Field of the Invention:
Present invention relates to a process for the preparation of (S)-4-(2-isopropyl-4-nitrobutyl)-1-methoxy-2-(3-methoxypropoxy) benzene, which is a key intermediate for synthesis of Aliskiren [I].
Background of the Invention:
Aliskiren [I], having IUPAC name (2S,4S,5S,7S)-5-amino-N-(2-carbamoyl-2,2-dimethylethyl)-4-hydroxy-7-{[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl}-8-methyl-2-(propan-2-yl)nonanamide and identified by the CAS registration No. 173334-57-1, is a renin

inhibitor that possesses potential antihypertensive property.
Process for synthesis of Aliskiren has been disclosed in US patent 5559111 and EP patent O678503.
A number of alternative processes for synthesis of compound [I] through various intermediates were reported in patents and publications (WO 01/09083, WO 01/09079, EP 1 215 201 , WO 02/02508, WO 02/02500, WO 02/02487, WO 02/08172, WO 02/092828, WO 02/02500, WO 03/103653, UK 2 431 640, GB 2 431 641 , GB 2 431 642, GB 2 431 643, GB 2 431 644, GB 2 431 645, GB 2 431 646, GB 2 431 647, GB 2 431 48, GB 2 431 649, GB 2 431 650, GB 2 431 651 , GB 2 431 652, GB 2 431 653, GB 2 431 654, WO 2005/054177, WO 2005/090305, WO 2005/ 051895, WO 2006/131304, WO2006/095020, WO2006/024501 , WO2007/054254, WO2007/039183, EP 2 062 874, EP 1958 666, WO 2007/006532, WO2007/045420, WO2008/155338, WO2008/1 19804, CA 2 634 513, WO2007/048620, WO2007/1 18681 , US2009/0076062, WO2010/010165, EP2189442, WO2009/049837, Tetrahedron Letters 2000, 41 , 10085, ibid. 2000, 41 , 10091 , ibid. 2001 , 42, 4819, Drugs Fut. 2001 , 1 139, J. Org. Chem. 2002, 67, 4261 , Helv. Chim Acta 2003, 86, 2848, Tetrahedron Letters 2005, 46, 6337, J. Org. Chem. 2006, 71 , 4766, Organic Process & Develop 2007, 1 1 , 584, Tetrahedron Letters 2008, 49, 5980 and Org. Lett. 2010, 12, 1816).
WO 2011/127797 A1 discloses the process for synthesis of compound [I] through nitro-aldol reaction of 4-(2-isopropyl-4-nitrobutyl)-1-methoxy-2-(3-methoxypropoxy)benzene [II] with (S)-N-(3-amino-2,2-dimethyl-3-oxopropyl)-2-isopropyl-N-(4-methoxybenzyl)-4-oxobutanamide [III], schematically represented in scheme-1,

WO 2011/127797 A1 has also disclosed the process for synthesis of compound [II], schematically represented in scheme-2. In the said patent application, compound [II] was synthesized via the reaction of (R)-4-(2-(iodomethyl)-3-methylbutyl)-1-methoxy-2-(3-methoxypropoxy)benzene, with very large excess of nitro-methane in presence of very large excess of cesium carbonate in organic solvent such as dimethyl sulfoxide .

Industrial scale use of nitro-methane is not recommended, as nitro-methane can be detonated when it is 1) exposed to very severe shock, 2) under severe and very rapid compression under adiabatic conditions and 3) heated under confined conditions to near its critical temperature. Moreover, nitro-methane gets sensitized and can be more easily detonated when it is mixed with a few percent of amines, acids and/or bases. Potential symptoms of overexposure to nitro-methane include human carcinogenicity and dermatitis.
Hence there is need for developing improved process for preparation of compound [II] which is “green”, cost effective as well as industrially feasible. This in turn leads to develop an eco-friendly, industrial process for aliskiren.

Brief Description of accompanying drawing
Fig 1: Schematic representation of present invention

Summary of the Invention:
Accordingly, the present invention provides a novel method of synthesis of (S)-4-(2-isopropyl-4-nitrobutyl)-1-methoxy-2-(3-methoxypropoxy) benzene (II) from (S)-4-(4-iodo-2-isopropylbutyl)-1-methoxy-2-(3-methoxypropoxy) benzene [VIII].

In accordance with the FIG. – 1, the present invention also provides a novel method of synthesis of (S)-4-(2-isopropyl-4-nitrobutyl)-1-methoxy-2-(3-methoxypropoxy) benzene (II) from (R)-4-(2-(chloromethyl)-3-methylbutyl)-1-methoxy-2-(3-methoxypropoxy) benzene [IV] via the following novel compounds:
(S)-3-(4-methoxy-3-(3-methoxypropoxy) benzyl)-4-methylpentanoic acid [VI] and its corresponding methyl or ethyl ester [Va or Vb]; and
(S)-4-(4-iodo-2-isopropylbutyl)-1-methoxy-2-(3-methoxypropoxy) benzene [VIII].

In another aspect, the present invention provides a novel method of synthesis of (S)-4-(2-isopropyl-4-nitrobutyl)-1-methoxy-2-(3-methoxypropoxy) benzene (II) from 4-methoxy-3-(3-methoxypropoxy)benzaldehyde via the following novel compounds:
1-(4-methoxy-3-(3-methoxypropoxy)phenyl)-3-methylbutan-1-ol [IX];
ethyl 3-(4-methoxy-3-(3-methoxypropoxy)benzoyl)-4-methylpentanoate [XI]; and
3-(4-methoxy-3-(3-methoxypropoxy)benzoyl)-4-methylpentanoic acid [XII].

In a further aspect, the present invention provides a novel method of synthesis of (S)-4-(2-isopropyl-4-nitrobutyl)-1-methoxy-2-(3-methoxypropoxy) benzene (II) from 4-methoxy-3-(3-methoxypropoxy)benzaldehyde via the following novel intermediates:
diethyl 2-(4-methoxy-3-(3-methoxypropoxy)benzyl)malonate [XVI]; and
diethyl 2-isopropyl-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)malonate [XVII].

Yet in another aspect, the present invention provides a novel method of synthesis of (S)-4-(2-isopropyl-4-nitrobutyl)-1-methoxy-2-(3-methoxypropoxy) benzene (II) from 4-(bromomethyl)-1-methoxy-2-(3-methoxypropoxy)benzene [XXII] and ethyl 2-cyano-3-methylbutanoate [XXIII] via the following novel intermediates:
ethyl 2-cyano-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutanoate [XXIV];
2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutanenitrile [XXV];
(R)-4-(2-isopropyl-4-nitrobut-3-en-1-yl)-1-methoxy-2-(3-methoxypropoxy) benzene [XXVIII]; and
(R,E)-4-(2-isopropyl-4-nitrobut-3-en-1-yl)-1-methoxy-2-(3-methoxypropoxy)benzene.

In another aspect, the present invention provides a novel method of preparation of aliskiren wherein said compound [II], i.e., (S)-4-(2-isopropyl-4-nitrobutyl)-1-methoxy-2-(3-methoxypropoxy) benzene, has been prepared according to the novel methods described herein.
Description of the schemes of the present invention:
As mentioned hereinbefore, the present invention is directed towards novel methods for the preparation of the aliskiren intermediate (S)-4-(2-isopropyl-4-nitrobutyl)-1-methoxy-2-(3-methoxypropoxy) benzene (II). Given below is a summary of the Schemes A, B, C and D.

In scheme A, detailed schematic representations of novel process for synthesis of (S)-4-(2-isopropyl-4-nitrobutyl)-1-methoxy-2-(3-methoxypropoxy) benzene [II] from (R)-4-(2-(chloromethyl)-3-methylbutyl)-1-methoxy-2-(3-methoxypropoxy)benzene [IV] is given.

In scheme B, detailed schematic representations of novel process for synthesis of (S)-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentanoic acid [VI] through Grignard reaction of 4-methoxy-3-(3-methoxypropoxy)benzaldehyde with isobutyl magnesium bromide is given which is subsequently converted into (S)-4-(2-isopropyl-4-nitrobutyl)-1-methoxy-2-(3-methoxypropoxy)benzene [II].

In scheme C, detailed schematic representations of novel process for synthesis of (S)-3-(4-methoxy-3-(3-methoxypropoxy) benzyl)-4-methylpentanoic acid [VI] through Knoevenagel condensation of 4-methoxy-3-(3-methoxypropoxy)benzaldehyde and diethyl malonate is given which is subsequently converted into (S)-4-(2-isopropyl-4-nitrobutyl)-1-methoxy-2-(3-methoxypropoxy)benzene [II].

In scheme D, detailed schematic representations of novel process for synthesis of (S)-4-(2-isopropyl-4-nitrobutyl)-1-methoxy-2-(3-methoxypropoxy)benzene [II] through reaction of 4-(bromomethyl)-1-methoxy-2-(3-methoxypropoxy)benzene [XXII] with ethyl 2-cyano-3-methylbutanoate [XXIII] is given.

Detailed description of the present invention:
Scheme A:
According to the Scheme A of the present invention, (S)-4-(2-isopropyl-4-nitrobutyl)-1-methoxy-2-(3-methoxypropoxy) benzene [II] is prepared from (R)-4-(2-(chloromethyl)-3-methylbutyl)-1-methoxy-2-(3-methoxypropoxy) benzene (IV) involving the following novel compounds:
(S)-3-(4-methoxy-3-(3-methoxypropoxy) benzyl)-4-methylpentanoic acid [VI] and its corresponding methyl or ethyl ester [Va or Vb]; and
(S)-4-(4-iodo-2-isopropylbutyl)-1-methoxy-2-(3-methoxypropoxy) benzene [VIII].

