Title of Invention | NOVEL PROCESS FOR THE SYNTHESIS OF 4-[2-(5-ETHYI-2-PYRIDINY)-ARYI DERIVATIVES |
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Abstract | The present invention relates to a novel process for the synthesis of 4-[2-(S-ethyl-2-pyridinyl) ethoxy]-aryl derivatives of formula I where G1 is selected from one or more of the following groups NO2, NH2, NHR1, COOH or COOR2; Rl is acetyl or trifluoro acetyl group and R2 is an alkyl group. |
Full Text | Novel process for the synthesis of 4-[2-(5-ethyl-2-pyridinyl)ethoxy]-aryl derivatives FIELD OF THE INVENTION The present invention relates to a novel process for the synthesis of 4-[2-(5-ethyl-2-pyriclinyl) ethoxy]-aryl derivatives. BACKGROUND OF THE INVENTION The instant invention relates to a new and industrially advantageous process for the preparation of 4-[2-(5-ethyl-2-pyrldinyl)ethoxy] aryl derivatives of formula I Formula I where G1 is selected from one or more of the following groups NO2, NH2, NHR1, COOH or COOR2; Ri is acetyl or trifluoro acetyl group and R2 is an alkyl group. This compound is the key intermediate for the synthesis of the thiazolidinediones, oral hypoglycemic agents. Previously Known methods for the synthesis of some of the 4-[2-(5-ethyl-2-pyrldlnyl) ethoxy]-aryl derivatives were reported in EP 0 139 256, EP 0 257 781, WO 93/13095, EP 0 816 340. EP 0 193 256, WO 93/13095 disclosed a reaction of 4-fluoronitroaryl compounds with 2-(5-ethyl-2-pyridinyl) ethanol to produce 4-[2-(5-ethyl-2-pyridlnyl)ethoxy] nitro aryl. EP 0 257 781 disclosed a reaction of 4-hydroxybenzaldehyde with 2-(5-ethyl-2-pyridinyl)ethanol, or Its derivatives to produce 4-[2-(5-ethyl-2-pyrldlnyl)ethoxy] benzaldehyde. It also disclosed a reaction of 4-cyanophenol with 2-(5-ethyl-2-pyridinyl) ethanol, or Its derivatives to produce 4-[2-(5-ethyl-2-pyrldlnyl)ethoxy] cyan aryl compounds. EP 0 816 340 disclosed a reaction of 4-hydroxybenzaldehyde with 2-(5-ethyl-2-pyrldlnyl)ethanol, or Its derivatives to produce 4-[2-(5-ethyl-2-pyrldlnyl)ethoxy] benzaldehyde. The above mentioned methods described in the prior art for the manufacture of compound of formula I or It"s derivatives suffers from the limitation that they use sodium hydride for the reaction, which is a hazardous chemical with potential fire hazard. The present Invention provides solution to this problem by using non-hazardous reagents. Also, the present process discloses use of novel starting materials and reagents for the production of 4-[2-(5-ethyl-2-pyridinyl)ethoxy] aryl derivatives. SUMMARY OF THE INVENTION The process for preparing of 4-[2-(5-ethyl-2-pyridinyl)ethoxy] aryl derivatives which is a useful intermediate for the synthesis of thiazolidinedione derivatives; comprise of reacting a compound of formula II, where G2 is selected from H, mesyl or tosyl; with a compound of formula III, where G1 is selected from one or more of the following groups NO2, NH2, NHRi, COOH or COOR2; Ri is acetyl or trifluoro acetyl group and R2 is an alkyl group to give the title compound of formula I. The advantages of the present invention as discussed in the present application over other reported methods include: (!) Use of non-hazardous reagents. (ii) Readily available and cheap raw materials. (ill) Economic and industrially viable process. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel process for the synthesis of 4-[2-(5-ethyl-2-pyridinyl) ethoxy]-aryl derivatives of formula I Formula I where G1 is selected from one or more of the following groups NO2, NH2, NHRi, COOH or COOR2; R1 is acetyl or trifluoro acetyl group and R2 is an alkyl group. The synthesis compounds of formula I comprises of reacting a compound of formula II with a compound of formula III Formula II Formula III where G2 is selected from H, mesyl or tosyl; where Gi is selected from one or more of the following groups NO2, NH2, NHRi, COOH or COOR2; Ri is acetyl or trifluoro acetyl group and R2 is an alkyl group. The reaction is carried out in halogenated