CN114751852A - Preparation method of key intermediate of silodosin - Google Patents
Preparation method of key intermediate of silodosin Download PDFInfo
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Abstract
The invention discloses a preparation method of a key intermediate of silodosin, belonging to the technical field of drug synthesis. Carrying out a friedel-crafts reaction on indoline and trichloroacetonitrile to obtain a compound 1; bromination is carried out to obtain a compound 2; then substituted with 2- (3-bromopropoxy) tetrahydro-2H-pyran to obtain a compound 3; then nucleophilic addition is carried out on the compound and (S) -propylene oxide or (R) -propylene oxide at ultralow temperature to obtain a compound 4; then carrying out a photo-extension reaction with phthalimide to obtain a compound 5 (configuration inversion) or esterifying with p-toluenesulfonyl chloride, and obtaining the compound 5 with phthalimide potassium salt under the condition of inorganic base; then reducing by hydrazine hydrate to obtain a compound 6; then, the compound 7 is obtained by the tetrahydropyran deprotection of p-toluenesulfonic acid; amino Boc protection under alkaline conditions gives compound 8; esterifying with benzoyl chloride to obtain a compound 9; removing Boc with hydrochloric acid to obtain a compound 10; salifying with L-tartaric acid to obtain compound 11. Compared with the prior art, the invention avoids the introduction of 7-site cyano group synthesized by Vilsmeier reaction, hydroxylamine oximation and acetic anhydride dehydration and 5-site amino group by nitro group or reductive amination without using heavy metals such as Pd/Pt/Zn; the continuous operation of the whole steps is increased, the production cost of the silodosin intermediate is greatly reduced, and the industrial scale 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 key intermediate of silodosin.
Background
Silodosin is an α 1A receptor antagonist developed by Kissei pharmaceutical company, japan, 5 months in 2006, and is marketed under the trade name of uri. Silodosin is used clinically to treat symptoms associated with Benign Prostatic Hyperplasia (BPH) or hypertrophy. The preparation of the silodosin is mostly a capsule preparation, and is approved to be on the market by the U.S. food and drug administration in 2008.
The existing synthesis method of the key intermediate 5- [2(R) -aminopropyl ] -1- [3- (benzoyloxy) propyl ] -7-cyano-indoline tartrate of the silodosin mainly has the characteristics on a 7-position cyano group and a 5-position hand-type aminopropyl group, but most of the two amino groups are inevitably subjected to Vilsmeier reaction, hydroxylamine oximation and acetic anhydride dehydration to synthesize a cyano group, and the 5-position is subjected to amino acid substitution, sodium azide substitution, nitro reduction or L-tartaric acid resolution to synthesize the key intermediate of the silodosin. However, such a method has safety problems in large-scale production (for example, 7 sites are subjected to Vilsmeier reaction, hydroxylamine oximation and acetic anhydride dehydration to synthesize cyano groups, hydrocyanic acid is generated in the dehydration process), and explosive sodium azide or Pd and other heavy metals are used for catalysis, so that the product has heavy metal residues more or less, and the like.
