Title of Invention

AN IMPROVED PROCESS FOR THE SYNTHESIS OF 3,4-DISUBSTITUTED-1,5-DIHYDRO-2H-PYRROLIN-2-ONE.

Abstract

The invention relates to an improved process for the synthesis of 3,4-disubstituted-l, 5-dihydro-3-pyrrolin-2-one. The process has advantage in terms of operational efficiency (low pressure and low temperature hydrogenation) and yield. In the present invention the high pressure and high temperature hydrogenation and prolonged refluxing of acetic anhydride after hydrogenation has been eliminated leading to quantitative yield (80%-90%) of the novel intermediate 2 which in turn was cyclised to pyrrolin-2-one . The isolation of the novel intermediate 2 is the key step in the improvement of the process.

Full Text

This invention relates to an improved process for the synthesis of 3-4-disubstituted-l, 5-dihydro-2H-3 -pyrrolin-2-one. The 3-4-disubstituted-l, 5-dihydro-2H-3-pyrrolin-2-one of formula 3 of the drawing accompanying this specification prepared by the process of the present invention are useful indirect building blocks for the synthesis of biologically important tetrapyrrole pigments such as bilirubin analogs (Y.S. Buyn & D.A. Lightner, J. Het. Chem.28 (7) (1991) 1683 - 92),chlorin system (F. Peter Montforts , Angew. chem, 93(9) (1981) 793-96), phycocyanobilin (H. Ngwe, H. Kinoshita & K. Inomata,Bull. Chem. Soc. Jpn.67 (12) (1994) 3320-6), porphyrins for photodynamic therapy (PTD) and for magnetic resonance imaging (MRI) (R. Bohme & E. Breitmaier, Synthesis, (12), 1999, 2096-2102) and also is an essential indirect intermediate for the synthesis of Glimepiride an antidiabetic drug (Drug of the Future 17(9) (1992) 774 -778). Two processes have hitherto been known for the preparation of 3,4-disubstituted-l,5-dihydro-2H-3-pyiiolin-2-one of formula 3. In the first two steps process (H. Plieninger and J. Kurze, Liebigs Ann. Chem. Bd. 680 (1964) 61 - 68) the cynanohydrin of formula 1 (R1 = CH3 , R2 = C2H5, R3= C2H5) is hydrogenated, in acetic anhydride at 100 °C/ 105 arm. in presence of Raney Ni for several hours in Parr autoclave followed by refluxing of filtrate for 6 hrs to give l-acetyl-3-ethyl-4- methyl dihydro-2H-3 pyrrolin-2-one which on subsequent treatment with sodium carbonate gave 3 in 52% yield . Hence this process is industrially/commercially not . X feasible because of high pressure and high temperature hydrogenation and longer time . The second process also comprised of two steps (J.E. Bishop, J.F.O'Connel & H. Raport, J.Am.Chem.Soc.(1991)113, 8024-8035). The cyanohydrin of formula 1 (R1 = CH3, R2 = C2H5, R3= C2H5) was hydrogenated with Raney Ni at lower pressure and temperature followed by prolonged heating (8 hrs.) to give a residue which was not identified. The residue was hydrolysed with Na2CO3 and after cumbersome work up gave the product 3 in only 29% yield. (Formula Removed) The main objective of the present invention is therefore to provide an improved process for the synthesis of 3,4-disubstituted-I,5-dihydro-2H-3-pyrrolin-2-one of formula 3 as defined above in terms of operational efficiency (low pressure and low temperature hydrogenation) and yield. In the present invention the high pressure and high temperature hydrogenation and prolonged refluxing of acetic anhydride after hydrogenation has been eliminated leading to quantitative yield (80%-90%) of the novel intermediate 2 which in turn was cyclised to 3. The isolation of the novel intermediate 2 is the key step in the improvement of the process. Accordingly the present invention relates to an improved process for the synthesis of 3,4-disubstituted-l, 5-dihydro-3-pyrrolin-2-one as given below, wherein R1 and R2 is H, a lower alkyl group is selected from methyl, ethyl, propyl, butyl, a