"A PROCESS FOR THE PREPARATION OF 6-ISOPROPYLISOQUINOLINE"
FIELD OF THE INVENTION:
The present invention provides commercially and industrial applicable process for the preparation of 6-isopropylisoquinoline of formula (I).
BACKGROUND OF THE INVENTION:
U.S.Pat.No.7989461 discloses process for the preparation of analogously 6-isopropylisoquinoline formula(XI), which comprising condensation of formula (VII) with 2, 2-dimethoxyethanamine in presence of toluene and water to get formula (VIII) and which is reduction with sodiumborohydride in presence of methanol to get formula (XIV) which is tosylation with p-toluenesulfonyl chloride in presence of triethylamine and dichloromethane to get formula (X) which is cyclization with sulfuric acid to get formula (XI). The above synthetic process is illustrated as per the following Scheme-I:

However, the above said process analogously 6-isopropylisoquinoline formula (XI) disclosed. The present invention discloses a process for the preparation of 6-isopropylisoquinoline formula (I) by providing a simple, cost effective with high purity and good yield on industrial applicable process.
SUMMARY OF THE INVENTION
The present invention provides a process for the preparation of 6-isopropylisoquinoline of formula I.
t ormuia-i
by comprising the steps of:
a. condensation of formula (II) with 2,2-dimethoxyethanamine in presence of p-toluenesulfonic acid and non-polar solvent to produce formula of (III),
reduction of formula (III) with reducing agent in presence of alcoholic solvent to produce formula (IV),
tosylation of formula (IV) with p-toluenesulfonyl chloride in presence of alkyl amine and polar aprotic solvent to produce formula (V),

DETAILEDDESCRIPTION OF THE INVENTION
The present invention provides a process for the preparation of 6-isopropylisoquinoline of formula (I). The present invention is also provides commercially and industrial applicable process for the preparation of formula (I).
In one aspect of the present invention provides a process for the preparation of 6-isopropylisoquinoline of formula (I),
by comprising the steps of:
a. condensation of formula (II) with 2,2-dimethoxyethanamine in presence of p-toluenesulfonic acid and non-polar solvent to produce formula of (III),

b. reduction of formula (III) with reducing agent in presence of alcoholic solvent to produce formula (IV),
I
c. tosylation of formula (IV) with p-toluenesulfonyl chloride in presence of alkyl amine and polar aprotic solvent to produce formula (V),
d. cyclization of formula (V) with sulfuric acid and butyrate hydroxytoluene and further treated with p-toluenesulfonic acid in presence of polar aprotic solvent to produce formula (I).
According to embodiment of the present invention, the reaction of the compound of formula (II) with 2, 2-dimethoxyethanamine in presence of p-toluenesulfonic acid and nonpolar solvent to obtain the compound of the formula (III), further it was reduced by

using reducing agent in presence of alcoholic solvent to obtain the compound of the formula (IV)
The compound of formula (IV) is treated with p-toluenesulfonic chloride in presence of alkyl amine and polar aprotic solvent to obtain compound of the formula (V), followed by treatment with sulfuric acid and butyrate hydroxytoluene in presence of polar aprotic solvent to obtain crude compound of the formula (I).
In an embodiment of the present invention, the reaction of the compound of formula (II) with the 2, 2-dimethoxyethanamine to obtain the compound of the formula (III) is carried out temperature of about 100°C-130°C for 1-2 hours; the reaction of the compound of formula (III) with reducing agent to obtain the compound of the formula (IV) is carried out at a temperature of about 20°C-40°C for 3-4 hours
In an embodiment of the present invention, the compound of formula (IV) with p-toluenesulfonic chloride to obtained compound of the formula (V)is carried out at a temperature of about 20°C-40°C for 3-4 hours; the compound of formula (V) with sulfuric acid and butyrated hydroxytoluene to obtain crude compound of the formula (I) is carried out at a temperature 20-3 5°C for 10-13 hours and further the pH of reaction mixture was adjusted to 9-9.5 with ammonia solution.
The compound of the formula (I) may be isolated by filtration, decantation, extraction, distillation, evaporation, precipitation, concentration, crystallization, centrifugation, or recrystallization. The compound of the formula (I) may be dried using conventional techniques for example, drying, drying under vacuum, spray drying, air dring, or agitated thin film drying.
According to the embodiment of the present invention, the non-polar solvent is select from the group consisting of toluene, hexane, cyclohexane, benzene, chloroform and diethyl ether or mixture thereof; the reducing reagent is selected form the group consisting of sodiumborohydride, sodium cyanoborohydride, sodium dithionite, sodium hydrogensulfite, sodium hydrosulfite, sodium hydroxymethanesulfinate, sodium tetrahydroborate, sodium triacetoxyborohydride, potassium borohydride, potassium iodide, potassium tetrahydroborate; the alcoholic solvent is selected from the group consisting of methanol, ethanol and isopropanol or mixture thereof; the alkyl

