Pyran fused ring compound, preparation method therefor and use thereof
The present invention relates to pyran-fused ring compounds, preparation methods thereof and use thereof, especially to pyran-fused ring compounds usable for preparing Halichondrin, Eribulin, or analogues thereof, preparation methods thereof and use thereof. Use of any of the compounds of formula (I) to (XIII) of the present invention in preparation of Halichondrin B, Eribulin, analogues thereof or C1-C13 moieties thereof. Provided in the present invention are intermediates usable for preparing Halichondrin B, Eribulin, or analogues thereof, especially the key product of C1-C13 moieties, preparation methods thereof and use thereof. The starting material for the synthesis pathway of the present invention is inexpensive and readily available with sustainable source and reliable quality. Since the structural characteristics of the reactants of theirself are made full use in choosing the method of constructing the chiral centers, the efficiency in the synthesis is considerably increased, the difficulty in and the risk on quality control of the product are reduced; and using a highly toxic and expensive high-valent osmium catalyst is avoided, which have the cost and environmental friendliness significantly improved.
1. A method for preparing a compound of formula (V), comprising:
reacting a compound of formula (IV) with B 2 (OR 7 ) 4 to obtain a compound of formula (IV-1), and removing the group —B(OR 7 ) 2 from the compound of formula (IV-1) to obtain the compound of formula (V):
wherein R 4 and R 6 are the same or different and independently selected from hydroxyl protecting groups;
wherein the R 7 groups in the compound of formula (IV-1) are independently an alkyl unsubstituted or optionally substituted with one or more of R a ; or,
in each of two —B(OR 7 ) 2 groups, the two adjacent R 7 groups bind to each other to form an alkylidene unsubstituted or optionally substituted with one or more of R a , two ends of said alkylidene each binding to the O atom via a chemical bond to form a ring with the B atom; and
the R a groups are independently selected from —F, —Cl, —Br, —I, ═O, alkyl, cycloalkyl, heterocycyl, aryl, heteroaryl, alkoxy, alkenyloxy, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl.
2. A method for preparing a compound of formula (VI), comprising the step of:
preparing the compound of formula (V) according to the method of claim 1 ;
reacting the compound of formula (V) with a hydroxyl-protecting agent to obtain a compound of formula (VI)
wherein R 8 , R 9 , and R 10 are the same or different and independently selected from hydroxyl protecting groups.
3. A method for preparing a compound of formula (VIII), comprising the steps of:
preparing the compound of formula (VI) according to the method of claim 2 ;
reacting the compound of formula (VI) under a condition for removing the R 6 group to obtain a compound of formula (VII)
and
reacting the compound of formula (VII) in the presence of the oxidizing agent to obtain a compound of formula (VIII)
4. A method for preparing a compound of formula (IX), comprising the step of:
preparing the compound of formula (VIII) according to the method of claim 3 ;
reacting the compound of formula (VIII) to obtain a compound of formula (IX)
X is selected from Cl, Br, I and R 14 S(O) 2 —, and
R 14 is selected from alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl unsubstituted, and heteroaryl substituted with one or more of R a .
5. A method for preparing a compound of formula (XIII), comprising the steps of:
preparing the compound of formula (IX) according to the method of claim 4 ;
reacting the compound of formula (IX) to obtain a compound of formula (X)
and
reacting the compound of formula (X) to obtain a compound of formula (XI) and/or tautomeric isomers thereof
wherein Y is an unsubstituted alkoxy or an alkoxy substituted with one or more of R a ; and
reacting the compound of formula (XI) to obtain a compound of formula (XII)
wherein X, Y are defined in the same way as in the formula (XI); and
reacting the compound of formula (XII) with the hydroxyl-protecting agent to obtain the compound of formula (XIII)
wherein X and Y are defined in the same way as in the formula (XI), and
R 11 , R 12 , and R 13 are the same or different and independently selected from hydroxyl protecting groups.
6. A compound selected from
and
wherein R 1 and R 2 are the same or different and independently selected from H and —B(OR 7 ) 2 ,
R 4 and R 6 are the same or different and independently selected independently from hydroxyl protecting groups,
wherein, in —B(OR 7 ) 2 , R 7 is selected from an unsubstituted alkyl an alkyl optionally substituted with one or more of R a ; or two adjacent R 7 groups bind to each other to form an alkylidene unsubstituted or optionally substituted with one or more of R a , two ends of said alkylidene each binding to the 0 atom via a chemical bond, thereby forming a ring with the B atom;
R 8 , R 9 , and R 10 are the same or different and independently selected from hydroxyl protecting groups,
X is Cl, Br, I, or R 14 S(O) 2 —,
R 14 is selected from alkyl, cycloalkyl, heterocyclyl, aryl, unsubstituted heteroaryl, and heteroaryl substituted with one or more of R a
Y is an alkoxy unsubstituted or optionally substituted with one or more of R a , and each of the R a is the same or different and independently selected independently of one another from —F, —Cl, —Br, —I, ═O, alkyl, cycloalkyl, heterocycyl, aryl, heteroaryl, alkoxy, alkenyloxy, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl.
7. The method of preparing the compound of formula (IV),
wherein R 4 and R 6 are the same or different and independently selected from hydroxyl protecting groups,
comprising the steps of:
1) selectively epoxidized a diene compound (III) or compound (III-4) at the positions C 8 , C 9 :
wherein R 5 is selected from hydroxyl protecting groups; or
2) causing a compound (III-3) or compound (III-5) to undergo an intra-molecular S N 2 reaction
8. The method of preparing the compound of formula (IX), comprising the steps of:
reacting the compound of formula (VIII) to obtain the compound of formula (IX)
wherein R 4 is a hydroxyl protecting group,
R 8 , R 9 , and R 10 are the same or different and independently selected from hydroxyl protecting groups,
X is Cl, Br, I or R 14 S(O) 2 —,
R 14 is selected from alkyl, cycloalkyl, heterocyclyl, aryl, unsubstituted heteroaryl, and heteroaryl substituted with one or more R a , and
each of the R a is the same or different and independently selected from —F, —Cl, —Br, —I, ═O, alkyl, cycloalkyl, heterocycyl, aryl, heteroaryl, alkoxy, alkenyloxy, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl.
9. The method of preparing the compound of formula (VII), comprising the steps of:
reacting the compound of formula (VI) to obtain the compound of formula (VII),
wherein R 4 and R 6 are the same or different and independently selected from hydroxyl protecting groups, and
R 8 , R 9 , and R 10 are the same or different and independently selected from hydroxyl protecting groups.
10. The method of preparing the compound of formula (VIII), comprising the steps of:
reacting the compound of formula (VII) to obtain the compound of formula (VIII)
R 4 is a hydroxyl protecting group, and
R 8 , R 9 , and R 10 are the same or different and independently selected from hydroxyl protecting groups.
11. A method for preparing a compound of formula (XIII), comprising:
preparing the compound of formula (V) according the method of claim 1 ;
removing the hydroxyl protecting group R 4 from the compound of formula (V) to synthesize a compound (V-2);
subjecting the compound (V-2) to a stepwise or concurrent hydroxyl-protection to obtain a compound (V-3);
removing the protecting group R 6 from the compound (V-3) to generate a compound (V-4);
oxidizing the compound (V-4) to form an aldehyde (V-5); and
reacting the aldehyde (V-5) to form the compound of formula (XIII):