Title of Invention

AN IMPROVED PROCESS FOR THE PRODUCTION OF 4-HYDROXY-BUTAN-2-ONE

Abstract

This invention relates to an improved process for the production of 4-hydroxy-butan-2-one of formula (2) . The active compound 4- hydroxy-butan-2-one is one of the important raw materials for the preparation of Raspberry ketones and its derivatives. In the present invention 4-hydroxy-butan-2-one is prepared from readily available starting material 1,3- butane diol of formula (1), oxidising particularly with Na2S2O5/NaBrO3/H2O/PTC, Na2S2O5/NaIO3, DMSO/HI/H2O and DMSO/N2H4.H2O/I2/H2O more particularly using Na2S2O5/NaBrO3/H2O/PTC in a solvent.

Full Text

AN IMPROVED PROCESS FOR THE PRODUCTION OF 4-HYDROXY-BUTAN-2-ONE This invention relates to an improved process for the production of 4-hydroxy-butan-2-one of formula (2) Raspberry ketone (R=H) [Fig 1] is an important insect attractant for the scarabaeid subfamily and efficient perfume chemicals of modern time. Zingerone (R=OCH3) [Fig 1] is also a pharmaceutically active compound and a key intermediate en route to the bronchospasmolytic active compound. 4-hydroxy-butan-2-one (2) is one of the important raw materials for the preparation of Raspberry ketones and its derivatives [Fig-1, a & b]. The present invention relates to an improved process for the preparation of 4-hydroxy-butan-2-one (2) from readily available starting material 1,3- butane diol (1), oxidising particularly with Na2S205/NaBr03/H20/PTC, Na2S205/NaI03, DMSO/HI/H20 and DMSO/N2H4.H2O/I2/H2O more particularly using Na2S205/NaBr03/H20/PTC in a solvent. The compound (2) is one of the important raw materials for the production of Raspberry ketone (R =H) and Zingerone (R=OCH3) [Fig 1] (Figure Removed) The following are the references so far available in the literature for the preparation of 4-hydroxy-butan-2-one (2) from 1,3-butane diol (1) Hitherto 4-hydroxy-butan-2-one (2) has been prepared by the methods described below: 1. By selective oxidation of 1,3-butane diol (1) with Distannoxane/Br2 Tetrahedron Letters, No. 50, pp- 4597-4600, (1976). According to the method disclosed in this paper, the 1,3—butane diol (1) is allowed to react with (Bii3Sn)20-Br2 in DCM (dichloromethane) solvent at room temperature. The drawback of the method is that it involves poisonous Tin (Sn) metal in the reaction mixture and DCM, a health hazard is used as solvent along with Bromine (Br) .The yield of 4-hydroxy-butan-2-one (2) is only 66% 2. By oxidation of 1,3-butane diol (1) with t-butyl hydroperoxide (TBHP) and Zeolite Tetrahedron Letters, vol-53, No. 46, pp-15867-76, (1997). In this reported procedure oxidation of (1) is carried out with t-butyl hydroperoxide (TBHP) and Zeolite (3A°, M.S) under microwave irradiation (MW) at solid state. After completion of the reaction, extracted with ether and worked-up. The main drawback of the method is that the method involves complete anhydrous conditions and (TBHP) is an expensive reagent. The yield of the process is 64% only. 3. By Oxidation of (1) with K2Fe04-Al203-CuS04.5 H20 Tetrahedron Letters, Vol-27, No. 25, pp- 2875-78, (1986) The method selectively oxidise (1) to (2) in 85% yield at room temperature in benzene solvent. The main limitation of the process is that it involves highly carcinogenic solvent benzene though the yield is very good (85%). Also, the reaction time of the method is very longer (30 hours). 4. By selective oxidation of (1) with H2O2/TS-1 and DMDO Tetrahedron Letters, Vol-35, No. 45, pp- 8477- 80, (1994) The reagents H2O2/TS-I and DMDO selectively oxidise (1) to (2) in poor to very good yields. The yield of the selective oxidation (1) to (2) with DMDO (dimethyldioxirane) is very poor and it is not readily available. Though the yield of (1) to (2) with the oxidation TS-1 (Zeolite) is very good, but the preparation of TS-1 is not easy i.e it is prepared by using long procedure by dopping Titanium metal (Ti) in the Zeolite. The main objective of the present invention is to provide an improved process for the preparation of 4-hydroxy-butan-2-one (2) Another objective of the present invention is to provide a method for the oxidation of 1,3-butane diol (1) to 4-hydroxy-butan-2-one (2) Yet, another objective of the present invention is to provide oxidation of (1) to (2) by