Field of the Invention
The present invention relates to a novel process for preparation of a drug for hypertension and a renin inhibitor. More specifically, the present invention relates to processes for preparation of Aliskiren, its novel intermediates and certain novel compounds.
Background Art
Renin inhibitors are known in the art. Aliskiren as renin inhibitor is also generally known in the art and is depicted structurally as below.

A(XV)
US 5559111 granted to Richard Goschke et al teaches Aliskiren and process for making Aliskiren.
Publications EP-A-1215201, WO2006/131304 and WO2008/119804 teaches alternative route to make Aliskiren.
Although the existing processes may lead to the desired renin inhibitors, there exists a need to provide an alternative synthetic route to ensure Its manufacture in a simple and efficient manner.
Objects of the invention
It is an object of the invention to develop a novel method of preparing Aliskiren and its pharmaceutically acceptable salts.

It is another important object of the invention to develop an efficient process for making Aliskiren.
It is yet another important object of the invention to develop a safe and simple process for making Aliskiren.
It is yet another important object of the invention to develop novel intermediate compounds.
Summary of the Invention
Accordingly, to meet the stated objectives and to overcome the disadvantages of the prior art, it is herein disclosed a process of making a compound of the formula

A(XV)
and its pharmaceutically acceptable salts comprising the steps of: a) converting compound (A) of the formula

by adding p-Toluenesulfonic acid in a solvent, preferably acetone, at ambient temperature to yield compound A (I) of the formula


b) reacting A (I) in a suitable solvent, preferably a mixture of methanol and water in
the presence of hydrochloric acid, to give a compound A (II) of the formula

A (II) .
c) oxidizing A (II) with sodium periodate followed by reaction with ethyl
diethoxyphosphinyl acetate and extracting with ethyl acetate to yield compound
A(III) of formula


d) reducing A (III) over Palladium on carbon in a suitable solvent, preferably
methanol to yield a compound A (IV) of formula

A (IV)
9
e) acidifying A(IV) with a suitable reagent, preferably triflouroacetic acid, to yield a
compound A (V) of formula

f) activating A (V) with LiHMDS in the presence of TMEDA (tetra methyl ethylene
diamine) at subzero temperatures, followed by addition of acetone at the same
temperature to give a compound A (VI) of formula

g) dehydrating A (VI) in the presence of phosphprusoxychloride in a suitable
solvent, preferably pyridine at room temperature to yield a compound A (VII) of
formula


h) reducing A (VII) in the presence of Pd/C in a suitable solvent, preferably methanol to result in a compound A (VIII) of formula

i) reacting compound B(V) of formula

B (V)
with A (VIII) in a suitable solvent, preferably tetrahydrofuran, to yield a compound A (IX) of formula


j) sulphonating A (IX) at sub zero temperatures in the presence of a suitable solvent, preferably methylene chloride to yield a compound A (X) of formula

k) reacting A (X) with sodium azide to give a compound A (XI) of formula


1) hydrogenating of A (XI) to give A (XII)

m) reacting A (XII) with suitable reagents and solvent mixtures to give A (XIII)


n) reacting ofa compound B(VI) of formula

B(VI)
with A (XIII) in a suitable solvent, preferably triethylamine, to yield a compound A (XIV) of formula

A(XIV)

o) deprotecting A(XIV) in trifluoroacetic acid and hydrogenolyse in a mixture of solvents, preferably methanol-water to yield a compound A(XV).

A (XV) Also disclosed is a process of making a compound of the formula A(XV)

A(XV) and its pharmaceutically acceptable salts comprising the steps of:
a) de-oxygenating A(IX) in the presence of Pd/C in a suitable solvent preferably methanol to yield a compound C(I) of formula.

C(l) .

b) sulphonating C(I) at sub zero temperatures in the presence of a suitable solvent,
preferably methylene chloride to yield a compound C(II) of formula

c) reacting C(II) with sodium azide to give a compound C(III) of formula

d) hydrogenating C(III) with suitable reagents and solvent mixture to give (CIV)


e) reacting compound B(VI) with C(IV) in a suitable solvent , preferably
triethylamine to yield a compound C(V) of formula

C(V)
f) reacting compound C(V) with DEAD, TPP followed by deprotection with
trifluoroacetic acid yield a compound A(XV)

A(XV)

The compound of formula A(XV) as obtained can be converted into its hemifumerate salt as per the procedure disclosed in US 6,730,798. Novel Intermediates
The present invention further encompasses certain novel intermediate compounds of Aliskiren which form part of this invention: Also disclosed is a compound A (I) of the formula

A(l) or a salt thereof

or a salt thereof.
Also disclosed is a compound A (III) of the formula


or a salt thereof.
Also disclosed is a compound A (IV) of the formula

A (IV) or a salt thereof.
Also disclosed is a compound A (V) of the formula

or a salt thereof
Also disclosed is a compound A (VI) of the formula


Also disclosed is a compound A (VII) of the formula

A (VII) or a salt thereof.
Also disclosed is a compound A (VIII) of the formula

A (VIII) or a salt thereof. Also disclosed is a compound A (IX) of the formula


A (IX) or a salt thereof.
Also disclosed is a compound A (X) of the formula

A(X) or a salt thereof
Also disclosed is a compound A (XI) of the formula


A (XI) or a salt thereof.
Also disclosed is a compound A (XII) of the formula

A (XII) or a salt thereof.
Also disclosed is a compound A(XIII) of the formula


A (XIII) or a salt thereof.
Also disclosed is a compound A(XIV) of the formula

A(XIV) or a salt thereof.
Also disclosed is a compound A (XV) of the formula


A(XV)
and its pharmaceutically acceptable salts.
Also disclosed is a compound C (I) of the formula

C(I) or a salt thereof
Also disclosed is a compound C (II) of the formula


C(II) or a salt thereof.
Also disclosed is a compound C (III) of the formula

or a salt thereof.
Also disclosed is a compound C (IV) of the formula


C(IV) or a salt thereof.
Also disclosed is a compound C (V) of the formula

C(V) or a salt thereof
Detailed description of the invention
The invention will now be described in detail in connection with certain preferred and
optional embodiments, so that various aspects thereof may be more fully understood and
appreciated.
Accordingly, this invention describes novel processes for preparation of Aliskiren and its
novel intermediates. The invention further discloses certain novel intermediate
compounds of Aliskiren and salts thereof

