173334-58-2

Usage

Clinical Use

Renin inhibitor: Hypertension

Synthesis

The synthesis of aliskiren by Novartis is depicted in the scheme.Aliskiren (I) was synthesized through a convergent synthetic strategy by coupling key intermediate chloride 5 with aldehyde 10. Hydrogenation of cinnamic acid 1, followed by generation of the acid chloride of the corresponding acid and reaction with (+)-pseudoephedrine provided amide 2 in 91% yield. Deprotonation of amide 2 with LDA followed by alkylation with 2-iodopropane in refluxing THF gave 3 as a single diastereomer in 52% yield. Reduction of the amide functionality in 3 using n-butyl lithium boron trifluoride ammonium complex proceeded without epimerization of the chiral center to give alcohol 4 in 66% yield. Chlorination of 4 using phosphorus oxychloride gave chloride 5, in 78% yield as the organometallic precursor for the eventual coupling to aldehyde 10. Synthesis of fragment 10 commenced with (+)-pseudoephedrine isovaleramide 6, which was efficiently deprotonated with LDA and alkylated using allyl bromide; diastereomerically pure 7 was obtained upon crystallization of the crude reaction mixture in 78% yield. Bromolactonization of 7, using n-bromosuccinimide in the absence of acetic acid gave amide acetal 8 with a single configuration at the spirocenter and a 6:1 mixture of trans:cis ring substituents. Displacement of the bromide using tetrabutylammonium acetate followed by basic hydrolysis provided alcohol 9 in 85% yield. Oxidation of 9 using dimethyl sulfoxide-sulfur trioxide/pyridine proceeded without epimerization to furnish the masked lactone aldehyde 10 in 60% yield. Coupling of fragments 5 and 10 was achieved by treatment of 10 with the organocerium reagent of the corresponding Grignard reagent prepared from 5. Hydrolysis of the crude spirocyclic addition product revealed that the hydroxylactone 11 was formed in 51% overall yield as an inseparable epimeric mixture with a Felkin-Anh selectivity of 85:15. The requisite nitrogen functionality was installed via the brosylate to give azido lactone 12 in 68% yield. Aminolysis with 3-amino-2,2-dimethylpropionamide led to formation of the open chain azido alcohol 13 in 76% yield. The synthesis of aliskiren was completed by azide hydrogenolysis and formation of the hemifumarate salt. Generation of pure aliskiren was achieved via crystallization which removed the residual minor (R)-epimer carried through from the Grignard addition step to afford aliskiren (I) in 43% yield.

Drug interactions

Potentially hazardous interactions with other drugs Other antihypertensive agents: enhanced antihypertensive effect; concentration possibly reduced by irbesartan; increased risk of hyperkalaemia and hypotension with ACE-Is and ARBs. Antifungals: concentration increased by itraconazole and ketoconazole, avoid with itraconazole. Ciclosporin: concentration of aliskiren increased - avoid. Diuretics: may reduce concentration of furosemide; hyperkalaemia with potassium-sparing diuretics. Grapefruit juice: concentration of aliskiren reduced - avoid. Heparins: increased risk of hyperkalaemia. Potassium salts: increased risk of hyperkalaemia.

Metabolism

Approximately 1.4% of the total oral dose is metabolised by CYP3A4. Approximately 0.6% of the dose is recovered in urine following oral administration. Aliskiren is mainly eliminated as unchanged compound in the faeces (78%).

InChI:InChI=1/2C30H53N3O6.C4H4O4/c2*1-19(2)22(14-21-10-11-26(38-8)27(15-21)39-13-9-12-37-7)16-24(31)25(34)17-23(20(3)4)28(35)33-18-30(5,6)29(32)36;5-3(6)1-2-4(7)8/h2*10-11,15,19-20,22-25,34H,9,12-14,16-18,31H2,1-8H3,(H2,32,36)(H,33,35);1-2H,(H,5,6)(H,7,8)/b;;2-1+/t2*22-,23-,24-,25-;/m00./s1

