CN106083691A - A kind of preparation method of arbidol HCl - Google Patents
A kind of preparation method of arbidol HCl Download PDFInfo
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- CN106083691A CN106083691A CN201610701546.9A CN201610701546A CN106083691A CN 106083691 A CN106083691 A CN 106083691A CN 201610701546 A CN201610701546 A CN 201610701546A CN 106083691 A CN106083691 A CN 106083691A
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- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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Abstract
The invention discloses the preparation method of a kind of arbidol HCl; the paranitrophenol using cheaper starting materials to be easy to get of novelty of the present invention is raw material, through acetylation, nitro reduction, indole ring reaction, methylation reaction, bromo, phenylmercaptan. and deprotection, Mannich reaction, becomes salt to obtain arbidol HCl;Whole building-up process reaction condition is gentle, and raw material sources are convenient, and product characteristics are good, and yield is high, and by-product is few, and reaction selectivity and purity are high, and environmentally friendly, production cost is low, are suitable for industrialized production;Avoid poor selectivity of the prior art, by-product is many, yield is relatively low, avoid and use valuable catalyst and the drawback of the big reagent of environmental pollution.
Description
Technical field
The present invention relates to pharmaceutical chemistry technical field, be specifically related to the preparation method of a kind of arbidol HCl.
Background technology
Arbidol HCl, English name is arbidol hydrochloride, chinesization formal name used at school 1-methyl-4-diformazan
Amino methyl-5-hydroxyl-6-bromo-2-phenylthiomethyl-1H-indole-3-carboxylic acid's carbethoxy hydrochloride monohydrate, molecular formula is
C22H25BrN2O3S·HCI·H2O, molecular weight is 531.90.Its chemical structural formula is as follows:
Arbidol HCl 1993 is in Russia's Initial Public Offering.Medicinal for its monohydrate, it is adaptable to adult and child
Influenza A, influenza B, acute viral respiratory tract infection, serious acute respiratory disease syndrome and concurrently prop up gas
Guan Yan and the prevention of pneumonia and treatment.Clinical practice proves, arbidol HCl side effect is little, and is not likely to produce drug resistance, is
There is the antiviral drugs of good potential applicability in clinical practice.
The synthetic method of Abiduoer has been reported:
1, patent CN1687033 and king are blunt, Wu Xiujing, and palace equality people is at Chinese Journal of Pharmaceuticals 2004, in 35 (8)
In " synthesis of arbidol HCl " document, report is through Nenitzescu reaction, O-with 1,4-benzoquinone, 3-amino Ethyl crotonate
Acylated, N-methylates prepared key intermediate 5-acetoxyl group-1,2-dimethyl-1H-indole-3-carboxylic acid's ethyl ester, then through bromo,
Condensation, Mannich are synthesized target compound, and the Nenitzescu reaction that the method synthesis of indole ring uses, this portion reacts
Yield low (30-60%), causes total recovery relatively low (22.9%), and in intermediate 5-hydroxyl-1,2-dimethyl indole-3-carboxyl
The preparation process of ethyl ester and intermediate 6-bromo-2-bromomethyl-5-OHi-3-carboxyethyl employs a kind solvent respectively
1,2-dichloroethanes and carbon tetrachloride, because its toxicity is relatively big, country's suggestion limits it and uses, it is impossible to industrialized production.Its synthesis
Route is as follows:
2, Song Yanling, Zhao Yanfang, palace equality people reports first by benzene sulfur in " study on the synthesis of arbidol HCl " document
Phenol and chloro ethyl acetoacetate generation substitution reaction, introduce the thiophenyl fragment in molecule, then be condensed with methylamine, then with right
There is Nenitzescu reaction in benzoquinone, introduces dimethylamine methyl through Mannich reaction, carries out bromo after acetylation protection reaction
Reaction, then deprotection reaction, after through becoming salt to obtain arbidol HCl, the yield of the Nenitzescu reaction of the method is only
Have 33.7%, cause total recovery relatively low (11.2%);Its synthetic route is as follows:
The synthetic method of the above arbidol HCl is all to use Nenitzescu indole ring synthetic method synthetic hydrochloric acid
The indole ring of Abiduoer, causes overall reaction yield on the low side, about 10~20%.
