Claims:
1. A process for preparation of tetrahydroisoquinoline compounds of formula I,

(I)
Wherein R is selected from optionally substituted C1-10 alkylene groups;
R1, R2, R3, R4, R5, R6, R7, R8 and R9 are independently selected from hydrogen, optionally substituted -C1-10 alkyl, -C2-10 alkenyl, -C2-10 alkynyl, or form an optionally substituted 3 to 7 member cyclic ring which optionally includes at least one heteroatom selected from O, N and S in the cyclic ring; -C1-7 alkylphenyl, -phenyl, -phenylC1-7 alkyl, -OC1-10 alkyl, -OC1-7 alkylphenyl, -Ophenyl, -OphenylC1-7 alkyl, -SC1-7alkyl, -SC1-7 alkylphenyl, -Sphenyl, -SphenylC1-7 alkyl, -NH2, -NH(C1-7 alkyl), -NH(C1-7 alkylphenyl), -NH(phenyl), -NH(phenyl C1-7 alkyl), -N(C1-7 alkyl)(C1-7 alkyl) or two alkyl groups attached to N form an optionally substituted 3 to 7 member cyclic ring which optionally includes additional 1 or 2 heteroatoms selected from O, N and S in the cyclic ring, -N(C1-7 alkyl)(C1-7 alkylphenyl) or the alkyl groups attached to N along with alkylphenyl group form an optionally substituted 3 to 7 member cyclic or benzocyclic ring which optionally includes additional 1 or 2 heteroatoms selected from O, N and S in the cyclic ring, -N(C1-7 alkylphenyl)(C1-7 alkylphenyl), -N(phenyl)(phenyl), -N(phenyl)(C1-7 alkyl) or the alkyl and phenyl groups attached to N form an optionally substituted 4 to 7 member cyclic ring which optionally includes additional 1 or 2 heteroatoms selected from O, N and S in the cyclic ring, –CHO, –C(O)C1-7 alkyl, –C(O)C1-7 alkylphenyl, –C(O) phenyl, –C(O) phenyl C1-7 alkyl, –CO2H, –C(O)O C1-7 alkyl, –C(O)O C1-7 alkylphenyl, –C(O)O phenyl, –C(O)O phenyl C1-7 alkyl, – OC(O) C1-7 alkyl, – OC(O) C1-7 alkylphenyl, –OC(O) phenyl, –OC(O) phenyl C1-7 alkyl, –CONH2, –C(O)NH C1-7 alkyl, –C(O)NH C1-7 alkylphenyl, –C(O)NH phenyl, –C(O)NH phenyl C1-7 alkyl, –C(O)N (C1-7 alkyl)(C1-7 alkyl) or two alkyl groups attached to N form an optionally substituted 3 to 7 member cyclic ring which optionally includes additional 1 or 2 heteroatoms selected from O, N and S in the cyclic ring, –C(O)N (C1-7 alkyl) (C1-7 alkylphenyl) or the alkyl groups attached to N along with alkylphenyl group form an optionally substituted 3 to 7 member cyclic or benzocyclic ring which optionally includes additional 1 or 2 heteroatoms selected from O, N and S in the cyclic ring, –C(O)N(C1-7 alkylphenyl)(C1-7 alkylphenyl), –C(O)N (phenyl)(phenyl), – NHC(O) C1-7 alkyl, –NHC(O) C1-7 alkylphenyl, –NHC(O) phenyl, –NHC(O) phenylC1-7 alkyl, –N(C1-7 alkyl)C(O) C1-7 alkyl, –N(C1-7 alkyl)C(O) C1-7 alkylphenyl, –N(C1-7 alkyl)C(O)phenyl, –N(C1-7 alkyl)C(O) phenylC1-7 alkyl, –SO2C1-7 alkyl, –SO2C1-7alkylphenyl, –SO2phenyl, –SO2phenylC1-7 alkyl, –SO2NH2, –SO2NHC1-7 alkyl, –SO2NHC1-7alkylphenyl, –SO2NHphenyl, –SO2NHphenyl(C1-7 alkyl), –NHSO2C1-7 alkyl, –NHSO2C1-7 alkylphenyl, –NHSO2phenyl, –NHSO2phenylC1-7 alkyl, or any two groups selected from R1, R2, R3, R4, R5, R6, R7, R8 and R9 when placed ortho to each other form an optionally substituted 4 to 7 member cyclic ring which optionally includes 1 to 3 heteroatoms selected from O, N and S in the cyclic ring, -F, -Cl, -Br, -I, -CN, -NO2, -NO, -CF3, -OCF3, -SCF3; n is independently 0 or 1;
Comprising reacting compound of formula II,

(II)
Wherein, R1, R2, R3, R4, R5, R6, R7, R8, R9 and n are as defined above;
with compound of formula III,

(III)
Wherein, R is as defined above, in presence of a base or a solvent.

2. The process according to claim 1, wherein R is selected from optionally substituted C4-7 alkylene groups.
3. The process according to claim 2, wherein R is 1,5-pentylene, 3-methyl-1,5-pentylene, 1,5-hexylene, 1,6-hexylene or 1,6-heptylene.
4. The process according to claim 1, wherein R1, R2, R3, R4, R5, R6, R7, R8 or R9 are independently hydrogen, optionally substituted -C1-10 alkyl, -OC1-10 alkyl, -SC1-7 alkyl, -NH(C1-7 alkyl), -NH(phenyl), -NH(phenyl C1-7 alkyl), -N(C1-7 alkyl)(C1-7 alkyl), –C(O)C1-7 alkyl, –C(O)OC1-7 alkyl, –OC(O)C1-7 alkyl, –CONH2, –C(O)NH C1-7 alkyl, –C(O)N(C1-7 alkyl)(C1-7 alkyl) or –NHC(O) C1-7 alkyl.
5. The process according to claim 4, wherein R1, R2, R3, R4, R5, R6, R7, R8 or R9 are independently hydrogen or -OC1-10 alkyl.
6. The process according to claim 5, wherein R1, R4, R5, R8, R9 are hydrogen and R2, R3, R6, R7 are methoxy.
7. The process according to claim 1, wherein the base is organic or inorganic base.
8. The process according to claim 7, wherein the base is selected from N-methylmorpholine, diisopropylethylamine, triethylamine or a mixture thereof.
9. The process according to claim 1, wherein the solvent is polar or non-polar solvent.
10. The process according to claim 9, wherein the solvent is selected from dimethylformamide, acetonitrile, dimethylsulfoxide, dioxane or a mixture thereof.
11. The process according to claim 1, wherein compound of formula II is chiral.
12. A process for the synthesis of tetrahydroisoquinoline compounds of formula IV

