CN102786463A - Method for preparing 5-acetoxyl-3-indole carboxylic acid ethyl ester - Google Patents
Method for preparing 5-acetoxyl-3-indole carboxylic acid ethyl ester Download PDFInfo
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Abstract
A method for preparing 5-acetoxyl-3-indole carboxylic acid ethyl ester. The invention relates to a method for preparing the 5-acetoxyl-3-indole carboxylic acid ethyl ester which is a key intermediate of a widely-used antiviral drug Arbidol Hydrochloride. The method successively comprises the following steps that, by using 3-chlorine-4-nitrophenol as raw materials, phenolic hydroxyl groups are reacted with an acetylation reagent, then products obtained are subjected to a substitution reaction with sodium salt of malonate, and at last a hydrogenated cyclization reaction is carried out under pressurized conditions to get the 5-acetoxyl-3-indole carboxylic acid ethyl ester. The method provides a novel synthesizing route, and has advantages of concise steps, simple technology and cheap and easily-available raw materials. Each reaction step is relatively conventional operations and production cost can be effectively reduced.
Description
Technical field
The present invention relates to a kind of intermediates preparation of antiviral hydrochloric acid Ah Bi flower, be specifically related to the method for a kind of 5-of preparation acetoxy-3-indole-carboxylic acid ethyl ester.
Background technology
Hydrochloric acid Ah Bi flower (Arbidol Hydrochloride) is one type of broad-spectrum antiviral medicament by FSU's pharmaceutical chemistry research centre research and development; Chemistry 6-bromo-4-dimethylamino methyl by name-5-hydroxyl-1-methyl-2-(benzene thiomethyl)-1H-Indole-3-Carboxylic Acid carbethoxy hydrochloride; This medicine is Russian again Initial Public Offering in 1993; Medicinal is monohydrate; This medicine also has good antiviral activity except that having immunoregulation effect and interferon-induced effect, clinically be used to prevent and treat influenza and other acute viral respiratory tract infection.
The present main production technique of this medicine is similar, and the key distinction is the preparation method of its key intermediate 1-methyl-2-brooethyl-5-acetoxyl group-6-bromo-3-indole-carboxylic acid ethyl ester, mainly contains following two kinds:
One, paper " synthesizing of hydrochloric acid Ah Bi flower " (Chinese Journal of Pharmaceuticals, 2004; 35 (8), mentioning in 457-458) and adopting the amino ethyl crotonate of benzoquinone and 3-is raw material, passes through prepared in reaction such as cyclisation, protection, hydrocarbylation and bromination and obtains key intermediate 1-methyl-2-brooethyl-5-acetoxyl group-6-bromo-3-indole-carboxylic acid ethyl ester; This method operation is easy relatively, and yield is also better, but the pungency of the amino ethyl crotonate of the raw material 3-of its use is bigger; Production safety and workers ' health are had certain hidden danger, and domestic price is comparatively expensive, the three wastes that technology produces are more; Processing cost is big, directly causes production cost of products higher.
Two; Paper " 1-methyl-2-brooethyl-5-acetoxyl group-6-bromo-1H-Indole-3-Carboxylic Acid ethyl ester " (meticulous and specialty chemicals, 2007,15 (13); Mention 14-16) and also can adopt 3-methylamino--2-butylene acetoacetic ester and para benzoquinone to obtain key intermediate 1-methyl-2-brooethyl-5-acetoxyl group-6-bromo-3-indole-carboxylic acid ethyl ester through cyclisation, protection and bromination three-step reaction as raw material; This method uses the raw material that is easy to get to prepare 3-methylamino--2-butylene acetoacetic ester in advance, can effectively reduce cost, but wherein the cyclisation step yield is low excessively; Be merely 52%; Cause by product more, aftertreatment and separation and purification be difficulty comparatively, when having improved cost, has also influenced quality product.
Summary of the invention
The object of the present invention is to provide that a kind of equipment is simple, reaction conditions is comparatively gentle, be convenient to operate and the preparation method of the antiviral arbidol HCl midbody 5-acetoxy-3-indole-carboxylic acid ethyl ester of harmless environment.
The technical solution adopted for the present invention to solve the technical problems is:
The preparation method of a kind of 5-acetoxy-3-indole-carboxylic acid ethyl ester is characterized in that: the 5-acetoxy-3-indole-carboxylic acid ethyl ester with formula (I) expression obtains according to following steps:
As preferably, described alkaline environment is through adding yellow soda ash or salt of wormwood is realized in reaction system.
