PREPARATION OF PENICILLIN SULFOXIDE

Abstract: A process for the preparation of Penicillin V DOLLAR (b)-sulfoxide by oxidation of Penicillin V in a two-phase liquid system comprising hydrogen peroxide aqueous solution and an organic solvent or mixture of organic solvents. The process is characterized in that: (I) the hydrogen peroxide aqueous solution is devoid of organic acid promoter, has a concentration of 20-50% w/v H2O2 in water, and the molar ration of H2O2 to Penicillin V is from 1.5:1 to 7:1; (II) the organic solvent or mixture of organic solvents is water-immiscible, inert to hydrogen peroxide, capable of dissolving Penicillin V, and has less solubility for Penicillin V beta -sulfoxide than for Penicillin V; and (III) the Penicillin V is present in the water-immiscible organic solvent or mixture of organic solvents as a concentrated solution in the range of 35-120% w/v. The formed Penicillin V beta -sulfoxide crystallizes from the two-phase liquid system as the oxidation proceeds, in a relatively high degree of purity and yield.

Description: PREPARATION OF PENICILLIN SULFOXIDE BACKGROUND OF THE INVENTION This invention provides a process for the preparation of Penicillin V β-sulfoxide on an industrial scale, in which Penicillin V is oxidized to the β-sulfoxide form by a known reagent in a generally known type of solvent but under specific conditions as hereinafter defined, such that the following overall advantages are obtained: the process gives yields greater than 90%, which is better than literature results; the process is easy to carry out; the oxidation reagent is relatively inexpensive; the end product β-sulfoxide is easy to isolate; the process volumes are small, as process solutions are concentrated; the process solvents are easy to handle and to re-cycle; -industrial grade Penicillin V (ca. 93%) can be used; and only the β-sulfoxide crystallizes out of the process solution, any α-sulfoxide that may be formed (ca. 1% or less) remaining in the process solution. Penicillin sulfoxides, which can be prepared by the oxidation of penicillins, are key intermediates in the chemical manipulation of penicillins, especially the conversion of penicillins into cephalosporins. Penicillin V is one of the most readily available and least expensive penicillin of natural occurrence, and its oxidation to the β-sulfoxide is therefore of potential industrial importance. Many oxidants such as ozone, sodium etaperiodate, -chloroperbenzoic acid, peracetic acid, and the like, have been successfully used in such oxidation reaction, but most of these reagents are either too expensive or troublesome to handle in a large-scale preparation. Hydrogen peroxide, which is a cheaper and commercially available reagent, has been employed together with an excess of an organic acid such as formic acid or acetic acid as promoter, vide: A. Mangia, Synthesis, 361 (.1978) ; G.V. Kaiser, R.D.G. Cooper R.E. Koehler, C.F. Murphy, J.A. Webber, I.G. Wright, and E.M. Van Heyningen, J. Org. Cheπ , 35, 2430 (1970); E. Guddal, P. M rch, and L. Tybring, Tetrahedron Letters, 381 (1962); and E.H. Flynn, "Cephalosporins and Penicillins: Chemistry and Biology" , Academic Press, New York, N.Y., 1972, p. 667, but the use of such an organic acid creates problems in the isolation of the end product and the • treatment of the residual aqueous solutions. SUMMARY OF THE INVENTION in accordance with the present invention there is provided a simple process for industrial-scale preparation of Penicillin V β-sulfoxide by