CN101993407B - Indoline compound for preparing silodosin and preparation method thereof - Google Patents
Indoline compound for preparing silodosin and preparation method thereof Download PDFInfo
- Publication number
- CN101993407B CN101993407B CN200910194691.2A CN200910194691A CN101993407B CN 101993407 B CN101993407 B CN 101993407B CN 200910194691 A CN200910194691 A CN 200910194691A CN 101993407 B CN101993407 B CN 101993407B
- Authority
- CN
- China
- Prior art keywords
- compound
- structural formula
- formula
- propyl group
- indoline
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 0 CC(c1cc(CC*2CCCOC(c3ccccc3)=O)c2cc1)=O Chemical compound CC(c1cc(CC*2CCCOC(c3ccccc3)=O)c2cc1)=O 0.000 description 4
- DCHOYXVHHNKLEC-FBMGVBCBSA-N C/C(/[N+]([O-])=O)=C\c(cc1)cc2c1N(CCCOC(c(cc1)ccc1[F]CCCI)=O)CC2 Chemical compound C/C(/[N+]([O-])=O)=C\c(cc1)cc2c1N(CCCOC(c(cc1)ccc1[F]CCCI)=O)CC2 DCHOYXVHHNKLEC-FBMGVBCBSA-N 0.000 description 1
- UXKABLKYTPEZKU-UOHKNDMESA-N C/C=C\C(\C(OCCCN(CC1)c2c1cc(C=O)cc2)=O)=C/C=C Chemical compound C/C=C\C(\C(OCCCN(CC1)c2c1cc(C=O)cc2)=O)=C/C=C UXKABLKYTPEZKU-UOHKNDMESA-N 0.000 description 1
- BIJVHZSBBLPSON-UHFFFAOYSA-N CC(CC=C1)C=C1C(O)=O Chemical compound CC(CC=C1)C=C1C(O)=O BIJVHZSBBLPSON-UHFFFAOYSA-N 0.000 description 1
- BHLLICHVNQQHFQ-UHFFFAOYSA-N O=C(c1ccccc1)OCCCN(CC1)c2c1cccc2 Chemical compound O=C(c1ccccc1)OCCCN(CC1)c2c1cccc2 BHLLICHVNQQHFQ-UHFFFAOYSA-N 0.000 description 1
- IZNIRUMBHDBLKL-UHFFFAOYSA-N O=Cc(cc1)cc2c1N(CCCOC(c(cc1)ccc1F)=O)CC2 Chemical compound O=Cc(cc1)cc2c1N(CCCOC(c(cc1)ccc1F)=O)CC2 IZNIRUMBHDBLKL-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明提供了吲哚啉化合物1-(3-取代苯甲酰氧基丙基)-5-(2-硝基丙基)-7-氰基吲哚啉及其制备方法，该化合物可以作为中间体化合物，用于合成西洛多辛。该吲哚啉化合物是以取代的苯甲酸为原料，经多步反应制得，收率高，易于工业化生产。The invention provides an indoline compound 1-(3-substituted benzoyloxypropyl)-5-(2-nitropropyl)-7-cyanoindoline and a preparation method thereof. The compound can be used as Intermediate compounds for the synthesis of silodosin. The indoline compound is prepared from substituted benzoic acid through multi-step reactions, has high yield and is easy for industrial production.
Description
Technical field
The present invention relates to pharmaceutical chemistry field, be specifically related to a kind of new compound for the synthesis for the treatment of hyperplasia of prostate medicine silodosin (silodosin) and preparation method thereof.
Background technology
Silodosin shrinks and has selective inhibitory urethral smooth muscle, and reduces in urethra and press, and blood pressure is not had a significant impact, and is used for the treatment of benign prostatic hyperplasia.The synthetic method report of at present relevant silodosin is more, but it is high to lack yield, is applicable to the method for suitability for industrialized production.
JP200199956 has reported take phenylformic acid as raw material, make 1-(3-benzoyloxy propyl group) indoline hydrochloride (as structural formula (1), R is hydrogen atom), yield 60%, through polystep reaction, further make silodosin intermediate 1-(3-benzoyloxy propyl group)-5-(2-nitro propyl group)-7-cyanoindole quinoline (as structural formula VIII) again, total recovery is low, only has 20%.Compound (VIII) and salt of wormwood, hydrogen peroxide reacting generating compound (IX), impurity is many, needs column chromatography purification, is not suitable for suitability for industrialized production.Compound (IX), under platinum oxide catalysis, carries out asymmetric reaction with L-(S)-benzene glycinol, may be sterically hindered little due to blocking group, and chiral induction rate is low, is 3.8: 1.