As preferably, this method comprises the steps:
A.2-the preparation of chloro-4-acetoxyl group oil of mirbane:
Weight ratio according to 1:2-10 in reactor drum adds 3-chloro-4-nitrophenols (II) and acetone, is adding yellow soda ash or salt of wormwood, is warming up to 40 ℃ and stirs 10 minutes; Dripping acetyl chloride under this temperature then, the add-on of Acetyl Chloride 98Min. be 3-chloro-4-nitrophenols (II) weight 0.45-0.50 doubly, drip the process control mixture temperature and be no more than 50 ℃; Remove heating unit after dropwising; Continued stirring reaction 4-6 hour, reaction finishes the afterreaction mixed solution and is poured in the frozen water, filters and collects the solid of separating out; Obtain bullion after the drying; Bullion is used recrystallizing methanol, and the consumption of methyl alcohol is 1-2 a times of 3-chloro-4-nitrophenols (II) weight, obtains 2-chloro-4-acetoxyl group oil of mirbane (III);
B.2-the preparation of (5-acetoxyl group-2-nitrophenyl) ethyl malonate:
2-chloro-4-acetoxyl group oil of mirbane (III) and ethyl malonate are dissolved in organic solvent respectively; The consumption of ethyl malonate is 0.74-0.90 a times of 2-chloro-4-acetoxyl group oil of mirbane (III) weight; In the mixture of ethyl malonate and organic solvent, adding content is the sodium hydride of 80% (weight); The add-on of sodium hydride be 2-chloro-4-acetoxyl group oil of mirbane (III) weight 0.13-0.17 doubly, finished the back stirring at room 2 hours, and then add the 2-chloro-4-acetoxyl group oil of mirbane (III) that before prepared and the mixed solution of organic solvent; The mixture that obtains under agitation is warming up to 90-100 ℃ of reaction 6-8 hour; After reaction finished, mixed solution was poured in the water, and the solid of separating out is 2-(5-acetoxyl group-2-nitrophenyl) ethyl malonate (IV) bullion; Drying is after ethyl alcohol recrystallization obtains elaboration 2-(5-acetoxyl group-2-nitrophenyl) ethyl malonate (IV);
C.5-the preparation of acetoxy-3-indole-carboxylic acid ethyl ester:
Weight ratio according to 1:10-20 in middle pressure hydrogenation reactor adds 2-(5-acetoxyl group-2-nitrophenyl) ethyl malonate (IV) and organic solvent, adds the palladium-carbon catalyst that content is 10% (weight) again, after stirring, and closed reactor; Be warming up to 50-55 ℃, feed hydrogen then, making reactor pressure is 3-5MPa; Keep being warming up to 70-75 ℃ under this pressure, under this temperature stirring reaction 6-8 hour, after reaction finishes; The emptying reactor drum, making it pressure is about 0.1MPa, opens reactor drum; Filtering recovering catalyst, filtrate decompression concentrates except that after desolvating and obtains the product bullion, i.e. 5-acetoxy-3-indole-carboxylic acid ethyl ester (I).
As preferably, the organic solvent in the steps A is DMF, and the organic solvent among the step C is absolute ethyl alcohol or anhydrous methanol.
As preferably, in the steps A, the add-on of said yellow soda ash be 3-chloro-4-nitrophenols (II) weight 0.61-0.68 doubly, the add-on of salt of wormwood be 3-chloro-4-nitrophenols (II) weight 0.79-0.88 doubly.
As preferably, this method specifically comprises the steps:
A.2-the preparation of chloro-4-acetoxyl group oil of mirbane:
Weight ratio according to 1:2-10 in reactor drum adds 3-chloro-4-nitrophenols (II) and acetone; Adding yellow soda ash or salt of wormwood; The add-on of yellow soda ash is 0.61-0.68 a times of 3-chloro-4-nitrophenols (II) weight, and the add-on of salt of wormwood is 0.79-0.88 a times of 3-chloro-4-nitrophenols (II) weight; Be warming up to 40 ℃ and stirred 10 minutes, dripping acetyl chloride under this temperature then, the add-on of Acetyl Chloride 98Min. be 3-chloro-4-nitrophenols (II) weight 0.45-0.50 doubly; Drip the process control mixture temperature and be no more than 50 ℃, remove heating unit after dropwising, continued stirring reaction 4-6 hour; Reaction finishes the afterreaction mixed solution and is poured in the frozen water; Filter and collect the solid of separating out, obtain bullion after the drying, bullion is used recrystallizing methanol; The consumption of methyl alcohol is 1-2 a times of 3-chloro-4-nitrophenols (II) weight, obtains 2-chloro-4-acetoxyl group oil of mirbane (III);
B.2-the preparation of (5-acetoxyl group-2-nitrophenyl) ethyl malonate:
Weight ratio according to 1:2 in reactor drum adds 2-chloro-4-acetoxyl group oil of mirbane (III) and DMF (N, dinethylformamide), and stirring at room evenly back is for use; In another reactor drum, add ethyl malonate and DMF, the add-on of ethyl malonate is 0.74-0.90 a times of 2-chloro-4-acetoxyl group oil of mirbane (III) weight, and the add-on of DMF is 4-8 a times of 2-chloro-4-acetoxyl group oil of mirbane (III) weight; Stir after finishing; Add content again and be 80% sodium hydride, the add-on of sodium hydride be 2-chloro-4-acetoxyl group oil of mirbane (III) weight 0.13-0.17 doubly, finished the back stirring at room 2 hours; And then add the 2-chloro-4-acetoxyl group oil of mirbane (III) before prepared and the solution of DMF; Mixture under agitation is warming up to 90-100 ℃ of reaction 6-8 hour then, and after reaction finished, mixed solution was poured in the water; The solid of separating out is 2-(5-acetoxyl group-2-nitrophenyl) ethyl malonate (IV) bullion; Drying is after ethyl alcohol recrystallization, consumption of ethanol be 2-chloro-4-acetoxyl group oil of mirbane (III) weight 1-2 doubly, obtain elaboration 2-(5-acetoxyl group-2-nitrophenyl) ethyl malonate (IV);
C.5-the preparation of acetoxy-3-indole-carboxylic acid ethyl ester:
In middle pressure hydrogenation reactor, add 2-(5-acetoxyl group-2-nitrophenyl) ethyl malonate (IV) and absolute ethyl alcohol or anhydrous methanol according to the weight ratio of 1:10-20, add content again and be 10% palladium-carbon catalyst, the add-on of palladium-carbon catalyst is 0.05-0.1 a times of 2-(5-acetoxyl group-2-nitrophenyl) ethyl malonate (IV) weight; After stirring, closed reactor is warming up to 50-55 ℃; Feed hydrogen then, making reactor pressure is 3-5MPa, keeps being warming up to 70-75 ℃ under this pressure; Under this temperature stirring reaction 6-8 hour, after reaction finishes, the emptying reactor drum; Making it pressure is about 0.1MPa, opens reactor drum, filtering recovering catalyst; Filtrate decompression concentrates except that after desolvating and obtains the product bullion, and through ethyl alcohol recrystallization, amount of ethanol is 2 times of 2-(5-acetoxyl group-2-nitrophenyl) ethyl malonate (IV) weight; Obtain elaboration, i.e. 5-acetoxy-3-indole-carboxylic acid ethyl ester (I).
The present invention proposes synthetic its midbody 5-acetoxy-3 of a new synthetic route-indole-carboxylic acid ethyl ester; This midbody can obtain key intermediate 1-methyl-2-brooethyl-5-acetoxyl group-6-bromo-3-indole-carboxylic acid ethyl ester through bromomethylation and bromination reaction again; And bromomethylation and bromination step all have comparatively sophisticated technology, and with the domestic 3-chloro-4-nitrophenols that is easy to get as raw material, through replacing and reduction is closed the ring two-step reaction and obtained 5-acetoxy-3-indole-carboxylic acid ethyl ester; Wherein reduction is closed and is pressed hydrogenation means single stage method to accomplish in the ring employing; Simplify the operation reduce cost in, the three wastes that also reduced whole technology produce, and almost do not have the generation of solid slag; Have only more tractable on a small quantity acid waste water to produce, meet the idea of Green Chemistry and Sustainable development.This method has that equipment is simple, reaction conditions is comparatively gentle, be convenient to operate and the advantage of harmless environment, is convenient to suitability for industrialized production.
Embodiment
Through specific embodiment, technical scheme of the present invention is further specified below.Should be appreciated that enforcement of the present invention is not limited to following embodiment, all will fall into protection domain of the present invention any pro forma accommodation and/or the change that the present invention made.
In the present invention, if not refer in particular to, all part, per-cents are weight unit, and all equipment and raw material etc. all can be buied from market or the industry is commonly used.
Embodiment 1
A.2-chloro-4-acetoxyl group oil of mirbane preparation
(173.5g 1.0mol) with acetone (1735g), after stirring, continues adding salt of wormwood (151.8g in reaction flask, to add 3-chloro-4-nitrophenols; 1.1mol), be warming up to 40 ℃ after finishing, stir after 10 minutes; Slowly to dripping acetyl chloride wherein (86.3g, 1.1mol), reaction mixture temperature is no more than 50 ℃ in the dropping process; Remove heating unit after dropwising, continued stirring reaction 6 hours, reaction finishes the back mixed solution and is poured in the frozen water; Separate out solid, filter and collect, the bullion 2-chloro-4-acetoxyl group oil of mirbane that obtains after the drying; Bullion obtains light yellow solid with 347g anhydrous methanol recrystallization, is 2-chloro-4-acetoxyl group oil of mirbane elaboration (207.9g), yield about 96.5%.
Fusing point: 67-68 ℃,
1H-NMR (CDCl
3): δ 2.29 (3H), 1.34-1.62 (4H), 7.45 (1H), 7.77 (1H), 8.19 (1H). MS (EI), m/z 217 (M+H).
