CN106045892B

CN106045892B - The new preparation process of Silodosin and its intermediate

Info

Publication number: CN106045892B
Application number: CN201610361588.2A
Authority: CN
Inventors: 冷传新; 范传文; 房玺; 林栋�; 刘培元
Original assignee: Qilu Pharmaceutical Co Ltd
Current assignee: QILU PHARMACEUTICAL (HAINAN) Co.,Ltd.
Priority date: 2016-05-27
Filing date: 2016-05-27
Publication date: 2019-05-28
Anticipated expiration: 2036-05-27
Also published as: CN106045892A

Abstract

The invention belongs to technical field of medical chemistry, and in particular to the new midbody compound and its crystal form and preparation method of Silodosin, and provide a kind of method that Silodosin is prepared by new intermediate.The application improves product quality to effectively remove and reduce dehydrogenation impurity by the compound III that compound IV preparation is converted to hydrochloride form.And the preparation method is easy to operate, and reaction condition is mild, and safely controllable, reaction yield is high, and good product purity is more suitable for industrialized production.

Description

The new preparation process of Silodosin and its intermediate

Technical field

The invention belongs to field of pharmaceutical chemistry technology, and in particular to Silodosin new intermediate and preparation method, and it is specific Provide a kind of method that Silodosin is prepared by new intermediate.The preparation method is easy to operate, and reaction condition is mild, safety Controllably, reaction yield is high, and good product purity is more suitable for industrialized production.

Background technique

Silodosin (Silodosin), entitled 1- (3- hydroxypropyl) -5- [(2R) -2- ({ 2- [2- (2,2, the 2- trifluoros of chemistry Ethyoxyl) phenoxy group] ethyl } amino) propyl] -2,3- dihydro -1H- indoles -7- formamide, there is chemistry shown in formula I Structure, be grind that tangerine is raw by day basis and Japan the one or three altogether a new generation of pharmacy cooperative research and development sale to α 1- adrenoreceptor Retarding agent has selectivity outstanding to the adrenocepter of 1 A- hypotype of α, and can selectively relax urethral smooth muscle, right In other two kinds of subtype alphas₁The affinity of receptor is far weaker than other drugs, reduces low blood pressure and the generation of other adverse reactions Rate can be used for treating and dysuric symptom and other relevant diseases caused by benign prostatic hyperplasis (BPH) or hypertrophy Shape.

Formulas I

Although having patent document CN200910194691.2, CN201210199199.6, CN201310340656.3 at present And periodical Tetrahedron etc. discloses a variety of preparation methods, considerably improves reaction condition, but there are still impurity or pairs React more, especially dehydrogenation impurity due to its in structure it is extremely similar to intermediate and be difficult to effectively remove, and react week The defects of phase is long, cumbersome, product purity is not high, and yield is low, at high cost, unsuitable industrial-scale production.Therefore it still needs to Research and develop easy to operate, impurity is few, reaction condition is mild, process route with high purity, being conducive to large-scale production and Condition.

Summary of the invention

To overcome above-mentioned technological deficiency in the prior art, present inventor has carried out multi-faceted route research, has obtained A kind of new intermediate forms of Silodosin and preparation method thereof, are completed the present invention is based on this.

First aspect present invention provides a kind of method for preparing Silodosin intermediate compound III, which is characterized in that by Compound IV reacts to obtain compound III with hydrogen chloride (HCl)；

Wherein, the molar feed ratio of compound IV and hydrogen chloride is 1:1~5, preferred 1:1.2~3, more preferable 1:1.5~ 2；

Optionally, the reaction of prepare compound III carries out in reaction dissolvent I, and the reaction dissolvent I is selected from ethyl alcohol, third Ketone, ethyl acetate, methylene chloride, chloroform, 1,2- dichloroethanes, tetrahydrofuran, preferred alcohol, methylene chloride, three chloromethanes Alkane；

Optionally, hydrogen chloride is added in reaction system as a solution, and the solvent of the solution is selected from ethyl alcohol, third Ketone, ethyl acetate, methylene chloride, chloroform, 1,2- dichloroethanes, tetrahydrofuran, preferred alcohol, methylene chloride, three chloromethanes Alkane, more preferable ethanol solution；In one embodiment of the invention, hydrogen chloride is added in the form of an ethanolic solution, preferably with 2mol/ The ethanol solution of hydrogen chloride of L is added.

In an optimal technical scheme of the invention, the method for prepare compound III described in first aspect present invention It is stirred the following steps are included: compound IV is added in ethyl alcohol, the ethanol solution of hydrogen chloride of instillation is stirred to react 5~6h, mistake Filter, it is dry, obtain compound III.

