Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
  • C07D213/72—Nitrogen atoms
  • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents

Definitions

• This invention pertains to processes for preparing pyridonecarboxylic acid derivatives having antibacterial properties and intermediates which are useful in the process.
• R is phenyl or naphthyl, each of which is unsubstituted or substituted with one or two independently selected -0(CH 3 ) or -0(CH 2 CH 3 ) substituents, and
• R 2 is hydrogen, -CH 3 , -CH 2 CH 3 , or R 1 and a phosphate base at about 5O 0 C to about 70 0 C for a first reaction time and at about 15O 0 C to about 17O 0 C for a second reaction time, wherein the total reaction time is about 16 hours to about 24 hours, to provide a compound having formula (Ef)
• Another embodiment pertains to 2,6-diamino-3,5-difluoropyridine, or a salt thereof, prepared as described in the preceeding embodiment.
• Still another embodiment pertains to a process for making 2,6-diamino-3,5-difluoropyridine, or a salt thereof, comprising:
• N ,N -dibenzyl-2,6-diamino-3,5-difluoropyridine hydrogen and a hydrogenolysis catalyst in water and a co-solvent, wherein the water is present in about 0.1 to about 6 molar equivalents per molar equivalent of the N ,N -dibenzyl-2,6-diamino-3,5-difiuoropyridine.
• Still another embodiment pertains to 2,6-diamino-3,5-difluoropyridine, or a salt thereof, prepared as set forth in the preceeding embodiment.
• Still another another embodiment pertains to a process for making 2,6-diamino-3,5-difluoropyridine, or a salt thereof, comprising:
• Still another embodiment pertains to 2,6-diamino-3,5-difiuoropyridine, or a salt thereof, prepared as set forth in the preceeding embodiment.
• Still another embodiment pertains to a process for making 2,6-diamino-3,5-difluoropyridine, or a salt thereof, comprising:
• Still another embodiment pertains to 2,6-diamino-3,5-difluoropyridine, or a salt thereof, prepared as set forth in the preceeding embodiment. Still another embodiment pertains to a process for making a compound having formula (V)
• R is alkyl, comprising: (c) reacting, at about 100 0 C to about 14O 0 C, a compound having formula (IV)
• step (d) reacting the product of step (c) and 2,6-diamino-3,5-difluoropyridine to provide a product mixture comprising the compound having formula (V), mixing or not mixing the product mixture and water, and isolating or not isolating the compound having formula (V).
• Still another embodiment pertains to a compound having formula (V) prepared as set forth in the preceeding embodiment.
• Still another embodiment pertains to a process for making ethyl (2E/Z)-3-((6-amino- 3,5-difluoropyridin-2-yl)amino)-2-(2,4,5-trifluorobenzoyl)-2-propenoate, or a salt thereof, comprising:
• step (d) reacting the product of step (c) and 2,6-diamino-3,5-difiuoropyridine to provide a product mixture comprising ethyl (2E/Z)-3-((6-amino-3,5-difluoropyridin-2-yl)amino)-2-
• Still another embodiment pertains to (2E/Z)-3-((6-amino-3,5-difluoropyridin-2- yl)amino)-2-(2,4,5-trifluorobenzoyl)-2-propenoate, or a salt thereof, prepared as set forth in the preceeding embodiment.
• Still another embodiment pertains to a process for making ethyl (2E/Z)-3-((6-amino-
• step (c) reacting the product of step (c) and 2,6-diamino-3,5-difluoropyridine to provide a product mixture comprising the ethyl (2E/Z)-3-((6-amino-3,5-difluoropyridin-2-yl)-amino)-2-
• Still another embodiment pertains to (2E/Z)-3-((6-amino-3,5-difluoropyridin-2- yl)amino)-2-(2,4,5-trifluorobenzoyl)-2-propenoate, or a salt thereof, prepared as set forth in the preceeding embodiment.