eliminating the use of benzene and dichloromethane as solvent. Yet, another objective of the present invention is to carry out the reaction in an aqueous solvent eliminating the requirement of anhydrous conditions. Yet, another objective of the present invention is to carry out the reaction with readily available chemicals, eliminating the requirement of costly and toxic chemicals like Tin (Sn) and Bromine. Accordingly, an improves»process for the production of 4-hydroxy-butan-2-one of formula (2), as wherein shown in the drawing accompanying this specification which comprises stirring of compound of formula (1) in an organic system with Na2S205/NaBr03/PTC/H20 at a temperature ranging between 0 to 80 °C for a period in the range of 18-28 hours, removing the organic solvent by distillation under reduced pressure, treating the above said reaction mixture with acetic acid (5%) followed by extraction with water immiscible organic solvent, washing with sodium bicabonate solution( 5%), and removal of solvent under reduced pressure passing the residue through a coloumn and extracting with solvent to get compound of formula (2). (Scheme Removed) In an embodiment of the present invention the oxidising agents may be used such as Na2S2O5/NaBrO3/H2O/PTC, Na2S2O5/NaIO3/H2O, DMSO/HI and DMSO/N2H4.H2O/ H20/I2 In another embodiment of the invention the ratio of Na2S2O5 and NaBrO3 used may be in the range of 1:1 to 2:1 under PTC (phase transfer catalyst) conditions. In yet another embodiment of the invention the organic solvent may be used such as acetonitrile, chloroform and dichloromethane. In further embodiment of the invention water immiscible solvent used may be such as diethyl ether, ethyl acetate and toluene. In one more embodiment of the invention sodium bicarbonate solution used may be in the range of 5% tol5%. The process for the production of (2) by oxidation of (1) shown in the drawing Schemel accompanying this specification which comprises stirring of (1) in an organic solvent with water like dichloromethane, chloroform, acetonitrile with sodium/potassium meta bisulfite (Na2S2O5) and Na/K bromate in a ratio in the range of 1:1 to 2:1 at room temperature and or refluxing of (1) in an organic solvents like dichloromethane, chloroform and acetonitrile with DMSO/H20/HI (57%) or DMSO/N2H4.H2O/H2O/I2, removing the solvent by distillation under reduced pressure, treating with sodium bicarbonate solution, extracting the product using a water immiscible organic solvent like diethyl ether, ethyl acetate, dichloromethane, drying over anhydrous sodium sulphate and removing the solvent under reduced pressure. The details of the method disclosed in this invention have been described in the following specific examples, which are provided to illustrate the invention only and therefore, these should not be construed to limit the scope of the present invention. EXAMPLE IrOxidation of 1,3-butane diol (1) with Na2S205/NaBr03/PTC/H20 to 4-hydroxy-butan-2-one (2) 1,3-butane diol (1) (0.45 gm, 5mmol) and NaBr03 (0.905gm, 6mmol) were dissolved in 13 ml of acetonitrile and water mixture (10: 3) and stirred magnetically with a few crystals of PTC (TEBA, triethyl benzyl ammonium chloride) at room temperature. To this mixture a saturated solution of Na2S205 (1.14gm, 6 mmol) was added drop wise for a period of 0.05hr and stirring was continued for a perid of 20 hours. The progress of the reaction was monitored by TLC. Acetonitrile was distilled off under reduced pressure at 40 °C (bath temperature) then acetic acid 10 ml (5%) was added and stirred, extracted with dichloromethane (2 x 50 ml). The separated organic layer was treated with 5% sodium bicarbonate solution (2 x 25ml) and then with water (50 x 2 ml). The solution was dried over anhydrous sodium sulphate. The solvent was removed under reduced pressure and the residue was passed through a column using ethyl acetate and methanol (20: 1) as eluent, Evaporation of the solvent gave 4-hydroxy -butan-2 -one (2) as a liquid, Yield 0.405 gm, 92%. FTIR (KBr): Cm-1 3408, 1705, 1364, 1172, 1062, 770; lH NMR (90 MHz, CDC13): δ 2.14 (S, 3H, CH3), 2.65 (t, 2H, COCH3), 3.84 (t, 2H, CH20), 4.33 (S, 1H, OH); Mass m/z: 88 (M+), 70(M +-H20). Example 2: Oxidation of 1,3-butane diol (1) with Na2S205/NaBr03/H20 to 