4, Chen Shuyun, Gao Wen be the " synthesis technique of arbidol HCl in Qingyuan Profession Technology College's journal 2015,8 (4)
Improve research " document, patent US5198552 and WO9008135 report with 5-hydroxyl-1,2-dimethyl indole-3-formic acid
Ethyl ester is raw material, through bromo, condensation, Mannich reaction and salt-forming reaction synthesising target compound, although the method synthesis step
Shorter, but raw material 5-hydroxyl-1, and 2-dimethyl indole-3-Ethyl formate is difficult to obtain, and large-scale application is more difficult;Its synthesis
Route is as follows:
6, CN201110235221.3 discloses the synthesis technique of arbidol HCl: be former with 3-iodo-4-nitrophenol
Material, through hydroxyl protection, under alkali effect with ethyl acetoacetate generation substitution reaction after through reduction-condensation reaction synthesis of indole
Ring, methylates, bromination, phenylmercaptan., and Mannich is amine-methylated, and hydrochloric acid is acidified, and is refining to obtain arbidol HCl;But this route
There is 3-iodo-4-nitrophenol expensive starting materials, the step of indole cyclization is longer, it is loaded down with trivial details to process, yield is low, by-product is many etc. lacks
Point, its synthetic route is as follows:
Summary of the invention
For solving the above-mentioned technical problem that prior art exists, the invention provides the preparation side of a kind of arbidol HCl
Method, which obviates the disadvantages such as poor selectivity of the prior art, by-product is many, yield is relatively low.
Technical scheme is as follows:
The preparation method of a kind of arbidol HCl, it is characterised in that comprise the steps:
1) with paranitrophenol (9) as raw material, p-nitrophenyl yl acetate (8) is obtained through acetylation protection reaction;
2) p-nitrophenyl yl acetate (8) obtains 4-acetoxyl group aniline (7) through nitro-reduction reaction;
3) 4-acetoxyl group aniline (7) and ethyl acetoacetate (6) carry out indole ring and react and obtain 5-acetoxyl group-2-first
Base indole-3-carboxylic acid's ethyl ester (5);
4) 5-acetoxyl group-2 methyl indole-3-carboxylic acid, ethyl ester (5) carries out methylation reaction and obtains 5-acetoxyl group-1,
2-dimethyl indole-3-carboxylic acid, ethyl ester (4);
5) 5-acetoxyl group-1,2-dimethyl indole-3-carboxylic acid, ethyl ester (4) carries out bromo-reaction and obtains 1-methyl-2-(bromine
Methyl)-5-acetoxyl group-6-bromo indole-3-Ethyl formate (3);
6) 1-methyl-2-(bromomethyl)-5-acetoxyl group-6-bromo indole-3-Ethyl formate (3) carries out phenylmercaptan .ization and takes off
Protection reaction obtains 6-bromo-5-hydroxyl-1-methyl-2-(phenylthiomethyl) indole-3-carboxylic acid ethyl ester (2);
7) 6-bromo-5-hydroxyl-1-methyl-2-(phenylthiomethyl) indole-3-carboxylic acid ethyl ester (2) carries out Mannich reaction
Obtain Abiduoer, become salt to obtain arbidol HCl (1);Its synthetic route is as follows:
As preferably, step 1) in, paranitrophenol (9), under base catalysis, carries out hydroxyl with chloroacetic chloride or acetic anhydride
Reaction obtains p-nitrophenyl yl acetate (8);Described alkali is triethylamine, n-butylamine or pyridine;Response time is 1-5 hour.
As preferably, step 2) in, use ammonium chloride/reduced iron powder system to carry out nitro-reduction reaction, p-nitrophenyl
Yl acetate (8), reduced iron powder are 1.0:2.5~3.5:2.5~3.5 with the mol ratio of ammonium chloride.
As preferably, step 3) in, 4-acetoxyl group aniline (7) and ethyl acetoacetate (6) are at indium bromide InBr3's
Catalysis is lower generates corresponding enaminone intermediate, and reaction dissolvent is dichloromethane;Described enaminone intermediate is at alkali, catalyst Pd
(OAc)2With oxidant Cu (OAc)2Carry out ring-closure reaction under effect and obtain 5-acetoxyl group-2 methyl indole-3-carboxylic acid, ethyl ester
(5), described alkali is K2CO3Or K3PO4, reaction dissolvent is DMF.Further preferred, step 3) in, 4-acetyloxy phenyl
Amine (7) and InBr3Reaction mol ratio be 1:0.01~0.05;4-acetoxyl group aniline (7), Pd (OAc)2、Cu(OAc)2And alkali
Reaction mol ratio be 1:0.05~0.10:2.5~3.5:2.5~3.5.
