DESC:FIELD OF THE INVENTION
The present invention relates to novel phase-transfer catalyst (R)-1-((R)-hydroxy(phenyl)methyl)-5-azaspiro[4.4]nonan-5-ium bromide having the following formula PTC-A,

and novel phase-transfer catalyst (R)-1-((R)-hydroxy(phenyl)methyl)-5-azaspiro[4.5]decan-5-ium bromide having the following formula PTC-B ,

Further, the present invention relates to a process for the preparation of novel phase-transfer catalyst PTC-A or novel phase-transfer catalyst PTC-B.

Further, the present invention also relates to novel process for the preparation of pharmaceutical compounds or its intermediates thereof involves specific selective alkylation by using novel phase transfer catalyst (R)-1-((R)-hydroxy(phenyl)methyl)-5-azaspiro[4.4]nonan-5-ium bromide (PTC-A) or (R)-1-((R)-hydroxy(phenyl)methyl)-5-azaspiro[4.5]decan-5-ium bromide (PTC-B).

BACKGROUND OF THE INVENTION
Phase-transfer catalyst (PTC) is a catalyst that facilitates the migration of a reactant from one phase into another phase where reaction occurs. Phase-transfer catalysis is a special form of heterogeneous catalysis. Ionic reactants are often soluble in an aqueous phase but insoluble in an organic phase in the absence of the phase-transfer catalyst. The catalyst functions like a detergent for solubilizing the salts into the organic phase. Phase-transfer catalysis refers to the acceleration of the reaction upon the addition of the phase-transfer catalyst.

By using a Phase-transfer catalyst, one can achieve faster reactions, like specific selective alkylation obtain higher conversions or its specific isomer yields, make fewer byproducts, eliminate the need for expensive or dangerous solvents that will dissolve all the reactants in one phase, eliminate the need for expensive raw materials and/or minimize waste problems. Phase-transfer catalysts for anionic reactants are often quaternary ammonium salts. Commercially important catalysts include benzyltrimethylammonium chloride, benzyltriethylammonium chloride, methyltricaprylammonium chloride, methyltributylammonium chloride, and methyltrioctylammonium chloride. Organic phosphonium salts are also used like hexadecyltributylphosphonium bromide.

The discovery of new Phase-transfer catalyst is very useful to provide a new opportunity to improve the performance characteristics of a final pharmaceutical product. It enlarges the repertoire of materials that a scientist has available for designing, for example, a pharmaceutical active pharma ingredient with a targeted desired characteristics of purity and good yield.
Hence, there is a significant need in the art to develop novel Phase-transfer catalyst which are stable and also improves specific selective alkylation of a pharmaceutical intermediates or its final product thereof.

SUMMARY OF THE INVENTION
The present invention relates to novel phase-transfer catalyst (R)-1-((R)-hydroxy(phenyl)methyl)-5-azaspiro[4.4]nonan-5-ium bromide (PTC-A) and (R)-1-((R)-hydroxy(phenyl)methyl)-5-azaspiro[4.5]decan-5-ium bromide (PTC-B).


The present invention further relates to a process for the preparation of novel phase-transfer catalyst (R)-1-((R)-hydroxy(phenyl)methyl)-5-azaspiro[4.4]nonan-5-ium bromide (PTC-A) and (R)-1-((R)-hydroxy(phenyl)methyl)-5-azaspiro[4.5]decan-5-ium bromide (PTC-B).

The present invention also provides a novel process for the preparation of compound of formula I as shown in scheme-1 below;