Summary of the invention
In order overcoming, in prior art, to prepare that the processing step of silodosin is more and the shortcoming such as yield is on the low side, to have proposed the present invention.The present invention mainly provides a kind of new midbody compound for the preparation of silodosin and corresponding synthetic route.
Based on first aspect of the present invention, the present invention relates to the new midbody compound (I) for the preparation of silodosin, with and building-up process in relevant precursor midbody compound (II), (III), (IV), (V), (VI), (VII).
Particularly, described midbody compound provided by the invention (I)～(VII) comprising:
Compound 1-as shown in structural formula (I) (3-substituted benzoyl acyl-oxygen base propyl group)-5-(2-nitro propyl group)-7-cyanoindole quinoline,
Wherein, R is the halogen atom that 2-replaces, 3-replaces or 4-replaces, such as fluorine atom, chlorine atom etc.; Or the lower alkoxy that R also can replace for 2-, 3-replaces or 4-replaces, such as methyl, ethyl etc.Preferably, described R is fluorine atom or methyl.
Formula (II) compound is 4-fluorobenzoic acid 3-chlorine propyl ester.
Wherein, R is the fluorine atom of 4 replacements.
Formula (III) compound is 1-(3-(4-fluorobenzoyl oxygen base) propyl group) indoline hydrochloride, or 1-(3-(4-toluyl oxygen base) propyl group) indoline hydrochloride.
Formula (IV) compound is 1-(3-(4-fluorobenzoyl oxygen base) propyl group)-5-aldehyde indoline.
Formula (V) compound is 1-(3-(4-fluorobenzoyl oxygen base) propyl group)-5-(2-nitro propenyl) indoline.
Formula (VI) compound is 1-(3-(4-fluorobenzoyl oxygen base) propyl group)-5-(2-nitro) indoline.Shown in
Formula (VII) compound is 1-(3-(4-fluorobenzoyl oxygen base) propyl group)-5-(2-nitro)-7-aldehyde radical indoline.
Above-claimed cpd (I) is the key intermediate for the synthesis of silodosin, and above-claimed cpd (II), (III), (IV), (V), (VI), (VII) are followed successively by the precursor intermediate of synthetic described compound (I).Concrete synthetic route is as follows.
Based on second aspect of the present invention, it provides from described compound (II)～(VII) the prepare preparation method of described compound (I) and salt thereof.
The method is specially: 4-fluorobenzoic acid reacts and generates compound as shown in structural formula (II) under alkali exists with the bromo-3-chloropropane of 1-; Formula (II) compound reacts under alkali exists with indoline, makes formula (III) compound 1-(3-(4-fluorobenzoyl oxygen base) propyl group) indoline; And then and hydrochloric acid reaction, make its hydrochloride, preferably salt hydrochlorate.Two step yields are 85%.In document JP200199956, use phenylformic acid is reaction substrate, but not the 4-fluorobenzoic acid that the present invention adopts, it generates product is 1-(3-(4-benzoyloxy) propyl group) indoline hydrochloride, report yield is 60%.
Then, 1-shown in structural formula (III) (3-substituted benzoyl acyl-oxygen base propyl group) indoline hydrochloride reacts 1-(3-substituted benzoyl acyl-oxygen base the propyl group)-5-aldehyde indoline generating as shown in structural formula (IV) with Vilsmeier reagent (being prepared with Phosphorus Oxychloride by DMF).
1-shown in structural formula (IV) (3-(substituted benzoyl acyl-oxygen base) propyl group)-5-aldehyde indoline, with under ammonium acetate existence, reacts 1-(3-substituted benzoyl acyl-oxygen base propyl group)-5-(the 2-nitro propenyl) indoline making as shown in structure formula V with nitroethane.
