US2016152600A1PendingUtilityA1
Synthesis of (2s,5r)-5-ethynyl-1-pyrrolidine-2-carbonitrile
Est. expiryJul 20, 2026(~0 yrs left)· nominal 20-yr term from priority
Inventors:Todd McdermottSeble H. WagawKenneth M. EngstromJorge GandarillaAlbert W. KrugerMichael J. RozemaMichael G. FickesSteven J. WittenbergerLakshmi BhagavatulaThomas B. Borchardt
A61P 3/10C07F 7/0803C07D 401/04C07D 207/16C07D 213/803C07D 401/14
40
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Abstract
A process for making (2S,5R)-5-ethynyl-1-{N-(4-methyl-1-(4-carboxy-pyridin-2-yl)piperidin-4-yl)glycyl}pyrrolidine-2-carbonitrile and salts thereof, and intermediates used in the process are disclosed.
Claims
exact text as granted — not AI-modifiedWe claim:
1 . A process for preparing a compound of formula (I) or salts thereof,
comprising the steps of:
(a) treating a compound of formula (XVIII) wherein X 2 is Cl, Br, I, methanesulfonate or p-toluenesulfonate, with a compound of formula (XIX) or salts thereof wherein P 1 is an acid protecting group, an additive and a base, in a solvent, to provide a compound of formula (XX)
(b) optionally treating the compound of formula (XX) with an acid to provide a salt of the compound of formula (XX); and
(c) deprotecting the compound of formula (XX) or salts thereof to provide a compound of formula (I).
2 . The process according to claim 1 wherein the base used in step (a) is selected from the group consisting of tri(C 1-6 alkyl) amine, tertiary cyclic amine, pyridine, picoline, metal salt and metal hydroxide.
3 . The process according to claim 2 wherein the base is potassium phosphate or sodium phosphate.
4 . The process according to claim 1 wherein the additive is selected from the group consisting of potassium iodide, sodium iodide, lithium iodide and tetrabutylammonium.
5 . The process according to claim 1 wherein potassium phosphate and potassium iodide are added in step (a).
6 . The process according to claim 1 wherein the acid in step (b) is selected from the group consisting of D-tartaric acid, maleic acid, oxalic acid, S-mandelic acid, L-tartaric acid, L-malic acid, and succinic acid.
7 . The process according to claim 6 wherein the acid in step (b) is D-tartaric acid.
8 . The process according to claim 1 wherein the acid in step (b) is selected from the group consisting of trifluoroacetic acid, benzenesulfonic acid, p-toulenesulfonic acid, methanesulfonic acid, hydrogen chloride, and phosphoric acid is added in step (c).
9 . The process according to claim 8 wherein the acid is phosphoric acid.
10 . (2S,5R)-5-ethynyl-1-{N-(4-methyl-1-(4-carboxy-pyridin-2-yl)piperidin-4-yl)glycyl}pyrrolidine-2-carbonitrile prepared according to the process of claim 1 .
11 . (2S,5R)-5-ethynyl-1-{N-(4-methyl-1-(4-carboxy-pyridin-2-yl)piperidin-4-yl)glycyl}pyrrolidine-2-carbonitrile, L-malic acid salt prepared by treating an aqueous solution of (2S,5R)-5-ethynyl-1-{N-(4-methyl-1-(4-carboxy-pyridin-2-yl)piperidin-4-yl)glycyl}pyrrolidine-2-carbonitrile with an C 1-6 alcoholic solution of L-malic acid.
12 . (2S,5R)-5-ethynyl-1-{N-(4-methyl-1-(4-carboxy-pyridin-2-yl)piperidin-4-yl)glycyl}pyrrolidine-2-carbonitrile, L-malic acid salt.
13 . A process for preparing a compound of formula (XIX) or salts thereof, wherein P 1 is an acid protecting group
comprising the steps of:
(a) treating a compound of formula (XXIII) wherein P 1 is an acid protecting group and X is a F, Cl, Br, I, p-toluenesulfonate or methanesulfonate, with an amine of formula (XXII), or salts thereof, to provide a compound of formula (XXIV)
and
(b) treating the compound of formula (XXIV) with a halogenating reagent and a base to provide a compound of formula (XIX)
14 . The process according to 13 wherein step (a) further comprises adding a base selected from the group consisting of sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium phosphate, potassium phosphate, sodium hydrogen phosphate, potassium hydrogen phosphate, trialkylamine, pyridine and N-methylmorpholine.
