EP1789392A2

EP1789392A2 - Preparation of pyridonecarboxylic acid antibacterials

Info

Publication number: EP1789392A2
Application number: EP05777596A
Authority: EP
Inventors: Anthony Haight; David Barnes; Geoff Zhang
Original assignee: Abbott Laboratories
Current assignee: Abbott Laboratories
Priority date: 2004-07-30
Filing date: 2005-07-29
Publication date: 2007-05-30
Also published as: MX2007001134A; CA2575148A1; HK1156311A1; WO2006015194A3; EP2100892A1; CA2575148C; JP5274012B2; EP2816033A1; EP2305666B1; EP2305666A1; ES2482097T3; ES2506143T3; EP2100892B1; JP2008508309A; WO2006015194A2

Abstract

A process for making 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3-hydroxyazetidin-1-yl)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid, and therapeutically acceptable salts thereof, and intermediates used in the process are disclosed.

Description

PREPARATION OF PYRIDONECARBOXYLIC ACID ANTBACTERIALS

FIELD OF THE INVENTION

This invention pertains to processes for preparing pyridonecarboxylic acid derivatives having antibacterial properties and intermediates which are useful in the process.

BACKGROUND OF THE INVENTION

Many compounds having a pyridonecarboxylic acid moiety re known to be useful as antibacterials. For example, a series of novel quinolone antibacterials appears in PCT Application No. PCT/JP96/02710, published as WO97/11068 on March 27, 1997 and issued in United States as U.S. 5,998,436 on December 7, 1999, U.S. 6,133,284 on October 17, 2000, and U.S. 6,156,903 on December 5, 2000.

There is therefore an existing need for processes for making these compounds in large scale quantities.

SUMMARY OF THE INVENTION One embodiment of this invention, therefore, pertains to a process for making

2,6-diamino-3,5-difluoropyridine, or a salt thereof, comprising:

(a) reacting 2,3,5,6-tetrafluoropyridine, a compound having formula (I)

H₂NC HH((RR¹ )(R²)

(I), or a salt thereof, wherein R is phenyl or naphthyl, each of which is unsubstituted or substituted with one or two independently selected -0(CH₃) or -0(CH₂CH₃) substituents, and

R² is hydrogen, -CH₃, -CH₂CH₃, or R¹ and a phosphate base at about 5O⁰C to about 70⁰C for a first reaction time and at about 15O⁰C to about 17O⁰C 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)

(H), and isolating or not isolating the compound having formula (II);

(b) reacting, for about 45 minutes to about 2 hours, the compound having formula (II), 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 compound having formula (JT).

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:

(a) reacting 2,3,5,6-tetrafiuoropyridine, benzylamine and a phosphate base at about 5O⁰C to about 7O⁰C for a first reaction time and at about 150⁰C to about 17O⁰C for a second reaction time, wherein the total reaction time is about 16 hours to about 24 hours, to provide N ,N -dibenzyl-2,6-diamino-3,5-difluoropyridine; (b) reacting, for about 45 minutes to about 2 hours, the

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:

(a) reacting 2,3,5,6-tetrafiuoropyridine, benzylamine and a plurality of potassium phosphate particles having a mean diameter of about 420 micrometers (40 mesh) to about 2000 micrometers (10 mesh) at about 5O⁰C to about 7O⁰C for a first reaction time and at about 15O⁰C to about 17O⁰C for a second reaction time, wherein the total reaction time is about 16 hours to about 24 hours, to provide N ,N -dibenzyl-2,6-diamino-3,5-difluoropyridine;

(b) reacting for about 45 minutes to about 2 hours the formic acid and 20% palladium on carbon 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-difiuoropyridine, or a salt thereof, prepared as set forth in the preceeding embodiment.

(a) reacting 2,3,5,6-tetrafiuoropyridine, benzylamine and a plurality of potassium phosphate particles having a mean diameter of about 420 micrometers (40 mesh) to about 2000 micrometers (10 mesh) at about 50⁰C to about 7O⁰C for about 15 minutes to about 5 hours and at about 15O⁰C to about 17O⁰C for about 10 hours to about 20 hours to provide N ,N -dibenzyl-2,6-diamino-3,5-difluoropyridine.

