Process for preparing 6-o-substituted erythromycin derivatives

Details Process for preparing 6-o-substituted erythromycin derivatives Process for preparing 6-o-substituted erythromycin derivatives

2000-03-03

2002-08-20

Peselev, Elli (Department: 1623)

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

Organic compounds

Carbohydrates or derivatives

C536S007200, C536S018500

Reexamination Certificate

active

06437106

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a process for preparing 6-O-substituted erythromycin derivatives and 6-O-substituted erythromycin ketolides thereof. Specifically, the invention relates to a palladium-catalyzed process for preparing 6-O-substituted erythromycin derivatives from erythromycins using alkylating agents in presence of a phosphine and their subsequent conversion into 6-O-substituted erythromycin ketolides.
BACKGROUND OF THE INVENTION
6-O-Methylerythromycin A (clarithromycin) is a potent macrolide antibiotic disclosed in U.S. Pat. No. 4,331,803.
The process for making clarithromycin, in general, can be thought of as a four-step procedure beginning with erythromycin A as the starting material:
Step 1: optionally convert the 9-oxo group to an oxime;
Step 2: protect the 2′ and 4″ hydroxyl groups;
Step 3: methylate the 6-hydroxyl group; and
Step 4: deprotect at the 2′, 4″ and 9-positions.
A variety of means for preparing 6-O-methylerythromycin A have been described in the literature. 6-O-Methylerythromycin A can be prepared by methylating a 2′-O-3′-N-dibenzyloxycarbonyl-des-N-methyl derivative of erythromycin A (U.S. Pat. No. 4,331,803). 6-O-Methylerythromycin A can also be made from 9-oxime erythromycin A derivatives (See, e.g., U.S. Pat. Nos. 5,274,085; 4,680,386; 4,668,776; 4,670,549 and 4,672,109, 4,990,602 and European Patent Application 0260938 A2). Several commonly-owned U.S. Pat. Nos. 5,872,229; 5,719,272; 5,852,180; 5,864,023; 5,808,017; 5,837,829 and 5,929,219 disclose the use of alternate protecting groups for the oxime hydroxyl, and the 2′- and 4″-hydroxyls in the process of making the 6-O-methyl erythromycin derivatives.
Since the discovery of clarithromycin, new macrolide antibiotic compounds have been discovered. New classes of particularly effective macrolide antibiotics are disclosed in U.S. Pat. No. 5,866,549. The 6-O-position of the macrolide core can be substituted with a C
2
-C
6
alkenyl group. Such compounds generally have been prepared by the processes described for the preparation of 6-O-methylerythromycin A. However, the substitution at the 6-O-position with substituents other than the methyl group is not easy to accomplish and is accompanied by side reactions, by-products and low yields.
Therefore, there is considerable effort directed towards discovering more efficient and cleaner methods of introducing substituents other than the methyl in the 6-position of the erythromycin derivatives.
Palladium-catalyzed allylation of alcohol hydroxyl groups is known in the literature. See for example, Lakhmiri et al., “Synthesis De O-glycosides D'Alcenyles”,
J. Carbohydrate Chemistry,
12(2), 223, (1993); Lakhmiri et al.,
Tetrahedron Letters,
30(35), No. 35, pp 4673-4676, (1989); and Lakhmiri et al., “An Improved Synthesis of Allyl Ethers of Carbohydrates”,
Synthetic Communications,
20 (10), 1551-1554 (1990). Palladium-catalyzed allylation of phenol derivatives using allyl t-butyl carbonate is disclosed in Goux C. et al.,
Synlett.,
725 (1990). However, there are no known reports of palladium-catalyzed substitution, derivatization or selective allylation of hydroxyl groups of erythromycin derivatives.
SUMMARY OF THE INVENTION
In one aspect, therefore, the present invention relates to a process for preparing 6-O-substituted erythromycin derivatives comprising reacting an erythromycin derivative with an alkylating agent having the formula:
wherein
R is independently selected from the group consisting of:
hydrogen, an alkyl group of one to ten carbon atoms, halogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl at each occurrence;
R
1
is an alkyl group of one to ten carbon atoms, and
X is O or NR′, wherein R′ is alkyl or aryl, or R
1
and R′ taken together form an aromatic or non-aromatic ring;
