the new synthetic method that development and operation is simple, product is easy to purifying, high, the environment amenable argatroban intermediate of chemical yield.In addition, be also necessary to set up that specificity is strong, precision good, high performance liquid chromatography quantitative analysis method simple to operate, effectively to control the quality of argatroban intermediate, thereby guarantee security and the validity of follow-up argatroban product.
Summary of the invention
Technical problem to be solved by this invention is to overcome the deficiencies in the prior art, and a kind of preparation method of improved argatroban intermediate is provided.
For solving above technical problem, the present invention takes following technical scheme:
The preparation method of a kind of argatroban intermediate (II); the chemical name of argatroban intermediate is (2R; 4R)-ethyl-1-((S)-2-(tert.-butoxy amide group)-5-(3-nitroguanidine) pentanoyl)-4-methyl piperidine-2-carboxylic acid, ethyl ester; described preparation method comprises to be made compd A and compd B under condensing agent exists and the step that condensation reaction generates argatroban intermediate (II) occurs in aprotic solvent
Particularly, described condensing agent is for being selected from 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride, N, N-DIC and N, the combination of one or more in N'-carbonyl dimidazoles.
According to the present invention, described compd A, B, can adopt the compound of SILVER REAGENT or technical grade purity; Also can adopt existing or known method and technology to synthesize.
According to a concrete and preferred aspect of the present invention, the condensing agent of employing is 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride.
According to the present invention, described aprotic solvent is not particularly limited, for example can be for being selected from one or more the mixed solvent in acetone, acetonitrile, tetrahydrofuran (THF), toluene, dimethylbenzene, methylene dichloride, DMF and N,N-dimethylacetamide.Preferably, aprotic solvent is selected from acetonitrile, tetrahydrofuran (THF), toluene and methylene dichloride, more preferably acetonitrile.
According to the present invention, the temperature of condensation reaction can be for example-10 ~ 30 ℃, wherein preferred 0-20 ℃.Under different reaction conditions (comprising condensing agent and reaction solvent), in this temperature range, with other functional groups in not destroying reactant and the principle of conduct that enters that is conducive to reaction, select different temperature of reaction to carry out.
According to the present invention, the mol ratio of compd A and condensing agent is generally 1:0.9 ~ 3.0; The mass volume ratio of compd A and aprotic solvent is generally 1:1 ~ 50.
Preferably, described condensation reaction is for example carried out under nitrogen protection at rare gas element.
According to further embodiment of the present invention: described preparation method is also included in after condensation reaction finishes and carries out the step that aftertreatment obtains argatroban intermediate (II) finished product, post-treating method is as follows: in the reaction system after condensation reaction, add saturated common salt water washing, separatory, concentrating under reduced pressure, add organic solvent to disperse, stir, filter, washing is dry, obtains argatroban intermediate finished product.In post-processing step, organic solvent used can be for being selected from one or more the mixed solvent in alkane, aromatic hydrocarbon and ether solvent, specifically can being preferably one or more the mixed solvent being selected from normal hexane, hexanaphthene, heptane, dimethylbenzene, toluene, methyl tertiary butyl ether, ether and sherwood oil.
Further, described preparation method also comprises and utilizes high performance liquid chromatography quantitative analysis method to measure the purity of argatroban intermediate and content, thereby its quality is monitored, high performance liquid chromatography quantitative analysis adopts C-18 reversed-phase column, and trifluoroacetic acid aqueous solution-acetonitrile mixing solutions of take carries out gradient elution as moving phase.
Preferably, the analysis condition that described high performance liquid chromatography quantitative analysis method is taked is as follows:
Mobile phase A: 0.1% trifluoroacetic acid aqueous solution;
Mobile phase B: acetonitrile;
Chromatographic column: Zorbax Eclipse XDB-C18250mm*4.6mm, 5 μ m;
Gradient elution:
0-18min: mobile phase A/Mobile phase B (volume ratio)=75:25;
18-25min: mobile phase A/Mobile phase B (volume ratio)=10:90;
Flow velocity: 1.0mL/min;
Column temperature: 30 ℃;
Detect wavelength: 270nm.