1-shown in structure formula V (3-substituted benzoyl acyl-oxygen base propyl group)-5-(2-nitro propenyl) indoline, through sodium borohydride reduction, makes 1-(3-substituted benzoyl acyl-oxygen base propyl group)-5-(2-nitro) indoline as shown in structural formula (VI).
1-shown in structural formula (VI) (3-substituted benzoyl acyl-oxygen base propyl group)-5-(2-nitro) indoline reacts 1-(3-substituted benzoyl acyl-oxygen base propyl group)-5-(2-the nitro)-7-aldehyde radical indoline generating as shown in structural formula (VII) with Vilsmeier reagent (being prepared with Phosphorus Oxychloride by DMF).
1-shown in structural formula (VII) (3-substituted benzoyl acyl-oxygen base propyl group)-5-(2-nitro)-7-aldehyde radical indoline is under pyridine exists, react with hydroxylamine hydrochloride and generate oxime, through diacetyl oxide dehydration, make 1-as shown in structural formula (I) (3-substituted benzoyl acyl-oxygen base propyl group)-5-(2-nitro propyl group)-7-cyanoindole quinoline again.Based on the 3rd aspect of the present invention, it also provides 1-shown in formula (I) (3-substituted benzoyl acyl-oxygen base propyl group)-5-(2-nitro propyl group)-7-cyanoindole quinoline as midbody compound, to prepare the purposes of silodosin, see following reaction formula:
The invention has the advantages that: the new compound providing by the invention described above (II), (III), (IV), (V), (VI), (VII), so that last synthetic key intermediate compound (I), can realize the preparation of the silodosin of high combined coefficient.Particularly, the method has following advantage: 1. total recovery is high, by document 20%, is promoted to 46%; 2. continue reaction asymmetric induction rate high, by 3.8: 1, be promoted to 6: 1; 3. be easy to suitability for industrialized production.
For be easier to understand object of the present invention, feature with and advantage, will coordinate embodiment to be described in detail the present invention below.
Embodiment
In order to understand better technical scheme of the present invention, below in conjunction with specific embodiments of the invention, be described further, but it does not limit the present invention.
Embodiment 1: the preparation of compound (III)
264 grams of 4-fluorobenzoic acids, are dissolved in DMF550ml.By bromo-chloropropane 375ml, triethylamine 265ml, DMF300ml is placed in reaction flask, drips 4-fluorobenzoic acid under room temperature, drips and finishes, room temperature reaction 12h.Add water, be extracted with ethyl acetate, organic layer saturated sodium bicarbonate aqueous solution, salt solution is cleaned, organic layer anhydrous sodium sulfate drying, the lower removal of decompression solvent obtains oily matter compound (II)
This oily matter, mass spectrum shows: molecular ion peak [M+1] is 217.
391 grams of compounds (II), diisopropylethylamine 473ml, indoline 182ml) and DMF1600ml, 105 ℃ are stirred 16 hours. and add water, use ethyl acetate extracting, saturated sodium bicarbonate aqueous solution, salt solution is cleaned, organic layer anhydrous sodium sulfate drying, the lower solvent of removing of decompression.Residue acetic acid ethyl dissolution, drips concentrated hydrochloric acid 134ml, and crystallize out filters, and with acetone, washes, and dry, obtaining solid is 1-(3-(4-fluorobenzoyl oxygen base) propyl group) indoline hydrochloride (yield 85%).
Fusing point: 156～158 ℃
1nMR composes (DMSO-d6): δ ppm 2.0-2.1 (2H, m), 2.9-3.1 (2H, t), 3.33-3.35 (2H, t), 3.45-3.5 (2H, t), 4.3-4.4 (2H, t), 6.85-6.95 (1H, d), 7.0-7.2 (2H, m), 7.3-7.5 (3H, m), 8.0-8.2 (2H, m)
Embodiment 2:1-(3-(4-toluyl oxygen base) propyl group) indoline hydrochloride
With reference to the preparation method of embodiment 1, with 4-tolyl acid, substitute 4-fluorobenzoic acid, other reagent and operation are constant, react, and make 1-(3-(4-toluyl oxygen base) propyl group) indoline hydrochloride.