The phrase 'salt' as used herein means and includes of any salt of the novel intermediate compounds of the invention that may be stable under normal storage conditions and easy to process in further reactions in the method of obtaining aliskiren.
The general process for the preparation of compounds A(I) to A(XV) can be described as follows:
It is herein disclosed a process of making a compound A (XV) of the formula

A(XV)
and its pharmaceutically acceptable salts, comprising the steps of:
a) converting compound (A) of the formula

by adding p-Toluenesulfonic acid in a solvent, preferably acetone, at ambient temperature to yield compound A (I) of the formula


A(l)
5
b) reacting A (I) in a suitable solvent, preferably a mixture of methanol and
water in the presence of hydrochloric acid, to give a compound A (II) of
the formula

A (II) .
s
c) oxidizing A (II) with sodium periodate followed by reaction with ethyl
diethoxyphosphinyl acetate and extracting with ethyl acetate yields
compound A(III) of formula.

d) reducing A (III) over Palladium on carbon in a suitable solvent, preferably
methanol to yield a compound A (IV) of formula


A (IV)
e) acidifying A(IV) with a suitable reagent, preferably triflouroacetic acid, to
yield a compound A (V) of formula

f) activating A (V) with LiHMDS in the presence of TMEDA (tetra methy
ethylene diamine) at subzero temperatures, followed by addition of
acetone at the same temperature to give a compound A (VI) of formula

g) dehydrating of A (VI) in the presence of phosphorusoxychloride in a
suitable solvent, preferably pyridine at room temperature to yield a
compound A (VII) of formula

A (VII)

h) reducing A (VII) in the presence of Pd/C in a suitable solvent, preferably methanol to result in a compound A (VIII) of formula

A (VIII) i) reacting compound B(V) of formula

B(V) with A (VIII) in a suitable solvent, preferably tetrahydrofuiran, to yield a compound A (IX) of formula

A (IX)

j) sulphonating A (IX) at sub zero temperatures in the presence of a suitable solvent, preferably methylene chloride to yield a compound A (X) of formula

A(X) k) reacting A (X) with sodium azide to give a compound A (XI) of formula

1) hydrogenating A (XI) to give A (XII)


A (XII)
m) reacting A (XII) with suitable reagents and solvent mixtures to give A (XIII)

A (XIII) n) reacting compound B(VI) of formula

B(VI)

with A (XIII) in a suitable solvent, preferably triethylamine, to yield a compound A (XIV) of formula

A(XIV)
o) deprotecting A(XIV) ) in trifluoroacetic acid and hydrogenolyse in a mixture of solvents, preferably methanol-water to yield a compound A(XV).

A(XV)
In another embodiment, a process for preparation of compound of the formula


A(XV)
and its pharmaceutically acceptable salts comprising the steps of:
a) de-oxygenating A(IX) in the pressure of Pd/C in a suitable solvent preferably
methanol to yield a compound C(I) of formula.

C(I)
b) sulphonating C(I) at sub zero temperatures in the presence of a suitable solvent,
preferably methylene chloride to yield a compound C(II) of formula


C(II)
9
c) reacting C(II) with sodium azide to give a compound C(III) of formula

d) hydrogenating C(III) with suitable reagents and solvent mixture to give (CIV)


e) reacting compound B(VI) with C(IV) in a suitable solvent, preferably
triethylamine to yield a compound C(V) of formula

f) reacting compound C(V) with DEAD, TPP followed by deprotection with
trifluoroacetic acid yield a compound A(XV)

A(XV)

The preparation of Aliskiren and various novel intermediates involved in the processes of preparation of Aliskiren and the characterization of the same by spectral data according to the invention is further described in the following steps:
Step 1 Synthesis of A (I)
p-Toluenesulfonic acid is added to a solution of D-Mannitol, 2,2-Dimethoxy propane in acetone at ambient temperature. The solution is refluxed for 24 hours and acetone is removed under reduced pressure. The crude product is then poured into cold water and stirred for 30 minutes. The resulting white solid is filtered and dried under vacuum to yield A (I).
H'-NMR (300 MHz, CdCl3) - 6(ppm) 1.31 (s, 6H), 1.38 (s, 6H), 1.42 (s, 6H), 3.9-4.0 (dd, 4H), 4.06 (t, 2H), 4.2 (m, 2H)
C'^-NMR (300 MHz, CdCl3) - 5 (ppm) 25.22, 26.40, 27.38, 66.18, 76.29, 79.40, 109.41, 109.97 Mass - MH*: 303
Step2
Synthesis of A (II)
Hydrochloric acid is added drop wise to a solution of A (I) dissolved in a mixture of methanol and water at ambient temperature. The reaction mass is stirred and neutralized with potassium carbonate at ambient temperature. The solvent is removed under reduced pressure and the crude product is azeotroped with toluene to remove traces of water. Acetone is added to the crude product and stirred to obtain a solid that is filtered and washed with acetone. The filtrate is concentrated under reduced pressure and azeotroped with toluene to yield A (II) as solid.

H'-NMR (300 MHz, CdCla) - ?(ppm) 1.29 (s, 6H), 3.3-3.38 (m, 2H), 3.4-3.59 (m, 2H), 3.8-3.9 (d, 2H), 4.4-4.5 (t, 2H), 5.1 (d, 2H)
Step 3
Synthesis of A (III)
Sodium metaperiodate is added portion wise to a stirred solution of A (II) dissolved in aqueous sodium hydrogenocarbonate solution at O-S^C over a period of 1 hr. The resultant solution is stirred for 2 h at the same temperature. Then ethyl diethoxyphosphinyl acetate is added drop wise over a period of 1 hr followed by aqueous ION potassium carbonate solution and the reaction mixture was stirred for 16 hrs at ambient temperature. On completion, the reaction mixture is extracted into ethyl acetate. The organic layer is washed with saturated brine, dried over sodium sulphate and concentrated to give a yellow oil of A (III). The crude product is dissolved in hexane and passed through silica gel. Hexane is removed under reduced pressure to give A (III).
H'-NMR (300 MHz, CdCl3) - d, (ppm) 1.22-1.35 (t, 6H), 1.45-1.50 (s, 6H), 4.15-4.30 (qt, 4H), 4.25-4.35 (d, 2H), 6.1-6.2 (d, 2H), 6.8-6.9 (d, 2H)
C'^-NMR (300 MHz, CdCU) - 5 (ppm) 13.8, 26.4, 60.1, 79.40, 110.3, 123.2, 141.8, 165.02
Step 4
Synthesis of A (IV)
10% Palladium on carbon is added to a solution of A (III) in methanol and hydrogenated at 60 psi pressure. On completion of the reaction, the solution is filtered through celite and the residue is washed with methanol. The solvent is removed under reduced pressure to give A (IV).
H'-NMR (300 MHz, CdCl3) - § (ppm) 1.22-1.28 (t, 6H), 1.4 (s, 6H), 1.7-1.8 (m, 2H), 1.9-2.0 (m, 2H), 2.39-2.6 (m, 4H), 3.6 (d, 2H), 4.1-4.2 (qt, 4H)

