| Title of Invention | PROCESS FOR PREPARING AN INDOLE COMPOUND |
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| Abstract | An improved for the preparation of (E)-3-[3"-(4"-fluorophenyl_-l"-(1-"-methylethyl0-1H-indol-2-yl]prop-2-enal of Formula I from 3-(4"-fluorophenyl)-1-(methylethyl)indole-2-carboxaldehyde of Formula VI |
| Full Text | FIELD OF THE INVENTION The present invention relates to an improved process for the preparation of (E)-3-[3'-(4,,-FIuorophenyt)-r-(l-methylethyl)-lH-indoi-2-yl] prop-2-enal of Formula I. Formula I BACKGROUND OF THE INVENTION (E)-3-[3'(4'-FIuorophenyO-l'-(l'-methylethyO-lH-indoi-2-yl]prop-2-enal is an important intermediate in the preparation of Fluvastatin. Fluvastatin, chemically known as [R*,S*-(EH±)-7-(3-(4-Fluorophenyl)-l-(l-methylethyl)-lH-indo!-2-yI]-3,5-dihydroxy-6-heptenoic acid of Formula II, is an HMG-CoA reductase inhibitor. Formula II Fluvastatin is presently marketed as its monosodium salt under the Trade name LESCOL. It is a competitive inhibitor of HMG-CoA reductase, which is responsible for the conversion of 3-hydroxy-3-methyIglutaryl-coenzyme A (HMG-CoA) to mevalonate, a precursor of sterols, including cholesterol. Coronary heart disease is one of the major health problems in the developed world as well as in the developing world. A considerable amount of clinical data has emerged over the years linking elevated levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C) and very low-density lipoprotein cholesterol (VLDL-C) as an important risk factor for the development of cornary heart disease. In the recent years, several companies have focused on finding effective and safe therapeutic agents to lower LDL-cholesterol. Wide range of HMG-CoA reductase inhibitors have been developed from natural sources and also using synthetic chemistry skills. In view of the importance of Fluvastatin as cholesterol lowering agent several synthetic procedures have been reported in the literature. One such procedure, which caught our attention involves conversion of (E)-3-[3'-(4"-Fluorophenyl)-r(I"-methylethyl)-IH-indol-2-yI]prop-2-enal to Fluvastatin. However, only few synthetic methods are reported for the production of (E)-3-[3'-(4"-Fluorophenyl)-l '(1"-methylethyl)-1 H-indol-2-yl]prop-2-enal. US 5.354,772 discloses a process to prepare (E)-3-[3'-(4"-Fluorophenyl)-r(l"-methylethyl)-1 H-indol-2yl] prop-2-enal, which is shown in Scheme I. The disadvantage of the above process is more expensive with low yields. US 5,290,946 claims a process to prepare (E)-3-[3,-(4"-Fluorophenyl)-r-(l"-methylethyl)-1 H-indol-2-yl] prop-2-enal, which is shown in Scheme 2. The disadvantage of the above process is in the preparation of N-methyl-N-phenylacrolein of Formula III, which requires handling of highly hygroscopic salts and flammable reagents like butyl vinyl ether. In view of the above disadvantages, we have focused our research to develop a new economical and industrially advantageous method for the preparation of (E)-3-[3'-(4"-Fluorophenyl)-r( 1' "-methylethyl)- lH-indol-2-yl]prop-2-enal, an important intermediate in the synthesis of Fluvastatin. OBJECTIVE The objective of the present invention is to provide an improved process for preparing (E)-3-[3'(4'-Fluorophenyl)-1'(1 "-methylethyl)-! H-indol-2-yl]prop-2-enal, which is safe and non-hazardous. Yet another objective of the present invention is to provide an improved process for preparing (E)-3-[3'(4'-Fluorophenyl)-r(l"-methylethyl)-lH-indol-2-yl]prop-2-enal, which is simple, industrially feasible and economically viable. SUMMARY OF THE INVENTION ■-■"'— ^™^^—^^—^««>^"WBfi ■! ■ with an organometallic reagent in a suitable solvent to produce an alcohol of Formula VI1 ii) treating alcohol of Formula VII with Vilsmeier reagent in a suitable solvent and iii) isolating the compound of Formula I thus obtained. The present invention also provides a process for the conversion of (E)-3-[3,-(4"-Fluorophenyl)-r-(r,-methylethyl)-lH-indol-2-yl] prop-2-enal (indole acrolein) of Formula I to Fluvastatin by processes known in the art. DETAILED