CN114751852B - Preparation method of silodosin key intermediate - Google Patents
Preparation method of silodosin key intermediate Download PDFInfo
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Abstract
The invention discloses a preparation method of a silodosin key intermediate, and belongs to the technical field of drug synthesis. Indoline reacts with trichloroacetonitrile by a method of friedel-crafts reaction to obtain a compound 1; bromination gives compound 2; then 2- (3-bromopropyloxy) tetrahydro-2H-pyran is substituted to obtain a compound 3; then nucleophilic addition is carried out with (S) -epoxypropane or (R) -epoxypropane at ultralow temperature to obtain a compound 4; then carrying out a curtain coating reaction with phthalimide to obtain a compound 5 (configuration inversion) or esterifying with p-toluenesulfonyl chloride, and carrying out an inorganic base reaction with phthalimide potassium salt to obtain the compound 5; followed by reduction with hydrazine hydrate to give compound 6; followed by detetrahydropyran protection by p-toluenesulfonic acid to give compound 7; protection of amino Boc under basic conditions gives compound 8; esterifying with benzoyl chloride to obtain a compound 9; removing Boc protection with hydrochloric acid to obtain a compound 10; salifying with L-tartaric acid to give compound 11. Compared with the prior art, the invention avoids the synthesis of cyano and 5-amino at 7-position by Vilsmeier reaction, hydroxylamine oximation and acetic anhydride dehydration, and the introduction of nitro or reductive amination, and does not need to use Pd/Pt/Zn and other heavy metals; the continuous operation of the whole steps is increased, the production cost of the silodosin intermediate is greatly reduced, and the industrial mass production is facilitated.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of a silodosin key intermediate.
Background
Silodosin is an α1a receptor antagonist developed by Kissei pharmaceutical company in japan and is marketed in japan in month 5 of 2006 under the trade name uiief. Silodosin is clinically used to treat symptoms associated with Benign Prostatic Hyperplasia (BPH) or hypertrophy. Most of the preparation of silodosin is capsule preparation, and the U.S. food and drug administration approves the market in 2008.
The key intermediate 5- [2 (R) -aminopropyl ] -1- [3- (benzoyloxy) propyl ] -7-cyano-indoline tartrate of silodosin is characterized in that the current synthesis method is mainly characterized in that the 7-cyano group and the 5-chiral aminopropyl group respectively, but the synthesis of cyano groups at the 7-position through Vilsmeier reaction, hydroxylamine oximation and acetic anhydride dehydration and the synthesis of the key intermediate of silodosin at the 5-position through amino acid substitution, sodium azide substitution, nitro reduction or L-tartaric acid resolution are almost unavoidable. However, such a method has more or less large-scale production safety problems (such as cyano synthesis at position 7 through Vilsmeier reaction, hydroxylamine oximation and acetic anhydride dehydration, hydrocyanic acid generation during dehydration), and also can use some explosive sodium azide or be catalyzed by Pd and other heavy metals, so that the product has more or less heavy metal residues, and the like.
The invention obtains a reaction route which is convenient to operate, provides better, mild, safe and stable through deep research and optimization of the compound, does not need reagents or chemical reactions which are safe and unfavorable for production, avoids the reduction reaction by heavy metals through product quality consideration, skillfully designs and introduces chiral alcohol, obtains reduced amine through a series of reactions, and therefore, diastereoisomeric salt is not required to be separated out by crystallization of L-tartaric acid, and the atom utilization rate is low.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a preparation method of a key intermediate 5- [2- (R) -aminopropyl ] -1- [3- (benzoyloxy) propyl ] -7-cyano-indoline tartrate, which is simple and stable in operation, high in atom utilization rate, environment-friendly, low in production cost and suitable for industrial mass production of silodosin.