Compound (V) was prepared by reacting a Grignard reagent prepared from (R)-4-(2-(chloromethyl)-3-methylbutyl)-1-methoxy-2-(3-methoxypropoxy) benzene (IV) and dimethyl carbonate or diethyl carbonate in an ethereal solvent such as tetrahydrofuran at a temperature ranging from -30C to 00C to obtain the corresponding ester compound [V].
The compound (V) was then hydrolyzed to afford (S)-3-(4-methoxy-3-(3-methoxypropoxy) benzyl)-4-methylpentanoic acid [VI]. As known from the art, such hydrolysis reaction can be accomplished either in presence of a base or in presence of an acid. Typically, in the present invention the compound [V] was hydrolysed in presence of a base, preferably an alkali metal hydroxide base such as potassium hydroxide or sodium hydroxide or lithium hydroxide to give rise the corresponding carboxylic acid derivative [VI].
Reduction of the carboxylic acid functionality of compound (VI) to the corresponding alcohol was carried out using sodium borohydride-iodine in ethereal organic solvent such as tetrahydrofuran at -30 0C to get (S)-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentan-1-ol (VII). Alternatively, (S)-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentan-1-ol (VII) can be obtained from known literature methods through hydride source and hydrogenation of compound (VI).
Compound [VII] was converted to the corresponding iodo derivative [VIII]. However, as understood by a person ordinary skilled in the art from Scheme A, the iodo group of compound [VIII] can be replaced by any other suitable leaving group that can afford (S)-4-(2-isopropyl-4-nitrobutyl)-1-methoxy-2-(3-methoxypropoxy)benzene [II] upon subsequent step as mentioned in the said scheme. For example, [VII] can be converted to the corresponding bromo derivative, i.e., (S)-4-(4-bromo-2-isopropylbutyl)-1-methoxy-2-(3-methoxypropoxy)benzene.
(S)-4-(4-iodo-2-isopropylbutyl)-1-methoxy-2-(3-methoxypropoxy)benzene [VIII] was obtained through iodination of alcohol using imidazole-triphenylphosphine-iodine in organic solvent such as tetrahydrofuran.
Compound (VIII) was further converted to compound [II] by reacting with a metal nitrite of formula MNO2. Although not limited to, M is a metal selected from sodium, potassium and silver. The reaction is accomplished in an organic solvent such as dimethyl formamide or dimethyl sulphoxide.
Scheme B:
According to this scheme, (S)-4-(2-isopropyl-4-nitrobutyl)-1-methoxy-2-(3-methoxypropoxy) benzene [II] is prepared from the novel compound 1-(4-methoxy-3-(3-methoxypropoxy)-phenyl)-3-methylbutan-1-ol [IX] involving the following novel compounds:
ethyl 3-(4-methoxy-3-(3-methoxypropoxy)benzoyl)-4-methylpentanoate [XI]; and
3-(4-methoxy-3-(3-methoxypropoxy)benzoyl)-4-methylpentanoic acid [XII].

Compound (IX) was prepared by reaction of isobutyl magnesium bromide with 4-methoxy-3-(3-methoxypropoxy)benzaldehyde in ethereal solvents such as tetrahydrofuran at 0 0C. Compound (IX) was oxidized to compound [X] using methods known in the art. For example, such oxidation can be carried out in the presence of Dess–Martin periodinane (DMP) or TEMPO catalyst or pyridinium chlorochromate (PCC). In a typical aspect of the present invention, compound [X] was prepared by oxidizing [IX] with PCC in an organic solvent such as dichloromethane at 25 0C. Compound [X] was further reacted with bromoacetic acid alkyl esters in presence of base such as LiHMDS at -70 0C in organic solvent such as tetrahydrofuran to give compound [XI] which was subsequently hydrolyzed in presence of base such as potassium hydroxide or sodium hydroxide to yield compound [XII]. The conjugated carbonyl group, i.e., the carbonyl group at the alpha-position of the phenyl ring, of the compound [XII] was reduced with triethyl silane in trifluoroacetic acid to obtain compound [XIII]; enantiomer of compound [XIII] was separated through chiral separation. As known from the art, such chiral separation step involves preparative HPLC using chiral separation columns to afford pure enantiomeric compounds [VI] and [XIV]. Compound [VI] was subsequently converted into compound [II] as per chemistry described in scheme A.
Scheme C:
According to Scheme C of the present invention, the target compound (S)-4-(2-isopropyl-4-nitrobutyl)-1-methoxy-2-(3-methoxypropoxy) benzene (II) is prepared from 4-methoxy-3-(3-methoxypropoxy)benzaldehyde via the following novel intermediates:
diethyl 2-(4-methoxy-3-(3-methoxypropoxy)benzyl)malonate [XVI]; and
diethyl 2-isopropyl-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)malonate [XVII].

Knoevenagel condensation of 4-methoxy-3-(3-methoxypropoxy)benzaldehyde with diethyl malonate in presence of base such as piperidinium acetate in organic solvent such as ethanol gave compound [XV], which was subsequently hydrogenated in presence of noble metal catalysts such as Palladium-on-carbon (Pd/C) to yield compound [XVI]. Alkylation of compound [XVI] with isopropyl iodide in presence of sodium hydride in organic solvent such as DMF gave compound [XVII], which was further decarboxylated in presence of base such as potassium hydroxide in DMSO-water at 100 0C to yield compound [XVIII]. Compound [XVIII] was converted into compound [XX] by using methods known in the art (Tetrahedron Letters, 2000, 41, p. 10085 – 10090), which was subsequently converted into compound [II] employing chemistry described hereinbefore in the case of scheme A.
Scheme D:
According to the present scheme, the aliskiren intermediate (S)-4-(2-isopropyl-4-nitrobutyl)-1-methoxy-2-(3-methoxypropoxy) benzene (II) is prepared from 4-(bromomethyl)-1-methoxy-2-(3-methoxypropoxy)benzene [XXII] and ethyl 2-cyano-3-methylbutanoate [XXIII] involving the following novel intermediates:
ethyl 2-cyano-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutanoate [XXIV];
2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutanenitrile [XXV];
(R)-4-(2-isopropyl-4-nitrobut-3-en-1-yl)-1-methoxy-2-(3-methoxypropoxy) benzene [XXVIII]; and
(R,E)-4-(2-isopropyl-4-nitrobut-3-en-1-yl)-1-methoxy-2-(3-methoxypropoxy)benzene.

Compound [XXII] was alkylated with compound [XXIII] in presence of base such as sodium hydride in organic solvent such as DMF to yield compound [XXIV]. In the following step, Krapcho decarboxylation of compound [XXIV] was carried out in presence of an alkali metal chloride in a polar protic solvent to afford the compound [XXV]. In a typical aspect of the present invention, such alkali metal chloride was selected from sodium chloride, potassium chloride and cesium chloride. In another aspect, such polar protic solvent was dimethyl solfoxide (DMSO) or dimethyl formamide (DMF). Typically the reaction was accomplished in DMSO at 176 0C to give rise [XXV]. Compound [XXV] was reduced in presence of diisobutylaluminum hydride to yield compound [XXVI]. Compound [XXVI] was converted to compound [XXVII] by employing a process similar to that described in Green Chemistry, 2010, 12, 1747. Nitro-aldol reaction of compound [XXVII] with nitro-methane (mole equivalent with respect to compound XXVII) in presence of lithium aluminium hydride (LAH) in organic solvent such as tetrahydrofuran gave compound [XXVIII]. Compound [XVIII] on reaction with methane sulfonyl chloride in presence of base such as triethylamine in organic solvent such as dichloromethane yielded compound [XXIX], which was subsequently treated with sodium borohydride in alcoholic solvent to yield compound [II].
Nomenclatures used for the compounds mentioned herein are as understood from the CambridgeSoft® ChemOffice software ChemDraw Ultra version 6.0.1.
NMR spectra are obtained at 200 and 400 MHz Bruker instruments, with CDCl3 as solvent unless otherwise stated. Chemical shifts (δ) are given in ppm relative to tetramethylsilane (δ = 0 ppm). IR spectra are recorded on Perkin Elmer Spectrum (Model: Spectrum 100) and absorption bands are given in cm-1. Mass analyses are performed on Shimadzu LCMS 2010A instrument.
The present invention is now elaborated through the following non-limiting examples.

