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[ CAS No. 177036-94-1 ] {[proInfo.proName]}

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Chemical Structure| 177036-94-1
Chemical Structure| 177036-94-1
Structure of 177036-94-1 * Storage: {[proInfo.prStorage]}
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Product Details of [ 177036-94-1 ]

CAS No. :177036-94-1 MDL No. :MFCD08672619
Formula : C22H22N2O4 Boiling Point : -
Linear Structure Formula :- InChI Key :OUJTZYPIHDYQMC-LJQANCHMSA-N
M.W : 378.42 Pubchem ID :6918493
Synonyms :
LU 208075;BSF 208075;pulmonext.;Volibris;Ambrisentan. trade name Letairis

Calculated chemistry of [ 177036-94-1 ]

Physicochemical Properties

Num. heavy atoms : 28
Num. arom. heavy atoms : 18
Fraction Csp3 : 0.23
Num. rotatable bonds : 7
Num. H-bond acceptors : 6.0
Num. H-bond donors : 1.0
Molar Refractivity : 104.59
TPSA : 81.54 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : Yes
CYP2D6 inhibitor : No
CYP3A4 inhibitor : Yes
Log Kp (skin permeation) : -5.91 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.69
Log Po/w (XLOGP3) : 3.8
Log Po/w (WLOGP) : 3.41
Log Po/w (MLOGP) : 2.12
Log Po/w (SILICOS-IT) : 3.87
Consensus Log Po/w : 3.18

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.56

Water Solubility

Log S (ESOL) : -4.59
Solubility : 0.00964 mg/ml ; 0.0000255 mol/l
Class : Moderately soluble
Log S (Ali) : -5.21
Solubility : 0.00235 mg/ml ; 0.00000621 mol/l
Class : Moderately soluble
Log S (SILICOS-IT) : -6.74
Solubility : 0.0000689 mg/ml ; 0.000000182 mol/l
Class : Poorly soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 2.0
Synthetic accessibility : 3.91

Safety of [ 177036-94-1 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H332-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 177036-94-1 ]

* 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.

  • Downstream synthetic route of [ 177036-94-1 ]

