WO1997031891A1 - Procede de substitution regioselective du trifluorobenzoate ou du trifluorobenzonitrile - Google Patents

Procede de substitution regioselective du trifluorobenzoate ou du trifluorobenzonitrile Download PDF

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Publication number
WO1997031891A1
WO1997031891A1 PCT/US1997/002877 US9702877W WO9731891A1 WO 1997031891 A1 WO1997031891 A1 WO 1997031891A1 US 9702877 W US9702877 W US 9702877W WO 9731891 A1 WO9731891 A1 WO 9731891A1
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Prior art keywords
compound
alkyl
solvent
reaction
heterocyclic ring
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PCT/US1997/002877
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English (en)
Inventor
Joseph E. Lynch
Yao-Jun Shi
Kenneth M. Wells
Original Assignee
Merck & Co., Inc.
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Publication date
Priority claimed from GBGB9609335.6A external-priority patent/GB9609335D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Publication of WO1997031891A1 publication Critical patent/WO1997031891A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/84—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring
    • C07C69/92—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring with etherified hydroxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention provides a process for regioselective substitution of trifluorobenzoate and/or trifluorobenzonitrile. More particularly, regioselective nucleophilic substitution of 2, 4, 5-trifluoro- benzoate/trifluorobenzonitrile at the 4-position yields 2,5-difluoro- benzoate/difluorobenzonitrile in high yields. Subsequent substitution of the 2,5-difluorobenzoate/difluorobenzonitrile at the 2-position provides 5-fluorobenzoate/fluorobenzonitrile in good yields.
  • Tocolytic (uterine-relaxing) agents that are currently in use include ⁇ 2-adrenergic agonists, magnesium sulfate and ethanol.
  • Ritodrine the leading ⁇ 2-adrenergic agonist, causes a number of cardiovascular and metabolic side effects in the mother, including tachycardia, increased renin secretion, hyperglycemia (and reactive hypoglycemia in the infant).
  • Other ⁇ 2-adrenergic agonists, including terbutaline and albuterol have side effects similar to those of ritodrine.
  • Magnesium sulfate at plasma concentrations above the therapeutic range of 4 to 8 mg/dL can cause inhibition of cardiac conduction and neuromuscular transmission, respiratory depression and cardiac arrest, thus making this agent unsuitable when renal function is impaired.
  • Ethanol is as effective as ritodrine in preventing premature labor, but it does not produce a corresponding reduction in the incidence of fetal respiratory distress that administration of ritodrine does.
  • Oxytocin is believed to exert this effect in part by directly contracting the uterine myometrium and in part by enhancing the synthesis and release of contractile prostaglandins from the uterine endometrium/decidua. These prostaglandins may, in addition, be important in the cervical ripening process.
  • oxytocin at term has major effects only on the uterus, such an oxytocin antagonizing compound would be expected to have few. if any, side effects. It is also believed that an oxytocin antagonist compound would also be useful in the treatment of dysmenorrhea. This condition is characterized by cyclic pain associated with menses during ovulatory cycles. The pain is thought to result from uterine contractions and ischemia, probably mediated by the effect of prostaglandins produced in the secretory endometrium. By blocking both the direct and indirect effects of oxytocin on the uterus, a selective oxytocin antagonist can be more efficacious for treating dysmenorrhea than current regimens. An additional use for oxytocin antagonists is for stopping labor prior to cesarean delivery.
  • the present invention provides a process for forming a difluoro compound I
  • Y is selected from CN or C ⁇ 2-C] -6 alkyl
  • Rl is selected from OR- ⁇ SR3, CN, C ⁇ CR 4 , or a 4, 5, 6 or 7-membered monocyclic nitrogen containing heterocyclic ring containing one or two nitrogen atoms;
  • R3 is selected from Cl -10 alkyl, C3.8 cycloalkyl, phenyl-Ci-6 alkyl, phenyl or a 4, 5, 6 or 7-membered monocyclic nitrogen containing heterocyclic ring containing one or two nitrogen atoms wherein the nitrogen containing heterocyclic ring is either unsubstituted or substituted with R 5 and R 6 ;
  • R 4 is Ci-io alkyl
  • R 5 and R 6 are each independently selected from CO2R 4 , COR 4 or
  • Illustrative of the invention is the process wherein the difluoro compound is
  • Another aspect of the invention is a compound of the formula
  • Y is selected from CN, C ⁇ 2H or C ⁇ 2-Cl -6 alkyl
  • Ri and R2 are each independently selected from OR 3 , SR 3 , CN,
