WO2022149081A1 - Improved process for the preparation of a compound useful in the preparation of anti-androgenic compound - Google Patents
Improved process for the preparation of a compound useful in the preparation of anti-androgenic compound Download PDFInfo
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- WO2022149081A1 WO2022149081A1 PCT/IB2022/050083 IB2022050083W WO2022149081A1 WO 2022149081 A1 WO2022149081 A1 WO 2022149081A1 IB 2022050083 W IB2022050083 W IB 2022050083W WO 2022149081 A1 WO2022149081 A1 WO 2022149081A1
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- Prior art keywords
- formula
- compound
- preparation
- potassium
- sodium
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 44
- 150000001875 compounds Chemical class 0.000 title claims abstract description 35
- 238000002360 preparation method Methods 0.000 title claims abstract description 34
- 230000002280 anti-androgenic effect Effects 0.000 title abstract description 6
- FKLQNFXTDRYXEV-UHFFFAOYSA-N 2-(2-ethoxyphenoxy)ethyl methanesulfonate Chemical compound CCOC1=CC=CC=C1OCCOS(C)(=O)=O FKLQNFXTDRYXEV-UHFFFAOYSA-N 0.000 claims abstract description 19
- DRHKJLXJIQTDTD-OAHLLOKOSA-N Tamsulosine Chemical compound CCOC1=CC=CC=C1OCCN[C@H](C)CC1=CC=C(OC)C(S(N)(=O)=O)=C1 DRHKJLXJIQTDTD-OAHLLOKOSA-N 0.000 claims abstract description 16
- 150000003839 salts Chemical class 0.000 claims abstract description 16
- 229960002613 tamsulosin Drugs 0.000 claims abstract description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 19
- 238000006243 chemical reaction Methods 0.000 claims description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- 239000002585 base Substances 0.000 claims description 9
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical group [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 7
- 235000011181 potassium carbonates Nutrition 0.000 claims description 7
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 6
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 6
- -1 Alkali metal bicarbonates Chemical class 0.000 claims description 5
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- XLSZMDLNRCVEIJ-UHFFFAOYSA-N 4-methylimidazole Chemical compound CC1=CNC=N1 XLSZMDLNRCVEIJ-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 150000007529 inorganic bases Chemical group 0.000 claims description 3
- 150000007530 organic bases Chemical class 0.000 claims description 3
- AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 claims description 2
- LXBGSDVWAMZHDD-UHFFFAOYSA-N 2-methyl-1h-imidazole Chemical compound CC1=NC=CN1 LXBGSDVWAMZHDD-UHFFFAOYSA-N 0.000 claims description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 claims description 2
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 2
- 150000008044 alkali metal hydroxides Chemical group 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- WEHWNAOGRSTTBQ-UHFFFAOYSA-N dipropylamine Chemical compound CCCNCCC WEHWNAOGRSTTBQ-UHFFFAOYSA-N 0.000 claims description 2
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 2
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 229910052710 silicon Inorganic materials 0.000 claims description 2
- 239000010703 silicon Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 2
- QVCUKHQDEZNNOC-UHFFFAOYSA-N 1,2-diazabicyclo[2.2.2]octane Chemical compound C1CC2CCN1NC2 QVCUKHQDEZNNOC-UHFFFAOYSA-N 0.000 claims 1
- 239000012973 diazabicyclooctane Substances 0.000 claims 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- MOEFFSWKSMRFRQ-UHFFFAOYSA-N 2-ethoxyphenol Chemical compound CCOC1=CC=CC=C1O MOEFFSWKSMRFRQ-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- SZIFAVKTNFCBPC-UHFFFAOYSA-N 2-chloroethanol Chemical compound OCCCl SZIFAVKTNFCBPC-UHFFFAOYSA-N 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- QSQFARNGNIZGAW-UHFFFAOYSA-N 2-methylsulfonyloxyethyl methanesulfonate Chemical compound CS(=O)(=O)OCCOS(C)(=O)=O QSQFARNGNIZGAW-UHFFFAOYSA-N 0.000 description 3
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 3
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- KOFVDOFNEZNSKF-UHFFFAOYSA-N 2-(2-ethoxyphenoxy)ethanol Chemical compound CCOC1=CC=CC=C1OCCO KOFVDOFNEZNSKF-UHFFFAOYSA-N 0.000 description 1
- JECYNCQXXKQDJN-UHFFFAOYSA-N 2-(2-methylhexan-2-yloxymethyl)oxirane Chemical compound CCCCC(C)(C)OCC1CO1 JECYNCQXXKQDJN-UHFFFAOYSA-N 0.000 description 1