[ 177036-94-1 ] Synthesis Path-Downstream   1~8

  • 1
  • [ 177036-94-1 ]
  • [ 74-88-4 ]
  • [ 1106685-61-3 ]
YieldReaction ConditionsOperation in experiment
96% Stage #1: ambrisentan With potassium carbonate In acetone for 0.5h; Stage #2: methyl iodide In acetone for 3h; 9 A mixture of (S)-ambrisentan (15.0 g, 40.0 mmol) and potassium carbonate (8.28 g, 60.0 mmol) in acetone (100 mL) is stirred for 0.5 hr. Methyl iodide (3 mL, 47.0 mmol) is slowly added drop-wise and then the reaction mixture is stirred for 3 hr. The resulting mixture is concentrated to dryness under reduced pressure. The residue is mixed with water (100 mL) and extracted with ethyl acetate (4 X 100 mL). The yield of the title compound is 15.0 g (96%). MS m/z 392.9 (M+ + 1).
  • 2
  • [ 35144-22-0 ]
  • [ 178306-52-0 ]
  • ambrisentan [ No CAS ]
YieldReaction ConditionsOperation in experiment
95% 10 g (36.7 mmol) of (S) -2-hydroxy-3-methoxy-3,3-diphenylpropanoic acid was dissolved in 80 mL of N, N- dimethylformamide. After purging with nitrogen, 6.3 g (157 mmol) of 60% sodium hydride was slowly added over 1 hour 30 minutes at room temperature. After stirring for 1 hour, a solution of 9.56 g (51.3 mmol) of 4,6-dimethyl-2- (methylsulfonyl) pyrimidine in N, N-dimethylformamide (20 mL) was slowly added dropwise over 1 hour at room temperature , And the mixture was stirred for 15 hours. After cooling to 0 C, 10 mL of methanol was slowly added dropwise over 20 minutes, then 100 mL of cold water was added. After adding 75 mL of 10% hydrochloric acid, it was extracted twice with 100 mL of ethyl acetate. The organic layer was extracted 3 times with 1 N sodium hydroxide 50 mL. Further, 60 mL of 10% hydrochloric acid was slowly added to the aqueous layer, and the mixture was stirred for 1 hour. Precipitated crystals were collected by filtration and washed twice with 25 mL of water. The obtained crystals were dried under reduced pressure at 60 C. for 5 hours to obtain 13.1 g of ambrisentan (yield 95%, optical purity 98.6%).
75% (S) -2-hydroxy-3-methoxy-3,3-diphenylpropionic acid (40 g) was dissolved in DMF (200 ml), and then 3.6 g of lithium hydride (LiH) was slowly added thereto. The temperature of the reaction mixture was raised to 60 to 70 C , stirred for 1 hour, and then 30 g of 4,6-dimethyl-2- (methylsulfonyl) pyrimidine was added slowly. The mixture was stirred at an isothermal temperature for 5 hours, and when the reaction is finished, then cooled to room temperature. 360 ml of water was added and stirred for 30 minutes, and 200 ml of 3N HCl aqueous solution was slowly added to crystallize. The resulting crystals were collected by filtration, washed and vacuum dried to obtain 50 g of ambrisentan,(S) -2- (4,6-dimethylpyrimidin-2-yloxy) -3-methoxy-3,3-diphenylpropionic acid (Yield: 90%) (chemical purity = 97.28%, ee = 100%). 50 g of an ambrisentan containing impurities was suspended in 400 ml of an acetonitrile: water = 7: 3 mixed solution, and the temperature was raised to 50 to 55 C to dissolve completely. 5 g of activated carbon was added and stirred at an isothermal temperature for 1 hour. The activated carbon was removed by filtration and washed with a mixed solution of acetonitrile: water = 7: 3. The filtrate was heated to 50-55 C to completely dissolve the solid. The resulting solid was filtered, washed and vacuum-dried to obtain 37.5 g (yield: 75%) of a white solid (chemical purity = 100%, ee = 100%).
Example-19: Preparation of ambrisentan compound of formula-la:(S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid (20 grams in 20 ml of THF),, was added to a mixture of sodium hydroxide (8.5 grams) and tetrahydrofuran (110 ml) and stirred for 20 minutes at 25-35C. 456-dimethyl-2-(methylsulphonyl)pyrimidine , (19 grams) was added to the reaction mixture and heated to 40-450C then stirred for 24 hours. The reaction mixture was cooled to 25-350C and quenched with water then washed with cyclohexane. The reaction mixture was acidified with hydrochloric acid and then extracted into ethyl acetate. The combined ethyl acetate layer was washed with sodium chloride solution and then distilled off completely under reduced pressure. The reaction mixture was cooled to 25-35C, cyclohexane (100 ml) was added to it and then heated to 60-65C. The reaction mixture was cooled to 25-3O0C and stirred for 45 minutes. The solid obtained was filtered, washed with cyclohexane and then dried to get the title compound. Yield: 19 grams; S.O.R: + 144.87 (C = 0.5 in MeOH)