• Still another embodiment pertains to a process for making ethyl (2E/Z)-3-((6-amino-
• step (d) reacting the product of step (c) and 2,6-diamino-3,5-difluoropyridine to provide a product mixture comprising the ethyl (2E/Z)-3-((6-amino-3,5-difluoropyridin-2-yl)amino)-2-
• Still another embodiment pertains to (2E/Z)-3-((6-amino-3,5-difluoropyridin-2- yl)amino)-2-(2,4,5-trifluorobenzoyl)-2-propenoate, or a salt thereof, prepared as set forth in the preceeding embodiment.
• Still another embodiment pertains to a process for making ethyl (2E/Z)-3-((6-amino-
• step (c) reacting the product of step (c) and 2,6-diamino-3,5-difluoropyridine to provide a product mixture comprising the ethyl (2E/Z)-3-((6-amino-3,5-difluoropyridin-2-yl)amino)-2-
• (2,4,5-trifluorobenzoyl)-2-propenoate mixing the product mixture and water, and isolating the ethyl (2E/Z)-3 -((6-amino-3 ,5 -difluoropyridin-2-yl)amino)-2-(2,4,5-trifluorobenzoyl)-2- propenoate.
• Still another embodiment pertains to (2E/Z)-3-((6-amino-3,5-difluoropyridin-2- yl)amino)-2-(2,4,5-trifluorobenzoyl)-2-propenoate, or a salt thereof, prepared as set forth in the preceeding embodiment.
• 3-azetidinol hydrochloride comprising: (e) reacting ( ⁇ )-2-(chloromethyl)oxirane, sodium bicarbonate and the compound having formula (I) to provide a (VI),
• step (f) reacting or not reacting the product of step (e) and a base; and (g) reacting the product of step (f), hydrogen and a hydrogeno lysis catalyst in a reaction medium consisting essentially of water, an alcohol, and an organic acid, at about 40 psi to about 60 psi and at about 5O 0 C to about 7O 0 C, for about two hours to about four hours, and isolating the product, with the proviso that when the product of step (e) is the maleate salt, step (f) is conducted.
• a reaction medium consisting essentially of water, an alcohol, and an organic acid
• Still another embodiment pertains to 3-azetidinol hydrochloride prepared as set forth in the preceeding embodiment.
• Still another embodiment pertains to a process for making substantially pure 3-azetidinol hydrochloride comprising:
• step (f) reacting the product of step (e) and potassium carbonate;
• step (g) reacting the product of step (f), hydrogen and Pd(OH) 2 on carbon in a reaction medium comprising water, an alcohol and an organic acid at about 40 psi to about 60 psi and about 5O 0 C to about 7O 0 C for about two hours to about four hours, reducing the water in the reaction medium to less than about 4 mg per mL and treating the reaction medium first with hydrogen chloride gas between about 0 0 C and about 2O 0 C and then with toluene at about 4O 0 C.
• a reaction medium comprising water, an alcohol and an organic acid at about 40 psi to about 60 psi and about 5O 0 C to about 7O 0 C for about two hours to about four hours, reducing the water in the reaction medium to less than about 4 mg per mL and treating the reaction medium first with hydrogen chloride gas between about 0 0 C and about 2O 0 C and then with toluene at about 4O 0 C.
• Still another embodiment pertains to 3-azetidinol hydrochloride prepared as set forth in the preceeding embodiment.
• Still another embodiment pertains to a process for making substantially pure 3-azetidinol hydrochloride comprising:
• step (e) reacting ( ⁇ )-2-(chloromethyl)oxirane, sodium bicarbonate and benzylamine in acetonitrile and water to provide l-benzyl-3-azetidinol, reacting the l-benzyl-3-azetidinol and (2E/Z)-2-butenedioic acid at about 35 0 C to about 45 0 C, and isolating l-benzyl-3-azetidinol (2E/Z)-2-butenedioate; (f) reacting the product of step (e) and potassium carbonate; and
• step (g) reacting the product of step (f), hydrogen and Pd(OH) 2 on carbon in a reaction medium comprising water, isopropanol and acetic acid at about 40 psi to about 60 psi and about 5O 0 C to about 7O 0 C for about 2 to about 4 hours, reducing the water in the reaction medium to less than about 4 mg per mL, and treating the reaction medium first with hydrogen chloride gas between about 0 0 C and about 2O 0 C and then with toluene at about 4O 0 C.
