Aliskiren hemifumarate CAS 173334-58-2
Introduction：Basic information about Aliskiren hemifumarate CAS 173334-58-2, including its chemical name, molecular formula, synonyms, physicochemical properties, and safety information, etc.
Aliskiren hemifumarate Basic information
| Product Name: | Aliskiren hemifumarate |
| Synonyms: | (2S,4S,5S,7S)-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-5-amino-N-(3-amino-2,2-dimethyl-3-oxopropyl)-4-hydroxy-2-isopropyl-8-methylnonanamide hemifumarate;Aliskiren hemifumarate (2S,4S,5S,7S)-5-Amino-N-(2-carbamoyl-2-methylpropyl)-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropoxy)benzyl]-8-methylnonanamide hemifumarate;ALISKIREN FUMARATE;(2S,4S,5S,7S)-5-Amino-N-(2-carbamoyl-2-methylpropyl)-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropoxy)benzyl]-8-methylnonanamide hemifumarate;Benzeneoctanamide, delta-amino-N-(3-amino-2,2-dimethyl-3-oxopropyl)-gamma-hydroxy-4-methoxy-3-(3-methoxypropoxy)-alpha,zeta-bis(1-methylethyl)-, (alphas,gammas,deltas,zetas)-, (2E)-2-butenedioate (2:1) (salt);Aliskiren hemifumarate;(αS,γS,δS,ζS)-δ-Amino-N-(3-amino-2,2-dimethyl-3-oxopropyl)-γ-hydroxy-4-methoxy-3-(3-methoxypropoxy)-α,ζ-bis(1-methylethyl)benzeneoctanamide hemifumarate;Unii-C8A0p8G029 |
| CAS: | 173334-58-2 |
| MF: | C30H53N3O6 |
| MW: | 551.75832 |
| EINECS: | 630-415-8 |
| Product Categories: | Cardiovascular APIs;Amines;APIs;Chiral Reagents;Intermediates & Fine Chemicals;Pharmaceuticals |
| Mol File: | 173334-58-2.mol |
Aliskiren hemifumarate Chemical Properties
| Melting point | 72-75?C |
| storage temp. | Sealed in dry,Store in freezer, under -20°C |
| solubility | Methanol (Slightly), Water (Slightly) |
| form | Solid |
| color | White |
| InChIKey | UXOWGYHJODZGMF-LRQZUIEYNA-N |
| SMILES | c1(OCCCOC)cc(C[C@H](C(C)C)C[C@@H](N)[C@@H](O)C[C@@H](C(C)C)C(=O)NCC(C)(C)C(N)=O)ccc1OC |&1:10,15,17,20,r| |
Safety Information
| WGK Germany | WGK 3 |
| Storage Class | 11 - Combustible Solids |
| Description | Aliskiren hemifumarate (Tekturna(R)) was the first renin inhibitor approved by FDA in March 2007, and genomic analysis validated that Pgx-based dosing guidelines are not required for this drug. The once-daily, oral, direct renin inhibitor received FDA approval for treatment of high blood pressure as mono therapy or in combination with other antihypertensive medications. Furthermore, aliskiren demonstrated increased efficacy when used in combination with other commonly used blood pressure-lowering medications. Novartis is conducting a large outcome trial program to evaluate the long-term effects of aliskiren and of direct renin inhibition in general. |
| Chemical Properties | white to slightly yellowish crystalline powder. It is soluble in phosphate buffer, n-Octanol, and highly soluble in water. |
| Uses | Aliskiren hemifumarate is a potent renin inhibitor (IC50 = 0.6 and 80 nM for human and rat respectively). It has antihypertensive activity, decreasing plasma renin activity and inhibiting the conversion of angiotensinogen to Angiotensin I by binding to the S3 sub-pocket of renin. Exhibits selectivity for renin over a range of other aspartic proteinases (>5000 nM). Lowers blood pressure in a hypertensive rodent model. Orally active. Aliskiren hemifumarate (ALS) has been used to treat hypertension, alone or with other antihypertensive medications. It is suitable for oral administration. ALS regulates baseline systolic and diastolic blood pressure by blocking the catalytic activity of renin system at its rate-limiting step. |