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 1
- 206010027566 Micturition urgency Diseases 0.000 description 1
- 206010036018 Pollakiuria Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 1
- 206010051482 Prostatomegaly Diseases 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 206010046555 Urinary retention Diseases 0.000 description 1
- 239000002160 alpha blocker Substances 0.000 description 1
- 229940124308 alpha-adrenoreceptor antagonist Drugs 0.000 description 1
- 239000012455 biphasic mixture Substances 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 206010013990 dysuria Diseases 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 208000023127 incomplete bladder emptying Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- ZIBGPFATKBEMQZ-UHFFFAOYSA-N triethylene glycol Chemical compound OCCOCCOCCO ZIBGPFATKBEMQZ-UHFFFAOYSA-N 0.000 description 1
- 208000022934 urinary frequency Diseases 0.000 description 1
- 230000036318 urination frequency Effects 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
- C07C303/30—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reactions not involving the formation of esterified sulfo groups
Definitions
- the present invention relates to an improved process for the preparation of a compound useful in the preparation of anti-androgenic compound.
- the present invention specifically relates to an improved process for the preparation of Tamsulosin intermediate or its salts.
- the present invention specifically relates to an improved process for the preparation of 2-(2-ethoxyphenoxy)ethyl methanesulfonate having the Formula (I) or its salts, where R is C C 6 alkyl (substituted or unsubstituted), phenyl or substituted phenyl, wherein the substituents are halogen, C C 6 alkyl, nitro group.
- the present invention more specifically relates to an improved process for the preparation of 2-(2-ethoxyphenoxy)ethyl methanesulfonate having the Formula (la) or its salts.
- the present invention also relates to a process for the preparation of Tamsulosin having the Formula (II) l Formula (II) or its salts using compound of Formula (I).
- Tamsulosin is chemically known as s (-)-(R)-5-[2-[[2-(o-Ethoxyphenoxy) ethyl] amino]propyl]-2-methoxybenzenesulfonamide and having molecular structure of:
- Tamsulosin is used in men to treat the symptoms of an enlarged prostate (benign prostatic hyperplasia or BPH) which include difficulty urinating (hesitation, dribbling, weak stream, and incomplete bladder emptying), painful urination, and urinary frequency and urgency. Tamsulosin is in a class of medications called alpha blockers. It works by relaxing the muscles in the prostate and bladder so that urine can flow easily
- US 5,447,958 A discloses a process for the preparation of Tamsulosin which is shown in the scheme given below :
- 2-chloroethanol in basic medium the reaction needs to be carried out in pressure reactor and high temperature which is difficult to handling bulk scale. 2-chloroethanol with high purity of 99.9% or more, preferably 99.95% is required, but it is very difficult to synthesize in this purity.
- the inventors of the present invention have surprisingly found a simple, cost effective and industrially viable process.
- the process was designed with consideration like environmental, economical aspects and the optimal duration times of the individual stages were determined.
- the number of operations were reduced by establishing the in- situ reactions leading to lowering of energy consumption.
- the main objective of the present invention is to provide an improved process for the preparation of a compound useful in the preparation of anti-androgenic compound.
- Another objective of the present invention is to provide an improved process for the preparation of Tamsulosin intermediate or its salts.
- Yet another objective of the present invention is to provide an improved process for the preparation of 2-(2-ethoxyphenoxy)ethyl methanesulfonate having the Formula
- Yet another objective of the present invention is to provide improved process for the preparation of 2-(2-ethoxyphenoxy)ethyl methanesulfonate having the Formula (la) Formula (la) or its salts with high yield and high purity.