As preferably, step 4) in, 5-acetoxyl group-2 methyl indole-3-carboxylic acid, ethyl ester (5) enters by dimethyl sulfate
Row N-methylation reaction prepares 5-acetoxyl group-1,2-dimethyl indole-3-carboxylic acid, ethyl ester (4);Reaction dissolvent is dimethyl methyl
Amide;Response time is 2-6 hour.
As preferably, step 5) in, the brominated reagent used by described bromo-reaction is bromine or NBS;Reaction dissolvent is
Chloroform;Response time is 3-9 hour.
As preferably, step 6) in, 1-methyl-2-(bromomethyl)-5-acetoxyl group-6-bromo indole-3-Ethyl formate
(3) react with phenylmercaptan. in the basic conditions, after acidifying prepare 6-bromo-5-hydroxyl-1-methyl-2-(phenylthiomethyl) indole-
3-Ethyl formate (2);Described alkali is potassium hydroxide or sodium hydroxide, and the response time is 1-6 hour.
As preferably, step 7) in, use solid acid sulfamic acid to make catalyst, 6-bromo-5-hydroxyl-1-methyl-2-
(phenylthiomethyl) indole-3-carboxylic acid ethyl ester (2), formaldehyde, dimethylamine 3 component occur Mannich reaction to obtain in aqueous
Abiduoer, reaction temperature is 30~40 DEG C, and the response time is 1-4 hour.Further preferred, step 7) in, the bromo-5-of 6-
Hydroxyl-1-methyl-2-(phenylthiomethyl) indole-3-carboxylic acid ethyl ester, dimethylamine, formaldehyde with the reaction mol ratio of sulfamic acid are
1:1.2~1.8:1.2~1.8:1.0~1.2.
Relative to prior art, the present invention has a following beneficial effect:
1) paranitrophenol that is easy to get of cheaper starting materials that uses of novelty of the present invention is raw material, through acetylation, nitro reduction,
Indole ring reaction, methylation reaction, bromo, phenylmercaptan. and deprotection, Mannich react, become salt to obtain arbidol HCl;
Whole building-up process reaction condition is gentle, and raw material sources are convenient, and product characteristics are good, and yield is high, and by-product is few, reaction selectivity and
Purity is high, and environmentally friendly, production cost is low, is suitable for industrialized production;Avoid poor selectivity of the prior art, by-product
Many, yield is relatively low, avoid and use valuable catalyst and the drawback of the big reagent of environmental pollution.
2) in indole ring synthesizes, the employing catalyst indium bromide InBr of present invention innovation3By 4-acetoxyl group aniline (7)
With the corresponding enaminone intermediate of generation of ethyl acetoacetate (6) high yield (yield more than 95%), the most directly will
Described enaminone intermediate is at alkali and catalyst Pd (OAc)2, oxidant Cu (OAc)2Carry out ring-closure reaction under effect and obtain 5-second
Acyloxy-2 methyl indole-3-carboxylic acid, ethyl ester (5), this step yield more than 80% of the present invention, processing step is simple, reacts bar
Part is gentle, and conversion zone and selectivity are high, and no coupling product produces;Avoid reaction in Nenitzescu reaction ring-closure reaction to receive
Rate relatively low (34~60%), and use toxic solvent 1, the disadvantage of 2-dichloroethanes.
3) present invention uses solid acid sulfamic acid to make catalyst, and indole, formaldehyde, dimethylamine 3 component are entered in aqueous
Row Mannich reacts, this Mannich synthetic method environmental protection, low cost, and productivity is high, mild condition, and technique is simple, is suitable for
Industrialized production;And sulfamic acid is cheap and easy to get, catalysis activity is high and consumption is few, good stability.
Detailed description of the invention
In order to be better understood from present disclosure, it is described further below in conjunction with specific embodiment, but specifically
Embodiment be not the restriction that present disclosure is done.