In another optimal technical scheme of the invention, the side of prepare compound III described in first aspect present invention Method is cooled to 0 ~ 10 DEG C the following steps are included: stirring in ethyl alcohol is added in compound IV, the ethanol solution of hydrogen chloride of instillation, 15 ~ 25 DEG C are stirred to react 5~6h, filter, dry, obtain compound III.

Second aspect of the present invention provides a kind of method for preparing Silodosin midbody compound IV, which is characterized in that changes It closes object V and compound IV is prepared in peroxide reactions:

Preferably, the method for the prepare compound IV adds the following steps are included: compound V is dissolved in reaction dissolvent I Enter inorganic base aqueous solution, peroxide, be stirred to react 3~5h at room temperature, sodium sulfite aqueous solution is then added, extracts organic Phase, washing, drying, decompression steam solvent, obtain compound IV；

In a preferred embodiment of the invention, the method for the prepare compound IV is the following steps are included: by compound V It is added to stirring and dissolving in dimethyl sulfoxide, KOH aqueous solution, 30% H is added dropwise₂O₂, 15 ~ 25 DEG C of 3~5h of reaction, then addition is sub- Ethyl acetate extraction is added in aqueous sodium persulfate solution, filtering, filtrate, and decompression steams solvent at 40 ~ 45 DEG C after washed, drying, obtains To compound IV；

Wherein, the inorganic base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, excellent Select sodium hydroxide, potassium hydroxide；

The reaction dissolvent I is selected from dimethyl sulfoxide, methylene chloride, chloroform, tetrahydrofuran, preferably dimethyl sulfoxide, two Chloromethanes；

The peroxide is selected from hydrogen peroxide, sodium peroxide, potassium peroxide, calper calcium peroxide, strontium peroxide, preferred mass The H that score is 30%₂O₂Aqueous solution；

The molar feed ratio of compound V and peroxide is 1:2~10, preferably 1:3~6, more preferable 1:5；

The molar feed ratio of compound V and inorganic base is 1:1.1~3, preferably 1:1.6~2, more preferable 1:1.8；

The molar feed ratio of compound V and sodium sulfite is 1:2~10, preferably 1:3~6, more preferable 1:5.

Third aspect present invention provides the compound III purposes for being used to prepare compound II and compound I.

Fourth aspect present invention provides a kind of method by compound III prepare compound II, and this method includes following step Rapid: compound III reacts to obtain compound II and realize with alkaloid compound:

；

Wherein, the alkaloid compound have the general art-recognized meanings in this field, can be organic base or inorganic base, it is excellent Select inorganic base；The organic base is selected from triethylamine, pyridine, ammonium hydroxide, sodium methoxide, sodium ethoxide, sodium isopropylate；The inorganic base is selected from Alkali metal hydroxide, alkali carbonate, alkali metal hydrogencarbonate, alkaline-earth metal hydroxide, preferably sodium hydroxide, hydrogen Potassium oxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, saleratus, calcium bicarbonate；

The molar feed ratio of compound III and alkaloid compound is 1:1.2~2 or 1:1.2~1.8, more preferable 1:1.2 ~1.6；

Preferably, the reaction of above-mentioned prepare compound II carries out in reaction dissolvent III, and the reaction dissolvent III is selected from Ethyl alcohol, methanol, isopropanol, ethyl acetate, methylene chloride, chloroform, tetrahydrofuran, acetone, N,N-dimethylformamide, N, N- dimethyl acetamide；The dosage of reaction dissolvent III is this field conventional amount used, the chemical combination in a technical solution of the invention The mass volume ratio of object II and reaction dissolvent III are 1:20~120, preferably 50~100, more preferable 1:60~80；

More specifically, the method for fourth aspect present invention prepare compound II is the following steps are included: compound III is added Reaction dissolvent III stirring and dissolving is added sodium carbonate, is warming up to 30 ~ 60 DEG C (preferably 40~50 DEG C) 1 ~ 1.5h of stirring, filters；Filter Liquid decompression steams solvent, obtains compound II.

In one embodiment of the invention, fourth aspect present invention prepare compound II method the following steps are included: Ethyl alcohol stirring and dissolving is added in compound III, sodium carbonate is added, is warming up to 40 ~ 50 DEG C of 1 ~ 1.5h of stirring, is filtered；Filtrate decompression Solvent is steamed, compound II is obtained.