- Still another objective of the present invention is to provide process for the preparation of Tamsulosin having the Formula (II) or its salts using compound of Formula (II).
- the present invention relates to an improved process for the preparation of an compound useful in the preparation of anti- androgenic compound.
- the present invention specifically relates to an improved process for the preparation of Tamsulosin intermediate or its salts.
- the present invention relates to an improved process for the preparation of 2-(2- ethoxyphenoxy)ethyl methanesulfonate having the Formula (I) or its salts, where R is C C 6 alkyl (substituted or unsubstituted), phenyl or substituted phenyl, wherein the substituents are halogen, Ci-C 6 alkyl, nitro group which comprises reacting a compound of Formula (III) OH
- the present invention specifically relates to an improved process for the preparation of 2-(2-ethoxyphenoxy)ethyl me ZIthanesulfonate having the Formula (la) Formula (la) or its salts, which comprises reacting a compound of Formula (III)
- Formula (IVa) optionally in the presence of a base in a solvent.
- the present invention relates to a process for the preparation of Tamsulosin having the Formula (II)
- the base used in this reaction include not limiting to either inorganic base like alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate; Alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal alkoxides such as sodium methoxide, potassium methoxide, sodium tertiary butoxide, potassium tertiary butoxide or mixtures thereof or Silicon-based amides, such as sodium and potassium bis(trimethylsilyl)amide, Lithium hexamethyldisilazide, Sodium hexamethyldisilazide and potassium hexamethyldisilazide or organic bases such as LDA (lithium diisoprop ylamide), triethylamine, triethanolaminetributylamine, N-methylmorpholine, N,N-diisopropylethylamine, di
- the solvent system used in the reaction medium is one or more selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, acetone, tetrahydrofuran, diisopropyl ether, dichloromethane,, N,N-dimethylformamide and the like or mixtures thereof.
- the solvent used is acetone, dichloromethane, N,N- Dimethylformamide
- the advantages of the present invention involve reduction of steps for the preparation of compound of formula (la) by using l,2-bis(methanesulfonyloxy)ethane as starting material in stage- 1 which is giving desire product, 2-(2-ethoxyphenoxy)ethyl methanesulfonate.
- stage- 1 which is giving desire product, 2-(2-ethoxyphenoxy)ethyl methanesulfonate.
- the process is high yielding and good purity.
- 2-(2-ethoxyphenoxy)ethyl methanesulfonate was obtained with > 99.5% purity and ND level of other impurities.
- Ethane- 1,2-diol 100 g was dissolved in CH 2 C1 2 (1000 mL) and cooled to 0°C. Triethylamine (406.2 g) was added to the solution of the ethane- 1,2-diol. Methanesulfonyl chloride (407.6 g) was added in drop wise to the reaction mass at 0 °C. After methanesulfonyl chloride addition, the reaction mixture was allowed to warm to room temperature over 2h. A 5% aq HC1 solution was added, and the mixture was stirred for 15 min. The biphasic mixture was decanted into a separator funnel and the organic layer was separated. The organic solution was washed with saturated aq.
- Example-2 2-(2-ethoxyphenoxy)ethyl methanesulfonate:
- N,N-Dimethylformamide (2000 mL) was taken into the round bottom flask at RT.
- 2-ethoxyphenol 100 g
- Potassium carbonate 129 g
- 1,2- bis(methanesulfonyloxy)ethane 196 g
- the reaction was stirred at 70 °C, after completion of the reaction, check with HPLC, water 2000 mL and ethyl acetate 2000 mL was added. Separated the organic layer distilled the solvent and purified the compound in toluene results the title compound (147 g, HPLC content 99.7 %).
- Acetone (3000 L) was taken into the round bottom flask at RT.
- 2-ethoxyphenol 150 Kg
- Potassium carbonate (193.5 Kg)
- l,2-bis(methanesulfonyloxy)ethane (294 Kg) were added sequentially.
- the reaction was stirred at acetone reflux temperature.
- check with HPLC of the reaction filtered the solids.
- the filtrate was distilled and purified in toluene results the title compound (250.5 Kg, 88% yield, and HPLC content 99.8 %). All known and un known impurities below 0.1%.