Synthetic route

(1S,2S,4S)-4-(2-carbamoyl-2-methylpropyl-carbamoyl)-2-hydroxy-1-{(S)-2-[4-methoxy-3-(3-methoxypropoxy)-benzyl]-3-methylbutyl}-5-methylhexyl-carbamic acid benzyl ester (1236549-06-6) + (2E)-but-2-enedioic acid (110-17-8) → (2S,4S,5S,7S)-5-amino-N-(3-amino-2,2-dimethyl-3-oxypropyl)-4-hydroxy-7-[[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl]-8-methyl-(2-propan-2-yl)nonanamide hemifumarate (173334-58-2)

Conditions	Yield
Stage #1: (1S,2S,4S)-4-(2-carbamoyl-2-methylpropyl-carbamoyl)-2-hydroxy-1-{(S)-2-[4-methoxy-3-(3-methoxypropoxy)-benzyl]-3-methylbutyl}-5-methylhexyl-carbamic acid benzyl ester With palladium 10% on activated carbon; hydrogen In isopropyl alcohol at 20℃; under 760.051 Torr; Stage #2: (2E)-but-2-enedioic acid In ethanol	100%
Stage #1: (1S,2S,4S)-4-(2-carbamoyl-2-methylpropyl-carbamoyl)-2-hydroxy-1-{(S)-2-[4-methoxy-3-(3-methoxypropoxy)-benzyl]-3-methylbutyl}-5-methylhexyl-carbamic acid benzyl ester With palladium 10% on activated carbon In isopropyl alcohol at 20℃; under 760.051 Torr; Stage #2: (2E)-but-2-enedioic acid In ethanol	85%

tert-butyl (3S,5S,6S,8S)-8-(3-amino-2,2-dimethyl-3-oxopropylcarbamoyl)-6-hydroxy-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-2,9-dimethyldecan-5-ylcarbamate (173338-07-3) + (2E)-but-2-enedioic acid (110-17-8) → (2S,4S,5S,7S)-5-amino-N-(3-amino-2,2-dimethyl-3-oxypropyl)-4-hydroxy-7-[[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl]-8-methyl-(2-propan-2-yl)nonanamide hemifumarate (173334-58-2)

Conditions	Yield
Stage #1: tert-butyl (3S,5S,6S,8S)-8-(3-amino-2,2-dimethyl-3-oxopropylcarbamoyl)-6-hydroxy-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-2,9-dimethyldecan-5-ylcarbamate With hydrogenchloride In dichloromethane at 0℃; for 3h; Stage #2: (2E)-but-2-enedioic acid In ethanol	85%
Stage #1: tert-butyl (3S,5S,6S,8S)-8-(3-amino-2,2-dimethyl-3-oxopropylcarbamoyl)-6-hydroxy-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-2,9-dimethyldecan-5-ylcarbamate With hydrogenchloride In dichloromethane at 0℃; for 3h; Stage #2: (2E)-but-2-enedioic acid In ethanol	85%

(2E)-but-2-enedioic acid (110-17-8) + (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (2-carbamoyl-2-methyl-propyl)-amide (173334-57-1) → (2S,4S,5S,7S)-5-amino-N-(3-amino-2,2-dimethyl-3-oxypropyl)-4-hydroxy-7-[[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl]-8-methyl-(2-propan-2-yl)nonanamide hemifumarate (173334-58-2)

Conditions	Yield
In methanol Solvent; Concentration; Time; Temperature;	81.5%
In methanol at 35℃; for 1h; Product distribution / selectivity;	74.25%
In ethanol at 20℃; Product distribution / selectivity;

aliskiren (173399-03-6) + (2E)-but-2-enedioic acid (110-17-8) → (2S,4S,5S,7S)-5-amino-N-(3-amino-2,2-dimethyl-3-oxypropyl)-4-hydroxy-7-[[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl]-8-methyl-(2-propan-2-yl)nonanamide hemifumarate (173334-58-2)

Conditions	Yield
Stage #1: aliskiren With sodium hydroxide In water at 0℃; Stage #2: (2E)-but-2-enedioic acid In methanol