C'^-NMR (300 MHz, CdCl3) - 5 (ppm) 14.2. 27.2, 28.7, 30.6, 60.1, 60.4, 79.5, 108.4, 173.1
Step 5
Synthesis of A (V)
Trifluoroacetic acid is added to a solution of A (IV) containing acetonitrile and H20 at ambient temperature. The reaction mixture is then refluxed for 6 hrs. The solvent is removed under reduced pressure and the obtained crude compound is purified by column chromatography to yield A (V).
H'-NMR (300 MHz, CdCl3) - § (ppm) 2.2-2.4 (m, 4H), 2.4-2.78 (m, 4H), 4.5-4.62 (t,2H).
C'^-NMR (300 MHz, CdCl3) - 5 (ppm) 23.7, 27.9, 80.2,176.6
Mass-MH~: 169
Step 6
Synthesis of A (VI)
Lithium hexamethyldisilazide (LiHMDS) is added drop wise to a solution of A (V) and tetramethylethylenediamine in tetrahydrofuran at -78 °C over a period of 1 h. The reaction mixture is stirred at the same temperature for 2 h and acetone is added drop wise at -78 °C for 1 hr and stirred at the same temperature for 2 more hours. The reaction mixture is later quenched with 10% aqueous hydrochloric acid and diluted with ethyl acetate. The organic layer is separated and the aqueous layer is extracted with ethyl acetate. The combined organic layers are dried over sodium sulphate and concentrated under reduced pressure. The obtained residue is purified by column chromatography with silicagel to yield A (VI).

H'-NMR (300 MHz, CdCU) - 6. (ppm) 1.2 (s, 6H), 1.4 (s, 6H), 2.3-2.4 (m, 4H), 2.8-3.0 (m, 4H), 4.6 (m, 2H)
C'^-NMR (300 MHz, CdCl3) - 8 (ppm) 26.3, 28.9,49.2, 69.9, 78.6, 176.2
Step 7
Synthesis of A (VII)
Phosphorousoxychloride is added drop wise to a solution of A (YI) dissolved in pyridine at 10 °C for 30 min. The reaction mixture is stirred at room temperature for 12 hrs. On completion of reaction, pyridine is removed under reduced pressure and the residue is cooled to 0 °C. Cold water is added and the pH is adjusted to 5.5 using 10% aqueous hydrochloric acid. Then the compound is extracted into ethyl acetate and combined organic extracts are dried over sodium sulphate and removed under reduced pressure. The obtained compound is purified by column chromatography with silica gel using hexane and ethyl acetate as solvent to yield A (VII).
H*-NMR (300 MHz, CdCl3) - 5. (ppm) 1.9 (s, 6H), 2.2 (s, 6H), 2.78-3.0 (s, 4H), 4.5-4.6 (t, 2H),
C'^-NMR(300MHz,CdCl3)-5(ppm) 19.9,24.5,29.1,75.0,118.1,151.3,169.1
Mass-MH~: 249
Step 8
Synthesis of A (VIII)
10% Pd/C is added to a solution of A (VII) in of methanol and hydrogenated at 60 psi for 4 hrs. On completion, reaction mixture is filtered through celite and residue is washed with methanol. The filtrate is removed under reduced pressure and the residue is azeotroped with toluene to yield A (VIII) as white solid.

H'-NMR (300 MHz, CdCl3) - ^(ppm) 0.9-1.0 (d, 6H), 1.05-1.15 (d, 6H), 1.9-2.1 (m, 2H), 2.15-2.3 (m, 4H), 2.59-2.7 (m, 2H), 4.31-4.49 (t, 2H)
C'^-NMR (300 MHz, CdCl3) - 6 (ppm) 18.3, 20.6, 25.8, 27.7, 46.4, 176.7
Mass - MH": 253
Step 9
Synthesis of A (IX)
A mixture of B (V), tetramethylethylenediamine in tetrahydrofuran is added dropwise to a solution of n-Butyllithium in tetrahydropyran at -78 °C over a period of 20 min. The reaction mixture is stirred for 1 h and a solution of A (VIII) in tetrahydrofuran is added drop wise over a period of 20 min at -78 °C. The reaction mixture is stirred at the same temperature for 1 hr and then quenched with IN aqueous hydrochloric acid (pH to ~7). The reaction mixture is warmed to 0°C and extracted into ethyl acetate. The organic layer is separated, dried over sodium sulphate and concentrated under vacuum. The crude compound thus obtained is purified by column chromatography with silica gel using hexane and ethylacetate as solvent to yield A (IX).
H'-NMR (300 MHz, CdCl3) - 8(ppm) 0.9-1.1 (4d, 12H), 1.6-1.9 (m, 2H), 2-2.3 (m, 7H), 2.6 (m, 1H), 3.35 (s, 3H), 3.5 (m, 1H), 3.65 (t, 2H), 3.9 (s, 3H), 4.19 (m, 1H), 4.2 (t, 2H), 6.9 (d, 1H), 7.6 (s, 1H), 7.65 (d, 1H)
C'^-NMR (300 MHz, CdCh) - 5 (ppm) 18.5, 20.0, 20.6, 20.8, 25.6, 27.6, 29.4, 31.0, 32.3, 46.2, 47.5, 56.2, 58.3, 65.9, 68.9, 70.5, 80.4, 111.5, 112.3, 123.2, 131.2,148.3,153.5,178.0,201.9
Mass-MH^: 451 HPLC: 96.26%

