CN103420893A - Method for preparing silodosin intermediate - Google Patents
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- 0 CC(Cc1cc(CC*2CCCOC(c3ccccc3)=O)c2c(C(F)(F)F)c1)*1(CC1)C(OC(C)(C)C)=O Chemical compound CC(Cc1cc(CC*2CCCOC(c3ccccc3)=O)c2c(C(F)(F)F)c1)*1(CC1)C(OC(C)(C)C)=O 0.000 description 3
- TXKJDQDSCUFAHP-UHFFFAOYSA-N CC(Cc(cc1C#N)cc2c1N(CCCOC(c1ccccc1)=O)CC2)NC(OC(C)(C)C)=O Chemical compound CC(Cc(cc1C#N)cc2c1N(CCCOC(c1ccccc1)=O)CC2)NC(OC(C)(C)C)=O TXKJDQDSCUFAHP-UHFFFAOYSA-N 0.000 description 2
- VPPHCSVRGJBZOR-UHFFFAOYSA-N CC(Cc(cc1Br)cc2c1N(CCCOC(c1ccccc1)=O)CC2)NC(OC(C)(C)C)=O Chemical compound CC(Cc(cc1Br)cc2c1N(CCCOC(c1ccccc1)=O)CC2)NC(OC(C)(C)C)=O VPPHCSVRGJBZOR-UHFFFAOYSA-N 0.000 description 1
- BJTIXNLEUCYRBC-NSHDSACASA-N C[C@@H](Cc(cc1)cc2c1NCC2)NC(OC(C)(C)C)=O Chemical compound C[C@@H](Cc(cc1)cc2c1NCC2)NC(OC(C)(C)C)=O BJTIXNLEUCYRBC-NSHDSACASA-N 0.000 description 1
- GCKCREURICWFPY-UHFFFAOYSA-N O=C(c1ccccc1)OCCCCl Chemical compound O=C(c1ccccc1)OCCCCl GCKCREURICWFPY-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention provides a method for preparing a silodosin intermediate 5-[(2R)-2-(amino) propyl]-1-[3-(benzoyloxy) propyl]-7-cyano indoline (I) shown in the specification, as well as intermediates used in the preparation method and a production method of the intermediates. The silodosin intermediate uses easy-to-obtain indoline as an initial raw material to prepare the 5-[(2R)-2-(amino) propyl]-1-[3-(benzoyloxy) propyl]-7-cyano indoline through a series of reactions so as to prepare silodosin. The silodosin is a useful therapeutic agent for treating urination dysfunction associated with benign prostatic hyperplasia. The method is simple in operation, high in yield, free from resolution, low in cost and suitable for industrial production.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, be specifically related to prepare silodosin intermediate 5-[(2R)-2-(amino) propyl group]-1-[3-(benzoyloxy) propyl group]-method of 7-cyanoindole quinoline, and intermediate therefor and uses thereof in the preparation production method.
Background technology
Benign prostatic hyperplasia (BPH) is middle-aging male common disease and frequently-occurring disease, and the drug main that is used for the treatment of clinically BPH at present will be divided into two classes: α, 1 adrenoceptor (α-AR) antagonist and 5 alpha reductase inhibitors.Wherein α-AR antagonist have fast, safety, efficient characteristics.Silodosin is the α-AR antagonist of a kind of BPH, is used for the treatment of the misnicturition due to benign prostatic hyperplasia.
Silodosin shrinks and has selective inhibitory for urethral smooth muscle, and reduces in urethra and press, and blood pressure is not had a significant impact, and side effect is little, thereby can be used for treating benign prostatic hyperplasia.The synthetic method of at present relevant silodosin is more, but it is simple to lack technique, and yield is high, is applicable to the method for industrialized production.
JP2001199956 has reported take phenylformic acid and prepares 5-[(2R through polystep reaction as raw material)-2-aminopropyl [1-[3-(benzoyloxy) propyl group]--the method for 7-cyanoindole quinoline L-TARTARIC ACID salt, the method is by compound 5-[2-oxopropyl]-1-[3-(benzoyloxy) propyl group]-the asymmetric reduction amination of 7-cyanoindole quinoline and L-benzene glycinol obtains target product.The diastereomer intermediate of the mixing that reduction amination obtains (diastereomer ratio 3.8:1), then, under the effect of palladium carburetted hydrogen gas, slough the phenylethyl alcohol part, then purify with L-TARTARIC ACID, obtains target compound.In this route, the polystep reaction yield is low, and the column chromatography step is wherein arranged, and has used expensive L-benzene glycinol, is not suitable for scale operation.
JP2002265444 has reported 5-[(2R)-the 2-aminopropyl]-1-[3-(benzoyloxy) propyl group]--the preparation method of 7-cyanoindole quinoline, the method is passed through the fractionation to compound (11), and obtains target compound.The synthetic route of the method is long, and resolution yield is low, and resolution reagent used is difficult to obtain, and is not suitable for scale operation.
