WO1993023370A1 - Process for the preparation of fluoromethyl thio benzenes - Google Patents
Process for the preparation of fluoromethyl thio benzenes Download PDFInfo
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- WO1993023370A1 WO1993023370A1 PCT/US1993/003025 US9303025W WO9323370A1 WO 1993023370 A1 WO1993023370 A1 WO 1993023370A1 US 9303025 W US9303025 W US 9303025W WO 9323370 A1 WO9323370 A1 WO 9323370A1
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- acetonitrile
- ethylene glycol
- fluoride
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- 238000000034 method Methods 0.000 title claims abstract description 26
- ZDJQWFUQFDIBLS-UHFFFAOYSA-N fluoromethylsulfanylbenzene Chemical class FCSC1=CC=CC=C1 ZDJQWFUQFDIBLS-UHFFFAOYSA-N 0.000 title abstract description 11
- 238000002360 preparation method Methods 0.000 title abstract description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 51
- -1 poly(ethylene glycol) Polymers 0.000 claims abstract description 30
- 239000001257 hydrogen Substances 0.000 claims abstract description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 12
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 12
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 10
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 claims abstract description 10
- 125000006575 electron-withdrawing group Chemical group 0.000 claims abstract description 10
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 9
- 150000002367 halogens Chemical group 0.000 claims abstract description 9
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims abstract description 6
- 239000002904 solvent Substances 0.000 claims abstract description 6
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 claims description 18
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 claims description 10
- 239000000460 chlorine Chemical group 0.000 claims description 5
- 229910052801 chlorine Chemical group 0.000 claims description 5
- 235000003270 potassium fluoride Nutrition 0.000 claims description 5
- 239000011698 potassium fluoride Substances 0.000 claims description 5
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 4
- 229940127395 Ribonucleotide Reductase Inhibitors Drugs 0.000 abstract description 2
- 150000002431 hydrogen Chemical group 0.000 abstract 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 239000000284 extract Substances 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 239000012141 concentrate Substances 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
- 150000003457 sulfones Chemical class 0.000 description 6
- DENHPZASLKBBHA-UHFFFAOYSA-N fluoromethylsulfonylbenzene Chemical compound FCS(=O)(=O)C1=CC=CC=C1 DENHPZASLKBBHA-UHFFFAOYSA-N 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- VVPUIKNICYCXJZ-UHFFFAOYSA-N 4-iodobutyl benzoate Chemical compound ICCCCOC(=O)C1=CC=CC=C1 VVPUIKNICYCXJZ-UHFFFAOYSA-N 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 239000005909 Kieselgur Substances 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 238000010936 aqueous wash Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical compound [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 description 2
- 239000011877 solvent mixture Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- XPJUCMIJGVAEGF-UHFFFAOYSA-N 1-chloro-4-(chloromethylsulfanyl)benzene Chemical compound ClCSC1=CC=C(Cl)C=C1 XPJUCMIJGVAEGF-UHFFFAOYSA-N 0.000 description 1
- JMWLQGNTPBIYIE-UHFFFAOYSA-N 1-chloro-4-(fluoromethylsulfanyl)benzene Chemical compound FCSC1=CC=C(Cl)C=C1 JMWLQGNTPBIYIE-UHFFFAOYSA-N 0.000 description 1
- XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- 238000000023 Kugelrohr distillation Methods 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 239000012425 OXONE® Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- LTYMSROWYAPPGB-UHFFFAOYSA-N diphenyl sulfide Chemical compound C=1C=CC=CC=1SC1=CC=CC=C1 LTYMSROWYAPPGB-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- YACKEPLHDIMKIO-UHFFFAOYSA-N methylphosphonic acid Chemical compound CP(O)(O)=O YACKEPLHDIMKIO-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 125000005440 p-toluyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C(*)=O)C([H])([H])[H] 0.000 description 1
- FHHJDRFHHWUPDG-UHFFFAOYSA-L peroxysulfate(2-) Chemical compound [O-]OS([O-])(=O)=O FHHJDRFHHWUPDG-UHFFFAOYSA-L 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- OKBMCNHOEMXPTM-UHFFFAOYSA-M potassium peroxymonosulfate Chemical compound [K+].OOS([O-])(=O)=O OKBMCNHOEMXPTM-UHFFFAOYSA-M 0.000 description 1
- 235000013024 sodium fluoride Nutrition 0.000 description 1
- 239000011775 sodium fluoride Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
- C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
Definitions
- the present invention relates to a novel process for the preparation of an important intermediate used in the preparation of ribonucleotide reductase inhibitors.