hydrocarbon, alcohols, dimethylformamide or acetonitrile. The halogenated hydrocarbon is selected from dichloromethane or ethylene dichloride. The alcohol is selected from iso-propanol or ethanol. When G2 is H the reaction is carried out in the presence of PhsP-diisopropyl axodicarboxylate or LiOH-AbOs. When G2 is mesyl or tosyl the reaction is carried out in the presence of KOH, K2CO3, LiOH-AlzOs or NaOH. The invention is further illustrated with examples below, which are not intended to be limiting. EXAMPLE 1 5-ethyl-2-[2-(4-nitrophenoxy)ethyl]pyridine: A stirred suspension of potassium carbonate (91 g, 0.66 mol) in isopropyl alcohol (400 mL) was heated to 40-45 ° C and p-nitrophenol (64 g, 0.46 mol) was added. After stirring for 1 h at 40-45 ° C, a solution of 2-(5-ethylpyridin-2-yl)ethyl methanesulfonate (100 g, 0.44 mol) in isopropyl alcohol (400 mL) was added to the reaction mixture drop-wise. The mixture was stirred for 18 h maintaining the temperature between 60-70 ° C. The reaction mixture was filtered and concentrated, diluted with water (1 L), and extracted using ethyl acetate (3 x 500 mL). The combined extract was washed with water (500 mL), brine (500 mL) and concentrated. The residue was stirred with petroleum ether (150 mL) and filtered. Yield: 85 g (71 %). EXAMPLE 2 5-ethyh2-[2-(4-nitrophenoxy)ethyl]pyridine: A stirred suspension of potassium hydroxide (37 g, 0.66 mol) in isopropyl alcohol (400 mL) was heated to 40-45 ° C and p-nltrophenol (64 g, 0.46 mol) was added. After stirring for 1 h at 40-45 °C, a solution of 2-(5-ethylpyridin-2-yi)ethyl methanesulfonate (100 g, 0.44 mol) In isopropyl alcohol (400 mL) was added to the reaction mixture drop-wise. The mixture was stirred for 18 h maintaining the temperature between 60-70 ° C. The reaction mixture was filtered and concentrated, diluted with water (1 L), and extracted using ethyl acetate (3 x 500 mL). The combined extract was washed with water (500 mL), brine (500 mL) and concentrated. The residue was stirred with petroleum ether (150 mL) and filtered. Yield: 65 g (55 %). EXAMPLE 3 5-ethyl-2-[2-(4-nitrophenoxy)ethyl]pyridine: To A stirred suspension of p-nitrophenol (32 g, 0.23 mol) and 2-(5-ethylpyridin-2-yl)ethanol (35 g, 0.23 mol) in dichioromethane (200 mL), triphenyl phosphine (63 g, 0.24 mol) and diisopropyl azodicarboxylate (48.5 g. 0.24 mol) were added and stirred for 24 h at ambient temperature. The reaction mixture was filtered, washed with water (250 mL), brine (250 mL) and concentrated. The residue was stirred with petroleum ether (75 mL) and filtered. Yield: 35 g (56 %). EXAMPLE 4 5-ethyl-2-[2-(4-nitrophenoxy)ethyl]pyridine: To A stirred suspension of p-nitrophenol (32 g, 0.23 mol) and 2-(5-ethylpyridin-2-yl)ethanol (35 g, 0.23 mol) In acetonltrile (200 mL), LiOH-AbOa (15 g LiOH adsorbed on 90 g AI2O3) was added and stirred for 24 h at 70-80 °C. The reaction mixture was filtered, diluted with water (250 mL) and extracted using ethyl acetate (3 x 250 mL). The combined extract was washed with water (250 mL), brine (250 mL) and concentrated. The residue was stirred with petroleum ether (75 mL) and filtered. Yield: 32 g (51 %). EXAMPLE 5 5-ethyl-2-[2-(4-nitrophenoxy)ethyl]pyridine: A stirred suspension of potassium carbonate (68 g, 0.49 mol) in isopropyl alcohol (300 mL) was heated to 40-45 ° C and p-nitrophenol (48 g, 0.34 mol) was added. After stirring for 1 h at 40-45 ° C, a solution of 2-(5-ethylpyridln-2-yl)ethyl 4-methylarylsulfonate (100 g, 0.32 mol) In Isopropyl alcohol (300 mL) was added to the reaction mixture drop-wise. The mixture was stirred for 16 h maintaining the temperature between 60-70 ° C. The reaction mixture was filtered and concentrated, diluted with water (750 mL), and extracted using ethyl acetate (3 x 300 mL). The combined extract was washed with water (300 mL), brine (300 mL) and concentrated. The residue was stirred with petroleum ether (100 mL) and filtered. Yield: 52 g (60 %). EXAMPLE 6 5-ethyl-2-[2-(4-nitrophenoxy)ethyl]pyridine: A stirred suspension of