B.2-the preparation of (5-acetoxyl group-2-nitrophenyl) ethyl malonate
In reaction flask, add ethyl malonate (192g, 1.2mol) and DMF (1724g), it is 80% sodium hydride (36g that the back that stirs adds content; 1.2mol), continue at room temperature to stir 2 hours, add the 2-chloro-4-acetoxyl group oil of mirbane (215.5g for preparing in advance then; 1.0mol) and the mixing solutions of DMF (431g), be warming up to 100 ℃ of stirring reactions after finishing 8 hours, after reaction finishes; Mixed solution is poured in the water; The solid of separating out is 2-(5-acetoxyl group-2-nitrophenyl) ethyl malonate bullion, obtains light yellow solid behind the bullion process 431g absolute ethyl alcohol recrystallization, is elaboration 2-(5-acetoxyl group-2-nitrophenyl) ethyl malonate (292.5g;), yield about 86.3%.
1H-NMR(CDCl
3):δ?1.31(6H),2.24(3H),4.11-4.15?(4H),5.34(1H),?7.35(1H)?,?7.59(1H),8.11(1H).?MS(EI),m/z?340(M+H)。
C.5-the preparation of acetoxy-3-indole-carboxylic acid ethyl ester
In middle pressure hydrogenation reactor, add 2-(5-acetoxyl group-2-nitrophenyl) ethyl malonate (339g, 1.0mol) and anhydrous methanol (6750g), stirring the back, to add content be 10% palladium-carbon catalyst (33.5g), after stirring; Closed reactor is warming up to 55 ℃, feeds hydrogen then; Making reactor pressure is 5MPa, keeps being warming up to 75 ℃ under this pressure, and stirring reaction is 8 hours under this temperature; After reaction finishes, the emptying reactor drum, making it pressure is about 0.1MPa; Open reactor drum, filtering recovering catalyst, filtrate decompression concentrates except that after desolvating and obtains 5-acetoxy-3-indole-carboxylic acid ethyl ester bullion; Bullion obtains the off-white color solid behind absolute ethyl alcohol (678g) recrystallization, be elaboration 5-acetoxy-3-indole-carboxylic acid ethyl ester (202.5g), yield about 82.0%.
1H-NMR(CDCl
3):δ?1.27(3H),2.25(3H),4.31-4.35(2H),7.34-7.43(2H),
8.22(1H),8.39(1H).?MS(EI),m/z?248(M+H)。
Embodiment 2
Other steps are identical with embodiment 1, and just the preparation method of the 2-chloro-4-acetoxyl group oil of mirbane of A step is following:
(173.5g 1.0mol) with acetone (350g), after stirring, continues adding salt of wormwood (138g in reaction flask, to add 3-chloro-4-nitrophenols; 1.0mol), be warming up to 40 ℃ after finishing, stir after 10 minutes; Slowly to dripping acetyl chloride wherein (78.5g, 1.0mol), reaction mixture temperature is no more than 50 ℃ in the dropping process; Remove heating unit after dropwising, continued stirring reaction 4 hours, reaction finishes the back mixed solution and is poured in the frozen water; Separate out solid, filter and collect, the bullion 2-chloro-4-acetoxyl group oil of mirbane that obtains after the drying; Bullion obtains light yellow solid with 347g anhydrous methanol recrystallization, is 2-chloro-4-acetoxyl group oil of mirbane elaboration (188.3g), yield about 87.4%.
Embodiment 3
Other steps are identical with embodiment 1, and just the preparation method of the 2-chloro-4-acetoxyl group oil of mirbane of A step is following:
(173.5g 1.0mol) with acetone (1000g), after stirring, continues adding salt of wormwood (145g in reaction flask, to add 3-chloro-4-nitrophenols; About 1.05mol), is warming up to 40 ℃ after finishing, stirs after 10 minutes; Slowly to dripping acetyl chloride (82.5g, about 1.05mol) wherein, reaction mixture temperature is no more than 50 ℃ in the dropping process; Remove heating unit after dropwising, continued stirring reaction 5 hours, reaction finishes the back mixed solution and is poured in the frozen water; Separate out solid, filter and collect, the bullion 2-chloro-4-acetoxyl group oil of mirbane that obtains after the drying; Bullion obtains light yellow solid with 347g anhydrous methanol recrystallization, is 2-chloro-4-acetoxyl group oil of mirbane elaboration (195.6g), yield about 90.8%.
Embodiment 4
Other steps are identical with embodiment 1, and just the preparation method of the 2-chloro-4-acetoxyl group oil of mirbane of A step is following:
(173.5g 1.0mol) with acetone (1700g), after stirring, continues adding yellow soda ash (116.6g in reaction flask, to add 3-chloro-4-nitrophenols; 1.1mol), be warming up to 40 ℃ after finishing, stir after 10 minutes; Slowly to dripping acetyl chloride wherein (86.3g, 1.1mol), reaction mixture temperature is no more than 50 ℃ in the dropping process; Remove heating unit after dropwising, continued stirring reaction 6 hours, reaction finishes the back mixed solution and is poured in the frozen water; Separate out solid, filter and collect, the bullion 2-chloro-4-acetoxyl group oil of mirbane that obtains after the drying; Bullion obtains light yellow solid with 347g anhydrous methanol recrystallization, is 2-chloro-4-acetoxyl group oil of mirbane elaboration (203.4g), yield about 94.4%.
