[ CAS No. 178306-52-0 ] {[proInfo.proName]}

Name: 178306-52-0|(S)-2-Hydroxy-3-methoxy-3,3-diphenylpropanoic acid|97%
Brand: Ambeed
SKU: A330125
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Quality Control of [ 178306-52-0 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 178306-52-0 ]

Product Details of [ 178306-52-0 ]

CAS No. :	178306-52-0	MDL No. :	MFCD11113284
Formula :	C₁₆H₁₆O₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	RQJWOLFMWKZKCJ-CQSZACIVSA-N
M.W :	272.30	Pubchem ID :	15380898
Synonyms :

Calculated chemistry of [ 178306-52-0 ]

Physicochemical Properties

Num. heavy atoms :	20
Num. arom. heavy atoms :	12
Fraction Csp3 :	0.19
Num. rotatable bonds :	5
Num. H-bond acceptors :	4.0
Num. H-bond donors :	2.0
Molar Refractivity :	74.22
TPSA :	66.76 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.51 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.79
Log Po/w (XLOGP3) :	2.04
Log Po/w (WLOGP) :	1.91
Log Po/w (MLOGP) :	1.92
Log Po/w (SILICOS-IT) :	2.29
Consensus Log Po/w :	1.99

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.93
Solubility :	0.322 mg/ml ; 0.00118 mol/l
Class :	Soluble
Log S (Ali) :	-3.07
Solubility :	0.232 mg/ml ; 0.000851 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.94
Solubility :	0.0314 mg/ml ; 0.000115 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	2.94

Safety of [ 178306-52-0 ]

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

Application In Synthesis of [ 178306-52-0 ]

* 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.

Upstream synthesis route of [ 178306-52-0 ]
Downstream synthetic route of [ 178306-52-0 ]

[ 178306-52-0 ] Synthesis Path-Upstream 1~9

1
[ 178306-52-0 ]
[ 178306-47-3 ]

Reference： [1] Patent: US2014/256004, 2014, A1, . Location in patent: Page/Page column

2
[ 178306-52-0 ]
[ 178306-51-9 ]

Reference： [1] European Journal of Organic Chemistry, 2006, # 20, p. 4573 - 4577

3
[ 178306-51-9 ]
[ 178306-52-0 ]

Yield	Reaction Conditions	Operation in experiment
89%	With (S)-1,2,3,4-tetrahydronapht-1-yl-amine In tert-butyl methyl ether for 1 h; Reflux	500 mg (1.84 mmol) of (RS) -2-hydroxy-3-methoxy-3,3-diphenylpropanoic acid was dissolved in 8 mL of 2-propanol to prepare , 135 mg (0.92 mmol) of (S) - (+) -1,2,3,4-tetrahydro-1-naphthylamine was added. After stirring for 1 hour under heating reflux, it was cooled to room temperature and stirred for 2 hours. Precipitated crystals were collected by filtration, washed with 2-propanol, and dried under reduced pressure.The same operation as in Example 1 was carried out using the solvents in Table 1.
55%	With (S)-1-(p-nitrophenyl)ethylamine In tert-butyl methyl ether; acetone at 10 - 55℃; for 13 h; Resolution of racemate	Step-IV : preparation of S-2-hydroxy-3-methoxy-3,3-diphenyl propionic acid of the formula -(I) :Into a 3L round bottomed flask compound of formula(IV)from step-III(200g) was added to a mixture methyl tert-butyl ether(1.25L) and acetone(1.5L). Reaction mass was heated to reflux temperature (50-55°C) and S-(-)p-nitro phenyl ethyl amine(61g dissolved in 250ml of MTB) was added slowly during 30minutes at reflux temperature. Reaction mass was maintained at the same temperature for one hour and cooled to 10- 15°C and maintained at the same temperature for 12hours. It was filtered and washed with MTB(500ml) . The wet diastereomeric salt was suspended in a mixture of MTB(500ml) and water(1.5L) and acidified with concentrated hydrochloric acid (30ml). the resulting mixture was stirred for 30minutes and the organic layer was separated. Aqueous layer was extracted with MTB(500ml) and the combined MTB layer was washed with water and distilled completely under vacuum. Reaction mass was brought to 40°C and mixture of MTB (138ml)and n-heptane(322ml) were charged and the cooled to 25-30°CThe crystalline compound of formula -I was filtered and dried at 50-60°C Dry weight : 55g(55percent)Purity by HPLC : 99.97percent(chemical purity)99.98percent(chiral purity)Melting range : 123-125°C
35.6%	With sodium methylate; L-proline methyl ester monohydrochloride In methanol; tert-butyl methyl ether at 15 - 30℃; for 20 h; Resolution of racemate; Autoclave; Industrial scale	L-Proline methyl ester hydrochloride (6.5 kg, 39.25 mol) and anhydrous methanol (3.5 L) were added to a 10 L reaction flask. After stirring well, sodium methoxide (2.12 kg, 39.25 mol) Of anhydrous methanol (5.0L) mixture, after completion of the addition, the reaction was stirred at (15 ~ 30 ° C) for 20 ~ 30min,The mixture was charged to a 300-L reaction vessel, and then a solution of a raw material A (10.68 kg, 39.25 mol) in t-butyl methyl ether (90 L) was also charged to the above reaction vessel to control the temperature at 15-30 ° C ) Was stirred for 20h,Methyl tert-butyl ether (180L) was added to the reaction kettle, and the internal temperature was controlled by stirring at -5 ~ 0 ° C for 30min by circulating cooling. The mixture was filtered and the filtrate was transferred to a 500L reactor.Add hydrochloric acid 3.5L with stirring, purified water 130L, stirred for 3 ~ 5min, allowed to stand for 10 ~ 15min, discard the water layer,The organic layer was dried over anhydrous magnesium sulfate (10 kg), filtered, and the filtrate was concentrated and n-heptane wasadded(37L) crystallization 1.5h.Filtration and drying gave 3.81 kg, yield 35.6percent.HPLC Purity: 99.1percent, Chiral purity: 96.3percent.

