Intermediates in the synthesis of C3-substituted cephalosporins

Abstract

Disclosed herein are novel and inventive methods for preparing intermediates in the synthesis of C3-substituted cephalosporins. One preferred C3-substituted cephalosporin of clinical interest is Cefovecin. Accordingly, the present invention provides for methods of preparing reactive halogen intermediates for use in the synthesis of C3-substituted cephalosporins, such as Cefovecin. In the case of Cefovecin the reactive intermediates are of the formula: ##STR00001##

Claims

1. A method of synthesising a C3-substituted cephalosporin comprising steps of: (i) generating a compound of the formula (II) from a compound of the formula (I) ##STR00022## (ii) reacting the compound of formula (II) with a thiol of the formula (III-1) or (III-2) to yield a compound of the formula (IV-1) or (IV-2), and ##STR00023## (iii) further processing the compound of formula (IV-1) or (IV-2) to yield a C3-substituted cephalosporin, wherein Z is selected from the group consisting of C.sub.1-C.sub.20 aliphatic, C.sub.3-C.sub.20 cycloaliphatic, C.sub.2-C.sub.20 heteroaliphatic, C.sub.2-C.sub.20 heterocycloaliphatic, C.sub.6-C.sub.20 aryl, C.sub.2-C.sub.20 heteroaryl, and combinations thereof; X is selected from the group consisting of Cl, Br, and I; and R.sup.11, R.sup.12, R.sup.13 are the same or different and each of R.sup.11, R.sup.12, R.sup.13 is either H or is independently selected from the group consisting of C.sub.1-C.sub.20 aliphatic, C.sub.3-C.sub.20 cycloaliphatic, C.sub.2-C.sub.20 heteroaliphatic, C.sub.2-C.sub.20 heterocycloaliphatic, C.sub.6-C.sub.20 aryl, C.sub.2-C.sub.20 heteroaryl, and combinations thereof.

2. The method of claim 1 wherein Z is selected from the group consisting of C.sub.3-C.sub.20 cycloaliphatic, C.sub.2-C.sub.20 heterocycloaliphatic, C.sub.6-C.sub.20 aryl, and C.sub.2-C.sub.20 heteroaryl.

3. The method of claim 1 wherein Z is selected from the group consisting of C.sub.2-C.sub.20 heterocycloaliphatic, and C.sub.2-C.sub.20 heteroaryl.

4. The method of claim 1 wherein Z is selected from the group consisting of tetrahydrofuranyl, tetrahydrothiophenyl, and tetrahydropyrrolyl.

5. The method of claim 1 wherein Z is 2-tetrahydrofuranyl.

6. The method of claim 1 wherein Z is 2-tetrahydrofuranyl and C2 on the tetrahydrofuran ring has the (S) stereochemical configuration.

7. The method of claim 1 wherein R.sup.11 is C.sub.1-C.sub.20 aliphatic.

8. The method of claim 1 wherein R.sup.11 is tertiary-butyl.

9. The method of claim 1 wherein R.sup.12 is selected from the group consisting of C.sub.1-C.sub.20 aliphatic, C.sub.6-C.sub.20 aryl, C.sub.2-C.sub.20 heteroaryl, and combinations thereof.

10. The method of claim 1 wherein R.sup.12 is para-nitrobenzyl.

11. The method of claim 1 wherein R.sup.13 is selected from the group consisting of C.sub.1-C.sub.20 aliphatic, C.sub.6-C.sub.20 aryl, C.sub.2-C.sub.20 heteroaryl, and combinations thereof.

12. The method of claim 1 wherein R.sup.13 is benzyl.

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) It should be readily apparent to one of ordinary skill in the art that the examples disclosed herein below represent generalised examples only, and that other arrangements and methods capable of reproducing the invention are possible and are embraced by the present invention.

(2) Cefovecin is a preferred C3-Substituted Cephalosporin within the scope of the aspects of the present invention. An outline of the synthesis of Cefovecin from start to finish is illustrated in B the scheme below. Further particulars of the synthesis can be found in the citations disclosed supra.