  • R 3 is selected from Cl -io alkyl, C3-8 cycloalkyl, phenyl-Cl -6 alkyl, phenyl or a 4, 5, 6 or 7-membered monocyclic nitrogen containing heterocyclic ring containing one or two nitrogen atoms wherein the nitrogen containing heterocyclic ring is either unsubstituted or substituted with R5 and R°;
  • R 4 is Cl -10 alkyl;
  • R5 and R6 are each independently selected from CO2R 4 , COR 4 or Cl -lO alkyl.
  • Y is selected from CN, CO2H, CO2CH3, or C ⁇ 2C(CH3)3;
  • Ri and R2 are each independently selected from OR 3 , SR 3 , CN, C ⁇ CR 4 or a heterocyclic ring selected from
  • R 3 is selected from Cj -6 alkyl, C3.6 cycloalkyl, benzyl, phenyl or a heterocyclic ring selected from
  • R 4 is C 1 -6 alkyl
  • R5 and R6 are each independently selected from CO2R 4 .
  • R 1 is selected from
  • R2 is selected from
  • the instant invention provides a process for regioselective nucleophilic substitution of trifluorobenzoate and/or trifluoronitrile.
  • 2,4,5-trifIuoro- benzoate/trifluorobenzonitrile is regioselectively substituted at the 4- position by a nucleophile to afford the 2,5-difluorobenzoate/difluoro- benzonitrile in high yields.
  • the nucleophile is an oxygen nucleophile (e.g., alkoxide), a nitrogen heterocycle (e.g., piperidine), a sulfur nucleophile (e.g., thiol) or a carbon nucleophile (e.g., nitrile, acetylene).
  • the resultant 2,5-difluorobenzoate/difluoro- benzonitrile can be subsequently substituted at the 2-position by a second nucleophile to afford the 5-fluorobenzoate/fluorobenzonitrile which is useful as an intermediate in the synthesis of fluorinated oxytocin antagonists, e.g., Compound A.
  • the nucleophilic substitution of trifluorobenzoate/trifluoro- benzonitrile to form the difluorobenzoate/ difluorobenzonitrile can be run at a temperature range of -78 to 5°C, preferably, -78 to -30°C, most preferably, about -65°C.
  • Subsequent substitution of the difluoro- benzoate/difluorobenzonitrile with a nucleophile to form the monofluorobenzoate/monofluorobenzonitrile can be run at a temperature range of -50 to 50°C, preferably, 20 to 25°C, most preferably, about 5°C.
  • a variety of solvents can be utilized in the nucleophilic substitution reactions of the present invention.
  • the nucleophilic substitution reactions of the present invention can be run in a solvent selected from a hydrocarbon solvent (e.g., hexane, cyclohexane) an aromatic solvent (e.g., toluene, benzene) or an oxygenated organic solvent (e.g., DMF, NMP, an ether).
  • a hydrocarbon solvent e.g., hexane, cyclohexane
  • an aromatic solvent e.g., toluene, benzene
  • an oxygenated organic solvent e.g., DMF, NMP, an ether
  • an oxygenated organic solvent is utilized.
  • the reaction is run using THF, DMF or NMP as the solvent.
  • Boc or BOC tert-butyloxycarbonyl
  • DCM dichloromethane
  • DEAD diethyl azodicarboxylate
  • DIEA diisopropylethylamine
  • DMF N, N-dimethylformamide
  • EDC l-ethyl-3-(3-dimethylaminopropyl)carbodiimide
  • NMP 1 -methyl-2-pyrrolidinone
  • THF tetrahydrofuran
  • the compounds of the present invention may have chiral centers and occur as racemates, racemic mixtures and as individual diastereomers, or enantiomers with all isomeric forms being included in the present invention. Therefore, where a compound is chiral, the separate enantiomers, substantially free of the other, are included within the scope of the invention; further included are all mixtures of the two enantiomers. Also included within the scope of the invention are polymorphs and hydrates of the compounds of the instant invention.
  • preterm labor shall mean expulsion from the uterus of a viable infant before the normal end of gestation, or more particularly, onset of labor with effacement and dilation of the cervix before the 37th week of gestation. It may or may not be associated with vaginal bleeding or rupture of the membranes.
  • the term "dysmenorrhea” shall mean painful menstruation.
  • cesarean delivery shall mean incision through the abdominal and uterine walls for delivery of a fetus.
  • alkyl includes both straight and branched chain alkanes of the number of carbon atoms specified (e.g., Cl -8 alkyl), or any number within this range (i.e., methyl, ethyl, 1 -propyl, 2-propyl, n-butyl, s-butyl, t-butyl, etc.).
  • cycloalkyl shall mean cyclic rings of alkanes of three to eight total carbon atoms (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl).
  • alkoxy refers to straight or branched chain alkoxides of the number of carbon atoms specified (e.g., Cl-5 alkoxy), or any number within this range (i.e., methoxy, ethoxy, etc.).
  • phenyl-Cl -6 alkyl refers to a phenyl ring attached to a Cl -6 alkyl group, e.g., benzyl, phenylethyl, phenylpropyl, etc.
  • halogen shall include, iodine, bromine, chlorine and fluorine.