1NMR composes (DMSO-d6): δ ppm 2.0-2.1 (2H, m), 2.3-2.4 (3H, s), 2.9-3.1 (2H, t), 3.33-3.35 (2H, t), 3.45-3.5 (2H, t), 4.3-4.4 (2H, t), 6.5-6.6 (2H, d), 6.9-7.1 (2H, m), 7.2-7.5 (2H, m), 7.8-8.0 (2H, m)
Embodiment 3: the preparation of compound (IV)
N
2protection, cryosel is bathed, and phosphorus oxychloride 11ml is added drop-wise in DMF37ml, then adds 20 grams of compounds (III), room temperature reaction 3 hours.By in reaction solution injected water, separate out solid, dry to obtain compound (IV).(yield 95%)
Fusing point: 66～68 ℃
1nMR spectrum:
1nMR composes (DMSO-d6): δ ppm 2.0-2.1 (2H, m), 2.9-3.1 (2H, t), 3.3-3.4 (2H, t), 3.5-3.6 (2H, t), 4.3-4.4 (2H, t), 6.4-6.6 (1H, dd), 7.3-7.5 (4H, m), 8.0-8.1 (2H, m), 9.5-9.6 (1H, s)
Embodiment 4: the preparation of compound (V)
90 grams of compounds (IV), 27.6 grams of ammonium acetates, nitroethane 101ml, reflux 3 hours. add water 250ml, under stirring, solid is separated out, and recrystallization obtains compound (V), (yield 75%)
Fusing point is 94-96 ℃
1nMR spectrum:
1nMR composes (DMSO-d6): δ ppm 2.0-2.1 (2H, m), 2.9-3.1 (2H, t), 3.3-3.4 (2H, t), 3.5-3.6 (2H, t), 4.3-4.4 (2H, t), 6.4-6.6 (1H, d), 7.3-7.4 (4H, m), 8.0-8.1 (2H, m)
Embodiment 5: the preparation of compound (VII)
8 grams of sodium borohydrides (1.164mol), tetrahydrofuran (THF) 60ml, ethanol 20ml makes suspension liquid, and 20 grams of compounds (V) [tetrahydrofuran (THF) 90ml dissolving] are added drop-wise in above-mentioned suspension liquid.Reaction mixture is poured in beaker, then added the ethyl acetate extracting of water, reaction mixture, organic layer washs with salt solution, and with anhydrous sodium sulfate drying, solvent is removed in decompression, obtains brown oil compound (VI)
This oily matter, mass spectrum shows: molecular ion peak [M+1] is 387; HPLC purity assay is 96%.
N
2protection, cryosel is bathed, and phosphorus oxychloride 10ml is added drop-wise in DMF24ml, drips the compound (VI) (20ml DMF dissolving) making, and 50～53 ℃ are reacted 3 hours.Reaction solution is slowly poured in frozen water and stirred, and crystallization, filters solid (yield 80%)
Fusing point is 78～80 ℃.
1nMR composes (DMSO-d6): δ ppm 1.5-1.5 (3H, d), 1.9-2.1 (2H, m), 2.9-3.1 (4H, m), 3.3-3.4 (2H, t), 3.6-3.7 (4H, m), 4.3-4.4 (2H, t), 4.8-5.0 (1H, m), 7.0-7.1 (1H, s), 7.2-7.4 (3H, m), 8.0-8.1 (2H, m), 9.8-10.0 (1H, s)
Embodiment 6: the preparation of compound (I)
Compound (VII) 70 grams (0.169mol) is dissolved in to dry THF 180ml, then adds 16.8 grams of hydroxylamine hydrochlorides, pyridine 59ml, 50 ℃ are stirred 2h.Add aceticanhydride 43ml, 80 ℃ of reactions of reflux 3 hours.In reaction mixture, add water, ethyl acetate extracting, organic layer is washed with 1mol/LHCl, and saturated sodium bicarbonate is washed, saturated common salt washing, anhydrous sodium sulfate drying, concentrating under reduced pressure.Residue acetone heating for dissolving, adds Virahol, crystallize out slowly, and filtration drying obtains 65.39 grams of faint yellow materials (94.10%).Fusing point is 97～98 ℃
1nMR composes (DMSO-d6): δ ppm 1.5-1.5 (3H, d), 1.9-2.1 (2H, m), 2.9-3.1 (4H, m), 3.3-3.4 (2H, t), 3.6-3.7 (4H, m), 4.3-4.4 (2H, t), 4.8-5.0 (1H, m), 7.0-7.3 (4H, m), 8.0-8.1 (2H, m)
Embodiment 7: the preparation of compound (XI)
Compound (I) 100 grams (0.243mol) is dissolved in 450mlDMF, under 0-5 ℃ of condition, adds DBU 58ml (0.389mol), then by chlorotriethyl silane 125ml (0.738mol), under low temperature, be added dropwise to, react 3 hours, then drip 30%H
2o
241 grams (0.362mol), after dripping, reacts 1 hour.Reaction solution is dropped in water, and ethyl acetate extracting, obtains 97.27 grams of compound (3) oily matter
The mass spectrum of this oily matter shows: molecular ion peak [M+1] is 381; HPLC purity is 93%.
