Deprotection and recrystallization processes

Details Deprotection and recrystallization processes Deprotection and recrystallization processes

1998-12-09

2002-01-22

Kifle, Bruck (Department: 1611)

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

Organic compounds

Unsubstituted hydrocarbyl chain between the ring and the -c-...

C540S521000, C540S523000, C544S047000, C544S048000, C544S090000, C544S091000

Reexamination Certificate

active

06340752

ABSTRACT:

BACKGROUND OF THE INVENTION
Mercaptoalkanoylamino lactams have been disclosed as possessing useful cardiovascular properties as a result of their activity as dual angiotensin converting enzyme inhibitors and neutral metalloendopeptidase inhibitors. The lactam can be a moncyclic, fused bicyclic or fused tricyclic as taught by Karanewsky et al. in U.S. Pat. No. 5,552,397, Karanewsky in U.S. Pat. No. 5,504,080, Robl in U.S. Pat. No. 5,508,272, Robl in U.S. Pat. No. 5,525,723, Robl in U.S. Pat. No. 5,362,727, Robl in U.S. Pat. No. 5,587,375, Robl et al. in U.S. Ser. No. 443,278 filed May 17, 1995 and EP 744,319, Ryono et al. in U.S. Pat. No. 5,635,504 and Karanewsky et al. in U.S. Pat. No. 5,650,408.
These references disclose coupling an acylmercaptoalkanoic acid sidechain to the amino lactam ester followed by deprotection by treatment with sodium hydroxide or lithium hydroxide in aqueous alcohol or tetrahydrofuran followed by treatment with aqueous acid to give the desired mercaptoalkanoylamino lactam products.
SUMMARY OF THE INVENTION
This invention is directed to an improvement in the deprotection processes used to convert an acylmercaptoalkanoylamino lactam acid or ester of the formula
to the mercaptoalkanoylamino lactam acid or ester of the formula
and an improvement in the deprotection process used to convert the mercaptoalkanoylamino lactam ester of formula I to the mercaptoalkanoylamino lactam acid of formula I.
These deprotection reactions are performed under basic conditions. The mercapto group in the lactam acid or ester of formula I under such conditions is susceptible to the formation of disulfides of the formula
Such disulfides are themselves an unwanted impurity in the pharmaceutically active mercaptoalkanoylamino lactam acid products of formula I. Also, the disulfides of formula III can convert to other undesirable side-products. In particular, when R
1
is other than hydrogen, the disulfide of formula III can convert to the mercaptoalkanoyl lactam of formula I having the undesired chirality at the optically active carbon in the mercaptoalkanoyl sidechain.
Similarly, the formation of the disulfide impurity of formula III can occur during recrystallization of the mercaptoalkanoylamino lactam product of formula I.
The improvements of this invention reside in including within the above deprotection and recrystallization processes an agent that minimizes the amount of the disulfides of formula III and, in turn, minimizes the formation of the undesired epimer of the pharmaceutically active compound of formula I.
Preferred agents for this purpose are bismercaptans as well as reducing agents such as phosphines and phosphites, zinc metal powder, and sodium hydrosulfite.
DETAILED DESCRIPTION OF THE INVENTION
The amino lactam acids and esters X
1
shown above include:
Y
7
is —S— or —NH—
Y
8
is —S—, —O— or —NH—
R
18
and R
19
are independently selected from hydrogen, alkyl, —(CH
2
)
m
-aryl, or R
18
and R
19
together with the carbon and nitrogen atoms to which they are attached complete a five or six membered ring.
R
12
is hydrogen or an acid protecting group such as methyl, ethyl, propyl, phenyl or benzyl.
The term “alkyl” refers to straight or branched radicals of 1 to 7 carbons, preferably 1 to 4 carbons.
The term “substituted alkyl” refers to such straight or branched chain radicals of 1 to 7 carbons wherein one, two or three hydrogens have been replaced by a hydroxy, amino, cyano, Cl, Br, F, trifluoromethyl, —NH(alkyl of 1 to 4 carbons), —N(alkyl of 1 to 4 carbons)
2
, alkoxy of 1 to 4 carbons, alkylthio of 1 to 4 carbons, or carboxy. The preferred “substituted alkylf” is of 1 to 4 carbons with one hydrogen replaced by hydroxy, amino, Cl, or Br.