15 . The process according to claim 13 wherein the halogenating reagent in step (b) is 1,3-dibromo-5,5-dimethylhydantoin.
16 . The process according to claim 13 wherein the base in step (b) is metal hydroxide.
17 . The process according to claim 13 wherein step (b) further comprises adding a phase transfer catalyst.
18 . The process according to claim 17 wherein the phase transfer catalyst is tetrabutyl ammonium halide.
19 . A process for preparing a compound of formula (XIX) or salts thereof, wherein P 1 is an acid protecting group,
comprising the steps of:
(a) treating a compound of formula (XXI) wherein P 2 is an amine protecting group with a halogenating reagent and a base to provide a compound of formula (XXV)
(b) deprotecting the compound of formula (XXV) or salts thereof to provide a compound of formula (XXVI), or salts thereof
(c) treating a compound of formula (XXVII) or (XXIII) wherein P 1 is an acid protecting group, X is F, Br, Cl, I, methanesulfonate or p-toluenesulfonate, and Y is F, I, Cl or Br, with the compound of formula (XXVI), or salts thereof, to provide a compound of formula (XXVIII) or (XIX) respectively
and
(d) de-halogenating the compound of formula (XXVIII) to provide the compound of formula (XIX)
20 . The process according to claim 19 wherein the halogenating reagent in step (a) is 1,3-dibromo-5,5-dimethylhydantoin.
21 . The process according to claim 19 wherein the base in step (a) is a metal hydroxide.
22 . The process of claim 19 wherein step (b) comprises adding an acid selected from the group consisting of p-toluenesulfonic acid, trifluoroacetic acid, hydrogen chloride, methanesulfonic acid, and benzenesulfonic acid.
23 . The process of claim 19 wherein step (c) further comprises adding a base selected from the group consisting of trialkylamine, pyridine, N-methylmorpholine, metal hydroxide, metal carbonate, metal phosphate and metal hydrogen phosphate.
24 . The process according to claim 19 wherein step (d) comprises treating compound of formula (XXVIII) with hydrogen in the presence of a catalyst.
25 . The process according to claim 24 wherein the catalyst is selected from the group consisting of palladium/aluminum oxide and palladium/carbon.
26 . The process according to claim 24 further comprises adding a base.
27 . The process according to claim 26 wherein the base is selected from the group consisting of trialkylamine, metal hydroxide, metal carbonate, metal phosphate, metal hydrogen phosphate.
28 . The process according to claim 26 wherein the catalyst is palladium/aluminum oxide and the base is sodium phosphate or potassium phosphate.
29 . A process for preparing a compound of formula (XXVIIb) wherein X 1 is F, Cl, Br, I, methanesulfonate or p-toluenesulfonate, and Y 1 is H, F, Cl, Br or I, comprising the step of treating a compound of formula (XXVIIa) with di-tert-butyl dicarbonate in the presence of 4-dimethylaminopyridine (DMAP), in a solvent
30 . The process of claim 29 further comprises the step of adding a base.