The preparation of embodiment 1-1:4-acetoxyl group aniline (7)
Paranitrophenol (9,1.0mol, 139.1g) joins in acetone 1000mL, adds triethylamine 151.8g
(1.5mol), room temperature dropping 196.3g chloroacetic chloride (2.5mol), drip off in 1h, back flow reaction 1 hour, naturally cool to room temperature,
Reactant liquor is poured in 2000g frozen water, stirring, filters, and filter cake washes with water, be vacuum dried p-nitrophenyl yl acetate (8) is thick
Product 183.2g.It is not required to be further purified, directly carries out next step reaction.
3000mL water and 3000mL ethanol are joined in reaction bulb, add under stirring reduced iron powder (139.6g,
2.5mol) with ammonium chloride (133.7g, 2.5mol), it is heated to reflux 1h, is dividedly in some parts above-mentioned obtained p-nitrophenyl guanidine-acetic acid
Ester (8,183.2g), after continuing back flow reaction 2h, TLC determines that reaction is completely.Stopped reaction, while hot sucking filtration, add in filtrate
2000mL dichloromethane, extraction, separate organic layer and wash with water (3 × 500mL), organic layer anhydrous sodium sulfate is dried.Sucking filtration,
Filtrate decompression rotation is evaporated off solvent and obtains light yellow solid, then with re-crystallizing in ethyl acetate, is dried, obtains 131.7g4-acetyloxy phenyl
Amine (7);Total recovery 86.7%.
The preparation of embodiment 1-2:4-acetoxyl group aniline (7)
Paranitrophenol (9,1.0mol, 139.1g) joins in acetone 1000mL, adds pyridine 158.2g (2mol), room
Temperature dropping 196.3g chloroacetic chloride (2.5mol), drips off in 1h, back flow reaction 3 hours, naturally cools to room temperature, and reactant liquor is poured into
In 2000g frozen water, stirring, filter, filter cake washes with water, is vacuum dried to obtain p-nitrophenyl yl acetate (8) crude product 187.5g.No
Need to be further purified, directly carry out next step reaction.
3000mL water and 3000mL ethanol are joined in reaction bulb, add under stirring reduced iron powder (195.5g,
3.5mol) with ammonium chloride (187.2g, 3.5mol), it is heated to reflux 1h, is dividedly in some parts the p-nitrophenyl that previous step reaction prepares
Acetas (8), after continuing back flow reaction 2h, TLC determines that reaction is completely.Stopped reaction, while hot sucking filtration, add 2000mL in filtrate
Dichloromethane, extraction, separate organic layer and wash with water (3 × 500mL), organic layer anhydrous sodium sulfate is dried.Sucking filtration, filtrate subtracts
Pressure rotation is evaporated off solvent and obtains light yellow solid, then with re-crystallizing in ethyl acetate, is dried, obtains 137.9g compound 7;Total recovery
90.7%.
The preparation of embodiment 2-1:5-acetoxyl group-2 methyl indole-3-carboxylic acid, ethyl ester (5)
2000mL dichloromethane is joined in reaction bulb, stirring lower addition 4-acetoxyl group aniline (7,120.9g,
0.8mol), add thermosol clear, add 104.1g ethyl acetoacetate (6,0.8mol) and catalyst indium bromide InBr3(8,2.8g,
0.008mol), after back flow reaction 2h, TLC determines that reaction is completely.Stopped reaction, while hot sucking filtration, filtrate decompression rotation is evaporated off solvent
Obtain enaminone intermediate 203.7g;Yield 96.7%.It is not required to be further purified, directly carries out next step reaction.
Above-mentioned enaminone intermediate 203.7g is equipped with in the reaction bulb of 2000mLDMF, is separately added under stirring
K2CO3(345.5g, 2.5mol), catalyst Pd (OAc)2(9g, 0.04mol) and oxidant Cu (OAc)2(480g, 2.4mol),
Being heated to 80 DEG C to react 3 hours, TLC determines that reaction is completely.Stopped reaction, reactant liquor is cooled under room temperature, stirring add water
3000mL, stands crystallize, sucking filtration, is dried, by recrystallizing methanol, obtains 5-acetoxyl group-2 methyl indole-3-after filter cake washing
Carboxylic acid, ethyl ester (5) 179.1g, total recovery 85.7%.