Embodiment 5
Other steps are identical with embodiment 1, and just the preparation method of the 2-chloro-4-acetoxyl group oil of mirbane of A step is following:
(173.5g 1.0mol) with acetone (750g), after stirring, continues adding yellow soda ash (110.0g in reaction flask, to add 3-chloro-4-nitrophenols; About 1.04mol), is warming up to 40 ℃ after finishing, stirs after 10 minutes; Slowly to dripping acetyl chloride (83.0g, about 1.06mol) wherein, reaction mixture temperature is no more than 50 ℃ in the dropping process; Remove heating unit after dropwising, continued stirring reaction 5 hours, reaction finishes the back mixed solution and is poured in the frozen water; Separate out solid, filter and collect, the bullion 2-chloro-4-acetoxyl group oil of mirbane that obtains after the drying; Bullion obtains light yellow solid with 347g anhydrous methanol recrystallization, is 2-chloro-4-acetoxyl group oil of mirbane elaboration (191.1g), yield about 88.7%.
Embodiment 6
Other steps are identical with embodiment 1, and just the preparation method of 2-(5-acetoxyl group-2-nitrophenyl) ethyl malonate of B step is following:
In reaction flask, add ethyl malonate (160g, 1.0mol) and DMF (862g), it is 80% sodium hydride (30g that the back that stirs adds content; 1.0mol), continue at room temperature to stir 2 hours, add the 2-chloro-4-acetoxyl group oil of mirbane (215.5g for preparing in advance then; 1.0mol) and the mixing solutions of DMF (431g), be warming up to 90 ℃ of stirring reactions after finishing 6 hours, after reaction finishes; Mixed solution is poured in the water; The solid of separating out is 2-(5-acetoxyl group-2-nitrophenyl) ethyl malonate bullion, obtains light yellow solid behind the bullion process 431g absolute ethyl alcohol recrystallization, is elaboration 2-(5-acetoxyl group-2-nitrophenyl) ethyl malonate (271.3g;), yield about 80.0%.
Embodiment 7
Other steps are identical with embodiment 1, and just the preparation method of 2-(5-acetoxyl group-2-nitrophenyl) ethyl malonate of B step is following:
In reaction flask, add ethyl malonate (176g, 1.1mol) and DMF (1200g), it is 80% sodium hydride (33g that the back that stirs adds content; 1.1mol), continue at room temperature to stir 2 hours, add the 2-chloro-4-acetoxyl group oil of mirbane (215.5g for preparing in advance then; 1.0mol) and the mixing solutions of DMF (431g), be warming up to 95 ℃ of stirring reactions after finishing 7 hours, after reaction finishes; Mixed solution is poured in the water; The solid of separating out is 2-(5-acetoxyl group-2-nitrophenyl) ethyl malonate bullion, obtains light yellow solid behind the bullion process 431g absolute ethyl alcohol recrystallization, is elaboration 2-(5-acetoxyl group-2-nitrophenyl) ethyl malonate (288.6g;), yield about 85.1%.
Embodiment 8
Other steps are identical with embodiment 1, and just the preparation method of the 5-acetoxy-3-indole-carboxylic acid ethyl ester of C step is following:
In middle pressure hydrogenation reactor, add 2-(5-acetoxyl group-2-nitrophenyl) ethyl malonate (339g, 1.0mol) and anhydrous methanol (3400g), stirring the back, to add content be 10% palladium-carbon catalyst (17.0g), after stirring; Closed reactor is warming up to 50 ℃, feeds hydrogen then; Making reactor pressure is 3MPa, keeps being warming up to 70 ℃ under this pressure, and stirring reaction is 6 hours under this temperature; After reaction finishes, the emptying reactor drum, making it pressure is about 0.1MPa; Open reactor drum, filtering recovering catalyst, filtrate decompression concentrates except that after desolvating and obtains 5-acetoxy-3-indole-carboxylic acid ethyl ester bullion; Bullion obtains the off-white color solid behind absolute ethyl alcohol (678g) recrystallization, be elaboration 5-acetoxy-3-indole-carboxylic acid ethyl ester (178.4g), yield about 72.2%.