branched chain alkyl subsistent selected from isopropyl, isobutyl, an aryl alkyl where in the aryl substitute is phenyl or substituted phenyl, a naphthyl group, a hetroaryl group such as pyridyl, pyrrole, furan, which comprises: hydrogenating cyanohydrins of formula 1 wherein R1 and R2 as stated above and R3 is methyl or ethyl with Raney Ni in acid anhydride at a temperature in the range of 15 - 35°C and pressure up to 50 psi, recovering the novel amino acetyl propyl compound of formula 2 wherein R1 & R2 are as stated above and R3 is C2H5, R4 is CH3 or C2H5 in 80-90% yield, treating the compound of formula 2 with alcoholic alkali at reflux temperature to cyclizes the compound of formula 2 to give pyrrolin-2-one of formula as given above wherein R1 and R2 are as stated above. In an embodiment of the present invention the cyanohydrin of formula 1 can be prepared (Kuster, Beil, 311 298) from the commercially available ethyl acetoacetate or methyl acetoacetate, using conventional techniques, including but not limited to filtration, distillation and crystallization etc. such material may be characterised using conventional means including physical constants and spectral data. In another embodiment of the present invention the catalyst used is Raney Ni. In further another embodiment of the present invention the hydrogenation temperature is from 20°C-33°C. In further another embodiment of the present invention the pressure used in hydrogenation is 50 psi. Acid anhydride used may be selected from acetic anhydride or propionic anhydride. In further another embodiment of the present invention the alkanol used are ethanol or methanol and alkali used are KOH or NaOH. In further another embodiment of the present invention wherein the elevated (reflux) temperature is 60°C (in case of methanol) and 80°C (in case of ethanol). In further another embodiment of the present invention the aminoacetyl compound of formula 2 is novel. The novelty of the invention is as follows : (i) The use of acetic anhydride has been limited at the hydrogenation step only, (ii) After hydrogenation acetic anhydride was completely removed and the next step was carried out using methanolic potassium hydroxide. (iii) Potassium hydroxide was used in place of sodium carbonate, (iv) Compounds of formula three having substituents as following are novel compounds. R1 R2 CH3 C3H7 CH3 CH2C6H6 C2H5 This invention is further illustrated by the following examples which should not, however, be construed to limit the scope of the present invention. Preparation of compound of formula 3. In step A, the cyanohydrin of formula 1 is hydrogenated with Raney Ni at 50 psi at room temperature (20°-33°C) in acetic anhydride. The removal of acetic anhydride under reduced pressure and work up gave the novel aminoacetyl derivative of formula 2 (4-acetylamino-2,3-dialkyl-3-hydroxy butanoic acid alkyl ester ) which is cyclised to 3-pyrrolin-2-one of formula 3 in step B using alcoholic alkali under reflux. Example 1 : 3-Ethyl-l, 5-dihydro-4-methyl-2H-3-pyrrolm -2-one (3,R1= CH3, R2 = C2H5); Step A: The ethyl cc-ethylacetocetate cyanohydrin ( 1, R'=CH3, R2 = C2H5, R3= C2H5,20 g; 0.108 mol) was dissolved in acetic anhydride (120 ml) and freshly prepared Raney-Ni catalyst (2 g) was added carefully. The suspension was stirred for 20 mins at room temperature and the catalyst was filtered and filtrate was hydrogenated with Raney Ni catalyst (6 g) at 50 psi at room temperature till the absorption of hydrogen ceased (12 hours). The solution was filtered through celite bed (8 g) and filtrate was concentrated at reduced pressure using an oil bath (80° - 100° C) to afford an oily residue. The oily residue was treated with distilled water (100 ml) and extracted with ethyl acetate (4 x 40 ml) Organic layer was dried (anhyd. Na2 SO4) and concentrated to give 4-acetylamino-2-ethyl-3-hydroxy-3-methyl butanoic acid ethyl ester of formula 2 (R'= CH3, R2 = C2H5, R3= C2H5) in 84% yield (20.99 g), IR (neat): 3759, 3330, 3018, 1716, 1662, 1527; 1H NMR (CDC13; 200 MHz): 0.87-0.94 (t, 3H, CH2CH3), 1.17 (s, 3H, CHj); 1.29-1.33 (t, 3H, OCH2CH3), 1.67-1.73 (q, 2H, CH2CH3), 2.01 (s, 3H, CO CH3), 2.30-2.50 (m, 1H, CH), 3.10-3.60 (m, 2H, CH2NH), 4.14-4.21 (m, 2H, OCH2CH3). 