Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-02-04
2001-02-27
Aulakh, Charanjit S. (Department: 1611)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06194580
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to high yielding methods of acylating tertiary alcohols. In particular, the invention relates to methods of forming esters of tertiary alcohols while maintaining high degrees of stereoselectivity.
BACKGROUND OF THE INVENTION
Over the years, several methods of administering therapeutic substances to mammals have been proposed. Although the oral route of administration is highly desirable from a patient compliance standpoint, the route is not practical for a large number of therapeutic compounds. Consequently, parenteral administration of many compounds via the intravenous or intramuscular route must be employed. Even when these routes are employed, there often problems associated with administration of the medicinal. This is especially true when the compound is either poorly soluble or is rapidly degraded or eliminated in vivo.
As an outgrowth of the above, there has been significant effort directed to developing useful transport mechanisms for effectively delivering therapeutic compounds to patients in need of treatment. More recently, interest has been shown in preparing prodrug-based transport forms in order to solve problems such as poor solubility associated with particular therapeutic compounds. For example, commonly-assigned U.S. Pat. No. 5,880,139 discloses using amino acid spacer groups with poly(ethylene glycol)ester prodrugs of 20-(S)-camptothecin, an anti-cancer alkaloid having a highly hindered OH at the 20-position. Esterification of the 20-OH group was accomplished in high yield by employing diisopropyl carbodiimide (DIPC) in the presence of 4-dimethylaminopyridine (DMAP). The reaction, however, is accompanied by substantial racemization for each stereoisomer, usually about 25% for t-Boc (L)-alanine and about 40% for t-Boc-(D)-alanine. In cases where conservation of chiral purity is necessary or desired, increased costs are incurred by efforts to isolate the desired diasteriomer because the artisan must subject the intermediate to one or more recrystallizations which also drive down the final yield. It would therefore be highly desirable to eliminate crystallization steps, especially if large scale quantities are required.
Recent advances in the acylation of tertiary alcohols which produce high yields of esters employ symmetrical carboxylic acid anhydrides and the readily-available Lewis acid catalyst scandium triflate Sc(OTf)
3
. This procedure, however, has been determined to be unsuitable for acylating hindered tertiary alcohols with mixed anhydrides of complex acids. The same authors later reported in Synlett, September 1996, 839-841 that Sc(OTf)
3
and a related catalyst were extremely active acetalization catalysts which afforded highly diastereoselective reactions. No information was provided regarding acylation-type reactions.
Gibson, et al. in J. Org. Chem. 1994, 59, 7503-7507 reported that high yields of t-butyl esters were possible with little or no racemization. However this approach has been deemed to be not convenient by some practitioners because it entails the multi-step synthesis of a water-soluble carbodiimide that must be converted to a t-butyl isourea using a cuprous chloride catalyst.
In view of the foregoing, synthesis of esters of tertiary alcohols with complex acids, especially amino acids, while maintaining chirality remains a challenging task. A need exists, therefore, for an improved method of forming esters of tertiary alcohols, especially when stereoselectivity in esterification of compounds containing a tertiary alcohol is required. The present invention addresses this need.
SUMMARY OF THE INVENTION
In one preferred embodiment, the present invention is directed to methods of forming esters of tertiary alcohols. The methods include reacting an acyl heteroaromatic ion compound of the formula:
wherein:
A is an anion;
R
1
is an aromatic or aliphatic acid residue;
Y is O or S;
Z is CH or N;
X is selected from the group consisting of
wherein:
R
2
and R
3
are independently selected from the group consisting of H, C
1-6
alkyls, C
1-6
substituted alkyls, C
1-6
heteroalkyls, C
3-8
branched alkyls, C
3-8
cycloalkyls, C
1-6
substituted heteroalkyls, aryls, substituted aryls, C
1-6
alkyl aralkyls, C
1-6
heteroalkyl aralkyls, C
3-8
branched alkyl aralkyls and C
3-8
cycloalkyl aralkyls;
and R
2
′ is the same as R
2
except that R
2
′ is not H;
with a compound containing a tertiary alcohol in the presence of a lanthanide
III
metal-based catalyst and a base.
The acyl heteroaromatic-ion based compound can be formed by either
1) reacting a carboxylic acid derivative with a condensing agent and a heteroaromatic-based catalyst of Formula (II):
where X and Z are defined as above with regard to Formula (I); or
2) reacting an acylating agent such as a mixed anhydride, N-hydroxysuccinimide ester or other active ester of a carboxylic acid or an acid halide with a heteroaromatic-based catalyst of Formula (II).
Preferred lanthanide
III
metal-based catalysts are scandium-based catalysts such as scandium triflate (scandium trifluoromethanesulfonate) and scandium trifluoromethanesulfonimide. Preferred bases include dimethylaminopyridine (DMAP) or diethylaminopyridine.
In other aspects of the invention the above methods are modified by using chiral compounds containing a tertiary alcohol and/or chiral acyl heteroaromatic ion-based compounds in order to produce high yields of essentially pure enantiomeric products. For example, a compound containing a tertiary alcohol can be reacted with a substantially pure isomer of a compound of Formula (I), i.e. an acyl heteroaromatic ion-based compound, and substantially maintain the chirality in the resultant ester of the tertiary alcohol.
As a result of the present invention, substantially single diastereomeric esters of compounds containing a tertiary alcohol are formed. The reactions are carried out under relatively mild conditions and maintain about 90%, and preferably up to about 95% diastereoselectivity when substantially pure optical isomers are used.
The esters of tertiary alcohols formed as a result of the invention have wide applicability. For example, they are especially useful in the field of pharmaceutical chemistry. The high degree of diastereoselectivity allows the artisan to make useful chiral prodrug intermediates in high optical purity and high isolated yield. For example, stereoselective esterification of compounds such as 20-S-camptothecin and derivatives thereof is readily accomplished in high yield and with substantially complete conservation of the chirality (i.e. >97% pure diasteriomer). The small amounts of undesired diastereomeric impurity which may be generated with the methods of the present invention can be removed via crystallization with minimal effect on the overall yield. Therefore, the time and expense of the recrystallization processes which were heretofore required to raise the optical purity of the desired intermediate is minimized or avoided.
REFERENCES:
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patent: 5614549 (1997-03-01), Greenwald et al.
patent: 5646159 (1997-07-01), Wall
patent: 5731316 (1998-03-01), Cao et al.
patent: 5840900 (1998-11-01), Greenwald et al.
patent: 5880131 (1999-03-01), Greenwald
Greenwald Tetrahedron: Asymeltry vol. 9 p. 915-918, Mar. 1998.
Greenwald, R. B. et a. : Stereoselective acylation of 20-(S)-camptothecin with amino acid derivatives using scandium triflate/DMAP. Tetrahed: Asymm. vol. 9, pp. 915-918, 1998.
Scriven, Eric F.V., 4-Dialkylaminopyridines: Super Acylation and Alkylation Catalysts, Chem. Soc. Rev., pp. 129-161; 1983.
Csanady, G. et al., A Convenient Synthesis of t-Butyl Esters of Amino Acids, OPPI Briefs Vol. 20, No. 2, pp. 180-184; 1988.
Chevallet, Pierre, et al. Facil Synthesis of Tert-Butyl Ester of N-Protected Amino Acids with Tert-Butyl Bromide, Tetrahedron Letters, vol. 34, No. 46; pp. 7409-7412; 1993.
Gibson, F. S., et al. Bis [[4-(2,2-dimethyl-1,3-dioxolyl)]methyl]-carbodiimide (BDDC) and Its Application to Residue-Free . . .
Greenwald Richard B.
Pendri Annapurna
Zhao Hong
Aulakh Charanjit S.
Enzon Inc.
Roberts & Mercanti LLP
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