The invention relates to a novel intermediate in the synthetic route of Glipizide. In
another aspect, the invention relates to the preparation of the novel intermediate. Further,
the process for the preparation of Glipizide from this novel intermediate forms the third
aspect of the present invention.
BACKGROUND OF THE INVENTION
Glipizide is a pharmacologically active hypoglycemic agent that is used in the treatment
of Diabetes. It belongs to the second generation of a class of compounds known as
benzenesulfonylureas which are more potent at lowering blood sugar. Glipizide, CAS
registry number [29094-61-9], has the chemical name N-{4-[β(5-methylpyrazine-2-
carboxamido)ethyl]benzenesulfonyl}, N'-cyclohexyl urea and is the compound of
Formula I.

There are various methods reported for the synthesis of Glipizide that employ the same
strategy of forming the sulfonyl urea moiety in the end, since it is the most susceptible to
hydrolysis. For example, US 3,669,966 (assigned to Carlo Erba S.p.A) describes a
method by which 5-methyl-pyrazine-2-carboxylic acid is reacted with p-(β-aminoethyl)-
benzenesulfonamide to form the carboxamide moiety and is then treated with
cyclohexylisocyanate to form the sulfonyl urea linkage.
2


An alternate route to obtain Glipizide that is described in this patent is by treating
cyclohexylamine with the isocyanate of 4-[2-(5-methyIpyrazine-2-
carboxamido)ethyl]benzenesulfone.

However, both methods involve an isocyanate which is not only lachrymatory but also
highly susceptible to hydrolysis. Further, the isocyanate is itself prepared from phosgene,
a colourless and noxious gas.
To circumvent the difficulties posed by isocyanates, carbamates were used instead as
claimed in the patent CA 952112 (assigned to Carlo Erba S.p.A), where Glipizide is
synthesized by treating cyclohexylamine with N-{4-[β-(5-methylpyrazine-2-
carboxamido)-ethyl]-benzenesulfonyl}-methyl carbamate. However the present inventors
have found this methyl carbamate to be unstable and difficult to handle. Secondly, the
process as described requires the reaction mixture to be heated to 140°C in xylol and the
reaction takes 10 to 12 hours to complete. Heating the reaction to such high temperatures
also results in the degradation of the carbamate which reflects on the yield of the desired
product. Further, xylol is classified according to the ICH guidelines as a Class 2 solvent;
3

solvents that are suspected of significant toxicities. Also the preparation of this
carbamate, which is not easily available, is not disclosed.
EP-1700848-A1 describes a method to synthesize similar carbamates by using
haloformates and substituted benzenesulfonamides, but the synthesis of these substituted
benzenesulfonamides in turn is not mentioned. Moreover, the carbamate is reacted with
cyclohexylamine in the presence of an activation catalyst like 4-pyrrolidinopyridine or 4-
(dimethylamino)pyridine (DMAP), which only serves to make the process more
expensive.
The Indian Patent IN 177976 discloses a lengthy method to prepare the 4-[2-(5-
methylpyrazine-2-carboxyamido)ethyl]benzenesulfonamide by starting from the ester of
5-methylpyrazine-2-carboxylic acid. This ester is treated with (2-aminoethyl)benzene to
form the amide linkage to which the sulfonyl group is added by chlorosulfonation.
Treatment of this compound with ammonia gives the required Sulfonamide. However, a
multi-step process such as the above is not industrially viable as the overall yield of the
final product suffers.
Thus, there is a need to synthesize Glipizide by starting from commercially available
compounds that are not poisonous and also by using a shorter synthetic scheme, and in
their endeavour to develop such a process for the manufacture of Glipizide, the inventors
of the present invention have come up with the novel intermediate of Formula II.

