Process for preparing benzoxazin-4-one polymer conjugates

Details Process for preparing benzoxazin-4-one polymer conjugates Process for preparing benzoxazin-4-one polymer conjugates

2001-06-26

2003-01-07

Shah, Mukund J. (Department: 1624)

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

Organic compounds

Chalcogen in the nitrogen containing substituent

C544S094000

Reexamination Certificate

active

06504028

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of benzoxazin-4-one polymer conjugates. The process of the present invention provides for one-pot high yield conversion of an anthranilate and a polymeric component to proteolytic and/or lipolytic enzyme inhibitors useful in preventing skin irritation caused by endogenic proteolytic and/or lipolytic enzymes, inter alia, trypsin, chymotrypsin, elastase, pancreatic lipase, which comprise human feces.
BACKGROUND OF THE INVENTION
Man-made enzyme inhibitors are widely used to modulate or inhibit the activity of enzymes. Control of enzymes has become critical in the prevention of skin irritation which is caused by the exposure of human skin to endogenic or exogenic enzymes. Particularly infants and incontinent adults have their skin routinely exposed to urine and feces which comprise proteolytic and/or lipolytic enzymes, inter alia, trypsin, chymotrypsin, elastase, pancreatic lipase. These enzymes promote skin degradation and therefore, might lead to discomfort.
Certain enzyme inhibitors have been successfully combined with polymeric materials to form benzoxazin-4-one polymer conjugates which modulate enzyme activity on exposed human skin while simultaneously providing the benefit of not being absorbed into the skin of the user. The process for preparing these polymer conjugates involves several discrete synthetic steps each of which involves isolation of a reaction intermediate or the use of reagents or solvents which present safety and cost issues.
There is therefore a long felt need for a process for forming a benzoxazin-4-one polymer conjugate which provides a direct, cost effective, and safe route.
SUMMARY OF THE INVENTION
The present invention meets the aforementioned needs in that it has been surprisingly discovered that benzoxaxine-4-one polymer conjugates can be prepared by way of a direct synthesis which provides the formulator with a more facile, cost effective, and safer route. The improvement over our own prior art synthesis precludes the use of more hazardous solvents, inter alia, methylene chloride, and affords the desired polymer conjugate in high yield.
The process of the present invention comprises the steps of:
a) reacting a polymer or copolymer having the formula:
R—OH
wherein R is a hydrocarbyl moiety, a polyalkyleneoxy moiety, or a heteroatom comprising hydrocarbyl moiety, said polymer or copolymer having a molecular weight of from about 500 daltons, with phosgene to form a chloroformate having the formula:
b) combining a substituted or unsubstituted anthranilic acid having the formula:
wherein each R
1
unit is an enzyme interaction attenuating unit; and a base catalyst wherein said base catalyst is a supported base catalyst, to form a substrate reactive admixture; and
c) adding to said chloroformate formed in step (a) said substrate reactive admixture formed in step (b) to form a benzoxazin-4-one conjugate having the formula:
The process of the present invention also relates to the use of an auxiliary chloroformate, inter alia, a lower alkyl chloroformate to affect the benzoxazin-4-one ring closure.
The process of the present invention further relates to reacting a polymer or copolymer having the formula:
HO—R′—OH
which when reacted with an anthranilate forms a polymer conjugate having two benzoxazin-4-one moieties.
These and other objects, features and advantages will become apparent to those of ordinary skill in the art from a reading of the following detailed description and the appended claims. All percentages, ratios and proportions herein are by weight, unless otherwise specified. All temperatures are in degrees Celsius (° C.) unless otherwise specified. All documents cited are in relevant part, incorporated herein by reference.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a process for preparing benzoxazin-4-one polymer conjugates. The following is a description of the essential elements of the present invention.