6.24 (bs, 1H, NH); MS(m/z):231(M+),212, 157. Step B : The crude aminoacetyl derivative of formula 2 (20.99 g) was refluxed with methanolic potassium hydroxide ( 13 g in 120 ml) for 32 hours. Reaction mixture was concentrated to an oily residue and distilled water was added, neutralized with cone, hydrochloric acid. The neutral aqueous layer was extracted with ethyl acetate (50 ml x 5). Organic layer was dried ( anhyd. Na2 SO4) and solvent was distilled off to give the title compound 3 (3,R1= CH3, R2 = C2H5) as a yellow solid 8.6 g (75.7 %), m.p.lOO-101° (Lit. 102°, H.Plieninger, M.Decker, LeibegAnn. Chem., 598(1956) 198). Example 2 : 3 -Ethyl-1,5-dihydro-4-methyl-2H-pyrrolm-2-one (3,R1= CH3, R2 = QH5); Step A: Methyl α-ethyl acetoacetate cyanohydrin (1, R'= CH3, R2 = C2H5, R3 = CH3,10.99 g;0.064 mol) was stirred with Raney -Ni (1.0 g) in acetic anhydride (65 ml) for 20 mins. The filtrate was hydrogenated with Raney -Ni (3.105 g) at 50 psi till the absorption of hydrogen ceased (15 hours). The solution was filtered through celite bed (6 g) and the filtrate was concentrated under reduced pressure under suction at 100-110° C (oil bath) to give an oil. It was treated with distilled water (55 ml) and extracted with ethyl acetate (4 x 25 ml). The organic layer was dried (anhyd. Na2 SO4) and solvent was distilled off to give aminoacetyl compound 2 (R1= CH3, R2 = C2H5, R3 = CH3) as an oil (11.2 g; 81%). Spectral data as in example 1. Step B : The crude acetylated product 2 (R1= CH3) R2 = C2H5, R3 = CH3, 7.6 g) was refluxed with methanolic potassium hydroxide (4.92 g /60 ml) for 32 hours. Reaction mixture was concentrated to give an oil which was treated with distilled water (25 ml) neutralized with cone, hydrochloride acid (pH 7) and extracted with ethyl acetate (3 x 35 ml) organic extract was dried (anhyd. Na2 S04) and solvent distilled off to give the required 3-ethyl-l,5-dihydro-4-methyl-2H-pyrrolin-2-one (3, R'= CH3, R2 = C2H5, ) as a yellow solid 3.47 g (79%),mp, 100° C (Lit 102°C , H.Plieninger, M.Decker , LeibegAnn. Chem., 598(1956) 198). Example 3 : l,5-Dihydro-4-methyl-3-propyl-2H-3-pyrrolin -2-one (3, R'= CH3, R2 = C3H7); Step A: Ethyl a-propyl acetoacetate cyanohydrin (1, R1= CH3, R2 = C3H7, R3 = C2H5, 6.7 g;0.033 mol) was stirred with Raney-Ni (0.800 g) for 20 mins. The catalyst was filtered through celite bed (5 g). The filtrate was hydrogenated with Raney-Ni (2.05 g) for 15 hours till the absorption of hydrogen ceased. The catalyst was filtered through celite bed filtrate was concentrated to give an oily residue. The residue was treated with distilled water (30 ml) and extracted with ethyl acetate (3 x 30 ml). The organic layer was dried (anhyd. Na2 SO4 )and solvent was distilled off to give the aminoacetyl product 2 (R1= CH3, R2 = C3H7 , R3 = C2H5 ) as an oil 6.96 g (84%) IR (neat): 3436, 3020, 2968, 1712, 1658; ]H NMR (200 MHz; CDC13): 0.88-0.95 (t, 3H, CH3 propyl), 1.16 (s, 3H, CH3), 1.25-1.32 (m, 5H, OCH2CH3 and CH2 propyl) 1.58-1.65 (m, 2H, CH2 propyl), 2.02 (s, 3H, COCH3), 2.35-2.55 (m, 1H, CH ), 3.10-3.55 (m, 2H, CH2NH), 4.13-4.24 (m, 2H, OCH2CH3); MS (m/z): 246 (m+), 228, 173, 158. Step B : The crude aminoacetyl compound 2 (R'= CH3, R2 = C3H7) R3 = C2H5, 6.96 g) was refluxed in methanolic potassium hydroxide (3.93 g 740 ml) for 28 hours. Solvent was distilled off and residue obtained was treated with distilled water (15 ml), neutralized with cone, hydrochloric acid (1.8 ml) and extracted with ethyl acetate (3 x 20 ml). Organic layer was dried (anhyd. Naa S04) and solvent was concentrated to an oil which solidified to a yellow solid 3 (R1= CH3, R2 = C3H7, ) , 2.996 g (76%), m.p.50°C. Example 4 : l,5-Dihydro-3, 4-dimethyl-2H-3-pyrrolin-2-one (3, R1= CH3, R2 = CH3); Step A: Ethyl a-methylacetoacetate cyanohydrin(l, R1= CH3, R2 = CH3, R3 = C2H5 , 10.39g;0.063 mol) in acetic anhydride (50 ml) was stirred with Raney Ni (1g) for 20 mins. Catalyst was filtered off through celite bed (5 g). The filtrate was hydrogenated with Raney Ni (3-3.Ig) at 50 psi at room temperature, till the absorption of hydrogen ceased (20 hours). The catalyst was filtered off and the filtrate was concentrated under reduced pressure to an oil. Distilled water (30 ml) was added and extracted with ethyl acetate (4 x 30 ml). Organic layer was dried (anhyd. Na2 S04) and the solvent was distilled off to give aminoacetyl compound 2 (R1= CH3, R2 = CH3) R3 = C2H5 ), as an oil, 11.28 g (81%). IR (neat): 3982, 3760, 3019, 1716, 1662, 1H NMR (200 MHz; CDC13); 1.12-1.32 (m, 9H, 3 x CH3), 2.03 (s, 3H, COCH3), 2.48-2.60 (m, 1H, CH), 3.2-3.8 (m, 2H, CH2NH), 4.12-4.20 (m, 2H, OCH2CH3), 6.30(bs, 1H, NH), MS (m/z): 218(M++1),217(M+),203. Step B : The aminoacetyl compound 2 (R1= CH3, R2 = CH3, R3 = C2H5, 11.6 g) was refluxed with methanolic potassium hydroxide (7.2 g 750 ml) for 30 hours. Solvent was distilled off and distilled water (15 ml) was added. It was neutralized with cone, hydrochloric acid and extracted with ethyl acetate (4 x30 ml). Organic extract was dried (anhyd. Na2 S04) and solvent was distilled off to give the title compound 3 (R1= CH3, R2 = CH3), as a pale white solid, 4.02g (70%) m.p. 90° C (lit. 93°, M.Xie & D.A. Lightener, Tetrahedron 49, 11(1993) 2185-2200 Example 5 : 3-Benzyl-l, 5-dihydro-4-methyl- 2H-3-pyrrolin-2-one (3, R1= CH3, R = CH2C6H5); Step A: Ethyl a-benzyl acetoacetate cyanohydrin 1, R1= CH3, R2 = CH2C6H5, R3 = C2H5 (9.777 g; 0.034 mol) was stirred with Raney Ni (1 g) in acetic anhydride ( ml) for 20 mins. The catalyst was filtered through celite bed (5 g) and the filtrate was hydrogenated at 50 psi at room temperature with Raney Ni (2.5 g) till the hydrogen absorption ceased (15 hours). Catalyst was filtered through celite bed (5 g) and filtrate was concentrated under reduced pressure, diluted with water (50 ml) and extracted with ethyl acetate (3 x 30 ml). Organic layer was dried ( anhyd. Na2 864) and solvent was distilled off to give aminoacetyl compound 2 (R1= CH3, R2 = CH2C6H5, R3 = C2H5), 8.774 g (76.3%) as an oil. IR(Neat): 3672,3020,1720,1656, 1H NMR (200 MHz; CDC13): 0.93-1.04 (m,3H,CHj), 1.12-1.29 (m.SH.CHj), 2.02(s,3H, COCHj) ,2.5-3.8 (m, 3H, CH and CHjjNH), 3.92-4.10 (m, 2H, OQfc), 6.24 (bs, 1H, NH), 7.10-7.30 (m, 5H, ArH), MS (m/z): 294 (M++l),286,265. Step B: The crude aminoacetyl intermediate 2 (RI= CH3, R2 = CH2C6H5, R3 = C2H5, 8.7 g), was refluxed with methanolic potassium hydroxide (4.15 g 750 ml) for 24 hours. Solvent was distilled off and a residue was obtained which was treated with distilled water (20 ml), neutralized with cone, hydrochloric acid and extracted with ethyl acetate (3 x 30 ml). Organic layer was dried (anhyd. Na2 804) and the solvent was distilled off to give 3 (R'= CH3, R2 = CH2C6H5), 5.12 g (92 %) as an oil. Example 6 : 3-Ethyl-l, 5-dihydro-4-isopropyl 2H-3-pyrrolin-2-one (3, R1= isoC3H7, R2= C2H5); Step A: The cyanohydrin 1 (R1= isoC3H7, R2= C2H5, R3= C2H5, 7.05 g; 0.035mol) was stirred