- the novel process of the present invention utilizes starting material of structure (A)
- Y is chlorine, bromine or iodine
- X is a hydrogen or a suitable electron withdrawing group
- R 1 and R 2 are each independently hydrogen, halogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy.
- the present invention provides a novel process for preparing a compound of formula
- X is a hydrogen or a suitable electron withdrawing group and R 1 and R 2 are each independently hydrogen, halogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy comprising reacting a compound of the formula
- Y is a halogen with a fluoride
- ion source in a solvent comprising from about 20% to about
- C 1 -C 4 alkyl refers to a saturated straight or branched chain hydrocarbon radical of one to four carbon atoms. Included within the scope of this term are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and the like.
- Ar or "aryl” refers to an aromatic radical of from about 6 to 12 carbon atoms, such as phenyl, napnthyl or phenyl (C 1 -C 4 )alkyl groups, wherein said groups are optionally substituted with one, two or three
- C 1 -C 4 alkyl refers to a phenyl group substituted with a C 1 -C 4 alkyl including phenylmethyl, phenethyl and the like.
- Ar or "aryl” are phenyl, p-toluyl, naphthyl, p-chlorophenyl and the like.
- C 1 -C 4 alkoxy refers to an alkyloxy radical made up of an oxygen radical bearing a saturated straight or branched chain hydrocarbyl radical of one to four carbon atoms and
- halo refers to a chlorine, bromine, or iodine atom.
- X hydrogen or an electron withdrawing group
- step a the appropriately substituted halomethyl phenyl sulfide (A) wherein X is hydrogen or a suitable electron withdrawing group is dissolved in a solvent mixture of a suitable concentration of an
- Preferred suitable electron withdrawing groups are CO 2 Me, CO 2 Et, CO 2 Bu t , CONMe 2 , CONEt 2 , PO(OMe) 2 , PO(OEt) 2 , PO(OC 6 H 5 ) 2 and the like.
- the most preferred suitable electron withdrawing group is PO(OEt) 2 .
- An appropriate poly(ethylene glycol) should have a
- the preferred molecular weight for an appropriate poly (ethylene glycol) is about 200 g/mol.
- a suitable concentration of poly (ethylene glycol) in acetonitrile should fall between about 20% and 95%. The preferred concentration of
- poly (ethylene glycol) in acetonitrile is about 33%.
- the solution is then reacted with a fluoride ion source at about 20°C to 100°C for about 0.5 hours to 24 hours to provide the fluoromethyl phenyl sulfide of Formula I.
- a fluoride ion source is one that when placed in
- Fluoride ion sources are cesium fluoride, potassium fluoride, sodium fluoride, tetrabutylammonium fluoride and the like.
- the preferred fluoride ion source is cesium fluoride.
- the appropriately substituted halomethyl phenyl sulfide (A) is dissolved in a solvent mixture of 33% poly(ethylene glycol)-200 in acetonitrile.
- the solution is treated with excess cesium fluoride and heated to approximately 80°C for about 1.75 hours.
- the fluoromethyl phenyl sulfide of Formula I is isolated by techniques well known to one skilled in the art. For example, water is added to the cooled solution which is then extracted with a suitable organic solvent such as chloroform. The organic extracts are dried over a suitable drying agent such as anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide the fluoromethyl phenyl sulfide of Formula I.
- step b the fluoromethyl phenyl sulfide of Formula I is then oxidized to fluoromethyl phenyl sulfone (B) by techniques well known to one skilled in the art.