Scheme-1

DETAILED DESCRIPTION OF THE INVENTION

The term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" such as n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and the like; "ether solvents" such as dimethyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether, 1 ,2-dimethbxy ethane, tetrahydrofuran, 1,4-dioxane and the like; "ester solvents" such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; "polar-aprotic solvents such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) and the like; "chloro solvents" such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile and the like; "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol and the like; "polar solvents" such as water or mixtures thereof.
As used herein the term "chlorinating agent" is selected from pivaloyl chloride, thionyl chloride, sulfuryl chloride, phosphorus oxychloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride and the like.
The term "suitable base" used in the present invention refers to inorganic bases selected from "alkali metal carbonates" such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate lithium bicarbonate, cesium bicarbonate and the like; "alkali metal hydroxides" such as sodium hydroxide, potassium hydroxide, lithium hydroxide - and the like; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide, lithium tert.butoxide and the like; "alkali metal hydrides" such as sodium hydride, potassium hydride, lithium hydride and the like; "alkali metal amides" such as sodium amide, potassium amide, lithium amide and the like; ammonia; and organic bases like methylamine, ethylamine, dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, diisobutylamine, triethylamine, tributylamine, tert.butyl amine, pyridine, 4-dimethylaminopyridine (DMAP) or mixtures thereof.
Suitable amino acid protecting groups are described in numerous references, including T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2d Ed., John Wiley and Sons (1991). Examples of such amino acid protecting groups include, but are not limited to, carbamate containing groups such as Boc, Cbz or Alloc, or alternatively, the amine may be protected as an alkyl derivative such as N,N-dibenzyl or trityl. Such a-amino acid derivatives are often commercially available or may be conveniently prepared from commercially available a-amino acid derivatives using known techniques. The hydroxyl protecting groups are as described in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2d Ed., John Wiley and Sons (1991) or any known protecting groups such as Methoxymethyl ether, Tetrahydropyranyl ether, t-Butyl ether, Allyl ether benzyl, 1,2- and 1,3-diols, Benzylidene acetal, alkyl, alkyloxymethyl. Or commercially available protecting groups by using known techniques.
According to the present invention, (R)-1-((R)-hydroxy(phenyl)methyl)-5-azaspiro[4.4]nonan-5-ium bromide can be represented as PTC-A or compound of formula PCT-A, another novel phase-transfer catalyst (R)-1-((R)-hydroxy(phenyl)methyl)-5-azaspiro[4.5]decan-5-ium bromide can be represented as PTC-B or compound of formula PTC-B.
According to the present invention, wherein isolating the any of intermediate or final compound by removal of the solvent by using suitable techniques such as distillation, distillation by using a rotational distillation device for example Buchi Rotavapor, distillation under vacuum, filtration, filtration under vacuum, decantation and centrifugation, or any other technique known in the art.
One aspect of the present invention is to provide a novel phase-transfer catalyst of (R)-1-((R)-hydroxy(phenyl)methyl)-5-azaspiro[4.4]nonan-5-ium bromide (PTC-A).


Another aspect of the present invention is to provide an improved process for the preparation of a novel phase-transfer catalyst (R)-1-((R)-hydroxy(phenyl)methyl)-5-azaspiro[4.4]nonan-5-ium bromide (PTC-A) comprising the steps of;
a) L-Proline is treating with di-tert-butyl dicarbonate in presence of a base selected from Triethyl amine, diisopropyl ethyl amine, imidazole, 1-methyl imidazole, sodium hydroxide, potassium hydroxide, sodium carbonate, , sodium bicarbonate, potassium, potassium bicarbonate to give (tert-butoxycarbonyl)-D-proline (compound of formula C),
b) treating the product of step a) with N-O-Dimethylhydroxyl amine,
hydrochloride in presence of a base Triethyl amine, diisopropyl ethyl amine, imidazole, 1-methyl imidazole, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium, potassium bicarbonate and a catalyst to give tert-butyl (R)-2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate (compound of formula D),
c) treating the product of step, a) with N-O-Dimethylhydroxyl amine,
hydrochloride in presence of coupling agents 1, 1’ carbonyldimidazole, N,N'-Dicyclohexylcarbodiimide, 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide and a base is selected from Triethyl amine, diisopropyl ethyl amine, imidazole, 1-methyl imidazole, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium, potassium bicarbonate to give tert-butyl (R)-2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate (compound of formula D),
d) reacting the product of step b) with Phenyl magnesium bromide to give tert-butyl (R)-2-benzoylpyrrolidine-1-carboxylate (compound of formula E),
d) treating the product of step c) with a reducing agent selected from sodim borohydride or Lithium aluminium hydride to give tert-butyl (R)-2-((R)-hydroxy(phenyl)methyl)pyrrolidine-1-carboxylate (compound of formula F),
e) reacting the product of step d) with HCl to give (R)-phenyl((R)-pyrrolidin-2-yl)methanol (compound of formula G),
f) optionally purifying the compound of formula G to give pure (R)-phenyl((R)-pyrrolidin-2-yl)methanol (compound of formula H),
g) treating outcome of step f) with 1,4 dibromo butane to give PCT-A
h) optionally purifying the PCT-A.

Yet another aspect of the present invention above synthetic process is illustrated as per the following Scheme-II;

In yet another aspect of the present invention is to provide a novel phase-transfer catalyst (R)-1-((R)-hydroxy(phenyl)methyl)-5-azaspiro[4.5]decan-5-ium bromide (PTC-B).


