US2012029213A1PendingUtilityA1
Intermediates for the preparation of analogs of halichondrin b
Est. expiryJun 3, 2024(expired)· nominal 20-yr term from priority
Inventors:Brian C. AustadFarid BenayoudTrevor Lee CalkinsSilvio CampagnaCharles E. ChaseWilliam J. ChristFrancis G. FangYongbo HuBryan M. LewisMarc PesantMatthew J. SchnaderbeckGordon WilkieXiaojie Zhu
A61P 35/02A61P 35/00C07D 493/22C07D 493/20C07D 407/06C07D 493/08C07D 493/04C07D 493/18C07H 15/26C07F 7/188C07D 307/33C07D 317/72C07D 307/12A61K 31/341C07D 407/14C07D 307/28C07D 493/10C07C 33/423C07D 307/20C07F 7/1804C07F 7/18Y02P20/55
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Claims
Abstract
Intermediates and methods of their use in the synthesis of analogs of halichondrin B are provided.
Claims
exact text as granted — not AI-modified1 . A compound of formula F-1:
wherein:
each of PG 1 and PG 2 is independently hydrogen or a suitable hydroxyl protecting group, or PG 1 and PG 2 are taken together, with the oxygen atoms to which they are bound, to form a diol protecting group;
R 1 is R or OR;
R 2 is CHO or —CH═CH 2 ; and
each R is independently hydrogen, C 1-4 haloaliphatic, benzyl, or C 1-4 aliphatic, provided that, when R 1 is OMe, then PG 1 and PG 2 do not form an acetonide group.
2 . The compound of claim 1 , wherein said suitable hydroxyl protecting group, taken with the oxygen atom to which it is bound, is selected from an ester, an ether, a silyl ether, an alkyl ether, an arylalkyl ether, and an alkoxyalkyl ether.
3 . The compound of claim 1 having the formula:
4 . The compound of claim 1 having the formula:
5 . The compound of claim 4 in crystalline form.
6 . The compound of claim 1 having the formula:
7 . The compound of claim 6 in crystalline form.
8 . A compound having the formula F-2:
wherein:
each is independently a single or double bond, provided that both groups are not simultaneously a double bond;
LG 1 is a suitable leaving group;
X is —OSO 2 (R y );
R y is C 1-6 aliphatic or a 5-7 membered saturated, partially unsaturated, or fully unsaturated ring, wherein R y is optionally substituted with up to 3 groups selected from halogen, R, NO 2 , CN, OR, SR, or N(R) 2 ;
each R is independently hydrogen, C 1-4 haloaliphatic, or C 1-4 aliphatic; and
PG 3 is a suitable hydroxyl protecting group.
9 . The compound of claim 8 , wherein said suitable hydroxyl protecting group, taken with the oxygen atom to which it is bound, is selected from an ester, an ether, a silyl ether, an alkyl ether, an arylalkyl ether, and an alkoxyalkyl ether.
10 . The compound of claim 8 , wherein said suitable leaving group is selected from the group consisting of sulphonyloxy, optionally substituted alkylsulphonyloxy, optionally substituted alkenylsulfonyloxy, optionally substituted arylsulfonyloxy, or halogen.
11 . The compound of claim 8 having the formula:
12 . The compound of claim 8 having the formula:
13 . A compound having the formula:
14 . A compound having the formula:
15 . A method of preparing:
the method comprising synthesizing B1939 from a compound selected from the group consisting of:
16 . A method of preparing:
the method comprising reacting a compound of formula F-1:
wherein each of PG 1 and PG 2 is independently hydrogen or a suitable hydroxyl protecting group, or PG 1 and PG 2 are taken together, with the oxygen atoms to which they are bound, to form a diol protecting group; R 1 is R or OR; R 2 is CHO or —CH═CH 2 ; and each R is independently hydrogen, C 1-4 haloaliphatic, benzyl, or C 1-4 aliphatic, provided that when R 1 is OMe then PG 1 and PG 2 do not form an acetonide group,
under suitable conditions with a compound of formula F-2:
wherein each is independently a single or double bond, provided that both groups are not simultaneously a double bond; LG 1 is a suitable leaving group; X is halogen or —OSO 2 (R y ); R y is C 1-6 aliphatic or a 5-7 membered saturated, partially unsaturated, or fully unsaturated ring, wherein R y is optionally substituted with up to 3 groups selected from halogen, R, NO 2 , CN, OR, SR, or N(R) 2 ; each R is independently hydrogen, C 1-4 haloaliphatic, or C 1-4 aliphatic; and PG 3 is a suitable hydroxyl protecting group,
to produce a compound of formula F-4:
wherein each of PG 1 , PG 2 , and PG 3 is independently hydrogen or a suitable hydroxyl protecting group; R 1 is R or —OR; each R is independently hydrogen, C 1-4 haloaliphatic, benzyl, or C 1-4 aliphatic; and LG 1 is a suitable leaving group;
synthesizing from the compound of formula F-4a compound of formula F-5:
wherein each of PG 1 , PG 2 , and PG 3 is independently hydrogen or a suitable hydroxyl protecting group; R 1 is R or —OR; each R is independently hydrogen, C 1-4 haloaliphatic, benzyl, or C 1-4 aliphatic; and
synthesizing B1939 from the compound of formula F-5 and a compound of formula F-3:
wherein each PG 4 is an independently selected suitable hydroxyl protecting group;
R 3 is CHO or C(O)OR 4 ; R 4 is a suitable carboxyl protecting group; and LG 2 is a suitable leaving group.
17 . The method of claim 16 , wherein said suitable hydroxyl protecting group, taken with the oxygen atom to which it is bound, is selected from an ester, an ether, a silyl ether, an alkyl ether, an arylalkyl ether, and an alkoxyalkyl ether.
18 . The method of claim 16 , wherein said suitable leaving group is selected from the group consisting of sulphonyloxy, optionally substituted alkylsulphonyloxy, optionally substituted alkenylsulfonyloxy, optionally substituted arylsulfonyloxy, or halogen.
19 . The method of claim 16 , wherein said suitable carboxyl protecting group is selected from the group consisting of an optionally substituted C 1-6 aliphatic group and an optionally substituted aryl group.
20 . The method of claim 16 , wherein
(i) the compound of F-1 is
(ii) the compound of F-2 is
(iii) the compound of F-4 is
(iv) the compound of F-5 is
(v) the compound of F-3 isJoin the waitlist — get patent alerts
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