Into a 1L round bottomed flask a mixture of DMF(400ml) and S-2-Hydroxy-3-mehoxy- 3,3-diphenyl propionic acid(50g) were, charged and stirred for 30 minutes. sodium hydride(18.9g) was added slowly for lhour and reaction mass was maintained at room temperature for one hours. 2-(methylsulfonyl)-4,6-dimethyl pyrimidine(47.8g) was dissolved in DMF( 100ml) and added to the reaction mass at room temperature during 45-60 minutes and reaction mass was maintained overnight under stirring. After reaction completion methanol(50ml)l was added slowly to the reaction mass during 30 minutes. Reaction mass was quenched into DM water (5L) and acidified with diluted hydrochloric acid(600ml). Aqueous layer was extracted with ethyl acetate(2x500ml) and combined ethyl acetate layer was extracted with IN sodium hydroxide solution. Sodium hydroxide layer was separated and acidified with IN hydrochloride solution . Reaction mass was maintained under stirring for 2hours . The product of the formula-I was filtered and washed with purified water. It was dried in oven at 60-65CDry weight : 60gPurity by HPLC : related : 99.5%Chiral : 99.5%
Preparation of Ambrisentan Compound of Formula-1a (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid (20 grams in 20 ml of THF) was added to a mixture of sodium hydroxide (8.5 grams) and tetrahydrofuran (110 ml) and stirred for 20 minutes at 25-35 C. 4,6-dimethyl-2-(methylsulphonyl)pyrimidine (19 grams) was added to the reaction mixture and heated to 40-45 C. then stirred for 24 hours. The reaction mixture was cooled to 25-35 C. and quenched with water then washed with cyclohexane. The reaction mixture was acidified with hydrochloric acid and then extracted into ethyl acetate. The combined ethyl acetate layer was washed with sodium chloride solution and then distilled off completely under reduced pressure. The reaction mixture was cooled to 25-35 C., cyclohexane (100 ml) was added to it and then heated to 60-65 C. The reaction mixture was cooled to 25-30 C. and stirred for 45 minutes. The solid obtained was filtered, washed with cyclohexane and then dried to get the title compound.Yield: 19 grams;S.O.R: +144.87 (C=0.5 in MeOH)
Lithium amide (30.4 g; 1.32 mol) was suspended in N,N dimethylformamide (200 ml). A solution of (2S)-2-hydroxy-3-methoxy-3,3-diphenylpropanoic acid (120.0 g; 0.44 mol) in N,N-dimethylformamide (750 ml) was added dropwise at 20 C within 45 minutes, and the mixture was stirred for additional 10 minutes. A solution of 4,6-dimethyl-2 (methyl sulfonyl)pyrimidine (90.3 g; 0.48 mol) in N,N dimethylformamide (500 ml) was added dropwise within 20 minutes, and the mixture was stirred for 17 hours. Water (3000 ml) and 2M citric acid (800 ml) were added to the reaction mixture. The product was extracted three times with dichloromethane (2000 ml). The combined organic phases were dried over sodium sulfate and the solvent was evaporated under reduced pressure. The oily yellow residue was crystallized from a mixture of isopropanol (800 ml) and water (2000 ml). The formed crystals were filtered off, washed with water and dried (98.5 g), mp 156-158 C.
60 g Into a 1 L round bottomed flask a mixture of DMF (400 ml) and S-2-Hydroxy-3-mehoxy-3,3-diphenyl propionic acid (50 g) were, charged and stirred for 30 minutes. sodium hydride (18.9 g) was added slowly for 1 hour and reaction mass was maintained at room temperature for one hours. <strong>[35144-22-0]2-(methylsulfonyl)-4,6-dimethylpyrimidine</strong> (47.8 g) was dissolved in DMF (100 ml) and added to the reaction mass at room temperature during 45-60 minutes and reaction mass was maintained overnight under stirring. After reaction completion methanol (50 ml)1 was added slowly to the reaction mass during 30 minutes. Reaction mass was quenched into DM water (5 L) and acidified with diluted hydrochloric acid (600 ml). Aqueous layer was extracted with ethyl acetate (2×500 ml) and combined ethyl acetate layer was extracted with 1N sodium hydroxide solution. Sodium hydroxide layer was separated and acidified with 1N hydrochloride solution. Reaction mass was maintained under stirring for 2 hours. The product of the formula-I was filtered and washed with purified water. It was dried in oven at 60-65 C. Dry weight: 60 g Purity by HPLC: related: 99.5% Dry weight: 60 g Purity by HPLC: related: 99.5% Chiral: 99.5%

