N-(4-bromo-2-fluorobenzyl)carbamates and a process for their preparation

N-(4-Bromo-2-fluorobenzyl)carbamates and a process for their preparation The invention relates to N-(4-bromo-2-fluorobenzyl)carbamates of the formula (I), ##STR1## where R is (C.sub.1 -C.sub.12)alkyl, benzyl or phenyl, where the benzyl and phenyl radicals can also be substituted by (C.sub.1 -C.sub.3)alkyl or (C.sub.1 -C.sub.3)alkoxy, and to a process for preparing these compounds.

The invention relates to N-(4-bromo-2-fluorobenzyl)carbamates and a process 
for their preparation. 
The novel N-(4-bromo-2-fluorobenzyl)carbamates are starting products for 
nitrogen-containing heterocycles, pharmaceutical intermediates and crop 
protection agents. Compounds of this type are of importance, in particular 
in the synthesis of novel aldose-reductase inhibitors. (K. Ogawva, I. 
Yamawaki, Y. I. Matsusita, N. Nomura, P. F. Kador, J. H. Kinoshita, Eur. 
J. Med. Chem. 28, 769, (1993)). 
In the patent application WO 94 10 132 A1, substituted benzylcarbamates 
having herbicidal properties are described. The synthesis of 
N-benzylcarbamates is reported in JP 70 03 770 C.A. 72: 132344m (1970)!. 
There was therefore a need to provide novel compounds of this substance 
class in order, on the one hand, to increase the range of synthetic 
methods of previously known products and, on the other hand, to make novel 
products accessible. 
This object is achieved by N-(4-bromo-2-fluorobenzyl)carbamates of the 
formula I, 
##STR2## 
where R is (C.sub.1 -C.sub.12)alkyl, benzyl or phenyl, where the benzyl 
and phenyl radicals can also be substituted by (C.sub.1 -C.sub.3)alkyl or 
(C.sub.1 -C.sub.3)alkoxy. 
Of particular interest are compounds of the formula (I), in which R is 
(C.sub.1 -C.sub.4)alkyl, benzyl or methoxybenzyl. 
Important compounds are O-benzyl N-(4-bromo-2-fluorobenzyl)carbamate, 
O-methyl N-(4-bromo-2-fluorobenzyl)carbamate, O-ethyl 
N-(4-bromo-2-fluorobenzyl)carbamate, O-p-methoxybenzyl 
N-(4-bromo-2-fluorobenzyl)carbamate, O-butyl 
N-(4-bromo-2-fluorobenzyl)carbamate. 
The invention further relates to a process for preparing compounds of the 
formula (1), which comprises reacting a 4-bromo-2-fluorobenzyl halide with 
an alkali metal cyanate or ammonium cyanate in a dipolar aprotic solvent 
in the presence of the alcohol ROH. 
It has proved to be useful in this case to use 4-bromo-2-fluorobenzyl 
bromide, potassium cyanate and, as solvent, DMF, and to employ a 
temperature of 30.degree. to 150.degree. C., in particular 80.degree. to 
140.degree. C., preferably 100.degree. to 120.degree. C. 
The reaction generally concludes within 1 to 3 h. It has proved to be 
expedient to use the cyanate and the alcohol in excess, in particular a 
usage rate of 1.1 to 3 mol of cyanate and 1.1 to 4 mol of alcohol per mole 
of benzyl halide has proved to be useful.

The following examples serve to illustrate the invention, without 
restricting it thereto. 
EXAMPLE 1 
Synthesis of O-benzyl N-(4-bromo-2-fluorobenzyl)carbamate 
Anhydrous and amine-free DMF (180 ml) and benzyl alcohol (28 ml) and KOCN 
(0.247 mol, 20 g) are charged into a 500 ml 2-neck round bottom flask 
having a reflux condenser and drying tube. A solution of 
4-bromo-2-fluorobenzyl bromide (0.075 mol, 20 g) in DMF (20 ml) is added 
rapidly (in the course of 1 min) at room temperature to the stirred 
reaction mixture by means of a dropping funnel. The resulting suspension 
is subsequently heated with stirring to approximately 110.degree. C. and 
further stirred at this temperature for approximately 1.5 h. The mixture 
is then cooled to room temperature. The salt present in the reaction 
mixture is filtered off by suction via a frit. The solvent and excess 
benzyl alcohol are removed from the filtrate in vacuo. The light yellow 
oily residue is cooled with ice for crystallization. The bright 
crystalline mass produced is washed with water, filtered and dried. Yield: 
23.2 g (:91.5% of theory) M.p.: 82.degree.-84.degree. C. GC/MS: M.sup.+ 
=337, IR in KBr cm.sup.-1 !: 3342 (m) N--H, 1689 (s) C.dbd.O, 1535 (m) 
NH--C, 1276 (m) C--O--C 
EXAMPLE 2 
Synthesis of O-methyl N-(4-bromo-2-fluorobenzyl)carbamate 
Anhydrous and amine-free DMF (500 ml) and methanol (50 ml) and KOCN (0.62 
mol, 50 g) are charged into a 1000 ml 2-neck round bottom flask having a 
reflux condenser and drying tube. A solution of 4-bromo-2-fluorobenzyl 
bromide (0.186 mol, 50 g) in DMF (50 ml) is added rapidly at room 
temperature to the stirred reaction mixture by means of a dropping funnel. 
The resulting suspension is subsequently heated with stirring to 
approximately 100.degree. C. and further stirred at this temperature for 
approximately 1.5 h. The mixture is then cooled to room temperature. The 
salt present in the reaction mixture is filtered off by suction via a 
frit. The solvent and excess methanol are removed from the filtrate in 
vacuo. The oily residue is cooled for crystallization. The bright 
crystalline mass produced is washed with water, filtered and dried. Yield: 
44.3 g (91% of theory) M.p.: 66.degree.-67.5.degree. C. GC/MS: M.sup.+ 
=261, IR in KBr cm.sup.-1 !: 3338 (m) N--H, 1694 (s) C.dbd.O, 1536 (m) 
NH--C, 1280 (m) C--O--C 
Further O-organyl N-(4-bromo-2-fluorobenzyl)carbamates were prepared in a 
similar manner to Example 1: 
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Formula 
Ex. (I) Yield 
M.p. 
No. R Alcohol %! .degree.C.! 
MS IR (KBr) cm.sup.-1 ! 
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3 ethyl ethanol 89 39-43 275 3317 (m) N-H, 
1686 (s) C = O, 
1534 (m) NH-C, 
1280 (m) C-O-C 
4 n-butyl n-butanol 
85 waxy 303 3318 (m) N-H, 
1695 (s) C = O, 
1536 (m) NH-C, 
1257 (m) C-O-C 
5 p- p-anisyl 89 88-90 367 3338 (m) N-H, 
methoxy- alcohol 1686 (s) C = O, 
benzyl 1536 (m) NH-C, 
1278 (m) C-O-C 
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