Embodiment 9
Other steps are identical with embodiment 1, and just the preparation method of the 5-acetoxy-3-indole-carboxylic acid ethyl ester of C step is following:
In middle pressure hydrogenation reactor, add 2-(5-acetoxyl group-2-nitrophenyl) ethyl malonate (339g, 1.0mol) and anhydrous methanol (5300g), stirring the back, to add content be 10% palladium-carbon catalyst (25.5g), after stirring; Closed reactor is warming up to 53 ℃, feeds hydrogen then; Making reactor pressure is 4MPa, keeps being warming up to 72 ℃ under this pressure, and stirring reaction is 7 hours under this temperature; After reaction finishes, the emptying reactor drum, making it pressure is about 0.1MPa; Open reactor drum, filtering recovering catalyst, filtrate decompression concentrates except that after desolvating and obtains 5-acetoxy-3-indole-carboxylic acid ethyl ester bullion; Bullion obtains the off-white color solid behind absolute ethyl alcohol (678g) recrystallization, be elaboration 5-acetoxy-3-indole-carboxylic acid ethyl ester (190.5g), yield about 77.1%.
Embodiment 10
Other steps are identical with embodiment 1, and just the preparation method of the 5-acetoxy-3-indole-carboxylic acid ethyl ester of C step is following:
In middle pressure hydrogenation reactor, add 2-(5-acetoxyl group-2-nitrophenyl) ethyl malonate (339g, 1.0mol) and absolute ethyl alcohol (6500g), stirring the back, to add content be 10% palladium-carbon catalyst (33.8g), after stirring; Closed reactor is warming up to 55 ℃, feeds hydrogen then; Making reactor pressure is 4.5MPa, keeps being warming up to 75 ℃ under this pressure, and stirring reaction is 8 hours under this temperature; After reaction finishes, the emptying reactor drum, making it pressure is about 0.1MPa; Open reactor drum, filtering recovering catalyst, filtrate decompression concentrates except that after desolvating and obtains 5-acetoxy-3-indole-carboxylic acid ethyl ester bullion; Bullion obtains the off-white color solid behind absolute ethyl alcohol (678g) recrystallization, be elaboration 5-acetoxy-3-indole-carboxylic acid ethyl ester (198.3g), yield about 80.3%.
Embodiment 11
Other steps are identical with embodiment 1, and just the preparation method of the 5-acetoxy-3-indole-carboxylic acid ethyl ester of C step is following:
In middle pressure hydrogenation reactor, add 2-(5-acetoxyl group-2-nitrophenyl) ethyl malonate (339g, 1.0mol) and absolute ethyl alcohol (3400g), stirring the back, to add content be 10% palladium-carbon catalyst (17.5g), after stirring; Closed reactor is warming up to 50 ℃, feeds hydrogen then; Making reactor pressure is 3MPa, keeps being warming up to 70 ℃ under this pressure, and stirring reaction is 6 hours under this temperature; After reaction finishes, the emptying reactor drum, making it pressure is about 0.1MPa; Open reactor drum, filtering recovering catalyst, filtrate decompression concentrates except that after desolvating and obtains 5-acetoxy-3-indole-carboxylic acid ethyl ester bullion; Bullion obtains the off-white color solid behind absolute ethyl alcohol (678g) recrystallization, be elaboration 5-acetoxy-3-indole-carboxylic acid ethyl ester (172.7g), yield about 69.9%.
Embodiment 12
Other steps are identical with embodiment 1, and just the preparation method of the 5-acetoxy-3-indole-carboxylic acid ethyl ester of C step is following:
In middle pressure hydrogenation reactor, add 2-(5-acetoxyl group-2-nitrophenyl) ethyl malonate (339g, 1.0mol) and absolute ethyl alcohol (5000g), stirring the back, to add content be 10% palladium-carbon catalyst (28.0g), after stirring; Closed reactor is warming up to 52 ℃, feeds hydrogen then; Making reactor pressure is 4MPa, keeps being warming up to 72 ℃ under this pressure, and stirring reaction is 7 hours under this temperature; After reaction finishes, the emptying reactor drum, making it pressure is about 0.1MPa; Open reactor drum, filtering recovering catalyst, filtrate decompression concentrates except that after desolvating and obtains 5-acetoxy-3-indole-carboxylic acid ethyl ester bullion; Bullion obtains the off-white color solid behind absolute ethyl alcohol (678g) recrystallization, be elaboration 5-acetoxy-3-indole-carboxylic acid ethyl ester (187.2g), yield about 75.8%.
Above-described embodiment is a kind of preferable scheme of the present invention, is not that the present invention is done any pro forma restriction, under the prerequisite that does not exceed the technical scheme that claim puts down in writing, also has other variant and remodeling.
Claims (7)
1. the preparation method of 5-acetoxy-3-indole-carboxylic acid ethyl ester is characterized in that: the 5-acetoxy-3-indole-carboxylic acid ethyl ester with formula (I) expression obtains according to following steps:
2. the preparation method of a kind of 5-acetoxy-3 according to claim 1-indole-carboxylic acid ethyl ester is characterized in that: described alkaline environment is through adding yellow soda ash or salt of wormwood realization in reaction system.