In another technical solution of the invention, the method for fourth aspect present invention prepare compound II includes following step It is rapid: compound III is added in reaction dissolvent III-1, the aqueous solution or methanol solution of alkaloid compound are added after stirring and dissolving, 0.5~3h(preferably 1~2h is stirred at room temperature), saturated common salt water washing, drying is added, decompression steams solvent, obtains compound II；

Wherein, the reaction dissolvent III-1 is selected from methylene chloride, chloroform, ethyl acetate, 1,2- dichloroethanes, first Benzene, preferably methylene chloride, chloroform, ethyl acetate.

Fifth aspect present invention provides a kind of method for preparing Silodosin (compound I), method includes the following steps: Compound II reacts to obtain compound I with compound SM2；

More specifically, the method for preparing Silodosin described in fifth aspect present invention comprising following steps: inorganic In the presence of alkali, iodide, sodium sulfite, compound II reacts in reaction dissolvent IV with compound SM2；

Wherein, the feed ratio of compound II and compound SM2 is 1:1~2 or 1:1.2~1.8, preferably 1:1.2~1.5；

The molar feed ratio of compound II and inorganic base is 1:2~6, preferably 1:2~4；More preferable 1:2~3；

The molar feed ratio of compound II and iodide is 1:0.8~1.5, preferably 1:0.8~1.2, more preferable 1:1；

The molar feed ratio of compound II and sodium sulfite is 1:0.1~0.5, preferably 1:0.1~0.2；

The mass volume ratio of compound II and reaction dissolvent IV is 1:8~15, preferably 1:10~12, unit: g/ml；

Reaction dissolvent IV is selected from N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, ethyl alcohol, methanol, tetrahydrofuran；

The inorganic base is selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, carbonic acid Hydrogen potassium, calcium bicarbonate；

The iodide are selected from potassium iodide, sodium iodide, ammonium iodide, hydrogen iodide (hydroiodic acid)；

In a preferred embodiment of the invention, the method for Silodosin is prepared described in fifth aspect present invention comprising Following steps: compound II, potassium carbonate, potassium iodide, sodium sulfite, compound SM2 are added in n,N-dimethylacetamide, control 30 ~ 60 DEG C of temperature (preferably 40~50 DEG C) reaction 12~for 24 hours, reaction solution is added in suitable quantity of water, ethyl acetate extraction, organic phase warp Washing, dry, decompression steams solvent, obtains Silodosin；

Sixth aspect present invention provides the method for another preparation Silodosin (compound I), and this method includes following step Rapid: in the presence of inorganic base, iodide, sodium sulfite, compound III reacts in reaction dissolvent IV with compound SM2；

Wherein, the feed ratio of compound III and compound SM2 are 1:1~2 or 1:1.2~1.8, preferably 1:1.2~ 1.5；

The molar feed ratio of compound III and inorganic base is 1:4~8, preferably 1:3~6；More preferable 1:4；；

The molar feed ratio of compound III and iodide is 1:0.8~1.5, preferably 1:0.8~1.2, more preferable 1:1；

The molar feed ratio of compound III and sodium sulfite is 1:0.1~0.5, preferably 1:0.1~0.2；

The mass volume ratio of compound III and reaction dissolvent IV is 1:8~15, preferably 1:10~12, unit: g/ml；

Above-mentioned reaction can selected from one of ethyl alcohol, methanol, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide or A variety of is reaction dissolvent；

In one embodiment of the invention, the method that Silodosin is prepared described in sixth aspect present invention includes following step It is rapid: compound III, potassium carbonate, potassium carbonate, potassium iodide, sodium sulfite, compound SM2 are added in n,N-dimethylacetamide, 30 ~ 60 DEG C of temperature control (preferably 40~50 DEG C) reaction 12~for 24 hours, reaction solution is added in suitable quantity of water, ethyl acetate extraction, organic phase Washed, dry, decompression steams solvent and obtains Silodosin；

