SANNAREDDY MUNISEKHAR REDDY (IN)
VILASAGARAPU ANANDA KUMAR (IN)
MARRI MAHENDER REDDY (IN)
MUDDULURU HARIKRISHNA (IN)
SANNAREDDY MUNISEKHAR REDDY (IN)
VILASAGARAPU ANANDA KUMAR (IN)
MARRI MAHENDER REDDY (IN)
| KR20140088428A | 2014-07-10 | |||
| EP1734036B1 | 2011-08-31 | |||
| US20080177108A1 | 2008-07-24 |
| WE CLAIM 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). |
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 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).
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 C 6 alkyl (substituted or unsubstituted), phenyl or substituted phenyl, wherein the substituents are halogen, Ci-C 6 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 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
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)
H 3 C O
H 2 NO 2 S,
O ’
CH H 3 CO' 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 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. NaHCOs (1000 mL), distilled H 2 0 (1000 mL) and brine (1000 mL). The solvent was removed in vacuo. Solid products were recrystallized from ethyl acetate, gives 306 g. 1H NMR (CDCI 3 ) 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 (CDC1 3 ) 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%.