According to the invention, through deep research and optimization of the compound, a reaction route which is convenient to operate, better, mild in reaction, safe and stable is obtained, reagents or chemical reactions which are safe and unfavorable for production are not needed, reduction reaction of heavy metals is avoided by considering the product quality, chiral alcohol is introduced by ingenious design, and reduced amine is obtained through a series of reactions, so that diastereoisomer salt is not needed to be separated out by L-tartaric acid crystallization, and the atom utilization rate is low.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides the preparation method of the key intermediate 5- [2- (R) -aminopropyl ] -1- [3- (benzoyloxy) propyl ] -7 cyano-indoline tartrate, which is simple, convenient and stable to operate, high in atom utilization rate, environment-friendly, low in production cost and suitable for industrial large-scale 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: carrying out a friedel-crafts reaction on indoline and trichloroacetonitrile to obtain a compound 1; bromination is carried out to obtain a compound 2; then substituted with 2- (3-bromopropoxy) tetrahydro-2H-pyran to obtain a compound 3; then nucleophilic addition is carried out on the compound and (S) -propylene oxide or (R) -propylene oxide at ultralow temperature to obtain a compound 4; then carrying out a photo-extension reaction with phthalimide to obtain a compound 5 (configuration inversion) or esterifying with p-toluenesulfonyl chloride, and obtaining the compound 5 with phthalimide potassium salt under the condition of inorganic base; then reducing by hydrazine hydrate to obtain a compound 6; then, the compound 7 is obtained by the tetrahydropyran deprotection of p-toluenesulfonic acid; amino Boc protection under alkaline conditions gives compound 8; esterifying with benzoyl chloride to obtain a compound 9; removing Boc with hydrochloric acid to obtain a compound 10; salifying with L-tartaric acid to obtain 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 is as follows: refluxing indoline and boron trichloride/toluene solution for reaction, then 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-cyanoindoline;
the second step: dissolving 7-cyanoindoline in an organic solvent, adding NBS in batches to react to obtain 5-bromo-7-cyanoindoline, reacting with 2- (3-bromopropoxy) tetrahydro-2H-pyran and inorganic base in an acetonitrile solvent, and recrystallizing to obtain 5-bromo-7-cyano-1- (3- (propoxytetrahydropyran) indoline);
the third step: mixing 5-bromo-7-cyano-1- (3- (propoxytetrahydropyran) indoline) with tetrahydrofuran, cooling, dropwise adding n-butyllithium solution, then dropwise adding (S/R) -propylene oxide and boron trifluoride-diethyl ether solution to obtain a compound 4, then carrying out a light extension reaction with phthalimide or a reaction with p-toluenesulfonyl chloride, and then carrying out substitution with phthalimide potassium salt to obtain 5-R- (2- (1, 3-dioxoisoindolin-2-yl) propyl) -1- (3- (propoxytetrahydropyran) -7-cyano-indoline;
The 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, which is then reacted with p-toluenesulfonic acid 3eq in methanol to obtain compound 7, compound 7 is dissolved in tetrahydrofuran, sodium carbonate aqueous solution 2.3eq is added at 0 ℃, Boc2O 1.2.2 eq is added for reaction to obtain compound 8, which is then mixed with benzoyl chloride 1.1eq and dichloromethane, triethylamine 2.1eq is added at 20 ℃ for reaction to obtain compound 9, and then deprotection is carried out in ethyl acetate/hydrogen chloride at 0 ℃ to obtain 5- [2(R) - Aminopropyl ] -1- [3- (benzoyloxy) propyl ] -7 cyano-indoline;
the fifth step: mixing 5- [2(R) -aminopropyl ] -1- [3- (benzoyloxy) propyl ] -7-cyano-indoline, fumaric acid and methanol, heating and refluxing to form salt, cooling to room temperature, and filtering 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 and trichloroacetonitrile is 1: 1-1.12: 1.2-1.5.
Further, in the above technical scheme, the molar ratio of the 7-cyanoindoline, NBS and 2- (3-bromopropoxy) tetrahydro-2H-pyran in the second step is 1: 1-1.05: 1-1.1, and the recrystallization solvent is selected from the combination of ethyl acetate and petroleum ether.
Further, in the technical scheme, in the third step, the molar ratio of the 5-bromo-7-cyano-1- (3- (propoxytetrahydropyran) indoline), n-butyllithium, (S/R) -epoxypropane 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, the molar ratio of the compound 4(S), triphenylphosphine, phthalimide and the activating reagent in the third step 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, the molar ratio of the compound 4(R), p-toluenesulfonyl chloride, phthalimide potassium salt to the inorganic base in the third step is 1: 1.0-1.2: 1.2-1.5: 5.0-6.0.
Furthermore, in the technical scheme, the molar ratio of the 5-R- (2- (1, 3-dioxoisoindolin-2-yl) propyl) -1- (3- (propoxytetrahydropyran) -7-cyano-indoline to the hydrazine hydrate in the fourth step is 1: 20-50, and the molar ratio of the 5- ((R) -2-aminopropyl) -1- (3- (propoxytetrahydropyran) -7-cyano) indoline to the p-toluenesulfonic acid is 1: 2-3.
