Structure of 173338-07-3
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CAS No. : | 173338-07-3 |
Formula : | C35H61N3O8 |
M.W : | 651.87 |
SMILES Code : | O=C(OC(C)(C)C)N[C@H]([C@@H](O)C[C@H](C(NCC(C)(C)C(N)=O)=O)C(C)C)C[C@H](CC1=CC=C(OC)C(OCCCOC)=C1)C(C)C |
MDL No. : | MFCD20526609 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Example 1 1 : Preparation of Aliskiren Base.[0099] 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 (4.0 g, 6.1 mmol) was dissolved at 25 C in dichloromethane (DCM) (40 ml, 10V). The solution was cooled to 0 - 5 C and HC1 gas (2.5 g, 0.06 mol) was bubbled through the solution. The reaction mixture was maintained at 0 - 5 C for an additional 2-3h and monitored by HPLC. When the reaction was complete, as determined via HPLC by disappearance of starting material, a IN NaOH solution was added dropwise to adjust the pH of the mixture to pH 9. The organic layer was then separated and concentrated to provide Aliskiren base as a white foam in a quantitative yield. | |
90.4% | A solution of compound of Formula X-N- BOC (5.0 g, 0.0077 mol) in dichloromethane (50 mL) was cooled to 0-5C. Cone. HC1 (6.6 mL, 0.0770 mol) was slowly added at 0-5C and stirred reaction mass at 0-5C for 3h. After completion of reaction (TLC), 20% aqueous sodium carbonate (42 mL) was added at 0-5C and warmed to room temperature. The aqueous layer was extracted with dichloromethane (50 mL) and combined dichloromethane was washed with DM water (50 mL). The solvent was distilled off under reduced pressure at 40-45C to afford Aliskiren free base as colorless oil. Added toluene (50mL) and heated to 40-45C. Washed toluene layer with 1% sodium hydroxide solution (25 mL) at 40-45C, separated and evaporated under reduced pressure at 40-45C to afford Aliskiren free base as colorless oil (3.8, 90.4%). | |
90.4% | With hydrogenchloride; In dichloromethane; water; at 0 - 5℃; for 3h; | A solution of compound of Formula X-N-BOC (5.0 g, 0.0077 mol) in dichloromethane (50 mL) was cooled to 0-5 C. Conc. HCl (6.6 mL, 0.0770 mol) was slowly added at 0-5 C. and stirred reaction mass at 0-5 C. for 3 h. After completion of reaction (TLC), 20% aqueous sodium carbonate (42 mL) was added at 0-5 C. and warmed to room temperature. The aqueous layer was extracted with dichloromethane (50 mL) and combined dichloromethane was washed with DM water (50 mL). The solvent was distilled off under reduced pressure at 40-45 C. to afford Aliskiren free base as colorless oil. Added toluene (50 mL) and heated to 40-45 C. Washed toluene layer with 1% sodium hydroxide solution (25 mL) at 40-45 C., separated and evaporated under reduced pressure at 40-45 C. to afford Aliskiren free base as colorless oil (3.8, 90.4%). |
75% | With trifluoroacetic acid; In dichloromethane; at -15℃;Inert atmosphere; | Under nitrogen protection, methylene chloride (40 ml) and trifluoroacetic acid (10 ml) are added into a 100 ml reaction bottle and the reaction mixture is cooled down to - 15 C with ice-salt bath. under stirring, (1S, 2S, 4S)-4-(2-carbamoyl-2-methylpropyl- carbamoyl)-2-hydroxy-1-{(S)-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3methylbutyl}-5methylhexyl)-carbamic acid tert-butyl ester (the compound of formula XXIII-A) (6.5 g, 10 mmol) is added in one batch and the reaction is maintained until TLC monitoring indicates the starting materials are almost completely exhausted. The reaction mixture is then neutralized with sodium hydroxide water solution (1 mol/L) with reaction temperature maintained below 0 C. The organic phase is collected and the remained water phase is extracted with isopropyl ether (30 ml) for 3 times. All organic phases are combined and washed sequentially with saturated saline (30 ml), deionized water (30 ml) and dried with anhydrous sodium sulfate. After filtration and removal of solvent under reduced pressure, the residue is purified with short column of silica gel chromatography to obtain the Aliskiren compound of formula (I) (4.4 g) as a wax material. The yield is 75% as calculated from the compound of formula XXIII-A. The Aliskiren compound of formula I can be characterized by data collected from: MS m/z: 552.6 (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 6.88-6.75 (m, 3H), 4.08-4.04 (t, J = 6.3Hz, 2H), 3.79 (s, 3H), 3.60-3.55 (t, J = 6.3Hz, 2H), 3.30 (s, 3H), 3.30-3.25 (m, 3H), 2.69 (m, 2H), 2.49 (m, 1H), 2.27 (m, 1H), 2.04 (m, 2H), 1.78-1.35 (m, 7H), 1.10 (m, 6H), 0.90 (m, 12H) ppm |
