Bromination of pyridine derivatives

Abstract

The present invention relates to a process for the preparation pyridine derivatives of the formula (I). ##STR00001##

Claims

1. A process for preparing a compound of formula I, ##STR00022## in which R.sup.1 is in each case independently selected from hydrogen, halogen, C.sub.1-C.sub.6-alkyl and C.sub.1-C.sub.6-halogenalkyl; R.sup.2 is in each case independently selected from hydrogen and halogen; R.sup.10 is in each case independently selected from H, halogen, O(R.sup.95), C.sub.1-C.sub.6-alkyl and C.sub.1-C.sub.6-halogenalkyl; wherein R.sup.95 is C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-halogenalkyl; comprising: (i) reacting a compound of formula II ##STR00023## wherein R.sup.1, R.sup.2 and R.sup.19 are as defined above with 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) in the presence of oleum 65%.

2. The process according to claim 1, wherein R.sup.1 and R.sup.2 are hydrogen, and R.sup.10 is C.sub.1-C.sub.6-alkyl.

3. The process according to claim 1, wherein R.sup.1 and R.sup.2 are hydrogen and R.sup.10 is CH.sub.3.

4. A process for preparing 2,3-disubstituted pyridine compounds of the formula III ##STR00024## wherein R.sup.1 is in each case independently selected from hydrogen, halogen, C.sub.1-C.sub.6-alkyl and C.sub.1-C.sub.6-halogenalkyl; R.sup.2 is in each case independently selected from hydrogen and halogen; R.sup.3, R.sup.4 are independently selected from C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.1-C.sub.6-halogenalkyl, C.sub.2-C.sub.6-halogenalkenyl and C.sub.2-C.sub.6-halogenalkynyl; R.sup.5 is halogen; R.sup.6 is halogen; R.sup.7, R.sup.6 together with the carbon atoms to which they are bound form a ring A, wherein the ring A is phenyl and wherein the ring A is substituent by (A.sup.76).sub.o, wherein is 0, 1, 2 or 3; and R.sup.78 is independently selected from halogen, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-halogenalkyl and C.sub.1-C.sub.6-halogenalkoxy; R.sup.10 is in each case independently selected from H, halogen, O(R.sup.95), C.sub.1-C.sub.6-alkyl and C.sub.1-C.sub.6-halogenalkyl; wherein R.sup.95 is C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-halogenalkyl; comprising: (i) providing a compound of the formula I by a process according to claim 1; (ii) reacting the compound of the formula I with a compound of the formula IV ##STR00025## in which R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are each as defined for formula III; and X is a metal ion.

5. The process according to claim 4, wherein R.sup.1 and R.sup.2 are hydrogen, R.sup.3 and R.sup.4 is C.sub.1-C.sub.6-alkyl, R.sup.5 and R.sup.6 are halogen, R.sup.7 and R.sup.8 form a phenyl, o is 0 and R.sup.10 is C.sub.1-C.sub.6-alkyl.

6. The process according to claim 4, wherein R.sup.1 and R.sup.2 are hydrogen, R.sup.3 and R.sup.4 are CH.sub.3, R.sup.5 and R.sup.6 are F, R.sup.7 and R.sup.8 form a phenyl, o is 0 and R.sup.10 is CH.sub.3.

7. The process according to claim 4, wherein X is selected from the group consisting of Li, Na, K, and Cs.

Description

EXAMPLE 1—BROMINATION OF 2,3-DIMETHYLPYRIDINE WITH DBDMH

(1) To a stirred solution of 2,3-dimethylpyridine (10 g, 0.09 mol) in oleum 65% (30 mL) at 10° C.

(2) DBDMH (14.5 g, 0.05 mol) was added. There after the exothermic reactions started. The reaction mixture was then heated at 105° C. for 2 h. After cooling to room temperature, the mixture was poured onto ice (150 g) and the ph adjusted to 12 with aqueous sodium hydroxide solution. The product was extracted into MTBE (3×100 mL), the organic phases were dried with MgSO.sub.4 and evaporated under reduced pressure to give 5-bromo-2,3-dimethylpyridine as yellow oil (Purity acc. to GC 87.3%; yield: 83.3%.