Embodiment 8: the preparation of compound (XII)
97.27 grams of compounds (XI), 500mlTHF dissolves, and adds 29.5 grams of R-(+)-α-phenylethylamines (0.243mol), 0.4 gram of PtO
2, AcOH14.5ml (0.243mol), moves in hydriding reactor, and 40-70 ℃, under hydrogen pressure 2-5atm.Leach platinum oxide, concentrating under reduced pressure obtains oily matter, and ethyl acetate heating for dissolving adds water and extracts, and anhydrous sodium sulfate drying filters, and the concentrated solvent of removing obtains 119 grams of oily matter (being greater than theoretical amount).Obtaining diastereomer ratio is 6: 1 mixtures.
Embodiment 9: the preparation of compound (XIII)
82 grams of compounds (XII), methyl alcohol 600ml dissolves, and adds 3mol/L HCl 56ml under stirring, stirs, then adds 14 grams of 7%Pd/C, 2-10atm, 40-80 ℃ of reaction.After reaction finishes, filter out Pd/C, filtrate is concentrated dry, and methylene dichloride 300ml dissolves, and adds water, extraction, and anhydrous sodium sulfate drying, filtering and concentrating is dry, obtains 65 grams of oily matter (64.4 grams of theoretical amount).
180ml acetone heating for dissolving for oily matter, 40 ℃, drip the L-TARTARIC ACID aqueous solution [25.3 grams+90 water], solid is separated out; Drip and finish, reflux and dissolve, naturally cool to room temperature (15 ℃), stir 2 hours, filter, obtain 69.4 grams of solids
Embodiment 10: the preparation of compound (XIII) L-TARTARIC ACID
20 grams of the solids obtaining in embodiment 9, use methanol/water=75: 75 reflux dissolves, and naturally cools to 35 ℃ of crystallizatioies, and crystallization 3 hours, filters out solid; Use methanol/water=70ml: 70ml again, reflux and dissolve, naturally cool to 35 ℃ of crystallizatioies, crystallization 3 hours, filters out solid; Use methanol/water=73ml: 73ml again, reflux and dissolve, naturally cool to 35 ℃ of crystallizatioies, 3 hours, filtering drying obtained 10.58 grams of (52.9%) enantiomer ratio: 95.663:4.337 of solid
Embodiment 10: the preparation of compound (XIII) L-TARTARIC ACID
49 grams of acetone/water=120ml: the 120ml of solid that obtain in embodiment 9 dissolving that refluxes, naturally cools to 30 ℃ of crystallizatioies, and crystallization 3 hours, filters out solid; Use acetone/water=100ml: 100ml again, reflux and dissolve, naturally cool to 30 ℃ of crystallizatioies, crystallization 3 hours, filters out solid; Use acetone/water=100ml: 100ml again, reflux and dissolve, naturally cool to 30 ℃ of crystallizatioies, 3 hours, filtering drying obtained 21.3 grams of (43.4%) enantiomer ratio: 96.959:3.041 of solid
Fusing point: 185-190 ℃
Optical value: DMF, c=1, [α]
20 d=-15
1nMR composes (DMSO-d6): δ ppm 1.0-1.2 (3H, d), 2.0-2.2 (2H, m), 2.6-2.8 (2H, d), 2.9-3.0 (3H, m), 3.2-3.4 (2H, m), 3.2-3.4 (1H, m), 3.5-3.6 (2H, t), 3.6-3.7 (2H, m), 3.9-4.0 (2H, t), 4.3-4.4 (2H, t), 6.9-7.1 (2H, m), 7.2-7.4 (2H, m), 7.9-8.1 (2H, m)
Embodiment 11: the preparation of compound (XV)
Embodiment 10 is obtained to 20 grams of solids, 10 grams, salt of wormwood, 1 gram of Tetrabutyl amonium bromide, 0.5 gram of potassiumiodide is placed in reaction flask, adds water 120ml, is heated to 80 ℃, drips (6) 14 grams of compounds, drips at finishing 80 ℃ and reacts 6 hours again.Be extracted with ethyl acetate, sodium bicarbonate is washed, saturated common salt washing, and dried over mgso, concentrated.Oily matter, Virahol dissolves, and adds 4.2 grams of oxalic acid dihydrate, separates out solid, obtains 22 grams of white solids.