amine is selected form the group consisting of methylamine, ethylamine, n-propylamine, isopropyl amine and butylamine;the polar aprotic solvent selected form the group consisting of dichloromethane, tetrahydrofuran, ethyl acetate, acetonitrile, acetone, dimethylformamide, dimethylsulfoxide or mixture thereof.
The crude compound of formula (I) is further purified by treating with p-toluenesulfonic acid in presence of polar aprotic solvent at 20-40°C for about 1 hr to 3 hr; the obtain mixture was adjust pH at 9 to 9.5 with sodium hydroxide solution at 15-25°C, allow to raise the temperature 20-30°C and stir for 1-2 hrs. The resultant product was filtered and dried under reduced pressure at 40-45° C at 15-22 hrs to get pure 6-isopropylisoquinoline.
The process details of the invention are provided in the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.

EXPERIMENTAL PROCEDURE: Example-1:
Preparation of (E)-N-(4-isopropylbenzylidene)-2, 2-dimethoxyethanamine
A mixture of 4-isopropylbenzaldehyde (lOOgm, 0.67 moles),2,2-dimethoxyethanamine (70.9gm, 0.67 moles),and p-toluenesulfonic acid (lgm, 0.005 moles) in toluene (300 ml)were added to round bottom flask. The mixture was gradually heated to 110-115°C and stirred for 1 hr at same temperature, if the reaction complies (checked by TLC).
The reaction mixture was cooled to 25-30°C, added 5% solution of sodium
bicarbonate (200ml) and it was stirred for 30 minutes at 20-25°Cto separate layers.
The separated organic layer was washed with water and then concentrated under
reduced pressure to produce (E)-N-(4-isopropylbenzylidene)-2,2-
dimethoxyethanamine (Yield: 90%)
^-NMR (400 MHz, CDC13) 5 7.2(s, ID), 7.260-7.278(d, 1H), 7.659-7.679(d, 1H), 2.918-2.952(m, 1H), 1.250-1.278(d, 3H), 8.261(s, CH(imine)), 3.756-3771(d of d, N-CH2), 4.654-4.681(t, 1H), 3.418(s, 3H).
Example-2:
Preparation of N-(4-isopropylbenzyl)-2, 2-dimethoxyethanamine
(E)-N-(4-isopropylbenzylidene)-2,2-dimethoxyethanamine (lOOgm, 0.42 moles) was dissolved in methanol (350 ml)at room temperature and then slowly cooled to 0-5°C.Sodiumborohydride (16gm, 0.42 moles) was added portion wise to the reaction mass at 0-10°C and allow to stir at 25-30°C for 3 hrs, till completion of reaction. The reaction mixture was quenched with saturated sodium bicarbonate solution (500ml) and it was extracted with toluene (100 ml). The organic layer was washed with water (500 ml) and concentrated to get yellow oil of N-(4-isopropylbenzyl)-2, 2-dimethoxyethanamine (Yield: 95%)
^-NMR (400 MHz, CDCI3) 5 7.2(s, ID), 7.228-7.248(d, 1H), 7.171-7.191(d, 1H), 2.855-2.925(m, 1H), 1.23l-1.248(d, 3H), 3.773(s, N-CH2), 2.746-2.760(d, N-CH2), 4.475_4.503(t, 1H), 3.376(s, O-CH3).

