Synthesis of carbamate ketolide antibiotics

Details Synthesis of carbamate ketolide antibiotics Synthesis of carbamate ketolide antibiotics

2000-07-05

2002-06-11

Peselev, Elli (Department: 1623)

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

Organic compounds

Carbohydrates or derivatives

C536S018500

Reexamination Certificate

active

06403776

ABSTRACT:

This invention relates to a preparation of macrolide antibiotics that are useful as antibacterial and antiprotozoal agents in mammals, including man, as well as in fish and birds.
Macrolide antibiotics are known to be useful in the treatment of a broad spectrum of bacterial and protozoal infections in mammals, fish and birds. Such antibiotics include various derivatives of erythromycin A such as azithromycin which is commercially available and is referred to in U.S. Pat. Nos. 4,474,768 and 4,517,359 both of which are incorporated herein by reference in their entirety. Other macrolide antibiotics are disclosed and claimed in PCT publication number WO 98/56800, published Dec. 17, 1998 which designates the United States, and U.S. Provisional Applications 60/111,728 and 60/101,263 all of which are incorporated herein by reference in their entirety. The new process as described below provides macrolide compounds that possess activity against various bacterial and protozoal infection.
SUMMARY OF THE INVENTION
The present invention relates to the process for preparing a compound of the formula
wherein:
R
1
is an alpha-branched C
3
-C
8
alkyl, alkenyl, alkynyl, alkoxyalkyl or alkylthioalkyl group any of which may optionally be substituted by one to three hydroxyl groups; a (C
5
-C
8
cycloalkyl group wherein the alkyl group is an alpha-branched C
2
-C
5
alkyl group; a C
3
-C
8
cycloalkyl or C
5
-C
8
cycloalkenyl group, either of which may optionally be substituted by methyl or one to three groups independently selected from hydroxy, C
1
-C
4
alkyl, and halo; or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one to three C
1
-C
4
alkyl groups or halo atoms; or
R
1
is phenyl which may be optionally substituted with one to three groups independently selected from C
1
-C
4
alkyl, C
1
-C
4
alkoxy, C
1
-C
4
alkylthio, halo, hydroxyl, trifluoromethyl, and cyano; or
R
1
is formula (a) as shown below:
wherein X
1
is O, S or —CH
2
—, a, b, c, and d are each independently selected from an integer ranging from 0 to 2 and a+b+c+d≦5; or
R
1
is CH
2
R
24
, wherein R
24
is H, C
1
-C
8
alkyl, C
2
-C
8
alkenyl, C
2
-C
8
alkynyl, alkoxy alkylthioalkyl containing from 1 to 6 carbon atoms in each alkyl, alkylthio, alkylthio or alkoxy group wherein any of said alkyl, alkoxy, alkenyl or alkynyl groups may be substituted by one to three hydroxyl, or halo groups, or a C
3
-C
8
cycloalkyl or C
5
-C
8
cycloalkenyl either of which may be optionally replaced by methyl or one to three C
1
-C
4
alkyl groups or halo atoms; or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated or fully or partially unsaturated and which may optionally be substituted by one to three C
1
-C
4
alkyl groups or halo atoms; or a group of the formula SR
23
wherein R
23
is C
1
-C
8
alkyl, C
2
-C
8
alkenyl, C
2
-C
8
alkynyl, C
3
-C
8
cycloalkyl, C
5
-C
8
cycloalkenyl, phenyl or substituted phenyl wherein the substituent is C
1
-C
4
alkyl, C
1
-C
4
alkoxy or halo, or a 3 to 6 membered oxygen or sulphur-containing heterocyclic ring which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one to three C
1
-C
4
alkyl groups or halo atoms; and,
each R
2
and R
3
is independently H or C
1
-C
6
alkyl; and,
each R
4
is independently C
6
-C
10
aryl or 5 to 10 membered heterocycle, wherein said aryl and heterocycle groups are optionally replaced by 1 to 3 substituents independently selected from the group consisting of —C(O)O(C
1
-C
10
alkyl), C
1
-C
10
alkoxy, C
1
-C
10
alkanoyl, halo, nitro, cyano, 5 to 10 membered heterocycle, C
6
-C
10
aryl, C
1
-C
10
alkyl, —NR
2
R
3
, and —S(O)
n
(C
1
-C
10
alkyl) wherein n is an integer ranging from 0 to 2, and SO
2
NR
2
R
3
; and
R
5
is H or C
1
-C
10
alkyl, wherein 1 to 3 carbons of said alkyl are optionally replaced by a heteroatom selected from O, S, and NR