(IV)
Wherein R1, R2, R3, R4, R5, R6, R7, R8, R9 and n are as defined above; R10 is selected from OR11, NHR11, NR12R13 where R11, R12 and R13 are independently hydrogen, optionally substituted -C1-10 alkyl, -C2-10 alkenyl, -C2-10 alkynyl, -C3-10 cycloalkyl, -C3-10 cycloalkenyl, -C5-10 cycloalkynyl, -C1-7 alkylphenyl, -phenyl, -phenylC1-7 alkyl, aryl, heteroaryl, heterocycl or R12 and R13 along with N form an optionally substituted 3 to 7 member cyclic or benzocyclic ring which optionally includes additional 1 or 2 heteroatoms selected from O, N and S in the cyclic ring;
Comprising reacting compound of formula II,

(II)
Wherein, R1, R2, R3, R4, R5, R6, R7, R8, R9 and n are as defined above;
with compound of formula V,

(V)
Where R10 is as defined above, in presence of a base or a solvent.
13. The process according to claim 12, wherein R1, R2, R3, R4, R5, R6, R7, R8 or R9 are independently hydrogen, optionally substituted -C1-10 alkyl, -OC1-10 alkyl, -SC1-7 alkyl, -NH(C1-7 alkyl), -NH(phenyl), -NH(phenyl C1-7 alkyl), -N(C1-7 alkyl)(C1-7 alkyl), –C(O)C1-7 alkyl, –C(O)OC1-7 alkyl, –OC(O)C1-7 alkyl, –CONH2, –C(O)NH C1-7 alkyl, –C(O)N(C1-7 alkyl)(C1-7 alkyl) or –NHC(O) C1-7 alkyl.
14. The process according to claim 13, wherein R1, R2, R3, R4, R5, R6, R7, R8 or R9 are independently hydrogen or -OC1-10 alkyl.
15. The process according to claim 14, wherein R1, R4, R5, R8, R9 are hydrogen and R2, R3, R6, R7 are methoxy.
16. The process according to claim 12, wherein the base is organic or inorganic base.
17. The process according to claim 16, wherein the base is selected from N-methylmorpholine, diisopropylethylamine, triethylamine or a mixture thereof.
18. The process according to claim 12, wherein the solvent is polar or non-polar solvent.
19. The process according to claim 18, wherein the solvent is selected from dimethylformamide, acetonitrile, dimethylsulfoxide, dioxane or a mixture thereof.
20. The process according to claim 12, wherein compound of formula II is chiral.
, Description:FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:

“AN IMPROVED PROCESS FOR THE PREPARATION OF TETRAHYDROISOQUINOLINE COMPOUNDS”

2. APPLICANT:

(a) NAME: NEON LABORATORIES LTD.

(b) NATIONALITY: Indian Company incorporated under the
Companies Act, 1956

(c) ADDRESS: 140, Damji Shamji Industrial Complex,
Mahakali Caves Road, Andheri (East), Mumbai - 400093,
Maharashtra, India.

3.PREAMBLE TO THE DESCRIPTION:
The following specification describes the nature of this invention and the manner in which it is to be performed:

Technical Field:
The present invention relates to an improved process for preparation of tetrahydroisoquinoline compounds and its acid addition salts in good yields which are possible intermediates for the synthesis of neuromuscular-blocking drug. One of the important intermediates is pentamethylene bis(1-(3,4-dimethoxybenzyl)-3,4-dihydro-6,7-dimethoxy-1H-isoquinoline-2-propionate) and its acid addition salts. This tetrahydroisoquinoline compound and its acid addition salts can be used as an intermediates for manufacture of neuromuscular-blocking drugs or skeletal muscle relaxants.

Background & Prior Art:
The tetrahydroisoquinoline moiety has been found in variety of natural products such as those obtained from cactus alkaloids, mammalian alkaloids, the esteinascidine family and spiro-benzoisoquinoline alkaloids. Various substituted 1,2,3,4-tetrahydroisoquinolines are found to possess varied activity such as potent bronchodilators, anti-convulsant, peripheral vasodilators, analgesic, potent dopamine D2 receptor-blocking activity and specific bradycardic agents. The N-alkylated tetrahydroisoquinolines and their quarternary ammonium salts are kind of drugs which are used for the treatment of muscle relaxant during surgery, tracheal intubation, controlled ventilation and other conditions. They are also known to interfere with the anaesthetic drugs and other components in body which relaxes skeletal muscle.

US 4,179,507 disclose the preparation of pentamethylene bis(1-(3,4-dimethoxybenzyl)-3,4-dihydro-6,7-dimethoxy-1H-isoquinoline-2-propionate) first by reacting 1,5-pentanediol with acryloyl chloride in presence of triethylamine and pyrogallol as stabilizer to give 1,5-pentamethylene diacrylate. Further condensation of pentamethylene diacrylate with tetrahydropapaverine gives pentamethylene bis(1-(3,4-dimethoxybenzyl)-3,4-dihydro-6,7-dimethoxy-1H-isoquinoline-2-propionate), which is further converted in to its dioxalate salt. The process involves the use of acryloyl chloride which is light sensitive and results in to formation of polymerized products. Also the intermediate compound 1,5-pentamethylene diacrylate is sensitive to light and undergoes polymerization leading to concerns about storage and handling. The material thus obtained is impure and in low yields.

PCT int. application WO2010128518 A2 discloses a similar method for the preparation of pentamethylene bis(1R-1-(3,4-dimethoxybenzyl)-3,4-dihydro-6,7-dimethoxy-1H-isoquinoline-2-propionate). The only difference is that the pentamethylene diacrylate is prepared by reacting 1,5-pentanediol with methyl acrylate in presence of p-toluenesulfonic acid. The process involves the use of methyl acrylate which is a light sensitive compound and results in to formation of polymerized products. Also the intermediate compound 1,5-pentamethylene diacrylate is sensitive to light and undergoes polymerization leading to concerns about storage and handling. Also the material thus obtained is impure and in low yields.

US patents 5,453,510 and 5,556,987 disclose the preparation of pentamethylene bis(1R-1-(3,4-dimethoxybenzyl)-3,4-dihydro-6,7-dimethoxy-1H-isoquinoline-2-propionate).The process involves reacting 3-bromopropionic acid with 1,5-pentanediol in presence of p-toluenesulfonic acid to give pentamethylene diacrylate. Further condensation of pentamethylene diacrylate with (R)-tetrahydropapaverine gives bis(1R-1-(3,4-dimethoxybenzyl)-3,4-dihydro-6,7-dimethoxy-1H-isoquinoline-2-propionate). The intermediate compound 1,5-pentamethylene diacrylate is sensitive to light and undergoes polymerization leading to concerns about storage and handling. Also the material thus obtained is impure and in low yields.

EP0219616 A1 discloses preparation of pentamethylene bis(1-(3,4-dimethoxybenzyl)-3,4-dihydro-6,7-dimethoxy-1H-isoquinoline-2-propionate) first by reacting tetrahydropapaverine with beta-propiolactone to give N-(2-carboxyethyl)-1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline. This on further esterification with 1,5-pentanediol in toluene and p-toluenesulfonic acid as catalyst gives pentamethylene bis(1-(3,4-dimethoxybenzyl)-3,4-dihydro-6,7-dimethoxy-1H-isoquinoline-2-propionate).

The drawback of the process is the use of costly raw material like beta-propiolactone making the process industrially un-economical. Beta-propiolactone can react with nucluophile in two ways i.e. alkylation or acylation thus resulting in to poor yields due to formation of amide undesired product and other undesired products.

Indian patent application number 02725/ MUM/2008 A discloses the process for the preparation of pentamethylene bis(1R-1-(3,4-dimethoxybenzyl)-3,4-dihydro-6,7-dimethoxy-1H-isoquinoline-2-propionate) by the reaction of N-(2-carboxyethyl)-1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline with dihalopentane in presence of organic base to give bis(1R-1-(3,4-dimethoxybenzyl)-3,4-dihydro-6,7-dimethoxy-1H-isoquinoline-2-propionate). But the patent application does not discloses a method for the preparation of N-(2-carboxyethyl)-1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline which is the key raw material for the preparation of pentamethylene bis(1R-1-(3,4-dimethoxybenzyl)-3,4-dihydro-6,7-dimethoxy-1H-isoquinoline-2-propionate). The only method available is the preparation reported in EP0219616 A1 from tetrahydropapaverine and beta-propiolactone. The drawback of the process is the use of costly raw material like beta-propiolactone making the process industrially un-economical. Beta-propiolactone can react with nucluophile in two ways i.e. alkylation or acylation thus resulting in to poor yields due to formation of amide undesired product and other undesired products.

Solution of these problems associated with prior art becomes the objects of the present invention. Therefore, there remains a need in the art to provide industrially viable and economically feasible process for preparation of tetrahydroisoquinoline compounds thereby eliminating all the above-mentioned shortcomings, to suit industrial manufacture by using cheaper starting material and avoiding the additional process steps such as distillation, purifications of intermediates thus making the process resulting in better yields than reported. These advantages make the process more suitable for industrial scale-up being cost efficient and robust.

Objective of the invention:
It is an object of the invention to provide an improved, industrially viable and cost effective process for preparation of tetrahydroisoquinoline compounds (i.e. formula I and IV) and its acid addition salts in good yields and purity which are key intermediates for the synthesis of drugs such as neuromuscular-blocking agents or can themselves act as an active ingredient.

Another object of the invention is to provide the process for manufacture of such isoquinoline compounds and its acid addition salts by use of cheaper and easily available raw materials that can be stored for longer period of time and are easy to handle during manufacturing process.

Summary of the Invention
In accordance with the above objectives, the present invention provides a simple and mild process for condensation of (un)substituted tetrahydroisoquinoline with various esters of 3-chloropropionic acid to give tetrahydroisoquinoline compounds of formula I and IV.

The present invention also describes novel reactions which can easily be utilized in the synthesis of large number of active aromatic amino derivatives or salts of biological and physiological importance or can be used as intermediates in the development of active compounds.

Detailed Description of the Invention:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.

Accordingly, one aspect of the present invention provides an improved process for the synthesis of tetrahydroisoquinoline compounds of formula I,

(I)
Wherein R is selected from optionally substituted C1-10 alkylene groups;
R1, R2, R3, R4, R5, R6, R7, R8 and R9 are independently selected from hydrogen, optionally substituted -C1-10 alkyl, -C2-10 alkenyl, -C2-10 alkynyl, or form an optionally substituted 3 to 7 member cyclic ring which optionally includes at least one heteroatom selected from O, N and S in the cyclic ring; -C1-7 alkylphenyl, -phenyl, -phenylC1-7 alkyl, -OC1-10 alkyl, -OC1-7 alkylphenyl, -Ophenyl, -OphenylC1-7 alkyl, -SC1-7alkyl, -SC1-7 alkylphenyl, -Sphenyl, -SphenylC1-7 alkyl, -NH2, -NH(C1-7 alkyl), -NH(C1-7 alkylphenyl), -NH(phenyl), -NH(phenyl C1-7 alkyl), -N(C1-7 alkyl)(C1-7 alkyl) or two alkyl groups attached to N form an optionally substituted 3 to 7 member cyclic ring which optionally includes additional 1 or 2 heteroatoms selected from O, N and S in the cyclic ring, -N(C1-7 alkyl)(C1-7 alkylphenyl) or the alkyl groups attached to N along with alkylphenyl group form an optionally substituted 3 to 7 member cyclic or benzocyclic ring which optionally includes additional 1 or 2 heteroatoms selected from O, N and S in the cyclic ring, -N(C1-7 alkylphenyl)(C1-7 alkylphenyl), -N(phenyl)(phenyl), -N(phenyl)(C1-7 alkyl) or the alkyl and phenyl groups attached to N form an optionally substituted 4 to 7 member cyclic ring which optionally includes additional 1 or 2 heteroatoms selected from O, N and S in the cyclic ring, –CHO, –C(O)C1-7 alkyl, –C(O)C1-7 alkylphenyl, –C(O) phenyl, –C(O) phenyl C1-7 alkyl, –CO2H, –C(O)O C1-7 alkyl, –C(O)O C1-7 alkylphenyl, –C(O)O phenyl, –C(O)O phenyl C1-7 alkyl, – OC(O) C1-7 alkyl, – OC(O) C1-7 alkylphenyl, –OC(O) phenyl, –OC(O) phenyl C1-7 alkyl, –CONH2, –C(O)NH C1-7 alkyl, –C(O)NH C1-7 alkylphenyl, –C(O)NH phenyl, –C(O)NH phenyl C1-7 alkyl, –C(O)N (C1-7 alkyl)(C1-7 alkyl) or two alkyl groups attached to N form an optionally substituted 3 to 7 member cyclic ring which optionally includes additional 1 or 2 heteroatoms selected from O, N and S in the cyclic ring, –C(O)N (C1-7 alkyl) (C1-7 alkylphenyl) or the alkyl groups attached to N along with alkylphenyl group form an optionally substituted 3 to 7 member cyclic or benzocyclic ring which optionally includes additional 1 or 2 heteroatoms selected from O, N and S in the cyclic ring, –C(O)N(C1-7 alkylphenyl)(C1-7 alkylphenyl), –C(O)N (phenyl)(phenyl), – NHC(O) C1-7 alkyl, –NHC(O) C1-7 alkylphenyl, –NHC(O) phenyl, –NHC(O) phenylC1-7 alkyl, –N(C1-7 alkyl)C(O) C1-7 alkyl, –N(C1-7 alkyl)C(O) C1-7 alkylphenyl, –N(C1-7 alkyl)C(O)phenyl, –N(C1-7 alkyl)C(O) phenylC1-7 alkyl, –SO2C1-7 alkyl, –SO2C1-7alkylphenyl, –SO2phenyl, –SO2phenylC1-7 alkyl, –SO2NH2, –SO2NHC1-7 alkyl, –SO2NHC1-7alkylphenyl, –SO2NHphenyl, –SO2NHphenyl(C1-7 alkyl), –NHSO2C1-7 alkyl, –NHSO2C1-7 alkylphenyl, –NHSO2phenyl, –NHSO2phenylC1-7 alkyl, or any two groups selected from R1, R2, R3, R4, R5, R6, R7, R8 and R9 when placed ortho to each other form an optionally substituted 4 to 7 member cyclic ring which optionally includes 1 to 3 heteroatoms selected from O, N and S in the cyclic ring, -F, -Cl, -Br, -I, -CN, -NO2, -NO, -CF3, -OCF3, -SCF3; n is independently 0 or 1;
Comprising reacting compound of formula II,

(II)
Wherein, R1, R2, R3, R4, R5, R6, R7, R8, R9 and n are as defined above;
with compound of formula III,

(III)
Wherein, R is as defined above, in presence of a base or a solvent.

The resulting mixture of corresponding tetrahydroisoquinoline compound is concentrated and the isolated oily compound is converted in to its acid addition salt. Further purification of tetrahydroisoquinoline compounds of formula I is carried out by converting it into free base using aqueous sodium bicarbonate and further contacting it with organic or inorganic acid to give pure acid addition salt. In one of the embodiments such salts can be purified by crystallization from dimethylformamide and acetone mixtures.

In another aspect, the invention provides an improved process for the synthesis of tetrahydroisoquinoline compounds of formula IV or their acid addition salts.

(IV)
Wherein R1, R2, R3, R4, R5, R6, R7, R8, R9 and n are as defined above; R10 is selected from OR11, NHR11, NR12R13 where R11, R12 and R13 are independently hydrogen, optionally substituted -C1-10 alkyl, -C2-10 alkenyl, -C2-10 alkynyl, -C3-10 cycloalkyl, -C3-10 cycloalkenyl, -C5-10 cycloalkynyl, -C1-7 alkylphenyl, -phenyl, -phenylC1-7 alkyl, aryl, heteroaryl, heterocyclic or R12 and R13 along with N form an optionally substituted 3 to 7 member cyclic or benzocyclic ring which optionally includes additional 1 or 2 heteroatoms selected from O, N and S in the cyclic ring;

Comprising reacting compound of formula II,

(II)
Wherein, R1, R2, R3, R4, R5, R6, R7, R8, R9 and n are as defined above;
with compound of formula V,

(V)
Where R10 is as defined above, in presence of a base or a solvent.

The compound of formula II as used herein in the process of the present invention is a chiral molecule and thus the compounds of formula I and IV will have chirality in its structure and thus encompasses all the enantiomers and stereoisomers thereof.

The tetrahydroisoquinoline compounds of formula I and formula IV or its acid addition salts can be used as drugs or as intermediates for the synthesis of drugs such as but not limited to neuromuscular-blocking drugs or skeletal muscle relaxants.

Other aspects and embodiments will be apparent to those skilled in the art from the following detailed description.

As used in the present specification, the following words and phrases are generally intended to have the meaning as set forth below, except to the extent that the context in which they are used indicates otherwise.

A dash (“-“) that is not between two letters or symbols is used to indicate point of attachment of a substituent. For example, -C(O)OH is attached through carbon atom.

By “optional” or “optionally” is meant that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occur and instances in which it does not. For example, “optionally substituted alkyl” encompasses both “alkyl” and “substituted alkyl” such as but not limited to methyl, ethyl, isopropyl, 2-methylpropyl, neopentyl, 2-chloroethyl, 2-methoxyethyl, 2-nitropropyl, 3-acetyloxypropyl, 2-cyclobutylmethyl, etc. Also “optionally substituted -C1-10 alkyl, -C2-10 alkenyl, -C2-10 alkynyl” includes optionally substituted -C1-10 alkyl, optionally substituted -C2-10 alkenyl, optionally substituted -C2-10 alkynyl. It will be understood by those skilled in the art, with respect to any group containing one or more substituents, that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical, synthetically non-feasible and/or inherently unstable.

“Alkylene” encompasses: linear or branched bivalent saturated aliphatic radical of carbon atoms such as a methylene, 1,1- or 1,2- ethylene, 1,1- 1,2- or 1,3- propylene, 1,1- 1,2- 2,2- 1,3- or 1,4- butylene, methyl-1,3-propylene, 2,3- 2,4- or 1,5-pentylene, 1,6-hexylene or 1,6-heptylene group
“Alkyl” encompasses straight chain and branched chain having the indicated number of carbon atoms, usually from 1 to 20 carbon atoms, for example 1 to 8 carbon atoms, such as 1 to 6 carbon atoms. For example C1-6 alkyl encompasses both straight and branched chain alkyl or from 1 to 6 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, 3-methylpentyl, and the like. When an alkyl residue having a specific number of carbons is named, all branched and straight chain versions having that number of carbons are intended to be encompassed; thus, for example, “butyl” is meant to include n-butyl, sec-butyl, isobutyl and t-butyl; “propyl” includes n-propyl and isopropyl. “Lower alkyl” refers to alkyl groups having one to four carbons. Alkenyl is yet another subset of alkyl, referring to the same residues as alkyl, but having at least one carbon-carbon double bond. For example, ethenyl, 2-propenyl, 1-methylethenyl, etc. Alkynyl is yet another subset of alkyl, referring to the same residues as alkyl, but having at least one carbon-carbon triple bond. For example, 2-pentynyl, 3-pentynyl, etc.

By “alkylphenyl” is meant an group of formula (alkyl)(phenyl) attached through the alkyl carbon wherein the alkyl group has the indicated number of carbon atoms. Thus a C1-7 alkylphenyl is straight or branched alkyl group with 1 to 7 carbon atoms with a phenyl group substituted over it. For example, benzyl, 1-phenylethyl, 2-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, and the like.

By “phenylalkyl” is meant an group of formula (phenyl)(alkyl) attached through the phenyl ring carbon wherein the alkyl group has the indicated number of carbon atoms. Thus a phenylC1-7 alkyl is phenyl group with straight or branched alkyl group with 1 to 7 carbon atoms substituted over it. For example, 2-methylphenyl, 3-ethylphenyl, 4-ethylphenyl, 2-propylphenyl, 3-(2-propyl)phenyl, and the like.

“Cycloalkyl” encompasses a non-aromatic carbocyclic ring, usually having from 3 to 7 ring carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, as well as bridged and caged saturated ring groups such as norbornane.

“Cycloalkenyl” encompasses a non-aromatic carbocyclic ring, usually having from 4 to 7 ring carbon atoms and one or more carbon-carbon double bonds. Examples of cycloalkenyl groups include cyclopentenyl, cyclohexenyl, etc.

“Cycloalkynyl” encompasses a non-aromatic carbocyclic ring, usually having from 5 to 7 ring carbon atoms and one or more carbon-carbon triple bonds. Examples of cycloalkynyl groups include cyclohexynyl, cycloheptynyl, etc.

“Cyclic ring” encompasses: a non-aromatic carbocyclic ring, usually having from 3 to 7 ring carbon atoms which optionally includes at least one carbon-carbon double bonds or carbon-carbon triple bonds in the ring. For example, cyclopropyl, cyclobutyl, cyclopentenyl, cyclohexenyl, cyclohexynyl, cycloheptynyl, etc. For example, Cyclic ring includes non-aromatic carbocyclic ring fused to a aryl ring, heteroaryl ring or 5- to 7-membered heterocycloalkyl ring containing one or more heteroatoms selected from N, O and S. For such fused ring systems where in only one of the ring is cyclic ring the point of attachment is at the cyclic ring. “Cyclic ring” however does not encompass or overlap in any way with heterocyclic ring, separately defined below. Hence, if one or more heteroatom is included in the cyclic ring, the resulting ring system is heterocyclic ring, not cyclic, as defined herein.

“Aryl” encompasses: carbocyclic aromatic ring for example benzene; bicyclic ring systems such as carbocyclic and aromatic ring systems, for example, naphthalene, and azulene; tricyclic ring systems such as carbocyclic and aromatic ring systems, for example, anthracene, phenanthrene, etc. For example, aryl includes carbocyclic aromatic ring fused to a 5- to 7-membered heterocycloalkyl ring containing one or more heteroatoms selected from N, O and S. For such fused ring systems where in only one of the ring is carbocyclic aromatic ring the point of attachment is at the carbocyclic aromatic ring. “Aryl” however does not encompass or overlap in any way with heteroaryl, separately defined below. Hence, if one or more carbocyclic aromatic ring is fused with a heterocycloalkyl aromatic ring, the resulting ring system is heteroaryl, not aryl, as defined herein.

“Heteroaryl” encompasses: 5- to 7-membered aromatic, monocyclic rings containing one or more, for example, from 1 to 4, or in certain embodiments, from 1 to 3, heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon;
bicyclic heteroaryl rings containing one or more, for example, from 1 to 4, or in certain embodiments, from 1 to 3, heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon and wherein at least one heteroatom is present in an aromatic ring; and
tricyclic heteroaryl rings containing one or more, for example, from 1 to 5, or in certain embodiments, from 1 to 4, heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon and wherein at least one heteroatom is present in an aromatic ring.

For example, heteroaryl includes a 5- to 7-membered heterocycloalkyl, aromatic ring fused to a 5- to 7-membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring. For such fused, bicyclic heteroaryl ring systems wherein only one of the aromatic rings contains one or more heteroatoms, the point of attachment is at aryl or heteroaryl ring. When the total number of S and O atoms in the heteroaryl group exceeds one, those heteroatoms are not adjacent to one another.

“Fused rings” encompasses: bicyclic, tricyclic or polycyclic, aryl or heteroaryl rings where in two rings share a common C-C or C-N connecting bonds, for example, Naphthalene, Anthracene, Phenanthrene, benzofuran, benzothiophene, dibenzofuran, dibenzothiophene, and the like.

“Heterocyclic ring” encompasses: a non-aromatic carbocyclic ring, usually having from 3 to 7 ring atoms which includes one or more heteroatom included in the cyclic ring selected from N, O and S.

By “-Salkyl” is meant an alkyl group of the indicated number of carbon atoms attached through a sulfur bridge such as, for example, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, sec-butylthio, tert-butylthio, n-pentylthio, 2-pentylthio, isopentylthio, neopentylthio, hexylthio, 2-hexylthio, 3-hexylthio, 3-methylpentylthio, and the like. –SC1-7 alkyl groups will usually have from 1 to 7 carbon atoms attached through the sulfur bridge. “Lower -Salkyl” refers to alkylthio groups having one to four carbons.

By “-Salkylphenyl” is meant an alkylphenyl group of the indicated number of carbon atoms attached through a sulfur bridge such as, for example, benzylthio, 2-phenylethylthio, 2-phenylpropylthio, and the like. -SC1-7alkylphenyl groups are alkylthio groups which will usually have from 1 to 7 carbon atoms attached through the oxygen bridge and a phenyl ring substituted over it. For example, phenylmethylthio, 2-phenylethylthio, 1- phenylethylthio, and the like.
By “-SPhenyl” is meant a phenyl group is attached through a sulfur bridge, example, phenylthio.

By “-Sphenylalkyl” is meant a phenylalkyl group of the indicated number of carbon atoms in the alkyl group attached through a sulfur bridge such as, for example, 2-methylphenylthio, 2-ethylphenylthio, 4-ethylphenylthio, and the like.

The –SphenylC1-7 alkyl groups are phenylthio groups attached through the sulfur bridge and which will usually have alkyl group from 1 to 7 carbon atoms substituted over phenyl. For example, 2-methylphenylthio, 2-ethylphenylthio, 4-ethylphenylthio, and the like.

The present invention describes a convenient synthesis for preparation of tetrahydroisoquinoline compound of formula I or its acid addition salt and tetrahydroisoquinoline compound of formula IV or its acid addition salt with better yields and purity.

The following detailed description further illustrate the present invention but are not construed limiting in any manner to the scope of the invention as substantially described. The schematic representation for the synthesis of tetrahydroisoquinoline compound of formula I or its acid addition salt and tetrahydroisoquinoline compound of formula IV or its acid addition salt is given in Scheme I and Scheme II.

Reaction Scheme of tetrahydroisoquinoline compound of formula I or its acid addition salt is shown below in Scheme I.

Scheme 1

In accordance with the above scheme, the synthesis for preparation of tetrahydroisoquinoline compound of formula I or its acid addition salt comprising the steps of:
a) contacting compound of formula II with compound of formula III in presence of base or solvent to give tetrahydroisoquinoline compound of formula I;
b) contacting the tetrahydroisoquinoline compound of formula I with an acid in presence of solvent to give the corresponding acid addition salt;
c) purifying the acid addition salt by converting it into base using aqueous sodium bicarbonate and further contacting it with acid to give pure addition salt of tetrahydroisoquinoline compound of formula I or
d) optionally purifying the acid addition salt by crystallization from suitable solvents or mixtures thereof or by slurrying or repulping the acid addition salt from suitable solvents or mixtures thereof.

According to the process of the present invention the compound of formula II and compound of formula III may be employed in the ratio of 2:1 to 3.5: 1, more preferably in the ratio of 2.2: 1 to 3:1 and most preferably in the ratio of 2.4: 1 to 2.75:1.

Various solvents with different constitution may be used which are process specific and product specific. The process of condensation of compound of formula II and compound of formula III may be facilitated by the use of diverse group of solvents with or without heteroatom present in the molecular formula. The solvents used for the above process are selected from but not limited to dimethylformamide, acetonitrile, dimethylsulfoxide, dioxane and tetrahydrofuran either alone or a mixture thereof.