35%	With sodium methylate; L-proline methyl ester monohydrochloride In methanol; tert-butyl methyl ether at 20℃;	148.8 g (0.826 mol) of a methanol solution of 30percent concentration sodium methanolate,Was added dropwise to 240 g (0.826 mol) of methanol solution of L-proline methyl ester hydrochloric acid at 57percent concentration at room temperature,And 2.4 l MTB and 225 g (0.826 mol)Of 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid were added.While dropping 2.4 L of MTB at room temperature,At the same time, 2680 ml of the MTB / methanol mixture was distilled off,The mixture was slowly cooled at room temperature,The crystals (R-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid × L-proline methyl ester)This solid was washed with 150 ml of MTB.From this, 1.5 l of MTB was distilled off, the filtrate was concentrated,Then 1.0 liter of water was added.Concentrated hydrochloric acid was added at room temperature to adjust the pH to 1.2,After stirring and phase separation, the aqueous phase was separated and extracted with 0.4 l MTB.The combined organic phases were extracted with 0.4 l of water.After MTB was stripped, the residue was dissolved in toluene (65.0 ml) under reflux,And the seed was given to crystallize the product and allowed to cool slowly.The filtrate was suction filtered, washed with toluene,When dried in a vacuum oven,78.7 g of S-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid were obtained (yield 35percent based on racemate).
32.91%	Stage #1: With (S)-1-(1-Naphthyl)ethylamine In methanol; tert-butyl methyl ether at 25 - 30℃; for 1 h; Stage #2: With hydrogenchloride In tert-butyl methyl ether; water for 0.5 h;	To a stirred solution of 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid (compound VII; 240 gms/ 0.88 moles) in a mixture of tert-butyl methyl ether (1.2 lit) and methanol (1.2 lit) was added (S)-(-)- l-(l-Naphthyl) ethyl amine (82.8 gms/ 0.484 moles). The reaction mass was farther stirred for 1 hour at 25-30°C. The solid was isolated by filtration, washed with tert-butyl methyl ether (500 ml) and dried.The solid was stirred in a mixture of distilled water (1.2 lit) and tert-butyl methyl ether (1.2 lit) and cooled to 10-15°C. The reaction mass was acidified with cone. HC1 and stirred for 30 minutes. The organic phase was separated; aqueous phase was extracted with tert-butyl methyl , ether (1.0 lit). The organic phases were combined together, washed with brine, and concentrated under vacuum at 25-30°C. The residue was stirred in n-Hepatne (720 ml). The solid was isolated by filtration and dried to give 79 g of the title compound (VIII).Efficiency: 32.91 percentPurity by HPLC: 99.5percentChiral purity: 98.1percent