Abstract
The present invention relates to an improved process for the preparation of an compound useful in the preparation of anti-androgenic compound.The present invention specifically relates to an improved process for the preparation of Tamsulosin intermediate or its salts. The present invention specifically relates to an improved process for the preparation of 2-(2-ethoxyphenoxy)ethyl methanesulfonate having the Formula (I).
Description
IMPROVED PROCESS FOR THE PREPARATION OF A COMPOUND USEFUL IN THE PREPARATION OF ANTI-ANDROGENIC
COMPOUND
FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of a compound useful in the preparation of anti-androgenic compound.
The present invention specifically relates to an improved process for the preparation of Tamsulosin intermediate or its salts.
The present invention specifically relates to an improved process for the preparation of 2-(2-ethoxyphenoxy)ethyl methanesulfonate having the Formula (I)
or its salts, where R is C C6 alkyl (substituted or unsubstituted), phenyl or substituted phenyl, wherein the substituents are halogen, C C6 alkyl, nitro group.
The present invention more specifically relates to an improved process for the preparation of 2-(2-ethoxyphenoxy)ethyl methanesulfonate having the Formula (la)
or its salts.
The present invention also relates to a process for the preparation of Tamsulosin having the Formula (II) l
Formula (II) or its salts using compound of Formula (I).
BACKGROUND OF THE INVENTION
Tamsulosin is chemically known as s (-)-(R)-5-[2-[[2-(o-Ethoxyphenoxy) ethyl] amino]propyl]-2-methoxybenzenesulfonamide and having molecular structure of:
Tamsulosin is used in men to treat the symptoms of an enlarged prostate (benign prostatic hyperplasia or BPH) which include difficulty urinating (hesitation, dribbling, weak stream, and incomplete bladder emptying), painful urination, and urinary frequency and urgency. Tamsulosin is in a class of medications called alpha blockers. It works by relaxing the muscles in the prostate and bladder so that urine can flow easily
US 5,447,958 A discloses a process for the preparation of Tamsulosin which is shown in the scheme given below :
US 7,332,621 B2 claims a process for the preparation of Tamsulosin intermediate of formula (I) which is shown in the scheme given below :
Formula-2 Formula-3
EP 1 734 036 B1 discloses a process for the preparation of Tamsulosin intermediates which is shown in the scheme given below : wherei
The process described in the prior-art involves usage of 2-ethoxyphenol and 2- chloroethanol were used to synthesize the 2-(2-ethoxyphenoxy)ethanol, which is a pre step material of the compound. In basic condition the 2-chloroethanol converts into oxirane, which is easily demonized and polymerized into diethylene glycol, triethylene glycol and polyethylene glycol. These polymerized alcohols leads to side reactions which resulting low yield and less purity of the product, and the product needs to be purified by column chromatography, so it is expensive and difficult to synthesize in bulk quantity. Further, 2-chloroethanol has a safety problem, so it has a disadvantage of very low industrial applicability
2-chloroethanol, in basic medium the reaction needs to be carried out in pressure reactor and high temperature which is difficult to handling bulk scale. 2-chloroethanol with high purity of 99.9% or more, preferably 99.95% is required, but it is very difficult to synthesize in this purity.
In the second step, methanesulfonyl chloride treated with alcohol gives the 2-(2- ethoxyphenoxy)ethyl methanesulfonate. These polymerized alcohols leads to side reactions which resulting low yield and less purity of the product, and the product needs to be purified by column chromatography, so it is expensive and difficult to synthesize in bulk quantity.
The number of steps in the prior-art processes are more which results difficult to manufacture with high-purity of tamsulosin.
Accordingly, there is a need to industrially acceptable process acceptable with all known and unknown impurities below 0.15% preferable below 0.1%.
The inventors of the present invention have surprisingly found a simple, cost effective and industrially viable process. The process was designed with consideration like environmental, economical aspects and the optimal duration times of the individual stages were determined. The number of operations were reduced by establishing the in- situ reactions leading to lowering of energy consumption.
OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide an improved process for the preparation of a compound useful in the preparation of anti-androgenic compound.