• Still another embodiment pertains to 3-azetidinol hydrochloride prepared as set forth in the preceeding embodiment.
• Still another embodiment pertains to a process for making substantially pure 3-azetidinol hydrochloride comprising: (e) reacting ( ⁇ )-2-(chloromethyl)oxirane, sodium bicarbonate and benzylamine at about O 0 C to about 8O 0 C in acetonitrile and water to provide l-benzyl-3-azetidinol, reacting the l-benzyl-3-azetidinol and (2E/Z)-2-butenedioic acid at about 4O 0 C, and isolating 1 -benzyl-3-azetidinol (2E/Z)-2-butenedioate;
• step (g) reacting the product of step (f), hydrogen and Pd(OH) 2 on carbon in a reaction medium comprising water, isopropanol and acetic acid at about 40 psi and about 65°C for about two hours, reducing the water in the reaction medium to less than about 4 mg per mL and treating the reaction medium first with hydrogen chloride gas between about O 0 C and about 2O 0 C and then with toluene at about 4O 0 C.
• a reaction medium comprising water, isopropanol and acetic acid at about 40 psi and about 65°C for about two hours, reducing the water in the reaction medium to less than about 4 mg per mL and treating the reaction medium first with hydrogen chloride gas between about O 0 C and about 2O 0 C and then with toluene at about 4O 0 C.
• Still another embodiment pertains to 3-azetidinol hydrochloride, or a salt thereof, prepared as set forth in the preceeding embodiment.
• Still another embodiment pertains to a process for making a compound having formula (VET)
• R is hydrogen or C(O)R , wherein R is alkyl, phenyl or naphthyl, each of which is unsubstituted or substituted with one or two or three of independently selected OCH 3 , OCH 2 CH 3 , F, Cl or Br, comprising:
• step (i) reacting the product of step (h), 3-azetidinol hydrochloride and the bicyclic amine base and isolating or not isolating the product; and (j) reacting or not reacting the product of step (i) and a OH protecting group precursor and isolating or not isolating the product.
• Still another embodiment pertains to a compound having formula (VIT), or a salt thereof, prepared as set forth in the preceeding embodiment.
• Still another embodiment pertains to a compound having formula (VII), or a salt thereof, for use in preparing l-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3- (isobutyryloxy)azetidin- 1 -yl)-4-oxo- 1 ,4-dihydro-3-quinolinecarboxylic acid, l-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fiuoro-7-(3-hydroxy-l-azetidinyl)-4-oxo- l,4-dihydro-3-quinolinecarboxylic acid, or a salt, ester or salt of an ester thereof.
• Still another embodiment pertains to a compound having formula (VII), or a salt thereof.
• Still another embodiment pertains to a compound having formula (VHa)
• Still another embodiment pertains to a process for making ethyl l-(6-amino-3,5- difluoropyridin-2-yl)-6-fluoro-7-(3 -(isobutyryloxy)azetidin- 1 -yl)-4-oxo- 1 ,4-dihydroquinoline- 3-carboxylate, or a salt thereof, comprising:
• step (i) reacting the product of step (h), 3-azetidinol hydrochloride and a bicyclic amine base and not isolating the product;
• Still another embodiment pertains to l-(6-amino-3,5-difiuoro-2-pyridinyl)-6,7- difluoro-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid, or a salt thereof prepared as set forth in the preceeding embodiment.
• Still another embodiment pertains to ethyl l-(6-amino-3,5-difluoropyridin-2-yl)-6- fluoro-7-(3-(isobutyryloxy)azetidin-l-yl)-4-oxo-l,4-dihydroquinoline-3-carboxylate, or a salt thereof, prepared as set forth in the preceeding embodiment.