(b) reacting, for about 45 minutes to about 2 hours, the N ,N -dibenzyl-2,6- diamino-3,5-difluoropyridine, formic acid and 20% palladium on carbon in water and isopropyl acetate, wherein the water is present in about 1 to about 5 molar equivalents per molar equivalent of the N ,N -dibenzyl-2,6-diamino-3,5-difluoropyridine.

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)

or a salt thereof, wherein R is alkyl, comprising: (c) reacting, at about 100⁰C to about 14O⁰C, a compound having formula (IV)

(IV), and a trialkylorthoformate for about 30 minutes to about 2 hours and reacting the product therefrom and a carboxylic anhydride for about 30 minutes to about 12 hours; and

(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:

(c) reacting, at about 100⁰C to about 14O⁰C, ethyl 3-oxo-3-(2,4,5- trifluorophenyl)propanoate and a trialkylorthoformate for about 30 minutes to about 2 hours and reacting the product therefrom and a carboxylic anhydride for about 30 minutes to about

12 hours; and

(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-

(2,4,5-trifiuorobenzoyl)-2-propenoate, mixing or not mixing the product mixture and water, and isolating or not 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.

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: (c) reacting, at about 100⁰C to about 14O⁰C, ethyl 3-oxo-3-(2,4,5- trifluorophenyl)propanoate and triethylorthoformate for about 30 minutes to about 2 hours and reacting the product therefrom and acetic anhydride for about 30 minutes to about

12 hours; and (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-

(2,4,5-trifluorobenzoyl)-2-propenoate, mixing or not mixing the product mixture and water, and isolating or not 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.

3,5-difluoropyridin-2-yl)amino)-2-(2,4,5-trifluorobenzoyl)-2-propenoate, or a salt thereof, comprising:

(c) reacting, at about HO⁰C to about 115⁰C, ethyl 3-oxo-3-(2,4,5- trifluorophenyl)propanoate and triethylorthoformate for about 30 minutes to about 2 hours and reacting the product therefrom and acetic anhydride for about 30 minutes to about

12 hours; and

(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-

-A- (2,4,5-trifluorobenzoyl)-2-propenoate, mixing or not mixing the product mixture and water, and isolating or not isolating the ethyl (2E/Z)-3-((6-amino-3,5-difluoropyridin-2-yl)amino)-2-

(2,4,5-trifluorobenzoyl)-2-propenoate.

3,5-difiuoropyridin-2-yl)amino)-2-(2,4,5-trifluorobenzoyl)-2-propenoate, or a salt thereof, comprising: (c) reacting, at about 110⁰C to about 115⁰C, ethyl 3-oxo-3-(2,4,5- trifluorophenyl)propanoate and triethylorthoformate for about 30 minutes to about 2 hours and reacting the product therefrom and acetic anhydride for about 30 minutes to about

12 hours; and (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-

(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.

Still another embodiment pertains to a process for making substantially pure

3-azetidinol hydrochloride comprising: (e) reacting (±)-2-(chloromethyl)oxirane, sodium bicarbonate and the compound having formula (I) to provide a (VI),

(VI), reacting the compound having formula (VI) and either hydrogen chloride at about -10⁰C to about O⁰C or (2E/Z)-2-butenedioic (maleic) acid at about 35⁰C to about 45⁰C, and isolating either the hydrochloride salt or the maleate acid salt, respectively, of the compound having formula (VI);

(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 5O⁰C to about 7O⁰C, 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.

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 to provide l-benzyl-3-azetidinol, reacting the l-benzyl-3-azetidinol and (2E/Z)-2-butenedioic acid at about 35°C to about 45⁰C, and isolating l-benzyl-3-azetidinol (2E/Z)-2-butenedioate;

(f) reacting the product of step (e) and potassium carbonate; and

(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 5O⁰C to about 7O⁰C 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 0⁰C and about 2O⁰C and then with toluene at about 4O⁰C.