The invention provides a preparation method of 5- [2 (R) -aminopropyl ] -1- [3- (benzoyloxy) propyl ] -7 cyano-indoline tartrate, which comprises the following steps: indoline reacts with trichloroacetonitrile by a method of friedel-crafts reaction to obtain a compound 1; bromination gives compound 2; then 2- (3-bromopropyloxy) tetrahydro-2H-pyran is substituted to obtain a compound 3; then nucleophilic addition is carried out with (S) -epoxypropane or (R) -epoxypropane at ultralow temperature to obtain a compound 4; then carrying out a curtain coating reaction with phthalimide to obtain a compound 5 (configuration inversion) or esterifying with p-toluenesulfonyl chloride, and carrying out an inorganic base reaction with phthalimide potassium salt to obtain the compound 5; followed by reduction with hydrazine hydrate to give compound 6; followed by detetrahydropyran protection by p-toluenesulfonic acid to give compound 7; protection of amino Boc under basic conditions gives compound 8; esterifying with benzoyl chloride to obtain a compound 9; removing Boc protection with hydrochloric acid to obtain a compound 10; salifying with L-tartaric acid to give compound 11. The reaction equation is as follows:
further, in the above technical scheme, the reaction process specifically includes the following steps:
the first step: reflux-reacting indoline with boron trichloride/toluene solution, cooling to 50-60 ℃, adding trichloroacetonitrile for reaction overnight, quenching with methanol, filtering to obtain an intermediate, dissolving the intermediate in dichloromethane, adding sodium methoxide/methanol solution for dissociation, and crystallizing to obtain 7-cyano indoline;
and a second step of: dissolving 7-cyanoindoline in an organic solvent, adding NBS in batches to react to obtain 5-bromo-7-cyanoindoline, then reacting with 2- (3-bromopropyloxy) tetrahydro-2H-pyran and inorganic base in an acetonitrile solvent, and recrystallizing to obtain 5-bromo-7-cyano-1- (3- (propoxytetrahydropyran) indoline;
and a third step of: mixing 5-bromo-7-cyano-1- (3- (propoxytetrahydro-pyran) indoline) with tetrahydrofuran, cooling, dropwise adding n-butyllithium solution, dropwise adding (S/R) -propylene oxide and boron trifluoride-diethyl ether solution to obtain a compound 4, carrying out a curtain coating reaction with phthalimide or p-toluenesulfonyl chloride, and substituting with phthalimide potassium salt to obtain 5-R- (2- (1, 3-dioxoisoindoline-2-yl) propyl) -1- (3- (propoxytetrahydro-pyran) -7-cyano-indoline;
fourth step: 5-R- (2- (1, 3-dioxoisoindolin-2-yl) propyl) -1- (3- (propoxytetrahydropyran) -7 cyano-indoline 1eq is mixed with hydrazine hydrate 40eq and tetrahydrofuran and then heated to 70 ℃ for reflux reaction to obtain 5- ((R) -2-aminopropyl) -1- (3- (propoxytetrahydropyran) -7-cyano) indoline, then the 5- ((R) -2-aminopropyl) -1- (3- (propoxytetrahydropyran) -7-cyano) indoline is reacted with 3eq of p-toluenesulfonic acid in methanol to obtain a compound 7, the compound 7 is dissolved in tetrahydrofuran, 2.3eq of sodium carbonate aqueous solution is added at 0 ℃, boc2O 1.2eq is added to obtain a compound 8, then the compound 8 is mixed with benzoyl chloride 1.1eq and dichloromethane, triethylamine 2.1eq is added dropwise at-20 ℃ for reaction to obtain a compound 9, and then deprotection is carried out at 0 ℃ in ethyl acetate/hydrogen chloride to obtain 5- [2 (R) -aminopropyl ] -1- [3- (benzoyloxy) propyl ] -7 cyano-indoline;
fifth step: 5- [2 (R) -aminopropyl ] -1- [3- (benzoyloxy) propyl ] -7 cyano-indoline, fumaric acid and methanol are mixed, heated and refluxed to form a salt, cooled to room temperature and filtered to obtain 5- [2 (R) -aminopropyl ] -1- [3- (benzoyloxy) propyl ] -7 cyano-indoline tartrate.
Further, in the above technical scheme, in the first step, the molar ratio of indoline, boron trichloride to trichloroacetonitrile is 1:1-1.12:1.2-1.5.
Further, in the above technical scheme, in the second step, the molar ratio of 7-cyanoindoline, NBS to 2- (3-bromopropyloxy) tetrahydro-2H-pyran is 1:1-1.05:1-1.1, the recrystallization solvent is selected from ethyl acetate and petroleum ether.
Further, in the above technical scheme, in the third step, the molar ratio of the 5-bromo-7-cyano-1- (3- (propoxytetrahydropyran) indoline), n-butyllithium, (S/R) -propylene oxide to boron trifluoride diethyl etherate is 1:1.0-1.2:1.2-1.5:1.2-1.5.