Seventh aspect present invention provides a kind of compound IV of crystal form, the compound IV of the crystal form, uses Cu-K α radiation, the X-ray powder diffraction indicated with 2 θ angles at 6.5 ± 0.2 °, 10.8 ± 0.2 °, 13.2 ± 0.2 °, 16.7 ± 0.2 °, 17.4 ± 0.2 °, 18.5 ± 0.2 °, 19.6 ± 0.2 °, 19.8 ± 0.2 °, 20.1 ± 0.2 °, 20.6 ± 0.2 °, There is characteristic diffraction peak at 21.8 ± 0.2 °；Specifically, the compound IV of the crystal form, is radiated using Cu-K α, with 2 angles θ Spend the X-ray powder diffraction indicated at 6.5 ± 0.2 °, 10.8 ± 0.2 °, 13.2 ± 0.2 °, 14.3 ± 0.2 °, 15.7 ± 0.2 °, 16.7 ± 0.2 °, 17.4 ± 0.2 °, 18.4 ± 0.2 °, 19.6 ± 0.2 °, 19.8 ± 0.2 °, 20.1 ± 0.2 °, 20.6 ± There is characteristic diffraction peak at 0.2 °, 21.8 ± 0.2 °, 22.4 ± 0.2 °, 23.0 ± 0.2 °, 23.4 ± 0.2 °, 26.3 ± 0.2 °；More Specifically, the compound IV of the crystal form, is radiated using Cu-K α, is existed with the X-ray powder diffraction that 2 θ angles indicate 5.7 ± 0.2 °, 6.5 ± 0.2 °, 7.1 ± 0.2 °, 8.7 ± 0.2 °, 10.8 ± 0.2 °, 11.4 ± 0.2 °, 11.8 ± 0.2 °, 13.2 ± 0.2 °, 14.3 ± 0.2 °, 15.0 ± 0.2 °, 15.7 ± 0.2 °, 16.7 ± 0.2 °, 17.4 ± 0.2 °, 18.4 ± 0.2 °, 19.6 ± 0.2 °, 19.8 ± 0.2 °, 20.1 ± 0.2 °, 20.6 ± 0.2 °, 21.8 ± 0.2 °, 22.4 ± 0.2 °, 23.0 ± 0.2 °, 23.4 There is characteristic diffraction peak at ± 0.2 °, 26.3 ± 0.2 °；In one embodiment of seventh aspect present invention, the change of the crystal form Object IV is closed, is radiated using Cu-K α, with the X-ray powder diffraction that 2 θ angles indicate there is X-RPD substantially as shown in Figure 1 to scheme Spectrum.

Eighth aspect present invention provides a kind of compound III of crystal form, and the compound III of the crystal form makes With Cu-K α radiate, the X-ray powder diffraction indicated with 2 θ angles at 7.5 ± 0.2 °, 8.5 ± 0.2 °, 13.1 ± 0.2 °, 15.0 ± 0.2 °, 16.1 ± 0.2 °, 17.3 ± 0.2 °, 18.8 ± 0.2 °, 19.0 ± 0.2 °, 19.9 ± 0.2 °, 20.4 ± 0.2 °, 23.7 ± 0.2 °, 24.0 ± 0.2 °, 24.3 ± 0.2 °, 24.7 ± 0.2 °, 25.8 ± 0.2 °, 26.3 ± 0.2 °, 29.8 ± 0.2 ° There is characteristic diffraction peak at place；Specifically, the compound III of the crystal form, is radiated using Cu-K α, is indicated with 2 θ angles X-ray powder diffraction at 7.5 ± 0.2 °, 8.5 ± 0.2 °, 13.1 ± 0.2 °, 14.2 ± 0.2 °, 15.0 ± 0.2 °, 16.1 ± 0.2 °, 17.3 ± 0.2 °, 18.8 ± 0.2 °, 19.0 ± 0.2 °, 19.9 ± 0.2 °, 20.4 ± 0.2 °, 21.7 ± 0.2 °, 23.7 ± 0.2 °, 24.0 ± 0.2 °, 24.3 ± 0.2 °, 24.7 ± 0.2 °, 25.8 ± 0.2 °, 26.3 ± 0.2 °, 27.2 ± 0.2 °, 29.3 ± There is characteristic diffraction peak at 0.2 °, 29.8 ± 0.2 °；More specifically, the compound III of the crystal form, is radiated using Cu-K α, The X-ray powder diffraction that it is indicated with 2 θ angles at 7.5 ± 0.2 °, 8.5 ± 0.2 °, 13.1 ± 0.2 °, 14.2 ± 0.2 °, 15.0 ± 0.2 °, 16.1 ± 0.2 °, 17.3 ± 0.2 °, 18.8 ± 0.2 °, 19.0 ± 0.2 °, 19.9 ± 0.2 °, 20.4 ± 0.2 °, 21.7 ± 0.2 °, 23.7 ± 0.2 °, 24.0 ± 0.2 °, 24.3 ± 0.2 °, 24.7 ± 0.2 °, 25.8 ± 0.2 °, 26.3 ± 0.2 °, There is feature diffraction at 27.2 ± 0.2 °, 29.3 ± 0.2 °, 29.8 ± 0.2 ° 30.2 ± 0.2 °, 31.7 ± 0.2 °, 32.5 ± 0.2 ° Peak；In one embodiment of the invention, the compound III of the crystal form, is radiated using Cu-K α, with 2 θ angle tables The X-ray powder diffraction shown has X-RPD map substantially as shown in Figure 2.