(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 35⁰C to about 45⁰C, and isolating l-benzyl-3-azetidinol (2E/Z)-2-butenedioate; (f) reacting the product of step (e) and potassium carbonate; and

(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 5O⁰C to about 7O⁰C 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 0⁰C and about 2O⁰C and then with toluene at about 4O⁰C. 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 O⁰C to about 8O⁰C in acetonitrile and water to provide l-benzyl-3-azetidinol, reacting the l-benzyl-3-azetidinol and (2E/Z)-2-butenedioic acid at about 4O⁰C, and isolating 1 -benzyl-3-azetidinol (2E/Z)-2-butenedioate;

(f) reacting the l-benzyl-3-azetidinol (2E/Z)-2-butenedioate and potassium carbonate; and

(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 O⁰C and about 2O⁰C and then with toluene at about 4O⁰C.

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)

(vπ), or a salt thereof, wherein 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 OCH₃, OCH₂CH₃, F, Cl or Br, comprising:

(h) reacting the compound having formula (V) or a salt thereof, a non-protic acid and a bicyclic amine base;

(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)

(Vila) prepared as set forth in the preceeding embodiment. 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, a non-protic acid and a bicyclic amine base and not isolating or isolating the product;

(i) reacting the product of step (h), 3-azetidinol hydrochloride and a bicyclic amine base 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 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;

(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:

(k) reacting the compound having formula (VII), or a salt thereof, and a chlorinating agent and isolating or not isolating a compound having formula (VIH)

(Vm);

(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:

(k) reacting 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 and N-chlorosuccinimide and isolating or not isolating the product;

(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.

DETAILED DESCRIPTION OF THE INVENTION

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.

The term "alkyl," as used herein, means C]-alkyl, C₂-alkyl, C₃-alkyl, C₄-alkyl, C₅-alkyl, and C₆-alkyl. The term "C]-alkyl," as used herein, means methyl.

The term "C₂-alkyl," as used herein, means ethyl. The term "C₃-alkyl," as used herein, means prop-1-yl and prop-2-yl (isopropyl).

The term "C₄-alkyl," as used herein, means but-l-yl, but-2-yl, 2-methylprop-l-yl, and 2-methylprop-2-yl (tert-butyl).

The term "Cs-alkyl," as used herein, 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.

The term "Cg-alkyl," as used herein, 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.

The term "alcohol," as used herein, means methanol, ethanol, isopropanol, tert-butanol, and the like or a mixture thereof.

The term "alkanoyl halide," as used herein, 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 OCH₃, OCH₂CH₃, F, Cl or Br.

The term "aryloyl halide," as used herein, 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 OCH₃, OCH₂CH₃, F, Cl or Br.

4 .

The effect of the solubility of compounds having formula (VII), wherein R is ethyl and R ,6 i .s variable, in ethyl acetate, is shown in TABLE 1.

The term "amine base," as used herein, means triethylamine, N-methylmorpholine, and diisopropylethylamine.

The term "base," as used herein, means Na₂CO₃, NaHCO₃, K₂CO₃, KHCO₃, triethylamine, diisopropylethylamine and the like, or a mixture thereof.

The term "bicyclic amine base," as used herein, means l,5-diazabicyclo-[4.3.0]non-5- ene (DBN) and l,8-diazabicyclo[5.4.0]undec-7-ene (DBN).

The term "carboxylic anhydride," as used herein, means acetic anhydride, butyric anhydride, isobutyric anhydride and the like. The term "chlorinating agent," as used herein, means N-chlorosuccinimide, thionyl chloride, Cl₂, Cl₂O 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.

4 •

The yields of chlorinations of compounds having formula (VII), wherein R is

CH₂CH 3₃₃ a anndd R R⁵⁵ i iss C C((OO))RR⁶⁶,, w wlherein R⁶ is CH(CH₃)₂, with N-chlorosuccinimide in ethyl acetate is shown in TABLE 2.

The term "hydrogenolysis catalyst," as used herein, 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.

The term "hydroxide base," as used herein, means the hydroxide base of sodium, potassium, lithium, barium and the like or mixtures thereof.