  • nitrogen heterocycle represents an unsubstituted or substituted stable 4- to 7-membered monocyclic O 97/31891 PC17US97/02877
  • nitrogen heterocycles include, but is not limited to, piperidinyl, piperazinyl, azepinyl, pyrrolyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl.
  • oxygen nucleophile refers to an electron pair donor resided on an oxygen atom.
  • sulfur nucleophile refers to an electron pair donor resided on a sulfur atom.
  • carbon nucleophile refers to an electron pair donor resided on an carbon atom.
  • the reaction mixture was diluted with MTBE (100 ml), and the organic layer was washed with water (35 ml), then brine (35 ml). After drying over MgS04, the organic layer was evaporated to dryness to provide a waxy solid of monofluoronitrile 13 (0.83 g, 95% yield).
  • the starting material 9 (191 mg, 0.46 mmol), piperidine (0.0686 ml, 0.695 mmol) and potassium carbonate (128 mg, 0.928 mmol) were mixed together in DMF (5.0 ml) at 25°C.
  • the slurry was stirred and heated to 1 10°C for 12 h. After cooling to 25°C, the reaction mixture was diluted with water (15 ml) and extracted with MTBE (100 ml). The organic layer was separated and washed with water (25 ml x 2), sat. NaHC ⁇ 3 (20 ml) and brine (20 ml). The organic layer was dried over MgS ⁇ 4 and evaporated to dryness. Chromatography of the residue on silica gel and elution with 1 % ethyl acetate/hexane provided 15 in 75% yield ( 160 mg).
  • Benzyl alcohol (0.187 ml, 1.81 mmol) was added to a solution of t-BuOK in THF (1.0 M, 1.81 ml) at 5°C and the resulting solution stirred for 0.5 h at that temperature.
  • a solution of difluoroester 18 (538 mg, 1.81 mmol) in THF (2.0 ml) at 5°C over 10 min.
  • the resulting solution was kept at 5°C for 1.5 h, then warmed to 25°C, and stirring continued for 2.0 h.
  • the reaction was quenched with water (5.0 ml) at 25°C and extracted with MTBE (150 ml). The organic layer was washed with water (25 ml) and brine (25 ml).
  • reaction mixture was extracted with MTBE (150 ml) and the organic layer was separated, washed with water (25 ml) and dried over MgS04. The organic layer was evaporated to give a residue which was chromatographed on silica gel. Elution with 15% ethyl acetate/hexane gave a first fraction containing product 24a (64%) and a second fraction containing product 24b (14%).
  • Compound A was prepared from Monofluoroacid 5 according to Examples 15 to 17 which follow.
  • 1 H NMR spectra were measured at 300 MHz on a Varian XL-300, at 400 MHz on a Varian XL-400, and at 360 MHz on a Nicolet NT-360 using (CH3)4Si as an internal standard and Fast atom bombardment mass spectra (FAB MS) were obtained on a VG-ZAB-HF spectrometer. All NMRs for the compounds of Examples 15- 17 which follow were consistent with structures.
  • Step 1 l -t-Butyloxycarbonyl-4- ⁇ iperidinone (20 g, 0.10 mol), 2-aminobenzyl alcohol (13 g, 0.11 mol), and acetic acid (14 mL, 0.22 mol) were dissolved in dry toluene (500 mL). The solution was refluxed under inert atmosphere for 3 h with azeotropic removal of water. The solution was cooled to ambient temperature and concentrated under reduced pressure to one half of the original volume. To the solution was added NaBH3CN (20 g, 0.32 mol) and dry THF (300 mL). Acetic acid (10 mL, 0.15 mmol) was added dropwise over a period of about 1 h.
  • the reaction was stirred at ambient temperature for 24 h. The mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc (750 mL). The EtOAc layer was washed with saturated aqueous NaHC03 (3x 500 mL) and brine (250 mL). The EtOAc layer was dried (MgS ⁇ 4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography, using a gradient elution of 15-30% EtOAc-hexanes.
  • Step 2 l-t-Butyloxycarbonyl-4-((2-hydroxymethyl)- phenylamino)piperidine (24 g, 78 mmol) from Step 1 above was dissolved in dry THF (250 mL) and cooled to 0°C under an atmosphere of nitrogen. To the solution was added DIEA (41 mL, 0.24 mol) and triphosgene (8.54 g, 28.8 mmol).
  • Step 3 A stirred solution of l-(N-t-butyloxycarbonyl-4- piperidinyl)-4H-3,l -benzoxazin-2(l H)-one (19 g, 57 mmol) from Step 2 above in EtOAc (500 mL) was cooled to 0°C. HCI gas was bubbled through the solution for 30 min. Stirring was continued at 0°C for 1 h, during which time a precipitate had formed, and the reaction was warmed to ambient temperature for 1 h. The stirred suspension was cooled to 0°C and cold ether (250 mL) was added. The precipitate was collected by filtration and washed with ether.
  • Step 4 To a solution of the hydrochloride salt of 1 -(4- piperidinyl)-4(H)-3,l -benzoxazin-2(l H)-one (150 mg, 0.56 mmol) from Step 3 above in DMF (5 mL) was added 4-(N-tert-butyloxycarbonyl-4- piperidinyloxy)-5-fluoro-2-methoxybenzoic acid, 5 (206 mg, 0.56 mmol). HOBT (92 mg, 0.60 mmol), and EDC (140 mg, 0.73 mmol).