Further, in the technical scheme, the molar ratio of the compound 7, sodium carbonate and Boc2O in the fourth step is 1: 2-2.3: 1.2-1.5; the molar ratio of the compound 8, benzoyl chloride and triethylamine is 1: 1-1.2: 2-2.5.
Further, in the above technical scheme, the molar ratio of the compound 10 in the fifth step to fumaric acid is 1: 1.
the invention has the beneficial effects that:
compared with the prior art, the method has the advantages that raw materials are easy to obtain, the yield is relatively high, the environment is friendly, the synthesis of the cyano group at the 7 th position through Vilsmeier reaction, hydroxylamine oximation and acetic anhydride dehydration is avoided, phosphorus-containing wastewater is removed, and safety accidents caused by generation of trace HCN in the dehydration process are avoided; low utilization rate of L-tartaric acid resolution atoms is avoided; simultaneously avoiding the introduction of 5-amino through nitryl or reductive amination; avoids the application of heavy metals such as Pd/Pt/Zn and the like, and ensures that the product has no heavy metal residue. The optimized integral steps are operated continuously, so that the time cost and the production cost of the conventional silodosin intermediate are greatly reduced, and the industrial scale production is facilitated.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. These examples are to be construed as merely illustrative and not limitative of the remainder of the disclosure in any way whatsoever. After reading the description of the invention, one skilled in the art can make various changes and modifications to the invention, and such equivalent changes and modifications also fall into the scope of the invention defined by the claims.
Example 1 first step: synthesis of 7-cyanoindoline
Adding 50L of 1M BCl 3/toluene solution into a 200L reaction kettle, dropwise adding 20L of toluene/5.3 Kg of indoline solution, uniformly mixing, and heating and refluxing for reaction for 1 hour; then the temperature is reduced to 60 ℃, 7.72Kg CCl3CN is slowly added, and the temperature is controlled to 60 ℃ to stir and react overnight; after the reaction is finished, the temperature is reduced to 10 ℃, 30L of methanol is slowly added for quenching, a reaction intermediate is obtained through filtration (the intermediate can not be stored in the air for a long time, the product is easy to decompose after moisture absorption, if the product needs to be stored, the product needs to be stored after vacuumizing and then nitrogen charging is carried out for storage), the intermediate and 150L of dichloromethane are added into a 500L reaction kettle, the temperature is controlled to be not more than 25 ℃, and 18Kg of 30% sodium methoxide solution is added. After the reaction is completed, 100L of water is added, the mixture is stood for layering, 50L of dichloromethane in the upper aqueous phase is washed for two times, organic phases are combined, the mixture is concentrated to be a non-flowing liquid, 50L of petroleum ether is added, crystallization is carried out in an ice bath at the temperature of minus 5 ℃, and the mixture is filtered and dried to obtain 3.82Kg of 7-cyanoindoline and light-earth yellow solid.1H NMR (400MHz, CDCl3) δ 7.18(d, J ═ 7.3,1.4Hz,1H),7.15 to 7.08(m,1H),6.60(t, J ═ 7.6Hz,1H),3.69(t, J ═ 8.6Hz,2H),3.08(t, J ═ 8.4Hz,2H) in BCl3 catalyst system, 0.89mol (0.02eq) of B (C6F5)3 catalyst was additionally added to form a mixed catalyst, and 5.57Kg of 7-cyanoindoline was obtained after the reaction treatment.