75% | With trifluoroacetic acid; In dichloromethane; at -15℃;Inert atmosphere; | [Step 2]: Preparation of Aliskiren. Under nitrogen protection, methylene chloride (40 ml) and trifluoroacetic acid (10 ml) are added into a 100 ml reaction bottle and the reaction mixture is cooled down to -15 C. with ice-salt bath under stirring, (1S,2S,4 S)-4-(2-carbamoyl-2-methylpropyl-carbamoyl)-2-hydroxy-1-{(S)-2-[4-methoxy-3-(3-methoxypropoxy)-benzyl]-3 methylbutyl}-5-methyl-hexyl)-carbamic acid tert-butyl ester (the compound of formula XXIII-A) (6.5 g, 10 mmol) is added in one batch and the reaction is maintained until TLC monitoring indicates the starting materials are almost completely exhausted. The reaction mixture is then neutralized with sorb urn hydroxide water solution (1 mol/L) with reaction temperature maintained below 0 C. The organic phase is collected and the remained, water phase is extracted with isopropyl ether (30 ml) for 3 times. All organic phases are combined and washed sequentially with saturated saline (30 ml), deionized water (30 ml) and dried with anhydrous sodium sulfate. After filtration and removal of solvent under reduced pressure, the residue is purified with short column of silica gel chromatography to obtain the Aliskiren compound of formula (I) (4.4 g) as a wax material. The yield is 75% as calculated from the compound of formula XXIII-A. The Aliskiren compound of formula I can be characterized by data collected from: MS m/z: 552.6 (M+H) 1H-NMR (400 MHz, CDC13) δ 6.88-6.75 (m, 3H), 4.08-4.04 (t, J=6.3 Hz, 2H), 3.79 (s, 3H), 3.60-3.55 (t, 6.3 Hz, 2H), 3.30 (s, 3H), 3.30-3.25 (m, 3H), 2.69 (m, 2H), 2.49 (m, 1H), 2.27 (m, 1H),2.04 (m, 2H), 1.78-1.35 (m, 7H), 1.10(m, 6H), 0.90(m, 12H)ppm. |
Product 13 is dissolved in a mixture of 4.0M hydrochloric acid in dioxane. The solution is stirred for 24 hours at room temperature and neutralized with solid sodium bicarbonate. The suspension is filtered and the solvent removed in vacuum to give the product as a foam (for characterization see e.g. EP 0 678 503, Example 137). EPO <DP n="45"/>From the free compound or the hydrochloride salt obtainable, for example the hemifumarate salt of the title compound can be prepared, for example as described in US 6,730,798, example J1 (comprising mixing with fumaric acid, dissolution in ethanol, filtration, evaporation of the obtained solution, re-dissolving of the residue in acetonitrile, inoculation with a small amount of the title compound's hemifumarate salt and isolation of the precipitating material), incorporated by reference herein especially with regard to this salt formation reaction. | ||
Compound of formula (Xlb) is dissolved in a solution of trifluoroacetic acid in methylenechloride at room temperature. The reaction mixture is stirred for 2 hours and the pHadjusted to 10 with 37% sodium hydroxide solution. The aqueous phase is extracted threetimes with 100ml_ of dichloromethane. (for characterization see e.g. 678 503, Example137). | ||
Product XXIIa is dissolved in a mixture of 4.0M hydrochloric acid in dioxane. The solution is stirred for 24 hours at room temperature and neutralized with solid sodium bicarbonate. The suspension is filtered and the solvent removed in vacuum to give the product as a foam (for characterization see e.g. EP 0 678 503, Example 137). | ||
Example 6c2) Preparation of Compound (Ia, Aliskiren) from Compound (VIIa)Crude compound (VIIa) from the above experiment (Example 4) (5.5 g) was dissolved in aqueous ethanol (20 ml) and after addition of 2N-sodium (or alternatively lithium) hydroxide solution (10 ml) the solution was stirred for ca. 3 hrs at 50 C., then glacial acetic acid (20 ml) was added and the solvents evaporated under reduced pressure to dryness. The residue was dissolved under stirring in mixture of water/THF (50 ml, 3:1) and the aqueous phase extracted 3 times with ethylacetate (3×100 ml), the organic solvent dried over magnesium sulphate, filtrated, solvent evaporated under reduced pressure and the residue dissolved in THF (20 ml). To this solution N,N-dimethyl aminopyride (0.3 g) triethylamine (3 g) and di-tert-butyldicarbonate (3 g) were added at rt and the mixture stirred for 24 hrs to achieve complete BOC-protection of the amino group. After acidification of the reaction mixture with glacial acetic acid (10 ml), the mixture was extracted with toluene/water mixture and the organic phase separated and under reduced pressure evaporated. The residue was taken in glacial acetic acid (20 ml), heated for 24 hrs at ca. 100 C., the acid removed under vacuum and purified by column chromatography (eluens: ethyl acetate/hexane 1:1): 4.1 g of desired BOC-protected lactone [(1S,3S)-1-(2S,4S)-4-isopropyl-5-oxo-tetrahydro-furan-2-yl)-3-[4-methoxy-3-(3-methoxypropoxy)-benzyl]-4-methyl-pentyl]-carbamic acid tert.