In above-mentioned prior art, as shown in the formula the optical activity intermediate of (I), be the key intermediate for preparing silodosin:
Therefore, a kind of method that needs applicable suitability for industrialized production of the above-mentioned key intermediate that prepare silodosin.
Summary of the invention
When in prior art, preparing silodosin, due to intermediate, be 5-[(2R)-2-(amino) propyl group]-1-[3-(benzoyloxy) propyl group]-complicated process of preparation of 7-cyanoindole quinoline cause the shortcomings such as problem that cost is higher, the present invention has been proposed.
In order to reduce in prior art the reactions steps of the technique for preparing the silodosin intermediate, reduce costs, make it to be applicable to suitability for industrialized production, the invention provides intermediate used in a kind of synthetic route of the intermediate for the preparation of silodosin and production method and uses thereof.
One aspect of the present invention provides relevant precursor midbody compound in silodosin midbody compound I building-up process, suc as formula the compound shown in SLD-5A, SLD-5B, SLD-4B, SLD-4A, SLD-3A, SLD-3B, SLD-2 and SLD-1,
Another aspect of the present invention provides the method for compound shown in a kind of preparation formula I, comprises successively following 6 steps:
Described method specifically comprises the following steps:
1) will comprised under the condition of organic solvent by the compound shown in formula SLD-6, at 0-100 ℃ of temperature, and the reaction of N-bromo-succinimide, obtain the compound shown in formula SLD-5A,
2) under nitrogen protection, in DMF solution, at-10-20 ℃ of temperature, by the compound shown in formula SLD-5C, with zinc powder, reacted, make the organic zinc reagent shown in formula SLD-5C ',
Organic zinc reagent shown in formula SLD-5C ' is at nitrogen protection, 0-80 ℃, palladium and 2-dicyclohexyl phosphorus-2', and 4', under the catalysis of 6'-tri isopropyl biphenyl, react with the compound shown in above-mentioned formula SLD-5A, obtains the compound shown in formula SLD-4A,
3) compound shown in formula SLD-4A is under alkaline condition, and in organic solvent, the reaction that is hydrolyzed, obtain the compound shown in formula SLD-3A,
4) compound shown in the compound shown in formula SLD-3C and above-mentioned formula SLD-3A, in organic solvent, react under alkaline condition, obtains the compound shown in formula SLD-2,
5) compound shown in formula SLD-2 and zinc cyanide are under tetrakis triphenylphosphine palladium, organic solvent and nitrogen protection condition, and 20-150 ℃ is reacted 0.5-10 hour, obtains the compound shown in formula SLD-1,
6) compound shown in formula SLD-1, at ethyl acetate neutralized salt acid-respons 0.5-24 hour, obtains the compound shown in formula I.
The present invention also provides the method for compound shown in another kind of preparation formula I, comprises successively following 6 steps:
Described method specifically comprises the following steps:
1) nitrogen protection, in DMF solution, at-10-20 ℃ of temperature, reacted with zinc powder and made the organic zinc reagent shown in formula SLD-5C ' by the compound shown in formula SLD-5C,
Organic zinc reagent shown in formula SLD-5C ' is in nitrogen protection, 0-80 ℃, and palladium and 2-dicyclohexyl phosphorus-2', 4', under the catalysis of 6'-tri isopropyl biphenyl, react with the compound shown in formula SLD-6, obtains the compound shown in formula SLD-5B,
2) compound shown in formula SLD-5B is under alkaline condition, and in organic solvent, the reaction that is hydrolyzed, obtain the compound shown in formula SLD-4B,
3) compound shown in the compound shown in formula SLD-3C and above-mentioned formula SLD-4B, in organic solvent, react under alkaline condition, obtains the compound shown in formula SLD-3B,
4) will comprised under the condition of organic solvent by the compound shown in formula SLD-3B, at 0-100 ℃ of temperature, and the reaction of N-bromo-succinimide, obtain the compound shown in formula SLD-2,
5) by the compound shown in SLD-2 and zinc cyanide under tetrakis triphenylphosphine palladium, organic solvent and nitrogen protection condition, 20-150 ℃ of reaction 0.5-10 hour, obtain the compound shown in formula SLD-1,
6) compound shown in formula SLD-1, at ethyl acetate neutralized salt acid-respons 0.5-24 hour, obtains the compound shown in formula I.
Preparation method of the present invention, wherein said SLD-5C, SLD-5C ', SLD-4A, SLD-3A, SLD-2 and SLD-1 are chipal compounds.
Preparation method of the present invention, wherein said SLD-5C, SLD-5C ', SLD-5B, SLD-4B, SLD-3B, SLD-2 and SLD-1 are chipal compounds.
Preparation method of the present invention, wherein said organic solvent is to be selected from methyl alcohol, ethanol, glacial acetic acid, N-Methyl pyrrolidone, acetonitrile or N,N-dimethylacetamide.