31 . A process for preparing a compound of formula (XVIII) wherein X 2 is Cl or Br
comprising the steps of:
(a) treating a compound of formula (XXIX) wherein P 2 is an amine protecting group and R 1 is an acid protecting group, with a reagent having formula (R 2 ) 3 Si—CCMgX 3 , wherein X 3 is Cl, Br or I, to provide a compound of formula (XXX)
(b) treating the compound of formula (XXX) with an acid and a reducing agent, in a solvent, to provide a compound of formula (XXXI)
(c) treating the compound of formula (XXXI) with a base, followed by treatment with an acid, to provide a compound of formula (XXXII)
(d) treating the compound of formula (XXXII) with ammonia in the presence of a coupling reagent and a base, to provide a compound of formula (XXXIII)
(e) treating the compound of formula (XXXIII) with a dehydrating agent to provide a compound of formula (XXXIV)
(f) deprotecting the compound of formula (XXXIV) to provide a compound of formula (XXXV) or salts thereof
and
(g) treating the compound of formula (XXXV) or salts thereof with a reagent having formula X 2 CH 2 COY 2 wherein X 2 and Y 2 are independently Cl or Br, to provide a compound of formula (XVIII)
32 . The process according to claim 31 wherein the reagent having formula (R 2 ) 3 Si—CCMgX 3 is prepared in situ from an acetylene of formula (R 2 ) 3 Si—CC(H) wherein R 2 is C 1-6 alkyl and a Grignard reagent of formula R 3 MgX 3 wherein R 3 is C 1-10 alkyl, phenyl or benzyl and X 3 is Cl, Br or I, in a solvent.
33 . The process according to claim 32 wherein the acetylenes of formula (R 2 ) 3 Si—CC(H) is selected from the group consisting of ethylnyltrimethylsilane, ethynyltriisopropylsilane and ethynyltriethylsiline.
34 . The process according to claim 32 wherein R 3 is ethyl, isopropyl, hexyl, octyl, phenyl or benzyl.
35 . The process according to claim 32 wherein the reagent having formula (R 2 ) 3 Si—CCMgX 3 is prepared in situ by treating ethynyltrimethylsilane with octylmagnesium chloride in tetrahydrofuran.
36 . The process according to claim 31 wherein the acid in step (b) is selected from the group consisting of trifluoroacetic acid, methanesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid.
37 . The process according to claim 31 wherein the reducing reagent in step (b) is selected from the group consisting of sodium triacetoxy borohydride, sodium pivaloyloxy borohydride and triethylsilane.
38 . The process according to claim 31 wherein the coupling reagent in step (d) is selected from the group consisting of chloroformates, EDCI/HOBT, thionyl chloride and oxalyl chloride.
39 . The process according to claim 31 wherein the base in step (d) is selected from the group consisting of metal hydrogen carbonate, metal carbonate, metal phosphate, pyridine, tri(C 1-6 alkyl)amine and cyclic tertiary amine.
40 . The process according to claim 31 wherein the dehydrating agent in step (e) is a mixture of DMF and thionyl chloride.
41 . The process according to claim 31 wherein step (f) comprises adding an acid selected from the group consisting of benzenesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, hydrogen chloride, methanesulfonic acid and phosphoric acid.
42 . The process according to 31 wherein step (g) further comprises adding a base selected from the group consisting of pyridine, trialkylamine, cyclic tertiary amine, metal hydrogen carbonate, metal carbonate, metal phosphate, metal hydrogen phosphate and metal hydroxide.
43 . A compound of formula (XLII) wherein P 2 is an amine-protecting group and R 5 is COOH, C(O)NH 2 or CN.
44 . The compound according to claim 43 wherein P 2 is tert-butoxy carbonyl.
45 . A compound of formula (XXXII) wherein P 2 is an amine protecting group prepared by saponification of a compound of formula (XXXI) wherein R 1 and R 2 are C 1-6 alley and P 2 is an amine protecting group
46 . The compound according to claim 45 wherein P 2 is tert-butoxy carbonyl.
47 . A compound of formula (XXXIII) wherein P 2 is an amine protecting group, prepared by treating a compound of formula (XXXII) with ammonia in the presence of a coupling reagent and a base
48 . The compound according to claim 47 wherein P 2 is tert-butoxy carbonyl.
49 . A compound of formula (XXXIV) wherein P 2 is an amine protecting group, prepared by treating the compound of formula (XXXIII) with a dehydrating agent to provide a compound of formula (XXXIV)
50 . The compound according to claim 49 wherein P 2 is tert-butoxy carbonyl.
51 . A compound
or salts thereof.