- fluoromethyl phenyl sulfide of Formula I is dissolved in a suitable organic solvent, such as methanol, cooled to approximately 0°C and an excess of potassium
- the fluoromethyl phenyl sulfone (B) is isolated and purified by techniques well known to one skilled in the art. For example, the solvent is removed under vacuum and the resulting slurry suction filtered through diatomaceous earth, rinsing with chloroform. The organic phase is separated from the aqueous phase. The aqueous phase is then extracted with additional chloroform and the combined organic extracts are dried over anhydrous magnesium
- TLC refers to thin layer chromatography
- mg refers to milligrams
- ⁇ L refers to microliters
- ⁇ refers to parts per million downfield from tetramethlysilane.
- step a Flush a 3 neck 100 mL round bottom flask with nitrogen and charge with chloromethyl phenyl sulfide (9.9 g, 62.4 mmol), cesium fluoride (19.1 g, 126 mmol) and a mixture of poly(ethylene glycol)-200 and acetonitrile (38 mL of in a 1:2 ratio). Heat the reaction to 80°C with stirring for 1.75 hours. Then cool the reaction and dilute with water (125 mL). Extract the reaction with chloroform (2 ⁇ 125 mL), combine the organic extracts, wash with water (50 mL) and dry over anhydrous magnesium sulfate. Filter and concentrate under vacuum to yield the title compound as a yellow oil. The sulfide should be stored at low
- step b Dissolve the fluoromethyl phenyl sulfide prepared above in methanol (85 mL) and cool to 0°C. Add a solution of potassium peroxymonosulfate (38.9 g, 63.3 mmol in 85 mL water) slowly with stirring at 0°C.
- methanol 85 mL
- potassium peroxymonosulfate 38.9 g, 63.3 mmol in 85 mL water
- step a Heat a mixture of chloromethyl phenyl sulfide (1.6 g, 10 mmol), potassium fluoride (1.6 g, 27 mmol) and a mixture of poly(ethylene glycol)-200 and acetonitrile ( 6 mL in a 1:2 ratio) to a gentle reflux for 24 hours. Cool the reaction and dilute with diethyl ether (50 mL). Rinse the organic with water (2 ⁇ 50 mL) and saturated sodium bicarbonate (50 mL). Back extract the combined aqueous washes with diethyl ether (50 mL) and combine the organic extracts. Dry over anhydrous potassium carbonate, filter and concentrate to provide the title compound (1.9 g).
- the sulfone can be prepared by following essentially the same procedure as described in example 2.
- step a Heat a mixture of diethyl 1-chloro-1- (phenylsulfide)methanephosphonate (200 mg, 0.68 mmol), cesium fluoride (310 mg, 2 mmol) and a mixture of
- the sulfone can be prepared by following essentially the same procedure as described in example 2.
- step a Heat a mixture of diethyl 1-chloro-1-(phenylsulfide)methanephosphonate (200 mg, 0.68 mmol), potassium fluoride (230 mg, 4 mmol) and a mixture of poly(ethylene glycol)-200 and acetonitrile ( 4 mL in a 1:2 ratio) to 80°C for 6 hours. Cool the reaction and dilute with diethyl ether (50 mL). Rinse the organic with water (2 ⁇ 50 mL) and saturated sodium bicarbonate (50 mL). Back extract the combined aqueous washes with diethyl ether (50 mL) and combine the organic extracts. Dry over anhydrous potassium carbonate, filter and concentrate to provide the title compound.
- the sulfone can be prepared by following essentially the same procedure as described in example 2.
- step a Heat a mixture of chloromethyl p-chlorophenyl sulfide (1 g, 5.2 mmol), cesium fluoride (1.55 g, 10.4 mmol) and a mixture of poly(ethyleneglycol)-200 and acetonitrile ( 5 mL in a 1:2 ratio) to 80°C for 1 hour.
- the sulfone can be prepared by following essentially the same procedure as described in example 2.
