WO2018100565A1 - Process for the preparation of indoline compound - Google Patents
Process for the preparation of indoline compound Download PDFInfo
- Publication number
- WO2018100565A1 WO2018100565A1 PCT/IB2017/058395 IB2017058395W WO2018100565A1 WO 2018100565 A1 WO2018100565 A1 WO 2018100565A1 IB 2017058395 W IB2017058395 W IB 2017058395W WO 2018100565 A1 WO2018100565 A1 WO 2018100565A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- silodosin
- formula
- acid
- solvents
- Prior art date
Links
- HOJMCBMXHWZNKX-UHFFFAOYSA-N CS(OCCOc(cccc1)c1OCC(F)(F)F)(=O)=O Chemical compound CS(OCCOc(cccc1)c1OCC(F)(F)F)(=O)=O HOJMCBMXHWZNKX-UHFFFAOYSA-N 0.000 description 1
- KOPCPLUGJAGRLM-HXUWFJFHSA-N C[C@H](Cc1cc(C(N)=O)c2N(CCCO)CCc2c1)N(CCOc(cccc1)c1OCC(F)(F)F)C(OC(C)(C)C)=O Chemical compound C[C@H](Cc1cc(C(N)=O)c2N(CCCO)CCc2c1)N(CCOc(cccc1)c1OCC(F)(F)F)C(OC(C)(C)C)=O KOPCPLUGJAGRLM-HXUWFJFHSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
Definitions
- the obtained silodosin (I) is optionally purified by crystallization or slurry using a suitable organic solvent or mixture thereof for e.g. acetone, ethyl acetate, acetonitrile, 2- propanol or methanol. If desired, the obtained Silodosin is converted to the corresponding salt by treatment with pharmaceutically acceptable acids and followed by conversion to silodosin by treatment with suitable base to afford pure silodosin.
- a suitable organic solvent or mixture thereof for e.g. acetone, ethyl acetate, acetonitrile, 2- propanol or methanol.
- step (i) cooling the solution of step (i) to precipitate the solid or
- the process of present invention described herein has simple reaction steps, produces the intermediate surprisingly in high yields and purities than the processes reported in the literature and well amenable on commercial scale.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to an improved process for the preparation of Silodosin (I) which is useful in the treatment of Benign Prostate Hyperplasia (BPH) and related disorders. The present invention also relates to the purification process resulting in substantially pure Silodosin.
Description
PROCESS FOR THE PREPARATION OF INDOLINE COMPOUND
The following specification describes the invention
FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Silodosin (I) which is useful in the treatment of Benign Prostate Hyperplasia (BPH).
The present invention also relates to the purification process resulting in substantially pure Silodosin.
BACKGROUND OF THE INVENTION
Silodosin is chemically described as l-(3-hydroxypropyl)-5-[(2R)-2-( {2,2,2- trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-17J-indole-7-carboxamide and is represented by structural Formula I.
(I)
It is known to be selective antagonist of al-adrenoreceptors, suppressing urinary duct contractions, and exhibiting a minimal drop of blood pressure at the same time.
Silodosin received its first marketing approval in Japan in May 2006 under the trade name Urief.
It is marketed under the brand name RAPAFLO in United States and as Silodyx in Europe and South Africa in the form of 4mg and 8mg capsules for the treatment of the signs and symptoms of benign prostate hyperplasia.
As indicated by the structure above, Silodosin molecule possess a chiral carbon and hence exhibits stereoisomerism. During the manufacturing process of Silodosin and related compounds, there is a challenge that mixture of isomers may be obtained.
It has been developed and approve in the form of the (R)-enantiomer by the Japanese company Kissei Pharmaceutical for treatment of benign prostatic hyperplasia (BPH).
Kitazawa et al., in U.S. Patent No. 5,387,603 discloses various 1,5,7-trisubstituted indoline compounds including Silodosin and its related compounds. It also discloses the process for the preparation of Silodosin and salts and their therapeutic uses.
Below scheme summarizes the process as disclosed in the patent.
Yamaguchi et al., in U.S. Patent No. 7,834,193 B2 discloses another process for preparing Silodosin via formation of oxalate salt of Silodosin, which is shown in the scheme g
Joshi Shreerang et al., in U.S. Patent No. 8,471,039 B2 discloses process for preparing Silodosin using different intermediates as summarized by the below scheme
Despite various prior disclosures of the processes for preparing Silodosin, they suffer with one or more drawbacks including commercially non-viable processes, handling concerns in plant besides multistep impurities removal etc. Considering the therapeutic importance of Silodosin, there still exists a need to develop and provide an improved process which is simple, robust and commercially viable resulting in improved quality characteristics.