in the presence of a palladium catalyst and a phosphine.
The erythromycin derivative used in the process of the invention is represented by formula (1) below:
wherein:
R
p
is independently a hydrogen or a hydroxyl-protecting group at each ocurrence except that R
p
may not simultaneously be hydrogen at both positions;
V is selected from the group consisting of:
a) O
b) an oxime having the formula N—O—R
2
; wherein
R
2
is selected from the group consisting of:
hydrogen,
a loweralkenyl group,
an aryl(loweralkyl) group, and
a substituted aryl(loweralkyl) group;
c) an oxime having the formula
wherein
R
3
is selected from the group consisting of:
alkyl,
alkylaryl,
aryl, and
substituted aryl;
d) an oxime having the formula
wherein
R
4
is selected from the group consisting of:
a loweralkyl group,
a cycloalkyl group,
a phenyl group, and
an aryl(loweralkyl) group;
or R and R
5
or R
4
and R
6
and the atoms to which they are attached are taken together form a 5- to 7-membered ring containing one oxygen atom; and
R
5
and R
6
are independently selected from the group consisting of:
a hydrogen atom,
a loweralkyl group,
a phenyl group,
an aryl(loweralkyl) group;
or any pair of substituents selected from (R
4
and R
5
), (R
4
and R
6
) or (R
5
and R
6
) and the atoms to which they are attached are taken together to form a 5- to 7-membered ring optionally containing one oxygen atom; provided that only one pair of substituents (R
4
and R
5
), (R
4
and R
6
) or (R
5
and R
6
) may be taken together with the atoms to which they are attached to form a ring as defined above;
e) an oxime having the formula:
wherein R
7
, R
8
, and R
9
are independently selected at each occurrence from hydrogen, loweralkyl, aryl-substituted alkyl, aryl, cycloalkyl, and loweralkenyl;
f)
wherein R
10
and R
11
are independently selected at each occurrence from hydrogen, alkyl, or nitrogen-protecting group, or R
10
and R
11
taken together form a 5- to 7-membered cycloalkyl ring; and
g)
wherein R
12
and R
13
are independently selected at each occurrence from hydrogen, alkyl or a nitrogen-protecting group; or R
12
and R
13
taken together form a 5- to 7-membered cycloalkyl ring; and
Z is hydroxyl or a protected hydroxyl group.
The 6-O-substituted erythromycin derivative is represented by formula (II)
wherein R
a
is represented by the formula:
and wherein R, R
p
, V and Z are as defined above.
The compounds of formula (II) may be optionally deprotected and deoximated to obtain compounds of formula (III)
wherein R
p
, R
a
and Z are as defined above.
The compounds of formulas (I), (II) and (III) are useful intermediates in the synthesis of macrolide antibiotics as described in the U.S. Pat. No. 5,866,549, issued Feb. 2, 1999, represented by formula (IV)
Therefore, in another aspect, the process of invention further comprises the steps of:
(a) reacting the compound of formula (III)
with 1,1′-carbonyldiimidazole in the presence of an amine base or an amine base catalyst followed by a reaction with ammonia or ammonium hydroxide optionally carried out in the presence of a strong base to give a compound having the formula:
(b) removing the cladinose moiety from the compound obtained in step (a) by hydrolysis with acid to give a compound having the formula:
(c) oxidizing the 3-hydroxyl group, and optionally deprotecting and isolating the desired compound.
In yet another aspect, the present invention relates to the process for preparing a compound of formula (IV) by removing the cladinose moiety of a compound of formula (I′) with acid; protecting the 2′- and optionally the 3-hydroxyl functionalities; alkylating the compound obtained therefrom with an alkylating agent; deoximating; preparing an 11,12-cyclic carbamate; deprotecting the 3-hydroxyl, if protected; oxidizing the 3-hydroxyl group; and optionally deprotecting the 2′-hydroxyl to afford a compound of formula (IV). The process of the invention is an efficient process and provides higher yields of the desired compounds compared with known alkylation processes.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
A number of terms are used herein to designate particular elements of the present invention.

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