(2S,4S,5S,7S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)phenyl]octanamide + (2E)-but-2-enedioic acid (110-17-8) + (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (2-carbamoyl-2-methyl-propyl)-amide (173334-57-1) → (2S,4S,5S,7S)-5-amino-N-(3-amino-2,2-dimethyl-3-oxypropyl)-4-hydroxy-7-[[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl]-8-methyl-(2-propan-2-yl)nonanamide hemifumarate (173334-58-2) + 0.5C4H4O4*C30H53N3O6

Conditions	Yield
In ethanol at 40℃; Product distribution / selectivity;	A 93 %Chromat. B n/a

0.5C4H4O4*C30H53N3O6 → (2S,4S,5S,7S)-5-amino-N-(3-amino-2,2-dimethyl-3-oxypropyl)-4-hydroxy-7-[[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl]-8-methyl-(2-propan-2-yl)nonanamide hemifumarate (173334-58-2)

Conditions	Yield
In ethanol; acetonitrile at 20℃; Purification / work up;	98.8 %Chromat.

aminopivalinamide (324763-51-1) → (2S,4S,5S,7S)-5-amino-N-(3-amino-2,2-dimethyl-3-oxypropyl)-4-hydroxy-7-[[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl]-8-methyl-(2-propan-2-yl)nonanamide hemifumarate (173334-58-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: triethylamine; 2-hydroxypyridin / 16 h / 85 - 90 °C 2: hydrogen; ethanolamine / palladium 10% on activated carbon / isopropyl alcohol / 3 h 3: ethanol / 0.17 h / 25 - 30 °C View Scheme
Multi-step reaction with 2 steps 1.1: 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone / 4 h / 75 - 80 °C 1.2: 15 h / 85 - 90 °C 1.3: 3 h 2.1: ethanol / 0.17 h / 25 - 30 °C View Scheme
Multi-step reaction with 4 steps 1.1: thionyl chloride / 1,2-dichloro-ethane / 5 h / 75 - 80 °C 1.2: 90 - 95 °C 1.3: 10 - 15 °C / pH 14 2.1: triethylamine; 2-hydroxypyridin / 30 h / 80 - 90 °C 3.1: sodium hydroxide; dihydrogen peroxide / water / 20 - 40 °C 4.1: hydrogen; ethanolamine / 5%-palladium/activated carbon / ethanol / 2206.72 Torr View Scheme

3-methylbutyric acid (503-74-2) → (2S,4S,5S,7S)-5-amino-N-(3-amino-2,2-dimethyl-3-oxypropyl)-4-hydroxy-7-[[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl]-8-methyl-(2-propan-2-yl)nonanamide hemifumarate (173334-58-2)