Yet another aspect of the present invention is to provide an improved process for the preparation of a novel phase-transfer catalyst (R)-1-((R)-hydroxy(phenyl)methyl)-5-azaspiro[4.5]decan-5-ium bromide (PTC-B) comprising the steps of:
a) L-Proline is treating with di-tert-butyl dicarbonate in presence of a base to give (tert-butoxycarbonyl)-D-proline (compound of formula C),
b) treating the product of step a) with N-O-Dimethylhydroxyl amine,
hydrochloride in presence of a base to give tert-butyl (R)-2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate (compound of formula D),
c) reacting the product of step b) with Phenyl magnesium bromide to give tert-butyl (R)-2-benzoylpyrrolidine-1-carboxylate (compound of formula E),
d) treating the product of step c) with a reducing agent to give tert-butyl (R)-2-((R)-hydroxy(phenyl)methyl)pyrrolidine-1-carboxylate (compound of formula F),
e) reacting the product of step d) with HCl to give (R)-phenyl((R)-pyrrolidin-2-yl)methanol (compound of formula G),
f) optionally purifying the compound of formula G to give pure (R)-phenyl((R)-pyrrolidin-2-yl)methanol (compound of formula H),
g) treating the product of step f) with 1,4 dibromo Pentane to give PCT-B
h) optionally purifying the PCT-B.

Yet another aspect of the present invention is to provide above synthetic process is illustrated as per the following Scheme-III;

In yet another aspect of the present invention is to provide a novel process for the preparation of compound of formula I as shown in scheme-1 below;
Scheme-I


R3 is selected from C1-C4-alkyl groups which may be substituted by one, two or three hydrogen atoms or optionally halogen atoms substituted with the group selected from F, Cl and Br or by a CF3 group.

Yet another aspect of the present invention is to provide a novel process for the preparation of compound of formula I comprising the steps of;
a) compound of formula A is treating with novel phase-transfer catalyst (R)-1-((R)-hydroxy(phenyl)methyl)-5-azaspiro[4.4]nonan-5-ium bromide (PTC-A) or (R)- (R)-1-((R)-hydroxy(phenyl)methyl)-5-azaspiro[4.5]decan-5-ium bromide (PTC-B) in presence of a base to give compound of formula 1
b) optionally converting compound of formula 1 to angiotensin receptor blocker.

Another aspect of the present invention is to provide a process for the preparation of Valsaratan is illustrated in Scheme-IV:
Scheme-IV


Yet another aspect of the present invention is to provide process for the preparation of Valsaratan is illustrated as per the following Scheme-V:

SCHEME-V

According to embodiments of the present invention, the methods are in particular be more industrially scalable, and allow the desired compounds to be obtained with high yields, and use cheaper reagents which are simpler to handle and more industrial applicable.
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.

Example-1: Process for the preparation of novel phase-transfer catalyst PTC-A:

Step I: Process for the preparation of (tert-butoxycarbonyl)-D-proline (compound of formula C).

D-proline (250 g) was dissolved in DCM (2.5 Lit) at room temperature. TEA(439 g), BOC anhydride (947 g) was added to the above slurry at 25-30 °C and stirred for 5 hr, after completion of reaction added citric acid(3 Lit) . Removing the solvent, solid was filtered and dried under vacuum to obtained title compound. (454 g, 97%).

Step II: Process for the preparation of tert-butyl (R)-2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate (Weinreb amide-compound of formula D).

BOC-proline (150 g) was dissolved in DCM (2.5 Lit) at room temperature. CDI(137 g), N-O-aniline Hydrochloride (82 g) was added to the above slurry at 25-30 °C and stirred for 2 hr, after completion of reaction added water (3 Lit) . Removing the solvent and washed with DM water to obtained title oil compound. (160.8 g, 89%).

Step III: Process for the preparation of tert-butyl (R)-2-benzoylpyrrolidine-1-carboxylate (Weinreb ketone compound of formula E).

Weinreb amide compound of formula D (50 g) was dissolved in THF (500 ml) at room temperature. Cooled the mass to -45 to 55°C, added phenylmagnesium bromide (380 ml) and stirred for 30 min, after completion of reaction added ammonium chloride (500 ml), washed the mass with EtOAc. Removing the solvent to obtained title oil compound. (44.8 g, 84%).

Step IV: Process for the preparation of tert-butyl (R)-2-((R)-hydroxy(phenyl)methyl)pyrrolidine-1-carboxylate (compound of formula F).
Weinreb ketone compound of formula E (25 g) was dissolved in dry methanol (1200 ml) at room temperature. Cooled the mass to -20 °C, added NaBH4(7 gm) and stirred for 4 hr, after completion of reaction added DM water (575 ml), washed the mass with EtOAc. Removing the solvent and obtained title oil compound was purified by using Column chromatography (Solvent: EtOAc: n-Hexane) (23.33 g, 94%).