Above-mentioned high performance liquid chromatography quantitative analysis method provided by the invention, specificity is strong, precision good, simple to operate, it is separated and localizing objects compound, impurity III and impurity IV well, the quality of argatroban intermediate be can effectively control, thereby security and the validity of follow-up argatroban product guaranteed.
Be compared with the prior art discovery, in argatroban intermediate (II) prepared by preparation in accordance with the present invention, impurity IV do not detected, and the content of impurity III is desired below 1.50% at the intermediate (II) of the qualified argatroban finished product of follow-up preparation, especially the content of impurity III is below 1.2%.
Due to the enforcement of above technical scheme, the present invention compared with prior art has following advantage:
Method of the present invention is carried out condensation reaction under specific condensing agent exists, making raw material can highly selective change into target product is argatroban intermediate, after reaction finishes, only need can obtain HPLC purity by very simple aftertreatment and reach more than 97.0% argatroban intermediate finished product.Generally speaking, the inventive method raw material sources are extensive, manufacturing cost is cheap, simple to operate, reaction conditions is gentle, and environmentally friendly, product is easy to purifying, target product yield is high, thereby not only prepare on a small scale in applicable laboratory, is also applicable to large-scale industrial production.
Embodiment
Below with reference to embodiment, technical scheme of the present invention and the technique effect that produces thereof are described further, but therefore do not limit the present invention among described scope of embodiments.
In following examples, all adopt HPLC method to measure argatroban intermediate finished product, wherein, HPLC method adopts C-18 reversed-phase column, and trifluoroacetic acid aqueous solution-acetonitrile mixing solutions of take carries out gradient elution as moving phase, and concrete analysis condition is as follows:
Mobile phase A: 0.1% trifluoroacetic acid aqueous solution; Mobile phase B: acetonitrile; Chromatographic column: Zorbax Eclipse XDB-C18250mm*4.6mm, 5 μ m; Gradient elution: 0-18min mobile phase A/Mobile phase B (volume ratio)=75:25,18-25min mobile phase A/Mobile phase B (volume ratio)=10:90; Flow velocity: 1.0mL/min; Column temperature: 30 ℃, detect wavelength: 270nm.
Embodiment 1
Under nitrogen protection, in dry 500mL four-hole bottle, add 20.0g compd A; 24.0g1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride, 200mL tetrahydrofuran (THF), controls 20 ~ 30 ℃ of temperature; add 11.0g compd B, 20 ~ 30 ℃ are stirred 2h in batches.Reaction solution is concentrated into dry, adds 200mL toluene to dissolve material, saturated brine 150mL washing 1 time, separatory, concentrated organic phase are to 50mL, and 10 ~ 15 ℃ are stirred 8h, filter feed liquid, toluene 10mL washing for filter cake.Dry filter cake and obtain off-white color solid, be argatroban intermediate.Productive rate: 80.0%, HPLC purity: 98.0%, content 98.6%, impurity formula III 1.20%, impurity formula IV does not detect.
Embodiment 2
Under nitrogen protection, in dry 500mL four-hole bottle, add 20.0g compd A; 20.0g 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride, 20mL methylene dichloride, controls temperature-10 ~ 0 ℃; add 11.0g compd B ,-10 ~ 0 ℃ is stirred 8h in batches.Saturated brine 150mL washing 1 time, separatory, concentrated organic phase, to dry, add methyl tertiary butyl ether 50mL, and 10 ~ 15 ℃ are stirred 8h, filter feed liquid, and methyl tertiary butyl ether 10mL washing for filter cake is dried filter cake and is obtained off-white color solid, is argatroban intermediate.Productive rate: 82.0%, HPLC purity: 97.0%, content 98.1%, impurity formula III 1.26%, impurity formula IV does not detect.
Embodiment 3
Under nitrogen protection, in dry 3000mL four-hole bottle, add 20.0g compd A; 60.0g1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride, 1000mL acetonitrile, controls 0 ~ 10 ℃ of temperature; add 11.0g compd B, 0 ~ 10 ℃ is stirred 6h in batches.Reaction solution is concentrated into dry, adds 200mL toluene to dissolve material, saturated brine 150mL washing 1 time, separatory, concentrated organic phase are to 50mL, and 10 ~ 15 ℃ are stirred 8h, filter feed liquid, toluene 10mL washing for filter cake.Dry filter cake and obtain off-white color solid, be argatroban intermediate.Productive rate: 80.0%, HPLC purity: 98.2%, content 98.6%, impurity formula III 1.14%, impurity formula IV does not detect.
