CN103288742A - Preparation method for high-purity ingavirin raw material - Google Patents
Preparation method for high-purity ingavirin raw material Download PDFInfo
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- CN103288742A CN103288742A CN2013102177035A CN201310217703A CN103288742A CN 103288742 A CN103288742 A CN 103288742A CN 2013102177035 A CN2013102177035 A CN 2013102177035A CN 201310217703 A CN201310217703 A CN 201310217703A CN 103288742 A CN103288742 A CN 103288742A
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- jiaweilin
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P20/50—Improvements relating to the production of bulk chemicals
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Abstract
The invention discloses a preparation method for a high-purity ingavirin raw material. The preparation method comprises the following steps of: A. protecting amino group or imino group in histamine or histamine salt by adopting a nitrogen atom protecting method to obtain a compound in formula (II); B. refining the compound in formula (II) obtained from step A through using a recrystallization method; and C. removing nitrogen protecting group of the compound in formula (II) refined in step B to obtain a compound in formula (I). The preparation method is smart in conception, simple in flow, high in yield, the cost can be greatly lowered, and the high-purity histamine and pharmaceutically acceptable histamine salt can be prepared.
Description
Technical field
The invention belongs to technical field of pharmaceutical chemistry, relate to a kind of preparation method of high purity Ying Jiaweilin raw material.
Background technology
Ying Jiaweilin (ingavirin, chemical name: 5-((2-(1 hydrogen-imidazol-4 yl) ethyl) amino)-5-oxopentanoic acid) is at influenza virus, the active drug of adenovirus infection, and its structure is as follows:
Ying Jiaweilin is a kind of nontoxic, broad-spectrum antiviral medicament with complexing action mechanism, and arbidol and the Oseltamivir sold than existing market have remarkable advantages.Pharmaceuticals 2011,4, and 1518-1534 has reported the comparison of Ying Jiaweilin and Tamiflu and ribavirin, and the virus of Ying Jiaweilin has good inhibitory effect as can be seen.
Application number is to have mentioned compound 5-((2-(1 hydrogen-imidazol-4 yl) ethyl) amino)-5-oxopentanoic acid first in the patent application of WO9901103), namely Ying Jiaweilin has effect preferably to virus.Document T. A. Kromova, G. A. Zheltukhina. Pharmaceutical Chemistry Journal. Vol. 39, and No. 3,2005 has reported the synthetic method of Ying Jiaweilin: be raw material with the histamine dihydrochloric acid, DMF is solvent, obtains Ying Jiaweilin with the Pyroglutaric acid reaction.We find by test, and histamine is in light, warm, apt to deteriorate when oxygen exists, and in the various salt of commercially available histamine, are difficult to avoid histamine contact light, heat, oxygen, cause histamine rotten, cause Ying Jiawei Forest products purity not high.
At present, by directly histamine being carried out recrystallization, can remove relevant impurity, but its yield is lower, about 50%, and want recrystallization twice, and complicated operation, industrialized cost improves greatly.
Summary of the invention
The objective of the invention is at the deficiencies in the prior art, a kind of preparation method of high purity Ying Jiaweilin raw material is provided.This preparation method is skillfully constructed, flow process is simple, and yield height, cost reduce greatly, can make highly purified histamine and pharmacy acceptable salt thereof.
For achieving the above object, the technical solution adopted for the present invention to solve the technical problems is:
A kind of preparation method of high purity Ying Jiaweilin raw material may further comprise the steps:
A, with histamine or the histamine salt method with the protection nitrogen-atoms, with histamine amino or imino-protection, obtain the formula II compound
Wherein, R
1, R
2Be identical or different group;
B, the formula II compound that steps A is obtained are made with extra care by the method for recrystallization;
C, the formula II compound after step B is refining are sloughed nitrogen-protecting group, obtain formula (I) compound
As optimal way, among the described step C, also comprise formula (I) compound is converted into its pharmacy acceptable salt.
Further preferred, described pharmacy acceptable salt is hydrochloride, phosphoric acid salt, trifluoroacetate, Trichloroacetate, perchlorate, succinate, maleate, fumarate or tartrate.
Preferred again, described pharmacy acceptable salt is hydrochloride or phosphoric acid salt.
As optimal way, in the described steps A, histamine or histamine salt with the mol ratio of the reagent of protection amino or imino-are: 0.5 ~ 10.
