WO2013124868A2 - Solid form of aliskiren intermediate - Google Patents
Solid form of aliskiren intermediate Download PDFInfo
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- WO2013124868A2 WO2013124868A2 PCT/IN2013/000109 IN2013000109W WO2013124868A2 WO 2013124868 A2 WO2013124868 A2 WO 2013124868A2 IN 2013000109 W IN2013000109 W IN 2013000109W WO 2013124868 A2 WO2013124868 A2 WO 2013124868A2
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- aliskiren
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- 0 CC(C)[C@](C[C@](*)[C@](C[C@]1C(C)C)OC1=O)Cc(cc1)cc(OCCCOC)c1OC Chemical compound CC(C)[C@](C[C@](*)[C@](C[C@]1C(C)C)OC1=O)Cc(cc1)cc(OCCCOC)c1OC 0.000 description 2
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/24—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same saturated acyclic carbon skeleton
- C07C255/25—Aminoacetonitriles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Definitions
- the present invention relates to isolation of a novel solid form of Aliskiren intermediate, which is further converted into Aliskiren and its pharmaceutically acceptable salts with improved yield and quality.
- Aliskiren is marketed by Novartis as TEKTURNA® in the form of its hemifumarate salt in a once-daily formulation.
- U.S. pat. No. 5,559,111 discloses Aliskiren and related compounds along with the synthesis of Aliskiren.
- the synthesis of the enantiomerically pure compound is quite demanding. Considering more synthetic steps of Aliskiren, which involves almost all the intermediates are in liquid stage. It is highly beneficial, if any of the intermediate is isolated as a crystalline solid, which can give the intermediate as well as Aliskiren with good purity. Therefore, there is a need to develop a process, which involves the isolation of intermediate as a solid and further convention to pure Aliskiren.
- the present invention provides isolation of novel solid form of Aliskiren intermediate of Formula-Y and its further conversion into Aliskiren and its pharmaceutically acceptable salts.
- Principle object of the present invention is to provide a novel solid form of Aliskiren intermediate (2S,4S,5S,7S)-5-azido-N-(2-cyano-2-methylpropyl)-4-hydroxy-7- [4-methoxy-3-(3 methoxypropoxy) enzyl]-8-methyl-2-(propan-2-yl)nonanamide of compound of Formula-Y.
- Another object of the present invention is to provide an improved process for the isolation of solid form of compound of Formula-Y.
- Yet another object of the present invention is to provide further conversion of solid intermediate of Formula-Y into Aliskiren or its pharmaceutically acceptable salts.
- One aspect of the present is to provide process for the preparation of solid compound of Formula-Y comprising the steps of:
- One more aspect of the present is to provide process for the preparation of solid compound of Formula-Y comprising the steps of:
- Figure 1 illustrates Powder X-ray diffraction pattern of compound of Formula-Y.
- Figure 2 illustrates ⁇ -NMR spectrum of compound of Formula-Y.
- the present invention relates to isolation of a novel solid form of Aliskiren intermediate, which is further converted into Aliskiren and its pharmaceutically acceptable salts with improved yield and quality.
- the intermediate compounds play a vital role in the preparation of Aliskiren and its pharmaceutically acceptable salts thereof.
- US 7009078 patent disclosed the process for the preparation of Aliskiren, wherein Aliskiren intermediate lactone (Formula-X) is subjected to aminolysis reaction using 3-amino-2,2-dimethyl-propionamide resulting corresponding amide compound (Formula-Z) as an oil of about 88% purity. The impure intermediate is further converted into Aliskiren yielded with less purity.
- amide compound (Formula-Z) is synthesized from lactone compound (Formula-X) having the purity around of 93.8%.
- the amide compound obtained by the prior art need number of purification steps to get the desire quality of Aliskiren.