Ninth aspect present invention provides a kind of compound II of crystalline forms, the compound II of the crystal form, uses Cu-K α radiation, the X-ray powder diffraction indicated with 2 θ angles at 12.0 ± 0.2 °, 13.1 ± 0.2 °, 13.6 ± 0.2 °, 16.4 ± 0.2 °, 19.2 ± 0.2 °, 22.1 ± 0.2 °, 22.6 ± 0.2 °, 23.7 ± 0.2 °, 23.9 ± 0.2 °, 24.9 ± 0.2 °, There is characteristic diffraction peak at 26.1 ± 0.2 °, 27.9 ± 0.2 °, 31.7 ± 0.2 °；Specifically, the compound II of the crystal form, Radiated using Cu-K α, the X-ray powder diffraction indicated with 2 θ angles at 4.0 ± 0.2 °, 12.0 ± 0.2 °, 13.1 ± 0.2 °, 13.6 ± 0.2 °, 14.3 ± 0.2 °, 16.4 ± 0.2 °, 17.8 ± 0.2 °, 18.4 ± 0.2 °, 19.2 ± 0.2 °, 20.1 ± 0.2 °, 21.8 ± 0.2 °, 22.1 ± 0.2 °, 22.6 ± 0.2 °, 23.2 ± 0.2 °, 23.7 ± 0.2 °, 23.9 ± 0.2 °, 24.9 ± There is characteristic diffraction peak at 0.2 °, 26.1 ± 0.2 °, 27.9 ± 0.2 °, 31.7 ± 0.2 °, 32.1 ± 0.2 °；At of the invention one In embodiment, the compound II of the crystalline forms is radiated using Cu-K α, the X-ray powder diffraction tool indicated with 2 θ angles There is X-RPD map substantially as shown in Figure 3.

In the present invention, if not otherwise specified, the solvent is Conventional solvents, reaction it is general at room temperature into Row, the dosage of reaction dissolvent are the conventional amount used of reaction, and the dosage of catalyst is conventional catalytic amount, and organic phase drying is adopted It is dry with anhydrous sodium sulfate.Heretofore described alkali metal refers to lithium, sodium, potassium, rubidium, caesium, the alkaline-earth metal refer to beryllium, magnesium, Calcium, strontium, barium.Although (such as prepare compound II's is anti-for dosage or ingredient proportion of the present invention to part reactant and reaction dissolvent Answer) appropriate restriction has been carried out, but these limit the conventional amount used that range still falls within this field, and limited amount range is not explanation Dosage except range can not achieve the present invention or carry out chemical preparation reaction, but inventor combined reaction condition, after Processing operation specifies the dosage for being more suitable for the present invention or this reaction after the factors such as reaction cost in the range of conventional amount used Range.Skilled person still can according to the basic principles of chemistry of general knowledge known in this field in the reactant recorded of the present invention and Dosage is determined except reaction dissolvent consumption range in right amount.Reagent or raw material used in the present invention can by existing literature or Prior art preparation obtains, or can be commercially available.Such as compound V can be prepared by the method for embodiment 1.

The present invention provides new intermediate and its preparation process, dehydrogenation impurity Q2 in prepare compound IV is effectively reduced Content, thus effectively reduce it is subsequent preparation Silodosin during dehydrogenation impurity Q3~Q4 content, greatly reduce match Luo Duoxin clarification process, is conducive to the drug for obtaining high-purity, ensures that Drug safety.

The process conditions that the present invention respectively prepares reaction are mild, and reaction yield is high, environmental-friendly, easy to industrialized production, together When both avoided that trifluoroacetic acid pollution environment is serious, is not easy post-processing and problem at high cost, also avoid high-pressure catalytic hydrogenation To the rigors and operational danger of equipment, while avoiding heavy metal palladium pollution environment.

Detailed description of the invention

The X-RPD map of 2 gained compound IV of Fig. 1 embodiment；

The X-RPD map of 3 gained compound III of Fig. 2 embodiment；

The X-RPD map of 4 gained compound II of Fig. 3 embodiment.

Specific embodiment

Below by way of specific embodiment, above content of the invention is described in further detail, but should not be incited somebody to action This is interpreted as any restrictions to present invention protection theme.All technical solutions realized based on above content of the present invention are belonged to The scope of the present invention.The present invention to used in test to material and test method carry out general and/or specifically retouch It states.It will be apparent to those skilled in the art that hereinafter, if not specified, the operation that the present invention is carried out is this field routine Progress under room temperature, the room temperature have art-recognized meanings well known in the art, generally refer to 10~30 DEG C, preferably 15~25 DEG C, more preferable 20~25 DEG C.