Preparation method of the present invention, wherein said alkali is to be selected from sodium hydroxide, potassium hydroxide, salt of wormwood, sodium carbonate, sodium bicarbonate, diisopropyl ethylenediamine, pyridine or triethylamine.
The present invention also provides the method for compound shown in a kind of preparation formula SLD-3C, comprises the steps:
Described method specifically comprises the following steps:
By Benzoyl chloride and 3-propylene chlorohydrin, in organic solvent, under alkaline condition, react, obtain the compound meaned by formula SLD-3C:
The present invention also provides the method for compound shown in a kind of preparation formula SLD-5C, comprises the steps:
Described method specifically comprises the following steps:
1) will comprise organic solvent by the compound shown in formula SLD-9C, under the ice-water bath condition, react with sulfur oxychloride 3-10 hour, obtain the compound shown in formula SLD-8C,
2) compound shown in formula SLD-8C, in organic solvent, under alkaline condition, reacts with tert-Butyl dicarbonate 3-7 hour, obtains the compound shown in SLD-7C,
3) compound shown in formula SLD-7C is in organic solvent, under alkaline condition, and the sodium borohydride reaction, obtain the compound shown in formula SLD-6C,
Compound shown in formula SLD-6C, in triphenylphosphine, organic solvent, with Iod R, obtains the compound shown in formula SLD-5C,
The present invention also provides the method for compound shown in a kind of preparation formula SLD-6, comprises the steps:
Described method specifically comprises the following steps:
1) indoline formula SLD-8 meaned, in organic solvent, under alkaline condition, under-10-20 ℃ and excess acetyl chloride, obtain the compound shown in formula SLD-7,
2) compound shown in formula SLD-7, in organic solvent, react with the N-N-iodosuccinimide under 20-150 ℃ 0.5-10 hour, obtains the compound shown in SLD-6,
Further aspect of the present invention is to provide the purposes of a series of compounds as synthetic silodosin intermediate.
The accompanying drawing explanation
Fig. 1 is compound S LD-8C
1H NMR figure;
Fig. 2 is compound S LD-7C
1H NMR figure;
Fig. 3 is compound S LD-6C
1H NMR figure;
Fig. 4 is compound S LD-5C
1H NMR figure;
Fig. 5 is the MS figure of compound S LD-3C;
Fig. 6 is the MS figure of compound S LD-7;
Fig. 7 is the MS figure of compound S LD-6;
Fig. 8 is the MS figure of compound S LD-5A;
Fig. 9 is the MS figure of compound S LD-5B;
Figure 10 is compound S LD-5B
1H NMR figure;
Figure 11 is the MS figure of compound S LD-4B;
Figure 12 is compound S LD-4B
1H NMR figure;
Figure 13 is the MS figure of compound S LD-4A;
Figure 14 is the MS figure of compound S LD-3A;
Figure 15 is compound S LD-3B
1H NMR figure;
Figure 16 is compound S LD-2
1H NMR figure;
Figure 17 is compound S LD-1
1H NMR figure; And
Figure 18 is Compound I
1H NMR figure.
Embodiment
Below with reference to specific embodiments, the present invention is described.It should be noted that, the following examples are example of the present invention, only are used for illustrating the present invention, and are not used for limiting the present invention.
1) preparation of compound S LD-3C
Take the 140g Benzoyl chloride and join in 1L single port bottle, add the 600mL methylene dichloride, the 70g triethylamine, be cooled to 0 ℃, slowly drips 94g 3-propylene chlorohydrin, keeps temperature below 10 ℃.Drip rear continuation reaction 1h.
After the TLC monitoring reaction is complete, 300mL*3 washes methylene dichloride, and drying, be spin-dried for, and obtains 188g colourless liquid SLD-3C, purity 99%.MSm/z:198 (M
+), yield: 95%.
2) preparation of compound S LD-8C
Take 107g SLD-9C and join in the 2L there-necked flask, add 600mL methyl alcohol, drip the 131mL sulfur oxychloride under mechanical stirring ice-water bath, and build device for absorbing tail gas, drip off rear back flow reaction 5～8h.
After the TLC monitoring reaction is complete, directly concentrated the steaming except methyl alcohol, use the 120mL*3 toluene wash, and concentrated steaming is except residual toluene, and oil pump is taken out 24h, obtains 167g white solid SLD-8C, yield: 99.6%.
1H-NMR(d
6-DMSO)δ：8.71(s，1H)；8.52(s，2H)；3.71～4.05(m，1H)；3.36～3.46(s，3H)；1.19～1.62(d，3H)。
3) preparation of compound S LD-7C
Take 167g SLD-8C, the 242g triethylamine, the 1L methylene dichloride joins in the 2L there-necked flask, drips the 313g tert-Butyl dicarbonate, again adds the 200mL methylene dichloride, room temperature reaction 5h.