This intermediate can be easily synthesized and further extended to Glipizide.
4

OBJECT OF THE INVENTION:
An object of the present invention is to provide a novel compound of formula II.
Another object is to provide a process for the preparation of a compound of formula II.
A further object is to provide a process for the preparation of Glipizide using the
compound of formula II.
SUMMARY OF THE INVENTION:
According to one aspect of the present invention there is provided a compound of
formula II

5
According to a further aspect of the present invention there is provided a process for the
synthesis of the compound of Formula II, the process comprising the step of reacting 4-
[2-(5-methylpyrazine-2-carboxamido)ethyl]benzene sulfonamide of Formula III with
ethyl chloroformate.


According to another aspect of the present invention there is provided a process for
preparing Glipizide wherein the compound of Formula II acts as an intermediate.
DETAILED DESCRIPTION:
The novel compound of Formula II is useful as an intermediate in the synthesis of
Glipizide. This intermediate is prepared from 4-[2-(5-methylpyrazine-2-
carboxamido)ethyl]benzene sulfonamide of formula III as depicted in the synthetic
scheme below.
6
SYNTHETIC SCHEME


The benzenesulfonamide of Formula III could be prepared as reported in the prior art, for
example, by starting from 5-methylpyrazine-2-carboxylic acid as described in JP 06-
279418. 5-methylpyrazine-2-carboxylic acid (Formula IV) when treated with p-(β-
aminoethyl)-benzene sulfonamide in the presence of ethyl chloroformate and
triethylamine gives the product of Formula III. This product, 4-[2-(5-methylpyrazine-2-
carboxamido)ethyl]benzenesulfonamide, is then reacted with ethyl chloroformate in
dichloromethane to yield the novel intermediate of Formula II.
The compound of Formula II is a well-characterized solid that can be handled easily and
has the molecular formula C17H20N4O5S. The inventors have assigned to this compound
the chemical name Ethyl [4-(2-{[(5-methylpyrazin-2-
yl)carbonyl]amino}ethyl)phenyl]sulfonyl carbamate.
The novel intermediate of Formula II is characterized as follows:
Melting Point: 166-168°C
NMR 1H (DMSO, 200MHz) : δ 1.07(t, 3H), 2.57 (s, 3H), 2.97 (t, 2H), 3.56(q, 2H), 3.96
(q, 2H), 7.48(d, 2H), 7.79 (d, 2H), 8.59(s, 1H), 8.97(t,lH), 9.00 (s, 1H), 11.93 (bs,lH)
IR (KBr): 3352, 3155, 2972, 2797, 2747,1732, 1652, 1582, 1540, 1471, 1344, 1286,
1162,1088,1059 cm-1
MS(m/z): 393 (m+1), 415(m+Na+)
XRD: [2θ] (Cu - Kal=1.54060Å, Ka2=1.54443Å Kβ= 1.39225Å ; 40mA, 45kV):

Position [2θ] Relative Intensity [%]
6.8688 7.11
7.8555 1.02
8.5798 37.44
11.8053 1.08
13.7208 100.00
7

13.8907 8.33
14.1252 8.04
14.9492 5.23
15.2790 10.54
17.1739 3.11
18.4371 5.95
19.2818 19.69
19.8206 12.45
20.1208 5.81
21.4054 8.82
21.8257 22.77
22.3351 8.05
23.1485 4.72
23.6387 4.84
24.3958 3.77
24.6115 8.98
25.2257 1.98
25.7176 6.24
25.9509 3.25
26.3863 6.88
26.6580 12.53
26.9453 3.38
28.9215 3.22
29.5589 1.40
30.1041 1.17
30.4438 1.82
31.8122 1.05
34.6668 1.61
35.0929 1.06
39.9274 1.46
8

Further, the novel intermediate of Formula II can be converted to Glipizide, by dissolving
it in a ketonic solvent and reacting it with cyclohexylamine. Thus starting from the
compound of Formula III, Glipizide is obtained in excellent yields as a result of two
synthetic steps.