Further, in the above technical scheme, in the third step, the molar ratio of the compound 4 (S), triphenylphosphine, phthalimide and the activating agent is 1:1.2-1.5:1.2-1.5:1.2-1.5, wherein the activating agent is selected from DIAD or DEAD.
Further, in the above technical scheme, in the third step, the molar ratio of the compound 4 (R), p-toluenesulfonyl chloride, phthalimide potassium salt to inorganic base is 1:1.0-1.2:1.2-1.5:5.0-6.0.
Further, in the above technical scheme, in the fourth step, the molar ratio of 5-R- (2- (1, 3-dioxoisoindolin-2-yl) propyl) -1- (3- (propoxytetrahydropyran) -7 cyano-indoline to hydrazine hydrate is 1:20-50, and the molar ratio of 5- ((R) -2-aminopropyl) -1- (3- (propoxytetrahydropyran) -7-cyano) indoline to p-toluenesulfonic acid is 1:2-3.
Further, in the above technical scheme, in the fourth step, the molar ratio of the compound 7, sodium carbonate to Boc2O is 1:2-2.3:1.2-1.5; compound 8, benzoyl chloride to triethylamine molar ratio 1:1-1.2:2-2.5.
Further, in the above technical scheme, the molar ratio of the compound 10 to fumaric acid in the fifth step is 1:1.
the invention has the beneficial effects that:
the process has the advantages that raw materials are easy to obtain, the yield is relatively high, the environment is friendly, compared with the existing process, the cyano group is prevented from being synthesized at the 7 th position through Vilsmeier reaction, hydroxylamine oximation and acetic anhydride dehydration, and safety accidents caused by the generation of trace HCN in the phosphorus-containing wastewater and dehydration process are removed; the low utilization rate of the split atoms of the L-tartaric acid is avoided; simultaneously, the introduction of 5-amino through nitro or reductive amination is avoided; avoids the application of Pd/Pt/Zn and other heavy metals, and ensures that the product has no heavy metal residue. The optimized integral steps are continuous in operation, so that the time cost and the production cost of the traditional silodosin intermediate are greatly reduced, and the industrial mass production is facilitated.
Detailed Description
The invention will be further illustrated with reference to specific examples. These examples should be construed as merely illustrative of the present invention and not limiting the scope of the present invention. Various changes and modifications to the present invention may be made by one skilled in the art after reading the description herein, and such equivalent changes and modifications are intended to fall within the scope of the present invention as defined in the appended claims.
Example 1 the first step: synthesis of 7-cyanoindoline
50L of 1M BCl3/toluene solution is added into a 200L reaction kettle, 20L of toluene/5.3 Kg indoline solution is added dropwise, and after uniform mixing, reflux reaction is carried out for 1 hour; then cooling to 60 ℃, slowly adding 7.72Kg CCl3CN, controlling the temperature to 60 ℃ and stirring for reaction overnight; cooling to 10deg.C, slowly adding 30L methanol, quenching, filtering to obtain reaction intermediate (which can not be stored in air for a long time, and can be easily decomposed after moisture absorption, and can be stored under vacuum and nitrogen filling, if necessary), mixing the intermediate with 150L dichloromethaneAdding the mixture into a 500L reaction kettle, and adding 18Kg of 30% sodium methoxide solution at a temperature of not more than 25 ℃. After the reaction is completed, 100L of water is added, the mixture is kept still for layering, 50L of dichloromethane in the upper water phase is washed twice, the organic phases are combined and concentrated until no liquid flows, 50L of petroleum ether is added, crystallization is carried out in an ice bath at the temperature of minus 5 ℃, and 3.82Kg of 7-cyano indoline and light earthy yellow solid are obtained after filtration and drying. 1 H NMR (400 MHz, CDCl 3) delta 7.18 (d, J=7.3, 1.4Hz, 1H), 7.15-7.08 (m, 1H), 6.60 (t, J=7.6 Hz, 1H), 3.69 (t, J=8.6 Hz, 2H), 3.08 (t, J=8.4 Hz, 2H). In the BCl3 catalyst system, 0.89mol (0.02 eq) of B (C6F 5) 3 catalyst was additionally added to form a mixed catalyst, 5.57Kg of 7-cyanoindoline was obtained after the reaction treatment.