• Still another embodiment pertains to ethyl l-(6-amino-3,5-difiuoropyridin-2-yl)-6- fluoro-7-(3-(isobutyryloxy)azetidin- 1 -yl)-4-oxo- 1 ,4-dihydroquinoline-3-carboxylate, or a salt thereof, for use in preparing l-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3- hydroxyazetidin-l-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid, or a salt, ester or salt of an ester thereof.
• Still another embodiment pertains to ethyl l-(6-amino-3,5-difluoropyridin-2-yl)-6- fiuoro-7-(3-(isobutyryloxy)azetidin-l-yl)-4-oxo-l,4-dihydroquinoline-3-carboxylate, or a salt thereof.
• Still another embodiment pertains to a process for making ethyl l-(6-amino-3,5- difluoropyridin-2-yl)-6-fluoro-7-(3-(isobutyryloxy)azetidin- 1 -yl)-4-oxo- 1 ,4-dihydroquinoline- 3-carboxylate, or a salt thereof, comprising: (h) reacting ethyl (2E/Z)-3-((6-amino-3,5-difluoropyridin-2-yl)amino)-2-(2,4,5- trifluorobenzoyl)-2-propenoate, or a salt thereof, lithium chloride and DBU and not isolating the product;
• step (i) reacting the product of step (h), 3-azetidinol hydrochloride and DBU and not isolating the product; and (j) reacting the product of step (i) and isobutyric anhydride and isolating or not isolating the product.
• Still another embodiment pertains to ethyl l-(6-amino-3,5-difluoropyridin-2-yl)-6- fluoro-7-(3-(isobutyryloxy)azetidin-l-yl)-4-oxo-l,4-dihydroquinoline-3-carboxylate, or a salt thereof, prepared as set forth in the preceeding embodiment.
• Still another embodiment pertains to ethyl l-(6-amino-3,5-difluoropyridin-2-yl)-6- fluoro-7-(3-(isobutyryloxy)azetidin-l-yl)-4-oxo-l,4-dihydroquinoline-3-carboxylate, or a salt thereof, for use in preparing l-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3- hydroxyazetidin-l-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid, or a salt, ester or salt of an ester thereof.
• Still another embodiment pertains to a process for making l-(6-amino-3,5- difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3-hydroxyazetidin- 1 -yl)-4-oxo- 1 ,4-dihydro-3- quinolinecarboxylic acid, or a salt thereof, comprising:
• step (1) reacting the product of step (k) and a hydroxide base; and (m) isolating the product of step (1).
• Still another embodiment pertains to a compound having formula (VIH) , or a salt thereof, prepared as set forth in the preceeding embodiment.
• Still another embodiment pertains to a compound having formula (VHT) , or a salt thereof, for use in the preparation of l-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro- 7-(3-hydroxyazetidin-l-yl)-4-oxo-l,4-dihydroquinoline-3-carboxylic acid or a salt thereof. Still another embodiment pertains to a compound having formula (VIH).
• Still another embodiment pertains to a process for making l-(6-amino-3,5- difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3 -hydroxyazetidin- 1 -yl)-4-oxo- 1 ,4- dihydroquinoline-3-carboxylic acid, or a salt thereof, comprising:
• step (1) (1) reacting the product of step (k) and sodium hydroxide; and (m) isolating the product of step (1).
• Still another embodiment pertains to l-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6- fluoro-7-(3-hydroxyazetidin-l-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid prepared as set forth in the preceeding embodiment.
• This invention pertains to pyridonecarboxylic acid derivatives having antibacterial properties and intermediates which are useful in the process.
• Variable moieties are represented by identifiers (capital letters with numerical and/or alphabetical superscripts) and may be specifically embodied.
• alkyl means C]-alkyl, C 2 -alkyl, C 3 -alkyl, C 4 -alkyl, C 5 -alkyl, and C 6 -alkyl.
• C]-alkyl means methyl.
• C 2 -alkyl means ethyl.