(3) ##STR00015## ##STR00016##

(4) In the schematic above, an embodiment of the present invention is best illustrated by step 7; in particular the preparation of the reactive chlorofuran intermediate. Detailed methods for the preparation of this compound, and its coupling to the thiol as illustrated in step 7 are outlined here under.

Stage (i): Formation of 1,3-Dioxane-4,6-dione-2,2-dimethyl-5-[[(2S)-tetrahydro-2-furanyl]carbonyl]

(5) ##STR00017##

(6) (S)-THF acid (20 g, 0.17 moles) was dissolved in dichloromethane (100 mL, 1.7 M) and the resulting solution was stirred at room temperature. Carbonyldiimidazole (30.7 g, 1.1 eq.) was added portion-wise to this solution at room temperature and stirred for 3 hours. The reaction mixture was cooled to 0-5° C., then charged with Meldrum's acid (2.23 g, 0.9 eq.) and triethylamine (4.8 mL, 0.2 eq.) maintaining the temperature at 0-5° C. The reaction mixture was stirred at this temperature for 1-3 h. The resulting solution was warmed to room temperature and WFI (100 mL) was added. The organic layer was separated, charged with a 36% solution of HCl (100 mL) and then stirred at room temperature for 1-3 h, until a precipitate was obtained. The solid is filtered and washed with WFI (3×50 mL). Isolated yield 25.4 g, 61%. [M+1] 243.16. 1Hδ (DMSO-D6, 400 MHz): 1.73 (s, 6H), 1.94-1.96 (m, 1H), 2.00-2.02 (m, 2H), 2.55-2.57 (m, 1H), 4.08-4.10 (m, 2H), 4.11-4.14 (m, 2H), 5.64 (t, 1H, J=2.8).

Stage (ii): Formation of 3-Oxo-3-[2(S)-tetrahydrofuranyl] propionic acid tert-butyl ester

(7) ##STR00018##

(8) 1,3-Dioxane-4,6-dione-2,2-dimethyl-5-[[(2S)-tetrahydro-2-furanyl]carbonyl] (25.4 g, 0.1 moles) was dissolved in toluene (150 mL, 0.7 M) at room temperature. To the resulting solution tert-BuOH (49.4 mL, 5 eq.) was charged, the reaction mixture is then warmed to 80-85° C. and stirred for 3-4 h. The reaction mass was cooled down to 10-15° C. and saturated NaHCO.sub.3 solution (100 mL) was added gradually until a pH of ˜8.0-8.5 was obtained. The organic layer was separated and the aqueous layer further extracted with toluene (2×50 mL). The organic layers were combined and washed with WFI (2×100 mL). The layers were separated and the organic layer was concentrated under vacuum at less than 50° C. until approx. 50 mL (2 V, 2.3 M) remained. A solvent exchange was then undertaken whereby dichloromethane was added (3×80 mL) and upon final addition the solvent volume was concentrated to ˜50 mL (2 V, 2.3 M). The resulting solution was carried directly on to the next step. Yield: 21 g, 93%. [M+1]=215.18. 1Hδ (DMSO-d6, 400 MHz): 1.43 (s 9H), 1.53-1.56 (m, 1H), 1.89-1.92 (m, 2H), 1.94-1.96 (m, 1H), 3.45 (t, 2H, J=3.2 Hz), 3.86-3.89 (m, 2H), 4.32-4.35 (m, 1H).

Stage (iii): Formation of 3-Oxo-3-[2(S)-tetrahydrofuranyl]-2-Chloro propionic acid tert-butyl ester

(9) ##STR00019##

(10) 3-Oxo-3-[2(S)-tetrahydrofuranyl] propionic acid tert-butyl ester (21 g, 0.98 moles) in dichloromethane (40 mL, 2.3 M) was diluted further with dichloromethane (63 mL) at room temperature. The mixture was cooled to 0-5° C. and N-chlorosuccinimide (1.25 eq.) was added drop-wise over a 15 min period. The reaction mixture was heated to room temperature and stirred for 1-3 h. The solution was then cooled down to 5-10° C., after which the slow addition of sat. NaHCO.sub.3 solution occurred until a pH ˜8.0-8.5 was obtained. This addition must be carried out whilst maintaining the temperature below 25° C. The organic layer was separated and the aqueous layer was further extracted with dichloromethane (2×100 mL). The organic layers were combined, washed with WFI (2×250 mL) and reduced under vacuum maintaining the temperature at less than 50° C. The layers were concentrated until a volume of ˜40 mL (2V, 0.14 M) and the resulting solution was used directly in the next step. Yield: 18 g, 74%. [M+1]=249.12. 1Hδ (DMSO-d6, 400 MHz): 1.45 (s, 9H), 1.86-1.87 (m, 2H), 2.01-2.04 (m, 1H), 2.23-2.26 (m, 1H), 3.82-2.85 (m, 2H), 4.54-4.57 (m, 1H), 5.06 (d, 1H, J=4.2 Hz).