The preparation of embodiment 2-2:5-acetoxyl group-2 methyl indole-3-carboxylic acid, ethyl ester (5)
2000mL dichloromethane is joined in reaction bulb, stirring lower addition 4-acetoxyl group aniline (7,120.9g,
0.8mol), add thermosol clear, add 114.5g ethyl acetoacetate (6,0.88mol) and catalyst indium bromide InBr3(8,
14.2g, 0.04mol), after back flow reaction 3h, TLC determines that reaction is completely.Stopped reaction, while hot sucking filtration, filtrate decompression rotation is evaporated off
Solvent obtains enaminone intermediate 205.4g;Yield 97.5%.It is not required to be further purified, directly carries out next step reaction.
Above-mentioned enaminone intermediate is equipped with in the reaction bulb of 2000mLDMF, under stirring, is separately added into K2CO3
(276.4g, 2mol), catalyst Pd (OAc)2(18g, 0.08mol) and oxidant Cu (OAc)2(399.3g, 2mol), is heated to
100 DEG C are reacted 0.5 hour, and TLC determines that reaction is completely.Stopped reaction, reactant liquor is cooled under room temperature, stirring add water
3000mL, stands crystallize, sucking filtration, is dried, by recrystallizing methanol, obtains 5-acetoxyl group-2 methyl indole-3-after filter cake washing
Carboxylic acid, ethyl ester (5) 172.0g, total recovery 82.3%.
The preparation of embodiment 3-1:5-acetoxyl group-1,2-dimethyl indole-3-carboxylic acid, ethyl ester (4)
Add to, in DMF1500mL, add by 5-acetoxyl group-2 methyl indole-3-carboxylic acid, ethyl ester (5,156.7g, 0.6mol)
Enter Anhydrous potassium carbonate 138.2g (1mol), under stirring, be slowly added dropwise dimethyl sulfate 82g (0.65mol, liquid) in 100 DEG C, drip
Finishing insulation reaction 3 hours, reactant liquor is cooled to room temperature, and stirring is lower adds water 2000mL, stands crystallize, and sucking filtration, after filter cake washing
It is dried, by recrystallizing methanol, obtains 5-acetoxyl group-1,2-dimethyl indole-3-carboxylic acid, ethyl ester (4) 150g, yield 90.7%.
The preparation of embodiment 3-2:5-acetoxyl group-1,2-dimethyl indole-3-carboxylic acid, ethyl ester (4)
Add to, in DMF1500mL, add by 5-acetoxyl group-2 methyl indole-3-carboxylic acid, ethyl ester (5,156.7g, 0.6mol)
Enter Anhydrous potassium carbonate 165.8g (1.2mol), under stirring, be slowly added dropwise dimethyl sulfate 75.7g (0.6mol, liquid) in 100 DEG C,
Dripping complete insulation reaction 6 hours, reactant liquor is cooled to room temperature, and stirring is lower adds water 2000mL, stands crystallize, sucking filtration, and filter cake is washed
Rear dry, by recrystallizing methanol, obtain 5-acetoxyl group-1,2-dimethyl indole-3-carboxylic acid, ethyl ester (4) 152.8g, yield
92.5%.
The preparation of embodiment 4-1:1-methyl-2-(bromomethyl)-5-acetoxyl group-6-bromo indole-3-Ethyl formate (3)
By 137.6g5-acetoxyl group-1,2-dimethyl indole-3-carboxylic acid, ethyl ester (4,0.5mol) joins 1000mL chlorine
In Fang, stirring adds the benzoyl peroxide of catalytic amount to molten, is heated to reflux clearly, dropping 64.0mL bromine (200g,
1.25mol), dripping and finish, continue back flow reaction 3h, ice-water bath cooling reactant liquor, sucking filtration, filter cake washs with a small amount of methanol, by solid
It is dried, obtains 1-methyl-2-(bromomethyl)-5-acetoxyl group-6-bromo indole-3-Ethyl formate (3) 184.0g, yield: 85.0%.
The preparation of embodiment 4-2:1-methyl-2-(bromomethyl)-5-acetoxyl group-6-bromo indole-3-Ethyl formate (3)
By 137.6g5-acetoxyl group-1,2-dimethyl indole-3-carboxylic acid, ethyl ester (4,0.5mol) joins 1000mL chlorine
In Fang, stirring adds the benzoyl peroxide of catalytic amount to molten, is heated to reflux clearly, and dropping NBS (222.5g, 1.25mol) is dripped
Finishing, continue back flow reaction 8h, ice-water bath cooling reactant liquor, sucking filtration, filter cake washs with a small amount of methanol, is dried by solid, obtains 1-first
Base-2-(bromomethyl)-5-acetoxyl group-6-bromo indole-3-Ethyl formate (3) 180.8g, yield: 83.5%.