• C 3 -alkyl means prop-1-yl and prop-2-yl (isopropyl).
• C 4 -alkyl means but-l-yl, but-2-yl, 2-methylprop-l-yl, and 2-methylprop-2-yl (tert-butyl).
• Cs-alkyl means 2,2-dimethylprop-l-yl (neo-pentyl), 2-methylbut-l-yl, 2-methylbut-2-yl, 3-methylbut-l-yl, 3-methylbut-2-yl, pent-1-yl, pent-2-yl, and pent-3-yl.
• Cg-alkyl means 2,2-dimethylbut-l-yl, 2,3-dimethylbut-l-yl, 2,3-dimethylbut-2-yl, 3,3-dimethylbut-l-yl, 3,3-dimethylbut-2-yl, 2-ethylbut-l-yl, hex-l-yl, hex-2-yl, hex-3-yl, 2-methylpent-l-yl, 2-methylpent-2-yl, 2-methylpent-3-yl, 3-methylpent-l-yl, 3-methylpent-2-yl, 3-methylpent-3-yl, 4-methylpent-l-yl, and 4-methylpent-2-yl.
• alcohol means methanol, ethanol, isopropanol, tert-butanol, and the like or a mixture thereof.
• alkanoyl halide means a compound having formula .
• R C(O)Cl wherein R is alkyl which is unsubstituted or substituted with one or two or three of independently selected OCH 3 , OCH 2 CH 3 , F, Cl or Br.
• aryloyl halide means a compound having formula R C(O)Cl, wherein R is phenyl or naphthyl, each of which is unsubstituted or substituted with one or two or three of independently selected OCH 3 , OCH 2 CH 3 , F, Cl or Br.
• amine base means triethylamine, N-methylmorpholine, and diisopropylethylamine.
• base means Na 2 CO 3 , NaHCO 3 , K 2 CO 3 , KHCO 3 , triethylamine, diisopropylethylamine and the like, or a mixture thereof.
• bicyclic amine base means l,5-diazabicyclo-[4.3.0]non-5- ene (DBN) and l,8-diazabicyclo[5.4.0]undec-7-ene (DBN).
• chlorinating agent means N-chlorosuccinimide, thionyl chloride, Cl 2 , Cl 2 O and the like with or without water and with or without an acid such as sulfuric acid, phosphoric acid, trifluoroacetic acid, perchloric acid and the like.
• R 55 i iss C C((OO))RR 66
• w wlherein R 6 is CH(CH 3 ) 2
• N-chlorosuccinimide in ethyl acetate is shown in TABLE 2.
• hydrolysis catalyst means water-wet or not water-wet 5% palladium hydroxide, water- wet or not water-wet 10% palladium hydroxide, water-wet or not water-wet 5% palladium hydroxide on carbon, water- wet or not water-wet 10% palladium hydroxide on carbon, and the like or mixtures thereof.
• hydroxide base means the hydroxide base of sodium, potassium, lithium, barium and the like or mixtures thereof.
• non-protic acid means lithium chloride, magnesium chloride, zinc chloride and the like, or mixtures thereof.
• OH protecting group precursor means a carboxylic anhydride, an alkanoyl halide, an aryloyl chloride and the like.
• organic acid means formic acid, acetic acid, propionic acid and the like, or mixtures thereof.
• phosphate base means K 3 PO 4 , K 2 HPO 4 , KH 2 PO 4 , Na 3 PO 4 , Na 2 HPO 4 , NaH 2 PO 4 , and the like or mixtures thereof.
• substantially pure 3-azetidinol hydrochloride means 3-azetidinol hydrochloride having a low enough solvent content to be in powder form.
• Trialkylorthoformate means trimethylorthoformate, triethylorthoformate, triisopropylorthoformate and the like, or mixtures thereof.
• Compounds of this invention can have one or more than one asymmetrically substituted carbon atoms in the R or S configuration.