EXAMPLE 2—BROMINATION OF 2,3-DIMETHYLPYRIDINE WITH DBDMH

(3) To a stirred solution of 2,3-dimethylpyridine (20 g, 0.185 mol) in oleum 65% (60 mL) at 10° C. DBDMH (31.7 g, 0.11 mol) was added. There after the exothermic reactions started. The reaction mixture was then heated at 105° C. for 2 h. After cooling to room temperature, the mixture was poured onto ice (250 g) and the ph adjusted to 12 with aqueous sodium hydroxide solution. The product was extracted into MTBE (3×100 mL), the organic phases were dried with MgSO.sub.4 and evaporated under reduced pressure to give 5-bromo-2,3-dimethylpyridine as yellow oil (34.3 g). Purity acc. to GC 87.0%; yield: 86.7%.

EXAMPLE 3—ETHYL 3,3-DIMETHYL-4H-ISOQUINOLINE-1-CARBOXYLATE

(4) ##STR00014##

(5) At 15° C. a solution of 380 g (2.53 mol) 2-methyl-1-phenyl-propan-2-ol and 426 g (4.3 mol) ethyl cyanoformate in 500 ml cyclohexane has been added to a mixture of 500 ml cyclohexane and 1899 g (19 mol) concentrated sulfuric acid upon stirring. After ca. 15 min the reaction mixture was poured onto an ice/water mixture and cautiously basified upon addition of concentrated NaOH-solution. The phases were separated and the aqeous layer was extracted twice with methyl-t-butylether. The combined organic phases were dried over sodium sulfate and ant volatiles were evaporated to yield 584 g (99%) ethyl 3,3-dimethyl-4H-isoquinoline-1-carboxylate as a yellow oil.

(6) .sup.1H-NMR (CDCl.sub.3, δ in ppm):

(7) 7.55 (d, 1H); 7.4 (t, 1H); 7.3 (t, 1H); 7.18 (d, 1H); 4.45 (q, 2H); 2.75 (s, 2H); 1.4 (t, 3H); 1.28 (s, 6H)

EXAMPLE 4—ETHYL 4,4-DIBROMO-3,3-DIMETHYL-ISOQUINOLINE-1-CARBOXYLATE

(8) ##STR00015##

(9) 20 g (86 mmol) ethyl 3,3-dimethyl-4H-isoquinoline-1-carboxylate, 33.8 g (190 mmol) N-bromo succinimide and 2.8 g azo-bis-isobutyronitrile (17 mmol) in 250 ml chloroform were heated to reflux upon stirring. After ca. 60 min HPLC showed completion of the reaction. Subsequently the reaction mixture was cooled to room temperature and diluted with 200 ml heptane. Afterwards the precipitated solid was filtered off and the mother liquor was evaporated to yield 40 g (purity 80% (HPLC), yield 95%) of the title compound ethyl 4,4-dibromo-3,3-dimethyl-isoquinoline-1-carboxylate, which was subsequently used as crude product.

(10) HPLC-MS: HPLC-column Kinetex XB C18 1.7μ (50×2.1 mm); eluent: acetonitrile/water+0.1% TFA (5 gradient from 5:95 to 100:0 in 1.5 min at 60° C., flow gradient from 0.8 to 1.0 ml/min in 1.5 min). MS: Quadrupol Electrospray Ionisation, 80 V (positive mode).

(11) R.sub.t=1,034 min, M.sup.++H=245.9 (title compound, hydrolyzed to carbonyl compound upon measurement of HPLC-MS); R=1,275, M.sup.++H=389.8 (title compound ethyl 4,4-dibromo-3,3-dimethylisoquinoline-1-carboxylate)

EXAMPLE 5—ETHYL 4,4-DIFLUORO-3,3-DIMETHYL-ISOQUINOLINE-1-CARBOXYLATE

(12) ##STR00016##

(13) 79.6 g (493 mmol) Triethylamine×3 hydrogen fluoride (NEt.sub.3×3 HF) were added to 40 g (purity 80%, 82 mmol) ethyl 4,4-dibromo-3,3-dimethyl-isoquinoline-1-carboxylate in 100 ml acetonitrile. The mixture was heated to reflux for 2 hours, when HPLC showed completion of the reaction. Subsequently the reaction mixture was cooled to room temperature and cautiously poured onto ice cold 20% NaOH-solution. The aqueous layer was extracted twice with ethylacetate and the combined organic layers were extracted with brine. Afterwards the organic phase was dried over sodium sulfate and the volatiles were evaporated to yield 12 g (55%) of the title compound ethyl 4,4-difluoro-3,3-dimethyl-isoquinoline-1-carboxylate as brown oil.