The term “alkenyl” refers to straight or branched chain radicals of 3 to 7 carbon atoms having one or two double bonds. Preferred “alkenyl” groups are straight chain radicals of 3 to 5 carbons having one double bond.
The term “cycloalkyl” refers to saturated rings of 3 to 7 carbons with cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl being preferred.
The term “aryl” refers to phenyl, 1-naphthyl and 2-naphthyl with phenyl being preferred.
The term “substituted aryl” refers to phenyl, 1-naphthyl and 2-naphthyl having a substituent selected from alkyl of 1 to 4 carbons, alkoxy of 1 to 4 carbons, alkylthio of 1 to 4 carbons, Cl, Br, F, hydroxy,
In the above formulas, the various symbols have the definitions listed below.
R
1
and R
2
are independently selected from straight or branched chain alkyl of 1 to 6 carbons, —(CH
2
)
m
-aryl, —(CH
2
)m-substituted aryl, or —(CH
2
)
m
-heteroaryl.
m is zero or an integer from 1 to 6.
n is zero or one.
R
4
and R
5
are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, —(CH
2
)
m
-cycloalkyl, —(CH
2
)
m
-aryl, —(CH
2
)
m
-substituted aryl, or —(CH
2
)
m
-heteroaryl, or one of R
4
and R
5
is hydrogen and the other is hydroxy, or R
4
and R
5
taken together with the carbon to which they are attached complete a saturated cycloalkyl ring of 3 to 7 carbons, or R
4
and R
5
taken together with the carbon to which they are attached complete a keto substituent.
R
6
, R
8
and R
10
are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, —(CH
2
)
m
-cycloalkyl, —(CH
2
)
m
-aryl, —(CH
2
)
m
-substituted aryl, or —(CH
2
)
m
-heteroaryl.
R
7
, R
9
and R
11
are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, —(CH
2
)
m
-cycloalkyl, —(CH
2
)
m
-aryl, —(CH
2
)
m
-subsituted aryl, or —(CH
2
)
m
-heteroaryl or R
6
and R
7
taken together with the carbon to which they are attached complete a saturated cycloalkyl ring of 3 to 7 carbons, or R
8
and R
9
taken together with the carbon to which they are attached complete a saturated cycloalkyl ring of 3 to 7 carbons.
b is zero or one.
d is zero or one.
q is an integer from 1 to 4.
r is one or two.
t is an integer from 1 to 3.
v is one or two.
w is one or two.
Y
1
is —CH
2
—, —(CH
2
)
2
—, —(CH
2
)
3
—, —O—, —S—, —CH
2
—O—, or —CH
2
—S—.
Y
2
is —CH
2
— —S—, or —O—.
Y
3
is —CH
2
—, —(CH
2
)
2
, —(CH
2
)
3
—, —O— or —CH
2
—O—.
Z is O or two hydrogens.
R
17
is hydrogen, alkyl, substituted alkyl, alkenyl, —(CH
2
)
m
-cycloalkyl, —(CH
2
)
m
-aryl, —(CH
2
)
m
-substituted aryl, or —(CH
2
)
m
-heteroaryl.
Y
5
is —CH
2
—, —S—, or —O— provided that Y
5
is —S— or —O— only when d is one.
Y
6
is —S— or —O—.
the dashed line ---- represents an optional double bond between the two carbons.
represents an aromatic heteroatom containing ring selected from
trifluoromethyl, amino, —NH(alkyl of 1 to 4 carbons), or —N(alkyl of 1 to 4 carbons)2, di and tri-substituted phenyl, 1-naphthyl, or 2-naphthyl wherein said substituents are selected from methyl, methoxy, Cl, Br, methylthio, hydroxy or amino.
The term “heteroaryl” refers to unsaturated rings of 5 or 6 atoms containing one or two O and S atoms and/or one to four N atoms provided that the total number of hetero atoms in the ring is 4 or less. The heteroaryl ring is attached by way of an available carbon or nitrogen atom. Preferred heteroaryl groups include 2-, 3-, or 4-pyridyl, 4-imidazolyl, 4-thiazolyl, 2- and 3-thienyl and 2- and 3-furyl. The term heteroaryl also includes bicyclic rings wherein the five or six membered ring containing O, S and N atoms as defined above is fused to a benzene or pyridyl ring. Preferred bicyclic rings are 2- and 3-indolyl and 4- and 5-guinolinyl.
The acylmercaptoamino lactam esters of formula II are prepared by coupling the acylmercapto containing sidechain of the formula
with the amino lactam ester
H−X
1
  (XXV).
The above reaction can be performed in an organic solvent such as methylene chloride and in the presence of a coupling reagent such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, dicyclohexylcarbodiimide, benzotriazol-1-yloxytris-(dimethylamino)phosphonium hexafluorophosphate, or carbonyldiimidazole. Alternatively, the acylmercapto carboxylic acid of formula XXIV can be converted to an activated form such as an acid chloride, mixed anhydride, symmetrical anhydride, activat

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