Preparation of carbamates

Alcohols are reacted with silylated isocyanate compounds to produce the N-substituted carbamoyloxy derivatives which are cleaved to obtain the carbamate.

This invention relates to the preparation of carbamates and products useful 
in their preparation. More particularly, it is concerned with a method of 
converting alcohols to the corresponding carbamoyloxy derivatives, 
reagents suitable for this conversion, and with intermediate substituted 
carbamoyloxy compounds useful in their preparation. 
The carbamates are valuable derivatives of alcohols which are useful in 
their identification and characterization. In addition, carbamates such as 
meprobamate, carbachol, and novobiocin have been found to be useful 
medicinal products. More recently it has been found that 
3-carbamoyloxymethyl cephalosporins obtained by fermentation are valuable 
antibiotic substances. The process of the present invention is 
particularly valuable in providing a method suitable for the preparation 
of such cephalosporins as well as other carbamates. 
In accordance with one embodiment of this invention, it is now found that 
alcohols can be converted to the corresponding carbamoyloxy compounds by 
reacting the alcohol with triorganosilyl isocyanate and then replacing the 
labile triorganosilyl group with hydrogen. This process can be illustrated 
as follows: 
##STR1## 
The group represented by Si.tbd. is a triorganosilyl group which is readily 
cleaved and replaced by hydrogen. Although various triorganosilyl 
isocyanates can be used, it is preferred to use N-trimethylsilyl 
isocyanate since this product is most readily available. 
In this process the alcohol (I), wherein R' represents the organic radical 
of the alcohol, is reacted with the silyl isocyanate (II) to produce the 
N-substituted intermediate product (III), which is hydrolyzed to produce 
the desired carbamate (IV). 
The first step of the above-described process, namely, the preparation of 
the intermediate imidodicarboxylates or the N-triorganosilyl carbamoyloxy 
compound (III) is carried out by intimately contacting the alcohol with 
the isocyanate, preferably in a non-protic solvent such as methylene 
chloride, tetrahydrofuran, dimethylformamide, and the like. In general, we 
prefer to carry out the reaction under anhydrous conditions and to have at 
least an equimolar quantity of the isocyanate present in order to obtain 
maximum yields of the desired intermediate product. In general, the 
reaction can be carried out at temperatures between about 0.degree. C. and 
30.degree. C. However, it is generally preferred to carry out the reaction 
at about room temperature. The precise conditions for carrying out this 
process will depend in part upon the particular alcohol which is being 
reacted. The removal of the protecting group and its replacement by 
hydrogen is readily carried out by hydrolysis under slightly acidic 
conditions. 
The process of this invention is particularly valuable for producing 
cephalosporin compounds having a 3-carbamoyloxymethyl substituent. This 
embodiment of our invention can be represented as follows: 
##STR2## 
wherein Si.tbd. is as defined above, R" represents an acyl radical, 
R.sub.3 represents hydrogen or a group such as methoxy, and R represents 
hydrogen or a blocking substituent. In this process the 3-hydroxymethyl 
cephalosporin compound (V) is reacted with the isocyanate (II) to produce 
the intermediate N-substituted carbamoyloxy compound (VI) which is then 
deblocked to produce the 3-carbamoyloxymethyl ester (VII). The carboxy 
blocking substituent is then removed to afford the free acid (VIII). The 
acyl radical represented by R" can be an acyl group of a carboxylic acid 
or a substituted sulfonyl radical such as phenylsulfonyl, ethylsulfonyl, 
benzylsulfonyl, 2,5-dimethylphenylsulfonyl, 4-chlorophenylsulfonyl, 
4-methoxyphenylsulfonyl, and the like. Thus, R" can be an aliphatic, 
aromatic or heterocyclic, araliphatic or heterocyclylaliphatic carboxylic 
acid radical such as the acyl radical of the known cephalosporins and 
penicillins. The acyl substituents of the general formula R.sub.11 
R.sub.10 CHCO wherein R.sub.10 and R.sub.11 are as defined below represent 
a preferred group of substituents because of their generally useful 
antibiotic activity. R.sub.10 represents hydrogen, halo, amino, guanidino, 
phosphone, hydroxy, tetrazolyl, carboxy, sulfo or sulfamino. R.sub. 11 
represents phenyl, substituted phenyl, a monocyclic heterocyclic 5- or 
6-membered ring containing one or more oxygen, sulfur or nitrogen atoms in 