Embodiment 4
Under nitrogen protection, in dry 500mL four-hole bottle, add 20.0g compd A, 15.0g N, N-DIC, 200mL methylene dichloride, controls 30 ~ 40 ℃ of temperature, adds 11.0g compd B in batches, and 30 ~ 40 ℃ are stirred 4h.Saturated brine 150mL washing 1 time, separatory, concentrated organic phase, to dry, add 10 ~ 15 ℃ of methyl tertiary butyl ethers to stir 8h, filter feed liquid, methyl tertiary butyl ether 10mL washing for filter cake.Dry filter cake and obtain off-white color solid, be argatroban intermediate.Productive rate: 63.0%, HPLC purity: 85.0%.
Embodiment 5
Under nitrogen protection, in dry 500mL four-hole bottle, add 20.0g compd A, 15.0g N, N-DIC, 200mL toluene, controls 40 ~ 50 ℃ of temperature, adds 11.0g compd B in batches, and 30 ~ 40oC stirs 4h.Saturated brine 150mL washing 1 time, separatory, concentrated organic phase 50mL, 10 ~ 15oC stirs 8h, filters feed liquid, toluene 5mL washing for filter cake.Dry filter cake and obtain off-white color solid, be argatroban intermediate.Productive rate: 65.0%, HPLC purity: 88.0%.
Embodiment 6
Under nitrogen protection, in dry 500mL four-hole bottle, add 11.0g compd B, 12.0g N, N'-carbonyl dimidazoles, 9.0g triethylamine, 200mL tetrahydrofuran (THF), controls 20 ~ 30 ℃ of temperature, adds 20.0g compd A in batches, and 20 ~ 30oC stirs 24h.Reaction solution is concentrated into dry, adds 200mL toluene to dissolve material, saturated brine 150mL washing 1 time, concentrated organic phase is to 50mL, and 10 ~ 15oC stirs 8h, filters feed liquid, and filter cake washs with toluene 10mL.Dry filter cake and obtain off-white color solid, be argatroban intermediate.Productive rate: 60.0%, HPLC purity: 86.0%.
Comparative example 1
This comparative example provides a kind of method according to CN1951916 embodiment 4 to prepare the example of argatroban intermediate, specific as follows:
In 250ml dichloromethane solvent, add successively 17.2g compd B, 25gDC C, stir after 0.5 hour, add 32g compd A, at-5 ℃ ~ 0 ℃, stir 4 hours, TLC detects, raw material disappears substantially, reaction finishes, add 50ml water, stir 1 hour, reaction solution is cooled to 0 ℃ to be rented, solids removed by filtration, filtrate layering, remove water layer, 50ml 5% sodium hydroxide solution washed twice for organic layer, with 50ml 10% citric acid solution, wash once, use again the water washing of 50ml saturated common salt, anhydrous sodium sulfate drying, remove methylene dichloride, obtain the about 33.5g of yellow solid, by HPLC method of the present invention, analyze mensuration, HPLC content only has 75.0%, HPLC purity 74.6%, wherein impurity formula IV compound account for 21.88% and impurity formula III be 2.9%.
Above the present invention is described in detail; its object is to allow the personage who is familiar with this art can understand content of the present invention and be implemented; can not limit the scope of the invention with this; the equivalence that all spirit according to the present invention are done changes or modifies, and all should be encompassed in protection scope of the present invention.
Claims (10)
1. the preparation method of an argatroban intermediate (II); the chemical name of described argatroban intermediate is (2R; 4R)-ethyl-1-((S)-2-(tert.-butoxy amide group)-5-(3-nitroguanidine) pentanoyl)-4-methyl piperidine-2-carboxylic acid, ethyl ester; described preparation method comprises to be made compd A and compd B under condensing agent exists and the step that condensation reaction generates argatroban intermediate (II) occurs in aprotic solvent
It is characterized in that: described condensing agent is for being selected from 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride, N, N-DIC and N, the combination of one or more in N'-carbonyl dimidazoles.
2. preparation method according to claim 1, is characterized in that: described condensing agent is 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride.
