l|||||||||||||ll||l||||||||l|||||||||||||||||||||l||||||l||||||||||||||||||||||||||||||||| US 20030176707A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2003/0176707 A1 Pye (43) Pub. Date: Sep. 18, 2003

(54) PROCESS FOR PREPARING INTEGRIN Related US. Application Data ANTAGONIST INTERMEDIATE (60) Provisional application No. 60/352,601, ?led on Jan. 29, 2002. (76) Inventor: Philip J. Pye, Guttenberg, NJ (US) Publication Classi?cation

Correspondence Address; (51) Int. Cl.7 ...... C071) 213/78; C071) 213/72 MERCK AND CO INC (52) US. Cl...... 546/329; 546/330 P O BOX 2000 RAHWAY, NJ 070650907 (57) ABSTRACT

(21) Appl, No; 10/353,612 A novel process is provided for the preparation of 2,5-di (3‘-arninopropyl)pyridine Which is useful in the synthesis of otv[33 integrin receptor antagonists. Also provided are useful (22) Filed: Jan. 29, 2003 intermediates obtained from the process. US 2003/0176707 A1 Sep. 18, 2003

PROCESS FOR PREPARING INTEGRIN [0007] The novel process and novel intermediates are ANTAGONIST INTERMEDIATE illustrated in the folloWing embodiment denoted in Scheme 1 beloW. FIELD OF THE INVENTION

[0001] The present invention discloses a novel process and Schemel novel intermediates toward the preparation of 2,5-di-(3‘ RZOZC N aminopropyl)pyridine Which is useful in the synthesis of \ MeCN otv[33 integrin receptor antagonists. l base / cozR1 BACKGROUND OF THE INVENTION OM NC N [0002] The present invention provides a novel process for / \ the preparation of 2,5-di-(3‘-aminopropyl)pyridine of struc I Y—X tural formula I. / / CN —>

OM (I) OY HZN \ NC N

NHZ / / CN _2>H

OY [0003] Another aspect of the present invention is con cerned With novel intermediates useful in the disclosed process. [0004] A synthesis of the compound of formula I Was previously disclosed in US. Pat. No. 6,262,268 (Jul. 17, 2001). In the issued US. patent, the 2,5-bis-substituted pyridine ring system Was constructed by means of a one-pot double Suzuki cross-coupling of a 2,5-dihalopyridine With a protected allylamine in the presence of 9-BBN and subse quent removal of the primary amine protecting groups. DETAILED DESCRIPTION OF THE [0005] In the present invention, the compound of formula INVENTION I is produced in a highly efficient manner in a total of four [0008] The process of the present invention involves the chemical steps featuring a one-pot double addition of aceto preparation of the compound of structural formula I: anion to a 2,5 -pyridine dicarboXylate diester folloWed by activation of the resulting di-enolate and a tWo-step hydrogenation sequence to the ?nal product. (I) HZN SUMMARY OF THE INVENTION g2; NHZ [0006] The instant invention is concerned With an alter native process for preparing 2,5-di-(3‘-aminopropyl)pyri dine of structural formula I and useful intermediates [0009] comprising the steps of: obtained during that process. The process utiliZes a double [0010] (a) producing a compound of structural formula II: addition of acetonitrile anion to a 2,5 -pyridine dicarboXylate diester, activation of the resulting di-enolate, and a tWo-step hydrogenation sequence to the diamine I. (II) o-M+

NC / \ (I) HZN \ CN NHZ US 2003/0176707 A1 Sep. 18, 2003

[0011] wherein M is an alkali or alkaline earth metal, by [0017] by hydrogenating a compound of structural for treating a 2,5-pyridine dicarboXylate diester of structural mula IV: formula III: (IV) (III) 0

R20 \ / / 0R1 N / CN; N

O

[0012] Wherein R1 and R2 are each independently CL4 [0018] and (d) producing a compound of structural for alkyl or phenyl-C1_3 alkyl, With acetonitrile in a reaction mula I: solvent in the presence of a base; [0013] (b) producing a compound of structural formula IV: (I) HZN \

/ NHZ (IV) N Y\o

NC / \ [0019] by hydrogenating a compound of structural for mula VI: / N / CN (VI) NC 0 \Y