The term "non-protic acid," as used herein, means lithium chloride, magnesium chloride, zinc chloride and the like, or mixtures thereof. The term "OH protecting group precursor," as used herein, means a carboxylic anhydride, an alkanoyl halide, an aryloyl chloride and the like.

The term "organic acid," as used herein, means formic acid, acetic acid, propionic acid and the like, or mixtures thereof.

The term "phosphate base," as used herein, means K₃PO₄, K₂HPO₄, KH₂PO₄, Na₃PO₄, Na₂HPO₄, NaH₂PO₄, and the like or mixtures thereof.

The term "substantially pure 3-azetidinol hydrochloride," as used herein, means 3-azetidinol hydrochloride having a low enough solvent content to be in powder form.

The term "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. Accordingly, 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.

The terms "R", "S", "Z", and "E" are as defined by the IUPAC 1974

Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13-10.

Compounds of this invention may exist as acid addition salts or base addition salts and may be prepared during their isolation or following their purification. Acid addition salts of compounds are prepared by reaction with 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, tartrate, thiocyanate, trichloroacetate, trifluoroacetate, para-toluenesulfonate, and undecanoate salts of compounds of this invention are meant to be embraced thereby. 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.

The following examples are meant to further embody the compounds and processes of this invention.

EXAMPLE 1

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 75⁰C for

10-16 hours, cooled to ambient temperature, filtered through diatomaceous earth (Celite®), concentrated to 300L, added over 1 hour to a solution of maleic acid (52.8Kg) in acetonitrile (310Kg) at 4O⁰C, cooled to 0⁰C, and filtered. The filtrant was washed with isopropyl acetate and dried to provide 113.6Kg of product. Mp 127-129°C; ¹H NMR (CD₃OD) δ 7.54-7.51 (m, 5H), 6.33 (s, 2H), 4.98 (brs, 4H, exchangeable), 4.72 (quintet, J=6 Hz, IH), 4.45 (s, 2H), 4.39 (m, 2H), 4.01 (m, 2H), 3.38 (CHD₂OD). EXAMPLE 2

A suspension of EXAMPLE 1 (111.6Kg) in ethyl acetate (605Kg) was treated with 25% aqueous potassium carbonate (560Kg) until the suspension homogenized. The orgainc layer was isolated and concentrated with an isopropanol azeotrope. 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 40⁰C for 30 minutes, treated with toluene (210Kg) over 1 hour, stirred for 30 minutes, cooled to ambient temperature, and filtered. The filtrant was washed with toluene a anndd d drriieedd u unnddeerr v vaaccuuuumm a att 5500⁰⁰CC t too p prroovviiddee 3366..77KKgg o offf product. ¹H NMR (CD₃OD) δ 4.57 (m, IH), 4.08 (m, 2H), 3.80 (m, 2H), 3.38 (CHD₂OD).

EXAMPLE 3 A suspension of benzylamine (106Kg) and milled (20 mesh) potassium phosphate

(45Kg) in N-methylpyrrolidinone (100Kg) at 5O⁰C was treated with 2,3,5,6- tetrafluoropyridine (30Kg), stirred for 30 minutes at 50-70⁰C and at 165°C for 12-18 hours, cooled to 1O⁰C, treated sequentially with water (240L) and 50% (v/v) isopropyl acetate/heptane (240L), isopropyl acetate (37.9 Kg), and water (88.5 Kg), each at 10⁰C. The bottom and middle layers were separated and washed with 2M HCl (120L) and water (120L), each precooled to 1O⁰C, and concentrated. 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 (CDCl₃, 300 MHz) δ 7.29-7.24 (m, 10H), 6.97 (t, IH), 4.57 (s, 4H).