oxidation of Penicillin V in a two-phase liquid system comprising hydrogen peroxide aqueous solution and an organic solvent o mixture of organic solvents, which oxidation can be graphically illustrated as follows: Penicillin V COOH Penicillin V β-sulfoxide COOH, the process of the invention being characterized in that: (I) the hydrogen peroxide aqueous solution is devoid of organic acid promoter, has a concentration of 20-50% w/v H-O- in water, and the molar ratio of H 2 0 2 to Penicillin V is from 1.5:1 to 7:1; (II) the organic solvent or mixture of organic solvents is water-immiscible, inert to hydrogen peroxide, capable of dissolving Penicillin V, and has less solubility for Penicillin V β-sulfoxide than for Penicillin V; and (III) the Penicillin V is present in the water-immiscible organic solvent or mixture of organic solvents as a concentrated solution in the range of 35-120% w/v, whereby the formed Penicillin V β-sulfoxide crystallizes from the two-phase liquid system as the oxidation proceeds, in a relatively high degree of purity and yield. PREFERRED EMBODIMENTS OF THE INVENTION Many known organic solvents and mixtures of organic solvents possess the characteristics specified in item (II) above, in particular: (i) chlorinated hydrocarbon such as methylene chloride (dichlororhethane) , chloroform (.trichloromethane) , and ethylene chloride (1,2-dichloro- ethane) , as demonstrated in Examples 1, 14, 29, 31 and 32, below; (ii) esters, such as ethyl acetate, diethyl carbonat and butyl acetate, as demonstrated in Examples 30 and 33, below; (iii) alcohols such as butyl alcohol, as demonstrate in Example 34 below; and (iv) ketones, such as isobutyl ketone, as demonstrated in Example 35 below. The preferred water-immiscible organic solvent for use in the process of the invention is methylene chloride or ethylene chloride, on account of lower cost and lower flammability, particularly when compared with other solvents mentioned below. Water-immiscible organic solvents in which Penicillin V is either insoluble or only slightly soluble are not suitable for the purpose of the invention. Such solvents include aromatic or aliphatic hydrocarbons such as benzene, toluene, hexane, cyclohexane, and light petroleum. Organic solvents such as diethyl ether are too flammable to be considered for use in the process of the invention. Water-miscible organic solvents, such as acetone, methyl ethyl ketone, ethyl alcohol, tetrahydrofuran or acetonitrile, are unsuitable for use in the process of the invention, on account of the low yields obtained, as demonstrated in Examples 36 and 37 below. The concentration, of the Penicillin V in the water-immiscible organic solvent or mixture of solvents, which can be from 35% to 120% (w/v) , depends upon the particular nature of the solvent selected for the purpose. In general terms, higher yields are obtained from the more concentrated solutions, but yields may be limited by the solubility of Penicillin V in that solvent, ap,art from the efficiency of stirring/agitation applied to the reaction mixture. For example, the preferred concentration of Penicillin V in methylene chloride is 40-70% (w/v) , whilst the limiting concentration is about 100% (w/v) , as demon¬ strated in Examples 2, 3, 6, 9(4), 10, 11, 16 and 21 below. The concentration of the aqueous hydrogen peroxide solution used in the reaction can be between 20 and 50%, as demonstrated in Examples 2, 6, 9(4), 19 and 20 below. However, the use of the lower concentration, i.e., 20%, requires more efficient