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  • Organic Chemistry (AREA)
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Abstract

L'invention porte sur un procédé de substitution régiosélective du trifluorobenzoate/trifluorobenzonitrile permettant d'obtenir du difluorobenzoate/difluorobenzonitrile avec de bons rendements. Le difluorobenzoate/difluorobenzonitrile résultant peut à son tour être substitué régiosélectivement par un deuxième nucléophile pour donner du monofluorobenzoate/monofluorobenzonitrile avec également de bons rendements. Ce procédé est particulièrement utile pour former des intermédiaires clefs pour la synthèse de composés antagonistes de l'oxytocine.
PCT/US1997/002877 1996-03-01 1997-02-25 Procede de substitution regioselective du trifluorobenzoate ou du trifluorobenzonitrile WO1997031891A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US1264196P 1996-03-01 1996-03-01
US60/012,641 1996-03-01
GB9609335.6 1996-05-03
GBGB9609335.6A GB9609335D0 (en) 1996-05-03 1996-05-03 Process for regioselective substitution of trifuorobenzoate or trifuouobenzonitrile

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WO1997031891A1 true WO1997031891A1 (fr) 1997-09-04

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002020500A2 (fr) * 2000-09-01 2002-03-14 Icos Corporation Substances potentialisant un traitement anticancereux et methodes a cet effet
JP2009057299A (ja) * 2007-08-30 2009-03-19 Nippon Soda Co Ltd 置換フェノキシアザビシクロオクタン誘導体およびその製造方法
US8404681B2 (en) 2003-03-24 2013-03-26 Luitpold Pharmaceuticals, Inc. Xanthones, thioxanthones and acridinones as DNA-PK inhibitors

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4684734A (en) * 1983-02-18 1987-08-04 Nippon Shokubai Kk Co., Ltd. Method for manufacture or organic fluorine compounds
US5332851A (en) * 1989-11-17 1994-07-26 Asahi Glass Company Ltd. Processes for producing 5-fluorobenzoic acids and their intermediates

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4684734A (en) * 1983-02-18 1987-08-04 Nippon Shokubai Kk Co., Ltd. Method for manufacture or organic fluorine compounds
US5332851A (en) * 1989-11-17 1994-07-26 Asahi Glass Company Ltd. Processes for producing 5-fluorobenzoic acids and their intermediates

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002020500A2 (fr) * 2000-09-01 2002-03-14 Icos Corporation Substances potentialisant un traitement anticancereux et methodes a cet effet
WO2002020500A3 (fr) * 2000-09-01 2003-07-31 Icos Corp Substances potentialisant un traitement anticancereux et methodes a cet effet
US7179912B2 (en) 2000-09-01 2007-02-20 Icos Corporation Materials and methods to potentiate cancer treatment
US8242115B2 (en) 2000-09-01 2012-08-14 Luitpold Pharmaceuticals, Inc. Materials and methods to potentiate cancer treatment
US8404681B2 (en) 2003-03-24 2013-03-26 Luitpold Pharmaceuticals, Inc. Xanthones, thioxanthones and acridinones as DNA-PK inhibitors
JP2009057299A (ja) * 2007-08-30 2009-03-19 Nippon Soda Co Ltd 置換フェノキシアザビシクロオクタン誘導体およびその製造方法

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