4-BROMO-3-METHYL-5-PROPOXYTHIOPHENE-2-C ARBOXYLIC ACID 2,5-

DIOXO-PYRROLIDIN-1-YL ESTER, ITS REGIO-SPECIFIC SYNTHESIS AND

INTERMEDIATE THERETO

FIELD OF THE INVENTION This invention is directed to 4-bromo-3-methyl-5-propoxythiophene-2-carboxylic acid 2,5- dioxo-pyrrolidin-1-yl ester, which is useful as an intermediate in preparing the tryptase inhibitor [4-(5-aminomethyl-2-fluoro-phenyl)-piperidin- 1 -yl]-(4-bromo-3-methyl-5-propoxy- thiophen-2-yl)-methanone. The invention is also directed to its regio-specific synthesis, and 3-methyl-5-propoxythiophene-2-carboxylic acid 2,5-dioxo-pyrrolidin-l-yl ester, which is useful as an intermediate in the preparation of 4-bromo-3-methyl-5-propoxythiophene-2- carboxylic acid 2,5-dioxo-pyrrolidin-l-yl ester.

BACKGROUND OF THE INVENTION

WO2001/13811 discloses compounds including [(benzylamine)-piperidin-l-yl] (aryl or heteroaryl)methanone as tryptase inhibitors, and describes potential uses for such compounds due to tryptase being implicated in a variety of biological processes, including degradation of vasodilating and bronchorelaxing neuropeptides (Caughey, et al., J. Pharmacol. Exp. Ther., 1988, 244, pages 133-137; Franconi, et al., J. Pharmacol. Exp. Ther., 1988, 248, pages 947- 951; and Tarn, et al., Am. J. Respir. Cell MoI. Biol, 1990, 3, pages 27-32) and modulation of bronchial responsiveness to histamine (Sekizawa, et al., J. Clin. Invest., 1989, 83, pages 175- 179).

WO2005/097780 more particularly discloses the (benzylamine)-piperidin-l-yl thienylmethanone compound of formula A ([4-(5-aminomethyl-2-fluoro-phenyl)-piperidin-l- yl] -(4-bromo-3 -methyl-5 -propoxy-thiophen-2-yl)-methanone),

its preparation, and use for treating disease states capable of being modulated by the inhibition of tryptase. WO2005/097780 also discloses that the compound of the formula A is prepared through the coupling of the following compounds 16 and 10, and subsequent deprotection of the coupled product as follows

Intermediate compound 16 was prepared according to following multistep preparation

While the aforesaid procedure works to prepare intermediate 16, however it utilizes a number of steps, employs acyclic intermediates exhibiting unpleasant odor characteristics, and doesn't start from a readily available thienyl starting material. The process also requires an extra step in the conversion of the ester moiety in compound 15 to the corresponding acid moiety in compound 16, i.e., a manipulation of carboxy functional group in intermediates leading to compound 16.

SUMMARY OF THE INVENTION

The present invention is directed to 4-bromo-3-methyl-5-propoxythiophene-2-carboxylic acid 2,5-dioxo-pyrrolidin-l-yl ester.

The present invention is also directed to the regio-specific synthesis of 4-bromo-3-methyl-5- propoxythiophene-2-carboxylic acid 2,5-dioxo-pyrrolidin-l-yl ester compound comprising the steps of iodinating 3-methyl-thiophene with an iodinating agent in the presence of a strong base in an non-protic polar or hydrocarbon solvent to yield 2-iodo-4-methylthiophene; Ullmann coupling the 2-iodo-4-methylthiophene with an alkali metal propoxide salt using a copper catalyst in propanol to yield 4-methyl-2-propoxythiophene;

-A-

coupling the 4-methyl-2-propoxythiophene with CO ₂ using strong base in an non- protic polar or hydrocarbon solvent to yield 3 -methyl-5 -propoxy-thiophene-2- carboxylic acid; esterifying the 3-methyl-5-propoxy-thiophene-2-carboxylic acid with N-hydroxysuccinimide in the presence of a coupling agent in an non-protic polar, hydrocarbon or halohydrocarbon solvent to yield 3 -methyl-5 -propoxythiophene-2- carboxylic acid 2,5-dioxo-pyrrolidin-l-yl ester; and brominating the 3-methyl-5-propoxythiophene-2-carboxylic acid 2,5-dioxo-pyrrolidin- l-yl ester with a brominating agent in an inert solvent to yield 4-bromo-3 -methyl-5 - propoxythiophene-2-carboxylic acid 2,5-dioxo-pyrrolidin-l-yl ester.

The invention is further directed to 3 -methyl-5 -propoxythiophene-2-carboxylic acid 2,5- dioxo-pyrrolidin-l-yl ester of the following structure,

that is an intermediate useful in the for the preparation of 4-bromo-3 -methyl-5 - propoxythiophene-2-carboxylic acid 2,5-dioxo-pyrrolidin-l-yl ester.

DETAILED DESCRIPTION OF THE INVENTION

The present invention will be better appreciated by reference to the following Detailed Description.

Definitions

As used above, and throughout the description of the invention including the appended claims, the following abbreviations and terms, unless otherwise indicated, are understood to have the following meanings:

"Alkali metal" means lithium, sodium, potassium or cesium.

"Alkali metal propoxide salt" means the salt form by the treatment of propanol with a strong base such as Cs ₂ CO ₃ , alkali metal base such as NaH, NaHMDS, KHMDS, LiHMDS, lithium

diisopropylamide (LDA), or alkylmetal such as alkyllithium, alkylpotassium, alkylsodium and alkylmagnesium wherein the alkyl is Ci_ ₅ alkyl, more preferably butyl, i.e., CsOPr, NaOPr, LiOPr or KOPr.

"Amidization coupling"means coupling to form an amide.

"Brominating agent" means a bromine source such as Br ₂ or NBS.

"Copper catalyst" means a copper catalyst capable of effecting an Ullmann coupling is selected from the group consisting of CuSCN, CuBr, CuI, CuCl, CuBF ₄ , CuPF ₆ , CuOTf, CuPF ₆ , CuBr ₂ , CuCl ₂ , and Cu ₂ O.

"Coupling co-solvent" means an additional inert organic solvent such as THF, toluene, 2- methylTHF, or dimethoxyethane that could be combined with the propanol coupling solvent.

"Esterifying" means the conversion of the carboxylic group to its corresponding ester.

"Coupling agent" means a compound useful for effecting an esterification selected from the group consisting of CDI, DCC, PFP, HOBT and HBTU, and the like.

"Hydrolyzing co-solvent": means an inert polar organic solvent such as an ether such as 1 ,4-Dioxane, t-butyl methyl ether (TBME), isopropyl ethyl ether and diethyl ether.

"Basic hydrolyzing" means using alkali metal hydroxides such as lithium, sodium or potassium hydroxides, or alkaline earth hydroxide to effect the hydrolysis.

"Iodinating agent" means I ₂ , diiodoethylene, ICl, or NBI.

"Iodinating" means reacting with an iodinating agent in the presence of a strong base.

"Non-protic polar solvent" means a solvent such ether, t-butyl methyl ether (TBME), isopropyl ethyl ether, THF, 1,4-dioxane or 1,3-dioxolane, or the like.

"Hydrocarbon solvent" means a solvent such as toluene, xylene or heptane, or the like.

"Halohydrocarbon solvent" means a C ₃ _ ₅ halo, preferably fluoro or chloro, substituted hydrocarbon such as chloroform or methylene chloride.

"Inert solvent" means an non-protic polar solvent, hydrocarbon solvent, halohydrocarbon solvent, nitrile solvent such as acetonitrile, or organic acid solvent such as acetic or propanoic acid.

"Strong base" means an alkali metal base such as NaH, NaHMDS, KHMDS, LiHMDS, lithium diisopropylamide (LDA), or alkylmetal base such as alkyllithium, alkylpotassium, alkylsodium and alkylmagnesium wherein the alkyl is Ci_ ₆ alicyclic (straight, branched or cyclic alkyl), more preferably butyl.

"Tertiary amine base" means a Ci_ ₅ organic base wherein the nitrogen thereof does not bear a hydrogen, such as triethylamine.

Particular Embodiments In a particular embodiment of the method according to the present invention, the iodinating is effected in THF.

In another particular embodiment of the method according to the present invention, the strong base used in the iodinating is LDA.

In another particular embodiment of the method according to the present invention, the iodinating agent is I ₂ .

In another particular embodiment of the method according to the present invention, the iodinating is effected at about -8O ⁰ C to about O ⁰ C.

In another particular embodiment of the method according to the present invention, the alkali metal propoxide salt is NaOPr.

In another particular embodiment of the method according to the present invention, the copper catalyst is CuI.

In another particular embodiment of the method according to the present invention, the coupling is carried out with heating at about 70 ⁰ C to about 120 ⁰ C depending on the solvent used and pressure utilized.

In another particular embodiment of the method according to the present invention, the solvent used for carrying out the coupling with CO ₂ is effected in THF.

In another particular embodiment of the method according to the present invention, the strong base used for coupling with CO ₂ is n-BuLi.

In another particular embodiment of the method according to the present invention, the coupling with CO ₂ is carried out at a temperature below -14°C, more particular from about - 22°C to about -14°C.

In another particular embodiment of the method according to the present invention, the solvent for the esterifying is dichloromethane.

In another particular embodiment of the method according to the present invention, the coupling agent used for the esterifying is λ^iV-carbonyldiimidazole.

In another particular embodiment of the method according to the present invention, the esterifying is carried out at about rt.

In another particular embodiment of the method according to the present invention, the inert solvent for bromination is halohydro carbon; more particularly dichloromethane.

In another particular embodiment of the method according to the present invention, the brominating is effected from about O ⁰ C to about 100 ⁰ C.

In another particular embodiment of the method according to the present invention, the brominating agent is Br ₂ .

In another particular embodiment of the method according to the present invention, the alcohol solvent for the amidization coupling is ethanol.

In another particular embodiment of the method according to the present invention, the amidization coupling is effected at about rt to about 3O ⁰ C.

In another particular embodiment of the method according to the present invention, the base for the amidization coupling is triethylamine.

In another particular embodiment of the method according to the present invention, the deprotecting is effected using aqueous base; aqueous NaOH.

In another particular embodiment of the method according to the present invention, the deprotecting is effected from about 5 ⁰ C to about 3O ⁰ C.

Examples

Preparatory Details

The starting materials used herein may be purchased or prepared by the application or adaptation of known methods or their obvious chemical equivalents.

The present invention may be better understood by reference to the following non-limiting

Examples, which are exemplary of the invention. The following examples are presented in order to more fully illustrate a particular embodiment of the invention. They should in no way be construed, however, as limiting the broad scope of the invention.

In the nuclear magnetic resonance spectra (NMR), reported infra, the chemical shifts are expressed in ppm relative to tetramethylsilane. Abbreviations have the following significances: br = broad, dd = double doublet, s = singlet; m = multiplet.

The synthesis of 4-bromo-3-methyl-5-propoxythiophene-2-carboxylic acid 2,5-dioxo- pyrrolidin-1-yl ester as is described in the examples that follow is represented by the following Scheme I.

Scheme I

Example 1 2-iodo-4-methyl-thiophene

A 3 L 4-Neck flask, equipped with overhead stirring, rubber septum, thermocouple and nitrogen inlet/outlet is charged with 3-methylthiophene (135 mL, 1.38 mol) and THF (1 L). The mixture is cooled to -20 ⁰ C and LDA (800 mL of Aldrich 2.5 M solution in THF/Heptane/ethylbenzene) is added via 12 gauge cannula over 35 minutes, adjusting the addition rate and cooling as necessary to maintain the reaction temp between -25°C and -15°C. The mixture is allowed to stir for 30 min after conclusion of addition, keeping the temperature below 0 ⁰ C.

In a separate 5 L flask equipped with overhead stirring, cooling bath, nitrogen flow and thermocouple, iodine (454 g, 1.3 equiv) is dissolved in THF (1.65 L), stirred at rt for 20 min to ensure complete dissolution and cooled to -20 ⁰ C. By the time the solution had cooled to -10 ⁰ C, iodine began to precipitate.

The anion solution is brought to 0 ⁰ C and cannulated over 40 minutes into a solution of the iodide, adjusting the rate as necessary to keep the reaction at or below -15°C. At the conclusion of the addition, the mixture is allowed to warm to 10 ⁰ C over 2h. The reaction is diluted with MTBE (1.0 L) and the reaction is quenched with ¹ A sat'd ammonium chloride (500 mL). The organic layer is washed with 0.5 N sodium thiosulfate (2 x 750 mL), 2 x 1 L

water (2 x IL) and brine (200 mL). The organic layers are allowed to sit in the separator for 4h and any separated water is drawn-off. The organic layers are concentrated by rotary evaporation at 30 ⁰ C and 175 mbar to 1.2 L. Essentially no product is detected by HPLC in either the aqueous phase or distillates. A small and unquantifϊable amount of unreacted 3-methylthiophene is lost to the washes and evaporation. Based on recovered starting material, off-isomer formation, and the absence of product in either washings or rotovap distillates, the yield for this reaction is calculated as 73% for the purposes of estimating the reagents for the Ullmann coupling.

¹ H NMR (CDCl ₃ , δ) 7.05 (IH, tight m), (6.91 (IH, tight m), (2.21, 3H, s)

Example 2 4-Methyl-2-propoxythiophene

In a 3 L 3N flask equipped with a reflux condenser atop a Dean-Stark trap, overhead stirring, headspace thermocouple, and nitrogen in/outlets, the 1.2 L of solution from Example 1 is combined with n-propanol. (1 L). The mixture is heated to reflux and distillates drawn-off and partially replaced with n-propanol (ca 1.2 L removed and 500 mL n-propanol added) until the head temperature reached 96 ⁰ C. The mixture is cooled to 50 ⁰ C and sodium t-butoxide (192 g, 2 mol, ca 2 equiv) is added as a solid causing an exotherm to ca 75 ⁰ C. The mix is held between 75 and 85°C until all solids dissolved. The reaction mixture is re-cooled to 50 ⁰ C and freshly prepared copper iodide ¹ (100 mmol, 19 g) in n-propanol (50 ml) is added as a slurry.. The mixture is heated to 95 ⁰ C. An HPLC assay at 30 minutes after the reaction temperature is reached showed the reaction to be complete. The mixture is diluted with heptane (1 L). Celite (190 g) is added and the resulting slurry is stirred for 60 min while cooling to rt. The mixture is filtered and the cake washed with heptane (500 mL). The combined filtrates and washings are washed with 5% aqueous disodium EDTA, (3 x 500 mL), water (3 x 500 mL) and brine (500 mL), to give a very dark organic layer which is concentrated to <200 mL (170 mbar ,60 ⁰ C) to give 159 g of a dark brown liquid that is 51A% desired compound by ¹ H NMR. The major impurities are heptane, ethylbenzene (from commercial LDA) and 2-iodo- 3 -methy lthiophene .

¹ Copper iodide is freshly ground in a mortar and pestle and sonicated for 5 minutes as a slurry in n-propanol.

¹ H NMR (CDCl ₃ , δ) 6.18 (IH, d); 6.02 (IH, d); 3.98 (2H, t); 2.15 (3H, S); 2.80 (2H, m); 1.05 (3H, t).

Example 3 3-Methyl-5-propoxythiophene-2-carboxylic acid

Crude 4-methyl-2-propoxythiophene of example 2 (calculated 79 g, 506 mmol) is transferred to a 2 L 3N flask equipped with overhead stirring, thermocouple, nitrogen in/outlets, a pressure-equalized dropping funnel and a rubber septum and diluted with 600 mL THF. The mix is cooled to -22°C and 2.5 M n-butyllithium (283 mL, 1.4 equiv) in hexanes is added rapidly dropwise via addition funnel over 16 min and the temp range -22 to -14°C, stabilizing around -21°C. After 30 min, keeping the temperature below -15°C, a sample of the reaction mixture is assayed (via a D ₂ O quench) to show ca 96% lithiation. Carbon dioxide is bubbled into the mixture, controlling the gas flow rate in order to keep the reaction temperature below -15°C. Addition of CO ₂ is continued until the exotherm subsides and the reaction temperature begins to drop. The reaction is quenched with 0.5 Naq sodium hydroxide (600 mL) and celite (50 g) is added. The mixture is stirred for 30 min and filtered through cloth. The cake is washed with 0.5 N sodium hydroxide (30 mL). The combined filtrates and washings gives a dark brown solution which is washed with heptane (3 x 200 mL). The pH of the aqueous phase is adjusted to ca 6.8, at which point a sticky brown/black tar is formed. The solution is filtered through cloth, giving a pale brown filtrate. pH adjustment is continued to 4.5, to give a copious brown precipitate which is filtered through cloth, washed with ice water (100 mL), air-dried on the frit and vacuum oven dried (12 h, 30 ⁰ C, 1.3 mbar) to give 3-methyl-5- propoxythiophene-2-carboxylic acid as a beige solid (81.1 g, 80%).

¹ H NMR (CDCl ₃ , δ) 6.12 (IH, s); 4.02 (3H, t); 2.49 (3H, s); 1.82 (2H, m); 1.05 (3H, t).

Example 4 3-Methyl-5-propoxythiophene-2-carboxylic acid 2,5-dioxo-pyrrolidin-l-yl ester

A 2 L 3 N flask with overhead stirring, cooling bath, thermocouple and nitrogen inlet/ outlet is charged with 3-methyl-5-propoxythiophene-2-carboxylic acid (85.0 g, 424 mmol),

N-hydroxysuccinimide (68.3 g, 1.4 equiv) and dichloromethane (700 mL) and stirred at rt. to give a brown solution and a 3°C endotherm on mixing. The cooling bath is filled with rt water and is present only to mitigate a slight exotherm. JV,jV-carbonyldiimidazole (104 g, 1.1 equiv)

is added as a solid in four 26.0 g portions spaced 10 min apart. Each addition is followed by a 2-3°C exotherm and gentle gas evolution. After the final addition, the mixture is stirred a rt for 3h or overnight. The mixture is quenched with half saturated ammonium chloride (200 mL) and is washed with water (3 x 150 mL) and brine (150 mL). The product is isolated by solvent exchange with heptane at 170 mbar and 30 ⁰ C. After solid formed, the mixture is cooled to rt and then to 5°C to give a bright yellow solid which is isolated by filtration through cloth, washed with heptane, air dried on a frit for 20 min and further dried (30 ⁰ C, 1.5 in Hg) to give 3-methyl-5-propoxythiophene-2-carboxylic acid 2,5-dioxo-pyrrolidin-l-yl ester (104 g, 83%).

¹ H NMR (CDCl ₃ , δ) 6.20 (IH, s); 4.05 (3H, t); 2.95 (4H, s); 2.51 (3H, s); 1.82 (2H, m); 1.05 (3H, t).

Example 5 4-Bromo-3-methyl-5-propoxythiophene-2-carboxylic acid 2,5-dioxo-pyrrolidin- 1-yl ester

A 2 L 3 N round bottom flask equipped with thermocouple, ice bath and overhead stirring is charged with 3-methyl-5-propoxythiophene-2-carboxylic acid 2,5-dioxo-pyrrolidin-l-yl ester (81 g, 273 mmol), isopropanol (500 mL) and DCM (350 mL) to give a very thin slurry. The mixture is cooled to <5°C and a solution of bromine (22 mL, 328 mmol, 1.2 equiv) in heptane (80 mL) is added dropwise over the temperature range 4 to 11 ⁰ C. The thin slurry thinned still further but the mixture did not completely homogenize. The solution is added over 19 min and the reaction assayed as complete. The reaction is diluted with DCM (600 mL) and quenched with 1 N sodium thiosulfate (250 mL). The organic layer is washed with water (2 x 350 mL). HPLC assay at this point showed ca 6.3% unreacted starting material, presumably due to coating of glassware by starting material rendering it undetectable to a solution assay. The organic phases are dried (Na ₂ SO ₄ ) and concentrated (30 ⁰ C, 125 mbar) to give a brown solid which is re-dissolved in DCM (700 mL) and treated at 5°C with bromine (4 mL, 78 mmol, 0.3 equiv) in heptane (20 mL) to complete the reaction. The organic phase is partitioned against 250 mL 1 N aq sodium thiosulfate (250 mL) and washed with water (2 x 250 mL) and brine (250 mL). The solvent volume is reduced (30 ⁰ C, 125 mbar) to 300 mL and 400 mL heptane is added (effecting some crystallization). The mixture is concentrated to dryness by rotary evaporation to give 104 g of a brown solid. The crude product is

recrystallized from refluxing IPA (500 mL), and dried (40 ⁰ C, 1.5 in Hg) to give 93 g of 4- bromo-3-methyl-5-propoxythiophene-2-carboxylic acid 2,5-dioxo-pyrrolidin-l-yl ester as a tan solid (91%).

¹ H NMR (CDCl ₃ , δ) 4.19 (2H, t); 2.92 (4H, s); 3.59 (3H, s); 1.95 (2H, m); 1.08 (3H, t)

Example 6 [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin- 1 -yl]-(4-bromo-3-methyl-5 -propoxy-thiophen-2-yl)-methanone A 5-L, 3-neck round-bottom flask is charged with 2,2,2-trifluoro-N-(4-fluoro-3-piperidin-4-yl- benzyl)-acetamide hydrochloride (176.7 g, 0.518 mol) and 1.51 L of absolute EtOH. The mixture is stirred and triethylamine (215 mL, 1.55 mol) added. The mixture is stirred for 3 min and then 4-bromo-3-methyl-5-propoxythiophene-2-carboxylic acid 2,5-dioxo-pyrrolidin- l-yl ester (194 g, 0.516 mol) is added causing an exotherm that warms the mixture to 26 ⁰ C. The reaction mixture is stirred for 18 h, and then partitioned between 1.5 L of water and 1.5 L of TBME. The organic phase is washed with water (2 x 0.5 L), 1 N aq HCl (0.5 L) and brine (0.2 L). The dark amber organic phase is passed through a short pad of SiO ₂ (h=0.5", φ=3.5"), eluting with 0.3 L of EtOAc. No significant color reduction occurs. The solution is cooled to 7 ⁰ C, and 194 mL of aq. 50% NaOH is added causing an exotherm that warms the mixture to 24 ⁰ C. After 3 h, the mixture is washed with water (2 x 1 L, 1 x 0.8 L), brine (0.5 L) and then the organic phase is dried over sodium sulfate. The solution is cooled to 13 ⁰ C, and 4 N HCl in 1,4-dioxane (135 mL, 0.54 mol) is added dropwise. The mixture is stirred for 3 h, and then the product is isolated by filtration (quite slow), washed with MTBE and air-dried for 15 h to afford 130.2 g (50%) of [4-(5-aminomethyl-2-fluoro-phenyl)-piperidin-l-yl]-(4-bromo- 3- methyl-5

-propoxy-thiophen-2-yl)-methanone as a light-beige solid.