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Purification of HEEP

IP.com Disclosure Number: IPCOM000173019D
Publication Date: 2008-Jul-24
Document File: 8 page(s) / 146K

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The IP.com Prior Art Database

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Purification of HEEP

2-[2-(4-dibenzo [b, f] [1, 4] thiazepin-11-yl-1-piperazinyl) ethoxy] ethanol ("QTP") is a psychoactive organic compound that acts as an antagonist for multiple neurotransmitter receptors in the brain, and acts as an antipsychotic, antischizophrenics, having the following structure:

N

O OH

N

.

Various methods for the preparation of QTP have been described in the literature.

Many impurities are formed along with 1-[2-(2-hydroxyethoxy) ethyl] piperazine ("H.E.E.P"), an intermediate in the synthesis of QTP. Impurities that are formed along with H.E.E.P are:

N

S

N

O

HO

N O OH

(A)

(B)

N

HN NH

N

N

O

HN NH

N

(C)

(D)

NH

HO

N

NH

HN

(E)

The above impurities can lead to the impurities: I, II, III, IV, V, VI, and VII in QTP or its salt:

N

N O OH

O

O

N

S (I)

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N N

N

N

N S

 N S

(II)

N

N N

N

O

N

S (III)

N

N

HO

N S

 N S

(IV)

N

S

N

N N

S

(V)

O

N

S

N

N

N

S


(VI)

N

N O O N

S

N S

(VII)

The H.E.E.P impurities, mentioned above, may be removed by a method of fractional distillation, to obtain pure H.E.E.P. Condensation of purified H.E.E.P and 11- chlorodibenzo [b, f] [1, 4] thiazepine, gives pure QTP and its salt thereof free from impurities. The step of purifying H.E.E.P by the method of fractional distillation includes high vacuum fractional distillation. High vacuum fractional distillation is used utilizing vigorous column and other packed column of various lengths. The high vacuum fractional distillation collects different fractions (described in the examples as F1, F2 F3), thereby removes the above impurities from H.E.E.P. Temperature of about 130°C to about 200°C and vacuum of about 0.25 to about 13 mm/Hg is applied to the system. The

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most preferable temperature is about 130°C to about 150°C under vacuum of about 0.25 to about 1.3 mm/Hg.

Example 1: High Vacuum distillation of 1-[2-(2-hydroxyethoxy) ethyl] piperazine

In 250 ml single neck round bottom flask charged 50 gm 1-[2-(2- hydroxyethoxy)ethyl]piperazine, fitted with vigorous column, efficient water condenser with distillation head, fraction cutter and different single neck round bottom flask attached with fraction cutter. Vacuum of 0.25 mm/Hg is applied to system, and the mass is slowly heated to 130-160oC and collected different fraction at vapour temperature 110 to 113oC. The main fraction collected at constant vapour temperature 112 to 113oC. The different fractions are F1= 6gm, F2= 28gm, F3= 8gm, and Residue. The main fraction has G.C. purity more than 99%.

Example 2: High Vacuum distillation of 1-[2-(2-hydroxyethoxy) ethyl]piperazine

In 250 ml single neck round bottom flask charged 50 gm 1-[2-(2- hydroxyethoxy)ethyl]piperazine, fitted with vigorous column, efficient water condenser with distillation head, fraction cutter and different single neck round bottom flask attached with fraction cutter. Vacuum of 1.3 mm/Hg is applied to system, and the mass is slowly heated to 155-170oC and collected different f...