[0014] Wherein Y is an acyl, sulfonyl, or phosphoryl group, by reacting a compound of structural formula II: [0020] Compound I may be isolated from the reaction or used Without further puri?cation for additional chemical modi?cation in the synthesis of otv[33 integrin receptor (II antagonists. o-M+ [0021] The key steps in the process of the present inven NC / \ tion include a double acetonitrile addition to a 2,5-pyridine dicarboXylate diester, activation of the resulting di-enolate, and a tWo-step hydrogenation sequence to the ?nal product. N/ / CN [0022] The substrate for the double acetonitrile addition reaction is a 2,5-pyridine dicarboXylate diester of structural formula III Wherein R1 and R2 are each independently C1_ 4 alkyl or phenyl-C1_3 alkyl. In one embodiment, the dicar boXylate diester is a dimethyl or diethyl (R1=R2=Me or [0015] With an acylating, sulfonylating, or phosphorylat Et, respectively). ing reagent; [0023] The double acetonitrile addition reaction is effected [0016] (c) producing a compound of structural formula VI: With a 2,5-pyridine dicarboXylate diester and acetonitrile in the presence of a base in a suitable reaction solvent. In one embodiment, the base is selected from the group consisting (VI) of an alkali or alkaline earth metal hydride, such as sodium NC \ hydride, lithium hydride, magnesium hydride, and calcium hydride; an alkyl lithium, such as n-butyl lithium; an alkali / metal heXamethyldisilaZide, such as potassium and lithium N CN heXamethyldisilaZide; and an alkali or alkaline earth metal alkoXide, such as sodium methoXide, sodium ethoXide, and potassium tert-butoXide. In one class of this embodiment, the base is an alkali or alkaline earth hydride, in particular, US 2003/0176707 A1 Sep. 18, 2003

