CN102675182A - Preparing method of 1-(3-benzoyloxy propyl)-5-(2-oxopropyl)-7-indolinecarbonitrile - Google Patents
Preparing method of 1-(3-benzoyloxy propyl)-5-(2-oxopropyl)-7-indolinecarbonitrile Download PDFInfo
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Abstract
The invention provides a preparing method of a key intermediate 1-(3-benzoyloxy propyl)-5-(2-oxopropyl)-7-indolinecarbonitrile for synthesizing Silodosin. Materials in the whole synthetic route are cheap and easy to obtain, reaction steps are few, the operation is simple, the operation cost is low, yield coefficients of all reaction steps are far higher than those of the existing synthetic route, the preparation method is quite suitable for industrial production and is provided with high industrial application values.
Description
Technical field
The present invention relates to a kind of preparation method of preparation 1-(3-benzoyloxy propyl group)-5-(2-carbonyl propyl group)-7-itrile group indoline; Wherein, 1-(3-benzoyloxy propyl group)-5-(2-carbonyl propyl group)-7-itrile group indoline is the key intermediate that is used for synthetic treatment hyperplasia of prostate medicine silodosin (silodosin).
Background technology
Silodosin (silodosin) is the a1 adrenoceptor antagonists, urethral smooth muscle is shunk have selective inhibitory, and can reduce in the urethra and press, and to not very big influence of blood pressure, be used to treat benign prostatic hyperplasia.
1-(3-benzoyloxy propyl group)-5-(2-carbonyl propyl group)-7-itrile group indoline (being compound 8) is a key intermediate that is used for synthetic silodosin.Japan patent of invention JP200199956 discloses a kind of synthetic route of this compound:
This synthetic route is to be raw material with phenylformic acid (being compound 1), makes 1-(3-benzoyloxy propyl group) indoline hydrochloride (being compound 2), and yield is 60.09%; Aldehyde radical makes compound 3 on 5 of indoline then, and with nitroethane reaction synthesizing nitryl propene compound 4, the yield in these two steps is 69.83% again; Make compound 5 with the sodium borohydride reduction ethylene linkage then, yield is 99.65%; Aldehyde radical on 7 of indoline makes compound 6 again, and yield is 80.6%; With the oxammonium hydrochloride reaction and with the acetic anhydride dehydration, make 7 itrile group compounds 7 again, yield is 62.56%; Last and salt of wormwood and the reaction of 30% ydrogen peroxide 50 be after chromatography column is refining, acquisition compound 8, and yield is 59.71%.The total recovery that is blended into final compound 8 from compound 1 is merely 29.95%.
The disadvantage of this route is that total recovery is very low, be merely 30% less than, and synthesis step is many, it is refining to need through chromatography column, therefore is not suitable for suitability for industrialized production.
Summary of the invention
The object of the present invention is to provide that a kind of yield is high, reactions step is few, the preparation method of 1-(3-benzoyloxy propyl group)-5-(2-carbonyl the propyl group)-7-itrile group indoline of low operation cost.
For achieving the above object, the present invention has taked following technical scheme:
The preparation method of a kind of 1-(3-benzoyloxy propyl group)-5-(2-carbonyl propyl group)-7-itrile group indoline comprises following 7 steps successively:
Wherein, R is selected from benzoyl-, halogen substituted benzoyl, benzyl or halogen substituted benzyl; X is selected from Cl, Br or I, preferred Br.
Further, among the said step a, temperature of reaction is 20～120 ℃, and the reaction times is 10～24 hours; Solvent is selected from DMF, DMSO, acetone or C1 ~ C4 lower alcohol; Acid binding agent is selected from triethylamine, diisopropylethylamine, salt of wormwood, yellow soda ash, sodium hydrogencarbonate or sodium hydride; The mol ratio of the 3-bromine propoxy-of compound I, acid binding agent and band protection base is 1: (1～3): (1～2).