Detecting instrument used in the present invention:

(1) nuclear magnetic resoance spectrum

Instrument model: Varian INOVA-400 Nuclear Magnetic Resonance.

Test condition: solvent DMSO-d6.

(2) mass spectrum

Instrument model: Q-Tof micro mass spectrograph.

Test condition: ESI.

Embodiment 1, tert-butyl-(R) -1- (1- (3- (benzoyloxy) propyl) -7- cyanoindole quinoline -5- base) propyl - The preparation of 2- base-carbonic ester (compound V)

By 500g 5- [(2R) -2- aminopropyl] -2,3- dihydro -1- [3- (benzoyloxy) propyl] -1H- indoles -7- Nitrile tartrate (compound SM1) is added in 3.0L methylene chloride and stirs, and the aqueous solution of potassium carbonate (1.105kg) is then added (4.0L) is added dropwise 221g (Boc)₂O after being added dropwise, reacts 5 hours at 15 ~ 25 DEG C, stands liquid separation, methylene chloride phase is successively It is washed with 0.2mol/L HCl solution 3L, saturated sodium bicarbonate solution 2L, saturated salt solution 2L, then anhydrous sodium sulfate is dry, Filtering, filtrate decompression steam solvent, obtain 457g compound V, HPLC purity 99.57%；

MS[M+H]⁺: 464；

¹H NMR (400 MHz, DMSO): 8.01-7.99 (d, 2H), 7.67-7.63 (m, 1H), 7.52-7.49 (m, 2H), 7.04(s,1H), 6.95(s,1H), 6.72-6.70(m,1H), 4.37(m,2H), 3.67-3.54(m,5H), 22.94-2.90(m,2H), 2.51-2.47(m,1H), 2.05(m,2H), 1.33(s,9H), 1.32(m,2H), 1.00- 0.99(m,3H) 。

Embodiment 2, tert-butyl (R) -1- (7- carbonamido -1- (3- hydroxypropyl) indoline -5- base) propyl -2- base - The preparation of carbonic ester (compound IV)

178g(0.384mol) compound V is added to stirring and dissolving in 1.78L dimethyl sulfoxide, 20 ~ 25 DEG C of temperature control, is dripped Add 0.168L(0.84mol) concentration be 5mol/L KOH solution, be added dropwise 217g(1.91mol) mass fraction be 30% H₂O₂Water 5% sodium sulfite aqueous solution of 5.34L is added to reaction solution in solution, 15 ~ 25 DEG C of reaction 5h, and solid, filtering, filtrate is precipitated in stirring It is extracted with ethyl acetate, washed, dry, decompression steams solvent, obtains 119g compound IV, yield 81.5%, HPLC purity The content of 97.43%, dehydrogenation impurity Q1 are 1.83%, and after measured, X-RPD map is as shown in Figure 1；

MS[M+H]⁺: 378；

¹H NMR (400 MHz, DMSO): 7.64 (s, 1H), 7.31 (m, 1H), 6.91-6.86 (d, 2H), 6.73- 6.72(m,1H), 4.38(m,1H), 3.54-3.33(m,5H), 3.12(m,2H), 2.88-2.87(m,2H), 2.59(m, 1H), 2.40-2.35(m,1H), 1.62(m,2H), 1.35(s,9H), 0.97(m,3H)。

Embodiment 3,5- ((R) -2- aminocarbonyl propyl) -1- (3- hydroxypropyl) indoline -7- phosphinylidyne amine hydrochlorate (compound III it) prepares

Stirring in 300mL ethyl alcohol is added in 30g(54.04 mmol) compound IV and is cooled to 0 ~ 10 DEG C, it is dense to instill 36.2mL Degree is the HCl ethanol solution (72.4 mmol) of 2mol/L, and 15 ~ 25 DEG C are stirred to react 5~6h, is filtered, dry, obtains 23.8gization Object III, HPLC purity 99.59% are closed, the content of dehydrogenation impurity Q2 is 0.18%, and after measured, X-RPD map is as shown in Figure 2；

MS[M-Cl]⁺: 278；

¹H NMR (400 MHz, DMSO): 8.04 (m, 2H), 7.74 (s, 1H), 7.35 (s, 1H), 6.94-6.89 (d, 2H), 4.43(br,1H), 3.42-3.16(m,7H);2.91-2.50(m,4H), 1.62(m,2H),112-1.10(m,3H)。