2
, and said alkyl group is optionally replaced by 1 to 3 substituents independantly selected from the group consisting of —C(O)O(C
1
-C
10
alkyl), C
1
-C
10
alkoxy, C
1
-C
10
alkanoyl, halo, nitro, cyano, 5 to 10 membered heterocycle, C
6
-C
10
aryl, C
1
-C
10
alkyl, —NR
2
R
3
, —S(O)
n
(C
1
-C
10
alkyl) wherein n is an integer ranging from 0 to 2, and SO
2
NR
2
R
3
;
which comprises treating a compound of the formula
with a nucleophile or solvolysis to cleave the R
6
protecting group wherein:
R
1
to R
5
are as defined above; and
R
6
is H, —C(O)R
4
, or C
1
-C
18
alkanoyl, wherein one or two carbons in the alkyl portion of said alkanoyl may be optionally replaced by a heteroatom selected from O, S, and NR
2
.
In one embodiment the R
6
protecting group can be removed by solvolysis in an alcoholic or aqueous solvent with the optional addition of base to accelerate the reaction. In the process of preparing a compound of formula 15, examples of suitable alcoholic solvents include but are not limited to, methanol, ethanol, isopropanol and tert-butanol. Examples of bases include, but are not limited to, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium hydroxide, sodium hydroxide, potassium fluoride and barium hydroxide.
In addition the R
6
protecting group can be removed with a nucleophile, including, but not limited to, ammonium hydroxide, monoalkyl amine, dialkyl-amine, alkane thiol or hydroxide. Useable solvents include, but are not limited to, water, methanol, ethanol, isopropanol, tertbutanol, dimethylformamide, N-methyl pyrrolidinone, acetonitrile, dimethyl acetamide, tetrahydrofuran, N-methylpyrrolidinone, acetonitrile, dimethylacetamide, tetrahydrofuran ethylacetate, and toluene. Preferably the deprotection is run in methanol with the addition of potassium carbonate at room temperature.
According to the invention compound 14 maybe prepared by the oxidation of a compound of the formula
under Swern conditions wherein:
R
1
to R
6
are defined above.
Preferably, the Swern conditions are selected from the following:
(a) In an inert solvent including, but not limited to, dichloromethane, dichloroethane, and tetrachloroethane; dimethylsulfoxide is preactivated with activating agents including, but not limited to, oxalyl chloride, trifluoroacetic anhydride, sulfuryl chloride, and thionyl chloride; followed by addition of the compound 13. Trialkylamine base is added after a time period of about 5 minutes to 24 hours at a temperature range from about −80° C. to 50° C.;
(b) Compound 13 and dimethylsulfoxide are premixed in one of said inert solvents, followed by addition of said activating agent and then followed by the addition of trialkylamine base at a time period of about 5 minutes to 24 hours. This occurs at a temperature range from about −80° C. to 50° C. Preferably the reaction is run in methylene chloride at about −5° to 5° C., where the compound of the formula 13 and dimethylsulfoxide are premixed and activated by trifluoroacetic anhydride. This is followed by triethylamine about two hours later. The reaction is then warmed to room temperature.
According to the invention compound 13 may be prepared by the reduction of a compound of the formula
wherein:
R
1
to R
6
are defined above,
with a metal hydride reducing agent including, but not limited to, sodium triacetoxyborohydride or sodium cyanoborohydride under acidic conditions.
The solvent includes, but is not limited to, acetic acid, acetonitrile, or alcoholic solvent with an acid additive such as acetic acid. The alcoholic solvent includes, but is not limited to, ethanol, methanol, isopropanol, or tertbutanol. Preferably the reaction is run at room temperature in acetic acid with an excess of sodium triacetoxyborohydride.
According to the invention, compound 12 may be prepared by the reaction of a compound of formula
wherein:
R
2
to R
4
are defined above; and,
C and D together form oxo, or where C and D are independently hydroxy, C
1
-C
10
alkoxy, or C
1
-C
10
acyloxy,
with a compound of formula

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