- step a Heat a mixture of diethyl 1-chloro-1-(p-chlorophenylsulfide)methanephosphonate (0.68 mmol) which can be prepared according to Kim et al. [Tetrahedron Lett. 1985, 26, 3479], cesium fluoride (310 mg, 2 mmol) and a mixture of poly(ethylene glycol)-200 and acetonitrile (4 mL in a 1:2 ratio) to 80°C for approximately 1 hour. Cool the reaction and dilute with water and methylene chloride.
- the sulfone can be prepared by following essentially the same procedure as described in example 2.
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Abstract
This present invention is directed towards a novel process to prepare optionally substituted fluoromethyl phenyl sulfides (I) for use as intermediates in the preparation of ribonucleotide reductase inhibitors. In formula (I) X is a hydrogen or a suitable electron withdrawing group and R1 and R2 are each independently hydrogen, halogen, C1-C4 alkyl or C1-C4 alkoxy. The preparation comprises reacting a compound of formula (A) wherein Y is halogen with a fluoride ion source in a solvent comprising from about 20 % to about 95 % poly(ethylene glycol) in acetonitrile.
Description
PROCESS FOR THE PREPARATION OF FLUOROMETHYL THIO BENZENES
BACKGROUND OF THE INVENTION
The present invention relates to a novel process for the preparation of an important intermediate used in the preparation of ribonucleotide reductase inhibitors. A process for the preparation of several of these
intermediates was disclosed by Wemple et al. [Synthesis
1977, 791] which employs a fairly exotic and expensive reagent with extended reaction times under harsh conditions. More specifically, chloromethyl phenyl sulfide is treated with 18-crown-6 and potassium fluoride in acetonitrile at reflux for 100 hours to provide an 83% yield of fluoromethyl phenyl sulfide.
The novel process of the present invention utilizes starting material of structure (A)
SUMMARY OF THE INVENTION
The present invention provides a novel process for preparing a compound of formula
wherein X is a hydrogen or a suitable electron withdrawing group and R1 and R2 are each independently hydrogen, halogen, C1-C4 alkyl or C1-C4 alkoxy comprising reacting a compound of the formula
ion source in a solvent comprising from about 20% to about
95% poly(ethylene glycol) in acetonitrile.
DETAILED DESCRIPTION OF TEE INVENTION
As used herein the term "C1-C4 alkyl" refers to a saturated straight or branched chain hydrocarbon radical of one to four carbon atoms. Included within the scope of this term are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and the like. The term "Ar" or "aryl" refers to an aromatic radical of from about 6 to 12 carbon atoms, such as phenyl, napnthyl or phenyl (C1-C4)alkyl groups, wherein said groups are optionally substituted with one, two or three
substituents selected from the group consisting of C1-C4 alkyl, halo-substituted C1-C4 alkyl, halogen or C1-C4 alkoxy. The term "phenyl (C^Cj)alkyl" refers to a phenyl group substituted with a C1-C4 alkyl including phenylmethyl, phenethyl and the like. Specifically included within the scope of the term "Ar" or "aryl" are phenyl, p-toluyl, naphthyl, p-chlorophenyl and the like. The term " C1-C4 alkoxy" refers to an alkyloxy radical made up of an oxygen radical bearing a saturated straight or branched chain hydrocarbyl radical of one to four carbon atoms and
specifically includes methoxy, ethoxy, propyloxy,
isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy,
tertiary butyloxy and the like. The term "halogen" or
"halo" refers to a chlorine, bromine, or iodine atom.
The general synthetic process of the present invention is set forth in Scheme A. All the substituents, unless otherwise indicated, are previously defined. The reagents and starting materials for use in this process are readily available to one of ordinary skill in the art.