Conditions	Yield
Multi-step reaction with 13 steps 1.1: dmap / 1,1-dichloroethane / 0.5 h / 20 °C 1.2: 14.5 h / 10 - 30 °C 2.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / -70 °C / Inert atmosphere 2.2: -70 - 5 °C 3.1: dihydrogen peroxide; lithium hydroxide monohydrate / water; tetrahydrofuran / 0 - 30 °C 4.1: sodium tetrahydroborate / tetrahydrofuran / 1 h / 0 - 5 °C / Inert atmosphere 4.2: 5.75 h / 0 - 30 °C 5.1: N-chloro-succinimide; triphenylphosphine / dichloromethane / 5.5 h / -40 - 30 °C 6.1: magnesium; ethylene dibromide / tetrahydrofuran / 4.17 h / 63 - 68 °C / Inert atmosphere 6.2: 12.5 h / 0 - 5 °C 7.1: water; lithium hydroxide / tetrahydrofuran; methanol / 26 h / 65 - 70 °C 7.2: 0.5 h / 0 - 5 °C 8.1: hydrogenchloride / 1,1-dichloroethane; water / 0 - 5 °C / pH 2.5 8.2: 14.25 h / 0 - 30 °C 9.1: N-Bromosuccinimide; phosphoric acid / water; tetrahydrofuran / 1.25 h / 0 - 5 °C 10.1: sodium azide / ethylene glycol / 20 h / 80 - 85 °C 11.1: triethylamine; 2-hydroxypyridin / 16 h / 85 - 90 °C 12.1: hydrogen; ethanolamine / palladium 10% on activated carbon / isopropyl alcohol / 3 h 13.1: ethanol / 0.17 h / 25 - 30 °C View Scheme
Multi-step reaction with 10 steps 1.1: dmap / 1,1-dichloroethane / 0.5 h / 20 °C 1.2: 14.5 h / 10 - 30 °C 2.1: titanium(IV) isopropylate; N-ethyl-N,N-diisopropylamine; titanium tetrachloride / dichloromethane / 1 h / 0 - 5 °C / Inert atmosphere 2.2: -30 - -25 °C 2.3: -30 - 5 °C 3.1: hydrogen; acetic acid / palladium on activated charcoal / 60 - 70 °C / 2942.29 Torr 4.1: dihydrogen peroxide; lithium hydroxide monohydrate / water; tetrahydrofuran / 0 - 30 °C 5.1: sodium tetrahydroborate / tetrahydrofuran / 1 h / 0 - 5 °C / Inert atmosphere 5.2: 5.75 h / 0 - 30 °C 6.1: N-chloro-succinimide; triphenylphosphine / dichloromethane / 5.5 h / -40 - 30 °C 7.1: magnesium; ethylene dibromide / tetrahydrofuran / 4.17 h / 63 - 68 °C / Inert atmosphere 7.2: 1 h / 0 - 5 °C 8.1: N-Bromosuccinimide; phosphoric acid / water; tetrahydrofuran / 1.25 h / 0 - 5 °C 9.1: 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone / 4 h / 75 - 80 °C 9.2: 15 h / 85 - 90 °C 9.3: 3 h 10.1: ethanol / 0.17 h / 25 - 30 °C View Scheme
Multi-step reaction with 10 steps 1.1: dmap / 1,1-dichloroethane / 0.5 h / 20 °C 1.2: 14.5 h / 10 - 30 °C 2.1: titanium(IV) isopropylate; N-ethyl-N,N-diisopropylamine; titanium tetrachloride / dichloromethane / 1 h / 0 - 5 °C / Inert atmosphere 2.2: -30 - -25 °C 2.3: -30 - 5 °C 3.1: hydrogen; acetic acid / palladium on activated charcoal / 60 - 70 °C / 2942.29 Torr 4.1: sodium tetrahydroborate / tetrahydrofuran / 0 - 15 °C 4.2: 11 h / 60 - 65 °C 5.1: N-chloro-succinimide; triphenylphosphine / dichloromethane / 5.5 h / -40 - 30 °C 6.1: magnesium; ethylene dibromide / tetrahydrofuran / 4.17 h / 63 - 68 °C / Inert atmosphere 6.2: 1 h / 0 - 5 °C 6.3: 0.75 h / 0 - 5 °C 7.1: sodium azide / ethylene glycol / 20 h / 80 - 85 °C 8.1: triethylamine; 2-hydroxypyridin / 16 h / 85 - 90 °C 9.1: hydrogen; ethanolamine / palladium 10% on activated carbon / isopropyl alcohol / 3 h 10.1: ethanol / 0.17 h / 25 - 30 °C View Scheme

2-cyano-2-methylpropanamide (7505-93-3) → (2S,4S,5S,7S)-5-amino-N-(3-amino-2,2-dimethyl-3-oxypropyl)-4-hydroxy-7-[[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl]-8-methyl-(2-propan-2-yl)nonanamide hemifumarate (173334-58-2)

Conditions	Yield
Multi-step reaction with 4 steps 1: hydrogen; ammonia / raney nickel / methanol / 14 h / 40 - 45 °C / 2942.29 Torr 2: triethylamine; 2-hydroxypyridin / 16 h / 85 - 90 °C 3: hydrogen; ethanolamine / palladium 10% on activated carbon / isopropyl alcohol / 3 h 4: ethanol / 0.17 h / 25 - 30 °C View Scheme
Multi-step reaction with 3 steps 1.1: hydrogen; ammonia / raney nickel / methanol / 14 h / 40 - 45 °C / 2942.29 Torr 2.1: 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone / 4 h / 75 - 80 °C 2.2: 15 h / 85 - 90 °C 2.3: 3 h 3.1: ethanol / 0.17 h / 25 - 30 °C View Scheme