• Compounds having asymmetrically substituted carbon atoms enriched with one configuration over the other are assigned the configuration which is present in the higher amount, preferably 85% to 95% enrichment, more preferably 95% to 99% enrichment, and still more preferably greater than 99% enrichment.
• compounds of this invention can exist as enantiomers, mixtures of enantiomers, diastereomers having relative stereochemistry, diastereomers having absolute stereochemistry, diastereomers having at least one asymmetrically substituted carbon atom which is enriched in one configuration and at least one asymmetrically substituted carbon atom which is not enriched, and mixtures of the preceeding.
• Compounds of this invention can also have one or more than one carbon-carbon double bond or carbon-nitrogen double bond. Accordingly, compounds of this invention can exist as geometric isomers of either Z or E configuration or as mixtures of geometric isomers.
• Acid addition salts of compounds are prepared by reaction with acid.
• acid addition salts of compounds are prepared by reaction with acid.
• acid for example, the acetate, adipate, alginate, bicarbonate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsufonate, citrate, digluconate, formate, fumarate, glycerophosphate, glutamate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, lactobionate, lactate, maleate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, phosphate, picrate, propionate, succinate,
• Base addition salts of compounds of this invention may be prepared by reaction with a base such as the hydroxide, carbonate, bicarbonate, phosphate, hydrogen phosphate, or dihydrogen phosphate of cations such as calcium, iron, lithium, potassium, sodium or magnesium.
• a base such as the hydroxide, carbonate, bicarbonate, phosphate, hydrogen phosphate, or dihydrogen phosphate of cations such as calcium, iron, lithium, potassium, sodium or magnesium.
• a solution of benzylamine (73Kg) in water (650.4Kg) at 0°C was treated with epichlorohydrin (61Kg), stirred for approximately 2 hours until solid formed, stored at 10°C for 16 hours, and filtered.
• the filtrant was mixed with sodium bicarbonate (104Kg) in acetonitrile (1110Kg), and the mixture was azeotropically distilled with acetonitrile addition to maintain a volume of 900L, diluted with acetonitrile (400L), stirred at 75 0 C for
• the concentrate was mixed with acetic acid (25.8Kg), added to half-wet 5% palladium hydroxide on carbon (13.1Kg), stirred at 55-65°C under hydrogen at 40 psi for 2-8 hours, cooled to ambient temperature, filtered, washed with isopropanol, concentrated with an isopropanol azeotrope to 11OL, cooled to 5-10°C, treated with HCl gas (14Kg), stirred at ambient temperature for 1 hour and at 40 0 C for 30 minutes, treated with toluene (210Kg) over 1 hour, stirred for 30 minutes, cooled to ambient temperature, and filtered.
• the concentrate was treated with isopropyl acetate ( (227755KKgg)) a anndd s sttoorreedd i inn a ann o oppaaqquuee c coonnttaaiinneerr u unndder nitrogen.
• H NMR (CDCl 3 , 300 MHz) ⁇ 7.29-7.24 (m, 10H), 6.97 (t, IH), 4.57 (s, 4H).
• the filtrate was washed twice with 6% citric acid solution having its pH adjusted to 4 with potassium hydroxide (water (200Kg)/citric acid (12Kg)/potassium hydroxide (2Kg)), IM sodium bicarbonate solution (150Kg) and water (150Kg) and concentrated.
• the concentrate was treated with heptane(1005Kg) over 90 minutes, and the solution was cooled to O 0 C and filtered.
• the filtrant was washed with heptane (220Kg) and dried under vacuum at 4O 0 C to provide 61.5Kg of product, which was s sttoorreedd i inn a ann o oppaaqqiue container under nitrogen.
• H NMR (CDCl 3 , 300 MHz) ⁇ 7.03 (t, IH), 4.5-4.0 (brs, 4H).