(14) .sup.1H-NMR (CDCl.sub.3, δ in ppm):

(15) 7.75 (2d, 2H); 7.65 (2t, 2H); 4.45 (q, 2H); 1.4 (m, 9H)

(16) HPLC-MS: HPLC-column Kinetex XB C18 1.7μ (50×2.1 mm); eluent: acetonitrile/water+0.1% TFA (5 gradient from 5:95 to 100:0 in 1.5 min at 60° C., flow gradient from 0.8 to 1.0 ml/min in 1.5 min). MS: Quadrupol Electrospray Ionisation, 80 V (positive mode).

(17) R.sub.t=1,176 min, M.sup.++H=268

EXAMPLE 6-(4,4-DIFLUORO-3,3-DIMETHYL-ISOQUINOLINE-1-CARBONYL)OXYLITHIUM

(18) ##STR00017##

(19) 7.3 g (26 mmol) Ethyl 4,4-difluoro-3,3-dimethyl-isoquinoline-1-carboxylate and 1,143 g (27 mmol) lithium hydroxide in 100 ml methanol have been stirred at room temperature. After 2.5 hours HPLC showed total conversion of the starting material. Subsequently the solvent was evaporated at room temperature and the crystalline residue was stirred with diethylether. The crystals were filtered off and dried at 50° C. under vacuum to yield 6.3 g of the title compound as a light yellow solid (Mp>200° C., decomposition).

(20) HPLC-MS: HPLC-column Kinetex XB C18 1.7μ (50×2.1 mm); eluent: acetonitrile/water+0.1% TFA (5 gradient from 5:95 to 100:0 in 1.5 min at 60° C., flow gradient from 0.8 to 1.0 ml/min in 1.5 min). MS: Quadrupol Electrospray Ionisation, 80 V (positive mode).

(21) M.sup.++H=239.9 (Rt=0.797 min)

EXAMPLE 7-(4,4-DIFLUORO-3,3-DIMETHYL-ISOQUINOLINE-1-CARBONYL)OXYLITHIUM

(22) ##STR00018##

(23) 7.3 g (26 mmol) Ethyl 4,4-difluoro-3,3-dimethyl-isoquinoline-1-carboxylate and 1,143 g (27 mmol) lithium hydroxide in 100 ml methanol have been stirred at room temperature. After 2.5 hours HPLC showed total conversion of the starting material. Subsequently the solvent was evaporated at room temperature and the crystalline residue was stirred with diethylether. The crystals were filtered off and dried at 50° C. under vacuum to yield 6.3 g of the title compound as a light yellow solid (Mp>200° C., decomposition).

(24) HPLC-MS: HPLC-column Kinetex XB C18 1.7μ (50×2.1 mm); eluent: acetonitrile/water+0.1% TFA (5 gradient from 5:95 to 100:0 in 1.5 min at 60° C., flow gradient from 0.8 to 1.0 ml/min in 1.5 min). MS: Quadrupol Electrospray Ionisation, 80 V (positive mode).

(25) M.sup.++H=239.9 (Rt=0.797 min)

EXAMPLE 8-1-(5,6-DIMETHYL-3-PYRIDYL)-4,4-DIFLUORO-3,3-DIMETHYL-ISOQUINOLINE

(26) ##STR00019##

(27) 2.9 g (11.8 mmol) (4,4-Difluoro-3,3-dimethyl-isoquinoline-1-carbonyl)oxylithium and 2.0 g (10.75 mmol) 5-bromo-2,3-dimethyl-pyridine in 50 ml toluene/N-methyl-pyrrolidone 3:2 where heated at 70° C. upon stirring and a light stream of argon was passed over this mixture. Subsequently 0,231 g (1.6 mmol) copper(I)bromide and 0,145 g (0.18 mmol) Pd(dppf)Cl.sub.2×CH.sub.2Cl.sub.2 ([1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane) were added and the mixture was heated to reflux (122° C.) over night.

(28) Afterwards the volatiles were evaporated and the residue was taken up in methyl-t-butylether This heterogenous mixture was put on top of a short silica column which was eluted with methyl-t-butylether. The combined fractions were extracted with diluted ammonia solution and lithium chloride solution. The volatiles were evaporated to yield 3.2 g (purity (HPLC) 86%, yield 85%) of the title compound as a brown oil, which crystallized upon standing.

(29) .sup.1H-NMR (CDCl.sub.3, δ in ppm):

(30) 8.52 (s, 1H); 7.83 (d, 1H); 7.67 (s, 1H); 7.62 (t, 1H); 7.52, (t, 1H); 7.3 (d, 1H); 2.55 (s, 3H); 2.35 (s, 3H); 1.4 (s, 6H)

(31) HPLC-MS: HPLC-column Kinetex XB C18 1.7μ (50×2.1 mm); eluent: acetonitrile/water+0.1% TFA (5 gradient from 5:95 to 100:0 in 1.5 min at 60° C., flow gradient from 0.8 to 1.0 ml/min in 1.5 min). MS: Quadrupol Electrospray Ionisation, 80 V (positive mode).