Example 2
And a second step of: synthesis of 5-bromo-7-cyano-1- (3- (propoxytetrahydropyran) indoline
To a 200L reactor, 3.82Kg of Compound 1 and 50L of dichloromethane were added, 4.95Kg of NBS was added in portions at 0-5℃and the mixture was stirred at room temperature for 1 hour, and 40L of aqueous liquid was added to keep an organic phase. The organic phases were combined by extraction with dichloromethane and washed with 50L of 5% aqueous sodium bicarbonate. The organic phase was distilled under reduced pressure until no liquid was obtained, 45L of acetonitrile and 3.18Kg of sodium hydroxide were added, the temperature was raised to 45℃and a mixture of 20L of acetonitrile/2- (3-bromopropyloxy) tetrahydro-2H-pyran 6.71Kg was slowly added dropwise thereto, and the mixture was stirred and heated to reflux for reaction for 5 hours. Cooling to room temperature, adding saturated ammonium chloride solution into the reaction solution, concentrating under reduced pressure, extracting with ethyl acetate for three times, and mixing organic phases. Concentrating under reduced pressure until no fluid is obtained, and recrystallizing with ethyl acetate/petroleum ether to obtain 6.976Kg of 5-bromo-7-cyano-1- (3- (propoxytetrahydropyran) indoline with yield of 72.3% and HPLC of 98.9%. 1 H NMR(400MHz,CDCl3)δ7.17(d,J＝2.0Hz,1H),7.10(d,J＝1.9Hz,1H),3.83(tt,J＝7.2,4.9Hz,2H),3.75-3.53(m,4H),3.49(dt,J＝10.2,6.2Hz,2H),2.95(t,J＝8.8Hz,2H),1.92(t,J＝6.8Hz,2H),1.78(ddd,J＝12.7,7.5,2.8Hz,2H),1.68(ddd,J＝12.1,7.6,4.4Hz,2H),1.61-1.41(m,4H),0.83(dt,J＝13.6,8.2Hz,2H).
Example 3
And a second step of: synthesis of 5-bromo-7-cyano-1- (3- (propoxytetrahydropyran) indoline
To a 200L reaction vessel, 3.82Kg of Compound 1 and 32L of acetonitrile were added, 4.95Kg of NBS was added in portions at 0-5℃and then the mixture was warmed to room temperature and stirred for reaction for 1 hour. Adding 40L of water, distilling under reduced pressure to evaporate most acetonitrile, cooling to 20-25 ℃, filtering a filter cake, leaching with water, and drying to obtain an organic phase till no liquid flows. Then, 50L of acetonitrile and 12.82Kg of potassium carbonate were added and heated to 45-55℃and 20L of acetonitrile/2- (3-bromopropyloxy) tetrahydro-2H-pyran 6.71Kg of a mixture was slowly added dropwise and heated to reflux with stirring for 8 hours. Cooling to room temperature, adding 60L of water to the reaction solution, concentrating under reduced pressure, extracting with ethyl acetate three times, and combining organic phases. Concentrating under reduced pressure until no fluid is obtained, and recrystallizing ethyl acetate/petroleum ether to obtain 7.27Kg of 5-bromo-7-cyano-1- (3- (propoxytetrahydro pyran) indoline with a yield of 75.4% and an HPLC of 95.7%.
Example 4
And a third step of: synthesis of 5-R- (2- (1, 3-dioxoisoindolin-2-yl) propyl) -1- (3- (propoxytetrahydropyran) -7 cyano-indoline
50L of tetrahydrofuran and 6.719Kg of Compound 3 were added to a 200L stainless steel reaction vessel under nitrogen. The reaction kettle is cooled to-75 ℃, and 8.1L of 2.5mol/L n-butyllithium solution is added dropwise. After the completion of the dropwise addition, the reaction was stirred at a constant temperature for 0.5 hour. 1.63Kg of tetrahydrofuran solution containing propylene oxide/10L and 3.93Kg of boron trifluoride diethyl etherate solution are added dropwise, and the reaction is carried out for 1 hour under heat preservation and stirring. Slowly heating to-55 deg.C, and quenching with saturated ammonium chloride solution.