3. the preparation method of a kind of 5-acetoxy-3 according to claim 1 and 2-indole-carboxylic acid ethyl ester is characterized in that this method comprises the steps:
A.2-the preparation of chloro-4-acetoxyl group oil of mirbane:
Weight ratio according to 1:2-10 in reactor drum adds 3-chloro-4-nitrophenols (II) and acetone, is adding yellow soda ash or salt of wormwood, is warming up to 40 ℃ and stirs 10 minutes; Dripping acetyl chloride under this temperature then, the add-on of Acetyl Chloride 98Min. be 3-chloro-4-nitrophenols (II) weight 0.45-0.50 doubly, drip the process control mixture temperature and be no more than 50 ℃; Remove heating unit after dropwising; Continued stirring reaction 4-6 hour, reaction finishes the afterreaction mixed solution and is poured in the frozen water, filters and collects the solid of separating out; Obtain bullion after the drying; Bullion is used recrystallizing methanol, and the consumption of methyl alcohol is 1-2 a times of 3-chloro-4-nitrophenols (II) weight, obtains 2-chloro-4-acetoxyl group oil of mirbane (III);
B.2-the preparation of (5-acetoxyl group-2-nitrophenyl) ethyl malonate:
2-chloro-4-acetoxyl group oil of mirbane (III) and ethyl malonate are dissolved in organic solvent respectively; The consumption of ethyl malonate is 0.74-0.90 a times of 2-chloro-4-acetoxyl group oil of mirbane (III) weight; In the mixture of ethyl malonate and organic solvent, adding content is the sodium hydride of 80% (weight); The add-on of sodium hydride be 2-chloro-4-acetoxyl group oil of mirbane (III) weight 0.13-0.17 doubly, finished the back stirring at room 2 hours, and then add the 2-chloro-4-acetoxyl group oil of mirbane (III) that before prepared and the mixed solution of organic solvent; The mixture that obtains under agitation is warming up to 90-100 ℃ of reaction 6-8 hour; After reaction finished, mixed solution was poured in the water, and the solid of separating out is 2-(5-acetoxyl group-2-nitrophenyl) ethyl malonate (IV) bullion; Drying is after ethyl alcohol recrystallization obtains elaboration 2-(5-acetoxyl group-2-nitrophenyl) ethyl malonate (IV);
C.5-the preparation of acetoxy-3-indole-carboxylic acid ethyl ester:
Weight ratio according to 1:10-20 in middle pressure hydrogenation reactor adds 2-(5-acetoxyl group-2-nitrophenyl) ethyl malonate (IV) and organic solvent, adds the palladium-carbon catalyst that content is 10% (weight) again, after stirring, and closed reactor; Be warming up to 50-55 ℃, feed hydrogen then, making reactor pressure is 3-5MPa; Keep being warming up to 70-75 ℃ under this pressure, under this temperature stirring reaction 6-8 hour, after reaction finishes; The emptying reactor drum, making it pressure is about 0.1MPa, opens reactor drum; Filtering recovering catalyst, filtrate decompression concentrates except that after desolvating and obtains the product bullion, i.e. 5-acetoxy-3-indole-carboxylic acid ethyl ester (I).
4. the preparation method of a kind of 5-acetoxy-3 according to claim 3-indole-carboxylic acid ethyl ester, it is characterized in that: the organic solvent in the steps A is DMF, the organic solvent among the step C is absolute ethyl alcohol or anhydrous methanol.
5. the preparation method of a kind of 5-acetoxy-3 according to claim 3-indole-carboxylic acid ethyl ester; It is characterized in that: in the steps A; The add-on of said yellow soda ash is 0.61-0.68 a times of 3-chloro-4-nitrophenols (II) weight, and the add-on of salt of wormwood is 0.79-0.88 a times of 3-chloro-4-nitrophenols (II) weight.
6. the preparation method of a kind of 5-acetoxy-3 according to claim 4-indole-carboxylic acid ethyl ester; It is characterized in that: in the steps A; The add-on of said yellow soda ash is 0.61-0.68 a times of 3-chloro-4-nitrophenols (II) weight, and the add-on of salt of wormwood is 0.79-0.88 a times of 3-chloro-4-nitrophenols (II) weight.
7. the preparation method of a kind of 5-acetoxy-3 according to claim 1-indole-carboxylic acid ethyl ester is characterized in that this method specifically comprises the steps:
A.2-the preparation of chloro-4-acetoxyl group oil of mirbane:
Weight ratio according to 1:2-10 in reactor drum adds 3-chloro-4-nitrophenols (II) and acetone; Adding yellow soda ash or salt of wormwood; The add-on of yellow soda ash is 0.61-0.68 a times of 3-chloro-4-nitrophenols (II) weight, and the add-on of salt of wormwood is 0.79-0.88 a times of 3-chloro-4-nitrophenols (II) weight; Be warming up to 40 ℃ and stirred 10 minutes, dripping acetyl chloride under this temperature then, the add-on of Acetyl Chloride 98Min. be 3-chloro-4-nitrophenols (II) weight 0.45-0.50 doubly; Drip the process control mixture temperature and be no more than 50 ℃, remove heating unit after dropwising, continued stirring reaction 4-6 hour; Reaction finishes the afterreaction mixed solution and is poured in the frozen water; Filter and collect the solid of separating out, obtain bullion after the drying, bullion is used recrystallizing methanol; The consumption of methyl alcohol is 1-2 a times of 3-chloro-4-nitrophenols (II) weight, obtains 2-chloro-4-acetoxyl group oil of mirbane (III);
B.2-the preparation of (5-acetoxyl group-2-nitrophenyl) ethyl malonate:
Weight ratio according to 1:2 in reactor drum adds 2-chloro-4-acetoxyl group oil of mirbane (III) and DMF (N, dinethylformamide), and stirring at room evenly back is for use; In another reactor drum, add ethyl malonate and DMF, the add-on of ethyl malonate is 0.74-0.90 a times of 2-chloro-4-acetoxyl group oil of mirbane (III) weight, and the add-on of DMF is 4-8 a times of 2-chloro-4-acetoxyl group oil of mirbane (III) weight; Stir after finishing; Add content again and be 80% sodium hydride, the add-on of sodium hydride be 2-chloro-4-acetoxyl group oil of mirbane (III) weight 0.13-0.17 doubly, finished the back stirring at room 2 hours; And then add the 2-chloro-4-acetoxyl group oil of mirbane (III) before prepared and the solution of DMF; Mixture under agitation is warming up to 90-100 ℃ of reaction 6-8 hour then, and after reaction finished, mixed solution was poured in the water; The solid of separating out is 2-(5-acetoxyl group-2-nitrophenyl) ethyl malonate (IV) bullion; Drying is after ethyl alcohol recrystallization, consumption of ethanol be 2-chloro-4-acetoxyl group oil of mirbane (III) weight 1-2 doubly, obtain elaboration 2-(5-acetoxyl group-2-nitrophenyl) ethyl malonate (IV);
C.5-the preparation of acetoxy-3-indole-carboxylic acid ethyl ester:
In middle pressure hydrogenation reactor, add 2-(5-acetoxyl group-2-nitrophenyl) ethyl malonate (IV) and absolute ethyl alcohol or anhydrous methanol according to the weight ratio of 1:10-20, add content again and be 10% palladium-carbon catalyst, the add-on of palladium-carbon catalyst is 0.05-0.1 a times of 2-(5-acetoxyl group-2-nitrophenyl) ethyl malonate (IV) weight; After stirring, closed reactor is warming up to 50-55 ℃; Feed hydrogen then, making reactor pressure is 3-5MPa, keeps being warming up to 70-75 ℃ under this pressure; Under this temperature stirring reaction 6-8 hour, after reaction finishes, the emptying reactor drum; Making it pressure is about 0.1MPa, opens reactor drum, filtering recovering catalyst; Filtrate decompression concentrates except that after desolvating and obtains the product bullion, and through ethyl alcohol recrystallization, amount of ethanol is 2 times of 2-(5-acetoxyl group-2-nitrophenyl) ethyl malonate (IV) weight; Obtain elaboration, i.e. 5-acetoxy-3-indole-carboxylic acid ethyl ester (I).
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| CN1660807A (en) * | 2004-01-07 | 2005-08-31 | 沈阳药科大学 | New 5-hydroxy indole-3-ramification of carboxylic esters |
| CN1687033A (en) * | 2005-04-26 | 2005-10-26 | 武汉大学 | Medication for anti virus of respiratory tract and application |
| WO2006015191A2 (en) * | 2004-07-29 | 2006-02-09 | Threshold Pharmaceuticals, Inc. | Multicyclic lonidamine analogs |
| CN102351778A (en) * | 2011-08-17 | 2012-02-15 | 湖北华龙生物制药有限公司 | Preparation method of arbidol hydrochloride |
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| CN1660807A (en) * | 2004-01-07 | 2005-08-31 | 沈阳药科大学 | New 5-hydroxy indole-3-ramification of carboxylic esters |
| WO2006015191A2 (en) * | 2004-07-29 | 2006-02-09 | Threshold Pharmaceuticals, Inc. | Multicyclic lonidamine analogs |
| CN1687033A (en) * | 2005-04-26 | 2005-10-26 | 武汉大学 | Medication for anti virus of respiratory tract and application |
| CN102351778A (en) * | 2011-08-17 | 2012-02-15 | 湖北华龙生物制药有限公司 | Preparation method of arbidol hydrochloride |
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| CN109665985A (en) * | 2018-11-30 | 2019-04-23 | 中国科学院广州生物医药与健康研究院 | Polysubstituted Benzazole compounds and its application |
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