Mp 135-137℃
1nMR composes (DMSO-d6): δ ppm 1.1-1.2 (3H, d), 2.0-2.1 (2H, m), 2.5-2.6 (1H, dd), 2.8-2.9 (2H, t), 2.96-3.0 (1H, dd), 3.3-3.5 (3H, m), 3.5-3.7 (4H, m), 4.2-4.3 (2H, t), 4.3-4.4 (2H, t), 4.6-4.7 (2H, m), 4.8-5.2 (1H, broad peak), 6.9-7.15 (6H, m), 7.3-7.4 (2H, m), 8.0-8.1 (2H, m)
Embodiment 12: the preparation of silodosin
Embodiment 11 is obtained to 8 grams of solids, with DMSO 100ml, dissolve, add 5mol/L NaOH 12ml, be slowly added dropwise to 30%H at 18～20 ℃
2o
27 grams, then at 30 ℃, 4h reacts end.Ethyl acetate extraction, merge organic layer, organic layer is washed with 2N HCl again, and the water layer obtaining neutralizes with sodium hydroxide, use again ethyl acetate extracting, saturated sodium bicarbonate is washed, anhydrous sodium sulfate drying, concentrating under reduced pressure, use again acetic acid ethyl dissolution, naturally cooling crystallization, filtration, dry 5 grams (87%), and purity > 99%.
Mp105～108℃
[α]
20 D＝-16.2 C＝1，MeOH
1nMR composes (DMSO-d6): δ ppm 0.9-1.0 (3H, d), 1.5-1.6 (1H, s), 1.6-1.7 (2H, m), 2.3-2.4 (1H, dd), 2.6-2.7 (1H, dd), 2.8-3.0 (5H, m), 3.1-3.2 (2H, m), 3.3-3.4 (2H, m), 3.4-3.5 (2H, t), 4.0-4.1 (2H, t), 4.2-4.3 (1H, s), 4.6-4.8 (2H, t), 6.9-7.15 (6H, m), 7.2-7.3 (1H, s), 7.5-7.6 (1H, s)
Claims (9)
1. the compound as shown in structural formula (I),
2. for the synthesis of the midbody compound of the compound shown in structural formula claimed in claim 1 (I), its structural formula is suc as formula shown in (II),
3. for the synthesis of the midbody compound of the compound shown in structural formula claimed in claim 1 (I), its structural formula is suc as formula shown in (III),
Described compound is 1-(3-(4-fluorobenzoyl oxygen base) propyl group) indoline hydrochloride.
4. for the synthesis of the midbody compound of the compound shown in structural formula claimed in claim 1 (I), its structural formula is suc as formula shown in (IV),
Described compound is 1-(3-(4-fluorobenzoyl oxygen base) propyl group)-5-aldehyde indoline.
5. for the synthesis of the midbody compound of the compound shown in structural formula claimed in claim 1 (I), its structural formula as shown in formula V,
Described compound is 1-(3-(4-fluorobenzoyl oxygen base) propyl group)-5-(2-nitro propenyl) indoline.
6. for the synthesis of the midbody compound of the compound shown in structural formula claimed in claim 1 (I), its structural formula is suc as formula shown in (VI),
Described compound is 1-(3-(4-fluorobenzoyl oxygen base) propyl group)-5-(2-nitro propyl group) indoline.