Example 1
Process for synthesis of (S)-methyl 3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentanoic acid [VI] from (R)-4-(2-(chloromethyl)-3-methylbutyl)-1-methoxy-2-(3-methoxypropoxy)benzene [IV]

A 5 L reactor equipped with reflux condenser, dropping funnel, overhead stirrer and nitrogen gas inlet was charged with Magnesium turnings (77.0 g, 3.21 mol), tetrahydrofuran (350 mL, HPLC grade) and a crystal of iodine (0.1 g). A solution of (R)-4-(2-(chloromethyl)-3-methylbutyl)-1-methoxy-2-(3-methoxypropoxy)benzene [IV] (336 g, 1.07 mol), and 1, 2-dibromomethane (12 mL) in THF (1000 mL) was prepared and 20 mL of this solution was added to the Mg slurry. This mixture was heated to 70 0C and while maintaining efficient reflux, the remaining solution of compound [IV] was added slowly over a period of 2 h. The mixture was then heated under reflux conditions for another 4 h.
In another 5 L reactor equipped with reflux condenser, dropping funnel, overhead stirrer and nitrogen gas inlet was charged dimethyl carbonate (385 g) in tetrahydrofuran (700 mL, HPLC grade) and cooled to -40 0C. To this cooled solution was slowly added the Grignard solution of (R)-4-(2-(chloromethyl)-3-methylbutyl)-1-methoxy-2-(3-methoxypropoxy) benzene, keeping temperature of reaction mass below -10 0C. After complete addition of Grignard reagent, temperature of reaction mass was increased to room temperature and stirred for 2 h. After this time, the reaction mixture was heated to 65 0C and stirred for 2 h. Then reaction mixture was cooled to 30 0C and quenched with 200 mL of methanol. The solvent from the slurry was evaporated under reduced pressure and residue was suspended in 1 L aqueous hydrochloric acid (20%) and stirred for 15 min. Aqueous layer was extracted with di-iso-propyl ether (3 x 300 mL). The combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to yield 349 g crude ester as oil.
In another 5 L reactor equipped with reflux condenser, dropping funnel and overhead stirrer was charged aqueous solution of potassium hydroxide (120 g in 1.3 L water) and to this solution, was added solution of crude ester (349 g) in ethanol (200 mL). After complete addition, reaction mixture was heated to 100 0C for 5 h after which reaction mixture was cooled to RT and extracted with di-iso-propyl ether (3 x 700 ml) to remove any unreacted ester. Aqueous layer was acidified with aqueous hydrochloric acid (20 %) and then extracted with di-iso-propyl ether (3 x 1 L). The combined organic layer was dried over anhydrous Na2SO4 and evaporated under vacuum to give 220 g of pure (S)-methyl 3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentanoic acid as oil.
Compound [VI]:
FT IR Spectra: cm-1 2959, 2845, 1716, 1605, 1592, 1515.
1H NMR (400 MHz, CDCl3):  0.99-1.05. (t, 6H), 2.03-2.11 (m, 3H), 2.47-2.48 (d, 1H), 2.65-2.69 (m, 1H), 2.91-2.95 (m, 1H), 3.37 (s, 3H), 3.58-3.61 (t, 2H), 3.68 (s, 3H), 4.09-4.10 (t, 2H), 6.70-6.79 (m, 3H),
13C NMR (100 MHz, CDCl3): 18.5, 19.2, 22.8, 29.1, 29.5, 35.0, 36.5, 42.7, 56.0, 58.6, 66.0,69.4, 111.6, 114.3, 121.4, 133.1, 147.7, 148.2, 179.6
C18H28O5 requires 324.19, [M-H]- = 323.25

Example 2
Process for synthesis of (S)-methyl 3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentanoic acid [VI] from (R)-4-(2-(chloromethyl)-3-methylbutyl)-1-methoxy-2-(3-methoxypropoxy)benzene [IV]

A 1 L reactor equipped with reflux condenser, dropping funnel, overhead stirrer and nitrogen gas inlet was charged with Magnesium turnings (6.0 g, 250 mmol), tetrahydrofuran (100 mL, HPLC grade) and a crystal of iodine (0.1 g). A solution of (R)-4-(2-(chloromethyl)-3-methylbutyl)-1-methoxy-2-(3-methoxypropoxy)benzene [IV] (35.7 g, 113 mmol), and 1, 2-dibromomethane (1.5 mL) in THF (100 mL) was prepared and 5 ml of this solution was added to the Mg slurry. This mixture was heated to 70 0C and while maintaining efficient reflux, the remaining solution of compound [IV] was added slowly over a period of 2 h. The mixture was then heated under reflux conditions for another 4 h.
In another 1 L reactor equipped with reflux condenser, dropping funnel, overhead stirrer and nitrogen gas inlet was charged diethyl carbonate (50 g) in tetrahydrofuran (200 mL, HPLC grade) and cooled to -40 0C. To this cooled solution was slowly added the Grignard solution of (R)-4-(2-(chloromethyl)-3-methylbutyl)-1-methoxy-2-(3-methoxypropoxy) benzene, keeping temperature of reaction mass below -10 0C. After complete addition of Grignard reagent, temperature of reaction mass was increased to room temperature and stirred for 2 h. After this time, the reaction mixture was heated to 65 0C and stirred for 2 h. Then reaction mixture was cooled to 30 0C and quenched with 20 mL of methanol. The solvent from the slurry was evaporated under reduced pressure and residue was suspended in 250 mL aqueous hydrochloric acid (20 %) and stirred for 15 min. Aqueous layer was extracted with di-iso-propyl ether (3 x 100 mL). The combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to yield 40 g crude ester as oil.
In another 500 mL reactor equipped with reflux condenser, dropping funnel and overhead stirrer was charged aqueous solution of potassium hydroxide (19.8 g in 300 mL water) and to this solution was added solution of crude ester (40 g) in DMSO (100 mL). After complete addition, reaction mixture was heated to 100 0C for 5 h after which reaction mixture was cooled to RT and extracted with di-iso-propyl ether (3 x 100 ml) to remove any un-reacted ester. Aqueous layer was acidified with (amount or pH) aqueous hydrochloric acid (20%) and then extracted with di-iso-propyl ether (3 x 250 mL). The combined organic layer was dried over anhydrous Na2SO4 and evaporated under vacuum to give 18 g of pure (S)-ethyl 3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentanoic acid as oil.
Compound [VI]:
FT IR Spectra: cm-1 2959, 2845, 1716, 1605, 1592, 1515.
1H NMR (400 MHz, CDCl3):  0.99-1.05. (t, 6H), 2.03-2.11 (m, 3H), 2.47-2.48 (d, 1H), 2.65-2.69 (m, 1H), 2.91-2.95 (m, 1H), 3.37 (s, 3H), 3.58-3.61 (t, 2H), 3.68 (s, 3H), 4.09-4.10 (t, 2H), 6.70-6.79 (m, 3H),
13C NMR (100 MHz, CDCl3): 18.5, 19.2, 22.8, 29.1, 29.5, 35.0, 36.5, 42.7, 56.0, 58.6, 66.0,69.4, 111.6, 114.3, 121.4, 133.1, 147.7, 148.2, 179.6
C18H28O5 requires 324.19, [M-H]- = 323.25

Example 3
Process for synthesis of (S)-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentan-1-ol [VII] from (S)-methyl 3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentanoic acid [VI]

A 5 L reactor equipped with reflux condenser, dropping funnel, overhead stirrer and nitrogen gas inlet was charged with sodium borohydride (35 g) at 0 0C and to this tetrahydrofuran (500 mL, HPLC grade) was added slowly and stirred for 5 min. To above reaction mixture, solution of (S)-methyl 3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentanoic acid (200 g) in tetrahydrofuran (1.5 L, HPLC grade) was added slowly at -30 0C and stirred further for 1 h at -30 0C. A solution of iodine (110 g) in tetrahydrofuran (1 L,, HPLC grade) was added slowly to the above reaction mixture at -30 0C and stirred for 16 h at 0 0C, after which reaction mixture was quenched by adding methanol (500 mL) at 0 0C. Solvent from reaction mixture was evaporated under reduced pressure. Residue was suspended in ethyl acetate (500 mL) / 4% aq. sodium hydroxide (500 mL) and stirred for 15 min. Organic layer was separated and aqueous layer was extracted with ethyl acetate (2 x 300 mL). Combined organic layer was dried over anhydrous Na2SO4 and evaporated under vacuum to afford 190 g of pure (S)-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentan-1-ol as oil.
Compound [VII]:
FT IR Spectra: cm-1 3401, 2955, 2872, 1607, 1589, 1515, 1464, 1443, 1259, 1235.
1H NMR (400 MHz, CDCl3):  0.99-1.05. (m, 6H), 1.44-1.56 (m, 1H), 1.57-1.75 (m, 4H), 2.07-2.14 (m,2H), 2.33-2.56 (dd, 1H), 2.56-2.61 (dd,1H), 3.36 (s, 3H), 3.53-3.60 (m, 4H), 3.84 (s, 3H), 4.10-4.13 (t, 2H), 6.69-6.72 (m, 2H), 6.78-6.80 (d, 1H)
13C NMR (100 MHz, CDCl3): 18..5, 19.1, 29.1, 29.5, 29.9, 33.2,33.4, 36.9, 42.3,56.0,58.6, 61.6, 66..0, 69.45, 111.7, 114.2,121.2, 134.3, 147.5, 148.1
C18H30O4 requires 310.21, [M+H]+ = 311.5

Example 4
Process for synthesis of (S)-4-(4-iodo-2-isopropylbutyl)-1-methoxy-2-(3-methoxypropoxy) benzene [VIII] from (S)-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentan-1-ol [VII]

A 5 L reactor equipped with reflux condenser, dropping funnel, overhead stirrer and nitrogen gas inlet was charged with triphenylphosphine (329 g) and imidazole (173.6 g). To this, a solution of (S)-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentan-1-ol (195 g) in tetrahydrofuran (1 L) was added slowly at 25 oC. Resultant reaction mass was cooled to -30 0C and solution of iodine (322 g) in tetrahydrofuran (1 L) was added slowly over a period of 1 h after which reaction was stirred at room temperature for 3 h and subsequently quenched with 100 mL of water. Solvent was evaporated under reduced pressure to obtain crude product, which was further purified through column chromatography using silica gel (100-200 mesh size) as stationary phase and ethyl acetate/cyclohexane (1:9) as eluent to obtain 195 g of pure product as oil.
Compound [VIII]:
FT IR Spectra: cm-1: 2955, 2872, 1606, 1589, 1512, 1464, 1442, 1386, 1367, 1332, 1260, 1237, 1029.
1H NMR (400 MHz, CDCl3):  0.85-1.05. (m, 6H), 1.58 -1.88 (m, 4H), 2.10-2.16 (m,2H), 2.34-2.39 (dd, 1H), 2.55-2.60 (dd, 1H), 3.07-3.12 (m, 2H) 3.38 (s, 3H), 3.58-3.62 (t, 2H), 3.88 (s, 3H), 4.11-4.15 (t, 2H), 6.69-6.73 (m, 2H), 6.79-6.81 (d, 1H)
13C NMR (100 MHz, CDCl3): 6.2, 18.7, 18.9, 28.6, 29.6, 34.6, 36.2, 46.7, 56.0, 58.9, 66.1, 69.4, 111.7, 114.2, 121.1, 133.3, 147.6, 148.3
C18H29IO3 requires 420.12, [M+H]+ = 421.15