As optimal way, in the described steps A, the protecting group of used amino or imino-is for forming the protecting group of chemical bond with nitrogen.
As optimal way, described R
1, R
2For forming the protecting group of acid amides, nitrogen-carbon or nitrogen-chemistry of silicones key with nitrogen.
Further preferred, described R
1, R
2Respectively independently be hydrogen, formyl radical, ethanoyl, propionyl, trimethyl silicon based, tertiary butyl dimethyl is silica-based, tertbutyloxycarbonyl, trifluoroacetyl group, tribromo-acetyl base, replacement or unsubstituted benzyl, replacement or unsubstituted benzyloxy carbonyl acyl group, ditane or tritane.
As optimal way, among the described step B, the mass volume ratio of employed optimum solvent is 1:0.5 ~ 30 in Ying Jiaweilin and the recrystallization, and the mass volume ratio of Ying Jiaweilin and poor solvent is 1:0.5 ~ 50.
The alleged mass volume ratio of the present invention is g/ml.
Further preferred, described optimum solvent is selected from alcohols, ester class, ethers, ketone, halohydrocarbon, acetonitrile, N, in dinethylformamide or the dimethyl sulfoxide (DMSO) one or more, poor solvent is selected from ethers, water or the hydro carbons one or more.
Further preferred, described alcohols is selected from methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol or Pentyl alcohol.
Further preferred, described ester class is selected from ethyl acetate, ethyl formate, Iso Butyl Acetate, isobutyl acetate, n-butyl acetate, tert-butyl acetate, methyl-formiate, propyl formate, butyl formate, methyl acetate or tetryl formate.
Further preferred, described ethers is selected from methyl ether, ether, methyl ethyl ether, isopropyl ether, t-butyl methyl ether, tetrahydrofuran (THF) or dioxane.
Further preferred, described ketone is selected from acetone, butanone, methyl iso-butyl ketone (MIBK) or methyl isopropyl Ketone.
Further preferred, described halohydrocarbon is selected from tetracol phenixin, chloroform, 1,2-ethylene dichloride, 1 or methylene dichloride.
Further preferred, described hydro carbons is selected from benzene, chlorine benzene,toluene,xylene, isopropyl benzene, oil of mirbane, sherwood oil, normal hexane, normal heptane, methylcyclohexane, hexanaphthene, Skellysolve A or octane-iso.
As optimal way, among the described step B, the temperature that recrystallization adopts for-40 ℃ to solvent refluxing.
As optimal way, among the described step B, the mode of the used separate solid of recrystallization is filtration or centrifugal.
As optimal way, among the described step C, the mode of sloughing nitrogen-protecting group is that hydrogenolysis, acidolysis or alkali take off, and the ratio that the acid that acidolysis is used or alkali take off used alkali and the mole number of formula II compound is: 1 ~ 100:1.
Further preferred, among the described step C, the used acid of acidolysis is organic acid and/or mineral acid, and it is mineral alkali and/or organic bases that alkali takes off used alkali.
Preferred again, described organic acid is selected from one or more in trifluoracetic acid, Tricholroacetic Acid, formic acid, acetic acid, methylsulfonic acid, phenylbenzimidazole sulfonic acid or the tosic acid, and mineral acid is selected from one or more in hydrochloric acid, sulfuric acid, phosphoric acid, perchloric acid or the chloric acid.
Preferred again, described organic bases is selected from one or more in ammoniacal liquor, dimethylamine, methylamine, ethamine, diethylamine, triethylamine, pyridine, sodium methylate, potassium methylate, lithium methoxide, sodium ethylate, potassium ethylate, lithium ethoxide, n-propyl alcohol sodium, n-propyl alcohol potassium, n-propyl alcohol lithium, sodium tert-butoxide, potassium tert.-butoxide or the trimethyl carbinol lithium, and mineral alkali is selected from one or more in sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium hydride or the potassium hydride KH.
The less stable of histamine own, under room temperature or higher temperature, and all easily oxidations under illumination, so in Ying Jiaweilin synthetic, the raw material of purchase often for this reason, it is many that impurity becomes, and makes that synthetic Ying Jiawei Forest products are defective.
Prior art directly from histamine by recrystallization, just can reach for twice the purity of synthetic Ying Jiaweilin, the yield of each recrystallization is about 50%, so this method will reach high purity, must yield less than 25%, cost obviously just is higher than the present invention.
