Field of the Invention In general, this invention relates to the process for producing N-t-butyl-3(S)-carboxamide decahydro-(4as, 8as) isoquinoline. More specifically, but without restriction to the particular embodiments hereinafter described in accordance with the best mode of practice, this invention provides an improved process for producing N-t-butyl 3(S)carboxamide decahydro-(4as, 8as) isoquinoline employing low temperature, low pressure and selective amount of a catalyst
Background of the Invention The commercial use of (4as, 8as) decahydro isoquinoline t-Butyl-3(S) carboxamide is well known as a drug intermediate for antiviral Nelfinavir and Saquinavir. This important commercial use of the (4as, 8as) Decahydro isoquinoline has given rise to the development of research in this area.
Several processes are known for the preparation of (4as, 8as) decahydro isoquinoline t-Butyl-3(S) carboxamide. The known processes differ from each other in respect of different process chemistry followed.
European Patent No. EP 432695 describes a process in which L-phenyl alanine is cyclised using formaldehyde and cone. HC1, the product is purified by making p-toluene sulfonic acid salt, subsequently hydrogenated using 5% Rhodium on carbon at 140 kg pressure and a temperature of 80°C in acetic acid followed by reaction with t-butyl amine in presence of N-Hydroxy succinimide & dimethoxy ethane. The process involves high pressure and therefore, is industrially not suitable.
EP 533000 describes a process in which L-phenylalanine is reacted with formaldehyde in cone. HC1, then NH group is protected using benzyloxycarbonyl chloride, followed by reaction with t-butyl amine, subsequently benzyloxy carbonyl is deprotected using hydrogen / palladium on carbon, finally ring reduction using hydrogen / Rhodium on carbon at 120 Kg pressure to get decahydro isoquinoline-t-butylcarboxamide at an overall yield of 17-20%. This process also has a disadvantage since it involves the use of high pressure up to 120 Kg. United States Patent No. 5,256,783 describes a process in which N-benzyloxycarbonyl-L-phenylalanine is converted into N-benzyloxycarbonyl-L-phenylalanine-t-butyl amide using isobutyl chloroformate, N-Ethyl morpholine and t-butyl amine. The above compound is

cyclised using dimethoxy methane, toluene, sulphuric acid & acetic acid at room temperature to 40°C, deprotection using 10% palladium on carbon at 10 kg pressure, finally reduction using Rhodium on Alox at 90°C and at 80 kg pressure. Overall yield is only 29% and the process involves pressure up to 80 Kg and 10% Pd/C. Hence this process is not suitable at large scale.
F. Roessler, Chimia 1996,50,106 describes a process, in which L-phenyl alanine is cyclised using formaldehyde, HC1 and water, purified using ammonium hydroxide followed by reaction with t-butyl amine using phosgene and then high pressure to get the title compound. This process has disadvantage of using poisonous phosgene.
Tetrahedron letters, Vol. 34, No 16. PP, 2593-2596, 1993 describes the process starting from misocis-anhydride which is methanolysed with potassium carbonate in Methanol and then ephedrine salt is formed followed by cyclisation using Ethanol to give monoacid. Monoacid is converted to aldehyde, which is hydrogenated using 5% Pd/C at 40 kg pressure at 20°C. This aldehyde ester is condensed with enolate (formed by treating benzylamine protected glycine methyl ester with Li-HMDS in THF) at -40°C, which gives lactone. Hydrogenation at 40 psi gives decahydrolactone, and then reduction with BH3SMC2 gives decahydro ester. Further condensation with triisobutylammonium with t-Butylamine in THF/toluene at 45°C for 30 minutes gives mixture of 95:5 Decahydro isoquinoline carboxamide. Since process involves many stages and low temperature of -40°C, this process is inconvenient for large scale production of the title compound.
Objects and Summary of the Invention It is, therefore, an object of the present invention to improve upon limitations in the prior art. These and other objects are attained in accordance with the present invention wherein there is provided several embodiments of industrially viable process for producing N-t-butyl 3(S)carboxamide decahydro-(4as, 8as) isoquinoline of formula (I) employing low temperature, low pressure and a selective amount of a catalyst.
In accordance with one embodiment of the present invention, there is provided a process to produce N-t-butyl 3(S)carboxamide decahydro-(4as, 8as) isoquinoline of formula (I) in large scale, wherein the process comprises reacting N-benzyloxy carbonyl-L-phenyl alanine-t-butylamide of formula (II) with dialkoxy methane in presence of an acidic catalyst in an