- lactone compound is subjected to ring opening reaction by 3-amino-2,2-dimethyl-propionitrile followed by isolation of amide compound of Formula-Y as solid having the purity greater than equal to 99%. Accordingly one aspect of the present invention provides a solid compound of
- One more aspect of the present invention is to provide crystalline compound of Formula-Y.
- crystalline compound of Formula-Y is characterized by the Powder X-ray diffraction having peaks at about 6.84, 10.1 1, 12.73, 12.98, 16.49, 17.97, 18.69, 20.63, 22.76, and 23.02 ( ⁇ ) 0.2 20 values.
- crystalline compound of Formula-Y is further characterized by the Powder X-ray diffraction having peaks at about 6.84, 10.1 1, 12.73, 12.98, 14.82, 16.49, 17.97, 18.69, 19.32, 20.30, 20.63, 20.84, 21.30, 21.9, 22.76, 23.02, 23.77, 24.26, 25.20, and 26.26 ( ⁇ ) 0.2 20 values.
- the crystalline compound of Formula-Y is further characterized by Powder X-ray diffraction pattern as depicted in figure 1.
- the crystalline compound of Formula-Y is further characterized by ⁇ -NMR spectrum as depicted in Figurp 2.
- One aspect of the present is to provide process for the preparation of solid compound of Formula-Y comprising the steps of:
- the solid compound of Formula-Y is prepared by reacting compound of Formula-X with 3-amino-2,2-dimethyl-propionitrile in presence of a base and catalyst.
- the organic or inorganic base preferably organic base such as Triethylamine, diisopropylethylamine, etc., more preferably Triethylamine and a catalyst like 2-hydroxypyridine.
- hydrocarbon solvent such as toluene, Xylene and Chlorobenzene, preferably toluene and stirred with alkali solution to remove catalyst as an alkali salt.
- 3-amino-2,2-dimethyl- propionitrile and Triethylamine are extracted from hydrocarbon solvent layer using an organic acid like acetic acid.
- the hydrocarbon solvent layer is stirred with 1-10% aqueous base solution like sodium bicarbonate, sodium carbonate, potassium bicarbonate and potassium carbonate, preferably 3-5% sodium bicarbonate solution to crystallize compound of Formula-Y.
- the obtained product is filtered and dried under vacuum to get the compound of Formula-Y as white solid.
- the solid compound of Formula-Y is prepared by reacting compound of Formula-X with 3-amino-2,2-dimethyl-propionitrile in presence of a base like organic or inorganic base, preferably organic base such as Triethylamine, Tripropylamine, diisopropylethylamine, etc., more preferably Triethylamine and a catalyst like 2-hydroxypyridine.
- a base like organic or inorganic base
- organic base such as Triethylamine, Tripropylamine, diisopropylethylamine, etc., more preferably Triethylamine and a catalyst like 2-hydroxypyridine.
- water immiscible solvent like hydrocarbon solvent such as toluene, Xylene and Chlorobenzene, preferably toluene and optionally stirred with alkali solution to remove catalyst as an alkali salt.
- the organic layer pH was adjusted to 4-6 using aqueous acid like acetic acid to crystallize compound of Formula-Y
- Another aspect of the present invention is to provide further conversion of solid compound of Formula-Y into Aliskiren or its pharmaceutically acceptable salts by known methods as disclosed in our co-pending application IN 3087/CHE/2010 (WO 2012052829) comprising the steps of:
- the said crystal of the present invention is characterized by their X-ray powder diffraction pattern.
- the X-ray diffraction patterns of said polymorphs of the invention were measured on PANalytical, X'Pert PRO powder diffractometer equipped with goniometer of ⁇ / ⁇ configuration and X'Celerator detector.
- the Cu-anode X-ray tube was operated at 40kV and 30mA. The experiments were conducted over the 2 ⁇ range of 2.0°-50.0°, 0.030° step size and 50 seconds step time.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to isolation of a novel solid form of Aliskiren intermediate of compound of Formula-Y and further conversion into Aliskiren or its pharmaceutically acceptable salts with improved yield and quality.