After the TLC monitoring reaction is complete, shrend is gone out, and separates methylene dichloride, and, with dichloromethane extraction (500mL*2), merges organic phase, wash 2 times, and anhydrous sodium sulfate drying, steaming desolventizes, and obtains red liquid 224g SLD-7C after column chromatography, yield: 92.2%.
1H-NMR(d
6-DMSO)δ：7.26～7.28(d，1H)；3.86～4.18(m，1H)；3.61(s，3H)；1.33～1.37(s，9H)；0.97～1.02(d，3H)。
4) preparation of compound S LD-6C
Take after 134g calcium chloride grinds and join in the 2L there-necked flask, add 400mL methyl alcohol and 500mL tetrahydrofuran (THF), add in methanol process cooling with ice-water bath, add the 92g sodium borohydride after slightly cold in batches, after stirring 0.5h, dropping 224gSLD-7C(is dissolved in the 200mL tetrahydrofuran (THF)), slowly be warming up to 70 ℃ after stirring at room 1h, react 15～20h.
After the TLC monitoring reaction is complete, pour cancellation in a large amount of frozen water into, leach solid residue, residue is washed (500mL*3) three times with methylene dichloride, separate organic layer, water layer extracts with 1L*2, merges organic layer, washes twice, anhydrous sodium sulfate drying, steaming desolventizes, and obtains 185g white solid SLD-6C, yield: 95.8%.
1H-NMR(d
6-DMSO)δ：6.48～6.51(d,1H);4.56～4.59(m,1H);3.47～3.61(m,1H);3.26～3.45(m,1H);3.11～3.18(m,1H);1.47(s,9H);0.85～0.96(d,3H)。
5) preparation of compound S LD-5C
Take the 187.6g triphenyl, 48.7g imidazoles joins in the 2L there-necked flask, add the 1L methylene dichloride, add 200g iodine in batches, maintain the temperature at below 30 ℃ with ice-water bath, after adding stirring 10min, 125.3g SLD-6C is dissolved in to the 200mL methylene dichloride, be added dropwise in reaction solution, drip off rear room temperature reaction 10～20h.
After the TLC monitoring reaction is complete, be poured into water cancellation, separate organic layer, water layer 500mL*2 dichloromethane extraction, merge organic layer, wash twice, anhydrous sodium sulfate drying, steaming desolventizes, column chromatography, sherwood oil+methylene dichloride recrystallization obtains 60g white solid SLD-5C, yield: 29.4%.
1H-NMR(d
6-DMSO)δ：6.96(m,1H);3.46～3.51(m,1H);3.19～3.31(m,2H);1.39～1.48(s,9H);0.99～1.12(d,3H)。
6) preparation of compound S LD-7
Take 66g SLD-8 and join in 1L single port bottle, add the 600mL methylene dichloride, the 84g triethylamine, be cooled to 0 ℃, slowly drips Acetyl Chloride 98Min. (65g, 1.5eq), keeps temperature below 10 ℃.Drip rear continuation reaction 1h.
After the TLC monitoring reaction is complete, 300mL*3 washes methylene dichloride, and drying, be spin-dried for, and ethyl alcohol recrystallization obtains the micro-yellow solid SLD-7 of 76g, purity 99.5%.MSm/z:161 (M
+), yield: 85.4%.
7) preparation of compound S LD-6
Take 76g SLD-7 and join in 1L single port bottle, add the 600mL glacial acetic acid, be warmed up to 100 ℃, after all dissolving, add 127g N-N-iodosuccinimide, continue reaction 4h.
After the TLC monitoring reaction is complete, strengthen water gaging, separate out a large amount of solids, filter the 300mL ethyl alcohol recrystallization.Obtain the micro-yellow solid SLD-6 of 90g.MS m/z:287 (M
+), yield: 66.7%.
8) preparation of compound S LD-5A
Take 90g SLD-6 and join in 1L single port bottle, add DMF 67g, be warmed up to 60 ℃, after all dissolving, add 67g N-bromo-succinimide.Continue reaction 12h.
After reaction finishes, strengthen water gaging, separate out a large amount of solids, filter ethanol (120mL) and sherwood oil (20mL) recrystallization.Obtain the micro-yellow solid SLD-5A of 65g.MS m/z:365 (M
+), yield: 57%.
9) preparation of compound S LD-4A
Take 46g zinc powder, 50mL DMF in the 1L there-necked flask, slowly drip 38g trimethylchlorosilane, stirring at room 0.5h under nitrogen protection.Standing, to incline and the stillness of night, 20mL DMF washing for solid, so repeat 2 times, adds the 100mL DMF.Be cooled to 0 ℃, slowly drip the 100mL DMF solution of 100gSLD-5C under nitrogen protection, keep temperature-5 ℃ between 5 ℃, add rear continuation reaction 1h.Add 65g SLD-5A, 1.2g palladium, 6.8g 2-dicyclohexyl phosphorus-2,4,6-tri isopropyl biphenyl, nitrogen replacement 3 times, room temperature reaction 1.5h.
