CN102351778A - Preparation method of arbidol hydrochloride - Google Patents

Preparation method of arbidol hydrochloride Download PDF

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Publication number
CN102351778A
CN102351778A CN2011102352213A CN201110235221A CN102351778A CN 102351778 A CN102351778 A CN 102351778A CN 2011102352213 A CN2011102352213 A CN 2011102352213A CN 201110235221 A CN201110235221 A CN 201110235221A CN 102351778 A CN102351778 A CN 102351778A
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compound
reaction
acetone
hour
preparation
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操志斐
董俊
石林
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HUBEI HUALONG BIOLOGICAL PHARMACEUTICAL CO Ltd
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HUBEI HUALONG BIOLOGICAL PHARMACEUTICAL CO Ltd
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Abstract

The invention discloses a preparation method of arbidol hydrochloride. The preparation method comprises the following steps of: (1) performing hydroxylation reaction on 3-iodo-4-nitrophenol serving as a raw material by using acetyl chloride to obtain a compound I; (2) performing substitution reaction on the compound I and ethyl acetoacetate under the action of alkali to obtain a compound II; (3) performing reduction-condensation concerted reaction on the compound II under the conditions of acetic acid and iron powder to synthesize an indole ring, and obtaining a compound III; (4) performing N-methylation reaction on the compound III by using dimethyl sulfate to obtain a compound IV; (5) performing di-bromination reaction on the compound IV in carbon tetrachloride by using bromine to obtain a compound V; (6) reacting the compound V and thiophenol under the alkali condition, and obtaining a compound VI after acidifying; (7) preparing a compound VII from the compound VI in the presence of a reaction solvent, namely aqueous solution of dimethylamine and formaldehyde; and (8) acidifying the compound VII in hot acetone to obtain the arbidol hydrochloride. The preparation method is facile in raw materials, mild in reaction conditions, high in yield, easy in separation and purification, low in cost and suitable for industrialized production.

Description

A kind of preparation method of arbidol HCl
Technical field
The invention belongs to the field of chemical synthesis, specifically relate to a kind of preparation method of arbidol HCl.
Background technology
Arbidol HCl (Arbidol hydrochloride), chemistry is by name: 6-bromo-4-(dimethylamino methyl)-5-hydroxyl-1-methyl-2-(thiophenyl methyl)-1H-Indole-3-Carboxylic Acid carbethoxy hydrochloride, structural formula is following:
Arbidol HCl is the antiviral by Soviet Union's pharmaceutical chemistry research centre research and development, and medicinal was monohydrate first in Russia's listing in 1993.These article not only have immunomodulatory and interferon-induced effect, and have good anti-influenza virus activity, clinically are used to prevent and treat influenza and other acute viral respiratory tract infection.
The preparation of arbidol HCl has many synthetic routes; Chinese patent CN1687033A and king are blunt; Wu Xiujing, palace equality people " arbidol HCl synthetic " bibliographical information in Chinese Journal of Pharmaceuticals 2004,35 (8) is to be starting raw material with para benzoquinone with 3-amino ethyl crotonate; Obtain arbidol HCl, overall yield of reaction 22.9% through Nenitzescu reaction, O-acidylate, N-hydrocarbonylation, bromination, thiophenol reaction, Mannich Mannich reaction, hcl acidifying.
Synthetic route is following:
The Nenitzescu reaction that this method synthesis of indole ring uses, this step reaction yield causes total recovery 22.9% about 60%.
U.S. Pat 5198552 and world patent WO9008135 report with 5-hydroxyl-1,2-dimethyl indole-3-ethyl formate is a raw material, makes arbidol HCl through bromo, condensation, Mannich reaction and salt-forming reaction.
Though this method synthesis step is shorter, raw material 5-hydroxyl-1,2-dimethyl indole-3-ethyl formate is difficult to obtain, and large-scale application is difficulty.