Step (a): Formation of a chloroformate. Conversion of a hydroxyl moiety comprising polymer or copolymer to a chloroformate is the first required step of the process of the present invention. The polymer or copolymer may comprise one or more hydroxyl moieties thereby yielding a polymer conjugate which comprises more than one benzoxazin-4-one unit. However, the formulator may form the polymer conjugate having more than one hydroxyl unit in a manner wherein only an average of one hydroxyl unit links to a benzoxazin-4-one.
A polymer or copolymer having the general formula:
R—OH
wherein R is a hydrocarbyl moiety, a polyalkyleneoxy moiety, or a heteroatom comprising hydrocarbyl moiety, said polymer or copolymer having a molecular weight of from about 500 daltons, is reacted with phosgene to form a chloroformate having the formula:
Phosgene in the form of a gas or as a solution, inter alia, 20% solution by weight in toluene. Preferably a stoichiometric amount of phosgene is used. One equivalent of phosgene is used for every equivalent of —OH unit which is present in the polymer or copolymer molecule. For example, a mono-hydroxy polymer or copolymer will require one equivalent of phosgene, however, a polymer or copolymer comprising two —OH moieties, as in the preparation of a bis-benzoxazin-4-one conjugate analog, inter alia, bis-2-(PEG 4000)-5-methyl4H-3,1-benzoxazin-4-one, said formation requires at lease two equivalents of phosgene.
Examples of two preferred embodiments of the present invention relate to reacting a mono-hydroxy containing polymer or copolymer with phosgene to form a mono-chloroformate and reacting a dihydroxy polymer or copolymer with phosgene to form a bis-chloroformate.
The mono-hydroxy polymers or co-polymers of the present invention have the general formula:
R—OH
whereas the dihydroxy polymers or co-polymers have the general formula:
HO—R′—OH
wherein R′ is preferably a polyalkyleneoxy moiety further described herein below, however, for the purposes of the present invention the general formula:
R—OH
stands equally well for mono- as well as poly-hydroxy comprising polymers or co-polymers unless otherwise indicated.
For the purpose of the present invention the term “hydrocarbyl moiety” is defined herein as “any organic moiety which is comprised of carbon and hydrogen atoms in addition to the oxygen atoms which comprise the —OH units present. The only heteroatoms or atoms other than carbon and hydrogen are those atoms which are oxygen atoms comprising the hydroxyl moiety or moieties which react with phosgene in the first step of the present invention process.”
The polymers or copolymers of the present invention may comprise monomers all of which have a hydroxyl unit, for example the polymer having the general formula:
The formulator can include within the scope of the present invention lower molecular weight alcohols which when combined with the enzyme inhibitor elements do not diffuse into the skin cells and are therefore suitable for use as conjugates. Non-limiting examples of lower molecular weight alcohols useful according to the present invention include:
a) CH
3
—(CH
2
)
21
—OH;
c) HO—(CH
2
)
36
—OH;
For the purposes of the present invention a “polyalkyleneoxy moiety” is defined herein as a unit having the formula:
R
2
(OR
3
)
x
—
wherein R
2
is hydrogen, C
1
-C
22
alkyl, C
2
-C
6
hydroxyalkyl, C
6
-C
12
substituted or unsubstituted aryl, and mixtures thereof; preferably hydrogen, C
1
-C
4
alkyl, C
2
-C
4
hydroxyalkyl, said hydroxyalkyl having the formula HO(CH
2
)
2-4
-; more preferably hydrogen and methyl.
R
3
is C
2
-C
12
alkylene, phenylene, C
1
-C
4
alkyl substituted phenylene, C
7
-C
22
alkylenearylene, and mixtures thereof; preferably C
2
-C
6
alkylene, more preferably C
2
-C
6
alkylene, yet more preferably ethylene, 1,2-propylene, most preferably ethylene.
The index x has the value from about 10 to about 10,000; preferably x has a value such that the “polyalkyleneoxy moiety” has an average molecular weight of from about 500 daltons, preferably from about 1000 d

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