EXAMPLE 4

A mixture of half- wet 20% palladium hydroxide on carbon (68.1Kg) was treated sequentially with 39.1% (w/w) EXAMPLE 3 in isopropyl acetate (410Kg total, 160Kg EXAMPLE 3), isopropyl acetate (550Kg) and 88% formic acid (57Kg). The mixture was stirred at 5O⁰C for 2 hours and filtered under nitrogen through diatomaceous earth (Celite®) with isopropyl acetate (200Kg) rinsing. 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 O⁰C and filtered. The filtrant was washed with heptane (220Kg) and dried under vacuum at 4O⁰C to provide 61.5Kg of product, which was s sttoorreedd i inn a ann o oppaaqqiue container under nitrogen. H NMR (CDCl₃, 300 MHz) δ 7.03 (t, IH), 4.5-4.0 (brs, 4H). EXAMPLE 5

A solution of 2,4,5-trifluorobenzoic acid (139.5Kg) in DMF (8.4Kg) and toluene (613Kg) was treated with thionyl chloride (139.4Kg), stirred at 60°C for 3.5 hours, cooled to 25⁰C, concentrated to 20% of its original volume, treated with toluene (600Kg), distilled and stored at ambient temperature.

EXAMPLE 6 A suspension of potassium ethyl malonate (50.8Kg) and magnesium chloride (34.5Kg) in toluene (130Kg) below 0⁰C was treated with THF (265L), cooled to 0°C, treated with triethylamine (75Kg), warmed to 5O⁰C, stirred for 1-5 hours, cooled to 0⁰C, 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. This procedure was repeated, and the organic layers were combined, concentrated with an ethanol (150L) azeotrope, treated with water (30% by weight of the organic layer), stirred for 3 hours at 0⁰C, and filtered. The andfiltrant was washed with 3:1 ethanol/water and dried under vacuum at 35-45°C to provide 86Kg of product. H NMR (CDCl₃) (keto) δ 7.75 (ddd, J=10.8, 10.8, 6.0Hz, IH), 7.02 (ddd, IH), 4.27 (q, J=7.2Hz, 2H), 3.95 (d, 4.2Hz, 2H), 1.35 (t, J=7.3Hz, 3H); (enol) δ 12.72 (s, IH), 7.85 (ddd, J=10.5, 9.6, 6.6Hz, IH), 6.96 (ddd, J=10.5, 10.5, 6.6Hz, IH), 5.84 (s, IH), 4.23 (q, J=7.2Hz, 2H), 1.27 (t, J=7.4Hz, 3H).

EXAMPLE 7A

A solution of EXAMPLE 6 (83.2Kg) in triethyl orthoformate (80.1Kg) at reflux was stirred for 0.5-1 hour, treated with acetic anhydride (103.5Kg), stirred for 12 hours and cooled to ambient temperature to provide a solution that was used immediately.

EXAMPLE 7B

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 fϊltrant was washed with (2:1) acetonitrile/water and water and dried under vacuum at 60⁰C to provide 119.5Kg of product. Mp 157-16O⁰C; ¹H NMR (CDCl₃, 300 MHz) (E) δ 1.15 (t, 3H), 4.16 (q, 2H), 4.64 (br s, 2H), 6.90 (m, IH), 7.22 (t, IH), 7.32 (m, IH), 9.03 (d, IH), 12.44 (bd, IH); (Z) δ 1.03 (t, 3H), 4.11 (q, 2H), 4.60 (br s, 2H), 6.90 (m, IH), 7.20 (t, IH), 7.48 (m, IH), 8.90 (d, IH), 11.17 (bd, IH). EXAMPLE 8A

A mixture of EXAMPLE 7 (115Kg) and lithium chloride (24.3Kg) in N-methylpyrrolidinone (769Kg) below 35⁰C was treated with DBU (946.1Kg) and stirred for 2 hours to provide a solution of EXAMPLE 8 A that was used immediately.

EXAMPLE 8B

The solution of EXAMPLE 8A below 4O⁰C 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 8C

The solution of EXAMPLE 8B was treated with isobutyric anhydride (99.7Kg), stirred at 35⁰C for 1-2 hours, cooled to 20-30⁰C, treated with ethyl acetate (104Kg) and 10% aqueous citric acid (570Kg) and filtered. The filtrant was washed with water and dried under vacuum at 50⁰C to provide 136Kg of product. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.49 (s, IH), 8.00 (dd, J=9.0, 9.3 Hz, IH), 7.75 (d, J=12.8 Hz, IH), 6.79 (br s, 2H), 5.95 (dd, J=I.5, 7.6 Hz, IH), 5.21 (m, IH), 4.36 (t, J=7.4 Hz, 2H), 4.02 (q, J=7.0 Hz, 2H), 3.95 (dd, J=3.7, 9.2 Hz, 2H), 2.58 (hept, J=7.0 Hz, IH), 1.26 (t, J=7.0 Hz, 3H), 1.11 (d, J=7.0 Hz, 6H).