The reaction of steps A of the present invention is quantitative substantially, be that yield can reach 100%, among the step B, purification yield〉80%, among the step C, reaction yield is very high, and theoretical yield can reach 100%, the actually operating yield also can reach 80% and more than, so the yield of whole highly purified histamine or its salt can reach 64% and more than, when obtaining highly purified histamine or its salt, yield is higher, effectively reduces production costs.
Beneficial effect of the present invention is: the present invention is skillfully constructed, flow process is simple, and yield height, cost reduce greatly, can make highly purified Ying Jiaweilin raw material histamine and pharmacy acceptable salt thereof.
Figure of description
The HPLC collection of illustrative plates of the commercially available histamine of Fig. 1 and salt thereof;
The histamine of Fig. 2 the present invention preparation and the HPLC collection of illustrative plates of salt thereof.
Embodiment
Disclosed all features in this specification sheets, or the step in disclosed all methods or the process except mutually exclusive feature and/or step, all can make up by any way.
Comparative Examples: 100g joins in the round-bottomed flask with the raw material histamine dihydrochloric acid, adds 1.0 L MeOH, after dissolving under 70 ℃, behind stirring at room 2h, goes to ice bath and stirs 24h, filters, and reduced pressure at room temperature gets white solid 50.2g; With this white solid, under 70 ℃, behind 500ml MeOH, behind stirring at room 2h, go to ice bath and stir 24h, to filter, reduced pressure at room temperature gets white solid 26.2g, and twice total recovery is about 26.2%.
Histamine (the R of the two protections of embodiment 1:Boc
1, R
2=tertbutyloxycarbonyl) preparation
140g joins in the round-bottomed flask with the raw material histamine dihydrochloric acid, adds 1.2L MeOH, slowly adds 560ml triethylamine, 500g (Boc) down in-40 ℃ ~ 10 ℃
2O, go to stirring at room 18h after, raw material reaction is complete, reaction solution is spin-dried for (45 ℃ ~ 80 ℃), gets white solid, adds CH
2Cl
2And suitable quantity of water, the white solid dissolving is told organic layer, water layer CH
2Cl
2Extract again 3 times, merge organic layer, use saturated NaHCO successively
3Wash 2 times, wash 2 times, anhydrous sodium sulfate drying concentrate white object solid 269.07g.
Histamine (the R of the two protections of embodiment 2:Boc
1, R
2=tertbutyloxycarbonyl) refining
White object solid 269.07g with obtaining among the embodiment 1 uses sherwood oil 500mL, and ethyl acetate 800mL goes to crystallization 24h under-40 ℃ ~ 40 ℃ temperature in 40 ℃ ~ 100 ℃ dissolvings, filter pure product white solid 198.92g, yield: 84.04%.
Embodiment 3: the preparation of histamine dihydrochloric acid
The 50g white solid that obtains among the embodiment 2 places round-bottomed flask, adds saturated HCl methanol solution 200ml under-5 ℃, and the solid dissolving goes to stirring at room 15h, react completely, the adularescent solid is separated out, and adds acetone in reaction solution, behind the stirring 30min, filter filter cake washing with acetone 3 times, CH
2Cl
2Wash 2 times, filter pure product white solid 29.57g, yield: 85%.
Embodiment 4: the preparation of histamine phophate
The 50g white solid that obtains among the embodiment 2 places round-bottomed flask, adds CH
2Cl
2Dissolve, under-5 ℃, drip phosphoric acid, go to stirring at room 15h, react completely, in reaction solution, add acetone, behind the stirring 30min, filter, filter cake washing with acetone 3 times, CH
2Cl
2Wash 2 times, filter pure product white solid 46.44g, yield: 80%.
Embodiment 5: the histamine (R of diphenyl-methyl protection
1, R
2=diphenyl-methyl) preparation
10g joins in the round-bottomed flask with the raw material histamine dihydrochloric acid, adds the 100mL acetonitrile, slowly adds the 5ml triethylamine down in-40 ℃ ~ 10 ℃, the 33g diphenyl methyl chloride, go to stirring at room 18h after, raw material reaction is complete, reaction solution is spin-dried for (45 ℃ ~ 80 ℃), gets white solid, add CH
2Cl
2And suitable quantity of water, the white solid dissolving is told organic layer, water layer CH
2Cl
2Extract again 3 times, merge organic layer, use saturated NaHCO successively
3Wash 2 times, wash 2 times, anhydrous sodium sulfate drying concentrate the white object solid, get white solid 22.1g with the sherwood oil re-crystallizing in ethyl acetate, yield 91%.
Embodiment 6: histamine synthetic
Histamine 2 2.1g with the diphenyl-methyl protection of refining back behind the 300mL dissolve with methanol, adds 2.2gC/Pd, in 5atmH
2Down, 30 ℃ ~ 70 ℃ following stirring reaction 10h after reacting completely, remove by filter C/Pd, add isopropyl ether and stir, and the adularescent solid is separated out, and filters, and gets histamine 5.53g, yield 100%.
Embodiment 7: be converted into histamine dihydrochloric acid by histamine
With gained histamine 5.53g among the embodiment 6, behind the 60mL dissolve with methanol, under ice bath, feed HCl gas, the adularescent solid is separated out, and behind the 2h, filters, and gets white solid 8.3g, yield 90%.
Embodiment 8: compound III (R
1=COCF
3, R
2Synthesizing=trityl)
The 5g Histamine, monohydrochloride is joined in the 50ml methyl alcohol, under ice bath, add triethylamine 7.5ml, finish, the solid dissolving adds Trifluoroacetic Acid Ethyl Ester, goes to stirring at room 3 ~ 5h, after reacting completely, with reaction solution be spin-dried for white solid, add methylene dichloride 50ml, white solid is partly dissolved, add the 7.5ml triethylamine, under ice bath, add triphenylmethyl chloride, go to stirring at room 8 ~ 24h, react completely, in reaction solution, add sodium hydrogen carbonate solution, there is solid to separate out, adds methylene dichloride again, the solid dissolving, tell organic layer, wash 3 times, anhydrous sodium sulfate drying, concentrate off-white color solid 11.29g, with petrol ether/ethyl acetate=10:3 system recrystallization, get white solid 10.41g yield: 80.7%.
Embodiment 9: histamine hydrochloride (R
1=COCF
3, R
2Synthesizing=trityl)
The 10g raw material is joined in the methyl alcohol, and raw material is dissolving fully not, drips 4N sodium hydroxide under ice bath, go to 30 ℃ ~ 80 ℃, behind reaction 5 ~ 24h, reaction solution is spin-dried for, add suitable quantity of water and methylene dichloride, stir 30min, tell dichloromethane layer, water layer extracts 2 times again, the combined dichloromethane layer, wash 2 times, anhydrous sodium sulfate drying, concentrate faint yellow oily thing 8.0g.Add 80mL methyl alcohol, 0.8g Pd/C is in 2atmH
2Down, 40 ℃ of hydrogenolysis 16h, after reacting completely, the methanol solution (getting by feeding HCl gas in the methyl alcohol) that adds 6mol/LHCl is transferred PH to 2 ~ 3, add 80ml acetone then, behind-10 ℃ of following stirring and crystallizing 6h, filter, reduced pressure at room temperature gets white solid 3.89g, yield: 95%.
From above-mentioned experimental data as seen, the inventive method prepares the yield of Ying Jiaweilin raw material histamine or its salt, significantly better than prior art, thereby reduced production cost, improved production efficiency.The contriver is optimized parameter through testing many times, and has obtained technique effect beyond expectation.
The present invention is not limited to aforesaid embodiment.The present invention expands to any new feature or any new combination that discloses in this manual, and the arbitrary new method that discloses or step or any new combination of process.
Claims (22)
1. the preparation method of a high purity Ying Jiaweilin raw material is characterized in that, may further comprise the steps:
A, with histamine or the histamine salt method with the protection nitrogen-atoms, with histamine amino or imino-protection, obtain the formula II compound
Wherein, R
1, R
2Be identical or different group;
B, the formula II compound that steps A is obtained are made with extra care by the method for recrystallization;
C, the formula II compound after step B is refining are sloughed nitrogen-protecting group, obtain formula (I) compound
2. the preparation method of a kind of high purity Ying Jiaweilin raw material according to claim 1 is characterized in that: among the described step C, also comprise formula (I) compound is converted into its pharmacy acceptable salt.