DESCRIPTION OF THE INVENTION In an aspect of the present invention, the organometallic reagent is selected from R'-Mg-X or R1/M, wherein R1 is selected from an alkyl group having C1-3 carbon atoms such as methyl, ethyl, propyl, isopropyl etc.; n represents an integer 1 or 2; M represents a metal cation selected from Lithium, Zinc, Cadmium etc., X represents a halide selected from chlorine, bromine, iodine etc, but when M represents Lithium, n represents 1 and when M represents Zinc or Cadmium, n represents 2. Further the solvent used in the reaction is selected from ethers such as diethyl ether, dibutyl ether, tetrahydro furan, dimethyl ether and mixtures thereof; hydrocarbons such as benzene, toluene, xylene and mixtures thereof; halogenated solvents such as methylene dichloride, ethylene dichloride, chloroform and mixtures thereof and the reaction is carried out at a temperature of 0°C to 100°C, preferably 0°C to 20°C. In yet another aspect of the present invention, the Grignard reagent is added in 1 mole to 12 mole equivalents based on the indole carboxaldehyde of the Formula VI. In yet another aspect of the present invention, Vilsmeier reagent is used in 2 mole equivalents to the alcohol of Formula VII. The 2 moles of Vilsmeier reagent are used in one lot or can be used in two lots. If alcohol is treated with 2 mole equivalents of Vilsmeier reagent in one lot, indole acrolein of Formula I is obtained directly. On the contrary if alcohol is treated with 1 mole equivalent of Vilsmeier reagent, an intermediate 2-(3-(4,-fluorophenyl)-l-(r-methylethyl)-lh-indol-2-yl]ethylene of Formula VIII is obtained, Formula VIII which on treatment with another mole equivalent of Vilsmeier reagent yields indole acrolein of Formula I. In yet another aspect of the present invention, the Vilsmeier reagent is prepared using N, N-dimethylformamide and phosphorous oxychloride or N, N-dimethylformamide and oxalyl chloride. The solvent used in step (ii) is selected from N, N-dimethylformamide, methylene dichloride, ethylene dichloride or mixtures thereof. Yet another aspect of the present invention, the product is isolated in step (iii) using an aqueous inorganic base such as such as sodium hydroxide, potassium hydroxide, sodium carbonate or sodium acetate. Yet another aspect of the present invention, the crude indole acrolein is recrystallised from hexane / ethyl acetate. In an embodiment of the present invention, there is provided a novel intermediate, of Formula VII. Formula VII wherein R1 represents an alkyl group having C1-3 carbon atoms. In an embodiment of the present invention, there is provided a novel intermediate, of Formula VIII. Formula VIII The invention is illustrated by the following examples, which are provided by way of illustration only and should not be construed to limit the scope of the invention. EXAMPLES EXAMPLE 1 Step a PREPARATION OF 2-(l-HYDROXY ETHYL)-2-[3-(4-FLUOROPHENYL)-l-(l-METHYLETHYL)]-1H-IND0LE Methyl magnesium iodide was prepared in situ using methyl iodide (15 ml) and Mg turnings (5 g) in tetrahydrofuran (20 ml). 3-[(4'-Fluorophenyl)-l-(methylethyl)-lH-indole]-2-carbo\aldehyde (5 g) was dissolved in tetrahydrofuran (25 ml) and added to the Grignard reagent drop wise at 20-25°C in 20 min. The reaction mixture was stirred for 2 h at 15-20°C for completion of reaction. Thereafter, the reaction mixture was cooled to 0-5°C and quenched with saturated ammonium chloride solution (30 ml). The product was extracted into ethyl acetate (3x20 ml) and washed with DM water (2x20 ml). Then the ethyl acetate layer was dried over anhydrous sodium sulfate. Concentrated the organic layer at 40-45°C to give brown colour residue, which was further cooled to give title product as a solid. YIELD: 5.23 g 1H NMR (CDCI3): 1.69 - 1.71 (dd, 6H), 1.77 (d, 3H), 1.86 (s, 1H), 5.33 (q, 1H), 7.07-7.63(/77, 8H) Step b PREPARATION OF (E)-3-[3'-(4"-FLU0R0PHENYL)-1-(1'-METHYLETHYL)-1H-IND0L-2-YLJ PR0P-2-ENAL (INDOLEACROLEIN) Phosphorous oxychloride (5.16 g) was added to dimethyl formamide (2.45 g) at 0-3°C, and then the temperature