By practising the chemistry described herein, not only are the steps in synthesis reduced
but the reaction conditions too are more environment-friendly. Hence, the process of the
present invention is cost-effective and better suited to an industrial scale synthesis of
Glipizide.
The following examples illustrate the practice of the invention without being limiting in any
way.
EXAMPLES:
Process for the preparation of the novel intermediate: Ethyl [4-(2-{[(5-methylpyrazin-2-
yl)carbonyl] amino}ethyl)phenyl]sulfonyl carbamate
9

In a reaction vessel lOOg (0.31 moles) of 4-[2-(5-methylpyrazine-2-
carboxamido)ethyl]benzene sulfonamide [Formula III] was dissolved in dichloromethane
(800mL) and 101g (1.0 mole) triethylamine was added to it. The contents were cooled to
a temperature between -5 and -10°C and the temperature was maintained till the end of
the reaction. Ethyl chloroformate (101 g, 0.935 moles) was added drop-wise at this
temperature. After complete addition of ethyl chloroformate, the reaction mass was
stirred for about 4hrs. After completion of the reaction, it was quenched with water
(400mL), the layers were separated and the organic layer was washed with water. The
organic layer was evaporated to dryness and the residue was refluxed in acetone
(400mL), cooled to 0°C, maintained at this temperature for 2hrs and then filtered to get
95g of the desired product.
Yield: 77.5%
Preparation of Glipizide from Ethyl [4-(2-{[(5-methylpyrazin-2-
yl)carbonyl] amino}ethyl)phenyl] sulfonyl carbamate
In a reaction vessel 100g (0.255 moles) of the ethyl [4-(2-{[(5-methylpyrazin-2-
yl)carbonyl]amino}ethyl)phenyl]sulfonyl carbamate from Example 1 and 50g (0.5 moles)
of cyclohexylamine were dissolved in 800mL of methyl-isobutyl ketone (MIBK). The
reaction mass was refluxed for about 4 hrs. When the reaction was complete, the contents
were cooled to 20-25°C, filtered and washed with MIBK to get l00g Glipizide.
Yield: 90%
HPLC purity: 99.3%
10


We claim:
1) A compound of formula II
2) The compound of formula II according to Claim 1 as an intermediate in the synthesis
Glipizide.
3) A compound according to claim 1, characterized by
NMR 1H (DMSO, 200MHz): δ 1.07(t, 3H), 2.57 (s, 3H), 2.97 (t, 2H), 3.56(q, 2H),
3.96 (q, 2H), 7.48 (d, 2H), 7.79 (d, 2H), 8.59(s, 1H), 8.97(t, 1H), 9.00 (s, 1H), 11.93
(bs,lH)
4) A compound according to claim 1, characterized by
IR (KBr): 3352, 3155, 2972, 2797, 2747,1732, 1652, 1582, 1540, 1471, 1344, 1286,
1162, 1088,1059 cm-1.
5) A compound according to claim 1, characterized by the below XRD pattern

Position [2θ] Relative Intensity [%]
8.5798 37.44
13.7208 100.00
19.2818 19.69
19.8206 12.45
21.8257 22.77
26.6580 12.53
11

6) A process for the synthesis of the compound of Formula II, the process comprising
the step of reacting 4-[2-(5-methylpyrazine-2-carboxamido)ethyl]benzene
sulfonamide of Formula III with ethyl chloroformate.

A process according to claim 6 such that the reaction is carried out in the presence of
dichloromethane and triethylamine, at a temperature less than or equal to -5°C.
8) A process for preparing Glipizide wherein the compound of Formula II acts as an
intermediate.
9) A process for preparing Glipizide comprising treating the compound of Formula II
with cyclohexylamine in a ketone solvent.
10) A process according to claim 9, wherein the solvent used is methyl-isobutyl ketone.
Dated this 22nd day of March 2007
12

The invention relates to a compound of formula II

and a process for its synthesis from 4-[2-(5-methylpyrazine-2-
carboxamido)ethyl]benzene sulfonamide. The invention also relates to a process for
preparing Glipizide wherein the compound of Formula II acts as an intermediate.