3. preparation method according to claim 1, is characterized in that: the temperature of described condensation reaction is-10 ℃ ~ 30 ℃.
4. according to the preparation method described in claim 1 or 3, it is characterized in that: described aprotic solvent is for being selected from acetone, acetonitrile, tetrahydrofuran (THF), toluene, dimethylbenzene, methylene dichloride, N, the mixed solvent of one or more in dinethylformamide and N,N-dimethylacetamide.
5. preparation method according to claim 1, is characterized in that: the mol ratio of described compd A and condensing agent is 1:0.9 ~ 3.0; The mass volume ratio of described compd A and aprotic solvent is 1:1 ~ 50.
6. preparation method according to claim 1, it is characterized in that: described preparation method is also included in after described condensation reaction finishes and carries out the step that aftertreatment obtains argatroban intermediate (II) finished product, described post-treating method is as follows: in the reaction system after condensation reaction, add saturated common salt water washing, separatory, concentrating under reduced pressure, add organic solvent to disperse, stir, filter, washing is dry, obtains described argatroban intermediate finished product.
7. preparation method according to claim 6, is characterized in that: the organic solvent using in described aftertreatment is one or more the mixed solvent being selected from alkane, aromatic hydrocarbon and ether solvent.
8. preparation method according to claim 7, is characterized in that: the organic solvent using in described aftertreatment is one or more the mixed solvent being selected from normal hexane, hexanaphthene, heptane, dimethylbenzene, toluene, methyl tertiary butyl ether, ether and sherwood oil.
9. according to the preparation method described in claim 1 or 6, it is characterized in that: described preparation method also comprises and utilizes high performance liquid chromatography quantitative analysis method to measure the purity of argatroban intermediate and content, thereby its quality is monitored, described high performance liquid chromatography quantitative analysis adopts C-18 reversed-phase column, and trifluoroacetic acid aqueous solution-acetonitrile mixing solutions of take carries out gradient elution as moving phase.
10. preparation method according to claim 9, is characterized in that: the analysis condition that described high performance liquid chromatography quantitative analysis method is taked is as follows:
Mobile phase A: 0.1% trifluoroacetic acid aqueous solution;
Mobile phase B: acetonitrile;
Chromatographic column: Zorbax Eclipse XDB-C18250mm*4.6mm, 5 μ m;
Gradient elution:
0-18min: mobile phase A/Mobile phase B (volume ratio)=75:25;
18-25min: mobile phase A/Mobile phase B (volume ratio)=10:90;
Flow velocity: 1.0mL/min;
Column temperature: 30 ℃;
Detect wavelength: 270nm.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
| CN114605494A (en) * | 2022-02-24 | 2022-06-10 | 江苏美迪克化学品有限公司 | Preparation method of argatroban and intermediate thereof |
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| EP0008746A1 (en) * | 1978-08-31 | 1980-03-19 | Mitsubishi Kasei Corporation | Alpha-(N-arylsulfonyl-L-argininamides, processes for their preparation and pharmaceutical compositions containing these substances |
| CN1951916A (en) * | 2006-11-10 | 2007-04-25 | 天津市炜杰科技有限公司 | Process for preparing argatroban intermediates |
| CN101560244A (en) * | 2009-04-21 | 2009-10-21 | 深圳市翰宇药业有限公司 | New method for synthesizing argatroban by combining solid phase method and liquid phase method |
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2012
- 2012-08-30 CN CN201210315616.9A patent/CN103570803B/en active Active
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| EP0008746A1 (en) * | 1978-08-31 | 1980-03-19 | Mitsubishi Kasei Corporation | Alpha-(N-arylsulfonyl-L-argininamides, processes for their preparation and pharmaceutical compositions containing these substances |
| CN1951916A (en) * | 2006-11-10 | 2007-04-25 | 天津市炜杰科技有限公司 | Process for preparing argatroban intermediates |
| CN101560244A (en) * | 2009-04-21 | 2009-10-21 | 深圳市翰宇药业有限公司 | New method for synthesizing argatroban by combining solid phase method and liquid phase method |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
| CN114605494A (en) * | 2022-02-24 | 2022-06-10 | 江苏美迪克化学品有限公司 | Preparation method of argatroban and intermediate thereof |
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