7. for the synthesis of the midbody compound of the compound shown in structural formula claimed in claim 1 (I), its structural formula is suc as formula shown in (VII),
Described compound is 1-(3-(4-fluorobenzoyl oxygen base) propyl group)-5-(2-nitro propyl group)-7-aldehyde radical indoline.
8. a method of preparing the compound shown in structural formula according to claim 1 (I), it comprises the following steps:
A) take substituted benzoic acid reacts the 4-fluorobenzoic acid 3-chlorine propyl ester making as shown in structural formula (II) as raw material with the bromo-3-chloropropane of 1-;
B) formula (II) compound reacts the compound making as shown in structural formula (III) with indoline;
C) compound shown in formula (III) generates the compound as shown in structural formula (IV) with the Vilsmeier reagent react of being prepared by DMF and Phosphorus Oxychloride;
D) compound as shown in structural formula (IV), with under ammonium acetate existence, reacts the compound making as shown in structure formula V with nitroethane
E) compound as shown in structure formula V, through sodium borohydride reduction, makes the compound as shown in structural formula (VI)
F) compound as shown in structural formula (VI) generates the compound as shown in structural formula (VII) with the Vilsmeier reagent react of being prepared by DMF and Phosphorus Oxychloride
G) compound as shown in structural formula (VII), under pyridine exists, reacts with hydroxylamine hydrochloride and generates oxime, then through diacetyl oxide dehydration, makes compound as shown in structural formula (I)
Compound shown in structural formula as claimed in claim 1 (I) as synthetic intermediate the purposes for the preparation of silodosin.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910194691.2A CN101993407B (en) | 2009-08-27 | 2009-08-27 | Indoline compound for preparing silodosin and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910194691.2A CN101993407B (en) | 2009-08-27 | 2009-08-27 | Indoline compound for preparing silodosin and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101993407A CN101993407A (en) | 2011-03-30 |
| CN101993407B true CN101993407B (en) | 2014-01-29 |
Family
ID=43784224
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200910194691.2A Active CN101993407B (en) | 2009-08-27 | 2009-08-27 | Indoline compound for preparing silodosin and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101993407B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017051324A1 (en) * | 2015-09-23 | 2017-03-30 | Biocon Limited | The process of preparing indoline compounds and a novel indoline salt |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011124704A1 (en) * | 2010-04-09 | 2011-10-13 | Ratiopharm Gmbh | Process for preparing an intermediate for silodosin |
| CN102643221B (en) | 2011-02-22 | 2015-02-11 | 浙江九洲药业股份有限公司 | Silodosin intermediate and preparation method thereof |
| WO2012131710A2 (en) * | 2011-03-30 | 2012-10-04 | Panacea Biotec Ltd | Novel process for the synthesis of indoline derivatives |
| WO2012147107A2 (en) * | 2011-04-29 | 2012-11-01 | Msn Laboratories Limited | Novel & improved processes for the preparation of indoline derivatives and its pharmaceutical composition |
| CN102382029B (en) * | 2011-07-26 | 2016-06-29 | 浙江华海药业股份有限公司 | A kind of salt formation of silodosin intermediate preparation method |
| CN104302621A (en) * | 2011-10-21 | 2015-01-21 | 桑多斯股份公司 | Method for preparing silodosin |
| CN102702067B (en) * | 2012-06-18 | 2015-01-14 | 北京联本医药化学技术有限公司 | Novel intermediate for synthesizing silodosin as well as preparation method and purpose of novel intermediate |
| CN104140389A (en) * | 2013-05-06 | 2014-11-12 | 昆明积大制药股份有限公司 | Preparing method of silodosin and intermediate thereof |
| CN103396352B (en) * | 2013-08-07 | 2015-04-08 | 苏州明锐医药科技有限公司 | Preparation method of Silodosin |
| CN104974073B (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 |
| KR101725393B1 (en) * | 2014-07-24 | 2017-04-27 | 주식회사 경보제약 | Manufacturing method for Silodosin and new intermediate thereof |
| JP7054381B2 (en) | 2015-09-23 | 2022-04-13 | バイオコン・リミテッド | Process for the preparation of crystalline forms of posaconazole intermediates and amorphous posaconazole |
