Continuous process for the preparation of optically pure...

Details Continuous process for the preparation of optically pure... Continuous process for the preparation of optically pure...

2001-09-04

2003-07-01

Morris, Patricia L. (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06586597

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a continuous process for the preparation of [3S-(3&agr;,4a&bgr;,8a&bgr;)]-N-tert-butyl-decahydro-3-isoquinolinecarboxamide from the reduction of N-tert-butyl-1,2,3,4-tetrahydro-3(S)-isoquinolinecarboxamide with a supported noble metal catalyst in a fixed bed reaction system.
BACKGROUND ART
[3S-(3&agr;,4a&bgr;,8a&bgr;)]-N-tert-butyl-decahydro-3-isoquinolinecarboxamide (hereinafter, refer to as “DHIQ”) is one of the key intermediates in the synthesis of the compounds useful as antagonists of the excitatory amino acid receptor or HIV protease inhibitor for the treatment of the acquired immune deficiency syndrome (AIDS).
A process for synthesizng N-tert-butyl-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbox amide (hereinafter, refer to as “TICC”) by phosgenation and amination of a phenylalanine derivative is described in U.S. Pat. No. 5,587,481 to David R. Allen et al. U.S. Pat. No. 5,587,481 also teaches a method for producing DHIQ by hydrogenating HCC using 5 wt % Rh/C and/or Rh/alumina catalysts either in aqueous or organic media at 100° C. and 350 psi. After reaction, the solution should be filtered to remove the catalyst, followed by the removal of the solvent and crystallization to obtain DHIQ. However, under these reaction conditions, the yield of DHIQ is only 62 to 67% based on TICC because of the low chiroselectivity of the rhodium catalysts.
Hoffmann, EPO Application 0 432 695 A2, teaches the use of 5 wt % Rh/C catalysts in the reduction of tetrahydroisoquinoline-3-carboxylic acid to [3S-(4aS,8aS)]-decahydroisoquinoline-3-carboxylic acid in acetic acid at 80° C. and 140 atm:
The above reaction was carried out for 24 hours. Racemization occurred and the yield of the desired enantiomer was about 65%.
Sato et al, EPO Application 0 751 128 A1, describes a process for producing DHIQ from the reduction of TICC with the use of Rh, Pt and Ru. In synthesis example 3, TICC was reduced with a 5 wt % Ru/C catalyst at 30 atm and 100° C. for 20 hours. After filtration of the catalyst and subsequent treatment, the yields of DHIQ primary crystals and secondary crystals were 52.1% and 20.7%, respectively.
Generally a batch process for the preparation of DHIQ from TICC in the prior art consists of: 1) a powder catalyst is put into a batch reactor equipped with a stirrer and heating/cooling systems; 2) the reactant in a solvent is injected to the reactor; 3) the reactor is closed and purged with an inert gas; 4) pressurized hydrogen is introduced while heating the whole content to a desired temperature; 5) hydrogen is cut and reaction is carried out until the pressure drop due to the reduction of the reactant stops; 6) after cooling to room temperature, the product in the solvent is discharged.
As is manifest for those who are skilled in the art, the disadvantages of the above batch processes are: 1) the process inherently is not productive and is complicated owing to the adoption of batch reactors; 2) it is difficult to precisely control the reaction conditions, for example, hydrogen partial pressure, because the process is dynamic; 3) it requires a series of post-treatment processes to recover and to reuse powder catalysts; 4) it is in danger of the fire and explosion because the catalyst having already reduced is used; and 5) the yield of DHIQ is not good.
DISCLOSURE OF INVENTION
The intensive and thorough research of the present inventors for solving the above problems encountered in prior arts results in the development of a new process superior in optical yield.
Therefore, it is an object of the present invention to provide a process for the preparation of optically active [3S-(3&agr;,4a&bgr;,8a&bgr;)]-N-tert-butyl-decahydro-3-isoquinoline carboxamide, an intermediate useful in the synthesis of compounds for the treatment of viral diseases, by the continuous reduction of N-tert-butyl-1,2,3,4-tetrahydro-3(S)-isoquinolinecarboxamide with a supported noble metal catalyst in a fixed bed reaction system with a high optical yield.