EXAMPLE 9A

A suspension of EXAMPLE 8 (99.8Kg) in dichloromethane (813Kg) at 0-5⁰C was treated with l,3-dichloro-5,5-dimethylhydantoin (39.5Kg) in dichloromethane (540Kg) over 2 hours then with 10% aqueous sodium bisulfite (550Kg), separated from the water layer, washed with 5% sodium bicarbonate and water and concentrated. The concentrate was dissolved in methyl tert-butyl ether, crystallized at 5⁰C and dried at 65⁰C to provide 109 Kg of product as the methyl tert-butyl ether solvate. H NMR (CDCI₃) methyl tert-butyl ether solvate: δ 8.35 (s, IH), 7.95 (d, J=14.7Hz, IH), 7.24 (t, J=8.9Hz, IH), 5.19-5.11 (m, IH), 4.82-4.72 (m, 2H), 4.39-4.27 (m, 2H), 4.35 (q, J=7.5Hz, 2H), 3.19 (s, 3H), 2.57 (sept, J=7.1Hz, IH), 1.36 (t, J=7.4Hz, 3H), 1.17 (d, J=7.1Hz, 6H), 1.18 (s, 9H).

EXAMPLE 9B

A suspension of EXAMPLE 8 (110Kg) and N-chlorosuccinimide (31Kg) in ethyl acetate (785Kg) at 0-5⁰C was treated with phosphoric acid (2.5Kg) and water (IKg) while the temperature was kept at less than 5⁰C, warmed to 22⁰C, stirred for 3 hours, washed with sodium bicarbonate solution and 10% sodium sulfite solution and concentrated. The concentrate was treated with methyl tert-butyl ether (403Kg), and the slurry was stirred at 35⁰C for 30 minutes, cooled to 5⁰C and filtered. EXAMPLE 9C

A suspension of EXAMPLE 8 (4.91 g) and N-chlorosuccinimide (1.36 g) in ethyl acetate (500 mL) was treated with trifluoroacetic acid (0.15 mL) over 3 hours then with 5% aqueous sodium bicarbonate (25 mL), separated from the water layer, washed with 10% aqueous sodium hydrogen sulfate (10 mL) and concentrated to 50 mL with a methyl tert-butyl ether (250 mL) azeotrope. The concentrate was dissolved in methyl tert-butyl ether, and the solution was stirred at 45°C until solid formed, cooled to ambient temperature, and filtered. The filtrant was washed with methyl tert-butyl ether and dried under vacuum at 50⁰C to provide 5.33 g of product as the methyl tert-butyl ether solvate. ¹H NMR (CDCl₃) δ 8.35 (s, IH), 7.95 (d, J=14.7Hz, IH), 7.24 (t, J=8.9Hz, IH), 5.19-5.11 (m, IH), 4.82-4.72 (m, 2H), 4.39-4.27 (m, 2H), 4.35 (q, J=7.5Hz, 2H), 3.19 (s, 3H), 2.57 (sept, J=7.1Hz, IH), 1.36 (t, J=7.4Hz, 3H), 1.17 (d, J=7.1Hz, 6H), 1.18 (s, 9H).

