Process and intermediates

Details Process and intermediates Process and intermediates

2001-12-03

2003-05-27

Raymond, Richard L. (Department: 1624)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C562S450000, C562S556000, C562S575000, C548S545000

Reexamination Certificate

active

06570024

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a process for producing N-methyl-L-alanine derivatives and to novel process intermediates.
BACKGROUND OF THE INVENTION
Processes for the preparation of N-methyl-L-alanine derivatives from dithioalkanoic acid intermediates and N-methyl-L-alanine have been reported in U.S. Pat. No. 5,208,020. The compounds are useful for linking cytotoxic maytansinoids to cell-binding agents such as antibodies. Antibody/maytansinoid complexes are useful as tumor-activated pro-drugs.
For example, the multi-step synthesis of N-methyl-N-(3-methyldithio-propanoyl)-L-alanine has been disclosed. First, 3-methyldithiopropanoic acid was prepared by adding methyl methanethiosulfonate in ethanol to a solution of 3-mercaptopropanoic acid in water. After extraction, washing and concentration, the 3-methyldithiopropanoic acid was isolated by distillation. Isobutylchloroformate and triethylamine were added to the 3-methyldithiopropanoic acid in THF to form the corresponding mixed anhydride as intermediate. Subsequently, a mixture of N-methyl-L-alanine and triethylamine in water was added. After extraction, oncentration and chromatography, a 34% yield of N-methyl-N-(3-methyldithio-propanoyl)-L-alanine was obtained.
A major shortcoming of the prior art processes is the necessity of two chromatography steps to remove side products from the desired reaction products. Further, the use of isobutylchloroformate in the reaction scheme allows for racemization which leads to a final product containing the undesired D-enantiomer. Thus, there is a need in the art for improved methods to prepare N-methyl-L-alanine derivatives with an optical purity >95% enantiomeric excess (ee) where the intermediates are more stable, resulting in less undesired side products.
SUMMARY OF THE INVENTION
One aspect of the invention is processes for the preparation of N-methyl-L-alanine derivatives.
Another aspect of the invention is novel intermediates useful for the preparation of N-methyl-L-alanine derivatives.
Another aspect of the invention is processes for the preparation of the novel intermediates of the invention.
Yet another aspect of the invention is cell-binding agent/maytansinoid complexes prepared from the N-methyl-L-alanine derivatives or novel intermediates produced by the processes of the invention.
DETAILED DESCRIPTION OF THE INVENTION
All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as though fully set forth.
By the term “coupling reagent” as used herein and in the claims is meant a compound or compounds which are capable of forming an activated derivative of methyldithiopropionic acid or its homologues which is stable to hydrolysis under the employed reaction conditions and yields a compound of Formula I with an optical purity >95% ee when reacted with N-methyl-L-alanine.
The present invention provides a process for the preparation of compounds of Formula I
M is a direct bond, CH
2
,
a is 0 or an integer of 1 to 9 when M is a direct bond provided that when M is one or more carbon atoms a is 0 or an integer of 1 to 8;
d is an integer of 3 to 8; and
Z is H or SR
2
, where R
2
is linear alkyl, branched alkyl, cyclic alkyl, aryl, substituted aryl or heterocyclic.
The present invention also provides novel intermediates that are useful in the process of the invention.
The present invention also provides antibody/maytansinoid complexes produced by the process of the invention.
The process of the invention comprises the steps of reacting a salt of a mercaptoalkanoic acid of Formula II
where L is as defined above;
and thiolsulfonates of Formula III
QSO
2
SQ  (III)
where Q is H, linear alkyl, branched alkyl, cyclic alkyl, aryl, substituted aryl or heterocyclic,