The quenched solution was extracted with ethyl acetate, and the organic phase was dried and concentrated to give a crude solid, which was added with 70L of tetrahydrofuran, 6.29Kg of triphenylphosphine and 3.53Kg of phthalimide. Slowly dripping at 0deg.CTetrahydrofuran was dissolved/DIAD 4.85Kg, and the reaction was continued with stirring for 2 hours after the completion of the dropwise addition. The saturated ammonium chloride solution was quenched, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to give an oily solid. Purifying by silica gel column chromatography, wherein the mobile phase is PE: ea=5: 1, 5-R- (2- (1, 3-dioxoisoindolin-2-yl) propyl) -1- (3- (propoxytetrahydropyran) -7-cyano-indoline 4.124Kg was obtained as a yellow solid in 47.2% yield. 1 H NMR(400MHz,CDCl3)δ7.78(dt,J＝7.0,3.5Hz,2H),7.69(dd,J＝5.4,3.0Hz,2H),6.97(s,1H),6.90(s,1H),4.56(d,J＝4.1Hz,1H),4.55-4.45(m,1H),3.84(dt,J＝10.2,6.2Hz,2H),3.63(dt,J＝16.2,7.3Hz,2H),3.58-3.45(m,4H),3.14(dd,J＝13.9,9.1Hz,1H),2.90(dt,J＝17.0,7.9Hz,3H),1.91(p,J＝6.8Hz,2H),1.82(td,J＝10.1,9.5,6.3Hz,1H),1.75-1.65(m,2H),1.55(dd,J＝15.2,5.7Hz,3H),1.48(d,J＝6.9Hz,3H).
Example 5
And a third step of: synthesis of 5-R- (2- (1, 3-dioxoisoindolin-2-yl) propyl) -1- (3- (propoxytetrahydropyran) -7 cyano-indoline
50L of tetrahydrofuran and 6.719Kg of Compound 3 were added to a 200L stainless steel reaction vessel under nitrogen. The reaction vessel was cooled to-70 ℃. 8.1L of a 2.5mol/L n-butyllithium solution was added dropwise. After the completion of the dropwise addition, the reaction was stirred at a constant temperature for 0.5 hour. 1.63Kg of propylene oxide-containing tetrahydrofuran solution and 3.93Kg of boron trifluoride-diethyl ether solution were added dropwise, followed by stirring under heat preservation for reaction for 1 hour. Slowly heating to-55 deg.C, and quenching with saturated ammonium chloride solution. Ethyl acetate extraction, organic phase drying and concentration to obtain solid crude product. 45L of dichloromethane, 3.52Kg of p-toluenesulfonyl chloride and 22.6 g of DMAP are then added, the temperature is controlled at 15-20 ℃, 2.054Kg of triethylamine is added dropwise, the mixture is reacted at room temperature for 6 hours, 1M hydrochloric acid is added for quenching the layer, the organic phase is saturated with sodium bicarbonate and water for washing, and the mixture is concentrated until no liquid flows. Then, 60L of acetonitrile, 4.44Kg of phthalimide potassium salt and 12.75Kg of ground potassium carbonate are added, the temperature is raised to 70 ℃ for reaction for 6 hours, the filtrate is filtered and concentrated under reduced pressure, toluene and water are added, aqueous phase toluene extraction is carried out, the organic phases are combined, concentrated under reduced pressure, n-heptane is added to separate yellow solid out, and 5-R- (2- (1, 3-dioxoisoindolin-2-yl) propyl) -1- (3- (propoxytetrahydropyran) -7 cyano-indoline 4.92Kg is obtained after filtration and drying, and the yield is 56.3%.