Further, among the said step b, temperature of reaction is 0～80 ℃, the reaction times is 2～8 hours; Solvent is DMF; The mol ratio of compound I I and POCl3 is 1: (1～3).
Further, among the said step c, temperature of reaction is 0～100 ℃; Solvent is selected from methylene dichloride, ethylene dichloride, toluene, methyl alcohol or ethanol; Halogenating agent is selected from Cl
2, Br
2, NBS, NCS, C5H6Br2N2O2 or two chlordantoins; Catalyzer is selected from Zinc Chloride Anhydrous, aluminum chloride or BF3.Et2O; The mol ratio of compound III, halogenating agent and catalyzer is 1: (1～1.5): (0.01～3).
Further, in the said steps d, temperature of reaction is 0～120 ℃, the reaction times is 8～12 hours; Solvent is selected from anhydrous methanol, toluene or ethanol; Catalyzer is an ammonium acetate; The mol ratio of compound IV and nitroethane is 1: (1～50).
Further, among the said step e, temperature of reaction is 0～80 ℃, the reaction times is 8～12 hours; Reductive agent is selected from zinc powder, magnesium powder or iron powder, preferred iron powder; Solvent is selected from methyl alcohol, ethanol or Glacial acetic acid min. 99.5; The mol ratio of compound V and reductive agent is 1: (1～5).
Further, among the said step f, temperature of reaction is 80～150 ℃, the reaction times is 15～24 hours; Solvent is selected from DMF, DMSO, toluene or YLENE; Cyanidization agent is sodium cyanide or cuprous cyanide, preferred cuprous cyanide; The mol ratio of compound VI and cyanidization agent is 1: (1～2).
The preparation method of 1-(3-benzoyloxy propyl group)-5-(2-carbonyl propyl group)-7-itrile group indoline of implementing according to the present invention has following advantage:
(1), required supplementary material is the industrial chemicals of commercially available simple cheap, buying cost is low.
(2), compared with prior art, reactions step obtains simplifying, and simple to operate, yield is high.
Therefore, adopt present method to reduce implementation cost greatly, help realizing suitability for industrialized production, have extremely strong industrial application value.
Embodiment
Below will combine embodiment that embodiment of the present invention is elaborated.Embodiment of the present invention is including, but not limited to following embodiment, and it should not be regarded as the restriction to protection domain of the present invention.
Prepare 1-of the present invention (3-benzoyloxy propyl group)-5-(2-carbonyl propyl group)-7-itrile group indoline according to the method for the invention, comprise following 7 steps successively:
A, preparation 1-(3-benzoyloxy propyl group) indoline, i.e. compound I I:
Instance one: in flask, drop into 3-chloropropane benzoic ether 48g (0.24mol), indoline (being compound I) 24g (0.2mol), DMF100ml, triethylamine 24.5g;
Reacted 12 hours cool to room temperature down at 100 degrees centigrade;
In reaction mixture, add water, use ethyl acetate extraction, with organic layer water and saturated brine solution washing, Sodium sulfate anhydrous.min(99) is dry, and solvent is removed in underpressure distillation;
In residue, add acetone 350ml, agitation and dropping hydrochloric acid 20ml then, stir one night crystallization, promptly get the hydrochloride 51g of compound ii, yield is 80%, liquid phase purity is 98%.
Instance two: in flask, drop into 3-chloropropane benzoic ether 48g (0.24mol), indoline (being compound I) 24g (0.2mol), acetone 100ml, salt of wormwood 26g, Soiodin 2.4g, back flow reaction 24 hours, cool to room temperature; Add acetone 200ml, overanxious, the drip washing of 50ml acetone; Filtrating changes in the flask, stirs agitation and dropping hydrochloric acid 20ml, stir one night crystallization; Promptly get the hydrochloride 53g of compound ii, yield is 83%, and liquid phase purity is 97%.