The present invention provides use of a base in condensation of compound of formula II with compound of formula III. The base may be optionally used to enhance process of condensation thereby reducing the time required for the completion of the process or eliminate the formation of undesired products. The base used in the present invention is selected from organic or inorganic base. The organic bases are selected from but not limited to N-methylmorpholine, triethylamine, diisopropylethylamine, N-methylpiperidine and N-methylpyrrolidine either alone or a mixture thereof. The most preferred organic bases which can be advantageously used are selected from N-methylmorpholine, triethylamine and diisopropylethylamine either alone or a mixture thereof. The inorganic bases are selected from but are not limited to sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate and lithium carbonate either alone or a mixture thereof. The most preferred inorganic bases which can be advantageously used are selected from sodium bicarbonate, potassium bicarbonate and sodium carbonate either alone or a mixture thereof. After complete formation of tetrahydroisoquinoline compound of formula I, it can be isolated in the form of oil or solid or semisolid by any of the generalized workup procedures.

The tetrahydroisoquinoline compound of formula I can be optionally purified. The purification of tetrahydroisoquinoline compound of formula I may involve dissolving the compound in a solvent in which it possess high solubility and then precipitating using a solvent in which it possess low or no solubility. The generally used solvents with high solubility of tetrahydroisoquinoline compound of formula I are selected from but are not limited to methylene chloride, chloroform, ethyl acetate, dichloroethane, methanol, isopropyl alcohol, acetonitrile, acetone, 2-butanone and tetrahydrofuran either alone or a mixture thereof. The generally used solvents with low or no solubility of tetrahydroisoquinoline compound of formula I are selected from but are not limited to n-hexane, cyclohexane, heptane, isopropylether, benzene and toluene either alone or a mixture thereof.

Yet another and most preferred method for purification of tetrahydroisoquinoline compound of formula I which comprises contacting the base with a suitable acid in presence of solvent to give its acid addition salt. The acid used for the process is selected from the group of organic or inorganic acid. The organic acids are selected from but are not limited to oxalic acid, succinic acid, adipic acid, acetic acid, benzoic acid, citric acid, p-toluenesulfonic acid and trifluoroacetic acid either alone or a mixture thereof. The preferred organic acids are oxalic acid, succinic acid, citric acid and p-toluenesulfonic acid either alone or a mixture thereof. The inorganic acids are selected from but are not limited to hydrochloric acid, sulphuric acid, phosphoric acid, phosphinic acid and nitric acid either alone or a mixture thereof. The preferred inorganic acids are hydrochloric acid and sulphuric acid either alone or a mixture thereof. The most preferred acids are oxalic acid and citric acid. The solvents used for the preparation of acid addition salt are selected from polar or non-polar solvent either alone or a mixture thereof. The polar solvents are selected from but are not limited to acetone, 2-butanone, acetonitrile, methanol, ethanol, dimethylformamide, dimethylsulfoxide, sulfolane, hexamethylphosphoramide and isopropanol either alone or a mixture thereof. The non-polar solvents are selected from but are not limited to toluene, benzene, diethyl ether, tetrahydrofuran, heptanes, hexane and cyclohexane either alone or a mixture thereof. The most preferred solvent is selected from polar solvent. The most preferred solvents are acetone and acetonitrile.

The acid addition salt of tetrahydroisoquinoline compound of formula I thus obtained can be optionally purified to give the pure acid addition salt. Purification of such addition salt is carried out by converting it into its free base using an organic or inorganic base and further contacting it with an acid in a suitable solvent to give pure desired acid addition salt. The organic base is selected from but not limited to methylamine, diethylamine, N-methylmorpholine, triethylamine, diisopropylethylamine, N-methylpiperidine and N-methylpyrrolidine either alone or a mixture thereof. The most preferred organic base which can be advantageously used is selected from methylamine, diethylamine, and triethylamine either alone or a mixture thereof. The inorganic base is selected from but are not limited to sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate and lithium carbonate either alone or a mixture thereof. The most preferred inorganic base which can be advantageously used is selected from sodium bicarbonate, potassium bicarbonate and sodium carbonate either alone or a mixture thereof. The solvents and acids used for re-conversion of tetrahydroisoquinoline compound of formula I into desired acid addition salts are as mentioned above. Acid addition salt can also be purified by crystallization from suitable solvents or mixtures thereof. The solvents used for the crystallization of such acid addition salts are selected from but not limited to dimethylformamide, acetonitrile, acetone, 2-butanone methanol, ethanol and isopropanol either alone or a mixture thereof. These salts are also purified by stirring or repulping in any solvent preferably polar protic or aprotic solvent either alone or a mixture thereof. One of the methods involve dissolving acid addition salts in known quantity of dimethylformamide, adding known quantity of acetone to the mixture at elevated temperature and cooling the mixture at lower temperatures to give pure acid addition salts.

Reaction Scheme for the preparation of tetrahydroisoquinoline compounds of formula IV or their acid addition salts is show below.
Scheme II

In accordance with the above scheme II, the synthesis for preparation of tetrahydroisoquinoline compounds IV or its acid addition salt comprising the steps of:
a) contacting compound of formula II with compound of formula V in presence of base or solvent to give tetrahydroisoquinoline compounds of formula IV;
b) contacting tetrahydroisoquinoline compounds of formula IV with an acid in presence of solvent to give corresponding acid addition salt;
c) optionally purifying the acid addition salt of tetrahydroisoquinoline compounds IV by crystallization from suitable solvents or mixtures thereof or by slurrying or repulping the acid addition salt of tetrahydroisoquinoline compounds IV from suitable solvents or mixtures thereof.

According to the process of the present invention the compound of formula II and compound of formula V may be employed in the ratio of 1:1 to 1:5, more preferably in the ratio of 1:1.5 to 1:4 and most preferably in the ratio of 1:1.75 to 1:2.5.

Various solvents with different constitution may be used which are process specific and product specific. The process of condensation of compound of formula II with compound of formula V may be facilitated by the use of diverse group of solvents with or without heteroatom present in the molecular formula. The solvents used for the above process are selected from but not limited to dimethylformamide, acetonitrile, dimethylsulfoxide, dioxane and tetrahydrofuran either alone or a mixture thereof.

The present invention provides use of base in condensation of compound of formula II with compound of formula III. The base may be optionally used to enhance process of condensation thereby reducing the time required for the completion of the process or eliminate the formation of undesired products. The base used in the present invention is selected from organic or inorganic base. The organic bases are selected from but not limited to N-methylmorpholine, triethylamine, diisopropylethylamine, N-methylpiperidine and N-methylpyrrolidine either alone or a mixture thereof. The most preferred organic bases which can be advantageously used are selected from N-methylmorpholine, triethylamine and diisopropylethylamine either alone or a mixture thereof. The inorganic bases are selected from but are not limited to sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate and lithium carbonate either alone or a mixture thereof. The most preferred inorganic bases which can be advantageously used are selected from sodium bicarbonate, potassium bicarbonate and sodium carbonate either alone or a mixture thereof. After complete formation of tetrahydroisoquinoline compounds of formula IV, it can be isolated in the form of oil or solid by any of the generalized workup procedures.

The tetrahydroisoquinoline compounds of formula IV can be optionally purified to give the pure tetrahydroisoquinoline compounds of formula IV or can be used directly for further steps involved for the formation of neuromuscular-blocking drug or skeletal muscle relaxant. The purification of tetrahydroisoquinoline compounds of formula IV may involve dissolving the base in solvent in which it possess high solubility and then precipitating using solvent in which it possess low or no solubility. The solvents with high solubility of tetrahydroisoquinoline compounds of formula IV are selected from but are not limited to methylene chloride, chloroform, ethyl acetate, dichloroethane, methanol, isopropyl alcohol, acetonitrile, acetone, 2-butanone and tetrahydrofuran either alone or a mixture thereof. The solvent with low or no solubility of tetrahydroisoquinoline compounds of formula IV are selected from but are not limited to n-hexane, cyclohexane, heptane, isopropylether, benzene and toluene used either alone or a mixture thereof.

Yet another and most preferred method for purification of tetrahydroisoquinoline compounds of formula IV is by contacting the free base of tetrahydroisoquinoline compounds of formula IV with a suitable acid in presence of solvent to give its acid addition salt. The acid used for the process is selected from the group of organic or inorganic acid. The organic acids are selected from but are not limited to oxalic acid, succinic acid, adipic acid, acetic acid, benzoic acid, citric acid, p-toluenesulfonic acid and trifluoroacetic acid either alone or a mixture thereof. The preferred organic acids are oxalic acid, succinic acid, citric acid and p-toluenesulfonic acid used either alone or a mixture thereof. The inorganic acids are selected from but are not limited to hydrochloric acid, sulphuric acid, phosphoric acid, phosphinic acid and nitric acid used either alone or a mixture thereof. The preferred inorganic acids are hydrochloric acid and sulphuric acid either alone or a mixture thereof. The most preferred acids are oxalic acid and citric acid. The solvent used for the preparation of acid addition salt of tetrahydroisoquinoline compounds of formula IV are selected from polar or non-polar solvent either alone or a mixture thereof. The polar solvents are selected from but are not limited to acetone, 2-butanone, acetonitrile, methanol, ethanol, dimethylformamide, dimethylsulfoxide, sulfolane, hexamethylphosphoramide and isopropanol either alone or a mixture thereof. The non-polar solvents are selected from but are not limited to toluene, benzene, diethyl ether, tetrahydrofuran, heptanes, hexane and cyclohexane either alone or a mixture thereof. The most preferred solvent is selected from polar solvent. The most preferred solvents are acetone and acetonitrile.

The acid addition salt of tetrahydroisoquinoline compounds of formula IV can be optionally purified to give the pure acid addition salt of tetrahydroisoquinoline compounds of formula IV. Purification of acid addition salt of tetrahydroisoquinoline compounds of formula IV is carried out by converting it into tetrahydroisoquinoline compounds of formula IV using a base and further contacting it with an acid in a suitable solvent to give the corresponding pure acid addition salt of tetrahydroisoquinoline compounds of formula IV. The base used in the present invention is selected from organic or inorganic base. The organic bases are selected from but not limited to methylamine, diethylamine, N-methylmorpholine, triethylamine, diisopropylethylamine, N-methylpiperidine and N-methylpyrrolidine either alone or a mixture thereof. The most preferred organic bases which can be advantageously used are selected from methylamine, diethylamine, and triethylamine either alone or a mixture thereof. The inorganic bases are selected from but are not limited to sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate and lithium carbonate either alone or a mixture thereof. The most preferred inorganic bases which can be advantageously used are selected from sodium bicarbonate, potassium bicarbonate and sodium carbonate either alone or a mixture thereof. The solvents and acids used for re-conversion of tetrahydroisoquinoline compounds of formula IV into acid addition salt are as mentioned above. The acid addition salt of tetrahydroisoquinoline compounds of formula IV can also be purified by crystallization from suitable solvents or mixtures thereof. The solvents used for the crystallization of acid addition salts of tetrahydroisoquinoline compounds of formula IV are selected from but not limited to dimethylformamide, acetonitrile, acetone, 2-butanone, methanol, ethanol and isopropanol either alone or a mixture thereof. The acid addition salts of tetrahydroisoquinoline compounds of formula IV can also be purified by stirring or repulping in any solvent preferably polar protic or aprotic solvent either alone or a mixture thereof. One of the methods involve dissolving acid addition salts in known quantity of dimethylformamide, adding known quantity of acetone to the mixture at elevated temperature and cooling the mixture at lower temperatures to give pure acid addition salts of tetrahydroisoquinoline compounds of formula IV.

The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.

Example 1
Preparation of pentamethylene bis(1-(3,4-dimethoxybenzyl)-3,4-dihydro-6,7-dimethoxy-1H-isoquinoline-2-propionate) dioxalate
To a solution of 30.0 gms (0.105 mol) of pentane-1,5-diyl bis(3-chloropropanoate) in dimethyl formamide (60 ml) was added tetrahydropapaverine (90.14 gm, 0.263 mol) and N-methylmorpholine (37.02 gm, 0.316 mol). The reaction mixture was heated to 62-65 °C and stirred at same temperature for 48 hours. After completion of reaction on HPLC, it was quenched over water (400 ml) and extracted with dichloromethane (400 ml x 2 times). The organic layers were dried on Sodium Sulphate then evaporated under reduced pressure for complete removal of dichloromethane to yield 130 gms of a syrupy residue. The syrupy residue was dissolved in acetone (800 ml) then oxalic acid dihydrate (33 gm) was added to it. The solid compound thus obtained was collected by filtration to give 106 gm of off white solid. It was further crystallized from dimethylformamide and acetone mixture 600 ml (2:10) to afford 91 gm pure pentamethylene bis(1-(3,4-dimethoxybenzyl)-3,4-dihydro-6,7-dimethoxy-1H-isoquinoline-2-propionate) dioxalate.
HPLC Purity: 97.5 %.