  • 3
  • [ 1106685-61-3 ]
  • [ 177036-94-1 ]
YieldReaction ConditionsOperation in experiment
85.33% With water; sodium hydroxide In 1,4-dioxane at 40 - 45℃; for 33h; 5 Example 5:Preparation of (S)-2-(4,6-dimethylpyrimidin-2-yloxy)-3-methoxy-3,3-diphenyl propionic acid (compound I; R = methyl) Example 5:Preparation of (S)-2-(4,6-dimethylpyrimidin-2-yloxy)-3-methoxy-3,3-diphenyl propionic acid (compound I; R = methyl)To a stirred solution of (S)-methyl-2-(4,6-dimethylpyrimidin-2-yloxy)-3-methoxy-3,3- diphenylpropionate (compound II; R' = methyl, R= methyl) (79 gms /0.201 moles) in 1,4-dioxane (790 ml) was added 2 N NaOH solution (18.6 gms of NaOH in 450.0 ml of DI Water). The reaction mass was heated to 40-45°C and further stirred for 33 hours. The reaction mass was cooled to 25-30°C and quenched in water (7.9 Lit). The reaction mass was cooled to 10-15°C and acidified with cone. HCl. The solid was isolated by filtration and dried to yield 72.0 gms of the title compound (I).Compound (I) was further purified in N-methyl pyrrolidone/n-heptane, followed by DMSO/n-heptane to obtain 65.0 gms of the title compound (I).Efficiency: 85.33 %Chiral purity: 99.2%Purity by HPLC: 99.8%
Stage #1: (S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropionic acid methyl ester With water; sodium hydroxide In 1,4-dioxane at 25 - 90℃; Stage #2: With hydrogenchloride In water at 25 - 35℃; 13 Example-13: Preparation of ambrisentan compound of formula-la:Aqueous sodium hydroxide solution (10 grams in 250 ml of water) was added to the mixture of 1,4-dioxane (500 ml) and (+)-(2S)-2-[(4,6-dimethylpyrimidin-2-yi)oxy]-3- methoxy-3,3-diphenylpropanoic acid methyl ester (50 grams) compound of formula- 10a at 25-35°C, then heated to 85-90°C and stirred for 3 hours. The reaction mixture was cooled to 25-35°C and water (500 ml) was added. The reaction mixture was washed with ethylacetate. The pH of aqueous layer was adjusted to 1.8 with hydrochloric acid at 25-350C. The reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was distilled off under reduced pressure at below 60°C and then cooled to 0-5°C. The reaction mixture was stirred for 60 minutes at 0-50C. The obtained solid was filtered, washed with chilled ethyl acetate and dried at 60-700C to get the ambrisentan. Yield: 36 grams
Stage #1: (S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropionic acid methyl ester With water; sodium hydroxide In 1,4-dioxane at 25 - 90℃; for 3h; Stage #2: With hydrogenchloride In 1,4-dioxane; water at 25 - 35℃; 13 Preparation of ambrisentan compound of formula-1a Aqueous sodium hydroxide solution (10 grams in 250 ml of water) was added to the mixture of 1,4-dioxane (500 ml) and (+)-(2S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropanoic acid methyl ester (50 grams) compound of formula-10a at 25-35° C., then heated to 85-90° C. and stirred for 3 hours. The reaction mixture was cooled to 25-35° C. and water (500 ml) was added. The reaction mixture was washed with ethylacetate. The pH of aqueous layer was adjusted to 1.8 with hydrochloric acid at 25-35° C. The reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was distilled off under reduced pressure at below 60° C. and then cooled to 0-5° C. The reaction mixture was stirred for 60 minutes at 0-5° C. The obtained solid was filtered, washed with chilled ethyl acetate and dried at 60-70° C. to get the ambrisentan. Yield: 36 grams
  • 4
  • [ 1231755-49-9 ]
  • [ 177036-94-1 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride In water at 25 - 30℃; for 1.5h; 32 Example-32: Preparation of (+)-(2S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3- methoxy-3,3-diphenylpropanoic acid:Tert-butyl amine salt of (+)-(2S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy- 3,3-diphenylpropanoic acid (3.0 grams) was taken in water (12 grams) and acidified it using hydrochloric acid. The reaction mixture stirred for 90 minutes at 25-3O0C. The solid obtained was filtered, washed with water and then dried to get the title compound. Yield: 2.6 grams