Song Yanling, Zhao Yanfang, the bibliographical information of " study on the synthesis of arbidol HCl " that palace equality people reports in the 3rd national pharmaceutical engineering science and technology and Education seminar is to be starting raw material with the thiophenol; After chloro ethyl acetoacetate generation substitution reaction; Introduce the thiophenyl fragment in the molecule,, with para benzoquinone the Nenitzescu reaction takes place then again with the methylamine condensation; Introduce the n n dimetylaniline methyl through the Mannich reaction; After the acetylize protective reaction, carry out bromo-reaction, carry out deprotection reaction then, obtain the final product arbidol HCl through salt-forming reaction at last
Its synthetic route is following:
Because the Nenitzescu reaction yield in this method has only 33.7%, makes total recovery be merely 11.2%.
Bibliographical information (Wen Yanzhen is also arranged; Gao Zhiwei; Wei Wenlong, the emerald green plum of intelligence, people such as Wang Qi are at Chinese Journal of Pharmaceuticals 2006; In 37 (12) " graphical Synthetic Routes of arbidol HCl " of report) be to be starting raw material with methyl aceto acetate and methylamine, through Nenitzescu reaction, acidylate protection hydroxyl, bromination, thiophenol reaction, Mannich react, acidifying obtains arbidol HCl.
Synthetic route is following:
This method reaction conditions is gentle, and raw material ratio is easy to get, but total recovery is still on the low side, and about about 20%.
More than the compound method of these arbidol HCls all be to use the indole ring of Nenitzescu indole ring synthesis method synthetic hydrochloric acid Arbidol hydrochloride, cause the total reaction yield on the low side, about 10%~20%.
Summary of the invention
To the problems referred to above, the objective of the invention is to be to provide a kind of preparation method of arbidol HCl, starting material are easy to get, the reaction technology condition is simple relatively, reaction conditions is gentle, overall yield of reaction is high relatively; Reach more than 30%, low cost of manufacture is fit to suitability for industrialized production; This inventive method is with 3-iodo-4-nitrophenols starting raw material, and through hydroxyl protection, indole ring is synthetic; N-methylates, bromination, thiophenolization; The Mannich Mannich reaction, hcl acidifying, the refining arbidol HCl that obtains.
In order to realize above-mentioned purpose, the present invention adopts following technical measures:
A kind of preparation method of arbidol HCl may further comprise the steps:
(1) is raw material with 3-iodo-4-nitrophenols, under the base catalysis, carries out hydroxyl reaction with Acetyl Chloride 98Min. and make compound 1; Described alkali is wherein a kind of of triethylamine, n-Butyl Amine 99 or pyridine, preferred triethylamine or n-Butyl Amine 99; Reaction times is 1-5 hour.
(2) compound 1 under the effect of alkali with methyl aceto acetate generation substitution reaction, make compound 2; Described alkali is wherein a kind of of potassium tert.-butoxide, n-Butyl Lithium, lithium diisopropylamine, sodium tert-butoxide, sodium hydride or sodium methylate, preferred potassium tert.-butoxide lithium diisopropylamine; Reaction times is 1-10 hour.
(3) compound 2 reduces-condensation concerted reaction synthesis of indole ring under acetic acid and iron powder condition, makes compound 3; Described reaction solvent is wherein a kind of of acetic acid-water or hydrochloric acid; Compound 2 is 1: 2~5 with the mol ratio of iron powder; Reaction times is 3-8 hour.
(4) compound 3 usefulness methyl-sulfates carry out the N-methylation reaction and make compound 4; Described reaction solvent is a N; Methylating reagent is wherein a kind of of methyl-sulfate or methylcarbonate; Reaction times is 2-6 hour.
(5) compound 4 carries out the dibrominated reaction with bromine and makes compound 5 in tetracol phenixin; Described reaction solvent is a tetracol phenixin; Bromide reagent is wherein a kind of of bromine or NBS; Reaction times is 3-9 hour.