Another objective of the present invention is to provide an improved process for the preparation of Tamsulosin intermediate or its salts.
Yet another objective of the present invention is to provide an improved process for the preparation of 2-(2-ethoxyphenoxy)ethyl methanesulfonate having the Formula
(I)
Formula (I) or its salts, where R is C C6 alkyl (substituted or unsubstituted), phenyl or substituted phenyl, wherein the substituents are halogen, Ci-C6 alkyl, nitro group, which is commercially feasible / industrially scalable which involves use of simple and easily available starting materials.
Yet another objective of the present invention is to provide improved process for the preparation of 2-(2-ethoxyphenoxy)ethyl methanesulfonate having the Formula (la)
Formula (la) or its salts with high yield and high purity.
Still another objective of the present invention is to provide process for the preparation of Tamsulosin having the Formula (II)
or its salts using compound of Formula (II).
SUMMARY OF THE INVENTION
Accordingly, the present invention relates to an improved process for the preparation of an compound useful in the preparation of anti- androgenic compound.
The present invention specifically relates to an improved process for the preparation of Tamsulosin intermediate or its salts.
The present invention relates to an improved process for the preparation of 2-(2- ethoxyphenoxy)ethyl methanesulfonate having the Formula (I)
or its salts, where R is C C6 alkyl (substituted or unsubstituted), phenyl or substituted phenyl, wherein the substituents are halogen, Ci-C6 alkyl, nitro group which comprises reacting a compound of Formula (III)
OH
O CH '3 Formula (III) with a compound of formula (IV)
Formula (IV) wherein R is a defined earlier, optionally in the presence of a base in a solvent.
The present invention specifically relates to an improved process for the preparation of 2-(2-ethoxyphenoxy)ethyl me ZIthanesulfonate having the Formula (la)
Formula (la) or its salts, which comprises reacting a compound of Formula (III)
,0H
O CH 3 Formula (III) with a compound of formula (IVa)
H 3
Formula (IVa) optionally in the presence of a base in a solvent.
In still another aspect, the present invention relates to a process for the preparation of Tamsulosin having the Formula (II)
H3C O
H2NO2S,
O’
CH H3CO' 3
Formula (II)
or its salts using compound of formula (I).
DETAILED DESCRIPTION OF THE INVENTION
The term "comprising", which is synonymous with "including", "containing", or "characterized by" here is defined as being inclusive or open-ended, and does not exclude additional, unrecited elements or method steps, unless the context clearly requires otherwise.
In yet another preferred embodiment of the present invention provides an improved process for the preparation of 2-(2-ethoxyphenoxy)ethyl methanesulfonate having the Formula (la)
Formula (la) or its salts which comprises reacting a compound of Formula (III)
Formula (III) with a compound of formula (IVa)
Formula (IVa) in the presence of a base and a solvent.
The base used in this reaction include not limiting to either inorganic base like alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate; Alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal alkoxides such as sodium
methoxide, potassium methoxide, sodium tertiary butoxide, potassium tertiary butoxide or mixtures thereof or Silicon-based amides, such as sodium and potassium bis(trimethylsilyl)amide, Lithium hexamethyldisilazide, Sodium hexamethyldisilazide and potassium hexamethyldisilazide or organic bases such as LDA (lithium diisoprop ylamide), triethylamine, triethanolaminetributylamine, N-methylmorpholine, N,N-diisopropylethylamine, di-n-propylamine, N-methylpyrrolidine, pyridine, 4-(N,N- dimethylamino)pyridine, morpholine, imidazole, 2-methylimidazole, 4-methylimidazole, l,4-diazabicycloundec-7-ene (DBU), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4- diazabicyclo[2.2.2]-octane (DABCO) and the like. Preferably, the base used is potassium carbonate, cesium carbonate, Triethylamine.