X= hydrogen or an electron withdrawing group
Y=Cl, Br or I
In Scheme A, step a, the appropriately substituted halomethyl phenyl sulfide (A) wherein X is hydrogen or a suitable electron withdrawing group is dissolved in a solvent mixture of a suitable concentration of an
appropriate poly(ethylene glycol) and acetonitrile. An electron withdrawing group as described by March ["Advanced Organic Chemistry: Reactions, Mechanisms and Structure", McGraw-Hill Book Company, 2nd Ed., 1977, 21] is one that will draw electrons to itself more than a hydrogen atom would if it was in the same position. Examples of suitable electron withdrawing groups are CO2R, CON(R)2, PO(OR)2, CN, NO2 and the like, wherein R is a C1 -C4 alkyl or a
substituted phenyl group. Preferred suitable electron withdrawing groups are CO2Me, CO2Et, CO2But, CONMe2, CONEt2,
PO(OMe)2, PO(OEt)2, PO(OC6H5)2 and the like. The most preferred suitable electron withdrawing group is PO(OEt)2. An appropriate poly(ethylene glycol) should have a
molecular weight between about 100 and 400 g/mol. The preferred molecular weight for an appropriate poly (ethylene glycol) is about 200 g/mol. A suitable concentration of poly (ethylene glycol) in acetonitrile should fall between about 20% and 95%. The preferred concentration of
poly (ethylene glycol) in acetonitrile is about 33%. The solution is then reacted with a fluoride ion source at about 20°C to 100°C for about 0.5 hours to 24 hours to provide the fluoromethyl phenyl sulfide of Formula I. A fluoride ion source is one that when placed in
poly(ethylene glycol/acetonitrile mixture will sufficiently dissolve so as to produce dissociated negatively charged fluoride ions. Fluoride ion sources are cesium fluoride, potassium fluoride, sodium fluoride, tetrabutylammonium fluoride and the like. The preferred fluoride ion source is cesium fluoride.
More specifically, the appropriately substituted halomethyl phenyl sulfide (A) is dissolved in a solvent mixture of 33% poly(ethylene glycol)-200 in acetonitrile. The solution is treated with excess cesium fluoride and heated to approximately 80°C for about 1.75 hours. After cooling, the fluoromethyl phenyl sulfide of Formula I is isolated by techniques well known to one skilled in the art. For example, water is added to the cooled solution which is then extracted with a suitable organic solvent such as chloroform. The organic extracts are dried over a suitable drying agent such as anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide the fluoromethyl phenyl sulfide of Formula I.
In Scheme A, step b, the fluoromethyl phenyl sulfide of Formula I is then oxidized to fluoromethyl phenyl sulfone (B) by techniques well known to one skilled in the art.
For example, the appropriately substituted
fluoromethyl phenyl sulfide of Formula I is dissolved in a suitable organic solvent, such as methanol, cooled to approximately 0°C and an excess of potassium
peroxymonosulfate dissolved in water is slowly added to the reaction. After stirring for approximately 4 hours the fluoromethyl phenyl sulfone (B) is isolated and purified by techniques well known to one skilled in the art. For example, the solvent is removed under vacuum and the resulting slurry suction filtered through diatomaceous earth, rinsing with chloroform. The organic phase is separated from the aqueous phase. The aqueous phase is then extracted with additional chloroform and the combined organic extracts are dried over anhydrous magnesium
sulfate, filtered and concentrated under vacuum. The residue can be purified by distillation to provide the fluoromethyl phenyl sulfone (B).
The following examples present typical syntheses as described by Scheme A. These examples are understood to be illustrative only and are not intended to limit the scope of the invention in any way. As used in the following examples, the following terms have the meanings indicated: "g" refers to grams, "mmol" refers to millimoles, "mL" refers to milliliters, "ºC" refers to degrees Celsius,
"TLC" refers to thin layer chromatography, "mg" refers to milligrams, "μL" refers to microliters and "δ" refers to parts per million downfield from tetramethlysilane.
Example 1
Scheme A, step a; Flush a 3 neck 100 mL round bottom flask with nitrogen and charge with chloromethyl phenyl sulfide (9.9 g, 62.4 mmol), cesium fluoride (19.1 g, 126 mmol) and a mixture of poly(ethylene glycol)-200 and acetonitrile (38 mL of in a 1:2 ratio). Heat the reaction to 80°C with stirring for 1.75 hours. Then cool the reaction and dilute with water (125 mL). Extract the reaction with chloroform (2 × 125 mL), combine the organic extracts, wash with water (50 mL) and dry over anhydrous magnesium sulfate. Filter and concentrate under vacuum to yield the title compound as a yellow oil. The sulfide should be stored at low
temperature or immediately oxidized to the sulfone as it will rapidly polymerize at room temperature.