Example 2
The second step: synthesis of 5-bromo-7-cyano-1- (3- (propoxytetrahydropyran) indoline
Into a 200L reactor, 3.82Kg of Compound 1 and 50L of methylene chloride were added, 4.95KgNBS was added in portions at 0 to 5 ℃, the mixture was allowed to warm to room temperature and stirred for 1 hour, and 40L of aqueous solution was added to retain the organic phase. Extraction with dichloromethane, combining the organic phases and washing the organic phases with 50L of 5% aqueous sodium bicarbonate solution. Distilling the organic phase under reduced pressure to obtain a constant liquid, adding 45L of acetonitrile and 3.18Kg of sodium hydroxide, and heating to the temperatureAt 45 deg.C, slowly adding 20L acetonitrile/2- (3-bromopropoxy) tetrahydro-2H-pyran 6.71Kg mixture, stirring and heating to reflux 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 combining organic phases. Concentrating under reduced pressure to obtain a non-flowing liquid, and recrystallizing ethyl acetate/petroleum ether to obtain 6.976Kg of 5-bromo-7-cyano-1- (3- (propoxytetrahydropyran) indoline, wherein the yield is 72.3 percent and the HPLC is 98.9 percent.1H 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
The second step: synthesis of 5-bromo-7-cyano-1- (3- (propoxytetrahydropyran) indoline
Into a 200L reactor, 3.82Kg of Compound 1 and 32L of acetonitrile were added, and 4.95Kg of NBS was added in portions at 0 to 5 ℃ followed by warming to room temperature and stirring for 1 hour. Adding 40L of water, distilling under reduced pressure to remove most of acetonitrile, cooling to 20-25 ℃, leaching a filter cake with water, and drying to obtain an organic phase which is a non-flowing liquid. Then adding 50L of acetonitrile and 12.82Kg of potassium carbonate, heating to 45-55 ℃, slowly and dropwise adding a mixture of 20L of acetonitrile/6.71 Kg of 2- (3-bromopropoxy) tetrahydro-2H-pyran, stirring, heating to reflux and reacting for 8 hours. Cooling to room temperature, adding 60L water into the reaction solution, concentrating under reduced pressure, extracting with ethyl acetate for three times, and combining the organic phases. Concentrating under reduced pressure to obtain a non-flowing liquid, and recrystallizing ethyl acetate/petroleum ether to obtain 7.27Kg of 5-bromo-7-cyano-1- (3- (propoxytetrahydropyran) indoline, wherein the yield is 75.4 percent and the HPLC is 95.7 percent.
Example 4
The third step: 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 reactor under nitrogen protection. The temperature of the reaction kettle is reduced to-75 ℃, and 8.1L of 2.5mol/L n-butyllithium solution is added dropwise. After the dropwise addition, the mixture was stirred at constant temperature for 0.5 hour. And dropwise adding 1.63Kg/10L of tetrahydrofuran solution containing propylene oxide and 3.93Kg of boron trifluoride diethyl etherate solution, and reacting for 1 hour under heat preservation and stirring. Slowly heating to-55 ℃, and quenching by using saturated ammonium chloride solution.
After quenching, the solution is extracted by ethyl acetate, the organic phase is dried and concentrated to obtain a solid crude product, and 70L of tetrahydrofuran, 6.29Kg of triphenylphosphine and 3.53Kg of phthalimide are added. Tetrahydrofuran dissolved/DIAD 4.85Kg is slowly added dropwise at 0 deg.C, and the reaction is continued to stir for 2 hours after the addition is finished. Quenching with saturated ammonium chloride solution, extracting with ethyl acetate, drying with anhydrous sodium sulfate, and concentrating to obtain oily solid. Purifying by silica gel column chromatography, wherein the mobile phase is PE: EA is 5: 1, 4.124Kg of 5-R- (2- (1, 3-dioxoisoindolin-2-yl) propyl) -1- (3- (propoxytetrahydropyran) -7-cyano-indoline were obtained as a yellow solid in 47.2% yield. 1H 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
The third step: 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 reactor under nitrogen protection. The reaction kettle was cooled to-70 ℃. 8.1L of a 2.5mol/L n-butyllithium solution was added dropwise. After the dropwise addition, the reaction was carried out under stirring for 0.5 hour. 1.63Kg/10L of tetrahydrofuran solution containing propylene oxide and 3.93Kg of boron trifluoride-diethyl ether solution were added dropwise, followed by stirring and reaction for 1 hour under heat preservation. Slowly heating to-55 deg.C, and quenching with saturated ammonium chloride solution. Extracting with ethyl acetate, drying the organic phase, and concentrating to obtain a solid crude product. Then adding 45L of dichloromethane, 3.52Kg of p-toluenesulfonyl chloride and 22.6 g of DMAP, controlling the temperature to be 15-20 ℃, dropwise adding 2.054Kg of triethylamine, reacting for 6 hours at room temperature, adding 1M hydrochloric acid to quench and separate layers, washing an organic phase saturated sodium bicarbonate and water, and concentrating to obtain a non-flowing liquid. Then adding 60L acetonitrile, 4.44Kg potassium phthalimide salt and 12.75Kg ground potassium carbonate, heating to 70 ℃ for reaction for 6 hours, filtering the filtrate, concentrating under reduced pressure, adding toluene and water, extracting the aqueous phase with toluene, combining the organic phases, concentrating under reduced pressure, adding n-heptane to precipitate yellow solid, filtering and drying to obtain 4.92Kg 5-R- (2- (1, 3-dioxoisoindolin-2-yl) propyl) -1- (3- (propoxytetrahydropyran) -7 cyano-indoline with the yield of 56.3 percent.