SUMMARY OF THE INVENTION
dosin (I),
(VII)
(V)
reacting the compound of Formula V or a salt thereof with di-tertiary butyl dicarbonate to afford the compound of Formula IV
(IV)
reacting the compound of Formula IV with a base to afford the compound of Formula III
(III)
(Π)
e) deprotecting the compound of Formula II to afford Silodosin (I)
In another aspect, the present invention relates to an intermediate compound of Formula IV
(IV)
useful in the preparation of substantially pure Silodosin.
In yet another aspect, the present invention relates to a process for the purification of Silodosin of Formula I, comprising;
a) providing a solution of Silodosin of Formula I in a solvent or a mixture of solvents or their aqueous mixtures; and
b) cooling the solution of step (a) to precipitate the solid or
c) optionally adding the anti-solvent to the solution of step (a); and
d) isolating the desired pure Silodosin (I).
In yet further aspect, the present invention relates to Substantially pure Silodosin (I) having purily greater than 99.5% and total impurities less than 0.5% as measured by chiral HPLC.
In a further aspect, the present invention relates to Substantially pure Silodosin (I) characterized by X-ray powder diffraction pattern as depicted in fig.1 and differential scanning calorimetry (DSC) thermogram as depicted in fig.2.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 : is an example of X-ray powder diffraction ("XRPD") pattern of Silodosin crystalline
Fig. 2: is an example of Differential Scanning Calorimetry (DSC) thermogram of Silodosin crystalline form.
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, the present invention provides process for preparing Silodosin
(I),
(VII)
with the compound of F
(V)
b) reacting the compound of Formula V or a salt thereof with di-tertiary butyl dicarbonate to afford the compound of Formula IV
(IV)
c) reacting the compound of Formula IV with a base to afford the compound of Formula III
(III)
converting the compound of Formula III to the compound of Formula II
e) deprotecting the compound of Formula II to afford Silodosin (I).
The process step (a) is carried out in the presence of a base selected from the group consisting of alkali metal hydroxide such as sodium hydroxide, potassium hydroxide and the like; an alkali metal carbonate such as sodium carbonate, potassium carbonate and the like; organic base such as triethylamine, diisopropylamine and the like. Among them, an inorganic base, particularly an alkali metal carbonate or alkali metal hydroxide are preferable.
The suitable organic solvents that can be used in step (a) is selected from the group comprising of alcohols such as methanol, ethanol, isopropanol, n-propanol, butanol, and the like; halocarbonated solvents such dichloromethane, ethyl chloride, chlorobenzene and the
like; ethers such tetrahydrofuran (THF), 1 ,4-dioxane and the like; polar aprotic solvent such as Ν,Ν-dimethyl formamide (DMF), N,N-dimethyl acetamide, dimethyl sulfoxide (DMSO) and the like; or mixtures thereof in any proportion without limitation.
The process step (a) is performed at room temperature to about boiling point of an organic solvent or mixture of solvents used over a period of about 10 minutes to about 45 minutes, preferably, performed at room temperature for 10 to 30 minutes.
In one of the particular embodiment according to present invention, the process step
(a) was performed at room temperature for 15 minutes.
The mole ratios of reactants and the reagents used therein can be appropriate based on the resultant product and the side products or bye products.
The organic solvents that can be used in the process step (b) is selected from the group consisting of alcohols such as methanol, ethanol, isopropanol, n-propanol, butanol, and the like; halocarbonated solvents such as dichloromethane, ethyl chloride, chlorobenzene and the like; ethers such tetrahydrofuran (THF), 1 ,4-dioxane and the like; polar aprotic solvent such as Ν,Ν-dimethyl formamide (DMF), Ν,Ν-dimethyl acetamide, dimethyl sulfoxide (DMSO) and the like; or mixtures thereof in any proportion without limitation. Preferably alcohol solvent methanol is being used.
The process step (b) is performed at room temperature to a boiling point of an organic solvent used for the reaction for about 30 minutes to 1 hours, preferably, at room temperature for about 2 to 12 hours.
In one of the particular embodiment according to present invention, the process step
(b) was performed at room temperature for 12 hours.
