SYNTHESIS OF alpha -CHLORO OR FLUORO KETONES

Abstract: A simple, high yielding synthesis of alpha -chloro ketones is described, involving acylation of Grignard and organolithium reagents with N-methoxy-M-methylchloroacetamide. The efficiency of the process is further enhanced by recycling N,O-dimethylhydroxylamine.

Description: ΗTLE OF THE INVENTION SYNTHESIS OF α-CHLORO OR FLUORO KETONES BACKGROUND OF THE INVENTION This application is directed to an improved process for making α-chloro ketones such as 4-(methylthio)-2-chloroacetophenone, which compounds are intermediates useful in the preparation of certain non-steroidal anti-inflammatory agents. See, for example, WO 95/00501, published January 5, 1995, which is hereby encorporated by reference. The synthesis of α-chloro ketones such as 4-(methylthio)-2- chloroacetophenone 1 via Friedel-Crafts aeylation of thioanisole with chloroacetic acid derivatives, and via direct halogenation of 4-(methylthio)acetophenone is possible, but both of these approaches are problematic. For example, while the Friedel-Crafts aeylation of thioanisole using acetyl chloride- AICI3 is an efficient process (>90% yield, 100: 1 pararortho), the use of AlCl3-chloroacetyl chloride is not (<40% yield, 3:1 para:ortho). The situation is not improved by variation of Lewis acid, solvent, or by the use of other chloroacetic acid derivatives. Similarly, the direct halogenation of 4-(methylthio)acetophenone is accompanied by the formation of (usually >10%) di-halogenated ketone, which was difficult to remove by crystallisation. Moreover, of the many literature protocols for ketone synthesis based on aeylation of organometallic reagents, they are generally inapplicable to the synthesis of α-halogenated ketones. See Comprehensive Organic Synthesis, Pergamon 1991, Volume 1, 397 and Friour G., Cahiez G„ Normant J. F. Synthesis 37 1984, or - 4 - comprising compound of formula I and an aqueous solvent phase comprising compound of formula III' HNFKOR 1 )^ III' In a preferred aspect of this invention Y is chloro. The aqueous and organic phases may be separated by standard liquid-liquid separation means, such as by decantation or centrifugation. For purposes of this specification, the acid G includes, but is not limited to hydrochloric, hydrobromic, sulfuric, methanesulfonic, toluenesulfonic, phosphoric acid, and the like. For purposes of this specification the organic aprotie solvent includes, but is not limited to ethereal solvents including diethyl ether, di-n-butyl and di-isopentyl ethers, anisole, cyclic ethers such as tetrahydropyran, 4-methyl- 1,3-dioxane, tetrahydrofurfuryl methyl ether, ethyl ether, furan, and tetrahydrofuran. For purposes of this specification the carbon nucleophile A is defined to include optionally substituted: (1) phenyl, (2) 3,4-dimethoxyphenyl, (3) benzofuranyl, (4) furanyl, (5) imidazolyl, (6) indolyl, (7) isothiazolyl, (8) pyrazinyl, (9) pyrazolyl, (10) pyridyl, (11) pyrimidyl, (12) pyrrolyl, (13) thiazolyl, In one embodiment, the invention is directed to a process of making an α-chloro or fluoro ketone of the formula I l ^ I wherein Y is chloro or fluoro and A is a carbon nucleophile, comprising: (a) reacting an organometallic reagent of formula II A-M II wherein M is Li or Mg, with a compound of formula III III wherein X is -NR(0R!) R and Rl are each independently linear or branched Cl-3 alkyl, C3-6cycloalkyl, form a ring, or optionally substituted with Cl-3alkoxy, phenyl, substituted phenyl, wherein the substituent on the phenyl is selected from F, Cl, Br, methylthio, -OH, methoxy, aminothio, and Cl- 3 alkyl. in an organic aprotie solvent, and (b) reacting, without further purification, the product of step (a) with an aqueous solution of acid G, to yield an organic aprotie solvent phase - 6 - and X is -NCH3(OCH3). In a