Stage (iv): Formation of Ethanone-2-chloro-1-[(2S)-tetrahydro-2-furanyl]

(11) ##STR00020##

(12) 3-Oxo-3-[2(S)-tetrahydrofuranyl]-2-Chloro propionic acid tert-butyl ester (18 g, 0.07 moles) in dichloromethane (0.14 M) was charged with acetic acid (35 mL, 8.4 eq) and WFI (35 mL) at room temperature. The reaction mixture was heated to 105-108° C. and stirred at same temperature for 4-5 h. After completion of reaction the resulting solution was cooled to 5-10° C. The slow addition of sat. NaHCO3 solution was undertaken until pH 8.0-8.5 is obtained, maintaining the temperature <25° C. Dichloromethane (300 mL) was charged followed by the separation of the organic layer. The aqueous layer was further extracted with dichloromethane (2×300 mL), all three organic layers were combined and washed with WFI (2×400 mL). The organic layer was concentrated under vacuum at a temperature less than 50° C. until approx. 40 mL (2V, 0.07 M) and used in directly in the next reaction (coupling reaction). Yield: 10.9 g, 42.7% overall. [M+1]=149.12. 1Hδ (DMSO-d6, 400 MHz): 1.91-1.93 (m, 2H), 1.95-1.98 (m, 1H), 2.23-2.24 (m, 1H), 3.91-3.93 (m, 2H), 4.42-4.45 (m, 2H), 4.43-4.46 (m, 1H).

Stage (v): Coupling

(13) ##STR00021##

(14) Thiol (4 g, 8.9 mmoles) was suspended in dichloromethane (16 mL, 0.2 M). Then, ethanone-2-chloro-1-[(2S)-tetrahydro-2-furanyl] (0.9 g, 1.1 eq. in 0.07 M dichloromethane) was charged at room temperature. To this reaction mixture dimethyl acetamide (3.2 mL, 1.2 M) was added and the reaction mass stirred at room temperature for 10-14 h. After which, WFI (15 mL) was charged, stirred for 15 mins and the layers are separated. The aqueous layer was extracted twice with dichloromethane (2×15 mL). The organic layers were combined and washed with WFI (2×20 mL) followed by sat. NaCl solution (20 mL). The organic layer was separated and concentrated under vacuum to ˜20 mL (1V, 0.7 M). The resulting solution was added slowly to n-Hexane (80 mL) and the resulting precipitate was filtered and washed with n-hexane (2×10 mL) resulting in an off-white powder. Yield: 4.3 g, 86%. [M+1]=558.19. 1Hδ (CDCl3, 400 MHz): 1.81-1.84 (m, 2H), 2.08-2.11 (m, 2H), 2.02 (s, 1H), 2.99-3.02 (m, 1H), 2.48-3.52 (m, 2H), 3.61 (s, 1H), 3.84-3.88 (m, 2H), 4.32 (br. s, 1H, —OH), 5.04-5.08 (m, 1H), 5.31-5.36 (m, 3H, —CH2 and NH), 5.54 (d, 1H, J=4.2 Hz), 6.82-6.84 (m, 1H), 7.24-7.29 (m, 4H), 7.53-7.57 (m, 2H), 8.18-8.21 (m, 2H).

(15) The words “comprises/comprising” and the words “having/including” when used herein with reference to the present invention are used to specify the presence of stated features, integers, steps or components but do not preclude the presence or addition of one or more other features, integers, steps, components or groups thereof.

(16) It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination.