Title of Invention

METHOD OF PREPARATION OF (S)-N-TERT-BUTYL-1,2,3,4-TETRAHYDROISOQUINOLINE-3-CARBOXAMIDE

Abstract

A new method is described here for the synthesis of (S)-N-tert-butyl-1,2,3,4-tetrahydroiso-quinoline-3-carboxamide comprising the following steps: a) (3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid is reacted with formic acid to give the compound of formula: (I) b) the compound thus obtained is reacted with tert-butylamine to give the compound of formula: (I) c) the compound thus obtained is then treated with acids to give the desired compound.The method in question makes it possible to obtain (S)-N-tert-butyl-1,2,3,4-tetrahydroiso-quinoline-3-carboxamide with high yields and purity without using toxic and hazardous reagents

Full Text

METHOD OF PREPARATION OF (S)-N-TERT-BUTYL-1,2,3,4-TETRAHYDROISO-QUINOLINE-3-CARBOXAMIPE The present invention relates to a new method of preparation of (S)-N-tert-butyl-1,2,3,4-tetrahydroisoquinoline-3-carboxamide, the structural formula of which is given below, and which is a key intermediate in the preparation of compounds with high pharmacological activity, which can be used in particular in the treatment and prevention of infections caused by HIV. In the majority of these antiviral drugs, (S)-N-tert-butyl-1,2,3,4-tetrahydroisoquinoline-3-carboxamide is not used directly as such but is hydrogenated beforehand to give N-tert-butyldecahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide, the structural formula of which is also given below, and which, after suitable substitutions on the isoquinoline nitrogen that will be obvious to a person skilled in the art, is in its turn converted to the pharmacologically active derivative. US patent US-5,196,438 in fact describes pharmacologically active compounds with antiviral activity, the structural formula of which is given below and in which the decahydroisoquinoline residue derived from N-tert-butyldecahydro-(4aS.8aS)-isoquinoline-3(S)-carboxamide is immediately identifiable; among these, the derivative of most interest, and whose structural formula is given below, is known by the trade name Saquinavir. Another antiviral drug of considerable importance, which also contains the decahydroiso-quinoline residue present in Saquinavir, is Nelfinavir, the structural formula of which is also given below. and the preparation of which is described for example in US patents US-5,484,926 and US-5,952.343, the contents of which, as well as the contents of US-5,196,438, must be regarded as an integral part of the present description. Both Nelfinavir and Saquinavir are normally used in the form of the corresponding water-soluble salts and, in particular, of the associated mesylate salts. European patent application EP-533000-A1 describes a process for the preparation of (S)-N-tert-butyl-1,2.3,4-tetrahydroisoquinoline-3-carboxamide in which a compound of formula IV, which is then converted to the desired compound as a result of removal of the Z group. However, this method is of little industrial interest as it is characterized by mediocre yields. US patent US-5.587.481. European patent application EP-751128-A1 and international patent application WO 00/00494 describe a method for the synthesis of (S)-N-tert-butyl-1,2,3.4-tetrahydroisoquinoline-3-carboxamide in which (3S)-1,2.3,4-tetrahydro-isoquinoline-3-carboxylic acid The NCA is then reacted with tert-butylamine and next it is hydrogenated to give N-tert-butyldecahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide. The method described in US-5,587.481, EP-751128-A1 and WO 00/00494 does, however, have substantial drawbacks, for example the use of phosgene, diphosgene and triphosgene which are toxic and highly hazardous compounds. A method that enables (S)-N-tert-butyl-1,2,3,4-tetrahydroisoquinoline-3-carboxamide to be synthesized at high yield and with high optical purity and does not use reagents that are toxic and difficult to use, would therefore be of industrial interest. A new method of synthesis by which the intermediate in question can be prepared at high yields and with high optical purity without the use of hazardous reagents has now been found, and constitutes the subject of the present invention; this method of synthesis is made up of the following steps: i.e. (3S)-1.2,3.4-tetrahydroisoquinoline-3-carboxylic acid, is reacted with formic acid to give the compound of formula: c) the compound thus obtained is then treated with acids to give (S)-N-tert-butyl-1,2.3,4-tetrahydroisoquinoline-3-carboxamide. (S)-N-tert-Butyl-1,2,3,4-tetrahydroisoquinoline-3-carboxamide can then be hydro-genated to give N-tert-butyldecahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide according to the known methods in the prior art, for example those described in EP-533000-A1. US-5.587,481, EP-751128-A1 and WO 00/00494, which must be regarded as an integral part of the present description. A second subject of the invention is moreover represented by a method for the synthesis of compounds with antiviral activity and of their water-soluble salts, such as Nelfinavir and Saquinavir for example, characterized in that they comprise the synthesis steps described above. Further subjects of the invention are finally represented by the intermediates Steps (a), (b) and (c). can be effected in the conditions known in the industry by similar reactions. According to the preferred embodiment of the present invention, which is not however to be regarded as limiting, step (a) is normally carried out in toluene in the presence of acetic anhydride, operating at a temperature of 30-70°C. preferably at approx. 50°C. Step (b), reaction with t-butylamine, is normally earned out in ethyl acetate, possibly in the presence of triethylamine and ethyl chioroformate. operating at a temperature between -20 and +10°C. preferably at ai Drox. -2°C. Step (c), finally, is preferably carried out in dioxan and hydrochloric acid, normally at 36%, operating at a temperature between 10 and 40° C, preferably at approx. 25°C. As will be clear from the examples, which must be regarded purely as illustrating but not limiting the invention, (3S)-1,2.3,4-tetrahydroisoquinoline-3-carboxylic acid, used as starting product in the present method, can be obtained by reaction of l-phenylalanine filtered on a porous diaphragm, washing with a mixture of 0.6 kg of HBr 48% and 1.8 kg of H2O. The wet product is loaded into 5.3 kg of H2O and the pH is adjusted to 8-9 (T 4.5 kg of HCOOH 95-97% is loaded into a suitable reactor; it is cooled to approx. 5° C and 1.23 kg of the product obtained in Example 1 is added slowly at 7° C. 1.39 kg of product is obtained (yield 97.6 % of theor.) with a purity (HPLC) of 97%. EXAMPLE 2a 50 g of the product obtained in Example 1 and 250 ml of toluene (K.F. 0.06%) are loaded into a 500-ml flask at room temperature. The mixture is cooled to OX / 5°C and, maintaining that temperature, a mixture of formic acid 98% (19.5 g) and acetic anhydride (43.3 g), prepared by heating a mixture of the two at 50°C for 30 min, is poured in. Upon completion of pouring, the temperature is allowed to rise to 20°C / 25°C spontaneously and, after about two hours, the mixture is concentrated under vacuum at a maximum temperature of 35°C until there is a residue. The residue is absorbed in toluene (100 ml) and is concentrated to residue again. The operation is repeated once more. Finally, the residue is absorbed in toluene (200 ml), stirring for 30 min at 30°C until the "ginned" product is obtained. It is cooled to 0°C / 5°C and stirred for 60 min. It is filtered and the panel is washed with toluene (50 ml. twice); it is dried under vacuum at 55°C. 54 g of product is obtained (yield 1.08 based on phenylalanine) with HPLC purity of 98.4%. A suitable reactor is loaded with 1.39 kg of the product obtained in Example 2 (or 2a) and 7.5 kg of ethyl acetate; then 0.89 kg of trietriylamine is poured in slowly at 20°C; it is stirred for 30 min at room temperature and then 2.5 kg of ethyl acetate and 1.1 kg of ethyl chloroformate are added (at -2°C). It is stirred for 30 min and 0.74 kg of t-butylamine is poured in slowly at - 2°C; it is stirred for 30 min and a further 0,25 kg of ethyl chloroformate is added slowly at -2°C; it is stirred for 20 min and a further 0.15 kg of t-butylamine is added slowly at -2°C; the temperature is allowed to rise to 20°C and it is stirred for 2h from the end of addition. Then 2 kg of H2O is added, it is stirred for 30 min and it is left to decant, allowing the phases to separate; 2.8 kg of H2O with 5% of NaHCO3 is added to the organic phase, it is stirred for 30 min, leaving it to decant and allowing the phases to separate. 2 kg of H2O is added, it is stirred again for 30 min, and it is left to decant, allowing the phases to separate; it is distilled under vacuum at 40°C until there is an oily residue of a red-orange colour (HPLC purity approx. 90% 95 %). 1.4 kg of dioxan and 1.4 kg of H2O are added to the product obtained in Example 3; 3.3 kg of HCl 36% is poured in slowly at CLAIMS 1. A method of preparation of (S)-N-tert-butyl-l .2,3.4-tetrahyclroisoquinoline-3- carboxamide comprising the following steps: a) (3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid is reacted with fomnic acid to give the compound of formula: c) the compound thus obtained is then treated with acids to give (S)-N-tert-butyl-1,2,3,4-tetrahydroisoquinoiine-3-carboxamide. 2. A method according to Claim 1, characterized in that step (a) is carried out in toluene. 3. A method according to Claim 1. characterized in that step (a) is canied out in the presence of acetic anhydride. 4. A method according to Claim 1. characterized in that step (a) is carried out at a temperature of 30-70°C. preferably at approx. 50°C. 5. A method according to Claim 1. characterized in that step (b) is carried out in ethyl acetate. 6. A method according to Claim 1. characterized in that step (b) is carried out in the presence of triethylamine and/or ethyl chloroformate. 7. A method according to claim 1. characterized in that step (b) is carried out at a temperature between -20 and +10° C, preferably at approx. -2° C. 8. A method according to Claim 1. characterized in that step (c) is carried out in dioxan and hydrochloric acid. 9. A method according to Claim 1. characterized in that step (c) is carried out at a temperature between 10 and 40°C, preferably at approx. 25°C. 10. A method according to Claim 1, characterized in that (S)-N-tert-butyl-l ,2,3,4- letra-hydroisoquinoline-3-carboxamide is hydrogenated to give N-tert-butyl- decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide. 11. A method according to Claim 1, characterized in that (3S)-1,2,3,4-tetrahydroiso- quinoline-3-carboxylic acid is obtained by reaction of l-phenylalanine with formal- dehyde, preferably paraformaldehyde. 12. A method for the synthesis of compounds with antiviral activity and of their water- soluble salts, characterized in that it comprises a method according to any one of the preceding claims. 13. A method according to Claim 12, characterized in that the said compounds with antiviral activity are selected between Nelfinavir and Saquinavir. 14. A compound of formula 15. A compound of formula 16. A method of preparation of (S)-N-tert-butyl-l,2,3,4-tetrahydroiso-quinoline-3-carboxamide substantially as herein described and exemplified.

Documents:

462-chenp-2003-abstract.pdf

462-chenp-2003-claims filed.pdf

462-chenp-2003-claims granted.pdf

462-chenp-2003-correspondnece-others.pdf

462-chenp-2003-correspondnece-po.pdf

462-chenp-2003-description(complete) filed.pdf

462-chenp-2003-description(complete) granted.pdf

462-chenp-2003-form 1.pdf

462-chenp-2003-form 26.pdf

462-chenp-2003-form 3.pdf

462-chenp-2003-form 5.pdf

462-chenp-2003-other documents.pdf

462-chenp-2003-pct.pdf