After the TLC detection reaction finishes, by reaction solution, through diatomite filtration, filtrate adds water, the ethyl acetate extraction, merge organic layer, wash twice, saturated common salt is washed once, anhydrous sodium sulfate drying, concentrated, separate out solid, ethyl acetate and sherwood oil recrystallization, obtain 55g white solid SLD-4A.MS m/z:396 (M
+), yield: 78.6%.
10) preparation of compound S LD-3A
Take 55g SLD-4A, 300mL ethanol, 100mL water, 17g sodium hydroxide in 1L single port bottle, backflow 10h.
After the TLC detection reaction finishes, cooling, add 500mL water, by the extraction of 300mL*3 ethyl acetate, drying, concentrated, column chromatography obtains 40g white solid SLD-3A.MS m/z:354 (M
+), yield: 81.6%.
11) preparation of compound S LD-2
Take 40gSLD-3A, 23gSLD-3C, 24g sodium carbonate, the 2.4g potassiumiodide, 200mL DMF, in the single port bottle, is warmed up to 130 ℃, reaction 8h.
Reaction adds 500mL water after finishing, and the extraction of 200mL*3 ethyl acetate, merge organic layer, washing organic layer 3 times, and drying, concentrated, cross post and obtain 35g white solid SLD-2, yield 60%.
1H-NMR(d
6-DMSO)δ：7.324～7.345(m，5H)；6.950(s，1H)；6.846(s，1H)；6.683(d，1H)；3.485～3.527(m，4H)；3.302～3.447(m，3H)；2.857～2.914(t，2H)；1.779(t，2H)；1.333(s，9H)；1.234(s,2H)；0.972～0.992(d，3H)。
12) preparation of compound S LD-1
Take 35g SLD-2, the 15.8g zinc cyanide, 3.9g tetrakis triphenylphosphine palladium and 150mL DMF are in the single port bottle, and nitrogen protection, be warmed up to 80 ℃, reaction 48h.
The TLC detection reaction adds 300mL water after finishing, and the extraction of 200mL*3 ethyl acetate, merge organic layer, washing organic layer 3 times, and drying, concentrated, ethyl acetate and sherwood oil recrystallization, obtain 25g off-white color solid SLD-1, yield: 79.6%.
1H-NMR(d
6-DMSO)δ：7.265～7.336(m,5H);7.030(s,1H);6.934(s,1H);6.675～6.702(d,1H);3.484～3.575(m,7H);2.866～2.924(t,2H);2.494～2.506(M,2H);1.832～1.879(t,2H);1.324(s,9H);0.981～1.002(d,3H)。
13) preparation of Compound I
Take 25g SLD-1 and be added in 30mL concentrated hydrochloric acid and 200mL ethyl acetate, stirring at room 3h.Reaction is carefully regulated pH to 9 after finishing.Add 200mL water, the extraction of 200mL*3 ethyl acetate, merge organic layer, washing organic layer 3 times, and drying, concentrated, obtain 15g colourless oil liquid I, yield: 76.5%.
1H-NMR(d
6-DMSO)δ：7.2775～7.333(m,5H);7.032(s,1H);6.938(s,1H);3.480～3.581(m,6H);2.866～2.926(t,3H);2.341～2.363(d,2H);1.862～1.908(t,2H);0.910～0.931(d,3H)。
1) preparation of compound S LD-3C
Take the 140g Benzoyl chloride and join in 1L single port bottle, add the 600mL methylene dichloride, the 70g triethylamine, be cooled to 0 ℃, slowly drips 94g 3-propylene chlorohydrin, keeps temperature below 10 ℃.Drip rear continuation reaction 1h.
After the TLC monitoring reaction is complete, 300mL*3 washes methylene dichloride, and drying, be spin-dried for, and obtains 188g colourless liquid SLD-3C, purity 99%.MSm/z:198 (M
+), yield: 95%.
2) preparation of compound S LD-8C
Take 107g SLD-9C and join in the 2L there-necked flask, add 600mL methyl alcohol, drip the 131mL sulfur oxychloride under mechanical stirring ice-water bath, and build device for absorbing tail gas, drip off rear back flow reaction 5～8h.
After the TLC monitoring reaction is complete, directly concentrated the steaming except methyl alcohol, use the 120mL*3 toluene wash, and concentrated steaming is except residual toluene, and oil pump is taken out 24h, obtains 167g white solid SLD-8C, yield: 99.6%.
1H-NMR(d
6-DMSO)δ：8.71(s,1H);8.52(s,2H);3.71～4.05(m,1H);3.36～3.46(s,3H);1.19～1.62(d,3H)。
3) preparation of compound S LD-7C
Take 167g SLD-8C, the 242g triethylamine, the 1L methylene dichloride joins in the 2L there-necked flask, drips the 313g tert-Butyl dicarbonate, again adds the 200mL methylene dichloride, room temperature reaction 5h.