Description
"SOLID FORM OF ALISKIREN INTERMEDIATE
This application claims priority to Indian Patent application number 640/CHE/2012 filed on February 21, 2012
FIELD OF THE INVENTION:
The present invention relates to isolation of a novel solid form of Aliskiren intermediate, which is further converted into Aliskiren and its pharmaceutically acceptable salts with improved yield and quality.
BACKGROUND OF THE INVENTION:
Aliskiren, (2S, 4S, 5S, 7S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy- 2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)phenyl] octanamide having the Formula-I, a new antihypertensive has been developed which interferes with the renin- angiotensin system at the beginning of angiotensin II biosynthesis.
Formuh-I
Aliskiren is marketed by Novartis as TEKTURNA® in the form of its hemifumarate salt in a once-daily formulation. U.S. pat. No. 5,559,111 discloses Aliskiren and related compounds along with the synthesis of Aliskiren.
Further US 7132569, US 7009078, US 6730798 and US 6800769 patents claims novel intermediates, which are used in the preparation of Aliskiren which are incorporated here for reference. Our co-pending Indian patent application IN 3087/CHE/2010 discloses novel process for the preparation of Aliskiren as disclosed in scheme-I.
Formula-;
Aliskiren
SCHEME-I
The intermediate (2S,4S,5S,7S)-5-azido-N-(2-cyano-2-methylpropyl)-4-hydroxy-7-[4- methoxy-3-(3 methoxypropoxy) benzyl]-8-methyl-2-(propan-2-yl)nonanamide (compound of Formula- Y) obtained by the above process is in oil form.
As the Aliskiren comprises, 4 chiral carbon atoms, the synthesis of the enantiomerically pure compound is quite demanding. Considering more synthetic steps of Aliskiren, which involves almost all the intermediates are in liquid stage. It is highly beneficial, if any of the intermediate is isolated as a crystalline solid, which can give the intermediate as well as Aliskiren with good purity. Therefore, there is a need to develop a process, which involves the isolation of intermediate as a solid and further convention to pure Aliskiren.
Thus the present invention provides isolation of novel solid form of Aliskiren intermediate of Formula-Y and its further conversion into Aliskiren and its pharmaceutically acceptable salts.
OBJECT AND SUMMARY OF THE INVENTION
Principle object of the present invention is to provide a novel solid form of Aliskiren intermediate (2S,4S,5S,7S)-5-azido-N-(2-cyano-2-methylpropyl)-4-hydroxy-7- [4-methoxy-3-(3 methoxypropoxy) enzyl]-8-methyl-2-(propan-2-yl)nonanamide of compound of Formula-Y.
Formula-Y
Another object of the present invention is to provide an improved process for the isolation of solid form of compound of Formula-Y.
Yet another object of the present invention is to provide further conversion of solid intermediate of Formula-Y into Aliskiren or its pharmaceutically acceptable salts.
One aspect of the present is to provide process for the preparation of solid compound of Formula-Y comprising the steps of:
a) reacting compound of Formula-X with 3-amino-2j2-dimethyl-propionitrile in presence of a base,
Formula-X
b) diluting the reaction mass with water immiscible solvent,
c) optionally washing with aqueous alkali solution,
d) adjusting the pH with aqueous acid, and
e) isolating the solid compound of Formula-Y.
One more aspect of the present is to provide process for the preparation of solid compound of Formula-Y comprising the steps of:
a) reacting compound of Formula-X with 3-amino-2,2-dimethyl-propionitrile in presence of a base,
Formula-X
b) diluting the reaction mass with water immiscible solvent,
c) optionally washing with aqueous alkali solution,
d) washing with aqueous acid,
e) adding aqueous base, and
f) isolating the solid compound of Formula-Y.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 illustrates Powder X-ray diffraction pattern of compound of Formula-Y.
Figure 2 illustrates Ή-NMR spectrum of compound of Formula-Y.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to isolation of a novel solid form of Aliskiren intermediate, which is further converted into Aliskiren and its pharmaceutically acceptable salts with improved yield and quality.
