CN103570803B - Preparation method of argatroban intermediate - Google Patents
Preparation method of argatroban intermediate Download PDFInfo
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- CN103570803B CN103570803B CN201210315616.9A CN201210315616A CN103570803B CN 103570803 B CN103570803 B CN 103570803B CN 201210315616 A CN201210315616 A CN 201210315616A CN 103570803 B CN103570803 B CN 103570803B
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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, particularly relate 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 developed by Mitsubishi, successively by Japan's approval treatment periphery thrombus disease and acute ischemic cerebral apoplexy.On June 30th, 2000, U.S. FDA approval was used for the heparin thrombocytopenia of bringing out and thrombus syndromes.It is the unique synthetic drugs for acute ischemic cerebral apoplexy treatment ratified 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 prepares 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, and react with isobutyl chlorocarbonate and in triethylamine, carry out the synthetic method of condensation reaction with compd B, its synthetic route is as follows:
The method mainly has the following disadvantages:
A. compd A residue is more, there is wastage of material, and isobutyl chlorocarbonate toxicity is large;
B. impurity is more, purification difficult, reacts at needing low temperature-20 DEG C;
C. aftertreatment needed column purification, was difficult to suitability for industrialized production.
As can be seen from above 3, due to raw material restriction and factor such as consideration environment, operability etc., this process industry 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 (2R successively, 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 DEG C, reaction terminates, add 50ml water, stir 0.5-1 hour, reaction solution is chilled to 0 DEG C, solids removed by filtration, filtrate layering, removing water layer, organic layer washes twice with 5-10% sodium hydroxide solution respectively, wash once with 5-10% citric acid solution, use saturated common salt water washing again, anhydrous sodium sulfate drying, steam methylene dichloride, obtain yellow solid product.The method aftertreatment quite bothers, and need wash 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, but, wherein can generate formula III compound of 2.9%,
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, cause yield to lower.
In addition, CN1951916 uses 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 also not by recrystallize removing, aftertreatment is more difficult, can only cross post removing, be 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 add inapt Hazard Factor.Complete condition of giving according to embodiment 4 operates in addition, the said yield of this patent and quality standard (yield: 87.5% can not be obtained, content: 98.7% (HPLC quantitative analysis method)), in fact yield only about 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, there is a need 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, thus ensure security and the validity of follow-up argatroban product.
Summary of the invention
Technical problem to be solved by this invention overcomes the deficiencies in the prior art, provides a kind of preparation method of argatroban intermediate of improvement.
For solving above technical problem, the present invention takes following technical scheme:
A kind of preparation method 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 makes compd A and compd B that the step that condensation reaction generates argatroban intermediate (II) occur under condensing agent exists and in aprotic solvent
Particularly, described condensing agent is for being selected from one or more the combination in 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride, N, N-DIC and N, 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, such as can 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 such as-10 ~ 30 DEG C, wherein preferred 0-20 DEG C.Under different reaction conditionss (comprising condensing agent and reaction solvent), in this temperature range with do not destroy other functional groups in reactant and be conducive to reacting enter principle of conduct, 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 carried out under rare gas element such as nitrogen protection.
According to further embodiment of the present invention: described preparation method is also included in after condensation reaction terminates 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 dispersion, stir, filter, washing is dry, obtains argatroban intermediate finished product.Organic solvent used in post-processing step for being selected from one or more the mixed solvent in alkane, aromatic hydrocarbon and ether solvent, specifically can preferably can be selected from one or more the mixed solvent in 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, thus its quality is monitored, high performance liquid chromatography quantitative analysis adopts C-18 reversed-phase column, with trifluoroacetic acid aqueous solution-acetonitrile mixing solutions for moving phase carries out gradient elution.
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 μm;
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 DEG C;
Determined wavelength: 270nm.
Above-mentioned high performance liquid chromatography quantitative analysis method provided by the invention, specificity is strong, precision good, simple to operate, it can well be separated and localizing objects compound, impurity III and impurity IV, effectively can control the quality of argatroban intermediate, thus ensure security and the validity of follow-up argatroban product.
Be compared with the prior art discovery, impurity IV is not detected in argatroban intermediate (II) prepared by preparation in accordance with the present invention, and the content of impurity III required by the intermediate (II) of the qualified argatroban finished product of follow-up preparation less than 1.50%, 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 makes condensation reaction carry out under specific condensing agent exists, make raw material can change into target product and argatroban intermediate by highly selective, after reaction terminates, only need can obtain by very simple aftertreatment the argatroban intermediate finished product that HPLC purity reaches more than 97.0%.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, is thus not only applicable to laboratory preparation on a small scale, 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.
All adopt HPLC method to measure argatroban intermediate finished product in following examples, wherein, HPLC method adopts C-18 reversed-phase column, and with trifluoroacetic acid aqueous solution-acetonitrile mixing solutions for moving phase carries out gradient elution, 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 μm; 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 DEG C, determined wavelength: 270nm.
Embodiment 1
In dry 500mL four-hole bottle, 20.0g compd A is added under nitrogen protection; 24.0g1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride, 200mL tetrahydrofuran (THF), control temperature 20 ~ 30 DEG C; add 11.0g compd B, 20 ~ 30 DEG C are stirred 2h in batches.Be concentrated into by reaction solution dry, add 200mL toluene and dissolve material, saturated brine 150mL washs 1 time, and separatory, concentrated organic phase are to 50mL, and 10 ~ 15 DEG C are stirred 8h, and filter feed liquid, filter cake toluene 10mL washs.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
In dry 500mL four-hole bottle, 20.0g compd A is added under nitrogen protection; 20.0g 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride, 20mL methylene dichloride, control temperature-10 ~ 0 DEG C; add 11.0g compd B ,-10 ~ 0 DEG C is stirred 8h in batches.Saturated brine 150mL washs 1 time, and separatory, concentrated organic phase, to dry, add methyl tertiary butyl ether 50mL, and 10 ~ 15 DEG C are stirred 8h, and filter feed liquid, filter cake methyl tertiary butyl ether 10mL washs, and dry filter cake and obtain off-white color solid, be 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
In dry 3000mL four-hole bottle, 20.0g compd A is added under nitrogen protection; 60.0g1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride, 1000mL acetonitrile, control temperature 0 ~ 10 DEG C; add 11.0g compd B, 0 ~ 10 DEG C is stirred 6h in batches.Be concentrated into by reaction solution dry, add 200mL toluene and dissolve material, saturated brine 150mL washs 1 time, and separatory, concentrated organic phase are to 50mL, and 10 ~ 15 DEG C are stirred 8h, and filter feed liquid, filter cake toluene 10mL washs.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
In dry 500mL four-hole bottle, add 20.0g compd A, 15.0g N, N-DIC, 200mL methylene dichloride under nitrogen protection, control temperature 30 ~ 40 DEG C, adds 11.0g compd B in batches, and 30 ~ 40 DEG C are stirred 4h.Saturated brine 150mL washs 1 time, and separatory, concentrated organic phase are to dry, and add methyl tertiary butyl ether 10 ~ 15 DEG C and stir 8h, filter feed liquid, filter cake methyl tertiary butyl ether 10mL washs.Dry filter cake and obtain off-white color solid, be argatroban intermediate.Productive rate: 63.0%, HPLC purity: 85.0%.
Embodiment 5
In dry 500mL four-hole bottle, add 20.0g compd A, 15.0g N, N-DIC, 200mL toluene under nitrogen protection, control temperature 40 ~ 50 DEG C, adds 11.0g compd B in batches, and 30 ~ 40oC stirs 4h.Saturated brine 150mL washs 1 time, and separatory, concentrated organic phase 50mL, 10 ~ 15oC stir 8h, and filter feed liquid, filter cake toluene 5mL washs.Dry filter cake and obtain off-white color solid, be argatroban intermediate.Productive rate: 65.0%, HPLC purity: 88.0%.
Embodiment 6
In dry 500mL four-hole bottle, add 11.0g compd B, 12.0g N, N'-carbonyl dimidazoles, 9.0g triethylamine, 200mL tetrahydrofuran (THF) under nitrogen protection, control temperature 20 ~ 30 DEG C, adds 20.0g compd A in batches, and 20 ~ 30oC stirs 24h.Be concentrated into by reaction solution dry, add 200mL toluene and dissolve material, saturated brine 150mL washs 1 time, and concentrated organic phase is to 50mL, and 10 ~ 15oC stirs 8h, and filter feed liquid, filter cake toluene 10mL washs.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:
17.2g compd B is added successively in 250ml dichloromethane solvent, 25gDC C, stir after 0.5 hour, add 32g compd A, stir 4 hours at-5 DEG C ~ 0 DEG C, TLC detects, raw material disappears substantially, reaction terminates, add 50ml water, stir 1 hour, reaction solution is cooled to 0 DEG C to rent, solids removed by filtration, filtrate layering, removing water layer, organic layer 50ml 5% sodium hydroxide solution washes twice, wash once with 50ml 10% citric acid solution, use the water washing of 50ml saturated common salt again, anhydrous sodium sulfate drying, removing methylene dichloride, obtain yellow solid and be about 33.5g, carry out analysis by HPLC method of the present invention to measure, 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 to invention has been detailed description; its object is to allow the personage being 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 change that all spirit according to the present invention are done or modification, 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 makes compd A and compd B that the step that condensation reaction generates argatroban intermediate (II) occur under condensing agent exists and in aprotic solvent
It is characterized in that: described condensing agent is for being selected from one or more the combination in 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride, N, N-DIC and N, 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 DEG C ~ 30 DEG C.
4. the preparation method according to 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, one or more mixed solvent 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 terminates 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 dispersion, 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 used in process is in the rear one or more the mixed solvent be selected from alkane, aromatic hydrocarbon and ether solvent.
8. preparation method according to claim 7, is characterized in that: the organic solvent used in process is in the rear one or more the mixed solvent be selected from normal hexane, hexanaphthene, heptane, dimethylbenzene, toluene, methyl tertiary butyl ether, ether and sherwood oil.
9. the preparation method according to 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, thus its quality is monitored, described high performance liquid chromatography quantitative analysis adopts C-18 reversed-phase column, with trifluoroacetic acid aqueous solution-acetonitrile mixing solutions for moving phase carries out gradient elution.
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 μm;
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 DEG C;
Determined wavelength: 270nm.
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| 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 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Non-Patent Citations (1)
| Title |
|---|
| EDC在有机合成中的应用研究进展;喻平等;《广州化工》;20110423;第39卷(第08期);第9页左栏第1至右栏第3段 * |
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