-butyl ester. The analytical data were identical as reported e.g. in WO2006/024501, p. 58). The lactone was then converted into Aliskiren (Ia) as described above for Cbz-protected lactone in Example 5. | ||
The crude BOC-protected Aliskiren (4.5 g) was dissolved in a solution of trifluoroacetic acid and dichloromethane (30 ml, 1:5) at rt, stirred for 2 hrs and then pH adjusted to 10 with 37% sodium hydroxide solution. The aqueous phase was extracted 3times with dichloromethane (3×100 ml), dried with magnesium sulphate, filtrated and the filtrate evaporated under reduced pressure providing yellow oil of Aliskiren (Ia): 3.1 g: The analytical date were identical with reported in EP 0678 503, example 137. | ||
Example 5; Preparation of Compound (Ia) from Compound (Ivc) Via Compound (VIc); Crude lactone (IVc) from the above experiment (Example 4) (5 g) was dissolved in THF (40 ml), 10% Pd-C (400 mg), N,N-dimethyl aminopyride (0.1 g), triethylamine (4 g) and di-tert-butyldicarbonate (3 g) were added at rt and the mixture hydrogenated under slightly elevated pressure under intensive stirring for 24 hrs to achieve complete reduction and BOC-protection of the 5-amino group. After careful acidification of the reaction mixture with glacial acetic acid, the mixture was poured on toluene/water mixture (300 ml 1:1) and the organic phase separated, dried over MgSO4, filtered and the filtrate evaporated under reduced pressure: 4.9 g (90% isolated yield) of BOC-protected lactone (VIc) [(1S,3S)-1-((2S,4S)-4-isopropyl-5-oxo-tetrahydro-furan-2-yl)-3-[4-methoxy-3-(3-methoxypropoxy)-benzyl]-4-methyl-pentyl]-carbamic acid tert.-butyl ester. The analytical data were identical as reported e.g. in WO2006/024501, p. 58).A solution of BOC-protected lactone (VIc) (4.9 g), 3-amino-2,2-dimethyl propionamide (1.7 g) and 2-hydroxypyridine (1 g) in TBME (20 ml), containing triethylamine (0.25 ml), was stirred for 18 hrs at 80 C., then cooled to rt and diluted with toluene (20 ml) and washed with 10% aqueous sodium hydrogen sulphate solution (100 ml). The organic phase was separated, washed once with water (50 ml), dried with magnesium suphate, filtrated and evaporated under reduced pressure to give a yellow oil which was suspended in hexane (100 ml), slurry stirred a few min, filtrated and the filtrate evaporated under reduced pressure providing a foam of BOC-protected derivative of Aliskiren (Ia): 4.5 g. The crude BOC-protected Aliskiren (4.5 g) was dissolved in a solution of trifluoro acetic acid and dichloromethane (30 ml, 1:5) at rt, stirred for 2 hrs and then pH adjusted to 10 with 37% sodium hydroxide solution. The aqueous phase was extracted 3 times with dichloromethane (3×100 ml), dried with magnesium sulphate, filtrated and the filtrate evaporated under reduced pressure providing yellow oil of Aliskiren (Ia): 3.9 g: The analytical date were identical with reported in EP 0678 503, example 137. | ||
To a stirred solution of the compound of previous example (0.2 g) in acetone (2.0 mL), was added 12/V hydrochloric acid (0.1 mL). The resulting mixture was stirred for 3-4 hours at ambient temperature. After completion of the reaction, the solvent was evaporated and water (25.0 mL) was added. The pH of the resulting solution was adjusted to 8-9 using aqueous sodium hydroxide solution. The aqueous layer was extracted with ethyl acetate (2x25 mL) and the combined organic layers were washed with water (25 mL). The organic extract was evaporated to give the title compound. |
Tags: 173338-07-3 synthesis path| 173338-07-3 SDS| 173338-07-3 COA| 173338-07-3 purity| 173338-07-3 application| 173338-07-3 NMR| 173338-07-3 COA| 173338-07-3 structure
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Total Compounds: mg
The concentration of the dissolution solution you need to prepare is mg/mL