(32) M.sup.++H=301 (R=0.889 min)

EXAMPLE 9-1-[6-(DIFLUOROMETHYL)-5-METHYL-3-PYRIDYL]-4,4-DIFLUORO-3,3-DIMETHYL-ISOQUINOLINE

(33) ##STR00020##

(34) 2.43 g (9.9 mmol) (4,4-Difluoro-3,3-dimethyl-isoquinoline-1-carbonyl)oxylithium and 2.0 g (10.75 mmol) 5-bromo-2,3-dimethyl-pyridine in 50 ml toluene/N-methyl-pyrrolidone 3:2 where heated at 70° C. upon stirring and a light stream of argon was passed over this mixture. Subsequently 0,194 g (1.35 mmol) copper(I)bromide and 0,122 g (0.15 mmol) Pd(dppf)Cl.sub.2×CH.sub.2Cl.sub.2 ([1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane) were added and the mixture was heated to reflux (122° C.) over night.

(35) Afterwards the volatiles were evaporated and the residue was taken up in methyl-t-butylether This heterogenous mixture was put on top of a short silica column which was eluted with methyl-t-butylether. The combined fractions were extracted with diluted ammonia solution and lithium chloride solution. The volatiles were evaporated and the residue was purified via column chromatographie with heptane/methyl-t-butylether-mixtures to yield 2 g (5.9 mmol; yield 68%) of the title compound as a light brown oil.

(36) .sup.1H-NMR (CDCl.sub.3, δ in ppm):

(37) 8.65 (s, 1H); 7.87 (d, 1H); 7.83 (s, 1H); 7.67 (t, 1H); 7.55 (t, 1H); 7.25, (d, 1H); 6.75 (t, 1H); 2.58 (s, 3H); 1.4 (s, 6H)

(38) HPLC-MS: HPLC-column Kinetex XB C18 1.7μ (50×2.1 mm); eluent: acetonitrile/water+

(39) 0.1% TFA (5 gradient from 5:95 to 100:0 in 1.5 min at 60° C., flow gradient from 0.8 to 1.0 ml/min in 1.5 min). MS: Quadrupol Electrospray Ionisation, 80 V (positive mode).

(40) M.sup.++H=337 (R.sub.t=1,243 min)

EXAMPLE 10—ETHYL 4,4-DIFLUORO-3,3-DIMETHYL-ISOQUINOLINE-1-CARBOXYLATE

(41) ##STR00021##

(42) 79.6 g (493 mmol) Triethylamine×3 hydrogen fluoride (NEt.sub.3×3 HF) were added to 40 g (purity 80%, 82 mmol) ethyl 4,4-dibromo-3,3-dimethyl-isoquinoline-1-carboxylate in 100 ml acetonitrile. The mixture was heated to reflux for 2 hours, when HPLC showed completion of the reaction. Subsequently the reaction mixture was cooled to room temperature and cautiously poured onto ice cold 20% NaOH-solution. The aqueous layer was extracted twice with ethylacetate and the combined organic layers were extracted with brine. Afterwards the organic phase was dried over sodium sulfate and the volatiles were evaporated to yield 12 g (55%) of the title compound ethyl 4,4-difluoro-3,3-dimethyl-isoquinoline-1-carboxylate as brown oil.

(43) .sup.1H-NMR (CDCl.sub.3, δ in ppm):

(44) 7.75 (2d, 2H); 7.65 (2t, 2H); 4.45 (q, 2H); 1.4 (m, 9H)

(45) HPLC-MS: HPLC-column Kinetex XB C18 1.7μ (50×2.1 mm); eluent: acetonitrile/water+

(46) 0.1% TFA (5 gradient from 5:95 to 100:0 in 1.5 min at 60° C., flow gradient from 0.8 to 1.0 ml/min in 1.5 min). MS: Quadrupol Electrospray Ionisation, 80 V (positive mode).