Example 6
Fourth step: synthesis of 5- [2 (R) -aminopropyl ] -1- [3- (benzoyloxy) propyl ] -7 cyano-indoline
Into a 200L reaction kettle. 3.73Kg of Compound 5 and 60L of tetrahydrofuran were added, followed by heating to 30-40℃and dropwise adding 19.7Kg of 80% hydrazine hydrate, heating to 70℃and stirring for reflux reaction for 12 hours. The reaction was quenched by the addition of 80L of water. Extraction with ethyl acetate and concentration of the organic phase to a yellow oily liquid. 80L of methanol and 4.49Kg of p-toluenesulfonic acid were then added and reacted at room temperature for 4 hours. The reaction solution ph=9-10 was adjusted by adding saturated sodium carbonate solution. The product was extracted with dichloromethane and the organic phases were combined. The organic phase was concentrated to no flow to give a yellow solid. Then, the mixture was dissolved in 34L of tetrahydrofuran, 7.68Kg of 25% sodium carbonate was added thereto, and 1.89Kg of Boc2O was dissolved in tetrahydrofuran with stirring at 0-5℃and added to the reaction mixture, and the mixture was allowed to react at room temperature for 10 hours. After the reaction, ethyl acetate extraction was completed, and the mixture was concentrated to obtain a yellow oily liquid. After adding methylene chloride, the mixture was dissolved at-20℃and benzoyl chloride (1.218 Kg) was added thereto, triethylamine (1.594 Kg) was slowly added thereto, and the mixture was then heated to 0-5℃to react for 9 hours. After the reaction, saturated ammonium chloride was quenched, extracted with dichloromethane, and concentrated to give a brown oily liquid. The above product was transferred to an enamel reactor, dissolved with 4M hydrogen chloride/ethyl acetate 10L and cooled to 0 ℃. The reaction was carried out for 3 hours, concentrated under reduced pressure, and quenched with sodium bicarbonate to adjust ph=8-9. Ethyl acetate, and concentrating the organic phase to give 5- [2 (R) -aminopropyl]-1- [3- (benzoyloxy) propyl group]-7 cyano-indoline 1.55Kg, yield 54.1%. 1 H NMR(600MHz,CDCl3)δ7.99(d,J＝7.7Hz,2H),7.49(t,J＝7.3Hz,1H),7.37(t,J＝7.4Hz,2H),6.89(s,2H),4.41(t,J＝6.2Hz,2H),3.69(t,J＝7.0Hz,2H),3.52(t,J＝8.6Hz,2H),3.00(q,J＝6.2Hz,1H),2.89(t,J＝8.6Hz,2H),2.46(d,J＝18.7Hz,1H),2.30(dd,J＝13.4,7.9Hz,1H),2.09(p,J＝6.5Hz,2H),1.03(d,J＝6.1Hz,3H).
Example 7
Fifth step: synthesis of 5- [2 (R) -aminopropyl ] -1- [3- (benzoyloxy) propyl ] -7 cyano-indoline tartrate
To a 50L reactor, 0.62Kg of fumaric acid and 6L of methanol were added, and after stirring uniformly, the temperature was raised to 50℃to dissolve, and then 1.5Kg of Compound 10 and 10L of 98% methanol solution (containing 2% of water) were added dropwise, and the system turned to cloudy. Then, the reaction solution is heated up and refluxed (70-75 ℃) for 5 hours to obtain yellow liquid, the temperature is slowly reduced to 15-20 ℃, the mixture is stirred for 3 hours at the temperature, the mixture is filtered, the filter cake is leached by cold methanol, and the mixture is dried to obtain 5- [2 (R) -aminopropyl]-1- [3- (benzoyloxy) propyl group]-7 cyano-indoline tartrate 1.79Kg. The yield thereof was found to be 84.5%. 1 H NMR(600MHz,DMSO-d 6 )δ7.99(d,J＝7.7Hz,2H),7.65(t,J＝7.5Hz,1H),7.51(t,J＝7.6Hz,2H),7.09(s,1H),7.04(s,1H),4.38(t,J＝6.2Hz,2H),3.78(s,2H),3.70(t,J＝7.3Hz,2H),3.61(t,J＝8.7Hz,2H),3.31(q,J＝6.8Hz,1H),2.95(t,J＝8.7Hz,2H),2.71(dd,J＝13.8,5.9Hz,1H),2.07(p,J＝6.7Hz,2H),1.23(s,1H),1.08(d,J＝6.3Hz,3H).
The foregoing is only a preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art, who is within the scope of the present invention, should be covered by the protection scope of the present invention by making equivalents and modifications to the technical solution and the inventive concept thereof.
Claims (6)
1. A preparation method of a silodosin key intermediate is characterized in that the reaction equation is as follows:
wherein: the molar ratio of the compound 4-1 to triphenylphosphine to phthalimide to the activating reagent is 1:1.2-1.5:1.2-1.5:1.2-1.5, the activating agent is selected from DIAD or DEAD; the molar ratio of the compound 4-2, the p-toluenesulfonyl chloride, the phthalimide potassium salt and the potassium carbonate is 1:1.0-1.2:1.2-1.5:5.0-6.0.