Embodiment 4,5- ((R) -2- aminocarbonyl propyl) -1- (3- hydroxypropyl) indoline -7- carbamide (compound II) Preparation

2L ethyl alcohol stirring and dissolving is added in 23.8g(76mmol) compound III, sodium carbonate 12g(113.2mmol is added), 40 ~ 50 DEG C of 1 ~ 1.5h of stirring are warming up to, are filtered；50 ~ 55 DEG C of decompressions of filtrate steam solvent, obtain 21.5g compound II, yield 97.7%, HPLC purity 99.63%, the content of dehydrogenation impurity Q3 are 0.18%, and after measured, X-RPD map is as shown in Figure 3；

MS[M+H]⁺: 278；

¹H NMR (400 MHz, DMSO): 8.04 (m, 2H), 7.74 (s, 1H), 7.35 (s, 1H), 6.94-6.89 (d, 2H), 4.43(br,1H), 3.42-3.16(m,7H);2.91-2.50(m,4H), 1.62(m,2H),112-1.10(m, 3H).。

The preparation of embodiment 5, Silodosin (compound I)

By 14.32g(40.54mmol) compound II, potassium carbonate 14.95g(106.5mmol), potassium iodide 6.54g (39.4mmol), sodium sulfite 0.59g(4.7mmol) in sequentially add in 150 ml DMAC N,N' dimethyl acetamides, 14.72g Reaction solution is added in 450mL water after 55 ~ 60 DEG C of temperature control reactions for 24 hours for compound SM2 stirring, and the extraction of 300mL ethyl acetate has Machine mutually uses saturated common salt water washing, and anhydrous sodium sulfate dries, filters, and filtrate is concentrated into 60-100mL, is cooled to -10~0 DEG C of analysis Crystalline substance filters, dry, obtains 21.0 g Silodosin solids, yield 86.06%, purity 99.91%, dehydrogenation impurity Q4 content 0.05%。

Claims

1. a kind of method of prepare compound IV, which is characterized in that method includes the following steps: compound V is dissolved in instead Solvent I is answered, inorganic base aqueous solution, peroxide is added, is stirred to react 3~5h at 10~30 DEG C, sodium sulfite water is then added Solution, extracts organic phase, washing, drying, and decompression steams solvent, obtains compound IV；

Wherein, the inorganic base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate；It is described anti- Solvent I is answered to be selected from dimethyl sulfoxide, methylene chloride, chloroform, tetrahydrofuran；The peroxide is selected from hydrogen peroxide, peroxide Change sodium, potassium peroxide, calper calcium peroxide, strontium peroxide；The molar feed ratio of compound V and peroxide is 1:2~10；Compound The molar feed ratio of V and inorganic base is 1:1.1~3；The molar feed ratio of compound V and sodium sulfite is 1:2~10.

2. method according to claim 1, which is characterized in that the reaction dissolvent I is selected from dimethyl sulfoxide, methylene chloride.

3. method according to claim 1, which is characterized in that the peroxide is selected from the H that mass fraction is 30%₂O₂Water Solution.

4. method according to claim 1, which is characterized in that the molar feed ratio of compound V and peroxide is 1:3~6.

5. method according to claim 1, which is characterized in that the molar feed ratio of compound V and peroxide is 1:5.

6. method according to claim 1, which is characterized in that the molar feed ratio of compound V and inorganic base is 1:1.6~2.

7. method according to claim 1, which is characterized in that the molar feed ratio of compound V and inorganic base is 1:1.8.

8. method according to claim 1, which is characterized in that the molar feed ratio of compound V and sodium sulfite is 1:3~6.

9. method according to claim 1, which is characterized in that the molar feed ratio of compound V and sodium sulfite is 1:5.

10. method according to claim 1, which is characterized in that method includes the following steps: compound V is added to two KOH aqueous solution, 30%H is added dropwise in stirring and dissolving in methyl sulfoxide₂O₂, 15~25 DEG C of 3~5h of reaction, then be added sodium sulfite water Ethyl acetate extraction is added in solution, filtering, filtrate, and decompression steams solvent at 40~45 DEG C after washed, drying, obtains compound IV。

11. the method for Silodosin shown in a kind of preparation formula I, method includes the following steps: in inorganic base, iodide, Asia In the presence of sodium sulphate, compound III reacts in reaction dissolvent IV with compound SM2；

Wherein, the feed ratio of compound III and compound SM2 is 1:1~2；The molar feed ratio of compound III and inorganic base is 1:4~8；The molar feed ratio of compound III and iodide is 1:0.8~1.5；Mole throwing of compound III and sodium sulfite Material is than being 1:0.1~0.5；The mass volume ratio of compound III and reaction dissolvent IV is 1:8~15, unit: g/ml；The nothing Machine alkali is selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, saleratus, calcium bicarbonate； The iodide are selected from potassium iodide, sodium iodide, ammonium iodide, hydrogen iodide；The reaction dissolvent IV is selected from ethyl alcohol, methanol, N, N- bis- One of methylformamide, DMAC N,N' dimethyl acetamide are a variety of.

