CN102675182B - 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 the preparation method of a kind of 1-of preparation (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 for the synthesis for the treatment of hyperplasia of prostate medicine silodosin (silodosin).
Background technology
Silodosin (silodosin) is a1 adrenoceptor antagonists, urethral smooth muscle is shunk and has selective inhibitory, and can reduce in urethra and press, and blood pressure is not had a significant impact, and is used for the treatment of benign prostatic hyperplasia.
1-(3-benzoyloxy propyl group)-5-(2-carbonyl propyl group)-7-itrile group indoline (being compound 8) is a key intermediate for the synthesis of silodosin.Japan patent of invention JP200199956 discloses a kind of synthetic route of this compound:
This synthetic route is that to take phenylformic acid (being compound 1) be raw material, makes 1-(3-benzoyloxy propyl group) indoline hydrochloride (being compound 2), and yield is 60.09%; Then on 5 of indoline, aldehyde radical makes compound 3, then reacts synthesizing nitryl propene compound 4 with nitroethane, and the yield of this two step is 69.83%; Then by sodium borohydride reduction ethylene linkage, make compound 5, yield is 99.65%; Aldehyde radical on 7 of indoline, makes compound 6 again, and yield is 80.6%; React with oxammonium hydrochloride and with acetic anhydride dehydration, make 7 itrile group compounds 7, yield is 62.56%; Last reaction with salt of wormwood and 30% hydrogen peroxide by chromatography column refined, and obtains compound 8, and yield is 59.71%.The total recovery that is blended into final compound 8 from compound 1 is only 29.95%.
The disadvantage of this route is that total recovery is very low, be only 30% less than, and synthesis step is many, need be refining through chromatography column, be therefore 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 steps is few, the preparation method of the 1-of low operation cost (3-benzoyloxy propyl group)-5-(2-carbonyl propyl group)-7-itrile group indoline.
For achieving the above object, the present invention has taked following technical scheme:
A preparation method for 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, preferably Br.
Further, in described 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, sodium carbonate, sodium bicarbonate or sodium hydride; Compound I, acid binding agent and with the mol ratio of the 3-bromine propoxy-of protecting group, be 1:(1～3): (1～2).
Further, in described 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 phosphorus oxychloride is 1:(1～3).
Further, in described 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 described 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 ammonium acetate; The mol ratio of compound IV and nitroethane is 1:(1～50).
Further, in described 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, preferably iron powder; Solvent is selected from methyl alcohol, ethanol or Glacial acetic acid; The mol ratio of compound V and reductive agent is 1:(1～5).
Further, in described step f, temperature of reaction is 80～150 ℃, and the reaction times is 15～24 hours; Solvent is selected from DMF, DMSO, toluene or dimethylbenzene; Cyanidization agent is sodium cyanide or cuprous cyanide, preferably cuprous cyanide; The mol ratio of compound VI and cyanidization agent is 1:(1～2).
According to preparation method's tool of 1-of the invention process (3-benzoyloxy propyl group)-5-(2-carbonyl propyl group)-7-itrile group indoline, have the following advantages:
(1), required supplementary material is the industrial chemicals of commercially available simple cheap, buying cost is low.
(2), compared with prior art, reactions steps is simplified, and simple to operate, yield is high.
Therefore, adopt present method greatly to reduce implementation cost, be conducive to realize suitability for industrialized production, there is extremely strong industrial application value.
Embodiment
Below with reference to embodiment, embodiments of the present invention are elaborated.Embodiments of the present invention are including, but not limited to following embodiment, and it should not be regarded as limiting the scope of the invention.
The method according to this invention is prepared 1-of the present invention (3-benzoyloxy propyl group)-5-(2-carbonyl propyl group)-7-itrile group indoline, comprises successively following 7 steps:
A, preparation 1-(3-benzoyloxy propyl group) indoline, i.e. Compound I I:
Example one: drop into 3-chloropropane benzoic ether 48g(0.24mol in flask), indoline (being Compound I) 24g(0.2mol), DMF100ml, triethylamine 24.5g;
Under 100 degrees Celsius, react cool to room temperature 12 hours;
In reaction mixture, add water, be extracted with ethyl acetate, by 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, obtain the hydrochloride 51g of compound ii, yield is 80%, liquid phase purity is 98%.
Example two: drop into 3-chloropropane benzoic ether 48g(0.24mol in flask), indoline (being Compound I) 24g(0.2mol), acetone 100ml, salt of wormwood 26g, sodium iodide 2.4g, back flow reaction 24 hours, cool to room temperature, add acetone 200ml, overanxious, the drip washing of 50ml acetone, filtrate proceeds in flask, stir agitation and dropping hydrochloric acid 20ml, stir one night crystallization, obtain the hydrochloride 53g of compound ii, yield is 83%, and liquid phase purity is 97%.
Or protecting group also can be benzyl, that is, reaction raw materials is: 3-chloropropane methyl-phenoxide 45g(0.24mol), all the other are constant, obtains the hydrochloride 47g of Compound I I after reaction, 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 phosphorus oxychloride 18.8ml, and about 10min dropwises;
Stir 30min, then drip 1-(3-benzoyloxy propyl group) indoline (being Compound I I) hydrochloride 31.8g, room temperature reaction 3 hours;
In reactant, add frozen water to stir 30min, add sodium carbonate neutralization and stir again 30min, be extracted with ethyl acetate;
Use successively sodium bicarbonate, water and salt water washing, Sodium sulfate anhydrous.min(99) is dry, concentrates to obtain brown crystallization 32.7g, and yield is 100%.
