SYNTHESIS OF RAPAMYCIN ANALOG COMPOUNDS
The present disclosure relates to novel methods for preparing rapamycin analog compounds, as well as to related intermediates useful in such methods.
1 . A process for preparing a compound of formula (3), or a salt thereof, comprising:
(1a) contacting a compound of formula (1), or a salt thereof,
with a reducing agent, to yield a compound of formula (2), or a salt thereof,
(2a) contacting a compound of formula (2), or a salt thereof, with an amino protecting group reagent to yield a compound of formula (3), or a salt thereof,
wherein PG N1 is an amino protecting group.
2 . The process of claim 1 , wherein the reducing agent is sodium borohydride, and/or wherein step (1a) is performed in the presence of acetic acid.
3 . The process of claim 1 , wherein:
(a) the amino protecting group reagent is triphenylmethyl chloride; and/or
(b) PG N1 is triphenylmethyl (trityl).
4 . The process of claim 1 , wherein:
(a) step (2a) is performed in the presence of an activating reagent, optionally wherein the activating reagent is 4-dimethylaminopyridine (DMAP); and/or
(b) step (2a) is performed in dichloromethane (DCM).
5 . The process of claim 1 , further comprising isolating the compound of formula (3).
6 . The process of claim 1 , further comprising:
(3a′) contacting the compound of formula (3), or a salt thereof, with an organometallic/metal reagent and formaldehyde to yield a compound of formula (5), or a salt thereof,
(3a) contacting the compound of formula (3), or a salt thereof, with an organometallic reagent and dimethylformamide (DMF) to yield a compound of formula (4), or a salt thereof,
optionally wherein step (3a) is performed in tetrahydrofuran (THF), and/or wherein the organometallic reagent is an alkyl magnesium halide.
7 . The process of claim 6 , further comprising
(4a) contacting the compound of formula (4), or a salt thereof, with a reducing agent to yield a compound of formula (5), or a salt thereof,
optionally wherein the reducing agent is sodium borohydride and/or wherein step (4a) is performed in a solvent selected from the group consisting of methanol, THF, and mixture thereof.
8 . The process of claim 6 , further comprising
(5a) contacting the compound of formula (5), or a salt thereof, with a PG N1 deprotecting reagent to yield a compound of formula (6), or a salt thereof,
optionally wherein step (5a) is performed in DCM; and
(6a) contacting the compound of formula (6), or a salt thereof, with a Boc protecting group reagent to yield a compound of formula (7), or a salt thereof,
optionally wherein step (6a) is performed in THF, and/or wherein the process further comprises isolating the compound of formula (7).
9 . The process of claim 8 , wherein:
(a) the PG N1 deprotecting reagent is an acid; and/or
(b) the Boc protecting group reagent is Boc 2 O.
10 . The process of claim 8 , further comprising
(7a) contacting the compound of formula (7), or a salt thereof, with an alcohol activating reagent to yield a compound of formula (8), or a salt thereof,
wherein −LG O1 is a leaving group,
optionally wherein the process further comprises isolating the compound of formula (8).
11 . The process of claim 10 , wherein:
(a) the alcohol activating reagent is a sulfonyl halide or a halogenating reagent, optionally methanesulfonyl chloride (mesyl chloride; CH 3 SO 2 Cl); and/or
(b) −LG O1 is a sulfonate ester or a halide, optionally mesylate (—O—SO 2 CH 3 ).
12 . The process of claim 10 , wherein:
(a) step (7a) is performed in the presence of a base, optionally wherein the base is diisopropylethylamine (DIPEA); and/or
(b) step (7a) is performed in DCM.
13 . The process of claim 10 , further comprising
(8a) contacting the compound of formula (8), or a salt thereof, with a compound of formula (9), or a salt thereof,
to yield a compound of formula (10), or a salt thereof,
optionally wherein step (8a) is performed in DMF, and/or wherein the method further comprises isolating the compound of formula (10).
14 . The process of claim 13 , further comprising
(9a) contacting the compound of formula (10), or a salt thereof, with a compound of formula (11) or a salt thereof,
to yield a compound of formula (12), or a salt thereof,
optionally wherein the process further comprises isolating the compound of formula (12).
15 . The process of claim 14 , wherein the compound of formula (11) is prepared by borylation of a compound of formula (11a), or a salt thereof,
optionally wherein borylation is performed with contact with a boronic ester reagent, further optionally wherein the boronic ester reagent is bis(pinacolato)diboron (B 2 Pin 2 ).
16 . The process of claim 14 , wherein:
(a) step (9a) is performed in the presence of a palladium catalyst, optionally wherein the palladium catalyst is Pd(PPh 3 ) 4 ; and/or
(b) step (9a) is performed in a solvent selected from the group consisting of water, dioxane, and mixture thereof.
17 . The process of claim 14 , further comprising
(10a) contacting the compound of formula (12) with an acid to yield a compound of formula (13),
(11a) preparing a salt of a compound of formula (13);
optionally wherein step (10a) and step (11a) are performed in water.
18 . The process of claim 17 , wherein:
(a) the acid is hydrochloric acid, thereby yielding a hydrochloric salt of compound of formula (13a),
wherein x is 1, 2, or 3; or
(b) the acid is trifluoroacetic acid, thereby yielding a TFA salt of compound of formula (13c),
wherein y is 1, 2, or 3.
19 . The process of claim 17 , further comprising isolating the compound of formula (13), (13a), or (13c).
20 . A process for preparing a compound of formula (21), or a salt thereof, comprising:
(1b) contacting a compound of formula (20), or a salt thereof,
with a hydroxyl protecting group reagent, to yield a compound of formula (21), or a salt thereof,
wherein PG O1 and PG O2 are the same or different at each instance a hydroxyl protecting group, optionally wherein step (1b) is performed in the presence of imidazole, and/or wherein step (1b) is performed in DCM.
21 . The process of claim 20 , wherein:
(a) each hydroxyl protecting group reagent is triethylchlorosilane (TES-Cl);
(b) PG O1 is triethylsilyl ether (TES); and/or
(c) PG O2 is triethylsilyl ether (TES).
22 . The process of claim 20 , further comprising isolating the compound of formula (21).
23 . The process of claim 20 , further comprising:
(2b) contacting a compound of formula (21), or a salt thereof, with a reducing agent to yield a compound of formula (22), or a salt thereof,
optionally wherein the reducing agent is LiAl(Ot-Bu) 3 H, and/or wherein step (2b) is performed in THF.
24 . The process of claim 23 , wherein the product from step (2b) is subsequently contacted with Cu(OAc) 2 .
25 . The process of claim 23 , further comprising isolating the compound of formula (22).
26 . The process of claim 23 , further comprising:
(3b) contacting a compound of formula (22), or a salt thereof, with a PG O1 deprotecting reagent and a PG O2 deprotecting reagent to yield a compound of formula (23), or a salt thereof,
optionally wherein step (3b) is performed in THF, further optionally wherein the PG O1 deprotecting reagent is an acid, or wherein the PG O2 deprotecting reagent is an acid.
27 . The process of claim 26 , further comprising isolating the compound of formula (23).
28 . The process of claim 26 , further comprising
(4b) contacting the compound of formula (23), or a salt thereof, with a compound of formula (24), or a salt thereof,
to yield a compound of formula (25), or a salt thereof,
optionally wherein step (4b) is performed in DCM, and/or wherein the process further comprises isolating the compound of formula (25).
29 . A process for preparing a compound of formula (31), or a salt thereof, comprising:
(1c) contacting a compound of formula (30), or a salt thereof,
with a compound of formula (13), or a salt thereof,
to yield the compound of formula (31), or a salt thereof,
optionally wherein the process further comprises isolating the compound of formula (31).
30 . The process of claim 29 , wherein the compound of formula (13), or a salt thereof, is:
(a) a compound of formula (13a),
wherein x is 1, 2, or 3; or
(b) a compound of formula (13c),
wherein y is 1, 2, or 3.
31 . The process of claim 29 , wherein:
(a) step (1c) is performed in the presence of a coupling reagent, optionally wherein the coupling reagent is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI);
(b) step (1c) is performed in the presence of an activating reagent, optionally wherein the activating reagent is hydroxybenzotriazole (HOBt); and/or
(c) step (1c) is performed in dimethylacetamide (DMM).
32 . The process of claim 29 , further comprising
(2c) contacting the compound of formula (31) with a Boc removing agent to yield a compound of formula (32), or a salt thereof,
optionally wherein the Boc removing reagent is hydrochloric acid, and/or wherein step (2c) is performed in a solvent selected from the group consisting of water, DCM, dimethylacetamide (DMAc), and mixtures thereof.
33 . The process of claim 32 , further comprising isolating the compound of formula (32).
34 . The process of claim 32 , further comprising
(3c) contacting the compound of formula (32), or a salt thereof, with a compound of formula (25), or a salt thereof,
to yield a compound of formula (33), or a salt thereof,
optionally wherein step (3c) is performed in DMAc, and/or wherein the process further comprises isolating the compound of formula (33).
35 . A compound of:
(a) formula (13), or a salt thereof,
(b) formula (13a),
wherein x is 1, 2, or 3;
(c) formula (13c),
wherein y is 1, 2, or 3; or
(d) formula (32), or a salt thereof,