With hydrogenchloride In water at 25 - 30℃; for 1.5h; 32 preparation of (+)-(2S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropanoic acid Preparation of (+)-(2S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropanoic acidTert-butyl amine salt of (+)-(2S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropanoic acid (3.0 grams) was taken in water (12 grams) and acidified it using hydrochloric acid. The reaction mixture stirred for 90 minutes at 25-30° C. The solid obtained was filtered, washed with water and then dried to get the title compound.Yield: 2.6 grams
  • 5
  • [ 1260633-84-8 ]
  • [ 35144-22-0 ]
  • ambrisentan [ No CAS ]
YieldReaction ConditionsOperation in experiment
90.9% With sodium t-butanolate; In N,N-dimethyl-formamide; at 20 - 30℃; for 3h;Product distribution / selectivity; In a 1 liter four necked flask, (73.5 g) (0.17 mole) (S)-3-methoxyphenylethylammonium (S)-2-hydroxy-3-methoxy 3,3-diphenyl propionate, (50 g) sodium t-butoxide and 367.5 mL DMF were taken at room temperature. Reaction mixture was cooled to 20 C. then 48.5 g 4,6-dimethyl-2-methylsulfonyl pyrimidine was added. The reaction mixture was stirred at 30 C. for 3 hrs and subsequently dumped in water and again stirred for 10 min. The reaction mixture was extracted with cyclohexane, charcoalised and acidified to get crude Ambrisentan. Yield: 59.7 g (90.9%), HPLC Purity: 98.79%, Chiral purity: 99.92%. Similarly crude Ambrisentan was prepared in different batches using (R)-2,4-dichloro PEA salt or (S)-3-methoxy PEA salt and the results are summarized in Table 6 given below
88.37% Example 42: Preparation of ambrisentanIn a 1 liter four necked flask, (73.5 g) (0.17 mole) (S)-3- methoxyphenylethylammonium (S)-2-hydroxy-3-methoxy 3, 3-diphenyl propionate,(50 g) sodium f-butoxide and 367.5 mL DMF were taken at room temperature.Reaction mixture was cooled to 20 0C then 48.5 g 4, 6-dimethyl-2-methylsulfonyl pyrimidine was added. The reaction mixture was stirred at 30 0C for 3 hrs and subsequently dumped in water and again stirred for 10 min. The reaction mixture was extracted with cyclohexane, charcoalised and acidified to get crude Ambrisentan.Yield: 59.7 g (90.9%), HPLC Purity: 98.79 %, Chiral purity: 99.92 %.Similarly crude Ambrisentan was prepared in different batches using (R)-2, 4- dichloro PEA salt or (S)-3-methoxy PEA salt and the results are summarized in Table 6 given below.Table: 6* Input refers to diastereomeric salt of 3, 3-diphenyl-2-hydroxy-3-methoxy propionic acid
  • 6
  • [ 1334552-81-6 ]
  • [ 177036-94-1 ]
YieldReaction ConditionsOperation in experiment
90% With hydrogenchloride In water; isopropyl alcohol at 50℃; for 1h; Inert atmosphere;
With hydrogenchloride In water 2.III Ambrisentan .S(-) phenyl ethyl amine addition salt(40g) was suspended in DM water(2L)and stirred for 15minutes. Aqueous IN hydrochloric acid solution(330ml) was added over a period of 30 min to a pH of 1-2 and maintained at the same temperature for 2-3hours.The precipitated product was filtered and washed with purified water. The product was dried at temperature of60-70°C till constant weight.Dry weight of Ambrisentan : 30gPurity by HPLC : related : 99.90% (Single impurity less than 0.1 %)Chiral purity : 99.80% (Single impurity less than 0.1%)
30 g With hydrogenchloride In water 2.III Step-III: Preparation of highly pure Ambrisentan from Ambrisentan S(-) phenyl ethylamine addition salt (1:1): Ambrisentan .S(-) phenyl ethyl amine addition salt (40 g) was suspended in DM water (2 L) and stirred for 15 minutes. Aqueous 1N hydrochloric acid solution (330 ml) was added over a period of 30 min to a pH of 1-2 and maintained at the same temperature for 2-3 hours. The precipitated product was filtered and washed with purified water. The product was dried at temperature of 60-70° C. till constant weight. Dry weight of Ambrisentan: 30 g Purity by HPLC: related: 99.90% (Single impurity less than 0.1%) [0067] Chiral purity: 99.80% (Single impurity less than 0.1%)
2.32 kg With hydrogenchloride In water; isopropyl alcohol 4 Preparation of Anrisheng Add the above solid (3.51kg) to isopropanol (5.2 L), pure water (26.2 L), slowly add hydrochloric acid to adjust the pH to 1-2, filter after cooling, collect the solid, and dry to obtain ambrisentan (2.32 kg) The yield is 40%.