4-hydroxy-butan-2-one (2) 1,3-butane diol (1) (0.45 gm, 5mmol) and NaBr03 (0.905gm, 6mmol) were dissolved in 13 ml of acetonitrile and water mixture (10: 3) and stirred magnetically at room temperature. To this mixture a saturated solution of Na2S205 (1.14gm, 6 mmol) was added drop wise for a period of 0.05 hr and stirring was continued for a period of 24 hours. The progress of the reaction was monitored by TLC. Acetonitrile was distilled off under reduced pressure at 40 °C [bath temperature] and then acetic acid 10 ml (5%) was added, stirred, extracted with dichloromethane [2 x 50 ml]. The separated organic layer was treated with 5% sodium bicarbonate solution [2 x 25ml] and then with water [50 x 2 ml]. The solution was dried over anhydrous sodium sulphate. The solvent was removed under reduced pressure and the residue was passed through a column using ethyl acetate and methanol [20: 1] as eluent. Evaporation of the solvent gave 4-hydroxy-butan-2 -one (2) as a liquid; Yield 0.335 gm, 76%. Example 3: Oxidation of 1,3-butane diol (1) with DMSO/HI/H20 to 4-hydroxy-butan-2-one (2) Substrate 1 (0.09gm, 1 mmol) and HI (0.51 lgm, 4 mmol) were stirred in acetonitrile and water mixture (13 ml) [CH3CN: H20; 10: 1] for 5 minutes at room temperature and then DMSO (0.390 gm, 5 mmol) was added to the reaction mixture and refluxed at 80 °C for 15 hours. The solvent was distilled off to half of its volume under reduced pressure and poured into distilled water (100ml) and extacted the organic solvent with diethyl ether (2x25ml). The organic layer was washed with sodium thiosulphate solution (5 %, 20ml) then with water (2x 50 ml) and dried. Evaporation of the solvent gave a light yellow residue, after column chromatography using chloroform and methanol mixture (10:1) as eluent. Evaporation of the solvent gave 4-hydroxy -butan-2 -one (2) as a liquid; 0.035gm yield 40 %. Example 4: Oxidation of 1,3-butane diol (1) with DMSO/N2H4.H2O/I2/H2O to 4-hydroxy-butan-2-one (2) Hydrazine monohydrate (0.051 gm, 1 mmol) and Iodine (0.506gm, 2 mmol) were stirred in acetonitrile (10 ml) [CH3CN: H20; 5: 1] for 15 minutes and substrate (1) (0.09gm, 1 mmol) was added. The reaction mixture was stirred for another 5 minutes at room temperature. Thereafter DMSO (0.390 gm, 5 mmol) was added to the reaction mixture and refluxed at 80 °C for 4.5 hours under nitrogen. The solvent was distilled off to half of its volume under reduced pressure and poured into water (100ml) and extacted with diethyl ether (2x25ml). The organic layer was washed with sodium thiosulphate solution (5 %, 20ml) then with water (2x 50 ml) and dried. Evaporation of the solvent gave a light yellow residue, after column chromatography using chloroform and methanol mixture (10:1) as eluent. Evaporation of the solvent gave 4-hydroxy -butan-2 -one (2) as a liquid; 0.0 44 gm, yield 50 %. Example 5: Oxidation of 1,3-butane diol (1) with Na2S2O5/NaIO3/H2O to 4-hydroxy-butan-2-one (2) 1,3-Butane diol (1) (0.45 gm, 5mmol) and NaI03 (1.187gm, 6mmol) were dissolved in 13 ml of acetonitrile and water mixture (10: 3) and stirred magnetically at room temperature. To this mixture a saturated solution of Na2S205 (1.14gm, 6 mmol) was added drop wise for a period of 0.05hr and stirring was continued for a period of 14 hours. The progress of the reaction was monitored by TLC. Acetonitrile was distilled off under reduced pressure at 40 °C (bath temperature) and then acetic acid 10 ml (5%) was added and stirred, extracted with dichloromethane (2 x 50 ml). The separated organic layer was treated with 5% sodium bicarbonate solution [2 x 25ml] and then with water (50 x2 ml). The solution was dried over anhydrous sodium sulphate. The solvent was removed under reduced pressure and the residue was passed through a column using ethyl acetate and methanol (20: 1) as eluent. Evaporation of the solvent gave 4-hydroxy-butan-2-one (2) as a liquid, Yield 0.165 gm, 37.5 %. Example 6: Oxidation of 1,3-butane diol (D with Na2S205/NaBr03/PTC/H20 to 4-hydroxy-butan-2-one (2). 