(6) compound 5 reacts with thiophenol under alkaline condition, makes compound 6 after the acidifying, carries out recrystallization; Described alkali is elected Pottasium Hydroxide or sodium hydroxide as, and the reaction times is 1-6 hour, and recrystallization solvent is selected from wherein a kind of of ETHYLE ACETATE, Virahol, ethanol, THF, trichloromethane or acetone.
(7) compound 6 has in the presence of the aqueous solution of n n dimetylaniline and formaldehyde at reaction solvent, carries out the Mannich reaction and makes compound 7; Described reaction solvent is selected from wherein a kind of of ethanol, Glacial acetic acid min. 99.5, formic acid, THF or water, and temperature of reaction is 50 ℃-100 ℃, and the reaction times is 2-8 hour.
(8) compound 7 acidifying in hot acetone gets arbidol HCl 8, carries out recrystallization and gets refined prod.Described reaction solvent is an acetone, and recrystallization solvent is wherein a kind of of acetone-alcohol-water, acetone-THF, acetone-methyl alcohol or acetone-ethanol.
The inventive method is starting raw material owing to take above technical scheme by 3-iodo-4-nitrophenols, and various raw materials are easy to get, and it is simple relatively that each goes on foot the reaction technology condition, and reaction conditions is gentle, and yield is higher, and separation and purification is easy, is fit to suitability for industrialized production.
The reaction formula of the inventive method is following:
Fe represents iron powder
CH 3COOH represents acetic acid
H 2O represents water
(CH 3) 2SO 4Represent methyl-sulfate
K 2CO 3Represent salt of wormwood
represents thiophenol
Br 2Represent bromine
KOH represents Pottasium Hydroxide
HCHO represents formaldehyde
NH (CH 3) 2Represent n n dimetylaniline
HCl represents hydrochloric acid
CH 3COCH 3Represent acetone
In the above-mentioned reaction formula 1 representative:
2 representatives:
3 representatives:
4 representatives:
5 representatives:
6 representatives:
7 representatives:
8 representatives:
Wherein: OH is a hydroxyl in the reaction formula, and O is a Sauerstoffatom, H 2C is a methylene radical, and Cl is the chlorine atom, and Br is a bromine atoms, H 3C is a methyl, and S is a sulphur atom, and N is a nitrogen-atoms, NO 2Be nitro, I is the iodine atom.
The present invention compared with prior art has the following advantages and effect:
The synthesis of indole ring uses two-step reaction among the present invention, and yield is respectively 98% and 92.3%, and synthesis of indole ring yield reaches more than 90%, and overall yield of reaction is high relatively, reaches more than 30%.Starting material are easy to get in this reaction.The reaction technology condition is simple relatively, dangerous operation such as no HTHP.Reaction conditions is gentle, and all step reaction temperature are not used the step of extremely low temperature all below 100 ℃ yet.Low cost of manufacture is fit to suitability for industrialized production.
Embodiment
The preparation method of following examples is interpreted as only being used to further specify the present invention; Rather than limitation of the present invention; Under the prerequisite of the present invention's design, the present invention is made various corrections and change, these corrections and change are also included in the scope of the present invention.
Embodiment 1:
A kind of preparation method of arbidol HCl, its step are (preparation compounds 1):
A, preparation compound 1:3-iodo-4-nitrophenols 53g join (dry through Anhydrous potassium carbonate) in the 160g acetone, add triethylamine 30.3g, and room temperature (20-25 ℃, below identical) drips the 37.7g Acetyl Chloride 98Min.; Drip off in the 1h, reaction solution rises to reflux temperature T=56 ℃ automatically, and reaction 0.5h naturally cools to room temperature T=25 ℃; Reaction solution is poured in the 1000g frozen water, stirs, and filters; Filter cake is used water washing, and vacuum-drying gets compound 1 bullion 57.4g, yield 93.6%.Need not be further purified and directly carry out next step reaction.