Example 2
Preparation of pentamethylene bis(1-(3,4-dimethoxybenzyl)-3,4-dihydro-6,7-dimethoxy-1H-isoquinoline-2-propionate) dioxalate
To a solution of 30.0 gms (0.105 mol) of pentane-1,5-diyl bis(3-chloropropanoate) in acetonitrile (60 ml) was added tetrahydropapaverine (90.14 gm, 0.263 mol) and N-methylmorpholine (37.02 gm, 0.316 mol). The reaction mixture was heated to 62-65 °C and stirred at same temperature for 48 hours. After completion of reaction on HPLC, it was quenched over water (400 ml) and extracted with dichloromethane (400 ml x 2 times). The organic layers were dried on sodium sulphate then evaporated under reduced pressure for complete removal of dichloromethane to yield 130gms of a syrupy residue. The syrupy residue was dissolved in acetone (800 ml) then oxalic acid dihydrate (33 gm) was added to it. The solid compound thus obtained was collected by filtration to give 110 gm of off white solid. It was further purified by converting in to pentamethylene bis(1-(3,4-dimethoxybenzyl)-3,4-dihydro-6,7-dimethoxy-1H-isoquinoline-2-propionate) and treatment of the base thus obtained with oxalic acid in acetone to afford 88 gm pure pentamethylene bis(1-(3,4-dimethoxybenzyl)-3,4-dihydro-6,7-dimethoxy-1H-isoquinoline-2-propionate) dioxalate.
HPLC Purity : 98.9 %
Example 3
Preparation of pentamethylene bis(1-(3,4-dimethoxybenzyl)-3,4-dihydro-6,7-dimethoxy-1H-isoquinoline-2-propionate) dioxalate
To a solution of 30.0 gms (0.105 mol) of pentane-1,5-diyl bis(3-chloropropanoate) in dimethylformamide (60 ml) was added tetrahydropapaverine (90.14 gm, 0.263 mol) and diisopropylethylamine (40.8 gm, 0.316 mol). The reaction mixture was heated to 62-65 °C and stirred at same temperature for 48 hours. After completion of reaction on HPLC, it was quenched over water (400 ml) and extracted with dichloromethane (400 ml x 2 times). The organic layers were dried on Sodium Sulphate then evaporated under reduced pressure for complete removal of dichloromethane to yield 140gms of a syrupy residue. The syrupy residue thus obtained was dissolved in acetone (800 ml) then oxalic acid dihydrate (33 gm) was added to it. The solid compound thus obtained was collected by filtration to give 120 gm of off white solid. It was further purified by converting in to pentamethylene bis(1-(3,4-dimethoxybenzyl)-3,4-dihydro-6,7-dimethoxy-1H-isoquinoline-2-propionate) and treatment of the base thus obtained with oxalic acid in acetone to afford 101 gm pure pentamethylene bis(1-(3,4-dimethoxybenzyl)-3,4-dihydro-6,7-dimethoxy-1H-isoquinoline-2-propionate) dioxalate.
HPLC Purity : 96.2 %

Example 4
Preparation of pentamethylene bis(1-(3,4-dimethoxybenzyl)-3,4-dihydro-6,7-dimethoxy-1H-isoquinoline-2-propionate) dioxalate
To a solution of 30.0 gms (0.105 mol) of pentane-1,5-diyl bis(3-chloropropanoate) in acetonitrile (60 ml) was added tetrahydropapaverine (90.14 gm, 0.263 mol) and diisopropylethylamine (40.8 gm, 0.316 mol). The reaction mixture was heated to 62-65 °C and stirred at same temperature for 48 hours. After completion of reaction on HPLC, it was quenched over water (400 ml) and extracted with dichloromethane (400 ml x 2 times). The organic layers were dried on Sodium Sulphate then evaporated under reduced pressure for complete removal of dichloromethane to yield 135gms of a syrupy residue. The syrupy residue was dissolved in acetone (800 ml) then oxalic acid dihydrate (33 gm) was added to it. The solid compound thus obtained was collected by filtration to give 126 gm of off white solid. It was further crystallized from dimethylformamide and acetone mixture 600 ml (2:10) to afford 98.4 gm pure pentamethylene bis(1-(3,4-dimethoxybenzyl)-3,4-dihydro-6,7-dimethoxy-1H-isoquinoline-2-propionate) dioxalate.
HPLC Purity: 97.0 %

Example 5
Preparation of methyl 3-[1-(3,4-Dimethoxybenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl]propanoate
To a solution of 34.3 gms (0.10 mol) of tetrahydropapaverine and methyl 3-chloropropanoate (20.85 gm, 0.20 mol) in acetonitrile (150 ml) was added triethylamine (20.2 gm, 0.20 mol). The reaction mixture was heated to 60-65 °C and stirred at same temperature for 8 hours. After completion of reaction on TLC, it was quenched over water (500 ml) and extracted with dichloromethane (250 ml x 2 times). The organic layers were dried on Sodium Sulphate then evaporated under reduced pressure for complete removal of dichloromethane to yield 42 gms of a syrupy residue. The syrupy residue was dissolved in 200 ml of acetone and 15 gms (0.116 mol) of oxalic acid dihydrate was added to it. The reaction mixture was stirred for 2 hours, then cooled to 0 – 5 ?C. Stirring was continued for further 3 hours and the product precipitated was collected by filtration, washed with chilled acetone to afford 46 gms of pure oxalate salt of methyl 3-[1-(3,4-Dimethoxybenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl]propanoate. The oxalate salt was taken in water, to that was added sodium bicarbonate to make a pH of up to 7 – 8. The mixture was extracted twice with 50 ml MDC. The combined organic layers were then washed with 50 ml brine, dried over sodium sulfate and concentrated to dryness to give pure methyl 3-[1-(3,4-Dimethoxybenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl]propanoate.
Yield :37.8 gms (89.1%).
IR (KBr):- 3058.0, 2949.7, 2834.9, 1735.8, 1609.2, 1590.6, 1515.9, 1418.2, 1263.8, 1029.6, 860.6 CM-1.

Example 6
Preparation of isopropyl 3-[1-(3,4-Dimethoxybenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl]propanoate
Similarly according to Example 5 was prepared isopropyl 3-[1-(3,4-Dimethoxybenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl]propanoate from tetrahydropapaverine (9.0 gms, 0.026 mol) and isopropyl 3-chloropropanoate (7.8 gm, 0.052 mol) in acetonitrile (50 ml) and triethylamine (5.05 gm, 0.05 mol).
Yield of product is 10.2 gms (85.8%).
IR (KBr):- 3057.7, 2936.9, 2833.8, 1726.1, 1608.9, 1590.2, 1515.2, 1417.2, 1263.2, 1029.5, 860.9 CM-1.

Example 7
Preparation of N,N-diethyl-3-[1-(3,4-Dimethoxybenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl]propanamide
Similarly according to Example 5 was prepared N,N-diethyl-3-[1-(3,4-Dimethoxybenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl]propanamide from tetrahydropapaverine (9.0 gms, 0.026 mol) and 3-chloro-N,N-diethylpropanamide (8.5 gm, 0.052 mol) in acetonitrile (50 ml) and triethylamine (5.05 gm, 0.05 mol).
Yield of product is 9.7 gms (79.4%).
IR (KBr):- 3055.0, 2934.5, 2835.1, 1696.3, 1634.5, 1463.9, 1380.0, 1264.0, 805.9 CM-1.

Example 8
Preparation of compound N,N-dibenzyl-3-[1-(3,4-Dimethoxybenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl]propanamide
Similarly according to Example 5 was prepared N,N-dibenzyl-3-[1-(3,4-Dimethoxybenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl]propanamide from tetrahydropapaverine (9.0 gms, 0.026 mol) and 3-chloro-N,N-dibenzylpropanamide (15 gm, 0.052 mol) in acetonitrile (50 ml) was added triethylamine (5.05 gm, 0.05 mol). Yield of product is 12.5 gms (80.9%). IR (KBr):- 3059.3, 2998.6, 2835.3, 1643.3, 1589.9, 1515.3, 1464.08, 1263.9, 1028.8, 860.5 CM-1.