  • 7
  • [ 1349854-31-4 ]
  • [ 177036-94-1 ]
YieldReaction ConditionsOperation in experiment
90% With sodium hydroxide In 1,4-dioxane; water at 90℃; for 12h; Inert atmosphere;
120.1 g Stage #1: (S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropionic acid ethyl ester With water; sodium hydroxide In 1,4-dioxane at 20 - 90℃; Stage #2: With hydrogenchloride In 1,4-dioxane optical yield given as %ee;
103.9 g With water; sodium hydroxide In 1,4-dioxane at 80℃; for 8h; 1.4 (4) Preparation of (2S)-2-(4,6-dimethylpyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropanoic acid ((+)-ambrisentan) 237.7 g intermediate (2S)-2-(4,6-dimethylpyrimidin-2-yloxy)-3-methoxy-3,3-diphenyl ethyl propionate obtained in step (3) was dissolved in 1.2 L organic solvent 1,4-dioxane, 600 mL aqueous solution containing 92.3 g sodium hydroxide was added (wherein, the molar ratio of (2S)-2-(4,6-dimethylpyrimidin-2-yloxy)-3-methoxy-3,3-diphenyl ethyl propionate and sodium hydroxide is 1:4), the reaction temperature is 80° C., after the reaction of 8 hours, the reaction liquid was concentrated, and extracted with (1 L, 0.5 L, 0.5 L) aether to remove organic impurity, hydrochloric acid was added into the extracted water phase to adjust to pH 3, at this time a great deal of solid appeared; then, 1.0 L ethyl acetate was added into the water phase, the insoluble matter were filtered and removed (after analysis, these insoluble matter was found to be racemic ambrisentan, 23.37 g), the organic layer was concentrated, thereby obtaining 103.9 g optically pure (+)-ambrisentan. From 3,3-diphenylethyl acrylate to the optically pure (+)-ambrisentan, the yield is 52.3%. Take a little amount of the obtained ambrisentan to react with diazomethane, and obtain (2S)-2-(4,6-dimethylpyrimidin-2-yloxy)-3-methoxy-3,3-diphenyl methyl propionate, and the enantiomer of ambrisentan was detected to be excess. (2S)-2-(4,6-dimethylpyrimidin-2-yloxy)-3-methoxy-3,3-diphenyl ethyl propionate: detecting using high efficiency liquid chromatography, and the enantiomer excessed 99.1%. The analysis condition: column model is Chiralcel OD-H, the volume ratio of n-hexane and isopropanol is 98:2, the analysis wavelength is 210 nm, the flow velocity of the mobile phase is 1 mL/min, t1=11.61 min, t2=14.05 min, 99.1% ee. [0036] [a]D25=+174.2 (c=0.5, MeOH); m.p.>150° C. yellow, >180° C. black, 182° C. melt; 1H NMR [400 MHz, CDCl3] δ 7.43 (d, J=Hz, 2H), 7.29-7.19 (m, 8H), 6.63 (s, 1H), 6.30 (s, 1H), 3.26 (s, 3H) 2.31 (s, 6H); 13C NMR [100 MHz, CDCl3] δ 178.98, 170.54, 169.70, 163.48, 139.91, 138.91, 128.77, 128.67, 128.22, 128.08, 115.34, 84.67, 77.55, 53.49, 23.93; 1H NMR [400 MHz, DMSO] δ 12.53 (s, 1H), 7.34-7.20 (m, 10H), 6.95 (s, 1H), 6.14 (s, 1H), 3.37 (s, 3H) 2.34 (s, 6H); 13C NMR [100 MHz, DMSO] δ 169.01, 163.14, 142.59, 141.41, 127.80, 127.68, 127.64, 127.19, 126.95, 114.72, 83.12, 77.55, 52.99, 23.30.
  • 8
  • C16H15O4(1-)*Na(1+) [ No CAS ]
  • [ 35144-22-0 ]
  • ambrisentan [ No CAS ]
YieldReaction ConditionsOperation in experiment
73.4% 30.8 g (2s) of 2-hydroxy-3-methoxy-3,3-diphenylpropionate was placed in a 500 mL reaction flask.Add 124mL of tetrahydrofuran and stir, temperature control -5-5 C, dropwise addition of 2mol / L sodium di(ethyl) sodium hydride in tetrahydrofuran solution 55mL,Temperature control 0-10 C,22.3 g of a solution of 4,6-dimethyl-2-methanesulfonylpyrimidine in tetrahydrofuran was added dropwise.After the addition is completed, the heat preservation reaction is carried out for 2 hours.After TLC detection, the reaction was completed, 230 mL of water was added dropwise, and cyclohexane (50 mL×2) was added for extraction; the aqueous phase was acidified to pH 2 with hydrochloric acid.Extraction with methyl tert-butyl ether (75 mL × 2);Combining methyl tert-butyl ether phase,Extracted by adding 20% by weight aqueous sodium hydroxide solution,Adjust the pH of the aqueous phase to 2 with hydrochloric acid.Stir for 2h,Filtering,Wash the filter cake with water,Dry at 60-70 C, get white powder28.8g, yield 73.4%, HPLC purity: 99.80%, chiral purity: 99.89%.
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