The process step (c) is carried out in the presence of a base selected from alkali metal hydroxide such as sodium hydroxide, potassium hydroxide and the like; an alkali metal carbonate such as sodium carbonate, potassium carbonate and the like; organic base such as triethylamine, diisopropylamine and the like. Preferably potassium hydroxide is being used.
The suitable organic solvents that can be used in the process step (c) is selected from the group consisting of alcohols such as methanol, ethanol, isopropanol, n-propanol, butanol, and the like; esters such as ethyl acetate, isopropyl acetate, butyl acetate and the like; polar aprotic solvent such as Ν,Ν-dimethyl formamide (DMF), Ν,Ν-dimethyl acetamide, dimethyl sulfoxide (DMSO) and the like; or mixtures thereof in any proportion without limitation. Preferably, alcohol solvent methanol is being used.
The process step (c) is performed at room temperature to about boiling point of an organic solvent or mixture of solvents used and over a period of about 1 hour to about 15 hours, preferably, at room temperature for about 2 to about 12 hours.
In one of the particular embodiment according to present invention, the process step (c) was performed at 10-15°C for 12 hours.
The process step (d) is carried out in the presence of base selected from the group consisting of alkali metal hydroxide such as sodium hydroxide, potassium hydroxide and the like; alkali metal carbonate such as sodium carbonate, potassium carbonate and the like; organic bases such as triethylamine, diisopropylethylamine and in the presence of catalyst selected from hydrogen peroxide, sodium hypochlorite, perbenzoic acid, potassium permanganate and the like.
In one of the particular embodiment according to present invention, in step (d) sodium hydroxide used.
The suitable solvents that can be used in the process step (d) include but are not limited to water; alcohols such as methanol, ethanol, propanol, isopropyl alcohol and the like; aprolic polar solvents such as tetrahydrofuran (THF), 1,4-dioxan, dimethylsulfoxide (DMSO), Ν,Ν-dimethyl formamidc (DMF) and the like; or mixture thereof, preferably, dimethylsulfoxide (DMSO) is used.
The process step (d) is performed at room temperature to about boiling point of solvents used over a period of aboul 1 hour to about 15 hours, preferably at room temperature for about 2 to about 12 hours.
In one of the particular embodiment according to present invention, the process step (d) was performed at room temperature for 12 hours.
The suitable deprotecting agent that can be used for the conversion of compound of Formula II to the compound of Formula I in the process step (e) is selected from inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid; organic acids such as acetic acid, trifluoroacetic acid methanesulfonic acid and p-tolueiiesulfonie acid; preferably hydrochloric acid is used.
The organic solvents that can be used in the process step (e) is selected from alcohols such as methanol, ethanol, propanol, isopropyl alcohol and the like; esters such as ethyl acetate, isopropyl acetate, butyl acetate and the like; aprolic polar solvents such as acetonitrile, dimethyl formamidc (DMF), dimethyl sulfoxide (DMSO), dimethyl acetamide and the like; Preferably alcohol solvent methanol is being used.
The process step (e) is performed at room temperature to about boiling point of an organic solvents used over a period of about 1 hour to about 10 hours, preferably, for about 2 to about 5 hours.
In one of the particular embodiment according to present invention, the process step (e) was performed at room temperature for 4 hours.
The obtained silodosin (I) is optionally purified by crystallization or slurry using a suitable organic solvent or mixture thereof for e.g. acetone, ethyl acetate, acetonitrile, 2- propanol or methanol. If desired, the obtained Silodosin is converted to the corresponding salt by treatment with pharmaceutically acceptable acids and followed by conversion to silodosin by treatment with suitable base to afford pure silodosin.
In yet another embodiment, the present invention provides a process for the purification of Silodosin of Formula I, comprising:
i) providing a solution of Silodosin of Formula 1 in a solvent or a mixture of solvents or their aqueous mixtures; and
ii) cooling the solution of step (i) to precipitate the solid or
iii) optionally adding the anti-solvent to the solution of step (i); and
iv) isolating the desired pure Silodosin (I).
The step (i) of providing Silodosin solution, comprise adding / mixing crude / impure Silodosin obtained from any source into crystalline form at room temperature.
The solvent used for the dissolution of silodosin in step (i) is selected from the group consisting of esters such as ethyl acetate, isopropyl acetate, butyl acetate and the like; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; nitriles such as acetonitrile and the like; or mixtures thereof or their aqueous mixtures. .