Example 2
Scheme A, step b; Dissolve the fluoromethyl phenyl sulfide prepared above in methanol (85 mL) and cool to 0°C. Add a solution of potassium peroxymonosulfate (38.9 g, 63.3 mmol in 85 mL water) slowly with stirring at 0°C. The
temperature will increase to approximately 55°C. Cool the reaction to room temperature and allow to stir for an additional 4 hours. Then concentrate the reaction under vacuum and suction filter the remaining slurry through diatomaceous earth (10 g) rinsing with chloroform (150 mL). Separate the aqueous layer of the filtrate and extract with additional chloroform (2 × 100 mL). Combine the organic extracts, dry over anhydrous magnesium sulfate, filter and concentrate under vacuum. Purify the residue by Kugelrohr distillation (115-132°C/ ≥1mmHg). The distillate will crystallize upon cooling. Rinse the crystals with hexane and dry under vacuum to provide the title compound (7.6 g, 70% overall yield for steps a and b), mp 47-48.5°C.
Example 3
Fluoromethyl phenyl sulfide
Scheme A, step a; Heat a mixture of chloromethyl phenyl sulfide (1.6 g, 10 mmol), potassium fluoride (1.6 g, 27 mmol) and a mixture of poly(ethylene glycol)-200 and acetonitrile ( 6 mL in a 1:2 ratio) to a gentle reflux for 24 hours. Cool the reaction and dilute with diethyl ether (50 mL). Rinse the organic with water (2 × 50 mL) and saturated sodium bicarbonate (50 mL). Back extract the combined aqueous washes with diethyl ether (50 mL) and combine the organic extracts. Dry over anhydrous potassium carbonate, filter and concentrate to provide the title compound (1.9 g). The sulfone can be prepared by following essentially the same procedure as described in example 2.
Example 4
Scheme A, step a; Heat a mixture of diethyl 1-chloro-1- (phenylsulfide)methanephosphonate (200 mg, 0.68 mmol), cesium fluoride (310 mg, 2 mmol) and a mixture of
poly (ethylene glycol)-200 and acetonitrile (4 mL in a 1:2 ratio) to 80°C for 0.5 hours. Cool the reaction and dilute
with water and methylene chloride. Separate the layers and dry the organic phase over anhydrous magnesium sulfate, filter and concentrate the provide the title compound. The sulfone can be prepared by following essentially the same procedure as described in example 2.
Example 5
Scheme A, step a; Heat a mixture of diethyl 1-chloro-1-(phenylsulfide)methanephosphonate (200 mg, 0.68 mmol), potassium fluoride (230 mg, 4 mmol) and a mixture of poly(ethylene glycol)-200 and acetonitrile ( 4 mL in a 1:2 ratio) to 80°C for 6 hours. Cool the reaction and dilute with diethyl ether (50 mL). Rinse the organic with water (2 × 50 mL) and saturated sodium bicarbonate (50 mL). Back extract the combined aqueous washes with diethyl ether (50 mL) and combine the organic extracts. Dry over anhydrous potassium carbonate, filter and concentrate to provide the title compound. The sulfone can be prepared by following essentially the same procedure as described in example 2.
Example 6
Scheme A, step a; Heat a mixture of chloromethyl p-chlorophenyl sulfide (1 g, 5.2 mmol), cesium fluoride (1.55 g, 10.4 mmol) and a mixture of poly(ethyleneglycol)-200 and acetonitrile ( 5 mL in a 1:2 ratio) to 80°C for 1 hour.
Cool the reaction and dilute with water and methylene chloride. Separate the layers and dry the organic phase over anhydrous magnesium sulfate. Filter and concentrate to provide the title compound. The sulfone can be prepared by following essentially the same procedure as described in example 2.