was raised to room temperature and stirred for few minutes to give Vilsmeier reagent. A solution of 2-(l-Hydroxyethyl)-2-[3-(4-fluorophenyl)-l-(l-methylethyl)]-lH-indole (5 gm) in N, TV-dimethyl formamide (5 ml) was added to the above prepared Vilsmeier reagent drop wise at room temperature. Reaction mixture was stirred for 12 h at the same temperature and diluted with N, TV-dimethyl formamide (5 mi) and slowly transferred into a solution of sodium hydroxide (5 %) at 40°C. The product was extracted into toluene (2x25 ml). The organic layer was washed with DM water (4x50 ml) and stirred with silica gel (5 gm) for 1 h at RT. Toluene layer was filtered and silica gel was washed with toluene (2x25 ml). The combined organic layer was concentrated to give brown colour residue, which was further cooled to give title compound as a solid. YIELD: 5.4 g. 'H NMR (CDCh): 1.75 (d, 6H), 5.00 (m, 1H), 6.3 - 6.36 (dd, 1H), 7.59 (d, 1H), 7.12 - 7.59 (m,8H), 9.59(4 1H) EXAMPLE 2 PREPARATION OF 2-(l-HYDROXY ETHYL)-2-(3-(4-FLUOROPHENYL)-l-(l- METHYLETHYL)]-1H-IND0LE Step a Methyl magnesium iodide was prepared in situ using methyl iodide (18 ml) and Mg turnings (2.3 g) in tetrahydrofuran (25 ml). 3-[(4,-fluorophenyl)-l-(methylethyl)-lH-indole]-2-carboxaldehyde (9.0 g) was dissolved in tetrahydrofuran (25 ml) and added to the Grignard reagent drop wise at 0-10°C in 20 min. The reaction mixture was stirred for 2 h at 5-10°C for completion of reaction. Thereafter, the reaction mixture was cooled to 0-5°C and quenched with saturated ammonium chloride solution (30 ml). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2x50 ml). The organic layer was washed with DM water (2x20 ml) and then dried over anhydrous sodium sulfate. Concentrated the organic layer at 40-45°C lead to give brown colour residue, which was further cooled to give title product as a solid. YIELD: 8.6 g Step b PREPARATION OF 2-(3-(4'-FLUOROPHENYL)-l-(l'-METHYLETHYL)-lH- INDOL-2- YL/ETHYLENE 2-( 1 -Hydroxyethyl)-2-[3-(4-fluorophenyl)-1 -(1 -methylethyl)]-1 H-indole (4 g) was added to N, N-dimethyl formamide (20 ml) and cooled to 0-5°C. Phosphorous oxychloride (2.1 g) was added drop wise to the above reaction mass at 0-5°C. After completion of addition the temperature of reaction mass was raised to 20-25°C and stirred at the same temperature for 4 h. The reaction mass was quenched with aqueous sodium acetate (5 g in 20 ml of water) at room temperature. The organic layer was separated and the aqueous layer was extracted with toluene (2x20 ml). The organic layer was washed with DM water (3x30 ml) and then dried over anhydrous, sodium sulfate. Concentrated the organic layer at 40-45°C lead to give brown colour residue. Yield: 3.6 gm 1H NMR (CDCI3): 1.68 (d, 6H), 4.9 (w, 1H), 5.34 (d, 1H), 5.45 (d, 1H), 6.77 (dd,IH) 7.09 -7.58 (m, 8H) Step c PREPARATION OF (E)-3-f3'-(4"-FLUOROPHENYL)-1-(l"-METHYLETHYL)-1H-IND0L-2-YLJ PR0P-2-ENAL (INDOLEACROLEIN) Phosphorous oxychloride (1.646 g) was added to dimethyl formamide (0.78 g) at 0-5°C, and then the temperature was raised to room temperature and stirred for few minutes to give Vilsmeier reagent. A solution of 2-(3-(4,-Fiuorophenyl)-l-(l'-methylethyl)-lH-indo!-2-yl]ethylene (3 gm) in N, jV-dimethyl formamide (5 ml) was added to the above prepared Vilsmeier reagent drop wise at room temperature. Reaction mixture was stirred for 8 h at the same temperature and slowly sodium acetate solution (5 g in 20 ml water) was added. The layers are separated and aqueous layer was extracted with toluene (2x15 ml). The organic layer was washed with DM water (4x30 ml). The combined organic layer was concentrated under reduced pressure and to the residue 95% ethanol (2x15 ml) was added and further concentrated under reduced pressure. 