The preparation of embodiment 5-1:6-bromo-5-hydroxyl-1-methyl-2-(phenylthiomethyl) indole-3-carboxylic acid ethyl ester (2)
In 900mL methanol, add 30g sodium hydroxide (0.75mol), stir, obtain clear liquor, add 39.7g benzene sulfur
Phenol (0.36mol), after stirring 2h, adds 130g1-methyl-2-(bromomethyl)-5-acetoxyl group-6-bromo indole-3-formic acid second
Ester (3,0.3mol), stirs 3h, then with the most neutral with reactant liquor in acetic acid, has a large amount of solid to separate out, stand, sucking filtration, washing
Filter cake, by re-crystallizing in ethyl acetate, is dried, obtains 6-bromo-5-hydroxyl-1-methyl-2-(phenylthiomethyl) indole-3-carboxylic acid ethyl ester
(2) 114.5g, yield: 90.8%.
The preparation of embodiment 5-2:6-bromo-5-hydroxyl-1-methyl-2-(phenylthiomethyl) indole-3-carboxylic acid ethyl ester (2)
In 750mL methanol, add 30g sodium hydroxide (0.75mol), stir, obtain clear liquor, add 30.1g benzene sulfur
Phenol (0.3mol), after stirring 2h, adds 130g1-methyl-2-(bromomethyl)-5-acetoxyl group-6-bromo indole-3-formic acid second
Ester (3,0.3mol), stirs 6h, then with the most neutral with reactant liquor in acetic acid, has a large amount of solid to separate out, stand, sucking filtration, washing
Filter cake, by re-crystallizing in ethyl acetate, is dried, obtains 6-bromo-5-hydroxyl-1-methyl-2-(phenylthiomethyl) indole-3-carboxylic acid ethyl ester
(2) 110.3g, yield: 87.5%.
Embodiment 6-1: the preparation of arbidol HCl monohydrate
Reaction bulb is placed in ice-water bath, adds sulfamic acid 19.4g (0.2mol), 30% dimethylamine agueous solution 40.5mg
(0.3mol), then drip 37% formalin 22.5g (0.3mol), add water 1000mL, be finally dividedly in some parts 6-bromo-
5-hydroxyl-1-methyl-2-(phenylthiomethyl) indole-3-carboxylic acid ethyl ester (2,84.0g, 0.2mol), stirs at 30~40 DEG C
Reaction 3h, pours into reactant in a certain amount of frozen water, adjusts pH value more than 13 with 20% sodium hydroxide, and ice bath cools down, and crosses filter solid,
It is washed with distilled water to neutrality, through petrol ether/ethyl acetate mixed solvent recrystallization, obtains Abiduoer sterling.
Above-mentioned Abiduoer sterling adds acetone, stirring, controls reaction temperature 60 DEG C, is slowly added dropwise concentrated hydrochloric acid to pH1.0,
Dropping continues 30min, drips and reacts 2-3h after finishing, and cooling stands.Sucking filtration, obtains off-white color product.Above-mentioned white products is joined
In 95% ethanol 800mL, water 350mL solution, control temperature 25-30 DEG C, stir 1-2h, stand.Sucking filtration, is dried, obtains white solid
Body arbidol HCl monohydrate 91.3g (1), yield is 85.6%.Confirm that through nuclear-magnetism the product of synthesis produces consistent with target,
High-performance liquid chromatography detection level 99.7%.
Embodiment 6-2: the preparation of arbidol HCl monohydrate
Reaction bulb is placed in ice-water bath, adds sulfamic acid 23.3g (0.24mol), 30% dimethylamine agueous solution 32.5g
(0.24mol), then drip 37% formalin 18g (0.24mol), add water 1000mL, be finally dividedly in some parts 6-bromo-
5-hydroxyl-1-methyl-2-(phenylthiomethyl) indole-3-carboxylic acid ethyl ester (2,84.0g, 0.2mol), stirs at 30~40 DEG C
Reaction 3h, pours into reactant in a certain amount of frozen water, adjusts pH value more than 13 with 20% sodium hydroxide, and ice bath cools down, and crosses filter solid,
It is washed with distilled water to neutrality, through petrol ether/ethyl acetate mixed solvent recrystallization, obtains Abiduoer sterling.