The solvent system used in the reaction medium is one or more selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, acetone, tetrahydrofuran, diisopropyl ether, dichloromethane,, N,N-dimethylformamide and the like or mixtures thereof. Preferably, the solvent used is acetone, dichloromethane, N,N- Dimethylformamide
The advantages of the present invention involve reduction of steps for the preparation of compound of formula (la) by using l,2-bis(methanesulfonyloxy)ethane as starting material in stage- 1 which is giving desire product, 2-(2-ethoxyphenoxy)ethyl methanesulfonate. The process is high yielding and good purity. With the process of the present invention 2-(2-ethoxyphenoxy)ethyl methanesulfonate was obtained with > 99.5% purity and ND level of other impurities.
EXAMPLES
Example- 1: Preparation of l,2-bis(methanesulfonyloxy)ethane:
Ethane- 1,2-diol (100 g) was dissolved in CH2C12 (1000 mL) and cooled to 0°C. Triethylamine (406.2 g) was added to the solution of the ethane- 1,2-diol. Methanesulfonyl chloride (407.6 g) was added in drop wise to the reaction mass at 0 °C. After methanesulfonyl chloride addition, the reaction mixture was allowed to warm to
room temperature over 2h. A 5% aq HC1 solution was added, and the mixture was stirred for 15 min. The biphasic mixture was decanted into a separator funnel and the organic layer was separated. The organic solution was washed with saturated aq. NaHCOs (1000 mL), distilled H20 (1000 mL) and brine (1000 mL). The solvent was removed in vacuo. Solid products were recrystallized from ethyl acetate, gives 306 g. 1H NMR (CDCI3) d 4.49 (4H, s), 3.10 (6 H, s).
Example-2: 2-(2-ethoxyphenoxy)ethyl methanesulfonate:
Acetone (2000 mL) was taken into the round bottom flask at RT. To this 2- ethoxyphenol (100 g), Potassium carbonate (129 g) and 1,2- bis(methanesulfonyloxy)ethane (196 g) were added sequentially. The reaction was stirred at acetone reflux temperature. After completion, check with HPLC, of the reaction filtered the solids. The filtrate was distilled and purified in toluene results the title compound (165 g, HPLC content 99.8 %). 1H NMR (CDC13) d 7.02-6.87 (4H, m), 4.65 (2 H, t), 4.25 (2 H, t), 4.11-4.03 (2 H, m), 3.18 (3 H, s), 1.47-1.39 (3 H, m).
Example 3: 2-(2-ethoxyphenoxy)ethyl methanesulfonate
Acetone (2000 mL) was taken into the round bottom flask at RT. To this 2- ethoxyphenol (100 g), cesium carbonate (294 g) and l,2-bis(methanesulfonyloxy)ethane (196 g) were added sequentially. The reaction was stirred at acetone reflux temperature.
After completion of the reaction, check with HPLC, filtered the solids. The filtrate was distilled and purified in toluene results the title compound (154 g, HPLC content 99.6 %). Example 4: 2-(2-ethoxyphenoxy)ethyl methanesulfonate
N,N-Dimethylformamide (2000 mL) was taken into the round bottom flask at RT. To this 2-ethoxyphenol (100 g), cesium carbonate (294 g) and 1,2- bis(methanesulfonyloxy)ethane (196 g) were added sequentially. The reaction was stirred at 70 °C temperature. After completion of the reaction, check with HPLC, filtered the solids. The filtrate was distilled and purified in toluene results the title compound (154 g, HPLC content 99.5 %).
Example 5: 2-(2-ethoxyphenoxy)ethyl methanesulfonate:
N,N-Dimethylformamide (2000 mL) was taken into the round bottom flask at RT. To this 2-ethoxyphenol (100 g), Potassium carbonate (129 g) and 1,2- bis(methanesulfonyloxy)ethane (196 g) were added sequentially. The reaction was stirred at 70 °C, after completion of the reaction, check with HPLC, water 2000 mL and ethyl acetate 2000 mL was added. Separated the organic layer distilled the solvent and purified the compound in toluene results the title compound (147 g, HPLC content 99.7 %).