The temperature required for dissolution can range from about 25 °C to about reflux temperatures of the solvents used.
The solution of step (i) obtained is optionally filtered through celite or diatomous earth to separate the extraneous matter formed by using conventional filtration technique known in the art.
The precipitation of solid in step (i) is achieved but not limited to evaporation, cooling, drying, or by adding anti-solvent..
The suitable anti-solvent optionally used is selected from the group consisting of ethers such as diethyl ether, diisopropyl ether, 1,4-dioxane and the like; hydrocarbons such as methyl cyclohexane, cyclohexane, n-hexane, n-heptane and the like; optionally water.
In yet another embodiment, the present invention provides substantially pure Silodosin (I) having purity greater than 99.5% and less than 0.5 % of total impurities as measured by chiral HPLC.
The term "substantially pure silodosin" means that the silodosin is at least 99% free of pyridine. More preferred is where the analytical purity is at least 99.5%; even further preferred is where the silodosin may completely free of impurities.
The term "substantially pure silodosin" refers to the total absence, or near total absence, of impurities, such as related-substance impurities. For example, when silodosin is said to be substantially pure, there are either no detectable related-substance impurities, or if a single related-substance impurity is detected, it is present in an amount not greater than 0.1 % by weight, or if multiple related-substance impurities are detected, they are present in aggregate in an amount not greater than 0.5% by weight.
The mole ratios of reactants and the reagents used therein can be appropriate based on the resultant product and the side products or bye products.
For example, the working-up of reaction mixtures, especially in order to isolate desired compounds, follows customary procedures, known to the organic chemists skilled in the norms of the art and steps, e.g. selected from the group comprising but not limited to extraction, neutralization, crystallization, chromatography, evaporation, drying, filtration, centrifugation and the like.
Advantageously, the process of present invention avoids the use of hazardous reagents thus making the process ecofriendly.
The reagents used herein the process of present invention are cheaper, commercially . available and may not form impurities or side products unlike in the prior art processes.
The starting material compounds of Formula VI and VII are known in the art and can be prepared by any known methods described in the literature for example US 5,387,603.
After completion of the reaction, the desired compounds can be obtained from the reaction mixture by conventional means known in the art. For example, the working-up of reaction mixtures, especially in order to isolate desired compounds, follows customary procedures, known to the organic chemists skilled in the norms of the art and steps, e.g. selected from the group comprising but not limited to extraction, neutralization, crystallization, chromatography, evaporation, drying, filtration, centrifugation and the like.
The processes reported for the preparation of Silodosin (I) in the art results in the formation of various impurities and bye products leading to include additional purification steps intermittently at several stages thus resulting in very poor yields of the final product.
The processes reported in the art yields Silodosin (1) not more than 60%wt/wt whereas the yields of the final product by the process of present invention are usually more than 80%, more precisely, the yield is about 80% to about 90% by weight.
Advantageously, the process of present invention provides substantially pure Silodosin (I) with higher yields and purities by using novel intermediate compounds.
The present invention provides simple, ecofriendly, economical, reproducible, robust process for the preparation of Silodosin (I) which is well feasible on a commercial scale.
Advantageously, the process of present invention described herein has simple reaction steps, produces the intermediate surprisingly in high yields and purities than the processes reported in the literature and well amenable on commercial scale.
As used herein, the term "HPLC" refers to High-performance liquid chromatography. As used herein, the term "% area by HPLC" refers to the area in an HPLC chromatogram of one or more peaks compared to the total area of all peaks in the HPLC chromatogram expressed in percent of the total area.
Substantially pure Silodosin (I) obtained by the process of present invention was analyzed by chiral high performance liquid chromatography (HPLC) method with the conditions and instrument as given below,
Chromatographic conditions: The liquid chromatograph is equipped with a detector
Column: Chiral Pak AD-H 250X4.6mm, 5μιη.
Wave length: 270nm.
Flow: l .OmL/min.
Load: Ι ΟμΙ,
Run time: 45minutes.
Column oven temperature: 25°C.
Concentration: 1.Omg/mL.
Mobile phase:
n-Hexane : IPA : Diethylamine (800:200: l)v/v/v
Diluent: Ethanol.
S-isomer stock solution:
Weigh accurately about 5.0mg of S-isomer standard into a 10ml volumetric flask, add 5ml of diluent and sonicate to dissolve, to this solution add 30 of above S-isomer stock solution and make up to the mark with diluent.