1,3-Butane diol (1) (0.45 gm, 5mmol) and NaBr03 (0.905gm, 6mmol) were dissolved in 13 ml of chloroform and water mixture (10: 3) and stirred magnetically with a few crystals of PTC (TEBA, tetraethyl benzyl chloride) at room temperature. To this mixture a saturated solution of Na2S20s (1.14gm, 6 mmol) was added drop wise for a period of 0.05hr and stirring was continued for a period of 18 hours.. The progress of the reaction was monitored by TLC. Chloroform was distilled off under reduced pressure at 40 °C (bath temperature) and then acetic acid 10 ml (5%) was added, and stirred, extracted with dichloromethane (2x50 ml). The separated organic layer was treated with 5% sodium bicarbonate solution [2 x 25ml] and then with water (50x2 ml). The solution was dried over anhydrous sodium sulphate. The solvent was removed under reduced pressure and the residue was passed through a column using ethyl acetate and methanol (20: 1) as eluent. Evaporation of the solvent gave 4-hydroxy -butan-2 -one (2) as a liquid, Yield 0. 358 gm, 81.36%. Example 7: Oxidation of 1,3-butane diol (1) with Na2S205/NaBr03/PTC to 4-hydroxy-butan-2-one (2). 1,3-butane diol (1) (0.45 gm, 5mmol) and NaBrO3 (0.905gm, 6mmol) were dissolved in 13 ml of dichloromethane and water mixture (10: 3) and stirred magnetically with a few crystals of PTC (TEBA, triethyl benzyl ammonium chloride) at room temperature. To this mixture a saturated solution of Na2S2O3 (1.14gm, 6 mmol) was added drop wise for a period of 0.05hr and stirring was continued for a period of 20 hours. The progress of the reaction was monitored by TLC. Dichloromethane was distilled off under reduced pressure at 40 °C (bath temperature) and then acetic acid 10 ml (5%) was added and stirred, extracted with dichloromethane (2x50 ml). The separated organic layer was treated with 5% sodium bicarbonate solution (2 x 25ml) and then with water (50 x2 ml). The solution was dried over anhydrous sodium sulphate. The solvent was removed under reduced pressure and the residue was passed through a column using ethyl acetate and methanol (20: 1) as eluent. Evaporation of the solvent gave 4-hydroxy-butan-2-one (2) as a liquid; Yield 0.313 gm, 71.13%. EXAMPLE 8: Oxidation of 1,3-butane diol (1) with Na2S2O5/NaIO3 /H20 to 4-hydroxy-butan-2-one (2) 1,3-butane diol (1) (0.45 gm, 5mmol) and NaI03 (1.187gm, 6mmol) were dissolved in 13 ml of acetonitrile and water mixture (10: 3) and stirred magnetically at room temperature. To this mixture a saturated solution of Na2S2Os (1.14gm, 6 mmol) was added drop wise for a period of 0.05hr and stirring was continued for a period of 19 hours. The progress of the reaction was monitored by TLC. Acetonitrile was distilled off under reduced pressure at 40 °C (bath temperature) and then acetic acid 10 ml (5%) was added and stirred, extracted with dichloromethane (2 x 50 ml). The separated organic layer was treated with 5% sodium bicarbonate solution (2 x 25ml) and then with water (50 x2 ml). The solution was dried over anhydrous sodium sulphate. The solvent was removed under reduced pressure and the residue was passed through a column using ethyl acetate and methanol (20: 1) as eluent. Evaporation of the solvent gave 4-hydroxy-butan-2 -one (2) as a liquid; Yield 0.120 gm, 27.27%. EXAMPLE 9: Oxidation of 1,3-butane diol (1) with Na2S2O5/NaBrO3/PTC/H2O to 4-hydroxy-butan-2-one (2): 1,3-butane diol (1) (0.45 gm, 5mmol) and NaBr03 (0.453gm, 3 mmol) were dissolved in 13 ml of acetonitrile and water mixture (10: 3) and stirred magnetically with a few crystals of PTC (TEBA, triethyl benzyl ammonium chloride) at room temperature. To this mixture a saturated solution of Na2S20s (1.14gm, 6 mmol) was added drop wise for a period of 0.05hr and stirring was continued for a period of 24 hours. The progress of the reaction was monitored by TLC. Acetonitrile was distilled off under reduced pressure at 40 °C (bath temperature) and then acetic acid 10 ml (5%) was added, and stirred, extracted with dichloromethane (2 x 50 ml). The separated organic layer was treated with 5% sodium bicarbonate solution (2 x 25ml) and then with water (50 x 2 ml). The solution was dried over anhydrous sodium sulphate. The solvent was removed under reduced pressure and the residue was passed through a column using ethyl acetate and methanol (20: 1) as eluent. Evaporation of the solvent gave 4-hydroxy-butan-2-one (2) as a liquid; Yield 0.322 gm, 73.18%; FTIR (KBr): Cm"1 3408,1705,1364,1172,1062,770 ; 'H NMR ( 90 MHz, CDC13): δ 2.14 (s, 3H, CH3), 2.65(t, 2H, COCH3), 3.84( t, 2H, CH2O), 4.33( s, 1H, OH); Mass m/z : 88 (M+), 70( M +-H20). EXAMPLE 10 rOxidation of 1,3-butane diol (1) with Na2S2O5/NaBrO3/PTC/H2O to 4-hydroxy-butan-2-one (2) 1,3-butane diol (1) (1.125 gm, 12.5mmol) and NaBr03 (2.263gm, 15mmol) were dissolved in 13 ml of acetonitrile and water mixture (10: 3) and stirred magnetically with a few crystals of PTC (TEBA, triethyl benzyl ammonium chloride) at room temperature. To this mixture a saturated solution of Na2S20s (2. 