12. according to the method for claim 11, which is characterized in that the feed ratio of compound III and compound SM2 is 1:1: 1.2~1.8.

13. according to the method for claim 11, which is characterized in that the feed ratio of compound III and compound SM2 is 1: 1.2~1.5.

14. according to the method for claim 11, which is characterized in that the molar feed ratio of compound III and inorganic base is 1:4 ~6.

15. according to the method for claim 11, which is characterized in that the molar feed ratio of compound III and inorganic base is 1: 4。

16. according to the method for claim 11, which is characterized in that the molar feed ratio of compound III and iodide is 1: 0.8~1.2.

17. according to the method for claim 11, which is characterized in that the molar feed ratio of compound III and iodide is 1: 1。

18. according to the method for claim 11, which is characterized in that the molar feed ratio of compound III and sodium sulfite is 1:0.1~0.2.

19. according to the method for claim 11, which is characterized in that the mass volume ratio of compound III and reaction dissolvent IV For 1:10~12, unit: g/ml.

20. according to the method for claim 11, which is characterized in that this method comprises the following steps: by compound III, carbon Sour potassium, potassium iodide, sodium sulfite, compound SM2 are added in n,N-dimethylacetamide, and 30~60 DEG C of temperature control, reaction 12~ For 24 hours, reaction solution is added in suitable quantity of water, ethyl acetate extraction, organic phase is washed, and dry, decompression steams solvent, obtains celo It is mostly pungent.

21. according to the method for claim 20, which is characterized in that 40~50 DEG C of temperature control.

22. the method for Silodosin shown in a kind of preparation formula I, method includes the following steps: in inorganic base, iodide, sulfurous In the presence of sour sodium, compound II reacts to obtain compound I in reaction dissolvent IV with compound SM2；

Wherein, the feed ratio of compound II and compound SM2 is 1:1~2；The molar feed ratio of compound II and inorganic base is 1: 2~6；The molar feed ratio of compound II and iodide is 1:0.8~1.5；The molar feed ratio of compound II and sodium sulfite For 1:0.1~0.5；The mass volume ratio of compound II and reaction dissolvent IV is 1:8~15, unit: g/ml；Reaction dissolvent IV choosing From N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, ethyl alcohol, methanol, tetrahydrofuran；The inorganic base is selected from hydroxide Sodium, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, saleratus, calcium bicarbonate；The iodide are selected from Potassium iodide, sodium iodide, ammonium iodide, hydrogen iodide.

23. according to the method for claim 22, which is characterized in that the feed ratio of compound II and compound SM2 is 1:1.2 ~1.8.

24. according to the method for claim 22, which is characterized in that the feed ratio of compound II and compound SM2 is 1:1.2 ~1.5.

25. according to the method for claim 22, which is characterized in that the molar feed ratio of compound II and inorganic base is 1:2 ~4.

26. according to the method for claim 22, which is characterized in that the molar feed ratio of compound II and inorganic base is 1:2 ~3.

27. according to the method for claim 22, which is characterized in that the molar feed ratio of compound II and iodide is 1: 0.8~1.2.

28. according to the method for claim 22, which is characterized in that the molar feed ratio of compound II and iodide is 1:1.

29. according to the method for claim 22, which is characterized in that the molar feed ratio of compound II and sodium sulfite is 1: 0.1~0.2.

30. according to the method for claim 22, which is characterized in that compound II and the mass volume ratio of reaction dissolvent IV are 1:10~12, unit: g/ml.

31. according to the method for claim 22, which is characterized in that this method comprises the following steps: by compound II, carbonic acid Potassium, potassium iodide, sodium sulfite, compound SM2 are added in n,N-dimethylacetamide, and 30~60 DEG C of temperature control, reaction 12~for 24 hours, Reaction solution is added in suitable quantity of water, ethyl acetate extraction, organic phase is washed, and dry, decompression steams solvent, and it is more to obtain celo It is pungent.

32. according to the method for claim 31, which is characterized in that 40~50 DEG C of temperature control.