Above-mentioned Abiduoer sterling adds acetone, stirring, controls reaction temperature 60 DEG C, is slowly added dropwise concentrated hydrochloric acid to pH1.0,
Dropping continues 30min, drips and reacts 2-3h after finishing, and cooling stands.Sucking filtration, obtains off-white color product.Above-mentioned white products is joined
In 95% ethanol 800mL, water 350mL solution, control temperature 25-30 DEG C, stir 1-2h, stand.Sucking filtration, is dried, obtains white solid
Body arbidol HCl monohydrate 89.2g (1), yield is 83.5%.Confirm that through nuclear-magnetism the product of synthesis produces consistent with target,
High-performance liquid chromatography detection level 99.6%.
Embodiment 6-3: the preparation of arbidol HCl monohydrate
Reaction bulb is placed in ice-water bath, adds sulfamic acid 19.4g (0.2mol), 30% dimethylamine agueous solution 48.6g
(0.36mol), then drip 37% formalin 27g (0.36mol), add water 1000mL, be finally dividedly in some parts 6-bromo-
5-hydroxyl-1-methyl-2-(phenylthiomethyl) indole-3-carboxylic acid ethyl ester (2,84.0g, 0.2mol), stirs at 30~40 DEG C
Reaction 3h, pours into reactant in a certain amount of frozen water, adjusts pH value more than 13 with 20% sodium hydroxide, and ice bath cools down, and crosses filter solid,
It is washed with distilled water to neutrality, through petrol ether/ethyl acetate mixed solvent recrystallization, obtains Abiduoer sterling.
Above-mentioned Abiduoer sterling adds acetone, stirring, controls reaction temperature 60 DEG C, is slowly added dropwise concentrated hydrochloric acid to pH1.0,
Dropping continues 30min, drips and reacts 2-3h after finishing, and cooling stands.Sucking filtration, obtains off-white color product.Above-mentioned white products is joined
In 95% ethanol 800mL, water 350mL solution, control temperature 25-30 DEG C, stir 1-2h, stand.Sucking filtration, is dried, obtains white solid
Body arbidol HCl monohydrate 86.1g (1), yield is 80.8%.Confirm that through nuclear-magnetism the product of synthesis produces consistent with target,
High-performance liquid chromatography detection level 99.8%.
Claims (10)
1. the preparation method of an arbidol HCl, it is characterised in that comprise the steps:
1) with paranitrophenol (9) as raw material, p-nitrophenyl yl acetate (8) is obtained through acetylation protection reaction;
2) p-nitrophenyl yl acetate (8) obtains 4-acetoxyl group aniline (7) through nitro-reduction reaction;
3) 4-acetoxyl group aniline (7) and ethyl acetoacetate (6) carry out indole ring and react and obtain 5-acetoxyl group-2-methyl Yin
Diindyl-3-carboxylic acid, ethyl ester (5);
4) 5-acetoxyl group-2 methyl indole-3-carboxylic acid, ethyl ester (5) carries out methylation reaction and obtains 5-acetoxyl group-1,2-two
Methylindole-3-carboxylic acid, ethyl ester (4);
5) 5-acetoxyl group-1,2-dimethyl indole-3-carboxylic acid, ethyl ester (4) carries out bromo-reaction and obtains 1-methyl-2-(bromine first
Base)-5-acetoxyl group-6-bromo indole-3-Ethyl formate (3);
6) 1-methyl-2-(bromomethyl)-5-acetoxyl group-6-bromo indole-3-Ethyl formate (3) carries out phenylmercaptan. and deprotection
Reaction obtains 6-bromo-5-hydroxyl-1-methyl-2-(phenylthiomethyl) indole-3-carboxylic acid ethyl ester (2);
7) 6-bromo-5-hydroxyl-1-methyl-2-(phenylthiomethyl) indole-3-carboxylic acid ethyl ester (2) carry out Mannich reaction obtain
Abiduoer, becomes salt to obtain arbidol HCl (1);Its synthetic route is as follows:
2. preparation method as claimed in claim 1, it is characterised in that: step 1) in, paranitrophenol (9) under base catalysis,
Carry out hydroxyl reaction with chloroacetic chloride or acetic anhydride and obtain p-nitrophenyl yl acetate (8);Described alkali is triethylamine, n-butylamine or pyrrole
Pyridine;Response time is 1-5 hour.