After the TLC monitoring reaction is complete, shrend is gone out, and separates methylene dichloride, and, with dichloromethane extraction (500mL*2), merges organic phase, wash 2 times, and anhydrous sodium sulfate drying, steaming desolventizes, and obtains red liquid 224g SLD-7C after column chromatography, yield: 92.2%.
1H-NMR(d
6-DMSO)δ：7.26～7.28(d,1H);3.86～4.18(m,1H);3.61(s,3H);1.33～1.37(s,9H);0.97～1.02(d,3H)。
4) preparation of compound S LD-6C
Take after 134g calcium chloride grinds and join in the 2L there-necked flask, add 400mL methyl alcohol and 500mL tetrahydrofuran (THF), add in methanol process cooling with ice-water bath, add the 92g sodium borohydride after slightly cold in batches, after stirring 0.5h, dropping 224gSLD-7C(is dissolved in the 200mL tetrahydrofuran (THF)), slowly be warming up to 70 ℃ after stirring at room 1h, react 15～20h.
After the TLC monitoring reaction is complete, pour cancellation in a large amount of frozen water into, leach solid residue, residue is washed (500mL*3) three times with methylene dichloride, separate organic layer, water layer extracts with 1L*2, merges organic layer, washes twice, anhydrous sodium sulfate drying, steaming desolventizes, and obtains 185g white solid SLD-6C, yield: 95.8%.
1H-NMR(d
6-DMSO)δ：6.48～6.51(d,1H);4.56～4.59(m,1H);3.47～3.61(m,1H);3.26～3.45(m,1H);3.11～3.18(m,1H);1.47(s,9H);0.85～0.96(d,3H)。
5) preparation of compound S LD-5C
Take the 187.6g triphenyl, 48.7g imidazoles joins in the 2L there-necked flask, add the 1L methylene dichloride, add 200g iodine in batches, maintain the temperature at below 30 ℃ with ice-water bath, after adding stirring 10min, 125.3g SLD-6C is dissolved in to the 200mL methylene dichloride, be added dropwise in reaction solution, drip off rear room temperature reaction 10～20h.
After the TLC monitoring reaction is complete, be poured into water cancellation, separate organic layer, water layer 500mL*2 dichloromethane extraction, merge organic layer, wash twice, anhydrous sodium sulfate drying, steaming desolventizes, column chromatography, sherwood oil+methylene dichloride recrystallization obtains 60g white solid SLD-5C, yield: 29.4%.
1H-NMR(d
6-DMSO)δ：6.96(m,1H);3.46～3.51(m,1H);3.19～3.31(m,2H);1.39～1.48(s,9H);0.99～1.12(d,3H)。
6) preparation of compound S LD-7
Take 66g SLD-8 and join in 1L single port bottle, add the 600mL methylene dichloride, the 84g triethylamine, be cooled to 0 ℃, slowly drips Acetyl Chloride 98Min. (65g, 1.5eq), keeps temperature below 10 ℃.Drip rear continuation reaction 1h.
After the TLC monitoring reaction is complete, 300mL*3 washes methylene dichloride, and drying, be spin-dried for, and ethyl alcohol recrystallization obtains the micro-yellow solid SLD-7 of 76g, purity 99.5%.MSm/z:161 (M
+), yield: 85.4%.
7) preparation of compound S LD-6
Take 76g SLD-7 and join in 1L single port bottle, add the 600mL glacial acetic acid, be warmed up to 100 ℃, after all dissolving, add 127g N-N-iodosuccinimide, continue reaction 4h.
After the TLC monitoring reaction is complete, strengthen water gaging, separate out a large amount of solids, filter the 300mL ethyl alcohol recrystallization.Obtain the micro-yellow solid SLD-6 of 90g.MS m/z:287 (M
+), yield: 66.7%.
8) preparation of compound S LD-5B
Take 46g zinc powder, 50mL DMF in the 1L there-necked flask, slowly drip 38g trimethylchlorosilane, stirring at room 0.5h under nitrogen protection.Standing, to incline and the stillness of night, 20mL DMF washing for solid, so repeat 2 times, adds the 100mL DMF.Be cooled to 0 ℃, slowly drip the 100mL DMF solution of 100gSLD-5C under nitrogen protection, keep temperature-5 ℃ between 5 ℃, add rear continuation reaction 1h.Add 57.4g SLD-6,1.2g palladium, 6.8g 2-dicyclohexyl phosphorus-2,4,6-tri isopropyl biphenyl, nitrogen replacement 3 times, room temperature reaction 1.5h.