Example 6: 2-(2-ethoxyphenoxy)ethyl methanesulfonate :
Acetone (3000 L) was taken into the round bottom flask at RT. To this 2-ethoxyphenol (150 Kg), Potassium carbonate (193.5 Kg) and l,2-bis(methanesulfonyloxy)ethane (294 Kg) were added sequentially. The reaction was stirred at acetone reflux temperature. After completion, check with HPLC, of the reaction filtered the solids. The filtrate was distilled and purified in toluene results the title compound (250.5 Kg, 88% yield, and HPLC content 99.8 %). All known and un known impurities below 0.1%.
Claims
1. A improved process for the preparation of 2-(2-ethoxyphenoxy)ethyl methanesulfonate having the Formula (I)
Formula (I) or its salts, where R is C\-C6 alkyl (substituted or unsubstituted), phenyl or substituted phenyl, wherein the substituents are halogen, C C6 alkyl, nitro group which comprises reacting a compound of Formula (III)
Formula (III) with a compound of formula (IV) in a solvent
Formula (IV) wherein R is a defined above.
2. The process as claimed in claim 1, wherein the 2-(2-ethoxyphenoxy)ethyl methanesulfonate having the Formula (I) is 2-(2-ethoxyphenoxy)ethyl methanesulfonate having the Formula (la) .
3. The process as claimed in claims 1 and 2, wherein the process comprises preparation of 2-(2-ethoxyphenoxy)ethyl methanesulfonate having the Formula (la)
Formula (la) or its salts, which comprises reacting a compound of Formula (III)
Formula (III) with a compound of formula
Formula (IVa) in a solvent.
3. The process as claimed in claims 1 and 3, wherein the reaction takes place in the presence of a base.
4. The process as claimed in claims 1 and 3, wherein the reaction takes place in the absence of a base.
5. The process as claimed in claim 4, wherein base is inorganic base or an organic base.
6. The process as claimed in claim 5, wherein inorganic base is alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate; Alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal alkoxides such as sodium methoxide, potassium methoxide, sodium tertiary butoxide, potassium tertiary butoxide or mixtures thereof or Silicon-based amides, such as sodium and potassium bis(trimethylsilyl)amide, Lithium hexamethyldisilazide, Sodium hexamethyldisilazide and potassium hexamethyldisilazide.
7. The process as claimed in claim 5, wherein organic base is lithium diisoprop ylamide (LDA), triethylamine, triethanolaminetributylamine, N- methylmorpholine, N,N-diisopropylethylamine, di-n-propylamine, N- methylpyrrolidine, pyridine, 4-(N,N-dimethylamino)pyridine, morpholine, imidazole, 2-methylimidazole, 4-methylimidazole, l,4-diazabicycloundec-7-ene
(DBU), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), l,4-diazabicyclo[2.2.2]-octane (DABCO).
8. The process as claimed in claim 5, the base is preferably potassium carbonate, cesium carbonate, Triethylamine.
9. The process as claimed in claims 1 and 3, wherein the solvent is methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, acetone, tetrahydrofuran, diisopropyl ether, dichloro methane, N,N-dimethylformamide or mixtures thereof
10. The process as claimed in claims 1 and 3, wherein the compound of formula (I) and compound of Formula (la) is converted to Tamsulosin having the Formula (II).
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| IN202141000724 | 2021-01-07 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080177108A1 (en) * | 2006-09-04 | 2008-07-24 | Lutz Lehmann | Phenyloxyaniline derivatives |
| EP1734036B1 (en) * | 2005-06-14 | 2011-08-31 | Well-being Biochemical Corp. | Process for preparation of tamsulosin and its derivatives |
| KR20140088428A (en) * | 2013-01-02 | 2014-07-10 | 보령제약 주식회사 | Process for preparation of high purity tamsulosin or salt thereof |
-
2022
- 2022-01-06 WO PCT/IB2022/050083 patent/WO2022149081A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1734036B1 (en) * | 2005-06-14 | 2011-08-31 | Well-being Biochemical Corp. | Process for preparation of tamsulosin and its derivatives |
| US20080177108A1 (en) * | 2006-09-04 | 2008-07-24 | Lutz Lehmann | Phenyloxyaniline derivatives |
| KR20140088428A (en) * | 2013-01-02 | 2014-07-10 | 보령제약 주식회사 | Process for preparation of high purity tamsulosin or salt thereof |
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