stirring and a higher molar ratio of hydrogen peroxide to Penicillin V, as demonstrated in Example 9 below. The molar ratio of hydrogen peroxide to Penicillin V used in the process of the invention can be from 1.5:1 to 7:1, but preferably between 1.6 and 2.9 to 1 for good yields and low consumption, as demonstrated in Examples 1, 2, 4, 6, 9, 10, 16, 18 and 20 below. The reaction time depends on the reaction temperature, which may conveniently be between 0 and 40 C, the concentration of the reaction mixture, as indicated above, and the efficiency of stirring; it can be 6-9 hours at ambient (room) temperature, as demonstrated in Examples 1, 2, 3 and 7 below, or 24 hours at 0-5 C, as demonstrated in Examples 5, 6, 8 and 19 below. In any event, after completion of stirring, it is desirable to leave the reaction mixture overnight at 0-5 C to ensure that crystal- lization of the product is substantially complete, as demonstrated in Examples 5, 13, 12, 21 and 16 below. A comparatively limited improvement in yields in the process of the invention may be obtained by the addition of a relatively small quantity of an inorganic acid such as phosphoric acid, as demonstrated in Examples 14-21, 29, 31 and 32 below, or sulfuric acid, as demonstrated in Example 22 below. We surmise that an acidic solution promotes the oxidation, however, it is unnecessary to use catalysts, including phase-transfer catalysts, in the process, as demonstrated in Examples 23, 24 and 25 below. On the other hand, the addition of organic acids, such as formic acid or acetic acid, which is a frequently recommended procedure and which has previously been used for this oxidation, actually lowers the yield, as demonstrated in Examples 26, 27 and 28 below. The lowered yield probably is due to in the increased solubility of the Penicillin β -sulfoxide in the organic solvent of the liquid system. Penicillin V β-sulfoxide obtained by the process of the invention was identified utilizing the disclosures of D.O. Spry, J. Org. Chem. , 37, 793 (.1972) , the numbering system for Penicillin V β-sulfoxide being as follows: by way of its n.m.r., infrared, and elemental analysis as described below. H-n.m.r. spectra were recorded on a Perkin-Elmer R32 spectrometer at 90 MHz. N.m.r. (DMSO-dg) δ (ppm) : 1.11 (s, 3H, α-CH 3 ), 1.51 (s, 3H, β-CH_ 3 ) 4.31 (s, IH, CHCOO " ) , 4.54 (s, 2H, PhOCH 2 ) , 5.36 (d, IH, J = 5Hz, C5-H) , 5.82 (q, IH, J = 5Hz, 10Hz, C6-H) , 6.74-7.38 (m, 5H, Cg^-O-) , 8.1 (d, IH, J = 10Hz, CONH) . N.m.r. (_CDC1 3 + DMSO-dg) δ (ppm) : 1.31 (s, 3H) , 1.73 (s, 3H) , 4.49 (s, 2H) , 4.59 (s, IH) , 5.02 (d, IH, J = 5Hz) , 6.0 (q, IH, J •= 5Hz, 10Hz) , 6.73-7.27 ( , 5H) , 8.12 " (d, IH, J •= 10Hz) . C-n.m.r. spectra were recorded on a JEOL JUN- PS100 High Resolution n.m.r. instrument. N.m.r. (CDC1-, + DMSO-dg) δ(ppm): -173.277 (C8) , -169.520 (C7), -168.005 (C1 -156.895 (C15) , -129.593 (C17 and C19) , -122.070 (C18) , -114.790 (C16 and C20) , -76.203 (C13), -75.050 (C5) , -67.04 (C6) , -66.434 (C3) , -55.271 (C2) , -19.293 (C9) , -18.504 (CI Infrared spectra were recorded on a Perkin-Elmer 257 Grating Infrared Spectrophotometer. Infrared (KBr) v (cm~ ): 3330 (amide NH) , 1790 (β-lactam C=0) , 1730 (carboxy acid C=0) t 1670 (amide C=0) . Elemental analysis: Calculated for C, ,-H- o N.0,S: JLo J_α 2 6 C, 52.46; H, 4.92; N, 7.65; S, 8.74%. Found: C, 52.07; H, 4.77; N, 7.86; S, 8.60%. Thin-layer chromatogra s were run on Silica Gel 60.F 254 (Merck) using acetone : acetic acid (19 : 1) as developing solvents, and the results