The intermediate compounds play a vital role in the preparation of Aliskiren and its pharmaceutically acceptable salts thereof. US 7009078 patent disclosed the process for the preparation of Aliskiren, wherein Aliskiren intermediate lactone (Formula-X) is subjected to aminolysis reaction using 3-amino-2,2-dimethyl-propionamide resulting
corresponding amide compound (Formula-Z) as an oil of about 88% purity. The impure intermediate is further converted into Aliskiren yielded with less purity.
Considering more synthetic steps of Aliskiren, which involves almost all the intermediates are in liquid stage. It is highly beneficial, if any of the intermediate could be isolated as a crystalline solid, which can give the intermediate as well as Aliskiren with good yield and purity. Therefore, there is a need to develop a process, which involves the isolation one of Aliskiren intermediate as a solid and further convention to pure Aliskiren.
To avoid that prior art problems there is a need to improve the purity of Aliskiren. The present inventors tried to open the lactone compound (Formula-X) with 3-amino-2,2- dimethyl-propionitrile and not only succeeded in getting fruitful aminolysis reaction, but also isolating the corresponding amide compound of Formula-Y as a pure crystalline compound of chromatographic purity greater than or equal to 99%. This results increase in the purity of Aliskiren.
In prior art US 7009078, amide compound (Formula-Z) is synthesized from lactone compound (Formula-X) having the purity around of 93.8%. The amide compound obtained by the prior art need number of purification steps to get the desire quality of Aliskiren. According to present invention lactone compound is subjected to ring opening reaction by 3-amino-2,2-dimethyl-propionitrile followed by isolation of amide compound of Formula-Y as solid having the purity greater than equal to 99%. Accordingly one aspect of the present invention provides a solid compound of
Formula-Y.
One more aspect of the present invention is to provide crystalline compound of Formula-Y.
In one embodiment, crystalline compound of Formula-Y is characterized by the Powder X-ray diffraction having peaks at about 6.84, 10.1 1, 12.73, 12.98, 16.49, 17.97, 18.69, 20.63, 22.76, and 23.02 (±) 0.2 20 values.
In another embodiment, crystalline compound of Formula-Y is further characterized by the Powder X-ray diffraction having peaks at about 6.84, 10.1 1, 12.73, 12.98, 14.82, 16.49, 17.97, 18.69, 19.32, 20.30, 20.63, 20.84, 21.30, 21.9, 22.76, 23.02, 23.77, 24.26, 25.20, and 26.26 (±) 0.2 20 values.
The crystalline compound of Formula-Y is further characterized by Powder X-ray diffraction pattern as depicted in figure 1.
The crystalline compound of Formula-Y is further characterized by Ή-NMR spectrum as depicted in Figurp 2.
One aspect of the present is to provide process for the preparation of solid compound of Formula-Y comprising the steps of:
a) reacting compound of Formula-X with 3-amino-2,2-dimethyl-propionitrile in presence of a b
b) diluting the reaction mass with water immiscible solvent,
c) optionally washing with aqueous alkali solution,
d) washing with aqueous acid,
e) adding aqueous base, and
f) isolating the solid compound of Formula-Y.
According to the present invention, the solid compound of Formula-Y is prepared by reacting compound of Formula-X with 3-amino-2,2-dimethyl-propionitrile in presence
of a base and catalyst. The organic or inorganic base, preferably organic base such as Triethylamine, diisopropylethylamine, etc., more preferably Triethylamine and a catalyst like 2-hydroxypyridine. After completion of the reaction the reaction mass is diluted with hydrocarbon solvent such as toluene, Xylene and Chlorobenzene, preferably toluene and stirred with alkali solution to remove catalyst as an alkali salt. 3-amino-2,2-dimethyl- propionitrile and Triethylamine are extracted from hydrocarbon solvent layer using an organic acid like acetic acid. The hydrocarbon solvent layer is stirred with 1-10% aqueous base solution like sodium bicarbonate, sodium carbonate, potassium bicarbonate and potassium carbonate, preferably 3-5% sodium bicarbonate solution to crystallize compound of Formula-Y. The obtained product is filtered and dried under vacuum to get the compound of Formula-Y as white solid.
Alternatively the solid compound of Formula-Y is prepared by comprising the steps of:
a) reacting compound of Formula-X with 3-amino-2,2-dimethyl-propionitrile in presence of a base,
Formula-X
b) diluting the reaction mass with water immiscible solvent,
c) optionally washing with aqueous alkali solution,
d) adjusting the pH with aqueous acid, and
e) isolating the solid compound of Formula-Y.
As per the present invention, the solid compound of Formula-Y is prepared by reacting compound of Formula-X with 3-amino-2,2-dimethyl-propionitrile in presence of a base like organic or inorganic base, preferably organic base such as Triethylamine, Tripropylamine, diisopropylethylamine, etc., more preferably Triethylamine and a catalyst like 2-hydroxypyridine. After completion of the reaction the reaction mass is diluted with water immiscible solvent like hydrocarbon solvent such as toluene, Xylene
and Chlorobenzene, preferably toluene and optionally stirred with alkali solution to remove catalyst as an alkali salt. The organic layer pH was adjusted to 4-6 using aqueous acid like acetic acid to crystallize compound of Formula-Y. The obtained product is filtered and dried under vacuum to get the compound of Formula-Y as white solid..
Another aspect of the present invention is to provide further conversion of solid compound of Formula-Y into Aliskiren or its pharmaceutically acceptable salts by known methods as disclosed in our co-pending application IN 3087/CHE/2010 (WO 2012052829) comprising the steps of:
a) converting the cyano group of solid compound of Formula-Y into amide group to give compound of Formula-Z,
Formula-Z
b) reducing azide compound of Formula-Z to obtain Aliskiren, and
c) optionally converting Aliskiren into its pharmaceutically acceptable salts.
Instrumentation
Powder X-ray Diffraction iPXRD)
The said crystal of the present invention is characterized by their X-ray powder diffraction pattern. Thus, the X-ray diffraction patterns of said polymorphs of the invention were measured on PANalytical, X'Pert PRO powder diffractometer equipped with goniometer of Θ/Θ configuration and X'Celerator detector. The Cu-anode X-ray tube was operated at 40kV and 30mA. The experiments were conducted over the 2Θ range of 2.0°-50.0°, 0.030° step size and 50 seconds step time.
Nuclear Magnetic Resonance (NMR) spectroscopy
The 1HNMR spectrum was recorded in CDCI3 at 300MHz on Bruker Avance NMR spectrometer. The 1H chemical shifts are reported on δ scale in ppm, relative to TMS (O.OOppm) as internal standard.
The following examples are provided to illustrate the process of the present invention. They, are however, not intended to limiting the scope of the present invention in any way and several variants of these examples would be evident to person ordinarily skilled in the art.
Experimental procedure:
Example-1
A mixture of compound-X (100 g), 3-Amino-2,2-dimethyl-propionitrile (74.5 g), and 2-hydroxypyridine (22.5 g) in triethylamine was stirred for about 24 hours at 60- 70°C. The progress of the reaction was monitored by HPLC analysis. After completion of the reaction the reaction mass was diluted with toluene and stirred with aq NaOH solution to precipitate and remove 2-hydroxypyridine as sodium salt. The organic layer was washed with aqueous acetic acid. The organic layer was stirred with aqueous sodium bicarbonate solution to crystallize out the desired product. The product was filtered, washed with DM water followed by prechilled toulene and dried under vacuum to yield compound of Formula-Y as white solid. HPLC purity: >99%. Melting point: 62 °C.