second aspect, the invention is directed to a process of making a compound of formula III O "II wherein X is -NR(ORI) wherein R and Rl are described as above, comprising acylating HNR(OR^) hydrochloride with chloroacetyl chloride in a two phase mixture of aqueous base and a non-reactive water insoluble organic solvent to yield a compound of formula III. For purposes of this specification, the base includes both organic bases including pyridine, tri-Cl-3 alkylamine, and inorganic bases include sodium hydroxide, potassium hydroxide, sodium carbonate or bicarbonate or potassium carbonate or bicarbonate. For purposes of this specification the non-reactive water insoluble organic solvent includes, but is not limited to toluene, methyl t-butyl ether (MTBE), hexane, heptane, methylene chloride, dichloroethane, dichlorobenzene, monochlorobenzene. The reaction is allowed to proceed until substantially complete in 5 min. to 1 hr. The molar ratio of HNR(ORl) to chloroacetyl chloride is typically 1: 1 or greater (i.e. excess chloroacetyl chloride); preferably 1.1: 1 to 1.2: 1. The reaction is conducted at -10 to 20°C; preferably 0 to 5°C. A preferred procedure for making a compound of formula III comprising: separating from the product of reaction step (b) the aqueous solvent phase, said aqueous solvent phase comprising compound of formula III', and (14) thienyl, (15) triazolyl, (16) Cl-10 alkyl, (17) C2-3alkenyl (18) C2-3alkynyl, wherein the substitutent is selected from F, Cl, Br, methylthio, -OH, methoxy, aminothio, Cl-3 alkyl, C2-3alkenyl, C2-3alkynyl. The reaction step (a) is allowed to proceed until substantially complete in 10 min to 3 hr. The molar ratio of formula II to compound of formula III is typically 1: 1 or greater (i.e. excess amount of formula II); preferably 1: 1 to 1.2: 1. The reaction may be conducted to -30 to 20°C; preferably 0 to 10°C. The reaction step (b) is allowed to proceed until substantially complete in 5 min. to 3 hr; typically on the order of 15 minutes. The molar ratio of acid to compound of formula III is typically 1: 1 or greater (excess acid); preferably 1: 1 to 1.2: 1. The reaction may be conducted at -10 to 20 β C; preferably 0 to 5°C. Within this aspect, there is a class of process wherein the compound of formula I is the compound of formula II is - 8 - the Grignard formation included the corresponding phenol (oxidation) and biaryl (homocoupling). The former was significantly reduced by de-gassing the reaction solvent and the HCl used for quench.] The crude product was crystallised from toluene-hexane (1:2) to give 1 in 80% yield (>98% purity by HPLC analysis). A drawback commonly associated with the use of N- methoxy-N-methyl amides for ketone synthesis is the high cost of N,0- dimethylhydroxylamine hydrochloride. Although aqueous workup regenerates N,0-dimethylnydroxylamine (or its hydrochloride salt), there are few, if any, reports concerning its recovery from the aqueous extract. Recycling of this material is now possible via direct aeylation of N,0-dimethylhydroxylamine in the aqueous extract with chloroacetyl chloride. Thus, after workup (aq HCl) the aqueous extract was reacted with chloroacetyl chloride-K2C03 to give the amide 3 cleanly (80% yield based on N,0-dimethylhydroxylamine hydrochloride used initially). This material was re-used in reactions with Grignard reagent 2a to give 1 without loss in yield or product purity. The Following examples are intended to illustrate, but not limit the invention as disclosed herein: reacting, without further purification, the aqueous solvent phase with chloroacetyl chloride in a bi-phasic mixture of aqueous K2CO3 and MTBE or toluene, to yield a compound of formula III. The reaction is allowed to proceed until substantially complete in 5 to 50 minutes. The molar ratio of III' to K2CO3 is typically 1:2 to 1:3 (i.e. excess base); preferably 1 :2.5. The concentration of chloroacetyl chloride in the organic solvent (MTBE or toluene) is 0.2-0.5 M, preferably 0.5 M. The ratio of organic solvent to aqueous solution is 1:1 to 2: 1 (excess organic solvent), preferably 1: 1. The reaction is conducted to -10 to 5 °C; preferably 0 to 5 °C. One objective of the invention was to develop a practical synthesis of the amide 3b. A non-aqueous aeylation (Et3N, CH2CI2) of N,0-dimethylhydroxylamine hydrochloride with chloroacetyl chloride has been reported. See Nuzillard J.