Preparation of quinoline-substituted carbonate and carbamate...

Details Preparation of quinoline-substituted carbonate and carbamate... Preparation of quinoline-substituted carbonate and carbamate...

2000-03-03

2002-07-09

Seaman, D. Margaret (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S167000, C546S180000

Reexamination Certificate

active

06417366

ABSTRACT:

TECHNICAL FIELD OF THE INVENTION
The present invention relates to the preparation of quinoline-substituted carbonate and carbamate derivatives, which provide important intermediates in the synthesis of 6-O-substituted macrolide antibiotics. In one aspect, the invention relates to the processes for preparing quinolyl-substituted carbonate or carbamate compounds and processes for preparing the compounds via an alkenol derivative. In another aspect, the invention relates to preparing carbonate or carbamate compounds via a quinoline carboxaldehyde or a derivative thereof.
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.
Since the discovery of clarithromycin, new macrolide antibiotic compounds have been discovered and are disclosed in commonly-owned U.S. Pat. No. 5,886,549, filed Jul. 3, 1997. The compounds generally are prepared by known processes. However, the substitution at the 6-position with substituents other than the methyl group is not easy to accomplish and is accompanied by side reactions, by-products and low yields.
Recent developments provide more efficient and cleaner syntheses for alkylating the 6-hydroxyl group. Novel processes allow substituents other than the methyl in the 6-position of the erythromycin derivatives. Commonly-owned U.S. application Ser. No. 60/149,968, filed on Jun. 24, 1999, discloses a process for preparing 6-O-substituted erythromycin derivatives and for preparing 6-O-substituted erythromycin ketolides involving a palladium catalyzed process using carbonate or carbamate derivatives.
Preparation of the carbonate and carbamate derivatives involve use of a variety of quinoline substituted intermediates. In
Chem. Pharm. Bull.,
1979, 27(1), 270-273, synthesis of 3-(3-quinolyl)-2-propyn-1-ol is described. However, there are no known reports of quinoline substituted carbonate or carbamate derivatives or the methods of preparing them.
SUMMARY OF THE INVENTION
Various methods are disclosed for preparing quinoline-substituted intermediates from which a carbonate, preferably t-butyl carbonate or carbamate compound, is obtained. Processes described and claimed herein employ alcohols, esters, acetals, aldehydes, and carboxylic acids as suitable intermediate compounds. The intermediate compounds provide a suitable substrate from which a quinoline-substituted alkenol is obtained or the intermediate is directly hydrogenated to obtain carbonate or carbamate derivatives of the invention.
In one aspect, the invention relates to a process of preparing a compound of the formula:
R
1
—CH═CHCH
2
OC(O)—X—R
2
  (I),
wherein R
1
is independently selected from hydrogen and quinolyl optionally substituted with one or more of:
(i) alkyl,
(ii) alkoxy,
(iii) aryl,
(iv) nitro, and
(v) halo;
R
2
is C
1
-C
10
-alkyl; X is —O— or —NR
3
; and R
3
is hydrogen, C
1
-C
6
-alkyl or aryl, or R
2
and R
3
taken together form an aromatic or non-aromatic ring. The process comprises the steps of:
(a) preparing an intermediate selected from the group consisting of:
(i) R
1
—C≡CCH
2
OR
4
, wherein R
4
is hydrogen or a hydroxy protecting group;
(ii) R
1
—CH═CHC(O)OR
5
, wherein R
5
is C
1
to C
6
lower alkyl;
(iii) R
1
—CH═CHCH(OR
6
)(OR
7
), wherein R
6
and R
7
are independently C
1
to C
6
lower alkyl;
(iv) R
1
—CH═CHC(O)OH;
(v) R
1
—CH═CHCHO;
(vi) R
1
—C≡C—CH
2
—OC(O)—X—R
2
; and
(b) reducing or deprotecting an intermediate obtained in step (a); and
(c) optionally coupling the compound obtained from step (b) with an acylating reagent.