acidic medium at a temeperature of 20 to 27°C to prepare the compound benzyl 3(S)-(t-butyl carbamoyl)-1,2,3,4-tetrahydro-2-isoquinoline carboxylate of formula (III), deprotecting the compound benzyl 3(S)-(t-butyl carbamoyl)-1,2,3,4-tetrahydro-2-isoquinoline carboxylate of formula (III) employing 5% palladium over carbon in alcoholic media at a temperature of 25 to 30°C to produce the compound N-t-Butyl-l,2,3,4-tetrahydro-3(S)-isoquinoline carboxamide of formula (IV), reducing the N-t-Butyl-l,2,3,4-tetrahydro-3(S)-isoquinoline carboxamide of formula (IV) employing Rhodium on alumina type 524/525 in ethyl acetate at a pressure 40 to 45 kg and a temperature between 80 and 130°C to produce the compound of formula (I).
In accordance with another preferred embodiment, there is provided an improved process to produce N-t-butyl 3(S)carboxamide decahydro-(4as, 8as) isoquinoline of formula (I), wherein cyclising N-benzyloxy carbonyl-L-phenyl alanine-t-butylamide of formula (II) using dialkoxymethane preferably dimethoxy methane in a mixture of sulphuric acid, acetic acid and toluene at 20-27°C preferably 22-24°C produces the compound 3(S)-(t-butyl carbamoyl)-l,2,3,4-tetrahydro-2-isoquinoline carboxylate of formula (III) in pure form and good yield of about 80%.
In accordance with another embodiment of the present invention there is provided an improved process to produce N-t-butyl 3(S)carboxamide decahydro-(4as, 8as) isoquinoline of formula (I), wherein deprotection of benzyl 3(S)-(t-butyl carbamoyl)-1,2,3,4-etrahydro-2-isoquinoline carboxylate of formula (III) employing a selective amount of the catalyst (5% palladium over carbon) in alcoholic media at a temperature of 25 to 30°C produces a compound N-t-Butyl-l,2,3,4-tetrahydro-3(S)-isoquinoline carboxamide of formula (IV) in good yield of about 90%. This step resulting in good yield of N-t-Butyl-l,2,3,4-tetrahydro-3(S)-isoquinoline carboxamide of formula (IV) makes the process more industrially viable.
In accordance with another embodiment of the present invention, there is provided a process to produce N-t-butyl 3(S)carboxamide decahydro-(4as, 8as) isoquinoline of formula (I), wherein reduction of the compound N-t-Butyl-l,2,3,4-tetrahydro-3(S)-isoquinoline carboxamide of formula (IV) employing Rhodium on alumina type 524/525 in ethyl acetate at a low pressure of about 40 to 45 kg yields N-t-butyl 3(S)carboxamide decahydro-(4as, 8as) isoquinoline of formula (I), and thereby increases the operational efficiency and convenience on large-scale manufacturing.

Similarly other derivatives also can be prepared using N-benzyloxy carbonyl p-methyl-(DL)-phenylalanine, N-benzyloxy carbonyl-a-methyl (DL) phenylalanine.
Detailed Description of the Invention The present invention describes a convenient, industrially feasible and efficient process for the preparation of N-t-butyl 3(S)carboxamide decahydro-(4as, 8as) isoquinoline of formula (I) in large-scale. The disclosed process according to the present invention provides the production of the title compound in a cost efficient manner with lesser impurities and in better yield. Reaction Scheme

wherein R1and R2 are independently selected from the group consisting of hydrogen or a lower alkyl group preferably methyl. R is selected from methyl, ethyl or propyl.
The above reaction scheme discloses the process to produce N-t-butyl 3(S)carboxamide decahydro-(4as, 8as) isoquinoline of formula (I), wherein the process comprises reacting N-benzyloxy carbonyl-L-phenyl alanine-t-butylamide of formula (II) with dialkoxy methane in

presence of sulphuric acid in an acidic medium comprising a mixture of acetic acid & toluene at a temeperature of 20 to 27°C to prepare the compound benzyl 3(S)-(t-butyl carbamoyl)-l,2,3,4-tetrahydro-2-isoquinoline carboxylate of formula (III), deprotecting the compound benzyl 3(S)-(t-butyl carbamoyl)-l,2,3,4-tetrahydro-2-isoquinoline carboxylate of formula (III) employing 5% palladium over carbon in alcoholic media selected from any lower alcohol preferably methanol at a temperature of 25 to 30°C to produce a compound N-t-Butyl-l,2,3,4-tetrahydro-3(S)-isoquinoline carboxamide of formula (IV), reducing the N-t-Butyl-1, 2,3,4-tetrahydro-3(S)-isoquinoline carboxamide of formula (IV) employing Rhodium on alumina type 524/525 in ethyl acetate at a pressure of 40 to 45 kg and a temperature between 80 and 130°C to produce the compound of formula (I).
The cyclisation step at low temperature, i.e. 20-27°C, preferably 22-24°C, helps in faster completion of the reaction and reduces the impurity formation, hence results in better yield.
Use of 5% Pd/C which is cheaper and less pyrophoric and hence more safe than 10% Pd/C is preferred in large-scale preparation.
As used herein the lower pressure of 40-45 Kg in the reduction step is always preferred in industrial practices as a safer pressure level compared to high pressure, as high pressure processes require extra investment to establish safety measures.
The examples mentioned below explain all the aspects of the present invention. The examples are given to illustrate the details of the invention and should not be construed to limit the scope of the present invention:
Example 1
Preparation of Benzyl 3(S)-(t-butvl carbamoyl)- 1,2,3,4-tetrahydro-2-isoquinoline carboxylate 850.8 g of N-benzyloxy carbonyl-L-phenyl alanine-t-butylamide was dissolved in 3000 ml of toluene at Room Temperature (RT). A previously prepared mixture of 240 ml of 95.97% sulphuric acid and 636ml of 99.5% acetic acid was added drop wise to the turbid solution within 40 minutes while stirring, where upon 547 g of dimethoxy methane was added within 30 minutes and the solution which was still turbid was stirred at 20-27°C for 24-30 hrs. After the addition of 1800 ml of toluene the reaction mixture (RM) was cooled to 15°C in order to

buffer the system (pH = 8 - 8.5). 500 ml of water was added in order to dissolve the separated ammonium salt whereupon the mixture was stirred at RT for 10 minutes and left to stand for 20 minutes. The aqueous phase was removed, whereupon the organic phase was treated with 1000 ml of water and the mixture was stirred at RT for 15 minutes and left to stand for 20 minutes. After removal of the aqueous phase (pH 7 - 7.5), the organic phase was concentrated under reduced pressure. After approximately 4200 ml of toluene had distilled off, viscous oil remained, whereupon a Nitrogen atmosphere was applied & the internal temperature was increased to 45°C.
At a constant external temperature of 70°C, 2000 ml of hexane was added in such a manner that the internal temperature always remains 50 - 55°C, the solution is cooled slowly to -10°C for 1 hr, solid product obtained is filtered, washed with chilled n-Hexane & dried at 50 - 55°C under vacuum. Yield = 706 g (80%)
Example 2
Preparation of N-t-Butvl-1,2,3,4-tetrahvdro-3(S)-isoquinoline carboxamide 706 g of Benzyl 3(S)-(t-butoxy carbonyl)-l,2,3,4-tetrahydro-2-isoquinoline carboxylate was dissolved in 5000 ml of methanol & hydrogenated in an autoclave in the presence of 141 g of 5% Pd/C at a pressure of 10 kg, temperature of 20-25°C for 2-3 hrs. Reaction is monitored by TLC. After the reaction completion, the catalyst is filtered & washed with methanol and filtrate is distilled off to remove methanol. 5000 ml of n-Hexane is added and heated to 60 -65°C and distilled off 4000 ml of n-Hexane and slowly cooled to RT. Stirred for 24 hrs to get solid product. This solid is filtered and washed with n-Hexane, dried at 50 - 55°C. Yield = 405 g (90%).
Example 3
Preparation of N-t-butyl decahydro-(4as, 8as)isoquinoline-3(S)carboxamide 405 g of N-t-Butyl-l,2,3,4-tetrahydro-2-isoquinoline carboxamide was suspended in 2700 ml of Ethyl acetate & hydrogenated in the presence of 81 g of Rhodium on Alumina type 524/525 (5%) while stirring at a pressure of 45 - 50 kg and at a temperature of 120°C. The reaction completion is monitored by TLC. (Approx = 6-8 hrs). The RM is cooled to RT & the

catalyst is filtered. Ethyl acetate is evaporated and the residue is treated with 1080 ml of n-
Hexane, cooled to 10-13°C and the solid product is filtered.
The crude product is dissolved in 1100 ml of n-Hexane, solution is concentrated to 800 ml &
cooled to 10-13°C for 10-12 hrs to get pure compound.
Yield = 324 g
Purity- 100% by GC

While this invention has been described in detail with reference to certain preferred embodiments, it should be appreciated that the present invention is not limited to those precise embodiments. Rather, in view of the present disclosure, which describes the current best mode for practicing the invention, many modifications and variations would present themselves to those skilled in the art without departing from the scope and spirit of this invention.

We Claim:
1. A process for producing N-t-butyl 3(S)carboxamide decahydro-(4as, 8as) isoquinoline of formula (I),
the process comprising;
(a) reacting N-benzyloxy carbonyl-L-phenyl alanine-t-butylamide of formula (II) with
dialkoxy methane in presence of an acidic catalyst in an acidic medium at a temeperature of
20 to 27°C to prepare the compound benzyl 3(S)-(t-butyl carbamoyl)-1,2,3,4-tetrahydro-2-
isoquinoline carboxylate of formula (III);

7
(b) deprotecting the compound benzyl 3(S)-(t-butyl carbamoyl)-1,2,3,4-tetrahydro-2-
isoquinoline carboxylate of formula (III) employing 5% palladium over carbon in alcoholic
media at a temperature of 25 to 30°C to produce a compound N-t-Butyl-l,2,3,4-tetrahydro-
3(S)-isoquinoline carboxamide of formula (IV);


(c) reducing the N-t-Butyl-l,2,3,4-tetrahydro-3(S)-isoquinoline carboxamide of formula (IV) employing Rhodium on alumina type 524/525 in ethyl acetate at a pressure of 40 to 45 kg and a temperature between 80 and 130°C to produce the compound of formula
(I),
wherein R1and R2 are independently selected from the group consisting of hydrogen
or a lower alkyl group preferably methyl.
2. The process according to claim 1, wherein said dialkoxy methane is selected
from dimethoxy methane, dipropoxymethane or diethoxy methane
3. The process according to claim 1, wherein acidic catalyst is sulphuric acid.
4. The process according to claim 1, wherein the acidic media is a mixture of
acetic acid & toluene.
5. The process according to claim 1, wherein in step (a), the preferred
temperature is 22-24°C.
6. The process according to claim 1, wherein the alcoholic media is selected
from any lower alcohol preferably methanol.