-M., Boumendjel G., Massiot G. Tetrahedron xLett., 30 (29) 3779, 1989. This was accomplished via aeylation of N,0-dimethylhydroxylamine hydrochloride with chloroacetyl chloride, using a two phase mixture of aq K2CO3 and toluene/MTBE. The highly pure amide 3b was isolated in excellent yield (95%) after solvent removal (when MTBE used as solvent). For large scale runs the amide 3b (prepared using toluene as solvent) was used directly as a solution in toluene (after azeotropic drying) for reactions with organometallic reagents. Reaction of the amide 3b with the Grignard reagent 2a (IM solution in THF, 1.2 equiv., prepared from 4-bromothioanisole) proceeded cleanly and rapidly in THF (reaction complete within 1.5 h at 25 °C) to give, after aqueous workup (2N HCl), 4-(methylthio)-2- chloroacetophenone 1 in 90% yield. [Yield determined by quantitative HPLC analysis of the organic layer after workup, compared to a standard solution of chromatographed ketone 1.] No over addition was observed, and the only significant (>0.5%) by-products were derived from preparation of the Grignard reagent. [By-products from - 10 - over 30 min, the layers were separated and the aqueous layer was extracted with MTBE (5xl00mL). The combined organic extracts were concentrated to give 22.7 g (80% based on 20 g of N,0- dimethylhy droxy lamine hydrochloride used initially) of amide 3b. This material was identical spectroscopically and by HPLC analysis to 3b prepared from fresh N,0-dimethylhydroxylamine hydrochloride. The reactions listed as Examples 2 through 6 (Table I) were conducted using the procedure of Example 1 with appropriate substitution of reagent 2. EXAMPLE 1 Procedure for the preparation of the 4-fmethylthioV2- chloroacetophenone (1) 2a M= gBr 3a X=CI 2b M=Lι 3b X=NMe(OMe) A solution of N-methoxy-N-methylchloroacetamide 3b (26.8 g, 195 mmol) in toluene (250 mL, see ref 9) was diluted with de-gassed THF (530 mL) and the mixture was cooled to 0 β C. A solution of the Grignard reagent 2a (240 mL of a IM soln in THF, 1.2 equiv.) was added, via cannula, over 30 min (solution temperature <5°C) and the mixture was stined at 25°C for 1.5 h. The thick slurry was transfeπed, via cannula, into cold (0°C), de-gassed aq. 2N HCl (250 mL, 2.5 equiv.) and the layers were separated. The organic layer was washed with brine (100 mL), dried (MgSθ4), filtered and concentrated (to approx. 75 mL). Hexanes (150 mL) was added and the mixture was stined for 2 h. The slurry was filtered, the solid was washed with hexanes and dried to give 32.9 g (80% from N,0- dimethylhy droxvlamine hydrochloride) of 1, a yellow solid. lH NMR (CDCI3, 300 MHz) d 2.53 (s, 3H), 4.67 (s, 2H), 7.28 (d, 2 H, 7=8.5 Hz), 7.87 (d, 2H, 7=8.6 Hz); 13c NMR (CDCI3, 75 MHz) d 14.69, 45.77, 125.07, 128.95, 130.35, 147.48, 190.16. The aqueous layer was added to a biphasic mixture of K2CO3 (79 g, 570 mmol) in H2O (200 mL) and MTBE (500 mL) to give a heavy slurry. The vigorously stirred mixture was cooled to -5°C and chloroacetyl chloride (19.6 mL, 246 mmol) was added, over 5 min (solution temperature <1°C). The mixture was warmed to 15°C - 12 - EXAMPLE 2 A solution of N-methoxy-N-methylchloroacetamide 3b (1.65 g, 12 mmol) in toluene (15 mL) was diluted with de-gassed THF (27 mL) and the