Test solution preparation: Weigh accurately about l O.Omg of SDS-6C test sample into a lOmL volumetric flask, add 5mL of diluent and sonicate to dissolve and make up to the mark with diluent.
System suitability criteria:
Resolution between SDS-6C and S-isomer is not less than 2.0
The theoretical plates for SDS-6C peak obtained from the system suitability solution is not less than 2000.
Procedure:
Equilibrate the chromatographic system with mobile phase until stable baseline is observed.
Then proceed for the analysis as per below mentioned sequence.
Record the chromatograms for 45mins and measure the peak responses. Inhibit the peaks due to blank. Ensure the system suitability criteria. The retention time of SDS-6C peal is about 29mins. RRT of S-isomer is about 0.77. Integrate the peaks only due to the S-isomer and SDS-6C. Report the result in area normalization mode.
In yet another embodiment, the present invention provides substantially pure Silodosin (I) characterized by X-ray powder diffraction pattern as depicted in fig.l and differential scanning calorimetry (DSC) thermogram as depicted in fig.2.
Substantially pure Silodosin (I) obtained by the process of present invention was characterized by XRPD using the X PD method end instrument details as given below,
Method of Analysis:
Powder XRD make: Bruker D2 Phaser.
Two theta runge: 3 - 40°.
Step size: 0.012.
Time for step: 0.44s.
Generator KV: 30.
Generator mA: 10.
Detector: Lynx Eye (PSD electronic window -5° )
Spinner: 15 rpm.
Total scan time: 25 min 5sec.
X- Ray source: Cu Ka.
Instrument: Agilent 1260 infinity series having VWD detector.
Substantially pure Silodosin (I) obtained by the process of present invention was also characterized by Differential Scanning Calorimetry (DSC) using the method and instrument details as given below,
Method of analysis:
Equilibrate temperature : 30 °C .
Ramp rate: 5.00 °C / min.
End temperature: 300 °C.
Sample size: Approximately 2 mg.
Instrument: DSC Q 100.
Model: Q 100- 1001.
Make: TA instruments - Waters.
In further embodiment, the substantially pure silodosin crystalline form obtained by the process of present invention is substantially free of other polymorphs thai means the crystalline form of silodosin obtained contains less than about 5 percent other polymorphs of silodosin and specifically less than 1 percent other polymorphs forms of silodosin, and more specifically is essentially free of other polymorphs of silodosin.
In another embodiment, the present invention provides an intermediate compound of
Formula IV
useful in the synthesis of substantially pure silodosin.
The intermediate compound of formula IV is identified as novel and was isolated, characterized by NMR and MASS.
According to the inventors of the present invention, said novel intermediate was found to very useful in omitting out formation of many un-removable or difficult to remove impurities.
In another embodiment, the Silodosin (I) obtained by the processes of the present invention may be formulated as solid compositions for oral administration in the form of capsules, tablets, pills, powders or granules. In these compositions, the active product is mixed with one or more pharmaceutically acceptable excipients. The drug substance can be formulated as liquid compositions for oral administration including solutions, suspensions, syrups, elixirs and emulsions, containing solvents or vehicles such as water, sorbitol, glycerine, propylene glycol or liquid paraffin.
The compositions for parenteral administration can be suspensions, emulsions or aqueous or non-aqueous sterile solutions. As a solvent or vehicle, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, and injectable organic eslers, e.g. ethyloleate, may be employed. These compositions can contain adjuvants, especially wetting, emulsifying and dispersing agents. The sterilization may be carried out in several ways, e.g. using a bacteriological filter, by incorporating sterilizing agents in the composition, by irradiation or by heating. They may be prepared in the form of sterile compositions, which can be dissolved at the time of use in sterile water or any other sterile injectable medium.
Pharmaceutically acceptable excipients used in the compositions comprising Silodosin (I) obtained as per the process of present invention include, but are but not limited to diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, pre-gelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, Croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.
Certain specific aspects and embodiments of the present application will be explained in more detail with reference to the following examples, which are provided by way of illustration only and should not be construed as limiting the scope of the invention in any manner.