sodium hydride or calcium hydride. Suitable reaction sol formed in a suitable reaction solvent in the presence of a vents for the addition reaction include, but are not limited to, Raney nickel catalyst and ammonia. Suitable reaction sol toluene, , acetonitrile, dioxane, diethyl ether, tet vents include, but are not limited to, toluene; tetrahydrofu rahydrofuran, and dialkyl ethylene glycol ethers, such as ran; loWer alkanols, such as methanol and ; Water; ethylene glycol dimethyl ether. In one embodiment the and aqueous loWer alkanols, such as aqueous methanol and reaction solvent is acetonitrile or ethylene glycol dimethyl aqueous ethanol. ether. The addition reaction is carried out at a temperature range of about 0° C. to about 100° C. In one embodiment, [0027] Another aspect of the present invention provides the addition reaction is carried out at a temperature range of novel compounds of structural formula IV Which are inter about 70° C. to about 80° C. mediates in the instant process for the preparation of com pound I: [0024] The second step in the process of the present invention involves the activation of the dienolate of struc tural formula II. This is effected by treating the dienolate II (IV) in a suitable reaction solvent With an acylating, sulfonylat Y\ ing, or phosphorylating reagent Y-X, Wherein Y is an acyl, sulfonyl, or phosphoryl group, respectively, and X is a NC / \ leaving group, such as halide, acyloxy, and sulfonyloxy. Examples of an acylating reagent include an alkanoyl halide, an alkanecarboxylic acid anhydride, an aroyl halide, Wherein aroyl is benZoyl or naphthoyl, and an arylcarboxylic acid anhydride, Wherein aryl is phenyl or naphthyl. Examples of a sulfonylating agent include an alkanesulfonyl halide, an alkanesulfonic anhydride, an arylsulfonyl halide, and an arylsulfonic anhydride, Wherein aryl is phenyl or naphthyl. Examples of a phosphorylating agent include a dialkylphos [0028] Wherein Y is C1_4 alkanoyl, benZoyl, naphthoyl, phoryl halide and a diarylphosphoryl halide. Speci?c phenyl-C173 alkanoyl, C1_4 alkanesulfonyl, benZenesulfonyl, embodiments of the reagent Y-X include methanesulfonyl di-(Clr4 alkyl)phosphoryl, and diphenylphosphoryl, Wherein chloride, methanesulfonic anhydride, tri?uoromethane the benZene, benZoyl, naphthoyl, and phenyl groups are sulfonyl chloride, tri?uoromethanesulfonic anhydride, ben unsubstituted or substituted With one or tWo substituents Zenesulfonyl chloride, p-toluenesulfonyl chloride, p-tolu independently selected from halogen, nitro, cyano, methyl, enesulfonic anhydride, acetyl chloride, acetic anhydride, and methoxy. In one embodiment, Y is benZenesulfonyl pivaloyl chloride, pivalic anhydride, benZoyl chloride, and optionally substituted With one or tWo substituents indepen benZoic anhydride. In a preferred embodiment the reagent dently selected from halogen, nitro, cyano, methyl, and Y-X is benZenesulfonyl chloride or p-toluenesulfonyl chlo methoxy. ride. Suitable reaction solvents include, but are not limited [0029] A further aspect of the present invention provides to, loWer alkanols, such as methanol, ethanol, and isopropyl the novel compound of structural formula VI Which is an alcohol; toluene; tetrahydrofuran; methylene chloride; intermediate in the instant process for the preparation of Water; ethyl acetate; isopropyl acetate; and aqueous loWer compound I: alkanols. In one embodiment the reaction solvent is metha nol or ethanol. The reaction is carried out at a temperature range of about —10° C. to about 30° C. Abuffer is optionally (VI) added to the reaction mixture. In one embodiment the buffer NC is sodium carbonate, potassium carbonate, or dipotassium hydrogenphosphate. [0025] The third reaction step involves hydrogenation of N CN the activated enolate of structural formula IV. In one embodiment, the hydrogenation reaction is performed by applying hydrogen in the presence of a palladium catalyst [0030] The compound of structural formula I can be and base in a suitable reaction solvent. Palladium catalysts converted into 3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2 include Pd/C, Pd/Al2O3, Pd/CaCO3, Pd/BaCO3, Pd/BaSO4, yl)-propylamine (VII) as described in US. Pat. No. 6,262, and Pd(OH)2. The base is selected from an inorganic base or 268 (July 17, 2001). As disclosed in WO 01/34602, this an organic base. Inorganic bases include sodium carbonate, intermediate is useful to prepare otv[33 integrin receptor potassium carbonate, dipotassium hydrogenphosphate, and antagonists, such as the compound of structural formula VIII potassium dihydrogenphosphate. Organic bases include disclosed in US. Pat. No. 6,017,926 (Jan. 25, 2000), Which pyridine and substituted pyridines, such as 2,6-lutidine, is useful to inhibit bone resorption and to treat osteoporosis. 2,4,6-collidine, and polyvinylpyridine. Suitable reaction sol vents include, but are not limited to, toluene; tetrahydrofu ran; loWer alkanols, such as methanol and ethanol; Water; and aqueous loWer alkanols, such as aqueous methanol and aqueous ethanol. [0026] The fourth reaction in the sequence involves hydro genation of the derived di(cyanoethyl)2,5-pyridine of struc (I) tural formula VI. In one embodiment, this reaction is per US 2003/0176707 A1 Sep. 18, 2003

[0034] To a solution of dimethyl 2,5-pyridinedicarboXy -continued late (1-1) (21.1 g) in acetonitrile (500 mL) at 60° C. Was cautiously added sodium hydride (60% dispersion in mineral oil; 18.1 g). The reaction Was alloWed to cool and ethanol NHZ (30 mL) added. The product Was isolated by ?ltration and E Washed With three portions of ethanol (50 mL). The solid Was dried under a ?oW of nitrogen to afford 28.6 g of 1-2. (VII) 1H-NMR (400 MHZ; DMSO-dG): 6 8.61 (d, J=2.0 HZ, 1H), OMe 7.84 (dd, J=8.0, 2.0 HZ, 1H), 7.66 (d, J=8.0 HZ, 1H), 4.57(s, | \N 1H), 3.99 (s, 1H).