95% ethanol (10 ml) was added to the residue and cooled to 0-5°C for 1 h the product precipitates out. Filtered the product and washed with chilled 95% ethanol (2x5 ml) and dried at 35-40°C under reduced pressure. Yield: 1.83 g 'H NMR (CDC10: 1.75 (d, 6H), 5.00 (m, IH), 6.3 - 6.36 (dd, 1H), 7.59 (d, 1H), 7.12-7.59 (m,8H), 9.59 (4 IH) WE CLAIM 1. An improved process for the preparation of (E)-3-[3,-(4"-Fluorophenyl)-l'-(l"-methylethyl)-l H-indol-2-yI] prop-2-enal of Formula I, Formula I which comprises, i) reacting indole carboxaldehyde of the Formula VI, Formula VI with an organometallic reagent in a suitable solvent to produce an alcohol of Formula VII ii) treating alcohol of Formula VII with Vilsmeier reagent in a suitable solvent and iii) isolating the compound of Formula I thus obtained. 2. The process according to claim 1, wherein the organometallic reagent is selected from Rl-Mg-X or Rn'M, wherein R1 is selected from an alkyl group having C1-3 carbon atoms such as methyl, ethyl, propyl, isopropyl; n represents an integer from 1-2; M represents a metal cation selected from Lithium, Zinc, Cadmium etc.; X represents a halide selected from chlorine, bromine, iodine; when M represents Lithium, n represents 1 and when M represents Zinc or Cadmium, n represents 2. 3. The process according to claim I, wherein the Grignard reagent can be from 1 mole equivalents to 12 mole equivalents based on indole carboxaldehyde of Formula VI. 4. The process according to claim 1, wherein the solvent used in step (i) of the reaction is selected from ethers such as diethyl ether, dibutyl ether, tetrahydro furan, dimethyl ether and mixtures thereof; hydrocarbons such as benzene, toluene, xylene and mixtures thereof; halogenated solvents such as methylene dichloride, ethylene dichloride, chloroform and mixtures thereof. 5. The process according to claim 1, wherein the reaction of step (i) is carried out at a temperature of 0°C to 100°C, preferably 0°C to 20°C. 6. The process according to claim 1, wherein the Vilsmeier reagent is used in 2 mole equivalents to the alcohol of Formula VII. 7. The process according to claim 5, the 2 moles of Vilsmeier reagent is used in one lot or can be used in two lots. 8. The process according to claim 6, wherein alcohol is treated with 2 mole equivalents of Vilsmeier reagent in one lot to obtain prop-2-enal of Formula I directly. 9. The process according to claim 5, wherein alcohol is treated with 1 mole equivalent of Vilsmeier reagent, to obtain an intermediate 2-(3-(4'-tluorophenyl)-l-(r-methylethyl)-lh-indol-2-yl]ethylene of Formula VIII is obtained, Formula VIII which on treatment with another mole equivalent of Vilsmeier reagent yields prop-2-enal of Formula I. 10. The process according to claim 1, the solvent used in step (ii) is selected from dimethyl formamide, methylene dichloride, ethylene dichloride or mixtures thereof. 11. The process according to claim 1, the product is isolated in step (iii) using an aqueous inorganic base such as such as sodium hydroxide, potassium hydroxide, sodium carbonate and sodium acetate. 12. The process according to claim 1, the crude (E)-3-[3,-(4"-Fluorophenyl)-r-(l"-methylethyl)-lH-indol-2-yl] prop-2-enal (indole acrolein) of Formula I is recrystallised from hexane / ethyl acetate. 13. A process for converting (E)-3-[3'-(4"-Fluorophenyl)-1-(r'-methyIethyl)-lH-indol-2-yl] prop-2-enal prepared by a process of claim 1 to Fluvastatin. 14. 15. 2-(l -Hydroxy ethyl)-2-[3-(4-fluorophenyl)-l-(l-methylethyl)]-lH-indole of Formula VIII |
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| Patent Number | 269464 | ||||||||||||||||||
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| Indian Patent Application Number | 814/CHE/2005 | ||||||||||||||||||
| PG Journal Number | 44/2015 | ||||||||||||||||||
| Publication Date | 30-Oct-2015 | ||||||||||||||||||
| Grant Date | 23-Oct-2015 | ||||||||||||||||||
| Date of Filing | 28-Jun-2005 | ||||||||||||||||||
| Name of Patentee | AUROBINDO PHARMA LIMITED | ||||||||||||||||||
| Applicant Address | AUROBINDO PHARMA LIMITED PLOT NO.2, MAITRIVIHAR COMPLEX, AMEERPET, HYDERABAD. | ||||||||||||||||||
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| PCT International Classification Number | C07D 209/04 | ||||||||||||||||||
| PCT International Application Number | N/A | ||||||||||||||||||
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