Regioselective synthesis of rapamycin derivatives

Details Regioselective synthesis of rapamycin derivatives Regioselective synthesis of rapamycin derivatives

2000-09-27

2001-08-21

Kifle, Bruck (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Unsubstituted hydrocarbyl chain between the ring and the -c-...

Reexamination Certificate

active

06277983

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to the regioselective synthesis of derivatives of rapamycin at the 42-position, which are useful for inducing immunosuppression, and in the treatment of transplantation rejection, graft vs. host disease, autoimmune diseases, diseases of inflammation, adult T-cell leukemia/lymphoma, solid tumors, fungal infections, and hyperproliferative vascular disorders.
Rapamycin is a macrocyclic triene antibiotic produced by
Streptomyces hygroscopicus
, which was found to have antifungal activity, particularly against
Candida albicans
, both in vitro and in vivo [C. Vezina et al., J. Antibiot. 28, 721 (1975); S. N. Sehgal et al., J. Antibiot. 28, 727 (1975); H. A. Baker et al., J. Antibiot. 31, 539 (1978); U.S. Pat. No. 3,929,992; and U.S. Pat. No. 3,993,749].
Rapamycin alone (U.S. Pat. No. 4,885,171) or in combination with picibanil (U.S. Pat. No. 4,401,653) has been shown to have antitumor activity. R. Martel et al. [Can. J. Physiol. Pharmacol. 55, 48 (1977)] disclosed that rapamycin is effective in the experimental allergic encephalomyelitis model, a model for multiple sclerosis; in the adjuvant arthritis model, a model for rheumatoid arthritis; and effectively inhibited the formation of IgE-like antibodies.
The immunosuppressive effects of rapamycin have been disclosed in FASEB 3, 3411 (1989). Cyclosporin A and FK-506, other macrocyclic molecules, also have been shown to be effective as immunosuppressive agents, therefore useful in preventing transplant rejection [FASEB 3, 3411 (1989); FASEB 3, 5256 (1989); R. Y. Calne et al., Lancet 1183 (1978); and U.S. Pat. No. 5,100,899].
Rapamycin has also been shown to be useful in preventing or treating systemic lupus erythematosus [U.S. Pat. No. 5,078,999], pulmonary inflammation [U.S. Pat. No. 5,080,899], insulin dependent diabetes mellitus [U.S. Pat. No. 5,321,009], smooth muscle cell proliferation and intimal thickening following vascular injury [U.S. Pat. No. 5,516,781], adult T-cell leukemia/lymphoma [European Patent Application 525,960 A1], and ocular inflammation [U.S. Pat. No. 5,387,589].
Numerous rapamycin 42-derivatives are known, typically being esters (carbon and sulfur based) or ethers of the 42-hydroxyl group of rapamycin, that are produced by esterification or etherification of the 42-position. Esterification of rapamycin at the 42-position was commonly prepared by directly reacting rapamycin with acylating agents in order to afford the desired product. The chemistry appeared to be rather simple. However, as rapamycin contains two secondary hydroxyl groups at positions 31 and 42, attempts to discriminate between these two functional centers in order to achieve a selective synthesis of 42-monoacylated product, posed a difficult challenge. This type of non-regioselective reaction also produced a 31,42-bis-acylated by-product and as well, some unreacted rapamycin remained in the reaction mixture. The final result was a lower yield that required extensive purification to obtain pure 42-monoacylated product.
DESCRIPTION OF THE INVENTION
This invention provides a regioselective method for the preparation of a 42-ester or ether rapamycin having the structure
wherein R is an ester or ether, which comprises:
(a) treating rapamycin with a silylating agent to form rapamycin 31,42-bis-silyl ether;
(b) selectively hydrolyzing the 42-silyl ether in mild acid to provide rapamycin 31-silyl ether;
(c) treating the rapamycin 31-silyl ether with a suitable esterifying or etherifying reagent to form rapamycin 31-silyl ether 42-ester or ether; and
(d) selectively hydrolyzing the 31-silyl ether in mild acid to provide the desired rapamycin 42-ester or ether.
Preferred 42-esters and ethers of rapamycin which can be prepared by the method provided by this invention are disclosed in the following patents, which are all hereby incorporated by reference: alkyl esters (U.S. Pat. No. 4,316,885); aminoalkyl esters (U.S. Pat. No. 4,650,803); fluorinated esters (U.S. Pat. No. 5,100,883); amide esters (U.S. Pat. No. 5,118,677); carbamate esters (U.S. Pat. No. 5,118,678); silyl ethers (U.S. Pat. No. 5,120,842); aminoesters (U.S. Pat. No. 5,130,307); acetals (U.S. Pat. No. 5,51,413); aminodiesters (U.S. Pat. No. 5,162,333); sulfonate and sulfate esters (U.S. Pat. No. 5,177,203); esters (U.S. Pat. No. 5,221,670); alkoxycsters (U.S. Pat. No. 5,233,036); O-aryl, -alkyl, -alkenyl, and -alkynyl ethers (U.S. Pat. No. 5,258,389); carbonate esters (U.S. Pat. No. 5,260,300); arylcarbonyl and alkoxycarbonyl carbamates (U.S. Pat. No. 5,262,423); carbamates (U.S. Pat. No. 5,302,584); hydroxyesters (U.S. Pat. No. 5,362,718); hindered esters (U.S. Pat. No. 5,385,908); heterocyclic esters (U.S. Pat. No. 5,385,909); gem-disubstituted esters (U.S. Pat. No. 5,385,910); amino alkanoic esters (U.S. Pat. No. 5,389,639); phosphorylcarbamate esters (U.S. Pat. No. 5,391,730); carbamate esters (U.S. Pat. No. 5,411,967); carbamate esters (U.S. Pat. No. 5,434,260); amidino carbamate esters (U.S. Pat. No. 5,463,048); carbamate esters (U.S. Pat. No. 5,480,988); carbamate esters (U.S. Pat. No. 5,480,989); carbamate esters (U.S. Pat. No. 5,489,680); hindered N-oxide esters (U.S. Pat. No. 5,491,231); biotin esters (U.S. Pat. No. 5,504,091); and O-alkyl ethers (U.S. Pat. No. 5,665,772). These patents also disclose methods for esterification or etherification utilized in step (c), above.
The following scheme illustrates the regioselective preparation of rapamycin 42-ester with 2,2-bis-(hydroxymethyl)propionic acid, as a representative 42-ester of rapamycin, which can be prepared according to the method provided in this invention. The original synthesis of rapamycin 42-ester with 2,2-bis-(hydroxymethyl)propionic acid is disclosed in U.S. Pat. No. 5,362,718.
While the chemical preparation of rapamycin esters and ethers appears to be simple, and the desired products are obtainable, the synthetic yield of the esters and ethers is often poor. As rapamycin contains two secondary hydroxyl groups at positions 31 and 42, attempts to discriminate between these two functional centers in order to achieve a selective synthesis of 42-monoester such as compound [B] poses a difficult challenge. For example, the synthesis of rapamycin 42-ester with 2,2-bis-(hydroxymethyl)propionic acid described in U.S. Pat. No. 5,362,718, example 10, was non-regioselective, the 31,42-bisester by-product was also generated. As a result, the crude product [B] after work-up contains the desired product [B], 31,42-bisester by-product and unreacted rapamycin. In an effort to consume the remaining starting rapamycin, the reaction was allowed to proceed for a longer period with negative consequences, the quantity of the 31,42-bisester increased significantly. The resulting crude product [B] is contaminated with unreacted rapamycin and 31,42-bisester, and subsequent column chromatography purification effort has proved to be difficult as the 42,31-bisester has a very close retention time with product [B]. Overall, the major obstacle in large-scale production of compound [B] appears to be the non-regiospecificity that is further complicated by purification difficulties. This invention overcomes these difficulties by providing a regioselective synthesis of 42-esters or ethers of rapamycin by selectively protecting the 31-hydroxyl group as a silyl ether (i.e., compound [D]), leaving the 42-position hydroxyl accessible for regioselective esterification or etherification to produce 31-O-silyl, 42-esters or ethers (i.e., compound [E]). The 31-hydroxyl group can then be deprotected under mild acidic conditions (i.e., compound [B]).
In accordance with this invention, it is preferred that the 31, and 42-hydroxyl groups are protected as trialkyl silyl ethers. The 42-silyl protected hydroxyl group of the 31, 42-bis-silylated rapamycin can be selectively cleaved under mildly acidic conditions to provide 31-silyl rapamy

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