were observed unde ultraviolet light. The R- value of Penicillin V is about 0.6 whilst the R- value of Penicillin V β-sulfoxide is about 0.2. The products obtained from the procedures as described below showed in each case only the one spot corresponding to Penicillin V β-sulfoxide. The melting point (mp) of Penicillin V β-sulfoxid reported in the literature varies from 155 to 178 C. We have found that this discrepancy is due to different extent of hydration, and different crystal forms. When a sample of Penicillin V β-sulfoxide, obtained by the process of the present invention, was treated in different ways, the melti points of the resulting samples agreed with the correspondi values in the reference literature. The sample which was obtained from its acidified aqueous solution possesses a mp 156-157°C (literature reference, 155 C, vide: A. Mangia, supra) after being air-dried one day; after 4 days air-dryi its mp was 159-160 C (literature reference, 159 C, vide: E. Guddal, P. M rch and L. Tybring, supra) . A sample crystallized from a methanol-water mixture possesses a mp o 163-164 C (literature reference, 163-164 C, vide: R.B. Mori B.G. Jackson, R.A. Mueller, E.R. Lavagnino, W.3. Scanlon, and S.L. Andrews, J.Amer. Chem. Soc, 91, 1401 (1969)) afte being air-dried; it had a mp of 167-168 C (literature reference, 167-168 C, vide: E.H. Flynn, supra, and A.W. Cho N.M. Hall, and J.R.E. Hoover, ' J. Org. Chem. , 27, 1381 (1962 after being vacuum-dried at 60 C for 18 hours. A sample obtained from an acetone-water mixture and dried in a vacuu over phosphorus pentoxide for 20 hours possesses a mp of 177-178°C (literature reference, 176-178°C, vide: R.F. Erzsebet, G. Tamas, J. Csaba, and B. Rezs , Magyar Kemiai Folyoirat, 84, 257 (1978)). PRACTICAL/COMPARATIVE EMBODIMENTS OF THE INVENTION The process of the invention is generally illustrated in the following non-limitative practical examples, certain of which, however, deal with reaction conditions outside the scope of the invention for comparison purposes as indicated above. EXAMPLE 1 (1) Into a suspension of Penicillin V (Abbott Laboratories Pty. Ltd., 1585 units/mg, approx. 93.46% [^theoretical potency 1696 units/mg] ) (17.5g, 46.73 mmoles) in methylene chloride (40ml) was added 10ml of aqueous hydrogen peroxide (.30%, 88.24 mmoles). After having been stirred for about 10 minutes, the Penicillin V dissolved completely in the methylene chloride. The mixture was stirred at 25-30 C for a further 6 hours by which time the thin layer chromatogram indicated that the reaction was complete. The mixture was then left at 5 C overnight. The white Penicill β-sulfoxide was filtered off and washed successively with cold methylene chloride (2 x 10ml) and water (5 x 30ml) , th air-dried. The yield was 15.4 g (90%), mp.162-163°C. (2) The procedure is the same as described above except tha 37.5ml of aqueous hydrogen peroxide (30%,331 mmoles) was used. The yield was 15.25g (89.16%) , mp 164-165°C. EXAMPLE 2 Penicillin V 17.5 g (46.73 mmoles) Methylene chloride 40ml Hydrogen peroxide (30%) 15ml (132.4 mmoles) The procedure is the same as in Example 1 except that the stirring was continued for 9 hours at room temperature. Th yield was 15.4g (90%), mp 160-162°C. EXAMPLE 3 Penicillin V 17.5g (46.73 mmoles) Methylene chloride 30ml Hydrogen peroxide (30%) 15ml (132.4 mmoles) The procedure is the same as in Example 1 except that the stirring time was 7 hours rather than 6 hours. The yield was 15.4g (90%), mp 162-163°C. EXAMPLE 4 Penicillin V 17.5g (46.73 