B, preparation compound 2: in the exsiccant flask, add methyl aceto acetate 48.6g, newly steam THF 180ml.In 2 hours, add potassium tert.-butoxide 41.9g under stirring in batches.Be warming up to T=70 ℃ (backflow), begin to drip the solution that 57.4g compound 1 that the step makes and 75mL newly steam THF, dripped off in 2 hours.Thin-layer chromatography board monitoring reaction end.After reaction mixture is cooled to room temperature T=25 ℃, drip 4mol/L hydrochloric acid soln 93.5ml.Remove by filter the Repone K of separating out, pressure reducing and steaming solvent, gained solid are used 45mL water and 60mL petroleum ether successively, get compound 2 bullion 56.6g, productive rate 98%.Bullion can get pure article with sherwood oil and ethyl acetate mixture recrystallization.
C, preparation compound 3: in flask, add 56.6g compound 2, acetic acid 160mL and water 160mL stir under nitrogen protection; Add iron powder 30.8g in batches; The powerful stirring, reaction mixture is heated to T=80 ℃ simultaneously, and the 4h reaction finishes (TLCP detection).Remove by filter iron and oxide compound thereof, pressure reducing and steaming water and acetic acid are neutralized to weakly alkaline with saturated sodium carbonate solution, use ethyl acetate extraction, anhydrous magnesium sulfate drying, concentrate compound 3 bullion 44.1g, yield 92.3%.
D, preparation compound 3: in flask, add 10.0g compound 2, acetic acid 28mL and water 28mL stir under nitrogen protection, add iron powder 7.2g in batches, the powerful stirring, and reaction mixture is heated to T=80 ℃ simultaneously, and the 4h reaction finishes (TLCP detection).Remove by filter iron and oxide compound thereof, pressure reducing and steaming water and acetic acid are neutralized to weakly alkaline with saturated sodium carbonate solution, use ethyl acetate extraction, anhydrous magnesium sulfate drying, concentrate compound 3 bullion 7.5g, yield 89.4%.
E, preparation compound 4: the 44.1g compound 3 that makes among the step C is added among the DMF230ml, behind the adding Anhydrous potassium carbonate 35.0g, stir down and slowly drip methyl-sulfate 31.9g, Bi Tongwen T=100 ℃ of reaction 4h in 100 ℃.Reaction solution is cooled to T=25 ℃ of room temperature, adds entry 280ml under stirring, and leaves standstill crystallization, suction filtration, and filter cake washing after drying gets compound 4 bullion 44.6g, uses recrystallizing methanol, obtains compound 4 highly finished product 36.8g, yield 79.3%
F, preparation compound 5: 36.8g compound 4 is joined among the tetracol phenixin 200ml, add the 0.1g Lucidol, be heated to T=76 ℃ of backflow; Drip bromine 45.0g, drip off in the 2h, reaction 4h; Ice-water bath cooling reaction liquid filters, and filter cake washs with a small amount of tetracol phenixin; Dry compound 5 bullion 47.5g, the yield 82% of getting.
G, preparation compound 6: Pottasium Hydroxide 15.4g is dissolved among the methyl alcohol 360ml, stirs, ice-water bath is cooled to 0~10 ℃, adds thiophenol 12.7g; Behind the reaction 10min, add 47.5g compound 5, rise to room temperature, reaction 3~3.5h; Reaction solution is poured in the 1500ml frozen water, stirs down, transfers pH=2 with hydrochloric acid, filters; Filter cake with water washing after, vacuum-drying gets compound 6 bullion 42.9g, yield 93.1%.Bullion is used re-crystallizing in ethyl acetate, gac 10g decolouring, exsiccant compound 6 highly finished product 36.0g, refining yield 84%.Recrystallization mother liquor concentrates and reclaims.Or preparation compound 6, Pottasium Hydroxide 3.3g is dissolved among the methyl alcohol 75ml, stir, ice-water bath is cooled to 0~10 ℃; Add thiophenol 2.7g, behind the reaction 10min, add 10.0g compound 5, rise to room temperature; Reaction 3~3.5h, reaction solution is poured in the 300ml frozen water, stirs down, transfers pH=2 with hydrochloric acid; Filter, filter cake with water washing after, vacuum-drying gets compound 6 bullion 9.0g, yield 93.1%.Bullion is used the Virahol recrystallization, gac 2g decolouring, exsiccant compound 6 highly finished product 6.3g, refining yield 70%.Recrystallization mother liquor concentrates and reclaims.