step 10 Synthesis of A (X)
Methanesulfonyl chloride is added drop wise to a solution of A (IX) in methylenechloride at -10 °C. Triethylamine is added drop wise for a period of 5 min. The progress of the reaction is monitored, after completion, the reaction mixture is diluted with methylenechloride and washed with water. The organic layer is separated, dried over sodium sulphate and concentrated under vacuum. The crude compound obtained is purified by column chromatography with silicagel using hexane and ethylacetate as solvent to yield A (X).
H'-NMR (00 MHz, CdCl3) - 5(ppm) 0.6-1.1 (4d, 12H), 1.6-1.7 (m, 1H),1.7-1.95 (m, 1H), 2.1-2.19 (m, 4H), 2.2-2.4 (m, 3H), 2.6-2.7 (m, 1H), 3.1(s, 3H), 3.35 (s, 3H), 3.6 (t, 2H), 3.7-3.8 (d, 1H), 3.9 (s, 3H), 4.1-4.2 (t, 2H), 4.4 (d, 1H), 6.9 (d, 1H), 7.5 (s, 1H), 7.6 (d, 1H)
Mass-MH^: 529
Step 11
Synthesis of A (XI)
Sodium azide is added to a stirred solution of A (X) dissolved in dry N,N-dimethylformamide. tetrabutylammoniumhydrogen sulfate is added to the reaction mixture and heated to 90 °C for 36 h. After completion of the reaction, solvent is removed under reduced pressure to give crude compound. The crude compound is purified by column chromatography to give A (XI) as a thick liquid.
H'-NMR (300 MHz, CdCl3) - 5 (ppm) 0.8-1.1 (4d, 12H), 1.75-2.3 (m, 9H), 2.52-2.62 (m, 1H), 3.4 (s, 3H), 3.6-3.69 (t, 2H), 3.65-3.7 (m, 1H), 3.87-3.93 (s, 3H), 4.2-4.28 (t, 2H), 4.3-4.4 (m, 1H), 6.8-6.9 (d, 1H), 7.5 (Br-s, 2H)

C'^-NMR (300 MHz, CdCl3) - 8 (ppm) 17.00, 18.49, 19.4, 19.8, 24.2, 26.6, 28.4, 28.9, 30.3, 45.1, 47.8, 55.0, 57.6, 62.7, 65.1, 68.2, 78.1, 109.4, 111.1, 121.6, 129.7,147.7,152.8,175.8,200.1
Mass - MPf: 476
IR- 1778.05 (phCO) 1664.27 (CO) 2136.74 (N^)
Step 12
Synthesis of A (XII)
10% Palladium on carbon is added to etlianol/water (9:1) solution containing A (XI), di-tertiary-butyl dicarbonate and triethylamine. The resultant solution is hydrogenated at 60psi for 16h. On completion of the reaction, the reaction mixture is filtered through celite and concentrated under reduced pressure. The crude compound is purified by column chromatography with silicagel using hexane and ethylacetate as solvent to yield A (XII) as thick liquid.
H'-NMR (300 MHz, CdCl3) - ^ (ppm) 0.7-1.2 (4d, 12H), 1.3-1.58 (Br-s, 9H), 1.63-1.68 (m, 1H), 1.99-2.12 (Br-m, 3H), 2.14-2.4 (m, 4H), 2.53-2.58 (m, 1H), 3.34-3.38 (s, 3H), 3.58-3.62 (t, 2H), 3.84-3.9 (s, 3H), 3.9-4.0 (m, 1H), 4.19-4.21 (t, 2H), 4.7-4.8 (Br-s, 1H), 5.3-5.4 (Br-s, 1H), 6.7-6.8 (d, 1H), 6.86-6.9 (Br-s, 1H), 7.1 (s, 1H)
C^^-NMR (300 MHz, CdCl3) - 6 (ppm) 18.3, 20.6, 21.3, 22.0, 27.2, 27.5, 28.3, 29.4, 46.7, 50.1, 55.9, 58.5, 61.1, 65.7, 66.1, 69.6, 79.9, 110.7, 113.3, 121.3, 133.5, 148.1,148.2,155.6,177.4
Mass-MH^+NHa: 551 MH^: 534

IR- 3041.9, 2964.09, 1766.48, 1677.77, 1513.85, 1394.25, 1369.21
Step 13
Synthesis of A (XIII)
Aqueous solution of potassium hydroxide is added to a solution of A (XII) dissolved in a mixture of THF-water-methanol at 0°.C. The reaction mixture is stirred at the same temperature for lOhrs. After completion of reaction, the reaction mixture is extracted with ether and amberlite IR-120 resin (rf^) is added to the aqueous layer and stirred till PH~4 is attained. Then, DCM is added to the aqueous layer and extracted with DCM. The combined organic solutions are dried over sodium sulfate and concentrated under reduced pressure. The compound thus obtained is dried for Ihr to afford hydroxy-acid intermediate. Hydroxy-acid is dissolved in THF cooled to 0''c and triphenylphosphine followed by diethyl azodicarboxylate is added. The resulting yellow solution is stirred for lOhrs. at ambient temperature and the solvent is removed under reduced pressure. The crude compound thus obtained is purified by column chromatography with silica-gel using ethyl acetate: hexane as solvents to afford A (XIII).
H'-NMR (300 MHz, CdCl3) - □(ppm) 0.77-0.79 (d, 3H), 0.86-0.88 (d, 3H),0.88-0.90(d,3H),0.97-0.99 (d,3H),l.10-1.30 (br-pealc, 9H), 1.78-1.86(m,lH), 2.0-2.06 (m, 2H), 2.08-2.16 (br-m, 3H), 2.50 2.60(br-m,lH),3.27(s, 3H), 3.50 (t, 2H), 3.77(s,3H), 4.04-4,lO(br-m, 3H), 4.20-44.40 (br-pealc,2H), 6.72-6.74 (d,lH), 6.75-6.77(d,lH), 6.83(s,lH).
Step 14
Synthesis of A (XIV)
Compound A(XIII) in triethyl amine is added to a solution of 3-amino-2,2-dimethylpropionamide and 2-hydroxy pyridine. The reaction mixture is heated to 90° C for 48 hours. After completion of the reaction, excess triethylamine is distilled under vacuum and the crude compound thus obtained is dissolved in of ethyl acetate. Then the ethylacetate solution is washed with water, dried over sodium sulphate, and concentrated.