Reference： [1] Patent: JP2017/128528, 2017, A, . Location in patent: Paragraph 0005; 0041; 0042; 0045; 0046
[2] Patent: WO2012/17441, 2012, A1, . Location in patent: Page/Page column 11-12
[3] Patent: CN104098462, 2017, B, . Location in patent: Paragraph 0009; 0028; 0029; 0031
[4] Patent: JP5700378, 2015, B2, . Location in patent: Paragraph 0071; 0072
[5] Patent: WO2013/57468, 2013, A1, . Location in patent: Page/Page column 23-24
[6] Journal of Medicinal Chemistry, 1999, vol. 42, # 16, p. 3026 - 3032
[7] Patent: WO2010/70658, 2010, A2, . Location in patent: Page/Page column 19
[8] Patent: US2011/263854, 2011, A1, . Location in patent: Page/Page column 10
[9] Patent: US2011/263854, 2011, A1, . Location in patent: Page/Page column 8
[10] Patent: WO2014/1511, 2014, A1,
[11] Patent: WO2014/1511, 2014, A1,
[12] Patent: KR2016/39907, 2016, A,

4
[ 67-56-1 ]
[ 53884-87-0 ]
[ 178306-52-0 ]

Yield	Reaction Conditions	Operation in experiment
27 g	Stage #1: at 20 - 25℃; for 1 h; Stage #2: for 1.5 h; Reflux Stage #3: With L-proline methyl ester monohydrochloride In tert-butyl methyl ether at 20℃; for 6 h;	After dissolving 230 g of diphenyl-2,3-epoxypropionic acid in 600 mL of methanol at room temperature, 5.7 g of p-toluenesulfonic acid was added and the mixture was stirred at 20-25 ° C for 0.5 h. Reflux, and then dropping 10percent sodium hydroxide 800 mL, after the end of reflux stirring 1.5 h, methanol concentration after adding 90 ml of water, placed in ice bath stirring 0.5 h after filtration, solid and then washed with cold water, 60 ° C Blast dry. The resulting solid was mixed with 60 ml of ethanol and 30 ml of petroleum ether for 1 h, filtered, and dried in vacuo at room temperature to give about 160 g of a white solid. The results of the HPLC test of sodium 2-hydroxy-3-methoxy-3,3-diphenylpropionate are shown in Table 1 and Fig. 100 gSyntheticSodium 2-hydroxy-3-methoxy-3,3-diphenylpropionate was addedMethyl tert-butyl ether(MTB, 2000 ml) and methanol (40 ml), and then 56.lg of L-proline methyl ester hydrochloride (0.34 mol) was added and the mixture was stirred at room temperature for 6 h. After standing, the filtrate was filtered, Water, with 6N hydrochloric acid to adjust ρ Η = 1-2. The organic layer was separated and washed with MTB (400 ml). The combined organic layer was washed with 800 ml of water and saturated NaCl. 500 ml and allowed to stand overnight. The solid was filtered, ca. 27 g.

Reference： [1] Patent: CN105801404, 2016, A, . Location in patent: Paragraph 0021; 0022; 0023

5
[ 42882-31-5 ]
[ 178306-51-9 ]
[ 178306-52-0 ]

Reference： [1] Patent: US2014/256004, 2014, A1, . Location in patent: Page/Page column

6
[ 42142-15-4 ]
[ 4187-53-5 ]
[ 178306-51-9 ]
[ 178306-52-0 ]

Reference： [1] Patent: US2014/256004, 2014, A1, . Location in patent: Page/Page column

7
[ 119-61-9 ]
[ 178306-52-0 ]

Reference： [1] Patent: US2011/263854, 2011, A1,
[2] Patent: WO2012/17441, 2012, A1,
[3] Patent: KR2016/39907, 2016, A,
[4] Patent: JP2017/128528, 2017, A,

8
[ 76527-25-8 ]
[ 178306-52-0 ]

Reference： [1] Patent: WO2012/17441, 2012, A1,
[2] Patent: KR2016/39907, 2016, A,
[3] Patent: CN106699626, 2017, A,
[4] Patent: JP2017/128528, 2017, A,