mmoles) Methylene chloride 40ml Hydrogen peroxide (.30%) 8.5ml (75 mmoles) The procedure is the same as in Example 1 except that the stirring was continued for 7 hours at 30-35 C. The yield wa 16.4g C95.9%), mp 159-160°C. EXAMPLE 5 Penicillin V 17.5g (46.73 mmoles) Methylene chloride - 40ml Hydrogen peroxide. (.30%) 15ml (132.4 mmoles) The procedure is the same as in Example 1 except that the stirring was continued for 24 hours- at 5 C. The yield was 15.5g (90.6%), mp 162-163°C. EXAMPLE 6 Penicillin V 7g (18.69 mmoles) Methylene chloride 10ml Hydrogen peroxide (50%) 3.6ml (52.96 mmoles) The procedure is the same as in Example 5. The yield was 6.7g (97.94%), mp 161-163°C. EXAMPLE 7 Penicillin V 7g (18.69 mmoles) Methylene chloride 14ml Hydrogen peroxide (.30%) 6ml (52.96 mmoles) The reaction mixture was stirred at room temperature for 4.5 hours, then left at 5°C overnight. The yield was 5.9g (86.24%), mp 163-164°C. EXAMPLE 8 Penicillin V 7g (.18.69 mmoles) Methylene chloride 14ml Hydrogen peroxide (30%) 6ml (52.96 mmoles) The reaction mixture was stirred at 5 C for 16 hours, then iltered. The yield was 5.9g (.86.24%) , mp 161.5-162.5°C. EXAMPLE 9 (1) Penicillin V 17.5g (46.73 mmoles) Methylene .chloride 30ml Hydrogen peroxide (20%) 15ml (88 mmoles) The reaction mixture was stirred at room temperature for 6 hours, then left at 5 C overnight. The yield was 12.82g (74.96%), mp 159-160°C. (2) Penicillin V 17.5g (46.73 mmoles) Methylene chloride 40ml Hydrogen peroxide (20%) 22.2ml (132.4 mmoles) The mixture was stirred at 25-30 C for 6 hours, then left at 5 C overnight. The yield was 14.34g (83.84%), mp 159-160°C. (3) The same procedure as in (2 ) above except that the hydrogen peroxide was added dropwise over a period of 2 hours. The yield was 13.88g (.81.16%), mp 160-161°C. ( 4) Penicillin V 17.5g (46.73 mmoles) Methylene chloride 20ml Hydrogen peroxide (20%) 30ml (178.9 mmoles) The mixture was stirred at 25-35°C for 7 hours, then left at 5°C overnight. The yield was 15.25g (.89.17%) , mp 161.5-162.5°C. EXAMPLE 10 Penicillin V 17.5g (.46.73 mmoles) Methylene chloride 50ml Hydrogen peroxide (.30%) 11.4ml (100 mmoles) The procedure was the same as in Example 1. The yield was 15.08g (88%), mp 158-159°C. ' EXAMPLE 11 Penicillin V 1.75g (4.67 mmoles) Methylerie chloride "' 10ml Hydrogen peroxide (30%) 1ml (8.82 mmoles) The procedure is the same as in Example 1. The yield was 1.45g (84.8%) , mp 162-163°C. EXAMPLE 12 Penicillin V 1.75g (4.67 mmoles) Methylene chloride 10ml Hydrogen peroxide (30%) 1.5ml (13.24 mmoles) The reaction mixture was stirred at 25-35 C for 6 hours, th stirred at 0-5 C for 45 minutes. The mixture was filtered and the white powder of Penicillin V β-sulfoxide was washed with methylene chloride and water as described in Example 1 The yield was l.Q7g (.62.6%), mp 159-160°C. EXAMPLE 13 Penicillin V 7g (18.69 mmoles) Methylene chloride 14ml Hydrogen peroxide (30%) 6ml (52.96 mmoles) The reaction mixture was stirred at 25-30 C for 7 hours, then stirred at 0-5°C for 1 hour. It was filtered and washed with methylene chloride and water as mentioned above. The yield was 5.9g (.86.2%), mp 162-163 C. EXAMPLE 14 Penicillin V 17.5g (46.73 mmoles) Methylene chloride 40ml Hydrogen peroxide (.30%) 15ml (132.4 mmoles) Phosphoric acid (H,PO.) 5 drops (ca. 5 mmoles) The reaction mixture was stirred at 25-35 C for 6 hours, th left at 5 C overnight. The procedure of Example 1 was then followed. " The yield was 15.47g (90.45%), mp 162-163°C. EXAMPLE 15 Penicillin V 17.5g (46.73 mmoles) Methylene