EXAMPLE 10

A solution of N-chlorosuccinimide (25.3Kg) in methyl acetate (419Kg) at 17⁰C was treated with sulfuric acid (560 g), transferred to a slurry of EXAMPLE 8 (92.7Kg) in ethyl acetate (244Kg) at 17°C while maintaining the reaction temperature at 17°C, quenched/washed with 1.5% aqueous sodium bicarbonate (370Kg), washed with 10% aqueous sodium sulfite (200Kg) and concentrated. The concentrate was dissolved in isopropanol, treated with 4% (w/w) aqueous potassium hydroxide (750Kg), stirred at 5O⁰C 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 5O⁰C to provide 73Kg of product. ¹H NMR (CDCl₃) δ 14.63 (brs, IH), 8.70 (d, J=0.7Hz, IH), 7.95 (dd, J=9.9, 0.7Hz, IH), 7.83 (d, J=13.6Hz, IH), 6.75 (s, 2H), 5.75 (d, J=5.8Hz, IH), 4.61 (m, 12H), 4.47 (m, IH), 4.18 (m, 2H).

EXAMPLE HA

A solution of EXAMPLE 6 (3.65Kg) and triethyl orthoformate (4.93L) in toluene (18.5L) at reflux was stirred for 1 hour, treated with acetic anhydride (3.50L), stirred for 12- 24 hours, cooled to ambient temperature and concentrated with a toluene (8L) azeotrope until no triethyl orthoformate was detected by ¹H NMR (CDCl₃).

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 60-70⁰C for 1-2 hours, cooled to 30⁰C, 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. ¹H NMR (DMSO-d₆) δ 8.72 (s, IH), 8.14 (dd, J=I 1.4, 9.6Hz, IH), 8.03 (dd, J=I 1.2, 9.8Hz, IH), 7.51 (ddd, J=12.6, 6.6, 1.2Hz, IH), 6.82 (br s, 2H), 4.23 (q, J=7.5Hz, 2H), 1.28 (t, J=7.5Hz, 3H).

EXAMPLE 12 A mixture of EXAMPLE 2 (1.46Kg) and potassium bicarbonate (4.66Kg) in N-methylpyrrolidinone (36.8Kg) was stirred at 60⁰C 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 45⁰C, stirred until the intermediate alcohol was consumed, cooled to ambient temperature, and filtered. The filtrant was washed with N-methylpyrrolidinone (4.3Kg), and the filtrate was warmed to 7O⁰C, treated with water (40.4Kg), cooled to ambient temperature, and filtered. The filtrant was washed with water (2x12Kg) and dried under vacuum at 50⁰C to provide 4.36 Kg of product. ¹H NMR (DMSO-d₆) δ 8.31 (d, J=0.7 Hz, IH), 7.81 (dd, J=8.8, 9.9 Hz, IH), 7.55 (d, J=12.9 Hz, IH), 6.62 (br s, 2H), 5.75 (dd, J=1.5, 7.3 Hz, IH), 5.00 (m, IH), 4.16 (m, 2H), 4.02 (q, J=7.1 Hz, 2H), 3.77 (dd, J=3.3, 9.6 Hz, 2H), 1.87 (s, 3H), 1.07 (t, J=7.1 Hz, 3H).

EXAMPLE 13

A mixture of EXAMPLE 12 (1.97Kg) in dichloromethane (15.4Kg) at O⁰C was treated with l,3-dimethyl-5,5-dichlorohydantoin (890 g) in dichloromethane (7.7Kg) over 2.5 hours, stirred for 2 hours, treated with 10% aqueous sodium hydrogen sulfite (10.2Kg), separated from the water layer, washed with water, filtered, and concentrated with an ethyl acetate (4.2Kg) azeotrope. The concentrate was treated with ethyl acetate (9Kg) and heptane (3.5Kg), stirred at 5°C for 2 hours, and filtered. The filtrant was washed with 1:1 ethyl acetate/heptane (1.4Kg) and dried under vacuum to provide 1.84Kg of product. Mp 193-195⁰C; ¹H NMR (DMSOd₆, 300 MHz) δ 8.42 (d, J=0.7 Hz, IH), 7.93 (dd, J=9.9, 1.1 Hz, IH), 7.75 (d, J=13.9 Hz, IH), 6.72 (br s, IH), 5.11 (m, IH), 4.73 (m, 2H), 4.32 (m, 2H), 4.22 (dd, J=14.0, 7.0 Hz, 2H), 2.07 (s, 3H), 1.26 (t, J=14.0 Hz, 3H).