2. The method for preparing the silodosin key intermediate according to claim 1, which is characterized by comprising the following steps:
the first step: reflux-reacting indoline with boron trichloride/toluene solution, cooling to 50-60 ℃, adding trichloroacetonitrile for reaction overnight, quenching with methanol, filtering to obtain an intermediate, dissolving the intermediate in dichloromethane, adding sodium methoxide/methanol solution for dissociation, and crystallizing to obtain 7-cyano indoline;
and a second step of: dissolving 7-cyanoindoline in an organic solvent, adding NBS in batches to react to obtain 5-bromo-7-cyanoindoline, then reacting with 2- (3-bromopropyloxy) tetrahydro-2H-pyran and inorganic base in an acetonitrile solvent, and recrystallizing to obtain 5-bromo-7-cyano-1- (3- (propoxytetrahydropyran) indoline;
and a third step of: mixing 5-bromo-7-cyano-1- (3- (propoxytetrahydro-pyran) indoline) with tetrahydrofuran, cooling, then dropwise adding n-butyllithium solution, then dropwise adding (S/R) -propylene oxide and boron trifluoride-diethyl ether solution to obtain compounds 4-1 and 4-2, carrying out a casting reaction on the compound 4-1 and phthalimide or carrying out a reaction on the compound 4-2 and p-toluenesulfonyl chloride, and then carrying out substitution on the compound with phthalimide potassium salt to obtain 5-R- (2- (1, 3-dioxoisoindoline-2-yl) propyl) -1- (3- (propoxytetrahydro-pyran) -7-cyano-indoline;
fourth step: 1eq 5-R- (2- (1, 3-dioxoisoindolin-2-yl) propyl) -1- (3- (propoxytetrahydropyran) -7-cyano-indoline, 40eq hydrazine hydrate and tetrahydrofuran are mixed and then heated to 70 ℃ for reflux reaction to obtain 5- ((R) -2-aminopropyl) -1- (3- (propoxytetrahydropyran) -7-cyano) indoline, then 3eq p-toluenesulfonic acid is reacted in methanol to obtain a compound 7, and the compound 7 is dissolved in tetralinHydrofuran, 2.3eq of aqueous sodium carbonate solution are added at 0℃and 1.2eq of Boc are added 2 O is reacted to obtain a compound 8, which is then mixed with 1.1eq benzoyl chloride and dichloromethane, 2.1eq triethylamine is added dropwise at-20 ℃ to obtain a compound 9, which is then deprotected in ethyl acetate/hydrogen chloride at 0 ℃ to obtain 5- [2 (R) -aminopropyl]-1- [3- (benzoyloxy) propyl group]-7-cyano-indoline;
fifth step: 5- [2 (R) -aminopropyl ] -1- [3- (benzoyloxy) propyl ] -7-cyano-indoline, L-tartaric acid and methanol are mixed, heated, refluxed to form a salt, cooled to room temperature and filtered to obtain 5- [2 (R) -aminopropyl ] -1- [3- (benzoyloxy) propyl ] -7-cyano-indoline tartrate.
3. The method for preparing the silodosin key intermediate according to claim 2, which is characterized in that: in the first step, the molar ratio of indoline, boron trichloride and trichloroacetonitrile is 1:1-1.12:1.2-1.5.
4. The method for preparing the silodosin key intermediate according to claim 2, which is characterized in that: in the second step, the molar ratio of 7-cyanoindoline, NBS and 2- (3-bromopropyloxy) tetrahydro-2H-pyran is 1:1-1.05:1-1.1, the recrystallization solvent is selected from ethyl acetate and petroleum ether.
5. The method for preparing the silodosin key intermediate according to claim 2, which is characterized in that: in the third step, the molar ratio of the 5-bromo-7-cyano-1- (3- (propoxytetrahydro-pyran) indoline), n-butyllithium, the (S/R) -propylene oxide and the boron trifluoride diethyl etherate is 1:1.0-1.2:1.2-1.5:1.2-1.5.
6. The method for preparing the silodosin key intermediate according to claim 2, which is characterized in that: in the fifth step, the molar ratio of the compound 10 to the L-tartaric acid is 1:1.
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