(2E)-but-2-enedioic acid (110-17-8) + (2S,4S,5S,7S)-N-(3-amino-2,2-dimethyl-3-oxopropyl)-5-azido-4-hydroxy-2-isopropyl-7-(4-methoxy-3-(methoxypropoxy)benzyl)-8-methylnonanamide (324763-47-5) → (2S,4S,5S,7S)-5-amino-N-(3-amino-2,2-dimethyl-3-oxypropyl)-4-hydroxy-7-[[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl]-8-methyl-(2-propan-2-yl)nonanamide hemifumarate (173334-58-2)

Conditions	Yield
Stage #1: (2S,4S,5S,7S)-N-(3-amino-2,2-dimethyl-3-oxopropyl)-5-azido-4-hydroxy-2-isopropyl-7-(4-methoxy-3-(methoxypropoxy)benzyl)-8-methylnonanamide With hydrogen; ethanolamine; 5%-palladium/activated carbon In ethanol under 2206.72 Torr; Stage #2: (2E)-but-2-enedioic acid In ethanol Product distribution / selectivity;

3-amino-2,2-dimethyl-propionitrile (67744-70-1) → (2S,4S,5S,7S)-5-amino-N-(3-amino-2,2-dimethyl-3-oxypropyl)-4-hydroxy-7-[[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl]-8-methyl-(2-propan-2-yl)nonanamide hemifumarate (173334-58-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: triethylamine; 2-hydroxypyridin / 30 h / 80 - 90 °C 2: sodium hydroxide; dihydrogen peroxide / water / 20 - 40 °C 3: hydrogen; ethanolamine / 5%-palladium/activated carbon / ethanol / 2206.72 Torr View Scheme
Multi-step reaction with 4 steps 1: 2-hydroxypyridin; triethylamine / 24 h / 60 - 70 °C 2: sodium hydroxide; dihydrogen peroxide / water; ethanol / 30 - 40 °C 3: hydrogen; palladium 10% on activated carbon; ammonia / ethanol / 20 °C / 5250.53 Torr 4: ethanol; acetonitrile / 22 h / 0 - 40 °C View Scheme

(2S,4S,5S,7S)-5-amino-N-(3-amino-2,2-dimethyl-3-oxypropyl)-4-hydroxy-7-[[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl]-8-methyl-(2-propan-2-yl)nonanamide hemifumarate (173334-58-2) → (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (2-carbamoyl-2-methyl-propyl)-amide (173334-57-1)

Conditions	Yield
With ammonia In water

Upstream product

• 173399-03-6 aliskiren 
• 110-17-8 (2E)-but-2-enedioic acid 
• 173334-57-1 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (2-carbamoyl-2-methyl-propyl)-amide 
• 1236549-06-6 (1S,2S,4S)-4-(2-carbamoyl-2-methylpropyl-carbamoyl)-2-hydroxy-1-{(S)-2-[4-methoxy-3-(3-methoxypropoxy)-benzyl]-3-methylbutyl}-5-methylhexyl-carbamic acid benzyl ester 
• 173338-07-3 tert-butyl (3S,5S,6S,8S)-8-(3-amino-2,2-dimethyl-3-oxopropylcarbamoyl)-6-hydroxy-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-2,9-dimethyldecan-5-ylcarbamate 
• 67744-70-1 3-amino-2,2-dimethyl-propionitrile 
• 324763-47-5 (2S,4S,5S,7S)-N-(3-amino-2,2-dimethyl-3-oxopropyl)-5-azido-4-hydroxy-2-isopropyl-7-(4-methoxy-3-(methoxypropoxy)benzyl)-8-methylnonanamide 
• 7505-93-3 2-cyano-2-methylpropanamide 
• 503-74-2 3-methylbutyric acid 
• 324763-51-1 aminopivalinamide 

Downstream Products

• 173334-57-1 (2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (2-carbamoyl-2-methyl-propyl)-amide 

Relevant academic research and scientific papers

Convergent Synthesis of the Renin Inhibitor Aliskiren Based on C5-C6 Disconnection and CO2H-NH2 Equivalence

A novel synthesis of the renin inhibitor aliskiren based on an unprecedented disconnection between C5 and C6 was developed, in which the C5 carbon acts as a nucleophile and the amino group is introduced by a Curtius rearrangement, which follows a simultaneous stereocontrolled generation of the C4 and C5 stereogenic centers by an asymmetric hydrogenation. Operational simplicity, step economy, and a good overall yield makes this synthesis amenable to manufacture on scale.

A new crystalline forms of lueck logical sequence half fumaric acid salt and its preparation and use

The invention relates to a new crystal form of Aliskiren hemifumarate. The X-ray powder diffraction pattern of the new crystal form of Aliskiren hemifumarate has absorption peaks when 2theta is at 7.0(+/-0.30)DEG, 8.6(+/-0.30)DEG and 10.0(+/-0.30)DEG. The invention also relates to a preparation method of the new crystal form of Aliskiren hemifumarate through a low alcohol re-crystallization process. The new crystal form of Aliskiren hemifumarate has the characteristics of good fluidity and easy granulation.

Chemical process for opening ring compounds

It is described a process for the opening of lactone or lactam rings useful in the synthesis of pharmaceutically active compounds and the intermediates thereof, particularly Aliskiren. It has found that by selecting a type of solvent it is possible to obtain excellent yields and high optical and chemical purity of the isolated products.

CHEMICAL PROCESS FOR OPENING RING COMPOUNDS

It is described a process for the opening of lactone or lactam rings useful in the synthesis of pharmaceutically active compounds and the intermediates thereof, particularly Aliskiren. It has found that by selecting a type of solvent it is possible to obtain excellent yields and high optical and chemical purity of the isolated products.

End-to-end continuous manufacturing of pharmaceuticals: Integrated synthesis, purification, and final dosage formation

A series of tubes: The continuous manufacture of a finished drug product starting from chemical intermediates is reported. The continuous pilot-scale plant used a novel route that incorporated many advantages of continuous-flow processes to produce active pharmaceutical ingredients and the drug product in one integrated system. Copyright

PROCESS FOR THE PREPARATION OF ALISKIREN

The present invention provides a novel process and novel intermediates useful in the synthesis of pharmaceutically active compounds, especially renin inhibitors, such as Aliskiren, or a salt thereof, preferably Aliskiren hemifumarate.

PROCESS FOR THE PREPARATION OF ALISKIREN

The present invention relates to an improved process for the preparation of Aliskiren and its pharmaceutically acceptable salts comprising reducing the compound of Formula-Z in presence of catalyst and ammonia. The present invention further relates to Aliskiren hemifumarate having diastereomeric impurity less than 0.2%.(F) H3C CH3 NH2 H3C 0 H3C CH3 Formula-Z

SYNTHESIS OF ALISKIREN

The present invention provides novel process for the preparation of renin inhibitor Aliskiren or its derivatives, and its pharmaceutically acceptable salts. The present invention also provides novel intermediates used in the preparation of Aliskiren.

ALISKIREN INTERMEDIATES AND A PROCESS FOR ANALYZING THE PURITY OF ALISKIREN

The present invention provides aliskiren intermediates and impurities, and processes for preparation thereof. The present invention also provides processes for preparing aliskiren using these intermediates and impurities. These impurities can also be used as reference markers or reference standards in the determination of the purity of aliskiren or intermediates of aliskiren.

PROCESS FOR THE PREPARATION OF (2S,4S,5S,7S)-N-(2-CARBAMYL-2- METHYLPROPYL)-5-AMINO-4-HYDROXY-2,7-DIISOPROPYL-8-[4-METHOXY-3-(3- METHOXYPROPOXY)PHENYL]-OCTANAMIDE HEMIFUMARATE AND ITS INTERMEDIATES THEREOF

The present invention relates to a process for the preparation of (2S,4S,5S,7S)-N-(2- Carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxy propoxy )phenyl]-octanamide compound of formula- 1 and its pharmaceutically acceptable salts thereof. Further, relates to the processes for the preparation of (R)-4-(2-(halomethyl)-3- methylbutyl)-l-methoxy-2-(3-methoxypropoxy) benzene and (R)-2-(4-methoxy-3-(3-methoxy propoxy) benzyl)-3-methyIbutan-l-ol useful intermediates in the synthesis of compound of formula- 1.