The preceeding is meant to be illustrative of this invention and not limiting. Obvious variations and changes are meant to be within the scope of this invention, as defined in the claims.

Claims

WE CLAIM:

1. A process for making 2,6-diamino-3,5-difluoropyridine or a salt thereof, comprising: (a) reacting 2,3,5,6-tetrafluoropyridine, benzylamine and a plurality of potassium phosphate particles having a mean diameter of about 420 micrometers (40 mesh) to about 2000 micrometers (10 mesh) at about 5O⁰C to about 7O⁰C for about 15 minutes to about 5 hours and at about 15O⁰C to about 17O⁰C for about 10 hours to about 20 hours to provide N ,N -dibenzyl-2,6-diammo-3,5-difluoropyridine. (b) reacting, for about 45 minutes to about 2 hours, the N ,N -dibenzyl-2,6- diamino-3,5-difluoropyridine, formic acid and 20% palladium on carbon in water and isopropyl acetate, wherein the water is present in about 1 to about 5 molar equivalents per molar equivalent of the N ,N -dibenzyl-2,6-diamino-3,5-difiuoropyridine.

2. 2,6-diamino-3,5-difluoropyridine, or a salt thereof, prepared as set forth in claim 1.

3. A process for making ethyl (2E/Z)-3-((6-amino-3,5-difIuoropyridin-2- yl)amino)-2-(2,4,5-trifluorobenzoyl)-2-propenoate, or a salt thereof, comprising:

(c) reacting, at about HO⁰C to about 115°C, ethyl 3-oxo-3-(2,4,5- trifluorophenyl)propanoate and triethylorthoformate for about 30 minutes to about 2 hours and reacting the product therefrom and acetic anhydride for about 30 minutes to about 12 hours; and

(d) reacting the product of step (c) and 2,6-diamino-3,5-difiuoropyridine 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.

4. (2E/Z)-3-((6-amino-3,5-difluoropyridin-2-yl)amino)-2-(2,4,5- trifiuorobenzoyl)-2-propenoate, or a salt thereof, prepared as set forth in claim 3.

5. A process for making substantially pure 3-azetidinol hydrochloride comprising:

(e) reacting (±)-2-(chloromethyl)oxirane, sodium bicarbonate and benzylamine at about O⁰C to about 8O⁰C in acetonitrile and water to provide l-benzyl-3-azetidinol, reacting the l-benzyl-3-azetidinol and (2E/Z)-2-butenedioic acid at about 4O⁰C, and isolating 1 -benzyl-3-azetidinol (2E/Z)-2-butenedioate;

(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 65⁰C 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 0⁰C and about 2O⁰C and then with toluene at about 4O⁰C.

6. Substantially pure 3-azetidinol hydrochloride prepared as set forth in claim 5.

7. A process for making 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, 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 l,8-diazabicyclo[5.4.0]undec-7-ene and not isolating the product;

(i) reacting the product of step (h), 3-azetidinol hydrochloride and l,8-diazabicyclo[5.4.0]undec-7-ene and not isolating the product; and

(j) reacting the product of step (i) and isobutyric anhydride and isolating or not isolating the product.

8. l-(6-amino-3,5-difluoro-2-pyridinyl)-6,7-difluoro-4-oxo-l,4-dihydro-3- quinolinecarboxylic acid, or a salt thereof, prepared as set forth in claim 7.

9. 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 claim 7.

10. 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.

11. A process for making 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, comprising: (k) reacting ethyl l-(6-amino-3,5-difiuoropyridin-2-yl)-6-fluoro-7-(3- (isobutyryloxy)azetidin-l-yl)-4-oxo-l,4-dihydroquinoline-3-carboxylate or a salt thereof and N-chlorosuccinimide and isolating or not isolating the product; and (1) reacting the product of step (k) and sodium hydroxide.

12. The process of claim 11 further comprising isolating the product of step (1).

13. ^(ό-Amino-S.S-difluoropyridin-Z-y^-S-chloro-β-fluoro-T-CS-hydroxyazetidin- l-yl)-4-oxo-l,4-dihydro-3-quinolinecarboxylic acid prepared as set forth in claim 12.