9
[ 178306-47-3 ]
[ 178306-52-0 ]

Reference： [1] Patent: US2011/263854, 2011, A1,
[2] Patent: KR2016/39907, 2016, A,
[3] Patent: JP2017/128528, 2017, A,

[ 178306-52-0 ] Synthesis Path-Downstream 1~42

1
[ 77-78-1 ]
[ 178306-52-0 ]
[ 177036-78-1 ]

Yield	Reaction Conditions	Operation in experiment
95.11%	With sodium methylate; In N,N-dimethyl-formamide; at 5 - 28℃;Inert atmosphere;	Example 9:Preparation of (S)-methyl-2-hydroxy-3-methoxy-3,3-diphenylpropionate (compound IV from compound VIII; R' = methyl)Stirred <strong>[178306-52-0](S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid</strong> (compound VIII; 79 gms/ 0.290moles) in dimethyl formamide (790 ml) under nitrogen and cooled to 5C. Sodium methoxide (17.3gms/0.320 moles) was added followed by slow addition of dimethyl sulfate (54.81 gms/ 0.44moles) under nitrogen. The reaction mass was further stirred for 3 hours at 25-28C and quenched in DI water (2.4 lit). The reaction mass was extracted with ethyl acetate (3 x 790.0 ml), washed with water and distilled completely under vacuum below 50C to obtain 79 gms of the title compound (IV). Efficiency: 95.1 1 %
	With sodium methylate; In N,N-dimethyl-formamide; at 50℃;	54.4 g (200 mmol) of <strong>[178306-52-0](S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid</strong> were introduced with 10.8 g (200 mmol) of sodium methoxide into 300 ml of DMF. 21 ml (210 mmol) of dimethylsulfate were added dropwise to this suspension over 15 minutes, during which the temperature rises to 50 C. and the suspension becomes mobile.. The mixture was stirred overnight and then added to 1.5 l of water and ice.. The aqueous phase was extracted twice with 500 ml of ether, and the ether phase was in turn washed with 200 ml of water twice.. The organic phase was dried over magnesium sulfate, the desiccant was filtered off, and the solvent was distilled off. 55.8 g of an oil were isolated and were immediately processed further.

Reference： [1]Patent: WO2013/57468,2013,A1 .Location in patent: Page/Page column 25
[2]Journal of Medicinal Chemistry,1999,vol. 42,p. 3026 - 3032
[3]Patent: US6670367,2003,B1 .Location in patent: Page column 16

2
[ 178306-51-9 ]
[ 178306-52-0 ]