52 . A process for preparing a compound of formula ((XXXVI) wherein R 1 is an acid protecting group and R 2 is C 1-6 alkyl
comprising the steps of:
(a) asymmetric reduction of the compound of formula (XXX) wherein P 2 is an amine-protecting group and R 1 is an acid protecting group and R 2 is C 1-6 alkyl to provide a compound of formula (XXXVII)
(b) activating the compound of formula (XXXVII) to provide a compound of formula (XXXVIII) wherein R 4 is trihaloacetyl, methanesulfonyl, benzenesulfonyl or p-toluenesulfonyl, without isolation
and
(c) deprotecting and cyclizing the compound of formula (XXXVIII) to provide a compound of formula (XXXVI) or salt thereof
53 . The process according to claim 52 wherein the asymmetric reduction in step (a) is asymmetric hydrogenation.
54 . The process according to claim 53 comprises adding a secondary C 1-6 alcohol as the hydrogen source and [(1S,2S)-N-(p-toluensulfonyl)-1,2-diphenylethanediamine](p-cymene) ruthenium (I) as the catalyst.
55 . The process according to claim 54 wherein the secondary C 1-6 alcohol is isopropanol.
56 . The process according to claim 52 wherein step (b) comprises adding an activating agent selected from the group consisting of trihaloacetic anhydride and a reagent of formula R 4 X wherein X is Cl, Br or I and R 4 is trihaloacetyl, methanesulfonyl, benzenesulfonyl or p-toluenesulfonyl, and a base selected from the group consisting of metal carbonate, metal hydrogen carbonate, metal phosphate, tri(C 1-6 alkylamine, tertiary clyclic amine and pyridine.
57 . The process according to claim 52 wherein steps (b) and (c) are conducted sequentially in a vessel, without isolating the compound of formula (XXXVIII)
58 . The process according to claim 52 wherein R 1 is C 1-6 alkyl and P 2 is alkyoxy carbonyl.
59 . The process according to claim 52 wherein R 1 is methyl, ethyl, isopropyl or tert-butyl and P 2 is tert-butoxy carbonyl.
60 . The process according to claim 52 wherein step (c) comprises adding an acid.
61 . The process according to claim 52 wherein step (c) further comprise adding a base after treatment with an acid.
62 . A compound of formula (XXXVI)
wherein R 1 an acid protecting group and R 2 is C 1-6 alkyl prepared according to the process of claim 52
63 . The compound according to claim 62 wherein R 1 and R 2 are independently C 1-6 alkyl.
64 . The compound according to claim 62 wherein R 1 is methyl, ethyl, isopropyl or tert-butyl and R 2 is methyl, ethyl or isopropyl.
65 . A process for preparing a compound of formula (XVIII) wherein X 2 is Cl or Br,
comprises the steps of:
(a) saponifying a compound of formula (XXXVI) or salts thereof wherein R 1 is an acid protecting group and R 2 is C 1-6 alkyl to provide a compound of formula (XXXIX)
(b) treating the compound of formula (XXXIX) or salts thereof with a reagent having formula X 2 CH 2 COY 2 wherein X 2 and Y 2 are independently Cl or Br, to provide a compound of formula (XL)
(c) treating the compound of formula (XL) with ammonia in the presence of a coupling reagent and a base, to provide a compound of formula (XLI) without isolation
and
(d) dehydrating the compound of formula (XLI) to provide a compound of formula (XVIII)
66 . The process according to claim 65 wherein step (a) comprises adding a base selected from the group consisting of metal hydroxides and metal carbonates.
67 . The process according to claim 65 wherein step (b) further comprises adding a base selected from the group consisting of pyridine, trialkylamine, cyclic tertiary amine, metal hydrogen carbonate, metal carbonate, metal phosphate, metal hydrogen phosphate and metal hydroxide.
68 . The process according to claim 65 the coupling reagent in step (c) is selected from the group consisting of chloroformates, EDCI/HOBT, thionyl chloride and oxalyl chloride.
69 . The process according to claim 65 wherein the base in step (c) is selected from the group consisting of sodium hydrogen carbonate, potassium hydrogen carbonate, pyridine, tri(C 1-6 alkylamine and cyclic tertiary amine.
70 . The process according to claim 65 wherein the dehydrating agent in step (d) is a mixture of DMF and thionyl chloride.Cited by (0)
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