Example 5
Process for synthesis of (S)-4-(2-isopropyl-4-nitrobutyl)-1-methoxy-2-(3-methoxypropoxy) benzene (II) from (S)-4-(4-iodo-2-isopropylbutyl)-1-methoxy-2-(3-methoxypropoxy) benzene [VIII]

A 2 L reactor equipped with reflux condenser, dropping funnel, overhead stirrer and nitrogen gas inlet was charged with (S)-4-(4-iodo-2-isopropylbutyl)-1-methoxy-2-(3-methoxypropoxy) benzene (100 g) and dissolved in dimethyl formamide (250 mL). To this, a solution of urea (15.7 g) and sodium nitrite (49.3 g) in dimethyl formamide (250 mL) was added slowly at 25oC and resultant reaction mixture was stirred for 4 h at room temperature after which reaction was quenched with 1.0 L water. Aqueous layer was extracted with di-iso-propyl ether (2 x 500 ml). Combined organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure to obtain crude product, which was further purified on column chromatography using silica gel (mesh size: 100-200) as stationary phase and ethyl acetate/ cyclohexane (1:9) as eluent to obtain 42.5 g of pure product as oil.

Compound [II]:
FT IR Spectra: cm-1 2959, 2875, 1737, 1606, 1589, 1552, 1515, 1464, 1385, 1260, 1238, 1140, 1120, 1027.
1H NMR (400 MHz, CDCl3):  0.91-0.92 (d, 3H), 0.95-0.97 (d, 3H), 1.57 -1.60 (m, 1H), 1.70-176 (m, 1H), 1.81-1.90 (m, 1H), 2.02-2.15 (m, 3H), 2.31-2.37 (dd, 1H), 2.64-2.69 (dd, 1H), 3.37 (s, 3H), 3.58-3.61 (t, 2H), 3.85 (s, 3H), 4.10-4.13 (t, 2H),4.19-4.23 (t, 2H) 6.68-6.70 (m, 2H), 6.79-6.81 (d, 1H)
13C NMR (100 MHz, CDCl3): 18.5, 18.9, 28.4, 29.4, 29.5, 36.7, 43.2, 56.0, 58.7, 66.0, 69.3, 74.6, 111.7, 113.9, 121.0, 132.9, 147.8, 148.4,
C18H29O5 requires 339.20, [M+H]+ = 340.2,

Example 6
Process for synthesis of 1-(4-methoxy-3-(3-methoxypropoxy)phenyl)-3-methylbutan-1-ol [IX] from 4-methoxy-3-(3-methoxypropoxy)benzaldehyde
A 5 L reactor equipped with reflux condenser, dropping funnel, overhead stirrer and nitrogen gas inlet was charged with 4-methoxy-3-(3-methoxypropoxy)benzaldehyde (267 g) in tetrahydrofuran (2 L, HPLC grade) and cooled to -10 0C. To this cooled solution was slowly added solution of isobutyl magnesium bromide in tetrahydrofuran (500 mL, HPLC grade), keeping the reaction mass temperature below 0 0C. After complete addition of Grignard reagent, temperature of reaction mass was increased to room temperature and stirred for 2 h at room temperature and quenched with methanol (200 mL). Solvent from slurry was evaporated under reduced pressure and residue was suspended in 1 L aqueous hydrochloric acid (20 %) and stirred for 15 min. Aqueous layer was extracted with di-iso-propyl ether (3 x 300 mL). The combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to give 349 g of 1-(4-methoxy-3-(3-methoxypropoxy)phenyl)-3-methylbutan-1-ol as oil.
C16H26O4 requires 282.18, [M-H] = 281.35

Example 7
Process for synthesis of 1-(4-methoxy-3-(3-methoxypropoxy)phenyl)-3-methylbutan-1-one [X] from 1-(4-methoxy-3-(3-methoxypropoxy)phenyl)-3-methylbutan-1-ol [IX]

A 5 L reactor equipped with reflux condenser, dropping funnel, overhead stirrer and nitrogen gas inlet was charged with a solution of pyridinium chlorochromate (PCC) (40.0 mg, 0.185 mmol) in anhydrous dichloromethane (3 mL) at room temperature and were added silica (40.0 mg) and NaOAc (15.1 mg, 0.184 mmol). After 10 min of stirring at room temperature, a solution of 1-(4-methoxy-3-(3-methoxypropoxy)phenyl)-3-methylbutan-1-ol (16.0 mg, 0.061 mmol) in anhydrous dichloromethane (3 mL) was added dropwise. The resultant mixture was stirred for 12 h at room temperature under argon, then filtered through a plug of Celite and washed with dichloromethane (3 × 10 mL). The filtrate was concentrated in vacuum, and the residue was purified by flash column chromatography on silica gel (100-200) (10 % ethyl acetate/petroleum ether to 30% ethyla acetate/petroleum ether) to give 1-(4-methoxy-3-(3-methoxypropoxy)phenyl)-3-methylbutan-1-one (13.8 mg, 87 %) as oil.

FT IR Spectra: cm-1 : 2956, 2931, 2872, 1674, 1594, 1514, 1464, 1425, 1295, 1263
1H NMR (400 MHz, CDCl3):  0.99-1.05. (m, 6H), 2.12-2.15 (t, 2H), 2.24- 2.31(m,1H), 2.78-2.79 (dd, 2H), 3.37 (s, 3H), 3.57-3.60 (t, 2H), 3.93 (s, 3H), 4.10-4.20 (t, 2H), 6.88-6.90 (d, 31H),7.56-7.58 (d, 2H)
13C NMR (100 MHz, CDCl3): 23.2, 25.5, 29.4, 47.0, 56.0, 58.7, 66.1, 69.4, 110.2, 111.5, 122.74, 130.64, 148.3, 153.46, 198.96
C16H24O4 requires 280.17, [M+H]+ = 281.15

Example 8
Process for synthesis of 3-(4-methoxy-3-(3-methoxypropoxy)benzoyl)-4-methylpentanoate [XI] from 1-(4-methoxy-3-(3-methoxypropoxy)phenyl)-3-methylbutan-1-one [X]

A 3 L reactor equipped with reflux condenser, dropping funnel, overhead stirrer and nitrogen gas inlet was charged with solution of 1-(4-methoxy-3-(3-methoxypropoxy)phenyl)-3-methylbutan-1-one (70 g) in tetrahydrofuran (700 mL) at room temperature, which was then cooled to -70 0C. At this temperature 1 M solution of LiHMDS (375 mL) was added drop wise into the above solution. After complete addition of LiHMDS solution, temperature of reaction mass was increased to -40 0C and stirred at this temperature for 1 h followed by cooling the reaction mass to -70 0C. At this temperature, solution of ethyl bromaoacetate (62.6 g) in tetrahydrofuran (100 mL) was added slowly after which reaction mixture was stirred for 16 h at 25 0C and then heated at 50 0C for 2h. After cooling the reaction mass to room temperature, it was quenched by adding ethanol (40 mL). Solvent was evaporated under reduced pressure to obtain residue, which was suspended in aqueous hydrochloric acid solution (10 %, 500 mL) and then extracted with ethyl acetate (3 x 400 mL). Combined organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure to obtain crude product (50 g) as oil.
FT IR Spectra: cm-1: 2947, 1731, 1673, 1589, 1514, 1431, 1367, 1337, 1020,
13C NMR (100 MHz, CDCl3): 22.7, 25.6, 25.7, 29.2, 29.3, 47.0, 56.0, 58.6, 66.0, 69.2, 110.2, 111.9, 123.0, 130.4, 148.3, 153.5, 170.9, 199.7
C20H30O6 requires 366.20, [M+H]+ = 367.15

Example 9
Process for synthesis of 3-(4-methoxy-3-(3-methoxypropoxy)benzoyl)-4-methylpentanoic acid [XII] from ethyl 3-(4-methoxy-3-(3-methoxypropoxy)benzoyl)-4-methylpentanoate [XI]

A reactor equipped with reflux condenser, dropping funnel and overhead stirrer was charged with aqueous solution of potassium hydroxide (33.6 g in 350 mL of water) and to this solution, was added a solution of crude ester (110 g) in dimethyl sulfoxide (200 mL). After complete addition, reaction mixture was heated at 125 0C for 2 h after which the reaction mixture was cooled to RT and extracted with di-iso-propyl ether (3 x 300 mL) to remove any un-reacted ester along with other impurities. Aqueous layer was acidified with 20% aqueous hydrochloric acid and extracted with di-iso-propyl ether (3 x 1 L). The combined organic layer was dried over anhydrous Na2SO4 and evaporated under vacuum to yield 76 g of 3-(4-methoxy-3-(3-methoxypropoxy)benzoyl)-4-methylpentanoic acid as oil.

FT IR Spectra: cm-1: 2965, 2877, 1720, 1670, 1592, 1583, 1514, 1465, 1427, 1372, 1264, 1129, 1019.
1H NMR (400 MHz, CDCl3):  0.80-0.82 (d, 3H), 0.96-0.97(d, 3H), 2.04-2.14 (m, 3H), 2.45-2.50(dd, 1H), 2.93-3.00(dd, 1H), 3.34 (s,3H), 3.55-3.58 (t, 2H), 3.69-3.74 (m,1H), 3.92 (s, 3H), 4.07-4.17 (t, 2H), 4.5-6.5 (bs, 1H), 6.87-6.89 (d, 1H), 7.54 (s, 1H), 7.58-7.60 (d, 1H)
C18H26O6 requires 338.17, [M+H]+ = 339.20

Example 10
Process for synthesis of (S)-methyl 3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentanoic acid [VI] from 3-(4-methoxy-3-(3-methoxypropoxy)benzoyl)-4-methylpentanoic acid [XII]

A reactor equipped with reflux condenser, dropping funnel, overhead stirrer was charged with 3-(4-methoxy-3-(3-methoxypropoxy)benzoyl)-4-methylpentanoic acid (50 g) and trifluoro acetic acid (250 mL) at 25 0C, after which reaction mixture was cooled to -10 0C and at this temperature, triethyl silane (51.4 mL) was added slowly by maintaining temperature of reaction mixture below -100C and after complete addition, reaction mixture was stirred at 25 0C for 16 h; in case the reaction was not complete within this time, it was heated to 50 0C and stirred for another 2 h, after which reaction mixture was cooled to RT and trifluoroacetic acid was removed under reduced pressure to obtain residue, which was suspended in water (500 mL) and extracted with dichloromethane (2 x 500 mL). Combined organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure to obtain crude product. Crude product was then suspended in 10 % aqueous solution of potassium hydroxide (330 mL) at room temperature and stirred for 2 h and extracted with di-iso-propyl ether (3 x 300 mL) to remove any impurity. Aqueous layer was acidified with hydrochloric acid (35% and 88 mL) and extracted with di-iso-propyl ether (3 x 300 mL). The combined organic layer was dried over anhydrous Na2SO4 and evaporated under vacuum to obtain 50 g of (RS)-methyl 3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentanoic acid.
(S)-methyl-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentanoic acid was obtained from (RS)-methyl-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentanoic acid through resolution by preparative chiral HPLC .
FT IR Spectra: cm-1 2959, 2845, 1716, 1605, 1592, 1515.
1H NMR (400 MHz, CDCl3):  0.99-1.05. (t, 6H), 2.03-2.11 (m, 3H), 2.47-2.48 (d, 1H), 2.65-2.69 (m, 1H), 2.91-2.95 (m, 1H), 3.37 (s, 3H), 3.58-3.61 (t, 2H), 3.68 (s, 3H), 4.09-4.10 (t, 2H), 6.70-6.79 (m, 3H),
13C NMR (100 MHz, CDCl3): 18.5, 19.2, 22.8, 29.1, 29.5, 35.0, 36.5, 42.7, 56.0, 58.6, 66.0,69.4, 111.6, 114.3, 121.4, 133.1, 147.7, 148.2, 179.6
C18H28O5 requires 324.19, [M-H]- = 323.25

Example 11
Process for synthesis of diethyl 2-(4-methoxy-3-(3-methoxypropoxy)benzyl)malonate [XVI]

A reactor was charged with 4-methoxy-3-(3-methoxypropoxy)benzaldehyde (224.0 g, 1.0 mol), diethyl malonate (160 g, 1.0 mol) and toluene (500 mL) and resulting reaction mixture was stirred for 15-20 min at room temperature. To above reaction mixture, was added a solution of piperidinium acetate (20 mL) in toluene (200 mL) slowly while stirring over a period of 25 min after which, sodium acetate (8.2 g) was added. The reaction mixture was stirred under reflux for 4 h using a Dean-Stark condenser. Reaction was monitored by TLC for complete consumption of starting materials and after completion of reaction, the solvent was evaporated under reduced pressure. Residue was dissolved in ethanol (1200 mL) and resulting solution was transferred into a Parr autoclave reactor followed by addition of 2 % palladium-on-carbon (50 % wet, 10 % Pd loading). Reactor was purged with nitrogen twice followed by hydrogen twice and charged with hydrogen and a pressure of 3 kg/cm2 was maintained in the Parr autoclave until hydrogen consumption ceased. Reaction was monitored by TLC. After completion of reaction, reaction mixture was filtered through Celite bed to remove Pd/C and filtrate was concentrated under reduced pressure to remove solvent. Residue was suspended in aqueous solution of sodium bicarbonate (10 %, 700 mL) and aqueous layer was extracted with di-iso-propyl ether (3 x 500 mL). Combined organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure to obtain diethyl 2-(4-methoxy-3-(3-methoxypropoxy)benzyl)malonate (345 g) as light yellow oil
1H NMR (400 MHz, CDCl3):  1.19-123 (t, 6H), 2.07-2.12 (m, 2H), 3.12-3.14 (d, 2H), 3.35-3.36 (d, 3H), 3.54 (s, 3H), 3.82 (s, 3H), 4.04-4.21(m, 6H), 6.74-6.75 (m, 3H)
C19H28O7 requires 368.18 [M+H]+ = 369.25

Example 12
Process for synthesis of diethyl 2-isopropyl-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)malonate [XVII] from diethyl 2-(4-methoxy-3-(3-methoxypropoxy)benzyl) malonate [XVI]

A 5 L reactor equipped with reflux condenser, dropping funnel, overhead stirrer and nitrogen gas inlet was charged with sodium hydride (23.6 g) and to this DMF (400 mL) was added slowly under stirring. The resulting reaction mixture was cooled to 0 0C and at this temperature, solution of diethyl 2-(4-methoxy-3-(3-methoxypropoxy)benzyl) malonate (300 g) in DMF (600 mL) was added slowly by maintaining reaction temperature around 0 0C and further stirred for 1 h at 25 0C after which reaction mixture was cooled to -300C and at this temperature under stirring, solution of isopropyl iodide (181 g) in DMF (500 mL) was added slowly. After complete addition, reaction mixture was stirred for 12 h at 25 0C. . Reaction was monitored by TLC for complete consumption of starting materials and after completion of reaction, reaction was quenched with drop wise addition of methanol (50 mL) at 25 0C and water was added (3 L). Aqueous layer was extracted with di-iso-propyl ether (3 x 1 L). Combined organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure to obtain 313 g of diethyl 2-isopropyl-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)malonate as oil.
FT IR Spectra: cm-1: 2976, 2933, 2876, 1728, 1681, 1514, 1465, 1444, 1390, 1370, 1248
C23H34O7 requires 410.23, [M+H]+ = 411.35

Example 13
Process for synthesis of 2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutanoic acid [XVIII] from diethyl 2-isopropyl-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)malonate [XVII]

A 5 L reactor equipped with reflux condenser, dropping funnel and overhead stirrer was charged with potassium hydroxide (310 g) and water (1 L) and to this, solution of diethyl 2-isopropyl-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)malonate (310g) in DMSO (700 mL) was slowly added. Resulting reaction mass was heated at reflux for 8 h after which reaction mass was cooled to room temperature. Aqueous layer was extracted with di-iso-propyl ether (2 x 500 mL) to remove un-reacted material as well as any impurity. Then aqueous layer was acidified with hydrochloric acid (10%) and extracted with di-iso-propyl ether (3 x 700 mL). Combined organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure to obtain 2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutanoic acid (205 g) as oil.
FT IR Spectra: cm-1: 2961, 2934, 1706, 1591, 1515, 1443, 1261, 1140.
1H NMR (400 MHz, CDCl3):  1.04-1.12 (t, 6H), 1.93-1.98 (m, 1H), 2.05-2.11 (m, 2H), 2.42-2.48 (m, 1H), 2.79-2.81 (t, 2H), 3.37 (s, 3H), 3.57-3.60 (m, 2H), 3.82 (s, 3H), 4.08-4.11 (t, 2H), 6.71-6.89 (m, 3H)
13C NMR (100 MHz, CDCl3): 20.0, 20.4, 29.37, 30.45, 35.13, 54.62, 55.97, 58.61, 65.88,69.45,111.76, 114.13, 120.99,132.31, 147.88, 148.03, 179.61
C17H26O5 requires 310.39, [M-H] = 309.25

Example 14
Process for synthesis of 2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutan-1-ol [XIX] from 2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutanoic acid [XVIII]

A 2 L reactor equipped with reflux condenser, dropping funnel, overhead stirrer and nitrogen gas inlet was charged with sodium borohydride (9 g) and to this, dimethoxyethane (370 mL) was added slowly and stirred for 5 min. Resulting reaction mixture was cooled to 0 0C. and a solution of 2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutanoic acid (37 g) in dimethoxyethane (165 mL) was added into it and further cooled to -30 0C. To the above reaction mixture, solution of iodine (30.4 g) in dimethoxyethane (165 mL) was added slowly by maintaining temperature at -30 0C and reaction mass was stirred for 24 h at 25 0C after which it was quenched by adding methanol (100 mL) at 0 0C. Solvent from reaction mixture was evaporated under reduced pressure. Residue was suspended in ethyl acetate (500 mL / aqueous solution of sodium hydroxide (4 %, 500 mL) and stirred for 15 min. Organic layer was separated and aqueous layer was extracted with ethyl acetate (2 x 300 mL). Combined organic layer was dried over anhydrous Na2SO4 and evaporated under vacuum to give 23 g of 2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutan-1-ol as oil.
FT IR Spectra: cm-1: 3430, 2955, 2931, 2873, 1607, 1589, 1515, 1465, 1442, 1424, 1332, 1260, 1235, 1159, 1139
13C NMR (100 MHz, CDCl3): 19.55, 20.21, 27.83, 29.55, 34.05, 48.72, 56.06, 58.71, 63.01, 65.96, 69.49, 111.73, 114.14, 121.14, 133.96, 147.56, 148.52
C17H28O4 requires 296.40, [M+H]+ = 297.25

Example 15
Process for synthesis of 4-(2-(chloromethyl)-3-methylbutyl)-1-methoxy-2-(3-methoxypropoxy)benzene from 2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutan-1-ol

A 250 mL reactor equipped with reflux condenser, dropping funnel, overhead stirrer and nitrogen gas inlet was charged with solution of 2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutan-1-ol (5 gm) in toluene (50 ml) and N,ndimethyl formamide (0.5ml). To this, a solution of thionyl chloride (3 g) in toluene (5 mL) was added slowly at 75 oC and resultant reaction was stirred for 3 h. After completion of reaction, reaction mass was cooled to room temperature and solvent was evaporated under reduced pressure to obtain crude product, which was further purified through column chromatography using silica gel (mesh size: 100-200) as stationary phase and ethyl acetate/cyclohexane (1:9) as eluent to obtain 3.5 g of pure product as white solid.

Example 16
Process for synthesis of 4-(2-(iodomethyl)-3-methylbutyl)-1-methoxy-2-(3-methoxypropoxy)benzene from 2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutan-1-ol

A 250 mL reactor equipped with reflux condenser, dropping funnel, overhead stirrer and nitrogen gas inlet was charged with triphenylphosphine (5.3 g) and imidazole (2.75 g). To this, a solution of (S)-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentan-1-ol (3 g) in tetrahydrofuran (50 mL) was added slowly at 25 oC. Resultant reaction mass was cooled to -30 0C and solution of iodine (5.17 g) in tetrahydrofuran (50 mL) was added slowly over a period of 1 h after which reaction was stirred at room temperature for 3 h and subsequently quenched with 10 mL of water. Solvent was evaporated under reduced pressure to obtain crude product, which was further purified through column chromatography using silica gel (mesh size: 100-200) as stationary phase and ethyl acetate/cyclohexane (1:9) as eluent to obtain 3.5 g of pure product as oil.
FT IR Spectra: cm-1 2930, 2832, 1606, 1589, 1511, 1459, 1441, 1425, 1386.
13C NMR (100 MHz, CDCl3): 14.5, 19.5, 19.9, 29.42, 30.41, 36.6, 47.6, 56.0, 58.7, 66.0, 69.3, 111.8, 113.7, 114.1, 121.2, 132.9, 1447.8, 148.3
C17H27IO3 requires 406.1, [M+H]+ = 407.15.

Example 17
Process for synthesis of (S)-methyl 3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentanoic acid [VI] from (RS)-4-(2-(chloromethyl)-3-methylbutyl)-1-methoxy-2-(3-methoxypropoxy)benzene [XX]

A 5 L reactor equipped with reflux condenser, dropping funnel, overhead stirrer and nitrogen gas inlet was charged with Magnesium turnings (77 g, 3.21 mol), tetrahydrofuran (350 mL, HPLC grade) and a crystal of iodine (0.1 g). A solution of (R)-4-(2-(chloromethyl)-3-methylbutyl)-1-methoxy-2-(3-methoxypropoxy)benzene (336 g, 1.07 mol), and 1, 2-dibromomethane (12 mL) in tetrahydrofuran (1 L, HPLC grade) was prepared and 20 mL of this solution was added to the Mg slurry. This mixture was heated to 70 0C and while under reflux, the remaining solution of above compound was added slowly over a period of 2 h. The mixture was then heated under reflux condition for another 4 h.
In another 5 L reactor equipped with reflux condenser, dropping funnel, overhead stirrer and nitrogen gas inlet was charged dimethyl carbonate (385 g) in tetrahydrofuran (700 mL, HPLC grade) and cooled to -40 0C. To this cooled solution, was slowly added the solution of (R)-4-(2-(chloromethyl)-3-methylbutyl)-1-methoxy-2-(3-methoxypropoxy)benzene, keeping the inside temperature below -10 0C. After complete addition of Grignard reagent, temperature of reaction mass was increased to room temperature and stirred for 2 h at RT after which reaction mixture was heated to 65 0C and stirred for 2 h. Reaction mixture was cooled to 30 0C and quenched with methanol (200 mL). Solvent from slurry was evaporated under reduced pressure and residue was suspended in 1 L aqueous hydrochloric acid (20 %) and stirred for 15 min. aqueous layer was extracted with di-iso-propyl ether (3 x 300 mL). The combined organic layer was dried over anhydrous Na2SO4 and evaporated under vacuum to afford 349 g of crude ester as oil.
In another 5 L reactor equipped with reflux condenser, dropping funnel, overhead stirrer was charged aqueous solution of potassium hydroxide (120 g in 1.3 L water) and to this solution, was added a solution of crude ester (349 g) in ethanol (200 mL). After complete addition, reaction mixture was heated at 100 0C for 5 h after which reaction mixture was cooled to RT and extracted with di-iso-propyl ether (3 x 700 mL) to remove any un-reacted ester. Aqueous layer was acidified with hydrochloric acid (20 %, 500 mL) and then extracted with di-iso-propyl ether (3 x 1 L). The combined organic layer was dried over anhydrous Na2SO4 and evaporated under vacuum to give (RS)-methyl 3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentanoic acid (220 g) as oil
(S)-methyl 3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentanoic acid was obtained from (RS)-methyl 3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentanoic acid through resolution by preparative chiral HPLC.
Compound [VI]:
FT IR Spectra: cm-1 2959, 2845, 1716, 1605, 1592, 1515.
1H NMR (400 MHz, CDCl3):  0.99-1.05. (t, 6H), 2.03-2.11 (m, 3H), 2.47-2.48 (d, 1H), 2.65-2.69 (m, 1H), 2.91-2.95 (m, 1H), 3.37 (s, 3H), 3.58-3.61 (t, 2H), 3.68 (s, 3H), 4.09-4.10 (t, 2H), 6.70-6.79 (m, 3H),
13C NMR (100 MHz, CDCl3): 18.5, 19.2, 22.8, 29.1, 29.5, 35.0, 36.5, 42.7, 56.0, 58.6, 66.0,69.4, 111.6, 114.3, 121.4, 133.1, 147.7, 148.2, 179.6
C18H28O5 requires 324.19, [M-H]- = 323.25

Example 18
Process for synthesis of ethyl 2-cyano-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutanoate [XXIV]

A 2 L reactor equipped with reflux condenser, dropping funnel, overhead stirrer and nitrogen gas inlet was charged with sodium hydride (5.93 g) and to this DMF (100 mL) was added slowly under nitrogen atmosphere at 0 0C followed by ethyl 2-cyano-3-methylbutanoate (35 g) in DMF (150 mL) slowly by maintaining reaction temperature around 0 0C and then further stirred for 1 h at 25 0C. Reaction mixture was cooled to -30 0C and at this temperature, under stirring, a solution of 4-(bromomethyl)-1-methoxy-2-(3-methoxypropoxy)benzene (65 g) in DMF (250 mL) was added slowly and after complete addition, reaction mixture was stirred for 12 h at 25 0C. . Reaction was monitored by TLC for complete consumption of starting materials and after completion of reaction, it was quenched with drop wise addition of methanol (50 mL) at 25 0C and then water was added (3 L). Aqueous layer was extracted with DIPE (3 x 250 mL). Combined organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure to obtain 65 g of ethyl 2-cyano-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutanoate as yellow oil.

FT IR Spectra: cm-1 2969, 2877, 2243, 1739, 1677, 1608, 1591, 1516.
1H NMR (400 MHz, CDCl3):  1.12-1.26 (m, 6H), 1.30-1.34 (m, 4H), 2.04-2.13 (m, 2H), 2.27-2.34 (m, 1H), 2.95-3.01 (m, 1H), 3.09-3.12 (m, 1H), 3.35 (s, 3H), 3.55-3.58 (t, 2H), 3.84 (s, 3H), 4.01-4.14 (m, 4H), 6.77-6.83 (m, 3H).
13C NMR (100 MHz, CDCl3): 13.8, 17.7, 19.2, 29.3, 35.4, 41.0, 55.9, 58.0, 58.6, 62.4, 65.9, 69.3, 111.5, 114.7, 118.0, 122.5, 127.1, 148.1, 148.9, 168.6.
C20H29NO5 requires 363.20, [M+H]+ = 364.20.

Example 19
Process for synthesis of 2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutanenitrile [XXV] from ethyl 2-cyano-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutanoate [XXIV]

A 500 mL reactor was charged with ethyl 2-cyano-2-(4-methoxy-3-(3-methoxypropoxy)-benzyl)-3-methylbutanoate (64 g), potassium chloride (18.5 g), dimethyl sulphoxide (300 mL) and water (4.3 mL). The resulting reaction mixture was heated at 160 0C and maintained at that temperature for 4 h. Reaction was monitored by TLC for complete consumption of starting material. The reaction mixture was cooled to 40 to 50 0C and treated with methyl tert-butyl ether (200 mL). The mixture was further cooled to 0 to 50C and treated with water (1 L) in small portions to maintain the temperature below 40 0C. After stirring for 30 min the phases are separated. The aqueous phase was extracted with methyl tert-butyl ether (3 x 800 mL). Organic phases were combined and washed twice with 100 mL water. The organic layer was decolorized by treating with 5.0 g of activated charcoal. The resultant mixture was filtered to remove charcoal and filtrate was evaporated to give 2-(4-methoxy-3-(3-methoxypropoxy)-phenyl)-3-methylbutanenitrile (40.1 g) as light brown colour oil.
FT IR Spectra: cm-1 2962, 2875, 2236, 1675, 1607, 1590, 1517.
1H NMR (400 MHz, CDCl3):  1.10-1.12 (m, 6H), 1.84-1.88 (m, 1H), 2.05-2.12 (m, 2H), 2.60-2.65 (m, 1H), 2.72-2.83 (m, 2H), 3.34 (s, 3H), 3.54-3.57 (t, 2H), 3.83 (s, 3H), 4.08-4.11 (t, 2H), 6.75-6.81 (m, 3H).
13C NMR (100 MHz, CDCl3): 18.2, 21.2, 29.5, 36.0, 40.9, 41.7, 56.0, 58.6, 66.0, 69.3, 111.8, 113.8, 120.7, 121.1, 130.0, 148.4, 148.5.
C17H25NO3 requires 291.18, [M+H]+ = 292.20.

Example 20
Process for synthesis of 2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutanal [XXVI] from 2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutanenitrile [XXV]

A 5 L reactor equipped with reflux condenser, dropping funnel, overhead stirrer and nitrogen gas inlet was charged with solution of 2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutanenitrile (75.0 g) in toluene (800 mL) under nitrogen atmosphere. Resulting reaction mass was cooled to -70 0C and at this temperature 20 % solution of DIBAL in toluene (280 ml) was added drop wise over a period of 1 h and stirred for 3 h at -700C. Reaction was monitored on TLC for complete consumption of starting material. The reaction was quenched with drop wise addition of acetic acid (200 mL) at -70 0C and water (200 mL) was added. Resultant reaction mixture was extracted with ethyl acetate (3 x 300 mL). Combined organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure to obtain 2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutanal (68 g) as yellow oil.
FT IR Spectra: cm-1 2959, 2875, 1722, 1606, 1590, 1514.
1H NMR (400 MHz, CDCl3):  0.99-1.05. (m, 6H), 2.03-2.11 (m, 3H), 2.47-2.48 (d, 1H), 2.65-2.69 (m, 1H), 2.91-2.95 (m, 1H), 3.34 (s, 3H), 3.56-3.59 (t, 2H), 3.76 (s, 3H), 4.07-4.10 (t, 2H), 6.68-6.78 (m, 3H), 9.67 (s, 1H)
13C NMR (100 MHz, CDCl3): 19.8, 28.3, 29.5, 31.7, 56.0, 58.6, 59.7, 65.8, 69.3, 111.8, 113.7, 121.0, 125.2, 128.2, 129.0, 132.1, 147.8, 148.3, 205.2.
C17H26O4 requires 294.18, [M+H]+ = 295.15

Example 21
Process for synthesis of (R) 2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutanal [XXVII] from 2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutanal [XXVI]

2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutanal (1.72 g) was added dropwise to a stirred suspension of (S)-1-(a-aminobenzyl)-2-naphthol (1.4 g) in methanol (28.8 mL) and the mixture was warmed to 55– 60 ◦C. After 30 min a solution of acetic acid in methanol (9 : 1 ratio, 28.8 mL) was added and the reaction was left to cool at ambient temperature under an efficient stirring. Within few minutes a solid product began to form and the resulting suspension was stirred for an additional 24 h. The naphthoxazine derivative was collected by filtration. The diastereoisomeric purity of naphthoxazine derivative was further increased to dr = 99.5 : 0.5 (1.94 g, 64% overall yield) by crystallization from diisopropyl ether (66 mL). Obtained solid was suspended in THF: EtOAc 1 : 1 (30ml) and 2% aqueous solution of TsOH (5 ml)) and Dowex 50WX8-100 (2g) were added. The resulting mixture was stirred for 13–14 h during which time the organic solids progressively dissolved. The resin was filtered and washed with diethyl ether. The organic solution was transferred into a separator funnel and the red aqueous phase was removed. The organic solution was then cooled with a water-ice bath and neutralized by addition of saturated aqueous solution of Na2CO3. After which, organic layer was then washed with water, brine and dried over Na2SO4 and solvent was evaporated under reduced pressure to obtain optically pure aldehydes

Example 22
Process for synthesis of (3R)-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methyl-1-nitropentan-2-ol [XXVIII] from (R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutanal [XXVII]

A reactor equipped with reflux condenser, dropping funnel, overhead stirrer and nitrogen gas inlet was charged with lithium aluminium hydride (0.03 g) under nitrogen atmosphere and anhydrous tetrahydrofuran (30 mL) was added slowly under mild stirring. To the above reaction mixture, nitromethane (2.6 g) was added drop wise and resultant reaction mixture was stirred for 1h at RT after which, a solution of (R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutanal (2.5 g) in tetrahydrofuran (15 mL) was added slowly and then stirred for 24 h at room temperature. The reaction was quenched by adding methanol (20 mL) and filtered through Celite bed to remove solids. The mother liquor was evaporated under reduced pressure to afford (3R)-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methyl-1-nitropentan-2-ol (2.2 g) as oil.
FT IR Spectra: cm-1: 3434, 2932, 2875, 1606, 1589, 1553, 1513, 1465, 1424, 1385, 1236.
1H NMR (400 MHz, CDCl3):  0.96-1.04. (m, 6H), 1.62-1.63 (m, 1H), 1.65-169 (m1H), 1.99-2.09 (m, 2H), 2.46-2.49 (m, 1H), 2.87-288 (m, 1H), 3.34 (s, 3H), 3.54-3.58 (t, 2H), 3.82 (s, 3H), 4.07-4.09 (m, 2H), 4.12-4.17 (m, 1H) 4.23-4.28 (m, 1H) 6.69-6.79 (m, 3H)
13C NMR (100 MHz, CDCl3): 18.2, 20.1, 21.5, 27.3, 29.5, 31.3, 49.4, 56.0, 58.6, 66.0, 69.9, 80.5, 112.0, 114.1, 121.1, 131.6, 147.9, 148.4
C18H29NO6 requires 355.20, [M+H]+ = 356.25

Example 23
Process for synthesis of (R)-4-(2-isopropyl-4-nitrobut-3-en-1-yl)-1-methoxy-2-(3-methoxypropoxy) benzene [XXIX] from (3R)-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methyl-1-nitropentan-2-ol [XXVIII]

A reactor equipped with reflux condenser, dropping funnel and overhead stirrer was charged with (3R)-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methyl-1-nitropentan-2-ol (1.5 g) and dissolved in dichloromethane (25 mL) at ambient temperature. To the above solution, was added triethylamine (0.65 mL) and reaction mass was cooled to 0 0C. At this temperature, methane sulfonyl chloride (0.54 mL) dissolved in dichloromethane (10 mL) was added to the reaction mass very slowly so as to maintain temperature at 0 0C. The resultant reaction mass was stirred at ambient temperature for 3 h while progress of reaction was monitored by TLC. After complete conversion of starting material, reaction mass was quenched by slowly adding 20 mL water at 0 0C and layers were separated. The organic layer was washed with water (2 x 20 mL) and brine and evaporated under reduced pressure to afford (R)-4-(2-isopropyl-4-nitrobut-3-en-1-yl)-1-methoxy-2-(3-methoxypropoxy) benzene (1.1 g) as yellow oil.
1H NMR (400 MHz, CDCl3):  0.96-1.04. (m, 6H), 1.80-1.87 (m, 1H), 2.06-2.12 (m, 2H), 2.31-2.36 (m, 1H), 2.56-2.59 (m, 1H), 2.84-2.89 (m, 1H), 3.36 (s, 3H), 3.56-3.59 (t, 2H), 3.83 (s, 3H), 4.05-4.09 (m, 2H), 6.60-6.77 (m, 4H), 7.09-7.15 (m, 1H)
13C NMR (100 MHz, CDCl3): 18.6, 20.8, 29.5, 31.1, 37.7, 47.9, 50.7, 55.9, 58.6, 66.1, 69.3, 111.7, 114.0, 121.1, 131.4, 139.9, 148.0, 148.3
C18H27NO5 requires 337.19, [M+H]+ = 338.40

Example 24
Process for synthesis of (S)-4-(2-isopropyl-4-nitrobutyl)-1-methoxy-2-(3-methoxypropoxy)benzene [II] from (R)-4-(2-isopropyl-4-nitrobut-3-en-1-yl)-1-methoxy-2-(3-methoxypropoxy) benzene [XXIX]

A reactor equipped with reflux condenser, dropping funnel and overhead stirrer was charged with (R)-4-(2-isopropyl-4-nitrobut-3-en-1-yl)-1-methoxy-2-(3-methoxypropoxy) benzene (1.0 g) and dissolved in methanol (25 mL) at ambient temperature. The reaction mass was cooled to 0 0C and sodium borohydride (0.13 g) was added to it in portions at the same temperature and stirred for 2 h during which the reaction was monitored by TLC. After complete conversion of starting material, reaction mass was quenched with dilute ammonium chloride solution (30 mL) and solvent evaporated under reduced pressure to give a residue to which was added water (50 mL) and ethyl acetate (50 mL). After separation of the layers, the organic layer was washed with brine and solvent evaporated to afford (S)-4-(2-isopropyl-4-nitrobutyl)-1-methoxy-2-(3-methoxypropoxy)benzene (0.88 g) as a clear oil.
FT IR Spectra: cm-1 2959, 2875, 1737, 1606, 1589, 1552, 1515, 1464, 1385, 1260, 1238, 1140, 1120, 1027.
1H NMR (400 MHz, CDCl3):  0.91-0.92 (d, 3H), 0.95-0.97 (d, 3H), 1.57 -1.60 (m, 1H), 1.70-176 (m, 1H), 1.81-1.90 (m, 1H), 2.02-2.15 (m, 3H), 2.31-2.37 (dd, 1H), 2.64-2.69 (dd, 1H), 3.37 (s, 3H), 3.58-3.61 (t, 2H), 3.85 (s, 3H), 4.10-4.13 (t, 2H),4.19-4.23 (t, 2H) 6.68-6.70 (m, 2H), 6.79-6.81 (d, 1H)
13C NMR (100 MHz, CDCl3): 18.5, 18.9, 28.4, 29.4, 29.5, 36.7, 43.2, 56.0, 58.7, 66.0, 69.3, 74.6, 111.7, 113.9, 121.0, 132.9, 147.8, 148.4,
C18H29O5 requires 339.20, [M+H]+ = 340.2

WE CLAIM:

1. A process for the preparation of (S)-4-(2-isopropyl-4-nitrobutyl)-1-methoxy-2-(3-methoxypropoxy) benzene of the formula [II]

comprising the reaction of (S)-4-(4-iodo-2-isopropylbutyl)-1-methoxy-2-(3-methoxypropoxy) benzene of the formula [VIII]

with a metal nitrite of the formula MNO2 wherein M is selected from sodium, potassium and silver.

2. The process as claimed in claim 1 wherein (S)-4-(2-isopropyl-4-nitrobutyl)-1-methoxy-2-(3-methoxypropoxy) benzene of the formula [II] is prepared by process

comprising
(i) preparing (S)-3-(4-methoxy-3-(3-methoxypropoxy) benzyl)-4-methylpentanoic acid of the formula [VI] by the reaction of (R)-4-(2-(chloromethyl)-3-methylbutyl)-1-methoxy-2-(3-methoxypropoxy) benzene of the formula [IV] with dimethyl carbonate or diethyl carbonate in the presence of metallic magnesium to prepare a compound of formula [V] and subsequent hydrolysis of the said compound of formula [V]

(ii) preparing (S)-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentan-1-ol of the formula [VII] by reduction of (S)-3-(4-methoxy-3-(3-methoxypropoxy) benzyl)-4-methylpentanoic acid of the formula [VI]

(iii) preparing (S)-4-(4-iodo-2-isopropylbutyl)-1-methoxy-2-(3-methoxypropoxy)benzene of the formula [VIII] by the reaction of (S)-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentan-1-ol of the formula [VII] with iodine

(iv) transforming (S)-4-(4-iodo-2-isopropylbutyl)-1-methoxy-2-(3-methoxypropoxy)- benzene of the formula [VIII] to (S)-4-(2-isopropyl-4-nitrobutyl)-1-methoxy-2-(3-methoxypropoxy) benzene of the formula [II] with an metal nitrite of the formula MNO2 wherein M is selected from sodium, potassium and ammonium.
3. 3. The process as claimed in claim 1 wherein (S)-4-(2-isopropyl-4-nitrobutyl)-1-methoxy-2-(3-methoxypropoxy) benzene of the formula [II] is prepared by process

comprising
(i) preparing 1-(4-methoxy-3-(3-methoxypropoxy)phenyl)-3-methylbutan-1-ol of the formula [IX] from 4-methoxy-3-(3-methoxypropoxy)benzaldehyde

(ii) preparing ethyl 3-(4-methoxy-3-(3-methoxypropoxy)benzoyl)-4-methylpentanoate of the formula [XI] from 1-(4-methoxy-3-(3-methoxypropoxy)phenyl)-3-methylbutan-1-ol of the formula [IX] by oxidation and alkylation

(iii) transforming ethyl 3-(4-methoxy-3-(3-methoxypropoxy)benzoyl)-4-methylpentanoate of the formula [XI] to 3-(4-methoxy-3-(3-methoxypropoxy)benzoyl)-4-methylpentanoic acid of the formula [XII]

(iv) preparing (S)-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentanoic acid of the formula [VI] from 3-(4-methoxy-3-(3-methoxypropoxy)benzoyl)-4-methylpentanoic acid of the formula [XII] by reduction of the conjugated carbonyl group followed by chiral separation of the resulting racemic product of the formula [XIII] to yield [VI]

(v) reducing the compound of formula [VI] to prepare (S)-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentan-1-ol of the formula [VII]

(vi) preparing (S)-4-(4-iodo-2-isopropylbutyl)-1-methoxy-2-(3-methoxypropoxy)benzene of the formula [VIII] by the reaction of (S)-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentan-1-ol of the formula [VII] with iodine

(vii) transforming (S)-4-(4-iodo-2-isopropylbutyl)-1-methoxy-2-(3-methoxypropoxy)- benzene of the formula [VIII] to (S)-4-(2-isopropyl-4-nitrobutyl)-1-methoxy-2-(3-methoxypropoxy) benzene of the formula [II] with an metal nitrite of the formula MNO2 wherein M is selected from sodium, potassium and ammonium.

4. The process as claimed in claim 1 wherein (S)-4-(2-isopropyl-4-nitrobutyl)-1-methoxy-2-(3-methoxypropoxy) benzene of the formula [II] is prepared by process

comprising
(i) preparing diethyl 2-(4-methoxy-3-(3-methoxypropoxy)benzyl)malonate of the formula [XVI] by the reaction of 4-methoxy-3-(3-methoxypropoxy)benzaldehyde with diethyl malonate and hydrogenation of the resulting compound of the formula (XV)

(ii) preparing diethyl 2-isopropyl-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)malonate of the formula [XVII] by alkylation of diethyl 2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-malonate of the formula [XVI]

(iii) preparing 4-(2-(chloromethyl)-3-methylbutyl)-1-methoxy-2-(3-methoxypropoxy)-benzene of the formula [XX] by decarboxylation of diethyl 2-isopropyl-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)malonate of the formula [XVII], reduction of the resulting compound [XVIII] to prepare a compound of formula [XIX] and transforming the compound of formula [XIX] to 4-(2-(chloromethyl)-3-methylbutyl)-1-methoxy-2-(3-methoxypropoxy)benzene of the formula [XX]

(iv) preparing 3-(4-methoxy-3-(3-methoxypropoxy) benzyl)-4-methylpentanoic acid of the formula [XIII] by the reaction of 4-(2-(chloromethyl)-3-methylbutyl)-1-methoxy-2-(3-methoxypropoxy) benzene of the formula [XX] with dimethyl carbonate or diethyl carbonate in the presence of metallic magnesium to prepare a compound of formula [XXI] and hydrolysis of the said compound of formula [XXI]

(v) preparing (S)-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentan-1-ol of the formula [VII] by chiral chromatography of 3-(4-methoxy-3-(3-methoxypropoxy) benzyl)-4-methylpentanoic acid of the formula [XIII] to yield (S)-3-(4-methoxy-3-(3-methoxypropoxy) benzyl)-4-methylpentanoic acid of the formula [VI] and reduction of the said compound of formula [VI]

(vi) preparing (S)-4-(4-iodo-2-isopropylbutyl)-1-methoxy-2-(3-methoxypropoxy)benzene of the formula [VIII] by the reaction of (S)-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentan-1-ol of the formula [VII] with iodine

(vi) transforming (S)-4-(4-iodo-2-isopropylbutyl)-1-methoxy-2-(3-methoxypropoxy)- benzene of the formula [VIII] to (S)-4-(2-isopropyl-4-nitrobutyl)-1-methoxy-2-(3-methoxypropoxy) benzene of the formula [II] with an metal nitrite of the formula MNO2 wherein M is selected from sodium, potassium and ammonium.
5. A process for the preparation of (S)-4-(2-isopropyl-4-nitrobutyl)-1-methoxy-2-(3-methoxypropoxy) benzene of the formula [II]

comprising
(i) preparing ethyl 2-cyano-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutanoate of the formula [XXIV] by reacting 4-(bromomethyl)-1-methoxy-2-(3-methoxypropoxy)benzene of the formula [XXII] with ethyl 2-cyano-3-methylbutanoate of the formula [XXIII] in presence of a base

(ii) transforming 2-cyano-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutanoate of the formula [XXIV] to 2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutanenitrile of the formula [XXV] by decarboxylation in presence of an alkali metal chloride

(iii) preparing (R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutanal of the formula [XXVII] by reduction of 2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutanenitrile of the formula [XXV] followed by separation of the said compound of formula [XXVII] in presence of S-Betti base

(iv) transforming (R)-2-(4-methoxy-3-(3-methoxypropoxy)benzyl)-3-methylbutanal of the formula [XXVII] to (3R)-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methyl-1-nitropentan-2-ol of the formula [XXVIII] with nitromethane

(v) preparing (R)-4-(2-isopropyl-4-nitrobut-3-en-1-yl)-1-methoxy-2-(3-methoxypropoxy) benzene of the formula [XXIX] from (3R)-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methyl-1-nitropentan-2-ol of the formula [XXVIII]

(vi) transforming (R)-4-(2-isopropyl-4-nitrobut-3-en-1-yl)-1-methoxy-2-(3-methoxy-propoxy) benzene of the formula [XXIX] to (S)-4-(2-isopropyl-4-nitrobutyl)-1-methoxy-2-(3-methoxypropoxy) benzene of the formula [II].
9. A compound selected from

wherein in the compound [V] R is selected from CH3 and C2H5.
10. A compound selected from
.
11. A process for the preparation of aliskiren of the formula [I]

comprising preparation of (S)-4-(2-isopropyl-4-nitrobutyl)-1-methoxy-2-(3-methoxypropoxy) benzene of the formula [II],

which comprises a reaction of (S)-4-(4-iodo-2-isopropylbutyl)-1-methoxy-2-(3-methoxypropoxy) benzene of the formula [VIII] with a metal nitrite of the formula MNO2

wherein M is selected from sodium, potassium and silver.

ABSTRACT

Present invention relates to a process for the preparation of (S)-4-(2-isopropyl-4-nitrobutyl)-1-methoxy-2-(3-methoxypropoxy) benzene [II], which is a key intermediate for synthesis of Aliskiren [I].