the ring, substituted heterocycles, phenylthio, heterocyclic or 
substituted heterocyclic thio groups; or cyano. The substituents can be 
halo, carboxymethyl, guanidino, guanidinomethyl, carboxamidomethyl, 
aminomethyl, nitro, methoxy or methyl. Examples of these preferred 
substituents that might be mentioned are phenacetyl, 3-bromphenylacetyl, 
p-aminomethylphenylacetyl, 4-carboxylmethylphenylacetyl, 
4-carboxamidomethylphenylacetyl, 2-furylacetyl, 5-nitrofurylacetyl, 
3-furylacetyl, 2-thienylacetyl, 5-chlorothienylacetyl, 
5-methoxythienylacetyl, .alpha.-guanidino2-thienylacetyl, 3-thienylacetyl, 
4-methylthienylacetyl, 3-isothiazolylacetyl, 4-methoxyisothiazolylacetyl, 
4-isothiazolylacetyl, 3-methylisothiazolylacetyl, 5-isothiazolylacetyl, 
3-chloroisothiazolylacetyl, 3-methyl-1,2,5-oxadiazolylacetyl, 
1,2,5-thiadiazolyl-4-acetyl, 3-methyl-1,2,5-thiadiazolyl-4-acetyl, 
3-chloro-1,2,5-thiadiazolyl-4-acetyl, 
3-methoxy-1,2,5-thiadiazolyl-4-acetyl, phenylthioacetyl, 
4-pyridylthioacetyl, cyanoacetyl, tetrazolylacetyl, 
.alpha.-fluorophenylacetyl, D-phenylglycyl, 3-hydroxy-D-phenylglycyl, 
2-thienylglycyl, 3-thienylglycyl, phenylmalonyl, 3-chlorophenylmalonyl, 
2-thienylmalonyl, 3-thienylmalonyl, .alpha.-phosphonophenylacetyl, 
.alpha.-sulfaminophenylacetyl, .alpha.-hydroxyphenylacetyl, 
.alpha.-tetrazolylphenylacetyl and .alpha.-sulfophenylacetyl. 
Particularly preferred 3-hydroxymethylcephalosporin compounds which can be 
converted to the corresponding 3-carbamoyloxymethyl cephalosporin 
compounds in accordance with this invention are those wherein R.sub.10 is 
hydrogen, amino, or carboxy and R.sub.11 is phenyl or a 5-membered 
heterocyclic ring having one oxygen or one sulfur hetero atom, and 
especially those wherein R" is benzylcarbonyl, 2- and 
3-thienylmethylcarbonyl or 2- and 3-furylmethylcarbonyl. 
The cephalosporin carbamates are prepared by reacting cephalosporin 
compounds having a 3-hydroxymethyl substituent, or a salt or ester of such 
cephalosporins, with the isocyanate and then cleaving the resulting 
reaction product as described above. If the cephalosporin being reacted 
contains other substituents which react with the isocyanate, such as other 
hydroxy groups or amino groups, these substituents are blocked or 
protected by groups such as trityl, tertiary butyloxycarbonyl, 
N-trichloroethoxycarbonyl, and the like, and then removed after the 
carbamoyloxy group is introduced. For example, 
7-tritylaminocephalosporanic acid is intimately contacted with citrus 
acetylesterase to produce 7-tritylaminodesacetylcephalosporanic acid 
which, on reaction with the isocyanate and hydrolysis of the reaction 
product, affords the 3-carbamoyloxymethyl compound. Removal of the 
protective trityl group by methods known in the art affords 
3-carbamoyloxymethyl-7-aminodesacetylcephalosporanic acid which can be 
acylated by known methods to produce 3-carbamoyloxymethyldesacetyl 
cephalosporins. 
Alternatively, 3-hydroxymethyl-7-acylamido-3-cephem-4-carboxylic acid and 
the corresponding compounds having a substituent at the 7-position, such 
as methoxy, in place of hydrogen, can be converted to the corresponding 
3-carbamoyloxymethyl cephalosporin compounds by the process of this 
invention. 
The 3-carbamoyloxymethyl cephalosporins prepared in accordance with the 
process of this invention are valuable antibiotics which are active at low 
levels against various gram-positive and gram-negative pathogens such as 
Staphylococcus aureus, Staphylococcus pyogenes, Proteus vulgaris, 
Escherichia coli and the like. These new cephalosporins are therefore 
useful in treating infections in humans and animals. They can also be used 
in dilute aqueous concentrations containing less than 100 parts of 
antibiotic per million parts of solution in removing susceptible organisms 
from pharmaceutical, medical and dental equipment, and for isolating 
microorganisms from mixtures of microorganisms. 
In carrying out the above-described process, the carboxy group of the 
cephalosporin compound is blocked or protected by forming a suitable 
derivative which can be readily cleaved without affecting the 
.beta.-lactam ring. Generally, it is preferred to block the carboxy 
substituent by forming a suitable ester. Examples of such esters that 
might me mentioned are the benzyl, benzhydryl, methoxymethyl, 
p-nitrophenyl, trimethylsilyl, trichloroethoxy, p-methoxybenzyl, 
phthalimidomethyl, and succinimidomethyl esters. These esters can be 
cleaved in accordance with methods known in the art to afford the free 
acid.

The following examples are provided to illustrate the above-described 
processes of the present invention. 