Step V: Process for the preparation of (R)-phenyl((R)-pyrrolidin-2-yl)methanol (compound of formula G).

BOC protected alcohol compound of formula F(19 g) was dissolved in EtOAc (95 ml) at room temperature. Cooled the mass to 10 to 15°C, added HCl(38 ml) and stirred for 3 hr, after completion of reaction added ammonium solution (45 ml),washed the mass with water. Removing the solvent, obtained title compound was purified by using Column chromatography (Solvent: methanol: DCM). (8.25 g, 68%).

Step VI: Process for the preparation of (R)-1-((R)-hydroxy(phenyl)methyl)-5-azaspiro[4.4]nonan-5-ium bromide (PTC-A)

Chiral alcohol compound of formula H (5 g) was dissolved in acetonitrile (50 ml) at room temperature, added potassium carbonate (5.8 g) and heat the reaction mass to 80°C. Gradually added 1,4-dibromobutane (6.7 g) for 30 min, stirred for 3 hr, after completion of reaction added acetone (25 ml). Removing the solvent, obtained title compound was recrystallized by using MDC and ether (5:2 ml). Solid was dried under vacuum to obtained title compound. (7.57 g, 86%).

Example-2: Process for the preparation of (R)-1-((R)-hydroxy(phenyl)methyl)-5-azaspiro[4.5]decan-5-ium bromide (PTC-B).

Chiral alcohol of formula H (5 g) was dissolved in acetonitrile (50 ml) at room temperature, added potassium carbonate (5.8 g) and heat the reaction mass to 80°C. Gradually added 1,4-dibromopentane (7 g) for 30 min, stirred for 3 hr, after completion of reaction added acetone (25 ml). Removing the solvent and solid was dried under vacuum to obtained title compound. (7.64 g, 83%).

Example-3: Process for the preparation of compound of Amide compound (formula II) by using novel phase transfer catalyst PTC-A

Amide compound of formula IIa (15 g) was dissolved in Toluene (75 ml) at room temperature, added 50% aq.potassium hydroxide (75 ml),2-bromo propane (6.2 g), phase-transfer catalyst PTC-A(0.75 g) and stirred for 3 hr, after completion of reaction. Removing the solvent and solid was purified by using Column chromatography (EtOAc: n-Hexane).

Example-4: Process for the preparation of Amide compound (formula II) by using novel phase transfer catalyst PTC-B

Amide compound of formula IIa (15 g) was dissolved in Toluene (75 ml) at room temperature, added 50% aq.potassium hydroxide (75 ml),2-bromo propane (6 g), phase-transfer catalyst PTC-B(0.7 g) and stirred for 4 hr, after completion of reaction. Removing the solvent and solid was purified by using Column chromatography (EtOAc: n-Hexane).

Example-5: Process for the preparation of compound of formula 3 by using novel phase transfer catalyst PTC-A

Amide compound of formula 3a (10 g) was dissolved in Toluene (75 ml) at room temperature, added 50% aq.potassium hydroxide (50 ml),2-bromo propane(2 gm), phase-transfer catalyst PTC-A(0.5 g) and stirred for 4 hr, after completion of reaction. Removing the solvent and the obtained solid was dried under vacuum. (9.72 g, 92%).

Example-6: Process for the preparation of compound of formula 3 by using novel phase transfer catalyst PTC-B

Amide compound of formula 3a (10 g) was dissolved in Toluene (50 ml) at room temperature, added 50% aq.potassium hydroxide (50 ml),2-bromo propane(2.1 gm), phase-transfer catalyst PTC-B(0.5 g) and stirred for 4 hr, after completion of reaction. Removing the solvent and the obtained solid was dried under vacuum. (10.14 g, 96%).
,CLAIMS:1. A novel phase-transfer catalyst (R)-1-((R)-hydroxy(phenyl)methyl)-5-azaspiro[4.4]nonan-5-ium bromide (PTC-A) having the following formula:


2. Novel phase-transfer catalyst (R)-1-((R)-hydroxy(phenyl)methyl)-5-azaspiro[4.5]decan-5-ium bromide (PTC-B) having the following formula:

3.The process for the preparation of novel phase-transfer catalyst (R)-1-((R)-hydroxy(phenyl)methyl)-5-azaspiro[4.4]nonan-5-ium bromide (PTC-A) comprising the steps of;
a) L-Proline is treating with di-tert-butyl dicarbonate in presence of triethyl amine to give (tert-butoxycarbonyl)-D-proline (compound of formula C),
b) treating the product of step a) with N-O-Dimethylhydroxyl amine,
hydrochloride in presence of CDI to give tert-butyl (R)-2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate (compound of formula D),
c) reacting the product of step b) with Phenyl magnesium bromide to give tert-butyl (R)-2-benzoylpyrrolidine-1-carboxylate (compound of formula E),
d) treating the product of step c) with sodim borohydride or Lithium aluminium hydride to give tert-butyl (R)-2-((R)-hydroxy(phenyl)methyl)pyrrolidine-1-carboxylate (compound of formula F),
e) reacting the product of step d) with HCl to give (R)-phenyl((R)-pyrrolidin-2-yl)methanol (compound of formula G),
f) optionally purifying the compound of formula G to give pure (R)-phenyl((R)-pyrrolidin-2-yl)methanol (compound of formula H),
g) treating outcome of step f) with 1,4 dibromo butane to give PTC-A,
h) optionally purifying the PTC-A.

4.The process for the preparation of a novel phase-transfer catalyst (R)-1-((R)-hydroxy(phenyl)methyl)-5-azaspiro[4.5]decan-5-ium bromide (PTC-B) comprising the steps of:
a) L-Proline is treating with di-tert-butyl dicarbonate in presence of a base to give (tert-butoxycarbonyl)-D-proline (compound of formula C),
b) treating the product of step a) with N-O-Dimethylhydroxyl amine,
hydrochloride in presence of a catalyst to give tert-butyl (R)-2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate (compound of formula D),
c) reacting the product of step b) with Phenyl magnesium bromide to give tert-butyl (R)-2-benzoylpyrrolidine-1-carboxylate (compound of formula E),
d) treating the product of step c) with a reducing agent to give tert-butyl (R)-2-((R)-hydroxy(phenyl)methyl)pyrrolidine-1-carboxylate (compound of formula F),
e) reacting the product of step d) with HCl to give (R)-phenyl((R)-pyrrolidin-2-yl)methanol (compound of formula G),
f) optionally purifying the compound of formula G to give pure (R)-phenyl((R)-pyrrolidin-2-yl)methanol (compound of formula H),
g) treating the product of step f) with 1,4 dibromo Pentane to give PCT-B,
h) optionally purifying the PCT-B.
5. The process as claimed in claim 4, wherein step a) base is selected from triethyl amine, diisopropyl ethyl amine, imidazole, 1-methyl imidazole, sodium hydroxide, potassium hydroxide, sodium carbonate, , sodium bicarbonate, potassium, potassium bicarbonate, step b) catalyst is CDI, step d) reducing agent is selected from sodim borohydride or Lithium aluminium hydride,in step h) purifying solvents were selected from dichloromethane, chloroform, methanol, IPA, acetone, ethylacetate, n-hexane, cyclohexane, diisopropyl ether or mixtures thereof.

6. The novel process for the preparation of angiotensin receptor blocker or its salts comprising the steps of;
a) treating compound of formula A with phase-transfer catalyst (R)-1-((R)-hydroxy(phenyl)methyl)-5-azaspiro[4.4]nonan-5-ium bromide (PTC-A) or (R)-1-((R)-hydroxy(phenyl)methyl)-5-azaspiro[4.5]decan-5-ium bromide (PTC-B) in presence of a base to give compound of formula 1

b) optionally converting compound of formula 1 to angiotensin receptor blocker or its salts thereof.

7. The process as claimed in claim 6, wherein base is selected from sodium hydroxide or potassium hydroxide.

8. The process as claimed in claim 6, wherein step i) compound of formula A is selected from
a)
or
b)

Step ii) Compound of formula I is selected from

Or

iii) Angiotensin receptor blocker is Valsartan.

9. The novel process for the preparation of Valsartan or its salts comprising the steps of;
a) treating Amide compound of formula IIa with phase-transfer catalyst (R)-1-((R)-hydroxy(phenyl)methyl)-5-azaspiro[4.4]nonan-5-ium bromide (PTC-A) or (R)-1-((R)-hydroxy(phenyl)methyl)-5-azaspiro[4.5]decan-5-ium bromide (PTC-B) in presence of potassium hydroxide to give Amide compound of formula II.

b) optionally converting Amide compound of formula II to Valsartan or its salts thereof.

10. The novel process for the preparation of Valsartan or its salts comprising the steps of;
a) treating Amide compound of formula 3a with phase-transfer catalyst (R)-1-((R)-hydroxy(phenyl)methyl)-5-azaspiro[4.4]nonan-5-ium bromide (PTC-A) or (R)-1-((R)-hydroxy(phenyl)methyl)-5-azaspiro[4.5]decan-5-ium bromide (PTC-B) in presence of potassium hydroxide to give Amide compound of formula 3.

b) optionally converting Amide compound of formula 3 to Valsartan or its salts thereof