| ES2607639B1 (en) * | 2015-09-30 | 2018-02-28 | Urquima, S.A | Maleic acid salt of a silodosin intermediate |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5387603A (en) * | 1992-12-02 | 1995-02-07 | Kissei Pharmaceutical Co., Ltd. | 1,5,7-trisubstituted indoline compounds and salts thereof |
| CN101048376A (en) * | 2004-10-27 | 2007-10-03 | 橘生药品工业株式会社 | Indoline compound and process for producing the same |
| WO2008106536A1 (en) * | 2007-02-28 | 2008-09-04 | Kissei Pharmaceuticals Co., Ltd. | Use of silodosin in a once daily administration for treating benign prostatic hyperplasia |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP4634560B2 (en) * | 2000-01-14 | 2011-02-16 | キッセイ薬品工業株式会社 | Process for producing optically active indoline derivative and production intermediate thereof |
| JP4921646B2 (en) * | 2001-03-08 | 2012-04-25 | キッセイ薬品工業株式会社 | 1- (3-Benzyloxypropyl) -5- (2-substituted propyl) indoline derivatives and methods of use thereof |
-
2009
- 2009-08-27 CN CN200910194691.2A patent/CN101993407B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5387603A (en) * | 1992-12-02 | 1995-02-07 | Kissei Pharmaceutical Co., Ltd. | 1,5,7-trisubstituted indoline compounds and salts thereof |
| CN101048376A (en) * | 2004-10-27 | 2007-10-03 | 橘生药品工业株式会社 | Indoline compound and process for producing the same |
| WO2008106536A1 (en) * | 2007-02-28 | 2008-09-04 | Kissei Pharmaceuticals Co., Ltd. | Use of silodosin in a once daily administration for treating benign prostatic hyperplasia |
Non-Patent Citations (2)
| Title |
|---|
| JP特开2001-199956A 2001.07.24 |
| JP特开2002-265444A 2002.09.18 |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017051324A1 (en) * | 2015-09-23 | 2017-03-30 | Biocon Limited | The process of preparing indoline compounds and a novel indoline salt |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101993407A (en) | 2011-03-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101993407B (en) | Indoline compound for preparing silodosin and preparation method thereof | |
| CN101993406B (en) | Optically active indoline compound and its preparation method | |
| JP5575921B2 (en) | Method for producing tetrazole methanesulfonate and novel compound used therefor | |
| CN110526859B (en) | Revinanexin intermediate, preparation method thereof and preparation method of Revinanexin | |
| CN101891649A (en) | Novel 3-cyano methyl benzoate preparing method | |
| CN105418483A (en) | Preparation method of crystalline nintedanib esylate | |
| CN118541351A (en) | Process for preparing pyrrole compounds and intermediates therefor | |
| CN103664677A (en) | Asymmetric synthesis method of (R,R)-formoterol tartrate | |
| CN105693603A (en) | Improved indacaterol maleate preparation technology | |
| CN102105433A (en) | 6-nitroacetophenone compound, its preparation method and use | |
| JP6248202B2 (en) | Method for producing silodosin and its intermediate | |
| CN103373963B (en) | Intermediate of pazopanib hydrochloride and preparation method thereof | |
| CN102153522B (en) | Novel method for preparing N-substituted 2-hydroxy-morpholin-3-one compound | |
| CN105461617A (en) | Preparation method for 4-[4-(trifluoromethoxy)phenoxyl]piperidine | |
| KR20160027536A (en) | Process for preparing an intermediate useful for the synthesis of silodosin | |
| CN115557882A (en) | Preparation method of (R) -1-Boc-3-aminopiperidine | |
| CN117242057A (en) | Process for preparing intermediates useful in the synthesis of sphingosine-1-phosphate receptor agonists | |
| KR20110111782A (en) | New Preparation Method of Diphenyl Acetate Derivatives | |
| CN109020977B (en) | Preparation method of Acaraburtinib | |
| CN115477607B (en) | A light stabilizer intermediate and preparation method thereof | |
| JPWO2015012271A1 (en) | Method for producing heterocyclic compound | |
| CN118580229B (en) | Preparation method of bripiprazole | |
| CN116715664B (en) | Preparation method of non-neridrone key intermediate | |
| CN102643273B (en) | A kind of preparation method of Zomaril | |
| CN118420493A (en) | Preparation method of 2, 5-disubstituted aminocaproate ester and method for preparing Li Texi tenib by using preparation method |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |