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(11) EP 2 483 243 B1

(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07D 211/18 (2006.01) C07F 5/02 (2006.01) 18.03.2015 Bulletin 2015/12 C07D 213/16 (2006.01)

(21) Application number: 10757923.7 (86) International application number: PCT/US2010/049737 (22) Date of filing: 22.09.2010 (87) International publication number: WO 2011/037947 (31.03.2011 Gazette 2011/13)

(54) SYNTHESISOF (4- FLUORO-3-PIPERIDIN-4-YL-BENZYL)-CARBAMIC ACIDTERT- BUTYLESTER AND INTERMEDIATES THEREOF SYNTHESE VON (4-FLUOR-3-PIPERIDIN-4-YL-BENZYL)-CARBAMINSÄURE-TERT- BUTYLESTER AND ZWISCHENPRODUKTEN DARAUS SYNTHÈSE DE L’ESTER TERT-BUTYLIQUE DE L’ACIDE (4-FLUORO-3-PIPÉRIDIN-4-YL- BENZYL)-CARBAMIQUE ET INTERMÉDIAIRES CORRESPONDANTS

(84) Designated Contracting States: • SLEDESKI, Adam W. AL AT BE BG CH CY CZ DE DK EE ES FI FR GB Bridgewater, New Jersey 08807 (US) GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO SE SI SK SM TR (74) Representative: Tepfenhárt, Dóra Andrea Designated Extension States: Chinoin Gyógyszer és Vegyészeti Termékek BA ME RS Gyàra Zrt Tó u. 1-5 (30) Priority: 24.09.2009 US 245325 P 1045 Budapest (HU)

(43) Date of publication of application: (56) References cited: 08.08.2012 Bulletin 2012/32 WO-A1-2005/097780

(73) Proprietor: Sanofi-Aventis U.S. LLC • VAZ R J ET AL: "Design of bivalent ligands using Bridgewater, NJ 08807 (US) hydrogen bond linkers: synthesis and evaluation of inhibitors for human beta-tryptase" (72) Inventors: BIOORGANIC & MEDICINAL CHEMISTRY • CHOY, Nakyen LETTERS,PERGAMON, ELSEVIER SCIENCE, GB Bridgewater, New Jersey 08807 (US) LNKD- DOI:10.1016/J.BMCL.2004.09.065, vol. 14, • SHAY, John J., Jr. no. 24, 20 December 2004 (2004-12-20), pages Bridgewater, New Jersey 08807 (US) 6053-6056, XP004645154 ISSN: 0960-894X

Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 483 243 B1

Printed by Jouve, 75001 PARIS (FR) EP 2 483 243 B1

Description

FIELD OF THE INVENTION

5 [0001] This invention is directed to a method of synthesis of 4-fluoro-3-piperidin-4-yl-benzyl)-carbamic acid tert-butyl ester (I), and the intermediates thereof.

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BACKGROUND OF THE INVENTION 20 [0002] WO2001/13811 discloses compounds including [(benzylamine)-piperidin-1-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. Phar- macol. Exp. Ther., 1988, 244, pages 133-137; Franconi, et al., J. Pharmacol. Exp. Ther., 1988, 248, pages 947-951; 25 and Tam, et al., Am. J. Respir. Cell Mol. Biol., 1990, 3, pages 27-32) and modulation of bronchial responsiveness to histamine (Sekizawa, et al., J. Clin. Invest., 1989, 83, pages 175-179). [0003] WO2005/097780 more particularly discloses the (benzylamine)-piperidin-1-yl thienylmethanone compound of formula A, its preparation, and use for treating disease states

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40 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 14 and I as shown in Scheme A, and subsequent deprotection of the coupled product.

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[0004] Compound I was prepared by the seven step synthesis as shown in the below Scheme B.

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[0005] While the aforesaid synthesis works to prepare compound I on a laboratory scale, compound I would be better prepared employing fewer steps. The instant invention represents a significant improvement over the Scheme B synthesis 35 route as it is significantly shorter.

SUMMARY OF THE INVENTION

[0006] The presentinvention is directedto an improved methodfor preparing4-fluoro-3-piperidin-4-yl-benzyl)-carbamic 40 acid tert-butyl ester (I); more particularly, to its synthesis in three steps. The first step comprises a boronic acid formation by treatment of (4-fluoro-benzyl)-carbamic acid tert-butyl ester under boronation conditions. The second step involves reacting the resultant 5-((tert-butoxycarbonyl)aminomethyl)-2-fluorobenzeneboronic acid of the first step with a 4-halo- pyridine such as 4-chloro-pyridine or 4-bromo-pyridine under Suzuki coupling conditions to yield (4-fluoro-3-pyridin-4- yl-benzyl)-carbamic acid tert-butyl ester. The third step involves employing selective hydrogenation conditions on the 45 product of the second step to yield compound I. The invention is also directed to the intermediates 5-((tert-Butoxycarb- onyl)aminomethyl)-2-fluorobenzeneboronic acid (compound 11), and (4-fluoro-2-pyridin-4-yl-benzyl)-carbamic acid tert- butyl ester (compound 13).

DETAILED DESCRIPTION OF THE INVENTION 50 [0007] As used throughout the specification, the following abbreviations and definitions, unless otherwise indicated, shall be understood to have the following meanings:

List of Abbreviations 55 [0008]

n-BuOAc n-butyl acetate

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n-BuLi n-butyl lithium t-Bu tert-butyl t-BuOH tert-butanol DCM dichloromethane, CH2Cl2 or methylenechloride 5 DMF dimethylformamide DMSO dimethylsulfoxide dppf 1,1 ’-bis(diphenylphosphino)ferrocene eq equivalent(s) Et ethyl 10 Et2O diethyl ether EtOH ethanol EtOAc ethyl acetate HPLC high performance liquid chromatography Me methyl 15 MTBE methyl t-butyl ether MeOH methanol

Na2CO3 sodium carbonate Na2SO4 sodium sulfate NMR nuclear magnetic resonance 20 Pd(PPh3)4 tetrakistriphenylphosphine palladium Pd(PPh3)2Cl2 bistriphenylphosphine palladium (II) dichloride PdCl2dppf 1,1’-bis(diphenylphosphino) ferrocene palladium (II) dichloride Pd(dtbpf)Cl2 (1,1’Bis(di-t-butylphosphino)ferrocene palladium dichloride Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0) 25 Pd(OAc)2 palladium(II) acetate P(Cy)3 tricyclohexylphosphine t-Bu3Ptri-t-butylphosphine PPh3 triphenylphosphine PrOH propanol 30 i-PrOH iso-propanol i-PrOAc iso-propyl acetate t-BuOK potassium tert-butoxide PPSE poly-phosphoric acid trimethylsilylester rt room temperature 35 Rt Retention time TFA trifluoroacetic acid TFAA trifluoroacetic anhydride THF tetrahydrofuran TLC thin layer chromatography 40 Terms

[0009] "aqueous acid" means an aqueous solution of an inorganic (mineral) acid such as hydrochloric acid, phosphoric acid and the like, or an aqueous solution of an organic acid such as acetic acid and the like. 45 [0010] "boronation conditions" mean conditions using a superbase, a boronic acid forming agent, boronation solvent, and boronation reaction temperature. [0011] "superbase" means an extremely strong base, such as combination of an organolithium reagent of formula RLi where R is an alkyl or aryl group having 1-12 carbons and a bulky potassium alkoxide such as potassium tert-butoxide or potassium tert-pentoxide and the like. 50 [0012] "boronic acid forming agent" means a trialkyl boronate such as trimethyl borate, triethyl borate, tripropyl borate, triisopropyl borate, tributylborate and the like. [0013] "boronation solvent" means a solvent an ether solvent such as diethyl ether, THF, 2-methyltetrahydrofuran, MTBE, dimethoxyethane and the like [0014] "boronation temperature" means from about -30 to -100 °C. 55 [0015] "4-halopyridine" means 4-(iodo, bromo or chloro)pyridine, or salt thereof [0016] "Suzuki coupling conditions" mean conditions using a Suzuki coupling solvent, Suzuki coupling catalyst and Suzuki coupling reaction temperature. [0017] "Suzuki coupling solvent" means an alcohol solvent with a boiling point ≥ of isopropyl alcohol, such as n-propyl

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alcohol, n-butyl alcohol or the like; polar aprotic solvent such as dimethylformamide, 1-methyl-2-pyrrolidone, dimethyl- sulfoxide, or the like; ether solvent such as THF, 2-methylTHF, dimethoxyethane, MTBE or the like; or mixture of any of the aforesaid mentioned solvents and water or toluene. [0018] "Suzuki coupling catalyst" means a Pd catalyst such as Pd(PPh 3)4, Pd(PPh3)2Cl2, Pd2(dba)3, PdCl 2dppf, Pd(dt- 5 bpf)Cl2, or the like; or Pd catalyst such as Pd(OAc)2, Pd2(dba); or the like in conjunction with a phosphine ligand such as PPh3, dppf, t-Bu3P, P(Cy)3 or the like. [0019] "Suzuki coupling reaction temperature" means a temperature from about 60 °C to about 100°C, the temperature of the boiling point of the Suzuki coupling reaction mixture. [0020] "hydrogenation conditions" means conditions using a hydrogenation catalyst, hydrogenation solvent, hydro- 10 genation reaction temperature, and hydrogenation pressure. [0021] "hydrogenation reaction solvent" means an ester solvent such as EtOAc, i-PrOAc, BuOAc and the like; alcohol solvent such as methanol, ethanol, isopropyl alcohol and the like; or AcOH; or a mixture of an alcohol or ester solvent and water and acetic acid

[0022] "hydrogenation catalyst" means Pt/C, PtO 2, Pd/C, Pd(OH)2, Rh/C and the like, with or without added inorganic 15 acid such as HCl and the like, or organic acid such as acetic acid and the like. [0023] "hydrogenation reaction temperature" means from about 10 to about 60 °C. [0024] "hydrogenation pressure" means from about 10 to about 1000 psi of hydrogen (upper limit dictated by equipment capability).

20 Particular Embodiments

[0025] In a particular embodiment of the method according to the present invention, the superbase means combination of n-butyl lithium and potassium tert-butoxide ("Schlosser base"). [0026] In another particular embodiment of the method according to the present invention, "boronation solvent" means 25 THF. [0027] In another particular embodiment of the method according to the present invention, "boronic acid forming agent" means triisopropyl borate. [0028] In another particular embodiment of the method according to the present invention, the boronation temperature is about -70°C to about -45°C. 30 [0029] In another particular embodiment of the method according to the present invention, the Suzuki coupling solvent is dimethoxyethane. [0030] In another particular embodiment of the method according to the present invention, the Suzuki coupling catalyst is Pd(PPh3)4. [0031] In another particular embodiment of the method according to the present invention, the Suzuki coupling is 35 effected at about 85°C. [0032] In another particular embodiment of the method according to the present invention, the hydrogenation solvent is EtOAc. [0033] In another particular embodiment of the method according to the present invention, the hydrogenation catalyst is Pt/C. 40 [0034] In another particular embodiment of the method according to the present invention, the hydrogenation reaction temperature is at about ambient temperature. [0035] In another particular embodiment of the method according to the present invention, the hydrogenation pressure is from about 10 to about 60 psi.

45 Preparatory Details

[0036] The starting materials for preparing compound I according to Scheme 1 below are commercially available.

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[0037] 4-(tert-Butoxycarbonyl)aminomethyl)-fluorobenzene (compound 10), prepared according to the method of Tet- 15 rahedron 2965, 57, 2001 is reacted with a superbase, in an ether solvent at a sufficiently low temperature as for example from about -100°C to about -30°C. The resultant mixture is reacted with a trialkyl boronate. Quenching the resultant mixture with an aqueous acid provides 5-((tert-butoxycarbonyl)aminomethyl)-2-fluorobenzeneboronic acid (compound 11). Compound 11 is reacted with a 4-halopyridine (compound 12) or their hydrohalide salt forms in an alcoholic solvent with a boiling point of at least that of isopropyl alcohol, a polar aprotic solvent or an ether solvent. Compound 11 and 20 compound 12 in mixture of any of the above mentioned solvents and water in the presence of a suitable Suzuki coupling catalyst at Suzuki coupling reaction temperature provides compound 13. [0038] Compound 13 is reduced under hydrogenation conditions to compound I by treatment with hydrogen in the presence of a hydrogenation catalyst, with or without added inorganic acid such as HCl and the like, or organic acid such as acetic acid and the like, in a hydrogenation reaction solvent; at hydrogenation reaction temperature, and hydro- 25 genation pressure.

Example

[0039] The present invention may be better understood by reference to the following non-limiting Example, which is 30 exemplary of the invention. The following example is 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. [0040] 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. 35 EXAMPLE 1

Step A: Preparation of 5-((tert-Butoxycarbonyl)aminomethyl)-2-fluorobenzeneboronic acid (11)

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[0042] To a mixture of 4-(tert-Butoxycarbonyl)aminomethyl)-fluorobenzene (Tetrahedron 2001, 57, page 2965 which is incorporated herein by reference) (2.84 g 12.6 mmol) and t-BuOK (2.83 g, 12.6 mmol) in THF (40 mL) at -60 to -70 °C, is added n-BuLi (15.75 mL, 1.6 M, 25.2 mmol) over a period of approximately 10 min. The reaction mixture is stirred 55 at this temperature for additional 1.5 h, after which triisopropyl borate (2.37 g, 12.6 mmol) is added. The mixture is allowed to warm to -45 °C, after which it was quenched with 2N aqueous HCl. The reaction mixture is allowed to warm to room temperature with stirring overnight. The resulting suspension is isolated by filtration and dried in a vacuum oven 1 to afford 1.9 g (56 %) of compound 11 as a white solid. H NMR (300 MHz, CDCl3) δ 7.72 (m, 1H), 7.38 (m, 1H), 7.01

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(m, 1H), 5.22 (d, J = 6.1 Hz, 2H), 4.28 (d, J = 5.4 Hz, 2H), 1.45 (s, 9H).

Step B: Preparation of (4-fluoro-3-pyridin-4-yl-benzyl)-carbamic acid tert-butyl ester (13)

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20 [0044] A mixture of compound 11 (135 mg, 0.5 mmol), 4-chloropyridine hydrochloride (107 mg, 0.713 mmol), tet- rakis(triphenylphosphine)palladium (45 mg, 0.04 mmol) and Na 2CO3 (160 mg, 1.51 mmol) in dimethoxyethane (2.2 mL) and water (0.7 mL) mixture, is heated to 85 °C for 5 h. The mixture is cooled to rt and partitioned between water and EtOAc. The organic phase is dried using Na2SO4 and concentrated on rotary evaporator to afford 100 mg (59 %) of 1 compound 13. H NMR (300 MHz, CDCl 3) δ 8.68-8.62 (m, 2H), 7.80-7.42 (m, 2H), 7.40-7.35 (m, 1H), 7.36-7.24 (m, 1H), 25 7.18-7.08 (m, 1H), 5.26-5.18 (br s, 1H), 4.25 (d, J = 5.5 Hz, 2H), 1.44 (s, 9H).

Step C: Preparation of (4-Fluoro-3-piperidin-4-yl-benzyl)-carbamic acid tert-butyl ester hydrochloride (I)

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[0046] A mixture of compound 13 (1.25g, 4.1 mmol) and PtO2 (200 mg) in EtOAc (20 mL) and acetic acid (10 mL) is hydrogenated in a Parr shaker under H2 (50 psi -60 psi) overnight.n -BuOAc is added (40 mL) to the mixture. The 45 resultant suspension is filtered through celite, and concentrated up to around 30 mL of crude solution. The crude solution was introduced to a solution of 2N HCl in ethyl ether (5 mL) and MTBE (35 mL) at 0°C. The resultant solid is collected by filtration followed by washing with an additional MTBE and drying in oven at 50°C to give 0.93 (65%) g of product I as an HCl salt. 1H NMR (300 MHz, DMSO-d6) δ 9.30-9.10 (br s, 2H), 7.44-7.35 (m, 1H), 7.16-7.03 (m, 3H), 4.08 (d,J = 6.0 Hz, 2H), 50 3.31 (br s, 2H), 3.20-2.87 (m, 3H), 1.95-1.80 (m, 4H), 1.39 (s, 9H).

Claims

55 1. A method for preparing 5-(( tert-butoxycarbonyl)aminomethyl)-2-fluorobenzene-boronic acid, comprising boronation of 4-(tert-butoxycarbonyl)aminomethyl)-fluorobenzene with a trialkyl boronate under boronation conditions, and then quenching the resultant mixture with an aqueous acid to yield 5-((tert-butoxycarbonyl)aminomethyl)-2-fluoro-ben- zeneboronic acid.

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2. The method of claim 1 wherein the boronation conditions uses a superbase.

3. The method of claim 2 wherein the superbase is a combination of an organolithium reagent of formula RLi where R is an alkyl or aryl group having 1-12 carbons and a bulky potassium alkoxide such as potassium tert-butoxide or 5 potassium tert-pentoxide and the like.

4. The method of claim 3 wherein the superbase is a combination of n-butyllithium and potassium tert-butoxide.

5. The method of claim 1 wherein the trialkyl boronate is selected from trimethyl borate, triethyl borate, tripropyl borate, 10 triisopropyl borate, tributylborate and the like.

6. The method of claim 1 wherein the boronation conditions uses a boronation solvent which is an ether solvent selected from diethyl ether, THF, 2-methyltetrahydrofuran, MTBE, dimethoxyethane and the like.

15 7. The method of claim 1 wherein the boronation conditions uses a boronation reaction temperature from about -100°C to about -30°C.

8. The method of claim 1 wherein the aqueous acid is HCl or H3PO4.

20 9. A method for preparing (4-fluoro-3-pyridin-4-yl-benzyl)-carbamic acid tert-butyl ester comprising coupling 5-(( tert-bu- toxycarbonyl)aminomethyl)-2-fluorobenzeneboronic acid prepared according to claim 1 and a 4-halopyridine under Suzuki coupling conditions to yield 4-fluoro-3-pyridin-4-yl-benzyl)-carbamic acid tert-butyl ester.

10. The method according to claim 9 wherein the Suzuki coupling conditions uses a Suzuki coupling solvent selected 25 from an alcoholic solvent with a boiling point of at least that of i-propyl alcohol, polar aprotic solvent, or ether solvent, or mixture of any of the aforesaid mentioned solvents and water or toluene.

11. The method according to claim 10 wherein the Suzuki coupling solvent is an ether solvent selected from THF, toluene, 2-methylTHF, or dimethoxyethane. 30 12. The method according to claim 9 wherein the Suzuki coupling conditions uses a Suzuki catalyst selected from Pd catalyst such as Pd(PPh3)4, Pd(PPh3)2Cl2, Pd2(dba)3, PdCl2dppf, Pd(dtbpf)Cl2, or the like; or Pd catalyst such as Pd(OAc)2, Pd2(dba)3 or the like in conjunction with a phosphine ligand such as PPh3, dppf, t-Bu3P, P(Cy)3 or the like, and a strong base. 35 13. The method according to claim 9 wherein the Suzuki coupling conditions uses a Suzuki coupling reaction temperature of from about 60°C to about 100°C.

14. The method in claim 9 wherein the 4-halopyridine is 4-chloropyridine. 40 15. A method for preparing (4-fluoro-3-piperidin-4-yl-benzyl)-carbamic acid tert-butyl ester hydrochloride (I), comprising reducing (4-fluoro-3-pyridin-4-yl-benzyl)-carbamic acid tert-butyl ester prepared according to claim 11 under hydro- genation reducing conditions, and then followed by HCl work-up to yield (4-fluoro-3-piperidin-4-yl-benzyl)-carbamic acid tert-butyl ester hydrochloride. 45 16. The method according to claim 15 wherein the hydrogenation reducing conditions uses a hydrogenation catalyst

selected from Pt/C, PtO2, Pd/C, Pd(OH)2, Rh/C and the like, with or without added inorganic acid such as HCl and the like, or organic acid such as acetic acid and the like.

50 17. The method according to claim 15 wherein the hydrogenation reducing conditions uses a hydrogenation solvent selected from an ester solvent such as EtOAc, i-PrOAc, BuOAc and the like; alcohol solvent such as methanol, ethanol, isopropyl alcohol and the like; or AcOH; or a mixture of an alcohol or ester solvent and water and acetic acid.

18. The method according to claim 15 wherein the hydrogenation reducing conditions uses a hydrogenation reaction 55 temperature from about 10 to about 60 °C.

19. The method according to claim 15 wherein the hydrogenation reaction temperature is at about ambient temperature.

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20. The method according to claim 15 wherein the hydrogenation reducing conditions uses a hydrogenation pressure from about 10 to about 1000 psi.

5 Patentansprüche

1. Verfahren zur Herstellung von 5-((tert-Butoxycarbonyl)aminomethyl)-2-fluorbenzolboronsäure, bei dem man 4-((tert-Butoxycarbonyl)aminomethyl)fluorbenzol unter Boronierungsbedingungen mit einem Boronsäuretrialkyles- ter boroniert und dann die erhaltene Mischung mit einer wässrigen Säure quencht, was 5-(( tert-Butoxycarbonyl)ami- 10 nomethyl)-2-fluorbenzolboronsäure ergibt.

2. Verfahren nach Anspruch 1, bei dem bei den Boronierungsbedingungen eine Superbase verwendet wird.

3. Verfahren nach Anspruch 2, bei dem es sich bei der Superbase um eine Kombination aus einem Organolithiumre- 15 agens der Formel RLi, wobei R für eine Alkyl- oder Arylgruppe mit 1-12 Kohlenstoffatomen steht, und einem sperrigen Kaliumalkoxid wie Kalium-tert-butoxid oder Kalium-tert-pentoxid und dergleichen handelt.

4. Verfahren nach Anspruch 3, bei dem es sich bei der Superbase um eine Kombination aus n-Butyllithium und Kalium- tert-butoxid handelt. 20 5. Verfahren nach Anspruch 1, bei dem man den Boronsäuretrialkylester aus Borsäuretrimethylester, Borsäuretriet- hylester, Borsäuretripropylester, Borsäuretriisopropylester, Borsäuretributylester und dergleichen auswählt.

6. Verfahren nach Anspruch 1, bei dem bei den Boronierungsbedingungen ein Boronierungslösungsmittel verwendet 25 wird, bei dem es sich um ein aus Diethylether, THF, 2-Methyltetrahydrofuran, MTBE, Dimethoxyethan und derglei- chen ausgewähltes Ether-Lösungsmittel handelt.

7. Verfahren nach Anspruch 1, bei dem bei den Boronierungsbedingungen eine Boronierungsreaktionstemperatur von etwa -100°C bis etwa -30°C verwendet wird. 30

8. Verfahren nach Anspruch 1, bei dem es sich bei der wässrigen Säure um HCl oder H 3PO4 handelt.

9. Verfahren zur Herstellung von (4-Fluor-3-pyridin-4-ylbenzyl)carbamidsäure-tert-butylester, bei dem man gemäß Anspruch 1 hergestellte 5-((tert-Butoxycarbonyl)aminomethyl)-2-fluorbenzolboronsäure und ein 4-Halogenpyridin 35 unter Suzuki-Kupplungsbedingungen kuppelt, was (4-Fluor-3-pyridin-4-ylbenzyl)carbamidsäure-tert-butylester er- gibt.

10. Verfahren nach Anspruch 9, bei dem bei den Suzuki-Kupplungsbedingungen ein aus einem alkoholischen Lösungs- mittel mit einem Siedepunkt von mindestens denjenigen von Isopropylalkohol, einem polaren aprotischen Lösungs- 40 mittel oder einem Ether-Lösungsmittel oder einer Mischung beliebiger der oben erwähnten Lösungsmittel und Was- ser oder Toluol ausgewähltes Suzuki-Kupplungslösungsmittel verwendet wird.

11. Verfahren nach Anspruch 10, bei dem es sich bei dem Suzuki-Kupplungslösungsmittel um ein aus THF, Toluol, 2- Methyl-THF oder Dimethoxyethan ausgewähltes Ether-Lösungsmittel handelt. 45 12. Verfahren nach Anspruch 9, bei dem bei den Suzuki-Kupplungsbedingungen ein aus einem Pd-Katalysator wie

Pd(PPh3)4, Pd(PPh3)2Cl2, Pd2(dba)3, PdCl2dppf, Pd(dtbpf)Cl2 oder dergleichen oder einem Pd-Katalysator wie Pd(OAc)2, Pd2(dba)3 oder dergleichen in Verbindung mit einem Phosphinliganden wie PPh 3, dppf, t-Bu3P, P(Cy)3 oder dergleichen ausgewählter Suzuki-Katalysator und eine starke Base verwendet werden. 50 13. Verfahren nach Anspruch 9, bei dem bei den Suzuki-Kupplungsbedingungen eine Suzuki-Kupplungstemperatur von etwa 60°C bis etwa 100°C verwendet wird.

14. Verfahren nach Anspruch 9, bei dem es sich bei dem 4-Halogenpyridin um 4-Chlorpyridin handelt. 55 15. Verfahren zur Herstellung von (4-Fluor-3-piperidin-4-ylbenzyl)carbamidsäure-tert-butylester-hydrochlorid (I), bei dem man gemäß Anspruch 11 hergestellten (4-Fluor-3-pyridin-4-ylbenzyl)-carbamidsäure- tert-butylester unter Hy- drierungsreduktionsbedingungen reduziert und anschließend mit HCl aufarbeitet, was (4-Fluor-3-piperidin-4-ylben-

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zyl)carbamidsäure-tert-butylester-hydrochlorid ergibt.

16. Verfahren nach Anspruch 15, bei dem bei den Hydrierungsreduktionsbedingungen ein aus Pt/C, 2 PtO, Pd/C, Pd(OH)2, Rh/C und dergleichen ausgewählter Hydrierungskatalysator mit oder ohne zugesetzt anorganische Säure 5 wie HCl oder dergleichen oder anorganische Säure wie Essigsäure oder dergleichen verwendet wird.

17. Verfahren nach Anspruch 15, bei dem bei den Hydrierungsreduktionsbedingungen ein aus einem Ester-Lösungs- mittel wie EtOAc, i-PrOAc, BuOAc und dergleichen, einem Alkohol-Lösungsmittel wie Methanol, Ethanol, Isopro- pylalkohol und dergleichen oder AcOH oder einer Mischung eines Alkohol- oder Ester-Lösungsmittels und Wasser 10 und Essigsäure ausgewähltes Hydrierungslösungsmittel verwendet wird.

18. Verfahren nach Anspruch 15, bei dem bei den Hydrierungsreduktionsbedingungen eine Hydrierungsreaktionstem- peratur von etwa 10 bis etwa 60°C verwendet wird.

15 19. Verfahren nach Anspruch 15, bei dem die Hydrierungsreaktionstemperatur etwa Umgebungstemperatur ist.

20. Verfahren nach Anspruch 15, bei dem bei den Hydrierungsreduktionsbedingungen ein Hydrierungsdruck von etwa 10 bis etwa 1000 psi verwendet wird.

20 Revendications

1. Procédé pour la préparation d’acide 5-(( tert-butoxycarbonyl)aminométhyl)-2-fluorobenzèneboronique, comprenant la boronation de 4-((tert-butoxycarbonyl)aminométhyl)fluorobenzène avec un boronate de trialkyle dans des con- 25 ditions de boronation et ensuite l’extinction du mélange résultant avec un acide aqueux pour produire de l’acide 5-((tert-butoxycarbonyl)aminométhyl)-2-fluorobenzèneboronique.

2. Procédé selon la revendication 1 dans lequel les conditions de boronation utilisent une superbase.

30 3. Procédé selon la revendication 2 dans lequel la superbase est une association d’un réactif organolithien de formule RLi où R est un groupe alkyle ou aryle ayant 1-12 atomes de carbone et d’un alcoolate de potassium volumineux tel que le tert-butylate de potassium ou le tert-pentylate de potassium et similaire.

4. Procédé selon la revendication 3 dans lequel la superbase est une association de n-butyllithium et de tert-butylate 35 de potassium.

5. Procédé selon la revendication 1 dans lequel le boronate de trialkyle est choisi parmi le borate de triméthyle, le borate de triéthyle, le borate de tripropyle, le borate de triisopropyle, le borate de tributyle et similaire.

40 6. Procédé selon la revendication 1 dans lequel les conditions de boronation utilisent un solvant de boronation qui est un solvant éther choisi parmi l’oxyde de diéthyle, le THF, le 2-méthyltétrahydrofurane, le MTBE, le diméthoxyéthane et similaire.

7. Procédé selon la revendication 1 dans lequel les conditions de boronation utilisent une température de réaction de 45 boronation d’environ -100 °C à environ -30 °C.

8. Procédé selon la revendication 1 dans lequel l’acide aqueux est HCl ou H 3PO4.

9. Procédé pour la préparation d’ester tert-butylique de l’acide (4-fluoro-3-pyridin-4-ylbenzyl)carbamique comprenant 50 le couplage d’acide 5-(( tert-butoxycarbonyl)aminométhyl)-2-fluorobenzèneboronique préparé selon la revendication 1 et d’une 4-halogénopyridine dans des conditions de couplage de Suzuki pour produire de l’ester tert-butylique de l’acide (4-fluoro-3-pyridin-4-ylbenzyl)carbamique.

10. Procédé selon la revendication 9 dans lequel les conditions de couplage de Suzuki utilisent un solvant de couplage 55 de Suzuki choisi parmi un solvant alcoolique ayant un point d’ébullition supérieur ou égal à celui de l’alcool isopro- pylique, un solvant polaire aprotique ou un solvant éther ou un mélange de l’un quelconque des solvants susmen- tionnés et d’eau ou de toluène.

11 EP 2 483 243 B1

11. Procédé selon la revendication 10 dans lequel le solvant de couplage de Suzuki est un solvant éther choisi parmi le THF, le toluène, le 2-méthylTHF ou le diméthoxyéthane.

12. Procédé selon la revendication 9 dans lequel les conditions de couplage de Suzuki utilisent un catalyseur de Suzuki 5 choisi entre un catalyseur au Pd tel que Pd(PPh 3)4, Pd(PPh3)2Cl2, Pd2(dba)3, PdCl2dppf, Pd(dtbpf)Cl2 ou similaire ; ou un catalyseur au Pd tel que Pd(OAc)2, Pd2(dba)3 ou similaire conjointement avec un ligand phosphine tel que PPh3, dppf, t-Bu3P, P(Cy)3 ou similaire, et une base forte.

13. Procédé selon la revendication 9 dans lequel les conditions de couplage de Suzuki utilisent une température de 10 réaction de couplage de Suzuki d’environ 60 °C à environ 100 °C.

14. Procédé selon la revendication 9 dans lequel la 4-halogénopyridine est la 4-chloropyridine.

15. Procédé pour la préparation de chlorhydrate d’ester tert-butylique de l’acide (4-fluoro-3-pipéridin-4-ylbenzyl)carba- 15 mique (I), comprenant la réduction d’ester tert-butylique de l’acide (4-fluoro-3-pyridin-4-ylbenzyl)carbamique préparé selon la revendication 11 dans des conditions de réduction par hydrogénation et ensuite suivie d’un traitement conclusif à l’HCl pour produire du chlorhydrate d’ester tert-butylique de l’acide (4-fluoro-3-pipéridin-4-ylbenzyl)car- bamique.

20 16. Procédé selon la revendication 15 dans lequel les conditions de réduction par hydrogénation utilisent un catalyseur d’hydrogénation choisi parmi Pt/C, PtO2, Pd/C, Pd(OH)2, Rh/C et similaire, avec ou sans acide inorganique tel qu’HCl et similaire ou acide organique tel que l’acide acétique et similaire ajouté.

17. Procédé selon la revendication 15 dans lequel les conditions de réduction par hydrogénation utilisent un solvant 25 d’hydrogénation choisi parmi un solvant ester tel qu’EtOAc, i-PrOAc, BuOAc et similaire ; un solvant alcool tel que le méthanol, l’éthanol, l’alcool isopropylique et similaire ; ou AcOH ; ou un mélange d’un solvant alcool ou ester et d’eau et d’acide acétique.

18. Procédé selonla revendication 15 dans lequel les conditions de réductionpar hydrogénation utilisent une température 30 de réaction d’hydrogénation d’environ 10 à environ 60 °C.

19. Procédé selon la revendication 15 dans lequel la température de réaction d’hydrogénation est à environ la tempé- rature ambiante.

35 20. Procédé selon la revendication 15 dans lequel les conditions de réduction par hydrogénation utilisent une pression d’hydrogénation d’environ 10 à environ 1000 psi.

40

45

50

55

12 EP 2 483 243 B1

REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description

• WO 200113811 A [0002] • WO 2005097780 A [0003]

Non-patent literature cited in the description

• CAUGHEY et al. J. Pharmacol. Exp. Ther., 1988, vol. • SEKIZAWA et al. J. Clin. Invest., 1989, vol. 83, 244, 133-137 [0002] 175-179 [0002] • FRANCONI et al. J. Pharmacol. Exp. Ther., 1988, • Tetrahedron, 2001, vol. 2965, 57 [0037] vol. 248, 947-951 [0002] • Tetrahedron, 2001, vol. 57, 2965 [0042] •TAMal.et Am. J. Respir. Cell Mol. Biol., 1990, vol. 3, 27-32 [0002]

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