3. preparation method as claimed in claim 2, it is characterised in that: step 2) in, use ammonium chloride/reduced iron powder system to enter
Row nitro-reduction reaction, p-nitrophenyl yl acetate (8), reduced iron powder are 1.0:2.5~3.5:2.5 with the mol ratio of ammonium chloride
~3.5.
4. preparation method as claimed in claim 2, it is characterised in that: step 3) in, 4-acetoxyl group aniline (7) and acetyl second
Acetoacetic ester (6) is at indium bromide InBr3Catalysis under generate corresponding enaminone intermediate, reaction dissolvent is dichloromethane;Described
Enaminone intermediate is at alkali, catalyst Pd (OAc)2With oxidant Cu (OAc)2Carry out ring-closure reaction under effect and obtain 5-acetyl oxygen
Base-2 methyl indole-3-carboxylic acid, ethyl ester (5), described alkali is K2CO3Or K3PO4, reaction dissolvent is DMF.
5. preparation method as claimed in claim 4, it is characterised in that: step 3) in, 4-acetoxyl group aniline (7) and InBr3's
Reaction mol ratio is 1:0.01~0.05;4-acetoxyl group aniline (7), Pd (OAc)2、Cu(OAc)2With the reaction mol ratio of alkali it is
1:0.05~0.10:2.5~3.5:2.5~3.5.
6. preparation method as claimed in claim 1, it is characterised in that: step 4) in, 5-acetoxyl group-2 methyl indole-3-
Carboxylic acid, ethyl ester (5) carries out N-methylation reaction by dimethyl sulfate and prepares 5-acetoxyl group-1,2-dimethyl indole-3-carboxylic acid second
Ester (4);Reaction dissolvent is dimethylformamide;Response time is 2-6 hour.
7. preparation method as claimed in claim 1, it is characterised in that: step 5) in, the bromo examination used by described bromo-reaction
Agent is bromine or NBS;Reaction dissolvent is chloroform;Response time is 3-9 hour.
8. preparation method as claimed in claim 6, it is characterised in that: step 6) in, 1-methyl-2-(bromomethyl)-5-acetyl
Epoxide-6-bromo indole-3-Ethyl formate (3) is reacted with phenylmercaptan. in the basic conditions, prepares 6-bromo-5-hydroxyl-1-after acidifying
Methyl-2-(phenylthiomethyl) indole-3-carboxylic acid ethyl ester (2);Described alkali is potassium hydroxide or sodium hydroxide, and the response time is
1-6 hour.
9. preparation method as claimed in claim 1, it is characterised in that: step 7) in, use solid acid sulfamic acid to be catalyzed
Agent, 6-bromo-5-hydroxyl-1-methyl-2-(phenylthiomethyl) indole-3-carboxylic acid ethyl ester (2), formaldehyde, dimethylamine 3 component are water-soluble
Occurring Mannich reaction to obtain Abiduoer in liquid, reaction temperature is 30~40 DEG C, and the response time is 1-4 hour.
10. preparation method as claimed in claim 8, it is characterised in that: step 7) in, 6-bromo-5-hydroxyl-1-methyl-2-(benzene
Base sulfidomethyl) indole-3-carboxylic acid ethyl ester, dimethylamine, the reaction mol ratio of formaldehyde and sulfamic acid be 1:1.2~1.8:1.2~
1.8:1.0~1.2.
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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 |
CN111440188A (en) * | 2020-04-10 | 2020-07-24 | 江苏海悦康医药科技有限公司 | Preparation method of Relugol (Relugolix) key 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 |
CN112694432A (en) * | 2020-12-28 | 2021-04-23 | 浦拉司科技(上海)有限责任公司 | Preparation method of arbidol key intermediate |
CN114397375A (en) * | 2021-12-09 | 2022-04-26 | 石家庄四药有限公司 | Method for detecting related substances of arbidol hydrochloride intermediate |
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CN116003308A (en) * | 2022-12-27 | 2023-04-25 | 石家庄中硕制药有限公司 | Abidol crystallization process |
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