H, preparation compound 7:
In ethanol 320ml, add (33%) dimethylamine agueous solution 29.2g, (37~40%) formalin 23.8g; Stir 10min, add 6,60 ℃ of reactions of 36.0g compound 5h; Reaction finishes, 5.0g activated carbon decolorizing, filtered while hot; Filtrate decompression is distilled away THF, dry compound 7 bullion 40.4g, the yield 99.0% of getting.Or preparation compound 7, under stirring and cooling conditions, with (33%) dimethylamine agueous solution 8.1g, (37~40%) formaldehyde solution 6.6g and 10g compound 6 among the Glacial acetic acid min. 99.5 100ml that is added to successively, reacted 6 hours down in 70 ℃.After reaction finished, the concentrating under reduced pressure reaction solution added entry 100ml, transfers pH=12 with trimethylamine solution.With dichloromethane extraction water three times (20ml * 3), anhydrous sodium sulfate drying organic phase.Concentrating under reduced pressure, dry compound 7 bullion 9.6g, the yield 85.0% of getting.
J, preparation compound 8:
The compound 7 bullion 40.4g that above-mentioned steps H obtains transfer pH=2 with hydrochloric acid while hot with acetone 150ml heating for dissolving, separate out solid; Ice-water bath is cooled to about 0 ℃, filters, and filter cake is used freezing washing with acetone; Vacuum-drying gets compound 8 bullion 40.5g, yield 89.8%.
Above-claimed cpd J bullion is with acetone-alcohol-water (3: 1: 1) recrystallization.Get product 36.5g, yield 90.0%.
The proton nmr spectra of product 1H-NMR (400MHz, DMSO-d 6): 1.25 (t, 3H ,-OCH 2CH 3), 2.74 [s, 6H ,-N (CH 3) 2], 3.70 (s, 3H ,=NCH 3), 4.19 (q, 2H ,-OCH 2CH 3), 4.74 (s, 2H ,-CH 2S-), 4.91 (s, 2H ,-CH2N=), 7.31~7.36 (m, 5H ,-PhH), 8.03 (s, 1H, indole-7-H), 9.11 (br s, 1H, HCl), 9.43 (s, 1H ,-0H).
The mass spectrum MS (m/z) of product: 477 (M+1, Br=79), 479 (M+1, Br=81).

Claims (2)

1. the preparation method of an arbidol HCl the steps include:
(1) is raw material with 3-iodo-4-nitrophenols, under the base catalysis, carries out hydroxyl reaction with Acetyl Chloride 98Min. and make compound 1; Described alkali is wherein a kind of of triethylamine, n-Butyl Amine 99 or pyridine; Reaction times is 1-5 hour;
(2) compound 1 under the effect of alkali with methyl aceto acetate generation substitution reaction, make compound 2; Described alkali is wherein a kind of of potassium tert.-butoxide, n-Butyl Lithium, lithium diisopropylamine, sodium tert-butoxide, sodium hydride or sodium methylate; Reaction times is 1-10 hour;
(3) compound 2 reduces-condensation concerted reaction synthesis of indole ring under acetic acid and iron powder condition, makes compound 3; Described reaction solvent is wherein a kind of of acetic acid-water or hydrochloric acid; Compound 2 is 1: 2~5 with the mol ratio of iron powder; Reaction times is 3-8 hour;
(4) compound 3 usefulness methyl-sulfates carry out the N-methylation reaction and make compound 4; Described reaction solvent is a N; Methylating reagent is wherein a kind of of methyl-sulfate or methylcarbonate; Reaction times is 2-6 hour;
(5) compound 4 carries out the dibrominated reaction with bromine and makes compound 5 in tetracol phenixin; Described reaction solvent is a tetracol phenixin; Bromide reagent is wherein a kind of of bromine or NBS; Reaction times is 3-9 hour;
(6) compound 5 reacts with thiophenol under alkaline condition, makes compound 6 after the acidifying, carries out recrystallization; Described alkali is elected Pottasium Hydroxide or sodium hydroxide as, and the reaction times is 1-6 hour, and recrystallization solvent is selected from wherein a kind of of ETHYLE ACETATE, Virahol, ethanol, THF, trichloromethane or acetone;
(7) compound 6 has in the presence of the aqueous solution of n n dimetylaniline and formaldehyde at reaction solvent, carries out the Mannich reaction and makes compound 7; Described reaction solvent is selected from wherein a kind of of ethanol, Glacial acetic acid min. 99.5, formic acid, THF or water, and temperature of reaction is 50 ℃-100 ℃, and the reaction times is 2-8 hour;
(8) compound 7 acidifying in hot acetone gets arbidol HCl 8, carries out recrystallization and gets refined prod, and described reaction solvent is an acetone, and recrystallization solvent is wherein a kind of of acetone-alcohol-water, acetone-THF, acetone-methyl alcohol or acetone-ethanol.