chloride 30ml Hydrogen peroxide (.30%) 15ml (132.4 mmoles) Phosphoric acid (H-,PO.) 5 drops (ca. 5 mmoles) The same procedure as described in Example 14 was followed. The yield was 15.5g (90.63%), mp 161-162°C. EXAMPLE 16 (1) Penicillin V 35g (93.46 mmoles) Methylene chloride 70ml Hydrogen peroxide (30%) 30ml (264.8 mmoles) Phosphoric acid (H -,iPO.) 10 drops (ca. 10 mmoles The same procedure as described in Example 14 was followed except that the mixture was stirred for 7 hours. The yield was 32.97g (.96.39%), mp 161-162°C. (2) The same quantities and procedure of (.1) above were used but the reaction mixture was left at 5 C for 48 hours, instead of just overnight. The yield was 32.17g (.94.05%), mp 162.5-163.5°C. EXAMPLE ' 17 Penicillin V 17.5 g (46.73 mmole Methylene chloride 30ml Hydrogen peroxide (30%) 10ml (88.24 mmole Phosphoric acid (H 3 P0 4 ) 5 drops (ca. 5 mmole The procedure was the same as in Example 14. The yield was 16g (.93.5%), mp 162-163°C. EXAMPLE 18 Penicillin V 17.5g (.46.73 mmole Methylene chloride 35ml Hydrogen peroxide (.30%) 12.5ml (110.3 mmole Phosphoric acid (H.,P0 4 ) 5 drops (ca. 5 mmole The procedure was the same as in Example 16 (1) . The yield was 15.41g (90.1%), mp 160-162°C. EXAMPLE 19 Penicillin V 17.5g (46.73 mmole Methylene chloride 35ml Hydrogen peroxide (30%) 15ml (132.4 mmole Phosphoric acid (H 3 P0 4 ) 5 drops (ca. 5 mmole The reaction mixture was stirred at 5°C for 24 hours, then filtered, and the product washed with methylene chloride an with water, and dried. The yield was 15.63g (91.36%), mp 167-168°C. EXAMPLE 20 Penicillin V 17.5g (46.73 mmole Methylene chloride 35ml Hydrogen peroxide (50%) 9ml (132.4 mmole Phosphoric acid (H-PO.) 5 drops (ca. 5 mmole The same procedure as described in Example 14 was used. Th yield was 15.6g (91.2%), mp 163-164°C. EXAMPLE 21 Penicillin V 17.5g (46.73 mmole Methylene chloride 100ml Hydrogen peroxide (.30%) 10ml (88.24 mmole Phosphoric acid (H^PO.) 5 drops (ca. 5 mmole The procedure was the same as in Example 14. The yield was 14.28g (83.5%), mp 162-163°C. EXAMPLE 22 . Penicillin V 7g (18.69 mmol Methylene chloride 14ml Hydrogen peroxide (30%) 6ml (52.96 mmol Sulfuric acid 2 drops The procedure was the same as in Example 14. The yield wa 6.2g (90.6%), mp 162-163°C. EXAMPLE 23 Penicillin V 7g (18.69 mmol Methylene chloride 20ml Hydrogen peroxide (30%) 6ml (52.96 mmol Tetrabutylammonium hydroxide solution (40%) 5 drops The procedure was the same as in Example 1. The yield was 5.82g (85.07%), mp 16Q.5-162°C. EXAMPLE 24 The quantities and procedure of Example 23 were used but tetrabutylammonium hydrogen sulfate solution was used in place of the hydroxide. The yield was 5.72g (.83.6%), mp 162-163°C. EXAMPLE 25 The quantities and procedure of Example 23 were used but 0.165g (0.5 mmoles) of sodium tungstate dihydrate was used instead of the tetrabutylammonium hydroxide. The yield was 5.64g (82.44%), mp 162-163°C. EXAMPLE 26 Penicillin V 7g (18.69 mmoles Methylene chloride 20ml Hydrogen peroxide (.30%) 2ml (26.5 mmoles) Formic acid 3ml (80 mmoles) The same procedure was used as described in Example 1. The yield was 4.65g (67.97%), mp 162-Ϊ63°C. EXAMPLE 27 Penicillin V 3.5g (9.35 mmoles) Ethyl acetate 10ml Hydrogen peroxide (30%) 1.4ml (12.4 mmoles) Acetic acid 1.4ml (24.5 mmoles) The procedure was the same as in Example 1. The yield was 2.18g (63.73%), mp 159-160°C. EXAMPLE 28 The procedure was the same as in Example 27 but butyl acetat (10ml) was used instead of ethyl acetate. The yield was 2.9 (84.78%) , mp 165-166°c. EXAMPLE 29 (1) Penicillin V 17.sg (46.73 mmoles) Chloroform 35ml Hydrogen peroxide (30%) 15ml (132.4 mmoles) Phosphoric acid H 3 P0 4 ) 5 drops (ca. 5 mmoles) The procedure was the same as in Example 1. The yield was 14.55g ( . 