US2017226124A1PendingUtilityA1
Phthalazinone derivatives
Est. expiryMar 12, 2023(expired)· nominal 20-yr term from priority
Inventors:Niall Morrison Barr MartinGraeme Cameron Murray SmithStephen Philip JacksonVincent Junior M LohXiao-Ling Fan CockcroftIan Timothy Williams MatthewsKeith Allan MenearFrank KerriganAlan Ashworth
A61P 35/00A61P 31/00A61P 31/20A61P 35/04C07D 403/14A61K 31/551C07D 413/12A61K 45/06C07D 403/10C07D 401/12C07D 409/14C07D 401/10A61K 31/00C07D 403/12C07D 243/08C07D 491/04A61K 31/506C07D 405/12C07D 495/04C07D 409/12C07D 237/32C07D 413/14C07D 401/14C07D 405/14A61K 31/502C07D 417/14A61K 31/5377C07D 417/12A61N 5/10
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Claims
Abstract
Compounds of the formula (I): wherein A and B together represent an optionally substituted, fused aromatic ring; X can be NR X or CR X R Y ; if X=NR X then n is 1 or 2 and if X=CR X R Y then n is 1; R X is selected from the group consisting of H, optionally substituted C 1-20 alkyl, C 5-20 aryl, C 3-20 heterocyclyl, amido, thioamido, ester, acyl, and sulfonyl groups; R Y is selected from H, hydroxy, amino; or R X and R Y may together form a spiro-C 3-7 cycloalkyl or heterocyclyl group; R C1 and R C2 are both hydrogen, or when X is CR X R Y , R C1 , R C2 , R X and R Y , together with the carbon atoms to which they are attached, may form an optionally substituted fused aromatic ring; and R 1 is selected from H and halo.
Claims
exact text as granted — not AI-modified1 .- 12 . (canceled)
13 . A method of synthesising a compound of formula I
from a compound of formula III:
Wherein:
R 1 is selected from H and halo;
R 2 is selected from optionally substituted C 1-20 alkyl, C 5-20 aryl and C 3-20 heterocyclyl; and
n is 1 or 2.
14 . A method according to claim 13 comprising the steps of:
(a) synthesising a compound of formula IV:
wherein R 1 and n are as defined in claim 13 , from a compound of formula III;
(b) synthesising a compound of formula V:
from a compound of formula IV;
(c) reacting a compound of formula V with an appropriate acid chloride in the presence of a base.
15 . A method according to claim 14 , wherein a compound of formula IV is not isolated in the synthesis.
16 . A method according to claim 14 , where n is 1, wherein step (a) is carried out in the presence of an amide coupling reagent which is added to a solution of Hünig's base, a compound of formula III, and 1-Boc-piperazine.
17 . A method according to claim 16 , wherein the amide coupling reagent is 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate.
18 . A method according to claim 14 , wherein step (b) is carried out in a solution of hydrochloric acid and ethanol.
19 . A method according to claim 14 , where in step (c), the base is Hünig's base.
20 . A method according to claim 14 , wherein step (c) is carried out in dichloromethane.
21 . A method according to claim 13 , wherein R 1 is fluoro, R 2 is cyclopropyl, and n is 1.
22 . A method of synthesising a compound of formula III:
from 2-carboxybenzaldehyde, wherein R 1 is selected from H and halo.
23 . A method according to claim 22 comprising the steps of:
(a) synthesising (3-oxo-1,3-dihydro-isobenzofuran-1-yl)phosphonic acid dimethyl ester from 2-carboxybenzaldehyde;
(b) synthesising a compound of formula II:
from (3-oxo-1,3-dihydro-isobenzofuran-1-yl)phosphonic acid dimethyl ester;
(c) reacting a compound of formula II with sodium hydroxide, followed by reaction with hydrazine hydrate, followed by acidification with an acid.
24 . A method according to claim 13 , where in step (a), 2-carboxybenzaldehyde is reacted with the sodium salt of dimethyl phosphite, which is formed in situ by adding dimethyl phosphite to a cooled solution of sodium methoxide in methanol.
25 . A method according to claim 24 , where in step (a), the reaction with the sodium salt of dimethyl phosphite is followed by reaction with methanesulphonic acid.
26 . A method according to claim 23 , wherein step (b) is carried out in tetrahydrofuran, with the addition of triethylamine.
27 . A method according to claim 23 , where in step (c), the acid is hydrochloric acid.
28 . A method according to claim 22 , wherein R 1 is fluoro.
29 . A method of synthesising a compound of formula I:
from a compound of formula II
wherein
R 1 is selected from H and halo;
R 2 is selected from optionally substituted C 1-20 alkyl, C 5-20 aryl and C 3-20 heterocyclyl; and
n is 1 or 2.
30 . A method according to claim 29 comprising the steps of:
(a) synthesising a compound of formula III:
from a compound of formula II by reaction with sodium hydroxide, followed by reaction with hydrazine hydrate;
(b) synthesising a compound of formula IV:
from a compound of formula III;
(c) synthesising a compound of formula V:
from a compound of formula IV;
(d) reacting a compound of formula V with an appropriate acid chloride in the presence of a base.
31 . A method of synthesising a compound of formula I:
from 2-carboxybenzaldehyde, wherein R 1 is selected from H and halo;
R 2 is selected from optionally substituted C 1-20 alkyl, C 5-20 aryl and C 3-20 heterocyclyl; and
n is 1 or 2.
32 . A method according to claim 31 , comprising the steps of:
(a) synthesising (3-oxo-1,3-dihydro-isobenzofuran-1-yl)phosphonic acid dimethyl ester from 2-carboxybenzaldehyde; (b) synthesising a compound of formula II:
from (3-oxo-1,3-dihydro-isobenzofuran-1-yl)phosphonic acid dimethyl ester;
(c) synthesising a compound of formula III:
from a compound of formula II by reaction with sodium hydroxide, followed by reaction with hydrazine hydrate;
(d) synthesising a compound of formula IV:
from a compound of formula III;
(e) synthesising a compound of formula
from a compound of formula IV;
(f) reacting a compound of formula V with an appropriate acid chloride in the presence of a base.Cited by (0)
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