• EXAMPLE 6 A suspension of potassium ethyl malonate (50.8Kg) and magnesium chloride (34.5Kg) in toluene (130Kg) below 0 0 C was treated with THF (265L), cooled to 0°C, treated with triethylamine (75Kg), warmed to 5O 0 C, stirred for 1-5 hours, cooled to 0 0 C, treated with 22% (w/w) of EXAMPLE 5 in toluene (163Kg), warmed to ambient temperature, stirred for 2 hours, added to 2M HCl (407Kg), stirred for 30 minutes, separated from the water layer and washed with water.
• EXAMPLE 7A The solution of EXAMPLE 7A was treated with N-methylpyrrolidinone (210Kg), acetonitrile (161Kg) and water (3Kg), added to a suspension of EXAMPLE 4 (57.4Kg) in 1 : 1 N-methylpyrrolidinone (210Kg) and acetonitrile (161Kg), stirred for 2 hours, added to water (662Kg) and filtered. The f ⁇ ltrant was washed with (2:1) acetonitrile/water and water and dried under vacuum at 60 0 C to provide 119.5Kg of product.
• EXAMPLE 8A below 4O 0 C was treated with EXAMPLE 2 (33.9Kg) and DBU (109Kg) and stirred for 2-5 hours to provide a solution of EXAMPLE 8B that was used immediately.
• EXAMPLE 8B The solution of EXAMPLE 8B was treated with isobutyric anhydride (99.7Kg), stirred at 35 0 C for 1-2 hours, cooled to 20-30 0 C, treated with ethyl acetate (104Kg) and 10% aqueous citric acid (570Kg) and filtered. The filtrant was washed with water and dried under vacuum at 50 0 C to provide 136Kg of product.
• isobutyric anhydride 99.7Kg
• 104Kg ethyl acetate
• 570Kg 10% aqueous citric acid
• the concentrate was dissolved in isopropanol, treated with 4% (w/w) aqueous potassium hydroxide (750Kg), stirred at 5O 0 C until hydrolysis was complete, passed through a polishing filter, treated with 12% aqueous acetic acid (410Kg) and filtered. The filtrant was washed with water and dried at 5O 0 C to provide 73Kg of product.
• EXAMPLE HB A solution of EXAMPLE 4 (2.58Kg) in DMSO (6.75Kg) at 14°C was treated with
• EXAMPLE 13 A in DMSO (9.50Kg) over 1 hour, stirred for 15 minutes, treated with potassium carbonate (2.25Kg), stirred at 60-70 0 C for 1-2 hours, cooled to 30 0 C, treated sequentially with acetonitrile (13.3Kg) and 9% aqueous citric acid (20.2Kg), each over 15 minutes, cooled to ambient temperature and filtered. The filtrant was washed with 9% aqueous citric acid (10Kg)/acetonitrile (9.1L) and acetonitrile (2> ⁇ 9.1L) and dried at 40-45°C to provide 4.49Kg of product.
• EXAMPLE 12 A mixture of EXAMPLE 2 (1.46Kg) and potassium bicarbonate (4.66Kg) in N-methylpyrrolidinone (36.8Kg) was stirred at 60 0 C for 1 hour, treated with EXAMPLE 13B (4Kg), stirred for 3 hours, cooled to ambient temperature, treated with N,N-dimethylaminopyridine (65 g) and acetic anhydride (5.34Kg) while keeping the temperature below 45 0 C, stirred until the intermediate alcohol was consumed, cooled to ambient temperature, and filtered.
• EXAMPLE 12 A mixture of EXAMPLE 2 (1.46Kg) and potassium bicarbonate (4.66Kg) in N-methylpyrrolidinone (36.8Kg) was stirred at 60 0 C for 1 hour, treated with EXAMPLE 13B (4Kg), stirred for 3 hours, cooled to ambient temperature, treated with N,N-dimethylaminopyridine (65 g) and acetic anhydride (5
• the filtrant was washed with N-methylpyrrolidinone (4.3Kg), and the filtrate was warmed to 7O 0 C, treated with water (40.4Kg), cooled to ambient temperature, and filtered.
• the filtrant was washed with water (2x12Kg) and dried under vacuum at 50 0 C to provide 4.36 Kg of product.

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