85.07%), mp 167-168°C. (2) . The same procedure as (1) above was used but the mixture was stirred at 5°C for 24 hours, rather than at room temperature for 6 hours. The yield was 15.13g (88.43% mp 163-164 W C. EXAMPLE 30 Penicillin V 35g (93.46 mmoles) Ethyl acetate 30ml Hydrogen peroxide (30%) 20ml (176.48 mmoles). The procedure was the same as in Example 1. The yield was 30.78g (90%), mp 162-163°C. EXAMPLE 31 (1) Penicillin V 7g (18.69 mmoles) 1,2-Dichloroethane 14ml Hydrogen peroxide (30%) 6ml (52.96 mmoles) Phosphoric acid (H 3 P0 4 ) 2 drops (ca. 2 mmoles) The reaction mixture was stirred at room temperature for 7 hours, then left at 5 C overnight. After having been filtered off in the usual way, 6.55g (.95.74%) of Penicillin V β-sulfoxide was obtained, mp 162-163°C. (2) The same procedure as described in (1) was used but a double volume (28ml) of 1,2-dichloroethane was used. - The - yield was 5.5g (80.4%) , mp 162-163°C. EXAMPLE 32 Penicillin V 7g (18.69 mmoles) 1,1,2,2,-Tetrachloroethane 14ml Hydrogen peroxide (30%) 6ml (52.96 mmoles) Phosphoric acid (H..PO.) 2 drops (ca. 2 mmoles) The procedure was the same as in Example 1. The yield was 5.1g (74.55%), mp 163-164°C. EXAMPLE 33 Penicillin V 7g (18.69 mmoles) Ethyl acetate 7ml Butyl acetate 7ml Hydrogen peroxide (30%) 6ml (52.96 mmoles) The procedure was the same as in Example 1. The yield was 5.8g (.84.78%), p 162-163°C. EXAMPLE 34.. Penicillin V 7g (18.69 mmoles) n-Butyl alcohol 9ml Hydrogen peroxide (30%) 6ml (52.96 mmoles) The mixture was stirred at 5 C for 24 hours, then filtered, washed with water, and dried. The yield was 4.5g (66.6%) , mp 155-156°C. EXAMPLE 35 Penicillin V 7g (18.69 mmoles) Isobutyl ketone 14ml Hydrogen peroxide (30%) 6ml (52.96 mmoles) Phosphoric acid (H-.PO.) 2 drops (ca. 2 mmoles) The procedure was the same as in Example 1. A white powder (4.2g) was obtained, but thin layer chromatography of this powder showed it was a mixture of Penicillin V and Penicillin V β-sulfoxide. The mp was 135-141 C. EXAMPLE 36 Penicillin V 7g (.18.69 mmoles) Methyl ethyl ketone 14ml Hydrogen peroxide (30%) 6ml (52-.96 mmoles) Phosphoric acid (H_,PO.) 2 drops (ca. 2 mmoles) The reaction mixture was stirred at room temperature for 7 hours, then diluted with 10ml of water and stirred for a further 2 hours in an ice bath. After filtering, 2.98g C43.6%) of a white powder of mp 155-157.5°C was obtained. A further 3.1 g of crude product was recovered from the filtrate. EXAMPLE 37 Penicillin V 7g (.18.69 mmoles) Ethyl alcohol 20ml Hydrogen peroxide (30%) 4ml (35.3 mmoles) This suspension was stirred at 5 C overnight, then diluted with 20 ml of water at 5 C. Stirring was continued for a further 2 hours. A white powder, 5.6g, of a mixture of Penicillin V and Penicillin V β-sulfoxide, was obtained. We have found that whilst the presence of an inorganic acid such as phosphoric or sulfuric acid in very small proportion in the liquid system, functions to provide a slight increase in the yield, such an acid additionally functions to improve the appearance of the product. We have also found that the process of the invention is specific for the oxidation of Penicillin V to Penicillin V β-sulfoxide, in that said process is not equally suitable for the equivalent oxidation of Penicillin G.