C, preparation 1-(3-benzoyloxy propyl group)-5-aldehyde radical-7-bromo indole quinoline, i.e. compound IV:
Example one: drop into 30.9g compound III, methylene dichloride 120ml, catalyzer aluminum chloride, at 0 ℃, add NBS 23.1g in batches;
Point plate after completion of the reaction, splashes into 300g frozen water, separates out solid, filters washing, dries to obtain compounds Ⅳ 35.3g, and yield is 91%, and liquid phase purity is 98%.
Example two: drop into 30.9g compound III, methyl alcohol 120ml, catalyst B F3.Et2O, at 0 ℃, drip bromine 29g;
Point plate after completion of the reaction, splashes into 300g frozen water, and sodium carbonate solution is adjusted to alkalescence, separates out solid, filters washing, dries to obtain compounds Ⅳ 34g, and yield is 90%, and liquid phase purity is 98%
D, preparation 1-(3-benzoyloxy propyl group)-5-(2-nitro propenyl)-7-bromo indole quinoline, i.e. compound V:
Example one: drop into 35.3g compound IV, ammonium acetate 7g, nitroethane 40ml, dehydrated alcohol 200ml;
Temperature rising reflux 8 hours, stirs the cooling solid of separating out, and filters and dries, and obtains 34.4g compound IV.Yield is 85%, and liquid phase purity is 95%.
Example 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 dehydrated alcohol 300ml, stirs the cooling solid of separating out, and filters and dries, and obtains 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:
Example one: drop into 22.3g EXAMPLE V, iron powder 6.5g, dehydrated alcohol 250ml, temperature rising reflux, drips concentrated hydrochloric acid 3g, back flow reaction 5 hours; Cooling, sodium carbonate is adjusted to alkalescence,
Cooling adds water, is then extracted with ethyl acetate, and organic layer is used saturated sodium bicarbonate solution and salt water washing successively, and Sodium sulfate anhydrous.min(99) is dry, the de-17g compound VI of doing to obtain, and yield is 82%.
Example two: drop into 22.3g EXAMPLE V, zinc powder 6.5g, acetic acid 50ml, temperature rising reflux 5 hours;
Cooling adds water, is then extracted with ethyl acetate, and organic layer is used saturated sodium bicarbonate solution and salt water washing successively, and Sodium sulfate anhydrous.min(99) is dry, the de-16.8g compound VI of doing to obtain, 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:
Example one: under nitrogen protection, drop into 20.8g compound VI, cuprous cyanide 5g, DMF50ml, temperature rising reflux 5 hours;
After treating to control raw material reaction in TLC, cooling adds 10% ammoniacal liquor, with EA, extracts;
Three times extremely nothing is blue with 10% ammonia scrubbing for organic layer, then uses salt water washing once, and Sodium sulfate anhydrous.min(99) is dry, filters, and precipitation is extremely done;
Add methyl tertiary butyl ether to pull an oar, filter, dry and to obtain 1-(3-benzoyloxy propyl group)-5-(2-carbonyl propyl group)-7-itrile group indoline (I) 15.4g.Yield is 85%.
Example two: under nitrogen protection, drop into 20.8g compound VI, the sub-sodium 2.5g of cyaniding, phase-transfer catalyst and toluene 180ml, temperature rising reflux 5 hours; After treating to control raw material reaction in TLC, cooling overanxious, filtrate adds 10% ammoniacal liquor; Three times extremely nothing is blue with 10% ammonia scrubbing for organic layer, then uses salt water washing once, and Sodium sulfate anhydrous.min(99) is dry, filters, and precipitation is extremely done;
Add methyl tertiary butyl ether to pull an oar, filter, dry and to obtain 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 is all higher than 80%, and generally higher than 90%, and reactions steps is few, and easy and simple to handle, implementation cost is cheap, is conducive to realize suitability for industrialized production, has extremely strong industrial application value.
Claims (10)
1. a preparation method for 1-(3-benzoyloxy propyl group)-5-(2-carbonyl propyl group)-7-itrile group indoline, is characterized in that: the method comprises following 6 steps successively:
Wherein, R is selected from benzoyl, halogen substituted benzoyl, benzyl or halogen substituted benzyl; X is selected from Cl, Br or I; The catalyzer of step c is selected from Zinc Chloride Anhydrous, aluminum chloride or BF3.Et2O; The catalyzer of steps d is ammonium acetate; The reductive agent of step e is selected from zinc powder or iron powder.
2. 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: 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: in described 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, sodium carbonate, sodium bicarbonate or sodium hydride;
Compound I, acid binding agent and with the mol ratio of the 3-bromine propoxy-of protecting group, be 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: in described 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 phosphorus oxychloride 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: in described 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;
The mol ratio of compound III, halogenating agent and catalyzer is 1:(1～1.5): (0.01～3).
6. 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: in described 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;
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: in described step e,
Temperature of reaction is 0～80 ℃, and the reaction times is 8～12 hours;
Solvent is selected from methyl alcohol, ethanol or Glacial acetic acid;
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, is characterized in that: described reductive agent is 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: in described step f,
Temperature of reaction is 80～150 ℃, and the reaction times is 15～24 hours;
Solvent is selected from DMF, DMSO, toluene or dimethylbenzene;
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, is characterized in that: described cyanidization agent is cuprous cyanide.
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