2. the preparation method of a kind of arbidol HCl according to claim 1, it is characterized in that: the reaction formula of described a kind of arbidol HCl is following:
Wherein: OH is a hydroxyl in the reaction formula, and O is a Sauerstoffatom, H 2C is a methylene radical, and Cl is the chlorine atom, and Br is a bromine atoms, H 3C is a methyl, and S is a sulphur atom, and N is a nitrogen-atoms, NO 2Be nitro, I is the iodine atom.
CN2011102352213A 2011-08-17 2011-08-17 Preparation method of arbidol hydrochloride Pending CN102351778A (en)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102786463A (en) * 2012-07-02 2012-11-21 浙江金伯士药业有限公司 Method for preparing 5-acetoxyl-3-indole carboxylic acid ethyl ester
CN106083691A (en) * 2016-08-22 2016-11-09 山东罗欣药业集团股份有限公司 A kind of preparation method of arbidol HCl
CN109734616A (en) * 2019-02-16 2019-05-10 安徽诺全药业有限公司 The method of two-step method synthesis (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl
CN111269168A (en) * 2020-04-14 2020-06-12 苏州敬业医药化工有限公司 Preparation method of arbidol intermediate
CN111533677A (en) * 2020-05-13 2020-08-14 大连万福制药有限公司 Method for synthesizing arbidol hydrochloride intermediate

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102786463A (en) * 2012-07-02 2012-11-21 浙江金伯士药业有限公司 Method for preparing 5-acetoxyl-3-indole carboxylic acid ethyl ester
CN106083691A (en) * 2016-08-22 2016-11-09 山东罗欣药业集团股份有限公司 A kind of preparation method of arbidol HCl
CN106083691B (en) * 2016-08-22 2018-11-27 山东罗欣药业集团恒欣药业有限公司 A kind of preparation method of arbidol HCl monohydrate
CN109734616A (en) * 2019-02-16 2019-05-10 安徽诺全药业有限公司 The method of two-step method synthesis (Z) -3- amino -2- (the fluoro- 3- methoxyphenyl of 2-) -2- butenoic acid ethyl
CN109734616B (en) * 2019-02-16 2022-05-13 安徽诺全药业有限公司 Method for synthesizing (Z) -3-amino-2- (2-fluoro-3-methoxyphenyl) -2-ethyl crotonate by two-step method
CN111269168A (en) * 2020-04-14 2020-06-12 苏州敬业医药化工有限公司 Preparation method of arbidol intermediate
CN111269168B (en) * 2020-04-14 2022-04-01 苏州敬业医药化工有限公司 Preparation method of arbidol intermediate
CN111533677A (en) * 2020-05-13 2020-08-14 大连万福制药有限公司 Method for synthesizing arbidol hydrochloride intermediate

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Application publication date: 20120215