The crude compound thus obtained is purified by column chromatography to yield A (XIV)
Mass-MH+ 650
Step 15
Synthesis of A (XV)
A(XIV) is dissolved in methylene chloride and Trifluoroacetic acid is added and stirred at room temperature for 3hours.After the reaction went to completion, solvents were removed under vaccum and the residue is dissolved in methanol. 10% Pd/C is added to the methanolic solution and hydrogenated in a parr shaker apparatus. The catalyst is filtered and the solvent is remoyed under reduced pressure to yield the product A(XV)
H-NMR (300MHZ,CDCl3): 6 6.82 (IH, d ),6.70 (IH, d), 6.68 (IH, dd), (IH, d ),6.32 (IH, dd), 5.40(1H, bs ),4.97 (IH, d), 4.65(1H, dd), (IH, d ),4.12 (2H, t), 4.00(1H, m), 3.86(3H, s), 3.58(2H, t), 3.56(1H ,dd), 3.36(1H, s), 3.23(1H, dd ),2.68 (IH ,dd), 2.40(2H, t), 2.02-1.42 (9H, m), 2.05 (3H, s), 1.82 (3H, s)1.23 (6H, s), 0.99 (3H, d), 0.91 (6H,d), 0.88(3H, d).
From the free base obtained, for example the hemifumarate salt of the title compound can be prepared as described in US 6,730,798, example Jl (comprising mixing with fumaric acid, dissolution in ethanol, filtration, evaporation of the obtained solution, redissolving of the residue in acetonitrile, inoculation with a small amount of the title compound hemifumarate salt and isolation of the precipitating material).
The following steps describe the syntheses of Aliskiren involving other novel intermediates as per another embodiment of the invention:
Stepl Synthesis of C (I)
10 % Pd/C is added to a solution A(IX) in methanol and hydrogenated at 60 psi

for 4 hrs. On completion, the reaction mixture is filtered through celite and residue is washed with methanol. The filtrate is removed under reduced pressure and the residue is purified by column chromatography to yield C(I).
H'-NMR (300 MHz, CdCl3) - 6(ppm) 0.8-0.9 (m, 9H), 1.0-1.1 (d, 3H),1.2-1.2(m, 2H), 1.4 -1.8 (m, 4H), 1.85-2.2 (m, 5H), 2.45-2.65 (m, 3H), 3.35-3.4(s, 3H), 3.5 -3.6(t, 2H); 3.8 (s, 3H); 4.05-4.15 (t, 3H), 6.65-6.85 (m, 3H).
Step-2 Synthesis of C(II)
Methanesulfonyl chloride is added drop wise to a solution of C(I) in methylene chloride at -10 °C. Triethylamine is added drop wise for a period of 5 min. The progress of the reaction is monitored, after completion, the reaction mixture is diluted with methylenechloride and washed with water. The organic layer is separated, dried over sodium sulphate and concentrated under vacuum. The crude compound obtained is purified by column chromatography with silicagel using hexane and ethylacetate as solvent to yield C (II).
NMR: 'H NMR (300 MHz)
0.8-0.9 (m, 9H); 1.0-1.1 (d, 3H); 1.2-1.3 (m, 2H); 1.4-1.8 (m, 4H); 1.85-2.2 (m, 5H); 2.45-2.65 (m, 3H); 3.15-3.16 (s, 3H); 3.35-3.36 (s, 3H); 3.55-3.62 (t, 2H); 3.8-3.83 (s, 3H); 4.07-4.15 (t, 2H); 4.25-4.35 (m, 1H); 4.5-4.6 (m, 1H); 6.65-6.85 (m, 3H).
Step 3
Synthesis of C(III)
Sodium azide is added to a stirred solution of C (II) dissolved in dry N,N-dimethylformamide. Tetrabutylammoniumhydrogen sulfate is added to the reaction mixture and heated to 90°C for 36 h. After completion of the reaction, solvent is removed

under reduced pressure to give crude compound. The crude compound is purified by column chromatography to give G(III) as a thick liquid.
[Mass - MH^: 462] included
Step 4
Synthesis of C(IV)
10% Palladium on carbon is added to Methanol solution containing C(III), di-tertiary-butyl dicarbonate and triethylamine. The resultant solution is hydrogenated at 60psi for 16h. On completion of the reaction, the reaction mixture is filtered through celite and concentrated under reduced pressure. The crude compound is purified by column chromatography with silicagel using hexane and ethylacetate as solvent to yield C(IV) as thick liquid.
Mass-MH^-652.
Steps Synthesis of C(V)
Compound C(IV) was dissolved in triethylamine. 2-hydroxy pyridine and 3-amino-2,2-dimethyl propionamide were added. The reaction mixture was heated to 80°C for 18h. After completion of the reaction, triethylamine was distilled and the crude compound was dissolved in ethyl acetate.The ethylacetate layer was washed with water ,dried over sodium sulphate and concentrated. The crude compound was purified by column chromatography to yield C(V).
Mass - MH^-652
Step 6
Synthesis of A(XV)
Compound C(V) is dissolved in THF cooled to 0°c triphenylphosphine, diethyl azodicarboxylate followed by p-Nitrobenzoic acid were added. The resulting yellow

solution is stirred for lOhrs.at ambient temperature. After completion of the reaction, 10% potassium hydroxide solution was added and stirred for 4h.The solvent is removed under reduced pressure and the crude compound thus obtained is purified by column chromatography with silica-gel using ethyl acetate: hexane as solvents to afford A(XV).
Mass - MH^-652
The following non-limiting examples further illustrate and describe the novel processes of preparation of Aliskiren and its novel intermediates without limiting the scope of the invention:
Example 1 Preparation of A (I)
30.0 g of p-Toluenesulfonic acid is added to a solution of l500g, D-Mannitol (8.24 mol), 2,2-Dimethoxy propane (634.5g, 6.10 mol) in ISOOmlacetone at ambient temperature. The solution is refluxed for 24 hours and acetone is removed under reduced pressure. The crude product is then poured into 5000 ml of cold water and stirred for 30 minutes. The resuhing white solid is filtered and dried under vacuum to yield A (I) -1600 g.
Example 2 Preparation of A (II)
184.6 ml (1.82 mol) of 36% Hydrochloric acid is added drop wise to a solution of 1000 g (3.31 mol) of A (I) dissolved in 1200 ml of methanol and 1000 ml of water at ambient temperature. The reaction mass is stirred for 3 h and neutralized with 138 g of potassium carbonate at ambient temperature. The solvent is removed under reduced pressure and the crude product is azeotroped with toluene (2 x 1000 ml) to remove traces of water. 4000 ml of acetone is added to the crude product and stirred for 30 minutes and the obtained solid was filtered and washed with 2 x 1000 ml of acetone. Filtrate is concentrated under reduced pressure and azeotroped with toluene (2 x 1000 ml) to yield 500g of A (II) as solid.

Example 3 Preparation of A (III)
1590 g (7.4 mol) of sodium metaperiodate is added portion wise to a stirred solution of 660 g (2.9 mol) of A (II) dissolved in 6.6 liters of 5% aqueous sodium hydrogenocarbonate solution at 0-8°C over a period of 1 hr. The resultant solution is stirred for 2 h at the same temperature. Then 1468 g (6.5 m) of ethyl diethoxyphosphinyl acetate is added drop wise over a period of 1 hr followed by 6.6 liters of aqueous ION potassium carbonate solution and the reaction mixture was stirred for 16 hrs at ambient temperature. On completion, the reaction mixture is extracted into ethyl acetate (3 x 2000 ml). The organic layer is washed with saturated brine (2000 ml), dried over sodium sulphate and concentrated to give a yellow oil of A (III). The crude product is dissolved in hexane and passed through 1.5 kg of silica gel. Hexane is removed under reduced pressure to give 330 g of A (III).
Example 4 Preparation of A (IV)
5 g of 10% Palladium on carbon is added to a solution of 100 g (0.3 mol) of A (III) in 1000 ml of methanol and hydrogenated at 60 psi pressure for 4 hrs. On completion of the reaction, the solution is filtered through celite and the residue is washed with methanol (250 ml). The solvent is removed under reduced pressure to give 98 g of A (IV).
Example 5 Preparation of A (V)
18.49 g (0.16 mol) of Trifluoroacetic acid is added to a solution of 98 g (0.324 mol) of A (IV) containing 980 ml of acetonitrile and 23.7 ml (1.29 mol) of H2O at ambient temperature. The reaction mixture is then refluxed for 6 hrs. The solvent is removed under reduced pressure and the obtained crude compound is purified by column chromatography to yield 40 g of A (V).
Example 6

Preparation of A (VI)
675.9 ml (0.67 mol) of Lithium hexamethydisilazide (LiHMDS) is added drop wise to a solution of 50 g (0.29 mol) of A (V) and 17.0 g (0.147 mol) of tetramethylethylenediamine in 750 ml of tetrahydrofuran at -78 °C over a period of 1 h. The reaction mixture is stirred at the same temperature for 2 h and 170.5 g (2.94 mol) of acetone is added drop wise at -78 °C for 1 hr and stirred at the same temperature for 2 more hours. The reaction mixture is later quenched with 10% aqueous hydrochloric acid (250 ml) and diluted with ethyl acetate (500 ml). The organic layer is separated and the aqueous layer is extracted with ethyl acetate (500 ml). The combined organic layers are dried over sodium sulphate and concentrated under reduced pressure. The obtained residue is purified by column chromatography with silicagel to yield 30 g of A (VI).
Example 7 Preparation of A (VII)
64.4 g (0.416 mol) of phosphorousoxychloride is added drop wise to a solution of 30 g (0.104 m) of A (VI) dissolved in 300 ml of pyridine at 10 X for 30 min. The reaction mixture is stirred at room temperature for 12 hrs. On completion of reaction pyridine is removed under reduced pressure and the residue is cooled to 0 °C. 500 ml of cold water is added and the pH is adjusted to 5.5 using 10% aqueous hydrochloric acid. Then the compound is extracted into ethyl acetate (3 x 500 ml) and combined organic extracts are dried over sodium sulphate and removed under reduced pressure. The obtained compound is purified by column chromatography with silica gel using hexane and ethyl acetate as solvent to yield 20 g of A (VII).
Example 8 Preparation of A (VIII)
1.0 g of 10% Pd/C is added to a solution of 20 g (0.08 mol) A (VII) in 200 ml of methanol and hydrogenated at 60 psi for 4 hrs. On completion, reaction mixture is filtered through celite and residue is washed with methanol (2 x 50 ml). The filtrate is

removed under reduced pressure and the residue is azeotroped with toluene to yield 20 g of A (VIII) as white solid.
Example 9 Preparation of A (IX)
A mixture of 2.69g (0.0098 mol) of B(V), 0.22g (0.0019 mol) of tetramethylethylenediamine in 5 ml of tetrahydrofuran is added drop wise to a solution of 6.0 ml (0.0098 mol) of n-Butyllithium (1.6 m) in 2.5 ml of tetrahydropyran at -78 °C over a period of 20 min. The reaction mixture is stirred for 1 h and a solution of 2.5 g (0.0098 mol) of A (VIII) in 5 ml tetrahydrofuran is added drop wise over a period of 20 min at -78 °C. The reaction mixture is stirred at the same temperature for 1 hr and then quenched with IN aqueous hydrochloric acid (pH to ~7), The reaction mixture is warmed to 0°C and extracted into ethyl acetate (20 ml). The organic layer is separated, dried over sodium sulphate and concentrated under vacuum. The crude compound thus obtained is purified by column chromatography with silicagel using hexane and ethylacetate as solvent to yieldA(IX)(2.12g).
Example 10 Preparation of A (X)
1.83 g (0.016 mol) of methanesulfonyl chloride is added drop wise to a solution of 6.0 g (0.013 mol) A (IX) in 60 ml of methylenechloride at -10 °C. 1.61 g (0.016 mol) of triethylamine is added drop wise for a period of 5 min. The progress of the reaction is monitored, after completion, the reaction mixture is diluted with 30 ml of, methylenechloride and washed with (3 x 40 ml) of water. The organic layer is separated, dried over sodium sulphate and concentrated under vacuum. The crude compound obtained is purified by column chromatography with silicagel using hexane and ethylacetate as solvent to yield A (X) (5.5 g).
Example 11 Preparation of A (XI)

1.25 g (0.018 m) of sodium azide is added to a stirred solution of 2.0 g (0.0037 m) A (X) dissolved in 20 ml of dry N,N-dimethylformamide. 3.2 g (0.0094 m) of tetrabutylammoniumhydrogeri sulfate is added to the reaction mixture and heated to 90 °C for 36 h. After completion of the reaction, solvent is removed under reduced pressure to give crude compound. The crude compound is purified by column chromatography to give A (XI) (0.4 g) as a thick liquid.
Example 12 Preparation of A (XII)
138 mg of 10% Palladium on carbon is added to 14 ml ethanol/water (9:1) solution containing 1.38 g (0.002 mol) A (XI), 0.824 g (0.0037 mol) of di-tertiary-butyl dicarbonate 0.47 g (0.0046 mol) triethylamine. The resultant solution is hydrogenated at 60psi for 16h. On completion, of the reaction, the reaction mixture is filtered through celite and concentrated under reduced pressure. The crude compound is purified by column chromatography with silica gel using hexane and ethylacetate as solvent to yield A (XII) (0.7 g) as thick liquid.
Example 13 Preparation of A (XIII)
0.929ml (0.0009 mol) IM aqueous solution of potassium hydroxide is added to a solution of 0.5g (0.0009 mol) of A XII dissolved in 9ml of THF-water-methanol (4:1:1) at 0°.C. The reaction mixture is stirred at the same temperature for lOhrs. After completion of reaction, the reaction mixture is extracted with (3x15ml) of ether and amberlite IR-120 resin (H^) is added to the aqueous layer and stirred till PH~4 is attained. Then, 90ml of DCM is added to the aqueous layer and extracted with 5x50 ml of DCM .The combined organic solutions are dried over sodium sulfate and concentrated under reduced pressure. The compound thus obtained is dried for Ihr to afford hydroxy-acid intermediate 0.45 g (0.0008 mol). Hydroxy-acid is dissolved in 13.5 ml THF cooled to O^c and 0.214 g (0.0008 mol) of triphenylphosphine followed by 0.142 g (0.0008 mol) of diethyl azodicarboxylate is added. The resulting yellow solution is stirred for lOhrs. at ambient

temperature and the solvent is removed under reduced pressure. The crude compound thus obtained is purified by column chromatography with silica-gel using ethyl acetate: hexane as solvents to afford A XIII 0.25g.
Example 14 Preparation of A (XIV)
0.7g(0.0013mmol of A(XIII)in 7ml of triethyl amine is added to a solution of 2.7g (0.0232mol) of 3-amino-2,2-dimethylpropionamide and 0.025g(0.00026mol)of 2-hydroxy pyridine.The reaction mixture is heated to 90° C for 48 hours. After completion of the reaction, excess triethylamine is distilled under vacuum and the crude compound thus obtained is dissolved in 30ml of ethyl acetate. Then the ethylacetate solution is washed with 2x20ml of water, dried over sodium sulphate, and concentrated. The crude compound thus obtained is purified by column chromatography to yield A (XIV) (0.64g)
Example 15 Preparation of A (XV)
lOOmg (0.154mmol) of A(XIV )is dissolved in 1ml of methylene chloride and 0.175g (0.154 mmol) of Trifluoroacetic acid is added and stirred at room temperature for 3hours. After the reaction went to completion, solvents were removed under vaccum and the residue is dissolved in 5ml methanol. 15mg of 10% Pd/C is added to the methanolic solution and hydrogenated in a parr shaker apparatus for 6hours at 50psi. The catalyst is filtered and the solvent is removed under reduced pressure to yield the product A(XV) 0.63g.
Example 16 Preparation of C (I)
2.1g of 10 % Pd/C is added to a solution of 7g (0.015mol) A(IX) in 70ml methanol and hydrogenated at 75 psi for 72hrs. On completion, the reaction mixture is filtered through

celite and residue is washed with methanol. The filtrate is removed under reduced pressure and the residue is purified by column chromatography to yield C(I) 4.5g.
Example 17 Preparation of C (II)
Methanesulfonyl chloride 0.82g (0.007moles) is added drop wise to a solution of C(I) 2.4g(0.005mol) in 24ml methylenechloride at -10 °C. Triethylamine 0.789g (0.007mol) is added drop wise for a period of 5 min. The progress of the reaction is monitored, after completion, the reaction mixture is diluted with methylenechloride and washed with water. The organic layer is separated, dried over sodium sulphate and concentrated under vacuum. The crude ompound obtained is purified by column chromatography with silicagel using hexane and ethylacetate as solvent to yield 2.7g C(II).
Example 18 Preparation of C (III)
Sodium azidel.22g (0.019moles) is added to a stirred solution of C (II) 2.0g (O.OOSmoles) dissolved in 10ml of N-methylpyrrolidone .The reaction mixture is heated to 90°C for 6 h. After completion of the reaction, ethyl acetate is added to the reaction mixture and washed with water. Ethyl acetate layer was separated , dried over sodium sulphate and concentrated to yield 1.8g of C(ni).
Example 19 Preparation of C (IV)
180mg of 10% Palladium on carbon is added to 20ml of Methanol solution containing 1.8g (0.004moles) C(III), 1.7g (0.007moles)di- tertiary-butyl dicarbonate and 0.79g (0.008) triethylamine. The resultant solution is hydrogenated at 60psi for lOh. On completion of the reaction, the reaction mixture is filtered through celite and concentrated

under reduced pressure. The crude compound is purified by column chromatography with silicagel using hexane and ethylacetate as solvent to yield 0.950mg of C(IV).
Example 20 Preparation of C(V)
0.120mg (0.0002moles) of C(IV) was dissolved in 1.2ml of triethylamine.0.143mg (0.00004moles) of 2-hydroxy pyridine and 0.260mg (0.0022moles) of 3-amino-2,2-dimethyl propionamide were added. The reaction mixture was heated to 800C for 18h. After completion of the reaction, triethylamine was distilled and the crude compound was dissolved in ethyl acetate.The ethylacetate layer was washed with water, dried over sodium sulphate and concentrated. Then the crude compound was purified by column chromatography to yield 0.060mg of C(V).
Example 21 Preparation of A(XV)
C (V) 0.060g (O.OOOlmoles) is dissolved in 3.5 ml THF cooled to O^c and 0.0176g (0.0001 mol) of triphenylphosphine, ,0.028 g (0.0001 mol) of diethyl azodicarboxylate followed by 0.0106g (0.0001 mol) of p-Nitrobenzoic acid, were added. The resulting solution is stirred for lOhrs. at ambient temperature. After completion of the reaction 0.055ml of 10% potassium hydroxide solution is added and stirred for further 4h.THF is removed under reduced pressure and the crude compound obtained is purified by column chromatography with silica-gel using ethyl acetate: hexane as solvents to afford 0.045g. A (XV).

We claim:
1. A process of making a compound A (XV) of the formula

A(XV)
and its pharmaceutically acceptable salts comprising the steps of: a) converting compound (A) of the formula

by adding p-Toluenesulfonic acid in a solvent, preferably acetone, at ambient temperature to yield compound A (I) of the formula


b) reacting A (I) in a suitable solvent, preferably a mixture of methanol and water in
the presence of hydrochloric acid, to give a compound A (II) of the formula

c) oxidizing A (II) with sodium periodate followed by reaction with ethyl
diethoxyphosphinyl acetate and extracting with ethyl acetate to yield compound
A(III) of formula

d) reducing A (III) over Palladium on carbon in a suitable solvent, preferably
methanol to yield a compound A (IV) of formula


e) acidifying A(IV) with a suitable reagent, preferably triflouroacetic acid, to yield a
compound A (V) of formula

f) activating A (V) with LiHMDS in the presence of TMEDA (tetra methyl ethylene
diamine) at subzero temperatures, followed by addition of acetone at the same
temperature to give a compound A (VI) of formula

g) dehydrating A (VI) in the presence of phosphorusoxychloride in a suitable
solvent, preferably pyridine at room temperature to yield a compound A (VII) of
formula


h) reducing A (VII) in the presence of Pd/C in a suitable solvent, preferably methanol to result in a compound A (VIII) of formula

i) reacting compound B(V) of formula

B(V)
with A (VIII) in a suitable solvent, preferably tetrahydrofuran, to yield a compound A (IX) of formula


j) sulphonating A (IX) at sub zero temperatures in the presence of a suitable solvent, preferably methylene chloride to yield a compound A (X) of formula

k) reacting A (X) with sodium azide to give a compound A (XI) of formula


1) hydrogenating of A (XI) to give A (XII)

m) reacting A (XII) with suitable reagents and solvent mixtures to give A (XIII)


n) reacting of a compound B(VI) of formula

with A (XIII) in a suitable solvent, preferably triethylamine, to yield a compound A (XIV) of formula


o) deprotecting A(XIV) in trifluoroacetic acid and hydrogenolyse in a mixture of solvents, preferably methanol-water to yield a compound A(XV)

and converting into its pharmaceutically acceptable salts,
2. A compound of formula A (I) or a salt thereof, an intermediate for the preparation of compound of formula A(XV), prepared by process according to claim 1.

3. A compound of formula A (II) or a salt thereof, an intermediate for the preparation of compound of formula A(XV), prepared by process according to claim 1.


4. A compound of formula A (III) or a salt thereof, an intermediate for the
preparation of compound of formula A(XV), prepared by process according to
claim 1.

5. A compound of formula A (IV) or a salt thereof, an intermediate for the
preparation of compound of formula A(XV), prepared by process according to
claim 1.


6. A compound of formula A (V) or a salt thereof, an intermediate for the
preparation of compound of formula A(XV), prepared by process according to
claim 1.

7. A compound of formula A (VI) or a salt thereof, an intermediate for the
preparation of compound of formula A(XV), prepared by process according to
claim 1.

9. A compound of formula A (VI). or a salt thereof, an intermediate for the preparation
of compound of formula A(XV), prepared by process according to claim 1.

10. A compound of formula A (VII) or a salt thereof, an intermediate for the
preparation of compound of formula A(XV), prepared by process according to
claim 1.


11. A compound of formula A (IX) or a salt thereof, an intermediate for the preparation of
compound of formula A(XV), prepared by process according to claim 1.

12. A compound of formula A (X) or a salt thereof, an intermediate for the preparation of
compound of formula A(XV), prepared by process according to claim 1.


13. A compound of formula A (XI) or a salt thereof, an intermediate for the
preparation of compound of formula A(XV), prepared by process according to
claim 1.

14. A compound of formula A (XII) or a salt thereof, an intermediate for the
preparation of compound of formula A(XV), prepared by process according to claim
1.

15. A compound of formula A (XIII) or a salt thereof, an intermediate for the
preparation of compound of formula A(XV), prepared by process according to claim
1.


16. A compound of formula A (XIV) or a salt thereof, an intermediate for the preparation of compound of formula A(XV), prepared by process according to claim 1.


17. A process of making a compound A (XV) of the formula

A(XV)
and its pharmaceutically acceptable salts as in claim 1, further comprising the steps of:
a) de-oxygenating of A(IX) in the presence of Pd/C in a suitable solvent preferably
methanol to yield a compound C(I) of formula.

b) sulphonating of C(I) at sub zero temperatures in the presence of a suitable
solvent, preferably methylene chloride to yield a compound C(II) of formula


c) reacting C(II) with sodium azide to give a compound C(III) of formula

d) hydrogenatlng C(III) with suitable reagents and solvent mixture to give (CIV)


e) reacting compound B(VI) with C(IV) in a suitable solvent, preferably
triethylamine to yield a compound C(V) of formula

C(V)
f) reacting compound C(V) with DEAD, TPP followed by deprotection with
trifluoroacetic acid yield a compound A(XV)


p) converting into its pharmaceutically acceptable salts.
18. A compound of formula C (I) or a salt thereof, an intermediate for the
preparation of compound of formula A(XV), prepared by process according to claim 17.

C(I)
19. A compound of formula C (II) or a salt thereof, an intermediate for the
preparation of compound of formula A(XV), prepared by process according to claim 17.

20. A compound of formula C (III) or a salt thereof, an intermediate for the
preparation of compound of formula A(XV), prepared by process according to claim 17.


and its pharmaceutically acceptable salts.
21. A compound of formula C (IV) or a salt thereof, an intermediate for the
preparation of compound of formula A(XV), prepared by process according to claim 17.

22. A compound of formula C (V) or a salt thereof, an intermediate for the
preparation of compound of formula A(XV), prepared by process according to claim 17.