in a disulfide formation reaction where a salt of a compound of Formula II in water is added to a compound of Formula III in a water-immiscible polar organic solvent to form intermediates of Formula IV
where L and Q are as defined above; and
reacting a compound of Formula IV in an esterification reaction with a coupling reagent such as that of Formula V
where
R
3
is H or substituted uronium salt of the formula
where X
−
is PF
6
−
or BF
4
−
, R
7
and R
8
are independently linear alkyl, branched alkyl, cycloalkyl or (CH
2
)
e
where e is an integer of 3 to 8 with the proviso that when R
7
is (CH
2
)
e
, R
8
is a direct bond,
or a substituted phosphonium salt of the formula
where X
−
is PF
6
−
or BF
4
−
, R
9
and R
10
are independently linear alkyl, branched alkyl, cycloalkyl or heterocyclic; and
R
4
and R
5
are independently H, a double bond, linear alkyl, branched alkyl, cyclic alkyl, aryl, substituted aryl or heterocyclic.
If R
3
is H, the reaction is carried out in the presence of a carbodiimide reagent of Formula VI
where
R
11
and R
12
are independently linear alkyl, branched alkyl, cyclic alkyl, aryl, substituted aryl or heterocyclic. Preferably, the carbodiimide reagent of Formula VI is 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCI.HCl) where R
11
is ethyl and R
12
is dimethylaminopropyl or 1,3-dicyclohexylcarbodiimide (DCC) where R
11
and R
12
are cyclohexyl. Particularly preferred is EDCI.HCl.
Alternatively, if R
3
is a uronium or phosphonium salt, the reaction is carried out in the presence of a base, preferably triethylamine or diisopropylethylamine.
These reactions form compounds of Formula VII
where R
4
, R
5
, L and Q are as defined above.
Compounds of Formula VII are activated esters and are novel intermediates of the process of the invention and are stable to hydrolysis under the employed reaction conditions and allow racemization-free coupling with N-methyl-alanine. Preferably, the compounds are crystalline.
Compounds of Formula VII are subsequently reacted with N-methyl-L-alanine (Formula VIII)
to form a compound of Formula I.
Further, the present invention also includes a process for the preparation of compounds of Formula I comprising reacting a compound of Formula VII with N-methyl-L-alanine to form a compound of Formula I and compounds of Formula I prepared by the process.
The present invention also includes a process for the preparation of a compound of Formula VII
where
R
4
and R
5
are independently H, a double bond, linear alkyl, branched alkyl, cyclic alkyl, aryl, substituted aryl or heterocyclic,
M is a direct bond, CH
2
,
a is 0 or an integer of 1 to 9 when M is a direct bond provided that when M is one or more carbon atoms a is 0 or an integer of 1 to 8; and
d is an integer of 3 to 8; and
Q is H, linear alkyl, branched alkyl, cyclic alkyl, simple or substituted aryl or hetero cyclic which comprises the steps of:
(1) reacting a salt of a mercaptoalkanoic acid of Formula II
where L is as defined above;
and thiolsulfonates of Formula III
QSO
2
SQ  (III)
where Q is as defined above,
in a disulfide formation reaction where a salt of a compound of Formula II in water is added to a compound of Formula III in a water-immiscible polar organic solvent to form intermediates of Formula IV
where L and Q are as defined above; and
(2) reacting a compound of Formula IV in an esterification reaction with a coupling reagent of Formula V
where
R
3
is H or substituted uronium salt of the formula
where X
−
is PF
6
−
or BF
4
−
, R
7
and R
8
are independently alkyl, cycloalkyl or (CH
2
)
e
, where e is an integer of 3 to 8 with the proviso that when R
7
is (CH
2
)
e
, R
8
is a direct bond,
or a substituted phosphonium salt of the formula
where X
−
is PF
6
−
or BF
4
−
, R
9
and R
10
are independently linear alkyl, branched alkyl, cycloalkyl or heterocyclic; and
R
4
and R
5
are as defined above,
provided that when R
3
is H, the reaction is carried out in the presence of a carbodiimide reagent of Formula VI
R
11
—N═C═N—R
12
  (VI)
where
R
11
and R
12
are independently linear alkyl, branched alkyl, cyclic alkyl, aryl, su

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