mixture was cooled to 0°C. A solution of the Grignard reagent (14.4 mL of a IM soln in THF, 1.2 equ, prepared from the reaction of 4-bromo- 1 ,2-(methylenedioxy) benzene with Mg in THF) was added, via cannula, over 30 min (solution temperature <5°C) and the mixture was stined at 25°C for 2.5 h. The mixture was transferred, via cannula, into cold (0°C), de-gassed aq. 2N HCl (35 mL, 5.8 equ), diluted with tolune (10 mL), and the layers were separated. The organic layer was washed with brine (20 mL), dried (MgSθ4), filtered and concentrated to give the product in 83% yield. A solution of 4-bromo- 1 ,2-(methy lenedioxy) benzene (2.2 mL, 18 mmol) in de-gassed THF (50 mL) was cooled to -78°C and n- BuLi (11.3 mL of 1.6M soln, 1.2 equ) was added. After stirring for 50 min at -50°C, a solution of N-methoxy-N-methylchloroacetamide 3b (2.06 g, 15 mmol) in de-gassed THF (14 mL) was slowly added, and the mixture was aged 1 h at -20°C. The mixture was transfeπed, via cannula, into cold (0°C), de-gassed aq. 2N HCl (37.5 mL, 5.0 equ), diluted with ethyl acetate (20 mL), and the layers were separated. The organic layer was washed with brine (20 mL), dried (MgS04), filtered and concentrated to give the product in 76% yield. IH NMR (CDC13, 300 MHz) 94.62 (s, 2H), 6.06 (s, 2H), 6.86 (d, IH, J=8.1 Hz), 7.41 (d, IH, J=1.8Hz), 7.54 (m, IH; 13 C NMR (CDC13) 945.76, 102.16, 108.17, 108.26, 125.08, 128.91, 148.49, 152.59, 189.28. EXAMPLES 3 TO 5 Following the procedures of Examples 1 and 2 using the reagents listed in Table 1, the coπesponding product was produced. 1. Isolated yield after chromatography; 2. Yields in brackets conespond to reactions involving organolithium reagents; 3. Reaction canied out at -10°C for 45 min. - 14 - produce α -monochloro ketones in high yield. The ability to recycle the N,0-dimethylnydroxylamine in a highly efficient manner increases cost effectiveness and makes this procedure particularly attractive for large scale synthesis. EXAMPLE 7 Preparation of N-methoxy-N-methylchloroacetamide (3b). To a cold (0°C), stined solution of K2CO3 (62.4 g, 450 mmol) in H2O (250 mL) was added, successively, N,0- dimethylhydroxylamine hydrochloride (20 g, 205 mmol) and organic solvent (250 mL, toluene or MTBE). The resulting two phase mixture was cooled to -5°C and chloroacetyl chloride (19.6 ml, 246 mmol) was added over 5 min (solution temperature maintained below 0 β C). The vigorously stined mixture was allowed to warm to 15 β C over 30 min, the layers were separated, and the aqueous layer was extracted with organic solvent (3x100 mL, toluene or MTBE). The combined organic extracts were concentrated (MTBE used as solvent) to give the amide 3b (26.8 g, 95%) as a white solid. Alternatively, the combined organic extracts (toluene used as solvent) were concentrated to 250 mL to effect azeotropic drying (water content lOOμg/mL) and the solution of 3b was used directly in reactions with organometallic reagents. EXAMPLE 6 A solution of phenyl acetylene (2.0 mL, 18 mmol) in de¬ gassed THF (30 mL) was cooled to -78°C and n-BuLi (11.3 mL of 1.6M soln, 1.5 equ) was added. After stirring for 20 min, the solution was allowed to warm to -20°C. A solution of N-methoxy-N- methylchloroacetamide 3b (1.65 g, 12 mmol) in de-gassed THF (13 mL) was slowly added, and the mixture was aged 15 min at -20°C followed by 45 min at -10°C. The mixture was transfened, via cannula, into cold (0°C), de-gassed aq. 2N HCl (35 mL, 5.8 equ), diluted with ethyl acetate (10 mL), and the layers were separated. The organic layer was washed with brine (20 mL), dried (MgS04), filtered and concentrated. After silica gel chromatography (97:3 hexanes:ethyl acetate), the compound was isolated in 86% yield. ^H NMR (CVDcl3, 300 MHz) 94.33 (s, 2H), 7.41 (m, 2H), 7.51 (m, IH), 7.62 (m, 2H); 13c NMR (CDC13) 49.53, 85.55, 95.40, 