'HNMR: 6.79 (d, IH), 6.72 (d, IH), 6.70 (d, IH), 6.1 1 (t, IH), 4.10 (t, 2H), 3.84 (s, 3H), 3.58 (t, 2H), 3.39-3.43 (m, 3H), 3.36 (s, 3H), 2.86-2.90 (m, IH), 2.44-2.58 (m, 3H), 2.06- 2.19 (m, 3H), 1.87-1.92 (m, IH), 1.57-1.85 (m, 5H), 1.36 (s, 6H), 1.30-1.40 (m, IH), 0.86-0.97 (m, 12H).
Example-2
Synthesis of compound-Y:
A mixture of compound-X (100 g), 3-Amino-2,2-dimethyl-propionitrile (74.5 g), and 2-hydroxypyridine (22.5 g) in triethylamine was stirred for about 24 hours at 60- 70°C. The progress of the reaction was monitored by HPLC analysis. After completion of the reaction the reaction mass was diluted with toluene and stirred with aq NaOH solution to precipitate and remove 2-hydroxypyridine as sodium salt. pH of the organic layer was adjusted to 4-6 with aqueous acetic acid solution to crystallize out the desired product. The product was filtered, washed with cyclohexane and DM water and dried under vacuum to yield compound of Formula- Y as white solid. HPLC purity: >99%. Melting point: 62 °C.
'HNMR: 6.79 (d, IH), 6.72 (d, IH), 6.70 (d, IH), 6.11 (t, IH), 4.10 (t, 2H), 3.84 (s, 3H), 3.58 (t, 2H), 3.39-3.43 (m, 3H), 3.36 (s, 3H), 2.86-2.90 (m, IH), 2.44-2.58 (m, 3H), 2.06- 2.19 (m, 3H), 1.87-1.92 (m, IH), 1.57-1.85 (m, 5H), 1.36 (s, 6H), 1.30-1.40 (m, IH), 0.86-0.97 (m, 12H).
ExainpIe-3
Synthesis of compound-Z:
Formula-Z
To a mixture of Compound-Y (13g, obtained in example 1 or 2) and ethanol (65 ml) aqueous NaOH (5g dissolved in 45 ml of DM water) and 35% Hydrogen peroxide (20 ml) was added at room temperature and stirred the at 30°- 40 °C for 2-4h. The progress of the reaction was monitored by HPLC analysis. After completion of the reaction the peroxides were quenched by stirring with sodium bisulfite solution. Thereafter product was extracted in toluene. The toluene extract was washed with ethanolamine and water. The solvent was distilled off completely under vacuum to obtain compound Z. ExampIe-4
Synthesis of Aliskiren hemifumarate:
Compound-Z (12.3g, obtained in example 3) and of ethanolamine (1.3g) were dissolved in ethanol and hydrogenated at about 3Kg pressure in presence of Pd/C (600mg, 5% w/w) for 3-4h. The catalyst was filtered and the clear filtrate was treated with fumaric acid (1.23g). The solution was filtered through Celite pad to get a particle free solution which was further concentrated under reduced pressure below 40°C. Acetonitrile was added to the concentrate and distillation was continued to remove residual ethanol. To this residue a mixture of acetonitrile/ethanol (97:3) was added and the obtained solution was stirred overnight to crystallize the product. The product slurry was cooled, filtered and washed with pre chilled acetonitrile. The product was dried under vacuum at 35 °C to give the Aliskiren hemifumarate (9g).
Claims
A solid compound of Formula-Y.
Formula-Y
The compound according to claim 1, wherein compound of Formula-Y is in crystalline form.
Crystalline compound of Formula-Y characterized by Powder X-ray diffraction peaks at about
6.84, 10.11, 12.73, 12.98, 16.49, 17.97, 18.69, 20.63, 22.76, and 23.02 (±) 0.2 2Θ values.
The compound according to claim 3, wherein the crystalline compound of Formula- Y is further characterized by having Powder X-ray diffraction pattern as depicted in figure 1.