Intermediates (i) through (v) can be reduced to provide the alkenol derivative. The alkenol undergoes a coupling reaction with an acylating reagent, for example acyl halides, acid anhydrides, carbamoyl halides, and acid derivatives of aromatic and non-aromatic heterocycles, to afford compounds of formula (I). Intermediate (vi) can be directly hydrogenated to provide compound (I).
Therefore, one process for preparing a compound of formula (I) via the alkenol generally comprises:
(a) preparing a compound of the formula R
1
—CH═CHCH
2
OR
4
, wherein R
1
and R
4
are as previously defined;
(b) optionally deprotecting the compound obtained in step (a); and
(c) reacting the compound of the formula R
1
—CH═CHCH
2
OH with an acylating agent.
An alternative process for preparing the compound of formula (I) comprises:
(a) preparing a compound of the formula R
1
—C≡C—CH
2
—OC(O)—X—R
2
, wherein R
1
and R
2
are as previously defined; and
(b) hydrogenating the compound obtained in step (a).
In another aspect, the invention relates to a process of preparing a compound of the formula:
wherein
R
1
, R
2
and X are as previously defined, and R
8
is selected from the group consisting of:
(i) —CH═CH—R
11
; wherein R
11
is hydrogen or alkyl; and
(ii) —C≡CR
11
.
The process comprises the steps of:
(a) reacting a compound of the formula:
wherein X
1
is a halide, with an organometallic compound of the formula R
8
—M or R
8
—M—X
1
, wherein R
8
and X
1
are as defined above and M is metal, and an acylating reagent;
(b) optionally hydrogenating the compound obtained in step (a), wherein R
8
is alkynyl or substituted alkynyl, to afford the corresponding compound wherein R
8
is alkenyl or substituted alkenyl.
Yet another aspect of the invention relates to preparing a compound of formula (I) or (II) as defined above.
In yet another aspect, the invention relates to the compounds selected from:
(a) R
1
—CH═CHC(O)OR
5
;
(b) R
1
—CH═CHCH(OR
6
)(OR
7
);
(c) R
1
—CH═CHC(O)OH;
(d) R
1
—CH═CHCHO;
(e) R
1
—C≡C—CH
2
—OC(O)—X—R
2
; and
(f) R
1
—CH═CHCH
2
OH;
wherein R
1
, R
2
, R
5
, R
6
and R
7
are as previously defined.
Processes of the invention provide carbonate or carbamate compounds useful as intermediates in the synthesis of erythromycin derivatives, for example, macrolide antibiotics and erythromycin ketolide compounds. Compounds of formula (I) or (II) are suitable for preparing 6-O-substituted erythromycin derivatives having a 6-O-quinolyl-substituted propenyl substituent.
DETAILED DESCRIPTION OF THE INVENTION
A number of terms are used herein to designate particular elements of the present invention. When so used, the following meanings are intended:
The term “lower alkyl” or “alkyl” as used herein refers to straight or branched chain saturated hydrocarbon radicals. “C
x
to C
y
alkyl” and “C
x
-C
y
”, wherein x and y are each an integer from 1 to 20, denotes an alkyl group containing the number of carbons as designated by x and y, for example, the term “C
1
to C
6
alkyl” refers to a straight or branched chain saturated hydrocarbon radical containing from 1 to 6 carbon atoms. Exemplary lower alkyl or alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, hexyl, and the like.
The term “alkenyl” as used herein refers to straight- or branched-chain hydrocarbon radicals containing between two and six carbon atoms and possessing at least one carbon-carbon double bond. Examples of alkenyl radicals include vinyl, allyl, 2- or 3- butenyl, 2-, 3- or 4-pentenyl, 2-, 3-, 4-, or 5-hexenyl, and the like, and isomeric forms thereof.
The term “alkynyl” as used herein refers to straight or branched-chain hydrocarbon radicals containing between two and six carbon atoms and possessing at least one carbon-carbon triple bond. Examples of alkynyl radicals include ethynyl, propargyl, propylidyne, and the like, and isomeric forms thereof.
The term “polar aprotic solvent” refers to polar organic solvents lacking an easily removed proton including, but no

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