119.22, 128.79 (2C), 131.46, 133.40 (2C), 178.89. We have extended this chemistry to the preparation of α- monofluoro ketones via reaction of organometallic reagents with N- methoxy-N-methylfluoroacetamide (5). For example, phenacyl fluoride (6) was prepared in 88% yield via reaction of 5 with phenylmagnesium bromide. Many other extensions of this chemistry should be possible. In summary, we have described a practical synthesis of N- methoxy-N-methylchloroacetamide 3b and have shown that this compound reacts cleanly with Grignard and organolithium reagents to - 16 - comprising compound of formula I and an aqueous solvent phase comprising compound of formula III' HNRCOR^-G III * 2. A process according to Claim 1 wherein Y is chloro and acid G is selected from the group consisting of hydrochloric, hydrobromic, sulfuric, methanesulfonic, toluensulfonic, phosphoric acid. 3. A process according to Claim 1 wherein the organic aprotie solvent is selected from the group consisting of diethyl ether, di¬ n-butyl and di-isopentyl ethers, anisole, cyclic ethers such as tetrahydropyran, 4-methyl- 1,3-dioxane, tetrahydrofurfuryl methyl ether, ethyl ether, furan, and tetrahydrofuran or a mixture thereof. 4. A process according to Claim 1 wherein the carbon ile A is an optionally substituted: (1) phenyl, (2) 3,4-dimethoxyphenyl, (3) benzofuranyl, (4) furanyl, (5) imidazolyl, (6) indolyl, (7) isothiazolyl, (8) pyrazinyl, (9) pyrazolyl, (10) pyridyl, (11) pyrimidyl, (12) pyrrolyl, (13) thiazolyl, (14) thienyl,

Claims: WHAT IS CLAIMED IS: 1. A process of making an α-chloro or fluoro ketone of the formula I Ύ O I wherein Y is chloro or fluoro and A is a carbon nucleophile, comprising: (a) reacting an organometallic reagent of formula II A-M II wherein M is Li or Mg, with a compound of formula III JL. Ill wherein X is -NR(0R!) R and Rl are each independently linear or branched Cl-3 alkyl, C3-6cycloalkyl, or optionally substituted with Cl-3alkoxy, phenyl, substituted phenyl, wherein the substituent on the phenyl is selected from F, Cl, Br, methylthio, -OH, methoxy, aminothio, and Cl-3 alkyl in an organic aprotie solvent, and (b) reacting, without further purification, the product of step (a) with an aqueous solution of acid G, to yield an organic aprotie solvent phase 18 - I the compound of formula II is II and X is -NCH3(OCH3). 8. A process making a compound of formula III <>x l« wherein X is -NR(ORI), Y is chloro or fluoro and R and Rl are each independently linear or branched Cl-3 alkyl, C3-6cycloalkyl, or optionally substituted with Cl-3alkoxy, phenyl, subtstituted phenyl, wherein the substituent on the phenyl is selected from F, Cl, Br, methylthio, -OH, methoxy, aminothio, and Cl-3 alkyl, comprising acylating HNR(ORl) hydrochloride with chloroacetyl chloride in a two phase mixture of aqueous base and a non-reactive water insoluble organic solvent to yield a compound of formula III. 9. A process according to Claim 8 wherein Y is chloro and the base is selected from the group consisting of pyridine, tri-Cl-3 alkylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bi-carbonate, postassium carbonate and postassium bi- carbonate. 10. A process according to Claim 8 wherein R and Rl are each independently linear or branched Cl-3alkyl, C3-6cycloalkyl, or optionally substituted with Cl-3alkoxy, phenyl, substituted phenyl, (15) triazolyl, (16) Cl-10 alkyl, (17) C2-3alkenyl (18) C2-3alkynyl, wherein the substitutent is selected from F, Cl, Br, methylthio, -OH, methoxy, aminothio, Cl-3 alkyl, C2-3alkenyl or C2-3alkynyl. 5. A process according to Claim 4 wherein the carbon nucleophile is an optionally substituted: (1 ) phenyl, (2) 3,4-dimethoxyphenyl, (3) benzofuranyl, (4) thienyl, (5) Cl-io alkyl, (6) C2-3alkenyl (7) C2-3alkynyl, wherein the substitutent is selected from F, Cl, Br, methylthio, -OH, methoxy, aminothio and Cl-3 alkyl. 