3. the preparation method of a kind of high purity Ying Jiaweilin raw material according to claim 2, it is characterized in that: described pharmacy acceptable salt is hydrochloride, phosphoric acid salt, trifluoroacetate, Trichloroacetate, perchlorate, succinate, maleate, fumarate or tartrate.
4. the preparation method of a kind of high purity Ying Jiaweilin raw material according to claim 3, it is characterized in that: described pharmacy acceptable salt is hydrochloride or phosphoric acid salt.
5. according to the preparation method of the arbitrary described a kind of high purity Ying Jiaweilin raw material of claim 1-4, it is characterized in that: in the described steps A, the protecting group of used amino or imino-is for forming the protecting group of chemical bond with nitrogen.
6. according to the preparation method of the arbitrary described a kind of high purity Ying Jiaweilin raw material of claim 1-4, it is characterized in that: in the described steps A, histamine or histamine salt with the mol ratio of the reagent of protection amino or imino-are: 0.5 ~ 10.
7. according to the preparation method of the arbitrary described a kind of high purity Ying Jiaweilin raw material of claim 1-4, it is characterized in that: described R
1, R
2For forming the protecting group of acid amides, nitrogen-carbon or nitrogen-chemistry of silicones key with nitrogen.
8. the preparation method of a kind of high purity Ying Jiaweilin raw material according to claim 7 is characterized in that: described R
1, R
2Respectively independently be hydrogen, formyl radical, ethanoyl, propionyl, trimethyl silicon based, tertiary butyl dimethyl is silica-based, tertbutyloxycarbonyl, trifluoroacetyl group, tribromo-acetyl base, replacement or unsubstituted benzyl, replacement or unsubstituted benzyloxy carbonyl acyl group, ditane or tritane.
9. according to the preparation method of the arbitrary described a kind of high purity Ying Jiaweilin raw material of claim 1-4, it is characterized in that: among the described step B, the mass volume ratio of employed optimum solvent is 1:0.5 ~ 30 in Ying Jiaweilin and the recrystallization, and the mass volume ratio of Ying Jiaweilin and poor solvent is 1:0.5 ~ 50.
10. the preparation method of a kind of high purity Ying Jiaweilin raw material according to claim 9, it is characterized in that: described optimum solvent is selected from alcohols, ester class, ethers, ketone, halohydrocarbon, acetonitrile, N, in dinethylformamide or the dimethyl sulfoxide (DMSO) one or more, poor solvent is selected from ethers, water or the hydro carbons one or more.
11. the preparation method of a kind of high purity Ying Jiaweilin raw material according to claim 10 is characterized in that: described alcohols is selected from methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol or Pentyl alcohol.
12. the preparation method of a kind of high purity Ying Jiaweilin raw material according to claim 10 is characterized in that: described ester class is selected from ethyl acetate, ethyl formate, Iso Butyl Acetate, isobutyl acetate, n-butyl acetate, tert-butyl acetate, methyl-formiate, propyl formate, butyl formate, methyl acetate or tetryl formate.
13. the preparation method of a kind of high purity Ying Jiaweilin raw material according to claim 10 is characterized in that: described ethers is selected from methyl ether, ether, methyl ethyl ether, isopropyl ether, t-butyl methyl ether, tetrahydrofuran (THF) or dioxane.
14. the preparation method of a kind of high purity Ying Jiaweilin raw material according to claim 10 is characterized in that: described ketone is selected from acetone, butanone, methyl iso-butyl ketone (MIBK) or methyl isopropyl Ketone.
15. the preparation method of a kind of high purity Ying Jiaweilin raw material according to claim 10 is characterized in that: described halohydrocarbon is selected from tetracol phenixin, chloroform, 1,2-ethylene dichloride, 1 or methylene dichloride.
16. the preparation method of a kind of high purity Ying Jiaweilin raw material according to claim 10 is characterized in that: described hydro carbons is selected from benzene, chlorine benzene,toluene,xylene, isopropyl benzene, oil of mirbane, sherwood oil, normal hexane, normal heptane, methylcyclohexane, hexanaphthene, Skellysolve A or octane-iso.
17. the preparation method according to the arbitrary described a kind of high purity Ying Jiaweilin raw material of claim 1-4 is characterized in that: among the described step B, the temperature that recrystallization adopts for-40 ℃ to solvent refluxing.