After the TLC detection reaction finishes, by reaction solution, through diatomite filtration, filtrate adds water, the ethyl acetate extraction, merge organic layer, wash twice, saturated common salt is washed once, anhydrous sodium sulfate drying, concentrated, separate out solid, ethyl acetate and sherwood oil recrystallization, obtain 55g off-white color solid SLD-5B.MS m/z:318 (M
+), yield: 86%.
1H-NMR(d
6-DMSO)δ:7.926～7.898(d,1H);7.021(s,1H);6.938～6.911(d,1H);6.751～6.724(d,1H);4.080～4.023(t,2H);3.582～3.309(t,1H);3.117～3.061(t,2H);2.704～2.638(m,1H);2.501～2.316(m,1H);1.987(s,3H);1.346(s,9H);0.980～0.959(d,3H)。
9) preparation of compound S LD-4B
Take 55g SLD-5B, 300mL ethanol, 100mL water, 17g sodium hydroxide in 1L single port bottle, backflow 10h.
After the TLC detection reaction finishes, cooling, add 500mL water, by the extraction of 300mL*3 ethyl acetate, drying, concentrated, column chromatography obtains 40g white solid SLD-4B.MS m/z:276 (M
+), yield: 83.8%.
1H-NMR(d
6-DMSO)δ：6.830(s,1H);6.701～6.625(m,2H);6.404～6.378(d,1H);5.263(s,1H);3.511～3.385(t,1H);3.358～3.323(m,2H);2.872～2.816(m,2H);2.576～2.555(m,1H);2.374～2.304(m,1H);1.354(s,9H);0.958～0.936(d,3H)。
10) preparation of compound S LD-3B
Take 40g SLD-4B, 30g SLD-3C, 30g sodium carbonate, the 2.4g potassiumiodide, the 200mL DMF, in the single port bottle, is warmed up to 130 ℃, reaction 8h.
Reaction adds 500mL water after finishing, and the extraction of 200mL*3 ethyl acetate, merge organic layer, washing organic layer 3 times, and drying, concentrated, cross post and obtain 38g white solid SLD-3B, yield: 60%.
1H-NMR(d
6-DMSO)δ：7.274～7.375(m,5H);6.832(s,1H);6.754～6.780(d,1H);6.656～6.682(d,1H);6.348～6.374(d,1H);3.493～3.534(t,2H);3.307～3.331(m,1H);3.203～3.258(t,2H);3.035～3.082(t,2H);2.788～2.843(t,2H);2.564～2.585(m,1H);2.328～2.398(m,1H);1.750～1.839(m,2H);1.350(s,9H);0.944～0.965(d,3H)。
11) preparation of compound S LD-2
Take 18g N-bromo fourth acetyl diamines and join in the 250mL there-necked flask, add the 100mL DMF, take 38g SLD-3B and be dissolved in the 50mL DMF, be added dropwise in substrate, maintain the temperature at below 30 ℃ in the dropping process, drip off rear stirring at room 5h.
Reaction adds 500mL water after finishing, and the extraction of 200mL*3 ethyl acetate, merge organic layer, washing organic layer 3 times, and drying, concentrated, cross post and obtain 35g colourless liquid SLD-2, yield: 78%.
1H-NMR(d
6-DMSO)δ：7.324～7.345(m,5H);6.950(s,1H);6.846(s,1H);6.683(d,1H);3.485～3.527(m,4H);3.302～3.447(m,3H);2.857～2.914(t,2H);1.779(t,2H);1.333(s,9H);1.234(s,2H);0.972～0.992(d,3H)。
12) preparation of compound S LD-1
Take 35g SLD-2, the 15.8g zinc cyanide, 3.9g tetrakis triphenylphosphine palladium and 150mL DMF are in the single port bottle, and nitrogen protection, be warmed up to 80 ℃, reaction 48h.
The TLC detection reaction adds 300mL water after finishing, and the extraction of 200mL*3 ethyl acetate, merge organic layer, washing organic layer 3 times, and drying, concentrated, ethyl acetate and sherwood oil recrystallization, obtain 25g off-white color solid SLD-1, yield: 79.6%.
1H-NMR(d
6-DMSO)δ：7.265～7.336(m,5H);7.030(s,1H);6.934(s,1H);6.675～6.702(d,1H);3.484～3.575(m,7H);2.866～2.924(t,2H);2.494～2.506(M,2H);1.832～1.879(t,2H);1.324(s,9H);0.981～1.002(d,3H)。
13) preparation of Compound I
Take 25g SLD-1 and be added in 30mL concentrated hydrochloric acid and 200mL ethyl acetate, stirring at room 3h.Reaction is carefully regulated pH to 9 after finishing.Add 200mL water, the extraction of 200mL*3 ethyl acetate, merge organic layer, washing organic layer 3 times, and drying, concentrated, obtain 15g colourless oil liquid I, yield: 76.5%.