potassium hydroxide (27.5 g, 0.49 mol) In isopropyl alcohol (300 mL) was heated to 40-45 ° C and p-nitrophenol (48 g, 0.34 mol) was added. After stirring for 1 h at 40-45 ° C, a solution of 2-(5-ethylpyridin-2-yl)ethyl 4-methylarylsulfonate (100 g, 0.32 mol) in isopropyl alcohol (300 mL) was added to the reaction mixture drop-wise. The mixture was stirred for 18 h maintaining the temperature between 60-70 ° C. The reaction mixture was filtered and concentrated, diluted with water (750 mL), and extracted using ethyl acetate (3 x 300 mL). The combined extract was washed with water (300 mL), brine (300 mL) and concentrated. The residue was stirred with petroleum ether (100 mL) and filtered. Yield: 45 g (51 %). EXAMPLE 7 N-{4-[2-(5-ethylpyridin-2-yl)ethoxy]phenyl}acetamide: A stirred suspension of potassium carbonate (91 g, 0.66 mol) in isopropyl alcohol (400 mL) was heated to 40-45 ° C and /V-(4-hydroxyphenyl)acetamide (70 g, 0.46 mol) was added. After stirring for 1 h at 40-45 ° C, a solution of 2-(5-ethylpyridin-2-yl)ethyl methanesulfonate (100 g, 0.44 mol) in isopropyl alcohol (400 mL) was added to the reaction mixture drop-wise. The mixture was stirred for 18 h maintaining the temperature between 60-70 ° C. The reaction mixture was filtered and concentrated, diluted with water (1 L), and extracted using ethyl acetate (3 x 500 mL). The combined extract was washed with water (500 mL), brine (500 mL) and concentrated. The residue was stirred with petroleum ether (250 mL) and filtered. Yield: 88 g (70 %). WE CLAIM: We claim: 1. A process for the synthesis of compounds of formuia I Formuia I where G1 is selected from one or more of the following groups NO2,NH2, NHR1, COOH or COOR2; Ri is acetyl or tri-fluoro acetyl group and R2 Is an alkyl group comprising of reacting a compound of formula II with a compound of formula III in the presence of an organic solvent Formula II Formula III where G2 Is selected from H, mesyl or tosyl; G1 Is selected from one or more of the following groups NO2, NH2, NHR1, COOH or COOR2; R1 is acetyl or trifluoro acetyl group and R2 is an alkyl group. 2. The process as claimed in claim 1, wherein said organic solvent includes halogenated hydrocarbon, alcohols, dimethyl formamide or acetonitrile. 3. The process as claimed in claim 2, wherein the halogenated hydrocarbon is selected from dichloromethane or ethylene dichloride. 4. The process as claimed in claim 2, wherein the alcohol is selected from iso-propanol or ethanol. 5. The process as claimed in claim 1, when G2 is H the reaction is carried out in the presence of Ph3P-diisopropyl azodicarboxalate or LiOH-Al2Os. 6. The process as claimed in claim 1, when G2 is mesyl or tosyl the reaction is carried out in the presence of KOH, K2CO3, LiOH-AI2O3 or NaOH. 7. A process for the synthesis of compounds of formula I substantially as herein described with reference to the foregoing examples. |
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369-mas-2002 others document.pdf
369-mas-2002 abstract duplicate.pdf
369-mas-2002 claims duplicate.pdf
369-mas-2002 correspondence others.pdf
369-mas-2002 correspondence po.pdf
369-mas-2002 description (complete) duplicate.pdf
369-mas-2002 description (complete).pdf
Patent Number | 198938 | |||||||||||||||||||||
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Indian Patent Application Number | 369/MAS/2002 | |||||||||||||||||||||
PG Journal Number | 23/2006 | |||||||||||||||||||||
Publication Date | 09-Jun-2006 | |||||||||||||||||||||
Grant Date | 27-Feb-2006 | |||||||||||||||||||||
Date of Filing | 17-May-2002 | |||||||||||||||||||||
Name of Patentee | M/S. BIOCON LIMITED | |||||||||||||||||||||
Applicant Address | 20th KM HOSUR ROAD, HEBBAGODI 561 229, BANGALORE | |||||||||||||||||||||
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PCT International Classification Number | C07D 213/30 | |||||||||||||||||||||
PCT International Application Number | N/A | |||||||||||||||||||||
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