EXAMPLE 1 
3-Carbamoyloxymethyl-7-methoxy-7.beta.-(2-thienylacetamido)-3-cephem-4-carb 
oxylic acid 
To 10 ml. of a methylene chloride solution containing 650 mg. of benzhydryl 
3-hydroxymethyl-7-methoxy-7.beta.-(2-thienylacetamido)-3-cephem-4-carboxyl 
ate is added dropwise 115 mg. of N-trimethylsilyl isocyanate. The resulting 
reaction mixture is stirred at room temperature for 1 hour and then 
quenched onto ice and acidified to pH 5 with dilute HCl. The layers are 
separated and the organic phase is separated and dried over magnesium 
sulfate. Removal of the solvent under reduced pressure affords benzhydryl 
3-carbamoyloxymethyl-7-methoxy-7.beta.-(2-thienylacetamido)-3-cephem-4-car 
boxylate. 
A cold solution of the benzhydryl ester of 
3-carbamoyloxymethyl-7-methoxy-7.beta.-(2-thienylacetamido)-3-cephem-4-car 
boxylic acid (136 mg.) in 1.1 ml. of anisole is stirred with 0.55 ml. of 
trifluoroacetic acid at 0.degree. C. for 1/2 hour. The volatiles are 
removed in high vacuum, and the product is recrystallized from ethyl 
acetate. m.p. 165.degree.-167.degree. C. 
Following the above-described procedures, benzhydryl 
3-hydroxymethyl-7-methoxy-7.beta.-acetamido-3-cephem-4-carboxylate and 
benzhydryl 
3-hydroxymethyl-7-methoxy-7.beta.-(2-furylacetamido)-3-cephem-4-carboxylat 
e are converted to 
3-carbamoyloxymethyl-7-methoxy-7.beta.-acetamido-3-cephem-4-carboxylic 
acid and 
3-carbamoyloxymethyl-7-methoxy-7.beta.-(2-furylacetamido)-3-cephem-4-carbo 
xylic acid (m.p. 156.degree.-161.degree. C.), respectively. 
The starting materials in the foregoing example are prepared by incubating 
the benzhydryl esters of 7-methoxy-7.beta.-(2-thienylacetamido), 
acetamido, or (2-furylacetamido) cephalosporanate with citrus 
acetylesterase in accordance with procedures well known in this art. 
The benzhydryl esters of 
7-methoxy-7.beta.-(2-thienylacetamido)cephalosporanic acid, 
7-methoxy-7.beta.-acetamidocephalosporanic acid and 
7-methoxy-7.beta.-(2-furylacetamido)cephalosporanic acid are prepared as 
described in the pending U.S. application of Burton G. Christensen et al. 
Ser. No. 149,364 filed June 2, 1971. 
EXAMPLE 2 
3-Carbamoyloxymethyl-7.beta.-(2-thienylacetamido)-3-cephem-4-carboxylic 
acid 
Following the procedures in Example 1, an equivalent amount of 
methoxymethyl 3-hydroxymethyl-7.beta.-(2-thienylacetamido)-3-cephem-4-carb 
oxylic acid is reacted with N-trimethylsilyl isocyanate to obtain 
methoxymethyl 
3-carbamoyloxymethyl-7.beta.-(2-thienylacetamido)-3-cephem-4-carboxylate. 
A suspension of the methoxymethyl ester (920 mg.) in 9.2 ml. of methanol 
containing 10% concentration HCl is stirred at room temperature for 90 
minutes. A cold solution of 1.65 g. of sodium bicarbonate in 40 ml. of 
water is then added, and the clear solution concentrated to a volume of 
30-35 ml. at room temperature under reduced pressure. The aqueous solution 
is then extracted with ethyl acetate and the organic layer discarded. The 
aqueous layer is cooled to 0.degree.-5.degree. C., covered with 
ethylacetate (40 ml.), and the pH adjusted to 1.8 with cold 10% HCl with 
stirring. The layers are separated and the ethyl acetate layer washed with 
ice water. The aqueous layer and the washing are combined and re-extracted 
with 2.times.20 ml. of ethyl acetate. The second ethyl acetate extract is 
washed twice with cold water and then combined with the first extract. The 
solvent is evaporated to dryness and dried to constant weight to afford 
3-carbamoyloxymethyl-7.beta.-(2-thienylacetamido)-3-cephem-4-carboxylic 
acid. 
The starting material in this example is prepared by incubating the 
methoxymethyl ester of 7.beta.-(2-thienylacetamido)cephalosporanic acid 
with citrus acetylesterase in accordance with procedures well known in 
this art. The methoxymethyl ester is prepared by esterifying the 
di(cyclohexyl)amine salt of 7.beta.-(2-thienylacetamido)cephalosporanic 
acid with chloromethyl methylether in anhydrous methylene chloride 
solution which, upon evaporation of the solvent, affords the desired 
product. 
The process of the present invention is also effected using the free acid 
or a salt thereof in place of the ester of the cephalosporin compound. 
However, usually it is preferred to use the ester since maximum yields of 
the desired product are obtained under optimum conditions.