18. the preparation method according to the arbitrary described a kind of high purity Ying Jiaweilin raw material of claim 1-4 is characterized in that: among the described step B, the mode of the used separate solid of recrystallization is filtration or centrifugal.
19. the preparation method according to the arbitrary described a kind of high purity Ying Jiaweilin raw material of claim 1-4; it is characterized in that: among the described step C; the mode of sloughing nitrogen-protecting group is that hydrogenolysis, acidolysis or alkali take off, and the ratio that the acid that acidolysis is used or alkali take off used alkali and the mole number of formula II compound is: 1 ~ 100:1.
20. the preparation method of a kind of high purity Ying Jiaweilin raw material according to claim 19 is characterized in that: among the described step C, the used acid of acidolysis is organic acid and/or mineral acid, and it is mineral alkali and/or organic bases that alkali takes off used alkali.
21. the preparation method of a kind of high purity Ying Jiaweilin raw material according to claim 20, it is characterized in that: described organic acid is selected from one or more in trifluoracetic acid, Tricholroacetic Acid, formic acid, acetic acid, methylsulfonic acid, phenylbenzimidazole sulfonic acid or the tosic acid, and mineral acid is selected from one or more in hydrochloric acid, sulfuric acid, phosphoric acid, perchloric acid or the chloric acid.
22. the preparation method of a kind of high purity Ying Jiaweilin raw material according to claim 20, it is characterized in that: described organic bases is selected from one or more in ammoniacal liquor, dimethylamine, methylamine, ethamine, diethylamine, triethylamine, pyridine, sodium methylate, potassium methylate, lithium methoxide, sodium ethylate, potassium ethylate, lithium ethoxide, n-propyl alcohol sodium, n-propyl alcohol potassium, n-propyl alcohol lithium, sodium tert-butoxide, potassium tert.-butoxide or the trimethyl carbinol lithium, and mineral alkali is selected from one or more in sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium hydride or the potassium hydride KH.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105418512A (en) * | 2014-09-19 | 2016-03-23 | 江苏正大丰海制药有限公司 | Single crystal of ingavirin, preparation method and pharmaceutical composition of ingavirin |
| CN106257276A (en) * | 2015-06-19 | 2016-12-28 | 江苏正大丰海制药有限公司 | A kind of ingavirin and the method for detecting impurities of preparation thereof |
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| CN102477014A (en) * | 2010-11-27 | 2012-05-30 | 山东新时代药业有限公司 | Preparation method of histamine dihydrochloride |
| CN102757388A (en) * | 2012-07-04 | 2012-10-31 | 四川百利药业有限责任公司 | Preparation method of high-purity etravirine |
| CN102757387A (en) * | 2012-07-04 | 2012-10-31 | 四川百利药业有限责任公司 | Synthesis method of etravirine |
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2013
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| GB1565647A (en) * | 1975-07-31 | 1980-04-23 | Smith Kline French Lab | Pharmacologically active compounds 4-substituted-imidazole-5-methanols |
| US5047418A (en) * | 1989-07-25 | 1991-09-10 | Smith Kline & French Laboratories Limited | Method of stimulating histamine H3 -receptors |
| NZ337182A (en) * | 1997-02-14 | 2001-04-27 | Smithkline Beecham Corp | Process for preparing eprosartan with imidazole and thiophene intermediates |
| CN1331681A (en) * | 1998-12-23 | 2002-01-16 | 马克西姆药品公司 | Synthesis of histamine dihydrochloride |
| CN102477014A (en) * | 2010-11-27 | 2012-05-30 | 山东新时代药业有限公司 | Preparation method of histamine dihydrochloride |
| CN102757388A (en) * | 2012-07-04 | 2012-10-31 | 四川百利药业有限责任公司 | Preparation method of high-purity etravirine |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105418512A (en) * | 2014-09-19 | 2016-03-23 | 江苏正大丰海制药有限公司 | Single crystal of ingavirin, preparation method and pharmaceutical composition of ingavirin |
| CN105418512B (en) * | 2014-09-19 | 2018-05-01 | 江苏正大丰海制药有限公司 | Monocrystalline, preparation method and its pharmaceutical composition of ingavirin |
| CN106257276A (en) * | 2015-06-19 | 2016-12-28 | 江苏正大丰海制药有限公司 | A kind of ingavirin and the method for detecting impurities of preparation thereof |
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Application publication date: 20130911 |