Example 6
The fourth step: synthesis of 5- [2(R) -aminopropyl ] -1- [3- (benzoyloxy) propyl ] -7 cyano-indoline
The reaction kettle containing 200L of the crude product was charged. 3.73Kg of compound 5 and 60L of tetrahydrofuran were added, followed by heating to 30-40 deg.C, dropwise addition of 19.7Kg of 80% hydrazine hydrate, heating to 70 deg.C, and reflux reaction under stirring 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. Adding saturated sodium carbonate solution to regulate pH to 9-10. The product was extracted with dichloromethane and the organic phases were combined. The organic phase was concentrated to a non-flowing liquid to give a yellow solid. Then, the resulting mixture was dissolved in 34L of tetrahydrofuran, 7.68Kg of 25% sodium carbonate was added thereto, and 1.89Kg of Boc2O 1.89 was dissolved in tetrahydrofuran at 0 to 5 ℃ with stirring, added to the reaction mixture, and allowed to warm to room temperature for 10 hours. After the reaction is finished, extracting with ethyl acetate, and concentrating to obtain yellow oily liquid. Adding dichloromethane, dissolving, controlling the temperature at-20 ℃, adding 1.218Kg of benzoyl chloride, slowly adding 1.594Kg of triethylamine, and then heating to 0-5 ℃ for reaction for 9 hours. After the reaction, the mixture was quenched with saturated ammonium chloride, extracted with dichloromethane, and concentrated to give a brown oily liquid. The product was transferred to an enamel reactor, dissolved with 10L of 4M hydrogen chloride/ethyl acetate and cooled to 0 ℃. After 3 hours of reaction, the mixture was concentrated under reduced pressure and quenched with sodium bicarbonate to adjust the pH to 8-9. Extracting with ethyl acetate, and concentrating the organic phase to obtain 5- [2(R) -aminopropyl ]-1- [3- (benzoyloxy) propyl]1.55Kg of (E) -7 cyano-indoline with a yield of 54.1%.1H 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
The 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, stirred well and then heated to 50 ℃ to dissolve it clearly, followed by dropwise addition of 1.5Kg of compound 10 and 10L of 98% methanol solution (containing 2% water) to turn the system cloudy. Then, heating the reaction solution to reflux (70-75 ℃) for 5 hours to obtain yellow liquid, slowly cooling to 15-20 ℃, stirring for 3 hours at the temperature, filtering, leaching a filter cake with cold methanol, and drying to obtain 5- [2(R) -aminopropyl]-1- [3- (benzoyloxy) propyl]1.79Kg of (E) -7 cyano-indoline tartrate. The yield thereof was found to be 84.5%.1H NMR(600MHz,DMSO-d6)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 above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be able to cover the technical solutions and the inventive concepts of the present invention within the technical scope of the present invention.