with Raney Ni (1 g) in acetic anhydride (40 ml) for 20 mins. Catalyst was filtered through celite bed (5 g) and filtrate was hydrogenated at 50 psi with Raney Ni (2.1 g) till the absorption of hydrogen ceased (18 hours). Catalyst was filtered off through celite bed (1.9 g) and filtrate was concentrated under reduced pressure. The residue was treated with distilled water and extracted with ethyl acetate (3 x 30 ml). Combined organic layer was dried (anhyd. Na2SO4) and solvent was distilled off to give the aminoacetyl compound 2 (R1= isoC3H7, R2= C2H5, R3= C2H5) as an oil 6.86 g (85%). IR (Neat): 3859, 2939, 1708, 1660, 'H NMR (200 MHz, CDC13); 0.91-1.28 (m, 13H, 4x CH3 and CH (isopropyl), 1.6-2.22 (m, 5H, CHCH2CH3, COCH3), 2.79-3.50 (m, 3H, CH, CH2NH), 4.15-4.T7 (m, 2, OCH2), MS (m/z): 259 (M+), 216, 187. Step B: Aminoacetyl intermediate (2, R1= isoC3H7, R2= C2Hs, R3= C2Hs, 6.16 g) was refluxed with methanolic potassium hydroxide (3.55 g/ 40 ml) for 24 hours. The residue obtained after removal of solvent, was treated with cone, hydrochloric acid and extracted with ethyl acetate (3 x 30 ml). Organic layer was dried (anhyd Na2 S04) and solvent was distilled off to give the title compound 3 (R1= isoC3H7, R2= C2Hs, R3= C2H5), as an oil 2.72 g (71%). We Claim: 1. An improved process for the synthesis of 3,4-disubstituted-l, 5-dihydro-3-pyrrolin-2-one as given below, (Formula Removed) wherein R1 and R2 is H, a lower alkyl group is selected from methyl, ethyl, propyl, butyl, a branched chain alkyl subsistent selected from isopropyl, isobutyl, an aryl alkyl where in the aryl substitute is phenyl or substituted phenyl, a naphthyl group, a hetroaryl group such as pyridyl, pyrrole, furan, which comprises: hydrogenating cyanohydrins of formula 1 wherein R1 and R2 as stated above and R3 is methyl or ethyl with Raney Ni in acid anhydride at a temperature in the range of 15 - 35°C and pressure up to 50 psi, recovering the novel amino acetyl propyl compound of formula 2 wherein R1 & R2 are as stated above and R3 is C2H5, R4 is CH3 or C2H5 in 80-90% yield, treating the compound of formula 2 with alcoholic alkali at reflux temperature to cyclizes the compound of formula 2 to give pyrrolin-2-one of formula as given above wherein R1 and R2 are as stated above. 2. The process as claimed in claim 1 wherein the hydrogenation temperature is from 20-33°C. 3. The process as claimed in claims 1 to 2 wherein the pressure used is in the range of 45 to 50 psi. 4. The process as claimed in claims 1 to 3 wherein alcoholic alkali used is methanolic KOH/NaOH or ethanolic KOH/NaOH. 5. A process as claimed in claims 1 to 4 wherein the reflux temperature is 60°C (in case of methanol) and 80°C (in case of ethanol). 6. A process as claimed in claims 1-5 wherein the isolation of compound 3 is carried out by neutralizing the reaction mixture by hydrochloric acid. 7. A process as claimed in claims 1-6 wherein the compounds prepared by the process are: (i) 3-Ethyl-l, 5-dihydro-4-methyl-2H-3-pyrrolin-2-one (3,R1= CH3, R2 = C2H5); (ii) l,5-dihydro-4-methyl-3-propyl-2H-3-pyrrolin-2-one(3, R'= CH3, R2 - C3H7);(iii) l,5-Dihydro-3, 4-dimethyl-2H-3—pyrrolin-2-one(3, R1 =CH3, R2 = CH3 ); (iv) 3-benzyl -l,5-dihydro-4-methyl-2H-3- pyrrolin-2-one(3, R1 = CH3, R=CH2C6H5); (v) 3-Ethyl-l, 5-dihydro-4-isopropyl 2H-3-pyrrolin-2-one (3.R1 - isoC3H7, R2 = C2H5); 8. A process as claimed in claims 1 - 7 wherein the acid anhydride used is selected from acetic anhydride, prop ionic anhydride. 9. A process for the synthesis of 3,4-disubstituted-l, 5-dihydro-2H-3-pyrrolin-2-one substantially as herein described with reference to the examples and drawing accompanying the specification.

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