A process for the preparation of solid compound of Formula-Y comprising the steps of :
a) reacting compound of Formula-X with 3-amino-2,2-dimethyl- propionitrile in presence of a base,
b) diluting the reaction mass with water immiscible solvent,
c) optionally washing with aqueous alkali solution,
d) adjusting the pH with aqueous acid, and
e) isolating the solid compound of Formula-Y.
A process for the preparation of solid compound of Formula-Y comprising the steps of :
Fbrmula-X
b) diluting the reaction mass with water immiscible solvent,
c) optionally washing with aqueous alkali solution,
d) washing with aqueous acid
e) adding aqueous base, and
f) isolating the solid compound of Formula- Y..
7. The process according to claim 5 or 6, wherein the aqueous acid is aqueous acetic acid.
8. The process according to claim 5 or 6, wherein the solid compound of Formula-Y is further converted into Aliskiren or its pharmaceutically acceptable salts thereof comprising the steps of:
a) converting the cyano group of solid compound of Formula-Y into amide group to give compound of Formula-Z,
Formula— Z
b) reducing azide compound of Formula-Z to obtain Aliskiren, and
c) optionally converting Aliskiren into its pharmaceutically acceptable salts.
9. Use of solid compound of Formula-Y in the preparation of Aliskiren or its pharmaceutically acceptable salts thereof.
10. The compound according to claim 1, wherein the solid compound of Formula-Y is further converted into Aliskiren or its pharmaceutically acceptable salts thereof comprising the steps of:
d) converting the cyano group of solid compound of Formula-Y into amide group to give compound of Formula-Z,
Formula-Z
e) reducing azide compound of Formula-Z to obtain Aliskiren, and f) optionally converting Aliskiren into its pharmaceutically acceptable salts.
Applications Claiming Priority (2)
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IN640/CHE/2012 | 2012-02-21 | ||
IN640CH2012 | 2012-02-21 |
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5559111A (en) | 1994-04-18 | 1996-09-24 | Ciba-Geigy Corporation | δ-amino-γ-hydroxy-ω-aryl-alkanoic acid amides |
US6730798B2 (en) | 2000-07-05 | 2004-05-04 | Speedel Pharma Ag | Process for the preparation of substituted octanoyl amides |
US6800769B2 (en) | 2000-07-25 | 2004-10-05 | Speedel Pharma Ag | Process for the preparation of substituted octanoyl amides |
US7009078B1 (en) | 1999-07-29 | 2006-03-07 | Speedel Pharma Ag | Production of N-substituted 2,7-dialkyl-4-hydroxy-5-amino-8-arly-octanoylamides |
WO2012052829A1 (en) | 2010-10-19 | 2012-04-26 | Matrix Laboratories Ltd | Synthesis of aliskiren |
-
2013
- 2013-02-20 WO PCT/IN2013/000109 patent/WO2013124868A2/en active Application Filing
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5559111A (en) | 1994-04-18 | 1996-09-24 | Ciba-Geigy Corporation | δ-amino-γ-hydroxy-ω-aryl-alkanoic acid amides |
US7009078B1 (en) | 1999-07-29 | 2006-03-07 | Speedel Pharma Ag | Production of N-substituted 2,7-dialkyl-4-hydroxy-5-amino-8-arly-octanoylamides |
US7132569B2 (en) | 1999-07-29 | 2006-11-07 | Speedel Pharma Ag | Preparation of N-substituted 2,7-dialkyl-4-hydroxy-5-amino-8-aryl-octanoyl amides |
US6730798B2 (en) | 2000-07-05 | 2004-05-04 | Speedel Pharma Ag | Process for the preparation of substituted octanoyl amides |
US6800769B2 (en) | 2000-07-25 | 2004-10-05 | Speedel Pharma Ag | Process for the preparation of substituted octanoyl amides |
WO2012052829A1 (en) | 2010-10-19 | 2012-04-26 | Matrix Laboratories Ltd | Synthesis of aliskiren |
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