Example-3:
Preparation of N-(2, 2-dimethoxyethyl)-N-(4-isopropylbenzyl)-4-
methylbenzenesulfonamide
A solution of N-(4-isopropylbenzyl)-2,2-dimethoxyethanamine (lOOgm, 0.42 moles) and triethyl amine (51.16gm, 0.50 moles) were suspended in dichloromethane (400 ml) at 25-30°and allow to cool at 0-5°C, followed by portion wise addition of P-toluenesulfonyl chloride (84.34gm, 1.05 moles). The reaction mixture temperature was raised to 25-30°C and stir for 3 hrs, further added diluted with water (200 ml) to separate the layers. The separated organic layer was washed with IN sodium hydroxide solution (200 ml) and water (200 ml), and then organic layer was concentrated to get N-(2, 2-dimethoxyethyl)-N-(4-isopropylbenzyl)-4-methyl benzene sulfonamide (Yield: 91%).
^-NMR (400 MHz, CDC13) 5 7.2 (s, ID), 7.092-7.138(d, 1H), 2.832-2.901(m, 1H), 1.209-1.226(d, 3H), 4.431(s, N-CH2), 3.213(d, N-CH2), 4.319-4.346(t, 1H), 3.227-3.236(s, O-CH3), 7.279-7.299(d. 1H), 7.706-7.726(d, 1H), 2.43l(s, 3H).
Example-4:
Preparation of 6-isopropylisoquinoline
A solution of butylated hydroxytoluene (0.56gm, 0.002 moles) and sulfuric acid (500 ml)was cooled to 5-10°C, further added drop wise addition of N-(2,2-dimethoxyethyl)-N-(4-isopropylbenzyl)-4-methylbenzenesulfonamide (lOOgm, 0.25 moles) at same temperature. The reaction mass temperature was slowly raised to 20-25°C and stir for 12 hr at the same temperature, further it was cooled to 10-15°C. The reaction mixture pH was adjusted to 9 to 9.5 with ammonia solution and then extracted with dichloromethane (1000 ml). The organic layer was washed with water and concentrated to get crude product.
The obtained crude product was suspended in a solution of p-toluenesufonic acid monohydrate (48.58g, 0.25 moles) in acetone (100 ml) at 25-30°C. The reaction mass was stirred for 2 hrs at 25-30°C and the obtain solid was filtered. The resultant wet solid was dissolved in water (500 ml) and pH of the reaction mixture was adjusted to 9 to 9.5 with 10% sodium hydroxide solution, the resultant mixture was stirred for 2

hr at 25-30°C. The resultant solid was filtered and dried at 30-35°C for 12hrto get pure 6-isopropylisoquinoline (Yield: 50%)
^-NMR (400 MHz, CDCI3) 5 7.2(s, ID) 9.193 (s, 1H), 7.893-7.914(d, 1H), 7.503-7.527(d, 1H), 7.2261(s, 1H), 7.503-7.527(d, 1H), 8.476-8.490(d, 1H), 3.071-3.140(m, 1H), 1.345-1.362(d, 3H).

1. A process for the preparation of 6-isopropylisoquinoline of formula I,
Formula-I
by comprising the steps of:
a. condensation of formula (II) with 2,2-dimethoxyethanamine in presence of p-
toluenesulfonic acid and non polar solvent to produce formula of (III),
L. Ji H p-Toluenesulfonicacid T || i
ai) cm)
b. reduction of formula (III) with reducing agent in presence of alcoholic solvent to
produce formula (IV),
»T I Reducing agent T i] „ V
an) (IV)
c. tosylation of formula (IV) with p-toluenesulfonyl chloride in presence of alkyl
amine and polar aprotic solvent to produce formula (V),
/\^\ O^ p-Toluene sulfonyl /\^^v. Q_^_Q Q/
I H I chloride I l] ' I
(IV) (V)
d. cyclization of formula (V) with sulfuric acid and butyrate hydroxytoluene and
further treated with p-toluenesulfonic acid in presence of polar aprotic solvent to
produce formula (I).

2. The process as claimed in claim 1, wherein the reducing agent is selected from sodiumborohydride, sodium cyanoborohydride, sodium dithionite, sodiumhydrogensulfite, sodium hydrosulfite, sodium hydroxymethanesulfinate, sodium tetrahydroborate, sodium triacetoxyborohydride, potassium borohydride, potassium iodide, potassium tetrahydroborate.
3. The process as claimed in claim 1, wherein the alcoholic solvent is selected from the group consisting of methanol, ethanol, isopropanol, and non polar solvent is selected form toluene, hexane, cyclohexane, benzene, chloroform and diethyl ether and polar aprotic solvent is selected form dicloromethane , tetrahydrofuran, ethyl acetate, acetonitrile, acetone, dimethylformamide, dimethylsulfoxide or mixture thereof.
4. The process as claimed in claim 1, wherein the alkyl amine is selected form the group consisting of methylamine, ethylamine, n-propylamine, isopropyl amine and butylamine.