Perhaps, the protection base also can be benzyl, that is, reaction raw materials is: 3-chloropropane methyl-phenoxide 45g (0.24mol), and all the other are constant, and the reaction back obtains the hydrochloride 47g of compound I I, and yield is 81, and liquid phase purity is 98%.
B, preparation 1-(3-benzoyloxy propyl group)-5-aldehyde radical indoline, i.e. compound III:
In reaction flask, drop into the DMF of 62.5ml, ice bath drips POCl3 18.8ml, and about 10min dropwises;
Stir 30min, drip 1-(3-benzoyloxy propyl group) indoline (being compound I I) hydrochloride 31.8g again, room temperature reaction 3 hours;
In reactant, add frozen water and stir 30min, add in the yellow soda ash and restir 30min, use ethyl acetate extraction;
Use sodium hydrogencarbonate, water and brine wash successively, Sodium sulfate anhydrous.min(99) is dry, concentrate brown crystallization 32.7g, yield is 100%.
C, preparation 1-(3-benzoyloxy propyl group)-5-aldehyde radical-7-bromo indole quinoline, i.e. compound IV:
Instance one: drop into 30.9g compound III, methylene dichloride 120ml, catalyzer aluminum chloride, under 0 ℃, add NBS 23.1g in batches;
After some plate reaction finishes, splash into the 300g frozen water, separate out solid, filter washing, dry compound IV 35.3g, yield is 91%, liquid phase purity is 98%.
Instance two: drop into 30.9g compound III, methyl alcohol 120ml, catalyst B F3.Et2O, under 0 ℃, drip bromine 29g;
After some plate reaction finishes, splash into the 300g frozen water, sodium carbonate solution transfers to alkalescence, separates out solid, filters washing, dry compound IV 34g, yield is 90%, liquid phase purity is 98%
D, preparation 1-(3-benzoyloxy propyl group)-5-(2-nitro propenyl)-7-bromo indole quinoline, i.e. compound V:
Instance one: drop into 35.3g compound IV, ammonium acetate 7g, nitroethane 40ml, absolute ethyl alcohol 200ml;
Temperature rising reflux 8 hours stirs cooling and separates out solid, filters and oven dry, obtains the 34.4g compound IV.Yield is 85%, and liquid phase purity is 95%.
Instance two: drop into 50g compound IV, ammonium acetate 10g, nitroethane 60ml, toluene 300ml;
Temperature rising reflux dehydration 10 hours, reclaim under reduced pressure toluene adds absolute ethyl alcohol 300ml, stirs cooling and separates out solid, filters and oven dry, obtains the 52g compound IV.Yield is 88%, and liquid phase purity is 95%.
E, preparation 1-(3-benzoyloxy propyl group)-5-(2-carbonyl propyl group)-7-bromo indole quinoline, i.e. compound VI:
Instance one: drop into 22.3g EXAMPLE V, iron powder 6.5g, absolute ethyl alcohol 250ml, temperature rising reflux drips concentrated hydrochloric acid 3g, back flow reaction 5 hours; Cooling, yellow soda ash transfers to alkalescence,
Cooling adds entry, uses ethyl acetate extraction then, and organic layer is used saturated sodium bicarbonate solution and brine wash successively, and Sodium sulfate anhydrous.min(99) is dry, takes off dried 17g compound VI, and yield is 82%.
Instance two: drop into 22.3g EXAMPLE V, zinc powder 6.5g, acetic acid 50ml, temperature rising reflux 5 hours;
Cooling adds entry, uses ethyl acetate extraction then, and organic layer is used saturated sodium bicarbonate solution and brine wash successively, and Sodium sulfate anhydrous.min(99) is dry, takes off dried 16.8g compound VI, and yield is 81%.
