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US 10,208,058 B2Granted
Process for the preparation of macrocyclic ketone analogs of halichondrin B or pharmaceutically acceptable salts and intermediates thereof
AssigneeCipla Limited
InventorsDharmaraj Ramachandra Rao, Geena Malhotra, Venkata Srinivas Pullela, Vinod Parameshwaran Acharya, Nagarjuna Reddy Vantadou
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Abstract
The present invention discloses a novel process for the preparation of macrocyclic ketone analogs of halichondrin B or pharmaceutically acceptable salts thereof and to novel intermediates which are produced during the course of carrying out the novel process.
Claims19
A process for the preparation of a compound of formula I
- comprising:
- (i) reacting a compound of Formula (Ia)
- with a first protecting agent in the presence of a base to obtain a compound of Formula (Ib)
- (ii) reacting the compound of Formula (Ib) with a hydroxylating agent to form a vicinal diol of Formula (Ic)
- (iii) protecting the vicinal diol of Formula (Ic) with a second protecting agent to form a compound of Formula (Id):
- (iv) reducing the compound of Formula (Id) with a reducing agent to form a compound of Formula (Ie):
- (v) reacting the compound of Formula (Ie) with a halogenating agent to form a compound of Formula (If):
- and
- (vi) alkynation and haloboration of the compound of Formula (If) to form the compound of Formula (I);
- wherein PG1, PG2 and PG3 are independently hydrogen or hydroxyl protecting groups;
- and
- X1, X2 and X3 are leaving groups.
9 more elements
An intermediate useful in the preparation of eribulin, selected from the group consisting of:
- a compound of formula (I);
- a compound of formula (I-A):
- a compound of formula (V):
- a compound of formula (V-A):
- and
- wherein PG1, PG2, PG3, PG4, PG5, PG6, and PG7 are independently hydrogen or hydroxyl protecting groups;
- X1 is a leaving group;
- and
- R1 and R2 are each independently selected from the group consisting of H, and —CH2SO2Ar;
- or
- R1 and R2 together form ═CH2SO2Ar, where Ar is an aryl group;
- and
- R is H, C1-6 alkyl or C1-6 haloalkyl.
10 more elements
An intermediate useful in the preparation of eribulin, selected from the group consisting of:
- a compound of formula (I);
- and
- a compound of formula (I-A):
- wherein PG1, PG2, and PG3 are independently hydrogen or hydroxyl protecting groups;
- X1 is a leaving group.
2 more elements
Dependencies are inferred from the claim text.