(47) R.sub.t=1,176 min, M.sup.++H=268

EXAMPLE 11-1-(5,6-DIMETHYL-3-PYRIDYL)-4,4-DIFLUORO-3,3-DIMETHYL-ISOQUINOLINE

(48) To a suspension of 5-brom-1,3-dimethylpyridine (7,805 g; 40,693 mmol) and (4,4-difluoro-3,3-dimethyl-isoquinoline-1-carbonyl)oxylithium (9,976 g; 40,693 mmol) in 100 mL of dry N-methylpyrrolidone under N.sub.2 was added CuBr (875.6 mg; 6,104 mmol), Pd(dppf)Cl.sub.2 (664.6 mg; 0,814 mmol) and 902.4 mg (1,628 mmol) dppf×CH.sub.2Cl.sub.2 ([1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane). The reaction mixture was heated to 150° C. and stirred for 3 h. After the reaction was complete (H PLC) the mixture was cooled to 10° C.

(49) Subsequently 100 ml of 5 molar hydrochloric acid was slowly added via dropping funnel. The aqueous layer was extracted twice with 100 ml n-heptane each and the organic layers were discarded.

(50) 300 ml n-Heptane was added to the aqueous layer and the solution was basified with 50% sodium hydroxide solution to pH=10 at 25° C. A solid residue precipitated which was filtered off, washed with n-heptane (3×50 ml) and discarded. Afterwards the layers were separated and the aqueous layer was extracted with n-heptane (2×300 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, the drying agent was filtered off and the volatiles were evaporated to obtain 11.1 g of the title compound as orange crystals.

(51) Recrystallisation from heptane yielded 8.05 g beige crystals (purity 93.5% (quant. .sup.1H-NMR), yield 61.6%). Purification via column chromatography with cyclohexane/ethyl acetate mixtures afforded 1-(5,6-dimethyl-3-pyridyl)-4,4-difluoro-3,3-dimethyl-isoquinoline as white crystals, mp=104-105° C.

(52) .sup.1H-NMR (CDCl.sub.3, δ in ppm):

(53) 8.52 (s, 1H); 7.83 (d, 1H); 7.67 (s, 1H); 7.62 (t, 1H); 7.52, (t, 1H); 7.3 (d, 1H); 2.55 (s, 3H); 2.35 (s, 3H); 1.4 (s, 6H)

EXAMPLE 12-1-[6-(DIFLUOROMETHYL)-5-METHYL-3-PYRIDYL]-4,4-DIFLUORO-3,3-DIMETHYL-ISOQUINOLINE

(54) To a suspension of 5-bromo-2-(difluoromethyl)-3-methyl-pyridine (36.59 g; 163.16 mmol) and (4,4-difluoro-3,3-dimethyl-isoquinoline-1-carbonyl)oxylithium (40.00 g; 163,165 mmol) in 480 ml of dry N-methylpyrrolidone under N.sub.2 were added CuBr (3.51 g; 24.48 mmol), Pd(dppf)Cl.sub.2×CH.sub.2Cl.sub.2 (2.67 g; 3.26 mmol) and 3.62 g (6.53 mmol) dppf ([1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane). The reaction mixture was heated at 150° C. and stirred for 8 h. After the reaction was complete (HPLC) the mixture was cooled to 10° C. and subsequently added to a mixture of 300 ml water and 500 ml n-heptane. Afterwards the mixture was basified with 50 ml of 25% ammonia-solution at 25° C. (pH 11-12) and filtered over Celite. The Celite was washed with n-heptane and the aqueous ammonia layer was separated from the n-hexane layer.

(55) The combined heptane phases were washed twice with 250 ml of 5% hydrochloric acid. After the first extraction some insoluble material precipitated which was filtered off and discarded. The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to obtain 40.5 g of the title compound (purity ˜80% (quant.-HPLC)).

(56) This product was dissolved in 400 ml of n-heptane. The heptane-phase was extracted twice with 250 ml of 15% HCl and the heptane phase was discarded afterwards.

(57) The combined HCl-layers were treated three times with 500 ml of dichloromethane to extract the product into the organic phase.

(58) Thereafter the combined dichloromethane layers were stirred for 1 h with 300 ml of 20% Na.sub.2CO.sub.3-solution.

(59) The phases were separated and the organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to obtain 33.3 g 1-[6-(Difluoromethyl)-5-methyl-3-pyridyl]-4,4-difluoro-3,3-dimethylisoquinoline (purity 92.5% (quant. .sup.1H-NMR), yield 56%).

(60) The title compound could be further purified via column chromatography with cyclohexane/ethyl acetate mixtures.

(61) .sup.1H-NMR (CDCl.sub.3, δ in ppm):

(62) 8.65 (s, 1H); 7.87 (d, 1H); 7.83 (s, 1H); 7.67 (t, 1H); 7.55 (t, 1H); 7.25, (d, 1H); 6.75 (t, 1H); 2.58 (s, 3H); 1.4 (s, 6H)