In accordance with an aspect of the present invention, there is provided a method for preparing [3S-(3&agr;,4a&bgr;,8a&bgr;)]-N-tert-butyl-decahydro-3-isoquinolinecarboxamide from N-tert-butyl-1,2,3,4-tetrahydro-3(S)-isoquinolinecarboxamide with a high optical yield, comprising continuously reducing N-tert-butyl-1,2,3,4-tetrahydro-3(S)-isoquinoline carboxamide dissolved in an organic solvent to [3S-(3&agr;,4a&bgr;,8a&bgr;)]-N-tert-butyl-decahydro-3-isoquinolinecarboxamide with hydrogen in a fixed bed reactor charging a noble metal catalyst supported on an inorganic oxide carrier with the range of the metal content between 0.5 and 10 wt %, at a temperature in the range of about 50 and 200° C., under the pressure in the range of about 300 and 2,500 psig and at the WHSV in the range of about 0.1 and 10 h
−1
, wherein the molecular ratio of hydrogen to N-tert-butyl-1,2,3,4-tetrahydro-3(S)-isoquinolinecarboxamide is in the range of about 4 and 10, N-tert-butyl-1,2,3,4-tetrahydro-3(S)isoquinolinecarboxamide content in the organic solvent is in the range of about 2 and 50 wt % and the inorganic oxide carrier has the BET surface area in the range of about 10 and 1,000 m
2
/g, the median pore diameter of the major pores of less than 200 Å and the total pore volume in the range of about 0.2 and 1.2 cc/g.
The starting material in the present invention is a carboxamide of isoquinoline, N-tert-butyl-1,2,3,4-tetrahydro-3(S)-isoquinolinecarboxamide (TICC), which can be prepared by either a multi-step synthesis process including phosgenation and amination of a phenylalanine derivative (Allen, D.R., et al, U.S. Pat. No. 5,587,481) or by any other similar methods (Sato, T., et al., EPO Application 0 751 128 A1). To obtain DHIQ with a high optical yield, TICC with following specifications is preferred: (1) chromatographic purity by gas chromatography: not less than 99.2%; (2) R(+) enantiomer by chiral HPLC: not more than 1.0%; (3) melting point (range): 92~100° C.
To achieve a higher space time yield, to reuse the catalyst repeatedly without post-treatment steps and to reduce the workup steps, the reaction is performed in a fixed bed reactor in the present invention. There is no limitation in the type of the fixed bed reactor and the direction of the reactant flow. However, the reaction is preferably carried out in a trickle-bed type reactor with a down-flow mode of both hydrocarbon(s) and hydrogen to facilitate the contact between the reactants. The reactor should be equipped with suitable devices to evenly distribute all the reactants.
The reaction should be carried out in a solvent medium to easily pump TICC into the reactor and to remove the reaction heat easily as the reduction is highly exothermic. Hydrocarbons that do no react with hydrogen and TICC and can dissolve TICC substantially may be used as solvents. As a solvent of the present invention, any type of a single hydrocarbon or a mixture thereof, e.g., acetic acid, propionic acid, butyric acid, or isobutyric acid, methyl alcohol, ethyl alcohol, n-propyl alcohol, i-propyl alcohol, n-butyl alcohol, sec-butyl alcohol, tert-butyl alcohol, methyl acetate, ethyl acetate, n-propyl acetate, i-propyl acetate, n-butyl acetate, n-hexane, i-hexane, n-heptane, i-heptane, n-octane, or i-octane, can be used. But preferably, n-propyl alcohol, i-propyl alcohol, sec-butyl alcohol, tert-butyl alcohol, ethyl acetate, n-butyl acetate, n-hexane, or n-heptane is used. More preferably, i-propyl alcohol, tert-butyl alcohol, ethyl acetate, n-butyl acetate, n-hexane, or n-heptane is used. Most preferably, ethyl acetate, n-butyl acetate, n-hexane, or n-heptane is used. The concentration of TICC is 2 to 50 wt % in an organic solution. Preferably the concentration is 5 to 30 wt %. Depending on the concentration of TICC, the solvent may be heated to dissolve all solid particles. During dissolving TICC, TICC solution should not be injected to the reactor. So two TICC dissolving reactors or more should be prepared and alternatively

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