F, preparation 1-(3-benzoyloxy propyl group)-5-(2-carbonyl propyl group)-7-itrile group indoline, i.e. compound VI I:
Instance one: under nitrogen protection, drop into 20.8g compound VI, cuprous cyanide 5g, DMF50ml, temperature rising reflux 5 hours;
After treating that the control raw material reaction finishes among the TLC, cooling adds 10% ammoniacal liquor, extracts with EA;
Organic layer does not extremely have for three times blue with 10% ammonia scrubbing, again with brine wash once, Sodium sulfate anhydrous.min(99) is dry, filters, and precipitation is extremely done;
Add MTBE pull an oar, filter, dry 1-(3-benzoyloxy propyl group)-5-(2-carbonyl propyl group)-7-itrile group indoline (I) 15.4g.Yield is 85%.
Instance two: under nitrogen protection, drop into 20.8g compound VI, the inferior sodium 2.5g of cyaniding, phase-transfer catalyst and toluene 180ml, temperature rising reflux 5 hours; After treating among the TLC that the control raw material reaction finishes, cool off overanxious, filtrating adding 10% ammoniacal liquor; Organic layer does not extremely have for three times blue with 10% ammonia scrubbing, again with brine wash once, Sodium sulfate anhydrous.min(99) is dry, filters, and precipitation is extremely done;
Add MTBE pull an oar, filter, dry 1-(3-benzoyloxy propyl group)-5-(2-carbonyl propyl group)-7-itrile group indoline (I) 16g.Yield is 87%.
The productive rate of above-mentioned each step all is higher than 80%, generally is higher than 90%, and reactions step is few, and easy and simple to handle, implementation cost is cheap, helps realizing suitability for industrialized production, has extremely strong industrial application value.
Claims (10)
1. the preparation method of a 1-(3-benzoyloxy propyl group)-5-(2-carbonyl propyl group)-7-itrile group indoline, it is characterized in that: this method comprises following 7 steps successively:
Wherein, R is selected from benzoyl-, halogen substituted benzoyl, benzyl or halogen substituted benzyl; X is selected from Cl, Br or I.
2. the preparation method of 1-according to claim 1 (3-benzoyloxy propyl group)-5-(2-carbonyl propyl group)-7-itrile group indoline, it is characterized in that: X is Br.
3. the preparation method of 1-according to claim 1 (3-benzoyloxy propyl group)-5-(2-carbonyl propyl group)-7-itrile group indoline is characterized in that: among the said step a,
Temperature of reaction is 20～120 ℃, and the reaction times is 10～24 hours;
Solvent is selected from DMF, DMSO, acetone or C1 ~ C4 lower alcohol;
Acid binding agent is selected from triethylamine, diisopropylethylamine, salt of wormwood, yellow soda ash, sodium hydrogencarbonate or sodium hydride;
The mol ratio of the 3-bromine propoxy-of compound I, acid binding agent and band protection base is 1: (1～3): (1～2).
4. the preparation method of 1-according to claim 1 (3-benzoyloxy propyl group)-5-(2-carbonyl propyl group)-7-itrile group indoline is characterized in that: among the said step b,
Temperature of reaction is 0～80 ℃, and the reaction times is 2～8 hours;
Solvent is DMF;
The mol ratio of compound I I and POCl3 is 1: (1～3).
5. the preparation method of 1-according to claim 1 (3-benzoyloxy propyl group)-5-(2-carbonyl propyl group)-7-itrile group indoline is characterized in that: among the said step c,
Temperature of reaction is 0～100 ℃;
Solvent is selected from methylene dichloride, ethylene dichloride, toluene, methyl alcohol or ethanol;
Halogenating agent is selected from Cl
2, Br
2, NBS, NCS, C5H6Br2N2O2 or two chlordantoins;
Catalyzer is selected from Zinc Chloride Anhydrous, aluminum chloride or BF3.Et2O;
The mol ratio of compound III, halogenating agent and catalyzer is 1: (1～1.5): (0.01～3).