EXAMPLES
Example-1: Synthesis of (R)-3-(5-(2-(tert-butoxycarbonyl(2-(2-(2,2,2-trifluoroethoxy)- phenoxy)ethyl)amino)propyl)-7-cyanoindolin-l -yl)propyl benzoate (IV) l-[3-(Benzoyloxy)propyl]-2,3-dihydro-5-[(2R)-2-[[2-[2-(2,2,2-trifluoroethoxy)- phenoxy] ethyl] amino]propyl]-lH-indole-7-carbonitrile ethanedioate (0.0372mol), dichloromethane (150 ml) and water (60 ml) were charged into RBF. pH of the reaction mixture was adjusted to basic with aqueous ammonia. The resultant reaction mixture was stirred for about 10 to 15 mins. and the aqueous, organic layers were separated. Aqueous layer was extracted with dichloromethane (60 ml). The combined organic layers were dried with sodium sulphate and distilled completely under vacuum. The solid obtained was dissolved in methanol (250 ml) and charged Triethyl amine (8.7 gm). The resultant reaction mass was cooled to 0-5 °C and di-tertiary butyl dicarbonate was added at the same temperature. The reaction mass was stirred for 12 hrs at room temperature and the mass was distilled completely under vacuum. 350 ml of ethyl acetate and 100ml of citric acid solution was charged and stirred for about 10-15 min. The organic and aqueous layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and concentrated completely under vacuum to yield the title compound.
Yield: 30 gm (oily mass). 1H-NMR (δ): 8.05-8.07 (d, 2H), 7.57-7.53 (t, 1 H), 7.45-7.41 (I, 2H), 7.04-6.89 (m, 6H), 4.47- 4.44 (t, 2H), 4.38-4.32 (q, 2H), 4.00 (t, 2H), 3.74-3.71 (t, 2H), 3.57-3.50 (t, 2H), 3.38 (d, 2H), 2.92-2.88 (t, 211), 2.80-2.71 (m, 1H), 2.55-2.52 (t, 2H), 2.17-2.10 (m, 2H), 1.42 (s,9H), 1.25 (d, 3H).
Mass spectrum: [M++l] Peak at m/z 682.7. Example-2: Synthesis of (R)-tert-butyl l-(7-cyano-l-(3-hydroxypropyl)indolin-5-yl)propan- 2-yl(2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl)carbamate (III) :
Methanol (140 niL), and (R)-3-(5-(2-(tert-butoxycarbonyl(2-(2-(2,2,2-trifluoroethoxy) phenoxy)ethyl)amino)propyl)-7-cyanoindolin-l-yl)propyl benzoate (IV) (0.044 mol) were charged into RDF. The reaction mixture was stirred for about 5-10 min and cooled to about 10-15°C. Potassium hydroxide (25%) solution was added slowly to the reaction mixture at same temperature. After completion of addition the resultant reaction mass was allowed to reach room temperature and stirred for about 12 hrs. Then 240 ml of ethyl acetate and water
(240 mL) were charged and stirred for about 10 min. The organic and aqueous layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and washed with brine solution. The total organic layer was distilled completely under vacuum to yield the title compound.
Yield: 20 gm (oily mass).
Example-3: Synthesis of (R)-tert-butyl l-(7-carbamoyl-l-(3-hydroxypropyl)indolin-5- yl) propan-2-yl(2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl)carbamate (II):
Dimethylsulfoxide(DMSO)(250mL),(R)-tert-butyl-l-(7-cyano-l-(3-hydroxypropyl)-indolin- 5-yl)propan-2-yl(2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl)-carbamate (III) (0.0432 mol) were charged into a RBF. Sodium Hydroxide solution (5M, 18.75 mL) was charged to the reaction mixture and was cooled to 20-25°C. Hydrogen peroxide solution (10.7 ml) was added to the reaction mixture at 20-25 °C and stirred the reaction mass for about 12 hrs at room temperature. Sodium sulphite solution (625 ml) was added to reaction mass and charged ethyl acetate (250 ml). Organic and aqueous layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine solution and dried with sodium sulphate. The organic layer was distilled completely under vacuum to yield the title compound. Aliquot quantity was isolated by column chromatography and characterized by Mass & NMR.
Yield: 27 gm (oily mass).