Claims: CLAIMS 1. A process for the preparation of Penicillin V β-sulfoxide by oxidation of Penicillin V in a two-phase liquid system comprising hydrogen peroxide aqueous solution and an organic solvent or mixture of organic solvents, characterized in that: (I) the hydrogen peroxide aqueous solution is devoid of organic acid promoter, has a concentration of 20-50% w/v H 2 0 2 in water, and the molar ratio of H 2 0 2 to Penicillin V is from 1.5:1 to 7:1; (.II) the organic solvent or mixture of organic solvents is water-immiscible, inert to hydrogen peroxide, capable of dissolving Penicillin V, and has less solubility for Penicillin V β-sulfoxide than for Penicillin V; and (.III) the Penicillin V is present in the water-immiscible organic solvent or mixture of organic solvents as a concentrated solution in the range of 35-120% w/v, whereby the formed Penicillin V β-sulfoxide crystallizes from the two-phase liquid system as the oxidation proceeds, in a relatively high degree of purity and yield. 2. The process of Claim 1 wherein the water- immiscible organic solvent or mixture of water-immiscible organic solvents is selected from chlorinated hydrocarbons; esters; alcohols; ketones; or suitable mixtures thereof. 3. The process of Claim 1 wherein the water- immiscible organic solvent or mixture of water-immiscible organic solvents is selected from methylene chloride (dichloro ethane) , chloroform (.trichloromethane) , and ethylene chloride (1,2-dichloroethane) ; ethyl acetate, diethyl carbonate, and butyl acetate; butyl alcohol; and isobutyl ketone; or suitable mixtures thereof. 4. The process of Claim 1 wherein the water- immiscible organic solvent is methylene chloride or ethylene chloride. 5. The process of Claim 1 wherein the water- immiscible organic solvent is methylene chloride and the concentration of the Penicillin V therein is 40-70% w/v. 6. The process of Claim 1 wherein the molar ratio of hydrogen peroxide to Penicillin V is between 1.6 and 2.9:1. 7. The process of Claim 1 wherein the water- immiscible organic solvent is methylene chloride; the concentration of the Penicillin V therein is 40-70% w/v; and the molar ratio of hydrogen peroxide to Penicillin V is between 1-6 and 2.9:1. 8. The process f any one of Claims 1 to 7 wherein the liquid system contains a relatively small quantity of an. inorganic acid. 9. The process of any one of Claims 1 to 7 wherein the liquid system contains a relatively small quantity of phosphoric acid or sulfuric acid. 10. The process of any one of Claims 1 to 9 wherein the reaction is carried out with stirring at a temperature between 0 and 40 C. 11. The process of any one of Claims 1 to 9 wherein the reaction is carried out with stirring for 6-9 hours at ambient (room) temperature. 12. The process of any one of Claims 1 to 9 wherein the reaction is carried out with stirring for 24 hours at 0° to 5°c.

Inventors: DAVIS MICHAEL, WU WEN-YANG, DAVIS, MICHAEL, WU, WEN-YANG
Applicants: UNIV TROBE, LA TROBE UNIVERSITY
Application year: 1985
Main classification: C07D499
IPC codes: C07D499