6. A process according to Claim 1 wherein R and Rl are each selected from linear or branched Cl-3alkyl, C3-6cycloalkyl, or optionally substituted with Cl-3alkoxy, phenyl, substituted phenyl, wherein the substituent on the phenyl is selected from F, Cl, Br, methylthio, -OH, methoxy, aminothio, and Cl-3 alkyl. 7. A process according to Claim 1 wherein the compound of formula I is MeS - 20 - hydrobromic, sulfuric, methanesulfonic, toluenesulfonic, phosphoric acid. 14. A process according to Claim 12 wherein R and Rl are each independently linear or branched Cl-3alkyl, C3-6cycloalkyl, or optionally substituted with Cl-3alkoxy, phenyl, substituted phenyl, wherein the substituent on the phenyl is selected from F, Cl, Br, methylthio, -OH, methoxy, aminothio, and Cl-3alkyl. 15. A process of making an α-chloro or fluoro ketone of the formula I l Υ^ I wherein Y is chloro or fluoro and A is a carbon nucleophile, comprising: (a) reacting an organometallic reagent of formula II A-M II wherein M is Li or Mg, with a compound of formula III III wherein X is -NR(ORl) R and R are each independently linear or branched Cl-3 alkyl, wherein the substituent on the phenyl is selected from F, Cl, Br, methylthio, -OH, methoxy, aminothio, and Cl-3alkyl. 11. A process according to Claim 8 wherein the non- reactive water insoluble organic solvent includes, but is not limited to toluene, methyl t-butyl ether, hexane, heptane, methylene chloride, dichloroethane, dichlorobenzene, monochlorobenzene or a mixture thereof. 12. A process of making a compound of formula III III wherein X is -NR(ORI), Y is chloro or fluoro and R and R are each independently linear or branched Cl-3 alkyl, C3-6cycloalkyl, or optionally substituted with Cl-3alkoxy, phenyl, subtstituted phenyl, wherein the substituent on the phenyl is selected from F, Cl, Br, methylthio, -OH, methoxy, aminothio, and Cl-3 alkyl, comprising separating from the product of reaction step (b) the aqueous solvent phase according to Claim 1, said aqueous solvent phase comprising a compound of formula III' UNR(OR l )»G III' wherein G is an acid, and reacting, without further purification, the aqueous solvent phase with chloroacetyl chloride in a bi-phasic mixture of aqueous K2CO3 and MTBE or toluene, to yield compound of formula III. 13. A process according to Claim 12 wherein Y is chloro and acid G is selected from the group consisting of hydrochloric, C3-6cycloalkyl, or optionally substituted with Cl-3alkoxy, phenyl, subtstituted phenyl, wherein the substituent on the phenyl is selected from F, Cl, Br, methylthio, -OH, methoxy, aminothio, and Cl-3 alkyl in an organic aprotie solvent, and (b) reacting, without further purification, the product of step (a) with an aqueous solution of acid G, to yield an organic aprotie solvent phase comprising compound of formula I and an aqueous solvent phase comprising compound of formula III' HNR R^-G: III' separating the organic phase to obtain a Compound of formula I and acylating the aqueous phase containing HNR(ORl) hydrochloride with chloroacetyl chloride in a two phase mixture of aqueous base and a non¬ reactive water insoluble organic solvent to yield a compound of formula III where the two phase mixture is recycled and reacted with a compound of formula II to continuously repeat the preparation of the compound of formula I.

Inventors: DOLLING ULF H, FREY LISA F, TILLYER RICHARD D, TSCHAEN DAVID M, DOLLING, ULF, H., FREY, LISA, F., TILLYER, RICHARD, D., TSCHAEN, DAVID, M.
Applicants: DOLLING ULF H, FREY LISA F, MERCK & CO INC, TILLYER RICHARD D, TSCHAEN DAVID M, DOLLING, ULF, H., FREY, LISA, F., MERCK & CO., INC., TILLYER, RICHARD, D., TSCHAEN, DAVID, M.
Application year: 1996
Main classification: C07C45
IPC codes: C07C45, C07C259, C07C319, C07C323, C07D317, C07D333