85gm, 15mmol) was added drop wise for a period of 0.05hr and stirring was continued for a period of 20 hours. The progress of the reaction was monitored by TLC. Acetonitrile was distilled off under reduced pressure at 40 °C (bath temperature) and then acetic acid 10 ml (5%) was added, and stirred, extracted with dichloromethane (2 x 50 ml). The separated organic layer was treated with 5% sodium bicarbonate solution (2 x 25ml) and then with water (50 x 2 ml). The solution was dried over anhydrous sodium sulphate. The solvent was removed under reduced pressure and the residue was passed through a column using ethyl acetate and methanol (20: 1) as eluent. Evaporation of the solvent gave 4-hydroxy-butan-2 -one (2) as a liquid; Yield 1.012 gm, 92%. FTIR (KBr): Cm-1 3408,1705,1364,1172,1062,770; 'H NMR (90 MHz, CDC13): δ 2.14 (s, 3H, CH3), 2.65 (t, 2H, COCH3), 3.84(t, 2H, CH20), 4.33(s, 1H, OH); Mass m/z: 88 (M+), 70( M +-H20). The Main Advantages of the Present Invention are : 1 The method is very simple and can be carried out in one- pot at room temperature. 2 The work-up procedure is very simple. 3 The product obtained from the reaction mixture is highly pure and the yield is 92 %. 4 In this process the toxic solvents like benzene and dichloromethane are replaced with less toxic acetonitrile. 5 The reaction can be performed in hydrated media. We claim: 1. An improved process for the production of 4- hydroxy-butan-2-one of formula (2), which comprises: characterized in stirring 1,3-butane diol of formula ( 1 ) with oxidising agent in a mixture of an organic solvent and water (10:3) at a temperature in the range of 0-80 0C for a period in the range of 18-28 hours, removing the organic solvent by distillation under reduced pressure, treating the above said reaction mixture with acetic acid (5%) and extracting with water immiscible organic solvent followed by washing with sodium bi carbonate solution( 5%), drying using drying agent selected from sodium, magnesium and potassium sulphate and removing the solvent under reduced pressure to get compound of formula (2). 2. The process as claimed in claim 1, wherein the oxidising reagent used is a mixture of Na2S2O5/NaBrO3/H20Phase transfer catalyst, Na2S205Na103, DMSO/HI/H20 and DMSO/N2H4.H20/12/H20. 3. The process as claimed in claim 2, wherein the phase transfer catalyst is triethyl benzyl ammonium chloride. 4. The process as claimed in claim 1 , wherein the organic solvent is selected from chloroform, dilchloromethane, acetonitrile, more particulary hydrated acetonitrile. 5. The process as claimed in claim 1 , wherein the reaction mixture is stirred at a preferable temperature of 0-30°C. 6. The process as claimed in claim 1, wherein the water immiscible solvent used for the extraction of the product is selected from ethyl acetate, chloroform, dichloroform, petroleum-ether particularly ethyl acetate. 7. The process as claimed in claim 1, wherein the preferable drying agent is anhydrous sodium sulphate. 8. The process as claimed in claim 1, wherein the distillation of organic solvent is affected at a temperature of 20-40°C under reduced pressure. 9, An improved process for the production of 4- hydroxy-butan-2-one substantially as herein described with reference to the examples.

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1793-del-2004-Abstract-(03-11-2010).pdf

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1793-del-2004-Claims-(21-12-2010).pdf

1793-DEL-2004-Claims-(29-03-2011).pdf

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1793-DEL-2004-Correspondence Others-(03-06-2011).pdf

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1793-del-2004-Correspondence-Others-(03-11-2010).pdf

1793-del-2004-Correspondence-Others-(21-12-2010).pdf

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