1H-NMR(d
6-DMSO)δ：7.2775～7.333(m,5H);7.032(s,1H);6.938(s,1H);3.480～3.581(m,6H);2.866～2.926(t,3H);2.341～2.363(d,2H);1.862～1.908(t,2H);0.910～0.931(d,3H)。
Claims (9)
1. the method for the compound of a preparation formula I:
Described method comprises:
1) by the compound of formula SLD-6
Exist under the condition of organic solvent, at 0-100 ℃ of temperature, and N-bromo-succinimide reaction, obtaining the compound of formula SLD-5A
2) under nitrogen protection, in DMF solution, at the temperature of-10 ℃-20 ℃, by the compound of formula SLD-5C
React with zinc powder, make the organic zinc reagent of formula SLD-5C '
The organic zinc reagent of described formula SLD-5C ' is in nitrogen protection, and at the temperature of 0-80 ℃, at palladium and 2-dicyclohexyl phosphorus-2', 4', under the catalysis of 6'-tri isopropyl biphenyl, react with the compound of described formula SLD-5A, obtains the compound of formula SLD-4A
3) compound of described formula SLD-4A is under alkaline condition, and in organic solvent, the reaction that is hydrolyzed, obtain the compound of formula SLD-3A
4) compound of formula SLD-3C
With the compound of described formula SLD-3A, in organic solvent, under alkaline condition, react, obtain the compound of formula SLD-2
5) compound of described formula SLD-2 and zinc cyanide, under the catalysis of tetrakis triphenylphosphine palladium, in organic solvent and under the nitrogen protection condition, 20-150 ℃ of reaction 0.5-10 hour, obtain the compound of formula SLD-1
6) compound of described formula SLD-1, at ethyl acetate neutralized salt acid-respons 0.5-24 hour, obtains the compound of described formula I.
2. the method for claim 1, the compound of wherein said formula SLD-5C, SLD-5C ', SLD-4A, SLD-3A, SLD-2 and SLD-1 is chipal compounds.
3. the method for the compound of a preparation formula I
Described method comprises:
1) nitrogen protection, in DMF solution, at-10-20 ℃ of temperature, by the compound of formula SLD-5C
React the organic zinc reagent that makes formula SLD-5C ' with zinc powder
The organic zinc reagent of described formula SLD-5C ' is in nitrogen protection, the temperature of 0-80 ℃, and palladium and 2-dicyclohexyl phosphorus-2', 4', under the catalysis of 6'-tri isopropyl biphenyl, react with the compound of formula SLD-6,
Obtain the compound of formula SLD-5B
2) compound of described formula SLD-5B is under alkaline condition, and in organic solvent, the reaction that is hydrolyzed, obtain the compound of formula SLD-4B
3) compound of formula SLD-3C
With the compound of described formula SLD-4B, in organic solvent, under alkaline condition, react, obtain the compound of formula SLD-3B
4) by the compound of described formula SLD-3B, exist under the condition of organic solvent, at 0-100 ℃ of temperature, and N-bromo-succinimide reaction, obtain the compound of formula SLD-2
5) by the compound of described formula SLD-2 and zinc cyanide under the catalysis of tetrakis triphenylphosphine palladium, in organic solvent and under the nitrogen protection condition, 20-150 ℃ of reaction 0.5-10 hour, obtain the compound of formula SLD-1
6) compound of described formula SLD-1, at ethyl acetate neutralized salt acid-respons 0.5-24 hour, obtains the compound of described formula I.
4. method as claimed in claim 3, the compound of wherein said formula SLD-5C, SLD-5C ', SLD-5B, SLD-4B, SLD-3B, SLD-2 and SLD-1 is chipal compounds.
5. method as described as claim 1 or 3, wherein said organic solvent is selected from methyl alcohol, ethanol, glacial acetic acid, N-Methyl pyrrolidone, acetonitrile or N,N-dimethylacetamide.
6. method as described as claim 1 or 3, wherein said alkali is selected from sodium hydroxide, potassium hydroxide, salt of wormwood, sodium carbonate, sodium bicarbonate, diisopropyl ethylenediamine, pyridine or triethylamine.
7. the compound of formula SLD-5A, SLD-4A, SLD-3A, SLD-2 and SLD-1 is for the purposes of the compound according to the method for claim 1 preparation formula I.
8. the compound of formula SLD-5B, SLD-4B, SLD-3B, SLD-2 and SLD-1 is for the purposes of the compound according to method preparation formula I as claimed in claim 3.
9. for the preparation of the intermediate of the compound of formula I, described intermediate is selected from the compound of formula SLD-5A, SLD-5B, SLD-4B, SLD-4A, SLD-3A, SLD-3B, SLD-2 and SLD-1.
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| CN104974072B (en) * | 2014-04-10 | 2017-11-03 | 江苏和成新材料有限公司 | A kind of method for preparing Silodosin intermediate |
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| CN109574902B (en) * | 2017-09-28 | 2022-07-01 | 安徽省庆云医药股份有限公司 | Preparation method of silodosin intermediate |
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