Claims (10)
1. The preparation method of the key intermediate of silodosin is characterized in that the reaction equation is as follows:
2. A process for the preparation of a key intermediate of silodosin according to claim 1, comprising the steps of:
the first step is as follows: performing reflux reaction on indoline and a boron trichloride/toluene solution, then cooling to 50-60 ℃, adding trichloroacetonitrile for reacting overnight, quenching methanol, filtering to obtain an intermediate, then dissolving the intermediate in dichloromethane, adding a sodium methoxide/methanol solution for dissociation, and crystallizing to obtain 7-cyano indoline;
the second step: dissolving 7-cyanoindoline in an organic solvent, adding NBS in batches to react to obtain 5-bromo-7-cyanoindoline, reacting with 2- (3-bromopropoxy) tetrahydro-2H-pyran and inorganic base in an acetonitrile solvent, and recrystallizing to obtain 5-bromo-7-cyano-1- (3- (propoxytetrahydropyran) indoline);
the third step: mixing 5-bromo-7-cyano-1- (3- (propoxytetrahydropyran) indoline) with tetrahydrofuran, cooling, dropwise adding n-butyllithium solution, then dropwise adding (S/R) -propylene oxide and boron trifluoride-diethyl ether solution to obtain a compound 4, then carrying out a light extension reaction with phthalimide or a reaction with p-toluenesulfonyl chloride, and then carrying out substitution with phthalimide potassium salt to obtain 5-R- (2- (1, 3-dioxoisoindolin-2-yl) propyl) -1- (3- (propoxytetrahydropyran) -7-cyano-indoline;
The 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, then heated to 70 ℃ for reflux reaction to obtain 5- ((R) -2-aminopropyl) -1- (3- (propoxytetrahydropyran) -7-cyano) indoline, then reacted with p-toluenesulfonic acid 3eq in methanol to obtain compound 7, the compound 7 is dissolved in tetrahydrofuran, sodium carbonate aqueous solution 2.3eq is added at 0 ℃, Boc2O 1.2.2 eq is added for reaction to obtain compound 8, then mixed with benzoyl chloride 1.1eq and dichloromethane, triethylamine 2.1eq is added at-20 ℃ for reaction to obtain compound 9, and then deprotected in ethyl acetate/hydrogen chloride at 0 ℃ to obtain 5- [2(R) - Aminopropyl ] -1- [3- (benzoyloxy) propyl ] -7 cyano-indoline;
the fifth step: mixing 5- [2(R) -aminopropyl ] -1- [3- (benzoyloxy) propyl ] -7 cyano-indoline, fumaric acid and methanol, heating up, refluxing to form salt, cooling to room temperature, and filtering to obtain 5- [2(R) -aminopropyl ] -1- [3- (benzoyloxy) propyl ] -7 cyano-indoline tartrate.
3. The process for the preparation of key intermediates of silodosin according to claim 2, characterized by: in the first step, the mol ratio of indoline, boron trichloride and trichloroacetonitrile is 1: 1-1.12: 1.2-1.5.
4. The process for the preparation of key intermediates of silodosin according to claim 2, characterized by: in the second step, the molar ratio of 7-cyanoindoline, NBS and 2- (3-bromopropoxy) tetrahydro-2H-pyran is 1: 1-1.05: 1-1.1, and the recrystallization solvent is selected from the group consisting of ethyl acetate and petroleum ether.
5. The process for the preparation of key intermediates of silodosin according to claim 2, characterized by: in the third step, the molar ratio of 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.
6. The process for the preparation of key intermediates of silodosin according to claim 2, characterized by: in the third step, the molar ratio of the compound 4(S), triphenylphosphine, phthalimide and the activating reagent is 1: 1.2-1.5: 1.2-1.5: 1.2-1.5, wherein the activating reagent is selected from DIAD or DEAD.
7. The process for the preparation of key intermediates of taslochin according to claim 2, characterized in that: in the third step, the molar ratio of the compound 4(R), the tosyl chloride, the potassium phthalimide salt and the inorganic base is 1: 1.0-1.2: 1.2-1.5: 5.0-6.0.
8. The process for the preparation of key intermediates of silodosin according to claim 2, characterized by: 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.
9. The process for the preparation of a key intermediate of silodosin according to claim 2, wherein: in the fourth step, the molar ratio of compound 7, sodium carbonate and Boc2O was 1: 2-2.3: 1.2-1.5; the mol ratio of the compound 8, benzoyl chloride and triethylamine is 1: 1-1.2: 2-2.5.
10. The process for the preparation of key intermediates of silodosin according to claim 2, characterized by: in the fifth step, the molar ratio of compound 10 to fumaric acid was 1: 1.
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