6. according to the preparation method of claim 1 or 6 described 1-(3-benzoyloxy propyl group)-5-(2-carbonyl propyl group)-7-itrile group indoline, it is characterized in that: in the said steps d,
Temperature of reaction is 0～120 ℃, and the reaction times is 8～12 hours;
Solvent is selected from anhydrous methanol, toluene or ethanol;
Catalyzer is an ammonium acetate;
The mol ratio of compound IV and nitroethane is 1: (1～50).
7. the preparation method of 1-according to claim 1 (3-benzoyloxy propyl group)-5-(2-carbonyl propyl group)-7-itrile group indoline is characterized in that: among the said step e,
Temperature of reaction is 0～80 ℃, and the reaction times is 8～12 hours;
Reductive agent is selected from zinc powder, magnesium powder or iron powder;
Solvent is selected from methyl alcohol, ethanol or Glacial acetic acid min. 99.5;
The mol ratio of compound V and reductive agent is 1: (1～5).
8. the preparation method of 1-according to claim 7 (3-benzoyloxy propyl group)-5-(2-carbonyl propyl group)-7-itrile group indoline, it is characterized in that: said reductive agent is an iron powder.
9. the preparation method of 1-according to claim 1 (3-benzoyloxy propyl group)-5-(2-carbonyl propyl group)-7-itrile group indoline is characterized in that: among the said step f,
Temperature of reaction is 80～150 ℃, and the reaction times is 15～24 hours;
Solvent is selected from DMF, DMSO, toluene or YLENE;
Cyanidization agent is sodium cyanide or cuprous cyanide;
The mol ratio of compound VI and cyanidization agent is 1: (1～2).
10. the preparation method of 1-according to claim 1 (3-benzoyloxy propyl group)-5-(2-carbonyl propyl group)-7-itrile group indoline, it is characterized in that: said cyanidization agent is a cuprous cyanide.
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| CN201210168732.2A CN102675182B (en) | 2012-05-24 | 2012-05-24 | Preparing method of 1-(3-benzoyloxy propyl)-5-(2-oxopropyl)-7-indolinecarbonitrile |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105102429A (en) * | 2013-04-09 | 2015-11-25 | 曼康德研究中心 | N-haloalkylindoline intermediates, process and use in preparation of silodosin and derivatives thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5387603A (en) * | 1992-12-02 | 1995-02-07 | Kissei Pharmaceutical Co., Ltd. | 1,5,7-trisubstituted indoline compounds and salts thereof |
| JP2001199956A (en) * | 2000-01-14 | 2001-07-24 | Kissei Pharmaceut Co Ltd | Method for producing optically active indoline derivative and intermediate for producing the derivative |
| JP2002265444A (en) * | 2001-03-08 | 2002-09-18 | Kissei Pharmaceut Co Ltd | 1-(3-benzyloxypropyl)-5-(2-substituted propyl) indoline derivative and method for using the same |
| CN101048376A (en) * | 2004-10-27 | 2007-10-03 | 橘生药品工业株式会社 | Indoline compound and process for producing the same |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5387603A (en) * | 1992-12-02 | 1995-02-07 | Kissei Pharmaceutical Co., Ltd. | 1,5,7-trisubstituted indoline compounds and salts thereof |
| JP2001199956A (en) * | 2000-01-14 | 2001-07-24 | Kissei Pharmaceut Co Ltd | Method for producing optically active indoline derivative and intermediate for producing the derivative |
| JP2002265444A (en) * | 2001-03-08 | 2002-09-18 | Kissei Pharmaceut Co Ltd | 1-(3-benzyloxypropyl)-5-(2-substituted propyl) indoline derivative and method for using the same |
| CN101048376A (en) * | 2004-10-27 | 2007-10-03 | 橘生药品工业株式会社 | Indoline compound and process for producing the same |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105102429A (en) * | 2013-04-09 | 2015-11-25 | 曼康德研究中心 | N-haloalkylindoline intermediates, process and use in preparation of silodosin and derivatives thereof |
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