Example-4: Synthesis of Silodosin (I)
Methanol (200 ml), aqueous HC1 (1.8 gm) and (R)-tert-butyl-l-(7-carbamoyl-l-(3- hydroxypropyr)indolin-5-yl)piOpan-2-yl(2 (2-(2,2,2 rifluoroeLhoxy)-phcnoxy)cthyl) carbamate (II) (0.0335 mol) were charged into RBF and stirred at 20-25°C for 3-4 hrs at. The resultant mass was distilled under vacuum, 50 ml of water (50 nil .) and ethyl acetate, (100 mL) were charged. Then the pH of the resultant reaction mass was adjusted to 10-12 with sodium hydroxide solution. Stirred for 10 min and the organic, aqueous layers were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried with sodium sulphate and the mass was concentrated upto 10 volumes and cooled to 0-5 °C and stirred for about 1 hr at same temperature. The solid separated was filtered and the solid was washed with ethyl acetate. The solid obtained was dried at 50°C for 10-12 hrs. to yield the title compound.
Yield: 15.5 gm. Purity by HPLC: 99.75%.
Example-5: Process for the purification of Silodosin (I)
Crude silodosin (20.0 g, HPLC: 91.08) was dissolved in mixture of toluene (5.0 ml) and isopropyl alcohol (0.5 ml) at room temperature. The mass was heated to 40-45°C. Stirred for 5-10 min at this temperature and allowed cool at room temperature. Stirred for 2 hrs and filtered the solid, washed with toluene (1.0 ml). The wet solid was added ethyl acetate (10 ml) and temperature was raised to 50-55°C. The solution was stirred for 10 - 15 min and cooled to 0-5°C. The contents were maintained for 1 hr at 0-5°C, filtered and the solid obtained was washed with ethyl acetate. The obtained solid was dried at 50°C for 10-12 hrs to yield high pure Silodosin.
Yield: 19 gm. Purity by HPLC: > 99.7%.
While the foregoing pages provide a deluded description of the preferred embodiments of the invention, it is to be understood that the summary, description and examples are illustrative only of the core of the invention and non-limiting. Furthermore, as many changes can be made to the invention without departing from the scope of the invention, it is intended that all material contained herein be interpreted as illustrative of the invention and not in a limiting sense.
Claims
We Claim:
1) Process for preparing Silodosin (I),
(I)
comprising, the steps of:
a) reacting the compound of rmula VII or a salt thereof
(VII)
with the compound of For la VI
(VI)
to afford the compound of Formula V or a salt thereof
(V)
b) reacting the compound of Formula V or a salt thereof with di-tertiary butyl dicarbonate to afford the compound of Formula IV
(IV)
c) reacting the compound of Formula IV with a base to afford the compound of Formula III
(III)
converting the compound of Formula III to the compound of Formula II
(I)
2) The process of according to claim 1, wherein the steps (a) and (c) are carried out in the presence of base selected from the group consisting of alkali metal hydroxide such as
sodium hydroxide, potassium hydroxide, alkali metal carbonate such as sodium carbonate, potassium carbonate, organic base such as triethylamine, diisopropylamine.
3) The process according to claim 1 , wherein the step (b) is carried out in organic solvents selected from the group consisting of alcohols such as methanol, ethanol, isopropanol, n- propanol, n-butanol; halocarbonated solvents such as dichloromethane, ethylene chloride, chlorobenzene; ethers such tetrahydrofuran (THF), 1,4-dioxane; polar aprotic solvents such as Ν,Ν-dimethyl formamide (DMF), Ν,Ν-dimethyl acetamide, dimethyl sulfoxide (DMSO) or mixture thereof.
4) The process according to claim 1, wherein the step (d) is carried out using bases selected from the group consisting of alkali metal hydroxide such as sodium hydroxide, potassium hydroxide; alkali metal carbonate such as sodium carbonate, potassium carbonate; organic base such as triethylamine, diisopropylethylamine and the catalyst selected from hydrogen peroxide, sodium hypochlorite, perbenzoic acid, potassium permanganate and the solvents used is selected from the group consisting of water, aprotic polar solvents such as tetrahydrofuran, 1,4-dioxane, dimethylsulfoxide (DMSO), N,N-dimethyl formamide (DMF) or mixture thereof.
5) The process according to claim 1, wherein the deprotection in step (e) is carried out in the presence of inorganic acids selected from hydrochloric acid, sulfuric acid and phosphoric acid; organic acids such as acetic acid, trifluoroacetic acid methanesulfonic acid and p- toluenesulfonic acid; and the organic solvents used is selected from the group consisting of alcohols such as mclhanol, ethanol, propa ol, isopropyl alcohol; esters such as ethyl acetate, isopropyl acetate, butyl acetate; aprotic polar solvents such as acetonitrile, dimethyl formamide, dimethyl sulfoxide (DMSO), dimethyl acetamide or mixture thereof.
6) Substantially pure Silodosin (I) obtained having purity greater than 99.5% and less than about 0.5 % of total impurities by chiral HPLC.
(IV)
8) Substantially pure Silodosin (I) according to claim 6, is characterized by X-ray powder diffraction pattern as depicted in fig.1 and differential scanning calorimetry (DSC) thermogram as depicted in fig.2.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ININ201641040888 | 2016-11-30 | ||
IN201641040888 | 2016-11-30 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2018100565A1 true WO2018100565A1 (en) | 2018-06-07 |
Family
ID=62241262
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IB2017/058395 WO2018100565A1 (en) | 2016-11-30 | 2017-12-25 | Process for the preparation of indoline compound |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2018100565A1 (en) |
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 |
CN102382029A (en) * | 2011-07-26 | 2012-03-21 | 浙江华海药业股份有限公司 | Preparation method of salt formation of silodosin intermediate |
WO2012147019A1 (en) * | 2011-04-26 | 2012-11-01 | Orchid Chemicals And Pharamceuticals Limited | An improved process for the preparation of silodosin |
-
2017
- 2017-12-25 WO PCT/IB2017/058395 patent/WO2018100565A1/en active Application Filing
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 |
WO2012147019A1 (en) * | 2011-04-26 | 2012-11-01 | Orchid Chemicals And Pharamceuticals Limited | An improved process for the preparation of silodosin |
CN102382029A (en) * | 2011-07-26 | 2012-03-21 | 浙江华海药业股份有限公司 | Preparation method of salt formation of silodosin intermediate |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
KR102157608B1 (en) | Lfa-1 inhibitor and polymorph thereof | |
JP5535082B2 (en) | Method for synthesizing bosentan, polymorphic forms thereof and salts thereof | |
US10125115B2 (en) | Process for the preparation of efinaconazole | |
EP3490973B1 (en) | Polymorphic forms of belinostat and processes for preparation thereof | |
JP6873053B2 (en) | Method for Producing Protein Deacetylation Inhibitor | |
US20180265482A1 (en) | Methods for producing viloxazine salts and novel polymorphs thereof | |
CA3077888A1 (en) | Indacaterol free base in solid form | |
US20170362212A1 (en) | Process for preparation of luliconazole | |
CA2594721A1 (en) | Process for producing (z)-1-phenyl-1-(n,n-diethylaminocarbonyl)-2-phthalimidomethylcyclopropane | |
MXPA03003459A (en) | Crystalline venlafaxine base and novel polymorphs of venlafaxine hydrochloride, processes for preparing thereof. | |
US9771317B2 (en) | Process for preparing lacosamide and related compounds | |
JP2020535193A (en) | Process for the preparation of crystalline linagliptin intermediates and linagliptin | |
EP3286168A1 (en) | A solid form of apremilast and a process for preparing the same | |
WO2017191565A1 (en) | Process for preparation of macitentan | |
AU2007309558B2 (en) | Crystal modifications -3- (1H-indol-3-yl) -4- [2- (4-methyl-piperazin-1-yl) -quinazolin-4-yl] -pyrrole-2, 5-dione | |
WO2018100565A1 (en) | Process for the preparation of indoline compound | |
JP2005501028A (en) | Kinetic separation of an intermediate useful for the production of benazepril and its analogs. | |
US20130085304A1 (en) | Processes for preparation of polymorphic forms of lacosamide | |
WO2015104602A2 (en) | A process for the preparation of anagliptin and its intermediates thereof | |
CN114072386A (en) | Improved process for the preparation of key intermediates for the synthesis of eltrombopag or salts thereof | |
CN117858866A (en) | Process for preparing tryptamine derivatives | |
WO2008137512A2 (en) | Process for preparing pregabalin via hofmann reaction and crystalline form thereof | |
JP5569397B2 (en) | Method for producing 2-hydroxymethylmorpholine salt | |
WO2024033632A1 (en) | An improved process for preparing antiviral phosphonate analogues | |
JP2023513418A (en) | Method for the preparation of purine derivatives exhibiting CDK inhibitory activity |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 17875353 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 17875353 Country of ref document: EP Kind code of ref document: A1 |