O 5/ Step B: g N\ N N/§\/CO2H ONa NC / N / \ —> (VIII) / / CN

ONa [0031] Representative experimental procedures utilizing 1-2 the novel process of the present invention are detailed below. They are given for purposes of illustration only and are not 0/ SOZPh intended to limit the process of the present invention to the speci?c conditions given for making the exempli?ed com NC / N pounds. \

[0032] By loWer alkanol is meant a C1_5 linear or / / CN branched-chain alkyl alcohol, such as methanol, ethanol, isopropanol, and 1-butanol. By halide is meant ?uoride, O chloride, bromide, and iodide. By halogen is meant ?uorine, \SOZPh chlorine, bromide, and iodine. By acyl is meant C1_4 alkan ecarbonyl, arylcarbonyl Wherein aryl is phenyl or naphthyl, 1-3 and phenyl-CL3 alkanecarbonyl. By sulfonyl is meant C1_4 alkanesulfonyl, Wherein alkane is optionally substituted With one to three ?uorine atoms; arylsulfonyl group, Wherein aryl [0035] The bis sodium enolate from Step A(1-2) (28.4 g) is phenyl or naphthyl; and phenyl-C1_3 alkanesulfonyl. By Was suspended in methanol (210 mL) With sodium carbonate phosphoryl is meant di(C1_4) alkanephosphoryl or dia rylphosphoryl, Wherein aryl is phenyl or naphthyl. (14 g) and cooled to 0° C. BenZenesulfonyl chloride (31 mL) Was added and the reaction aged for 2 h. The slurry Was EXAMPLE 1 ?ltered and Washed With ice-cold methanol (2x50 mL) to afford 61 g of 1-3. [0033] [0036] TWo isomers, major listed: 1H-NMR (400 MHZ; CDC13): 68.81 (d, J=2.4 HZ, 1H), 8.10 (dd, J=1.2, 8.4 HZ, Step A: 2H), 8.06 (dd, J=1.2, 8.4HZ, 2H), 8.00 (dd, J=8.4, 2.4 HZ, MeOZC N 1H), 7.85 (d, J=8.4 HZ, 1H), 7.80 (m, 2H), 7.63 (m, 4H), I \ 6.65 (s, 1H), 5.75 (s, 1H).

/ COZMe Step C: 1-1 OSOZPh ONa NC / N\ NC / N \

/ / CN CN OSOZPh ONa 1-2 1-3 US 2003/0176707 A1 Sep. 18, 2003

comprising the step of hydrogenating the compound of -continued structural formula VI: NC N \

(VI) / CN NC g2; 1-4

[0037] To a slurry of the bis-enol benZenesulfonate from Step B (1-3) in methanol (40 mL) Was added With an 2. The process of claim 1 additionally comprising the step additional 16 g of sodium carbonate, and the mixture Was of producing the compound of structural formula VI: hydrogenated under 40 psi hydrogen at 20° C. in the presence of 10% Pd—C (1.0 g) for 32 h. The reaction mixture Was ?ltered through a ?lter aid such as Celite® or (VI) solka ?oc® and concentrated under reduced pressure to NC afford 2,5-di(2-cyanoethyl)pyridine (1-4). [0038] 1H-NMR (400 MHZ; CDC13): 68.45 (d, J=2.0 HZ, /%2% 1H), 7.57 (dd, J=8.0, 2.0 HZ, 1H), 7.22 (d, J=8.0 HZ, 1H), CN 3.13 (t, J=7.2HZ, 2H), 2.97 (t, J=7.2HZ, 2H), 2.85 (t, J=7.2HZ, 2H), 2.65 (t, J=7.2HZ, 2H). by hydrogenating a compound of structural formula IV: Step D: (IV) NC I N \

/ CN

1-4 N HZN \ / NH2 Wherein Y is an acyl, sulfonyl, or phosphoryl group. 3. The process of claim 2 additionally comprising the step (1) of producing a compound of structural formula IV: [0039] A solution of 2,5-di(2-cyanoethyl)pyridine from Step C (3.16 g) Was dissolved in 7N ammonia in methanol solution (45 mL) and hydrogenated under 40 psi of hydro (IV) gen gas pressure at 50° C. in the presence of Raney nickel (1.6 g) for 20 h. The catalyst Was ?ltered through solka ?oc® and Washed With methanol. The ?ltrate and Wash Were combined and concentrated under reduced pressure to give 2,5-di(3-aminopropyl)pyridine (I) (2.95 g). [0040] 1H-NMR (400 MHZ; D20): 67.29 (d, J=2.0 HZ, 1H), 7.29 (dd, J=8.0, 2.0 HZ, 1H), 6.92 (d, J=8.0 Hs, 1H), 2.48 (t, J=7.7 HZ, 2H), 2.43-2.34 (m, 4H), 2.29 (t, J=7.7 HZ, 2H), 1.54 (pentet, J=7.7 HZ, 2H), and 1.42 (pentet, J=7.7 HZ, 2H). 13C-NMR (101 MHZ; D20): 6158.7, 147.8, 137.6, 135.5, 123.0, 40.4, 40.2, 34.1, 33.5, 32.6, and 29.2. by reacting a compound of structural formula II:

What is claimed is: 1. A process for preparing the compound of structural formula I: NC / \ (I) HZN \ CN

NH2

With an acylating, sulfonylating, or phosphorylating reagent. US 2003/0176707 A1 Sep. 18, 2003

4. The process of claim 3 additionally comprising the step phoryl, and diphenylphosphoryl, Wherein the benZene, ben of producing a compound of structural formula II: Zoyl, naphthoyl, and phenyl groups are unsubstituted or substituted With one or tWo substituents independently (II) selected from halogen, nitro, cyano, methyl, and methoXy. o-M+ 14. The compound of claim 13 Wherein Y is benZene NC / \ sulfonyl optionally substituted With one or tWo substituents independently selected from halogen, nitro, cyano, methyl, and methoXy. / N / CN 15. A process for preparing the compound of structural formula I: o-M+ by treating a 2,5-pyridine dicarboXylate diester of structural formula III: (I) HZN \ (III) / NHz N

comprising the steps of: (a) producing a compound of structural formula II:

0 wherein R1 and R2 are each independently CL4 alkyl or <11) phenyl-C173 alkyl; With acetonitrile in a reaction solvent in the O'M’r presence of a base. NC / \ 5. The process of claim 4 Wherein the base is selected from the group consisting of an alkali or alkaline earth metal hydride, an alkyl lithium, an alkali metal heXamethyldisi N/ / CN laZide, and an alkali or alkaline earth metal alkoXide. 6. The process of claim 5 Wherein the base is an alkali or alkaline earth metal hydride. 7. The process of claim 4 Wherein the reaction solvent is selected from the group consisting of toluene, benZene, by treating a 2,5-pyridine dicarboXylate diester of struc acetonitrine, dioXane, diethyl ether, tetrahydrofuran, and tural formula III: ethylene glycol dimethyl ether. 8. The process of claim 7 Wherein the reaction solvent is (III) acetonitrile or ethylene glycol dimethyl ether. 0 9. The process of claim 3 Wherein the sulfonylating reagent is benZenesulfonyl chloride or benZenesulfonic anhydride optionally substituted With one or tWo groups R20 \ independently selected from halogen, nitro, cyano, methyl / 0R1 and methoXy. N 10. The process of claim 3 Wherein the reaction is carried out in the presence of a buffer. 0 11. The process of claim 1 Wherein the hydrogenation is carried out in the presence of a Raney nickel catalyst and wherein R1 and R2 are each independently C1_4 alkyl or ammonia. phenyl-C173 alkyl, With acetonitrile in a reaction solvent 12. The process of claim 2 Wherein the hydrogenation is in the presence of a base; carried in the presence of a palladium catalyst and base. 13. A compound of the structural formula: (b) producing a compound of structural formula IV:

(IV) Y\o

/ NC / \ N / CN / N / CN Wherein Y is C1_ 4 alkanoyl, benZoyl, naphthoyl, phenyl-CL3 0 \Y alkanoyl, CL4 alkanesulfonyl optionally substituted With one to three ?uorines, benZenesulfonyl, di-(C1_4 alkyl)phos US 2003/0176707 A1 Sep. 18, 2003

by reacting a compound of structural formula II: by hydrogenating a compound of structural formula IV:

(IV) <11)

NC / \

/ / N / CN N / CN

Y

Wherein Y is an acyl, sulfonyl, or phosphoryl group; and (d) hydrogenating the compound of structural formula VI: With an acylating, sulfonylating, or phosphorylating (VI) reagent; NC (c) producing the compound of structural formula VI: / N CN. 16. A compound of structural formula VI: (VI) (VI) NC NC

N CN.