Example 7
Diethyl 1-fluoro-1-(p-chlorophenylsulfide)
methanephosphonate
Scheme A, step a; Heat a mixture of diethyl 1-chloro-1-(p-chlorophenylsulfide)methanephosphonate (0.68 mmol) which can be prepared according to Kim et al. [Tetrahedron Lett. 1985, 26, 3479], cesium fluoride (310 mg, 2 mmol) and a mixture of poly(ethylene glycol)-200 and acetonitrile (4 mL in a 1:2 ratio) to 80°C for approximately 1 hour. Cool the reaction and dilute with water and methylene chloride.
Separate the layers and dry the organic phase over
anhydrous magnesium sulfate, filter and concentrate the provide the title compound. The sulfone can be prepared by following essentially the same procedure as described in example 2.
Claims
1. A process for preparing compounds of formula
wherein X is a hydrogen or a suitable electron withdrawing group and R1 and R2 are each independently hydrogen, halogen, C1-C4 alkyl or C1-C4 alkoxy comprising reacting a compound of the formula
wherein Y is halogen with a fluoride
ion source in a solvent comprising from about 20% to about
95% poly(ethylene glycol) in acetonitrile.
2. A process according to claim 1 wherein X is PO(OR3)2 and R3 is C1-C4 alkyl or aryl.
3. A process according to claim 1 wherein cesium fluoride is the fluoride ion source.
4. A process according to claim 1 wherein potassium fluoride is the fluoride ion source.
5. A process according to claim 1 wherein the solvent comprises about 33% poly (ethylene glycol) in acetonitrile.
6. A process according to claim 1 wherein R1 and R2 are each independently hydrogen or methyl.
7. A process according to claim 1 wherein R1 and R2 are each independently hydrogen or chlorine.
8. A process according to claim 2 wherein X is
PO(OEt)2.
9. A process according to claim 8 wherein Y is
chlorine.
10. A pϊocess according to claim 9 wherein cesium fluoride is the fluoride ion source.
11. A process according to claim 10 wherein the solvent comprises about 33% poly(ethylene glycol) in acetonitrile.
12. A process according to claim 11 wherein wherein R2 and R2 are each hydrogen.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US88194792A | 1992-05-12 | 1992-05-12 | |
| US881,947 | 1992-05-12 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1993023370A1 true WO1993023370A1 (en) | 1993-11-25 |
Family
ID=25379543
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US1993/003025 WO1993023370A1 (en) | 1992-05-12 | 1993-04-01 | Process for the preparation of fluoromethyl thio benzenes |
Country Status (2)
| Country | Link |
|---|---|
| AU (1) | AU3971793A (en) |
| WO (1) | WO1993023370A1 (en) |
-
1993
- 1993-04-01 AU AU39717/93A patent/AU3971793A/en not_active Abandoned
- 1993-04-01 WO PCT/US1993/003025 patent/WO1993023370A1/en active Application Filing
Non-Patent Citations (4)
| Title |
|---|
| CHAMBERS R D 'Fluorine in Organic Chemistry' 1973 , WILEY , NEW YORK * |
| CHEMICAL ABSTRACTS, vol. 89, no. 15, 1978, Columbus, Ohio, US; abstract no. 129193, T KITAZUME ET AL 'Fluorination of activted halogens with potassium fluoride in polyethylene glycol-acetonitrile system' page 561 ;column 1 ; * |
| JOURNAL OF THE AMERICAN CHEMICAL SOCIETY vol. 96, 1974, WASHINGTON D.C. pages 2250 - 2252 C L LIOTTA ET AL 'The Chemistry of "Naked" Anions. I. Reactions of the 18-Crown-6 Complex of Potassium Fluoride with Organic Substrates in Aprotic Organic Solvents' * |
| SYNTHESIS no. 11, 1977, STUTTGART pages 791 - 792 J WEMPLE ET AL 'The Synthesis of Aryl Fluoromethyl Sulfoxides' cited in the application * |
Also Published As
| Publication number | Publication date |
|---|---|
| AU3971793A (en) | 1993-12-13 |
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