| Uses | An orally active, synthetic nonpeptide renin inhibitor. Antihypertensive. |
| Definition | ChEBI: Aliskiren fumarate is the hemifumarate salt of aliskiren. It has a role as an antihypertensive agent. It contains an aliskiren. |
| Clinical Use | Renin inhibitor: Hypertension |
| Synthesis | The synthesis of aliskiren by Novartis is depicted in the scheme.Aliskiren (I) was synthesized through a convergentsynthetic strategy by coupling key intermediate chloride 5with aldehyde 10. Hydrogenation of cinnamic acid 1, followedby generation of the acid chloride of the correspondingacid and reaction with (+)-pseudoephedrine providedamide 2 in 91% yield. Deprotonation of amide 2 with LDAfollowed by alkylation with 2-iodopropane in refluxing THFgave 3 as a single diastereomer in 52% yield. Reduction ofthe amide functionality in 3 using n-butyl lithium borontrifluoride ammonium complex proceeded without epimerizationof the chiral center to give alcohol 4 in 66% yield.Chlorination of 4 using phosphorus oxychloride gave chloride5, in 78% yield as the organometallic precursor for theeventual coupling to aldehyde 10. Synthesis of fragment 10commenced with (+)-pseudoephedrine isovaleramide 6,which was efficiently deprotonated with LDA and alkylatedusing allyl bromide; diastereomerically pure 7 was obtainedupon crystallization of the crude reaction mixture in 78%yield. Bromolactonization of 7, using n-bromosuccinimide inthe absence of acetic acid gave amide acetal 8 with a singleconfiguration at the spirocenter and a 6:1 mixture oftrans:cis ring substituents. Displacement of the bromide usingtetrabutylammonium acetate followed by basic hydrolysisprovided alcohol 9 in 85% yield. Oxidation of 9 usingdimethyl sulfoxide-sulfur trioxide/pyridine proceeded withoutepimerization to furnish the masked lactone aldehyde 10in 60% yield. Coupling of fragments 5 and 10 was achieved by treatment of 10 with the organocerium reagent of the correspondingGrignard reagent prepared from 5. Hydrolysis ofthe crude spirocyclic addition product revealed that the hydroxylactone11 was formed in 51% overall yield as an inseparableepimeric mixture with a Felkin-Anh selectivity of85:15. The requisite nitrogen functionality was installed viathe brosylate to give azido lactone 12 in 68% yield. Aminolysiswith 3-amino-2,2-dimethylpropionamide led to formationof the open chain azido alcohol 13 in 76% yield. The synthesis of aliskiren was completed by azide hydrogenolysisand formation of the hemifumarate salt. Generation ofpure aliskiren was achieved via crystallization which removedthe residual minor (R)-epimer carried through fromthe 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%). |
| storage | Store at -20°C |
| References | [1] Patent: WO2013/14191, 2013, A1. Location in patent: Page/Page column 19; 20 [2] Patent: EP2551260, 2013, A1. Location in patent: Paragraph 0106; 0107; 0108; 0109; 0110 |
Aliskiren hemifumarate Preparation Products And Raw materials
| Raw materials | δN-Benzyloxycarbonyl Aliskiren-->CarbaMic acid, [4-[[(3-aMino-2,2-diMethyl-3-oxopropyl)aMino]carbonyl]-2-hydroxy-1-[2-[[4-Methoxy-3-(3-Methoxypropoxy)phenyl]Methyl]-3-Methylbutyl]-5-Methylhexyl]-, 1,1-diMethylethyl ester, [1S-[1R*(R*),2R*,4R*]]--->Fumaric acid-->Aliskiren-->Palladium-->Hydrogen-->Isopropyl alcohol-->Activated carbon |