Yield	Reaction Conditions	Operation in experiment
89%	With (S)-1,2,3,4-tetrahydronapht-1-yl-amine; In tert-butyl methyl ether; for 1h;Reflux;	500 mg (1.84 mmol) of (RS) -2-hydroxy-3-methoxy-3,3-diphenylpropanoic acid was dissolved in 8 mL of 2-propanol to prepare , 135 mg (0.92 mmol) of (S) - (+) -1,2,3,4-tetrahydro-1-naphthylamine was added. After stirring for 1 hour under heating reflux, it was cooled to room temperature and stirred for 2 hours. Precipitated crystals were collected by filtration, washed with 2-propanol, and dried under reduced pressure.The same operation as in Example 1 was carried out using the solvents in Table 1.
55%	With (S)-1-(p-nitrophenyl)ethylamine; In tert-butyl methyl ether; acetone; at 10 - 55℃; for 13h;Resolution of racemate;	Step-IV : preparation of S-2-hydroxy-3-methoxy-3,3-diphenyl propionic acid of the formula -(I) :Into a 3L round bottomed flask compound of formula(IV)from step-III(200g) was added to a mixture methyl tert-butyl ether(1.25L) and acetone(1.5L). Reaction mass was heated to reflux temperature (50-55C) and S-(-)p-nitro phenyl ethyl amine(61g dissolved in 250ml of MTB) was added slowly during 30minutes at reflux temperature. Reaction mass was maintained at the same temperature for one hour and cooled to 10- 15C and maintained at the same temperature for 12hours. It was filtered and washed with MTB(500ml) . The wet diastereomeric salt was suspended in a mixture of MTB(500ml) and water(1.5L) and acidified with concentrated hydrochloric acid (30ml). the resulting mixture was stirred for 30minutes and the organic layer was separated. Aqueous layer was extracted with MTB(500ml) and the combined MTB layer was washed with water and distilled completely under vacuum. Reaction mass was brought to 40C and mixture of MTB (138ml)and n-heptane(322ml) were charged and the cooled to 25-30CThe crystalline compound of formula -I was filtered and dried at 50-60C Dry weight : 55g(55%)Purity by HPLC : 99.97%(chemical purity)99.98%(chiral purity)Melting range : 123-125C
35.6%	With sodium methylate; L-proline methyl ester monohydrochloride; In methanol; tert-butyl methyl ether; at 15 - 30℃; for 20h;Resolution of racemate; Autoclave; Industrial scale;	L-Proline methyl ester hydrochloride (6.5 kg, 39.25 mol) and anhydrous methanol (3.5 L) were added to a 10 L reaction flask. After stirring well, sodium methoxide (2.12 kg, 39.25 mol) Of anhydrous methanol (5.0L) mixture, after completion of the addition, the reaction was stirred at (15 ~ 30 C) for 20 ~ 30min,The mixture was charged to a 300-L reaction vessel, and then a solution of a raw material A (10.68 kg, 39.25 mol) in t-butyl methyl ether (90 L) was also charged to the above reaction vessel to control the temperature at 15-30 C ) Was stirred for 20h,Methyl tert-butyl ether (180L) was added to the reaction kettle, and the internal temperature was controlled by stirring at -5 ~ 0 C for 30min by circulating cooling. The mixture was filtered and the filtrate was transferred to a 500L reactor.Add hydrochloric acid 3.5L with stirring, purified water 130L, stirred for 3 ~ 5min, allowed to stand for 10 ~ 15min, discard the water layer,The organic layer was dried over anhydrous magnesium sulfate (10 kg), filtered, and the filtrate was concentrated and n-heptane wasadded(37L) crystallization 1.5h.Filtration and drying gave 3.81 kg, yield 35.6%.HPLC Purity: 99.1%, Chiral purity: 96.3%.

35%	With sodium methylate; L-proline methyl ester monohydrochloride; In methanol; tert-butyl methyl ether; at 20℃;	148.8 g (0.826 mol) of a methanol solution of 30% concentration sodium methanolate,Was added dropwise to 240 g (0.826 mol) of methanol solution of L-proline methyl ester hydrochloric acid at 57% concentration at room temperature,And 2.4 l MTB and 225 g (0.826 mol)Of 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid were added.While dropping 2.4 L of MTB at room temperature,At the same time, 2680 ml of the MTB / methanol mixture was distilled off,The mixture was slowly cooled at room temperature,The crystals (R-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid × L-proline methyl ester)This solid was washed with 150 ml of MTB.From this, 1.5 l of MTB was distilled off, the filtrate was concentrated,Then 1.0 liter of water was added.Concentrated hydrochloric acid was added at room temperature to adjust the pH to 1.2,After stirring and phase separation, the aqueous phase was separated and extracted with 0.4 l MTB.The combined organic phases were extracted with 0.4 l of water.After MTB was stripped, the residue was dissolved in toluene (65.0 ml) under reflux,And the seed was given to crystallize the product and allowed to cool slowly.The filtrate was suction filtered, washed with toluene,When dried in a vacuum oven,78.7 g of S-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid were obtained (yield 35% based on racemate).
32.91%		To a stirred solution of 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid (compound VII; 240 gms/ 0.88 moles) in a mixture of tert-butyl methyl ether (1.2 lit) and methanol (1.2 lit) was added (S)-(-)- l-(l-Naphthyl) ethyl amine (82.8 gms/ 0.484 moles). The reaction mass was farther stirred for 1 hour at 25-30C. The solid was isolated by filtration, washed with tert-butyl methyl ether (500 ml) and dried.The solid was stirred in a mixture of distilled water (1.2 lit) and tert-butyl methyl ether (1.2 lit) and cooled to 10-15C. The reaction mass was acidified with cone. HC1 and stirred for 30 minutes. The organic phase was separated; aqueous phase was extracted with tert-butyl methyl , ether (1.0 lit). The organic phases were combined together, washed with brine, and concentrated under vacuum at 25-30C. The residue was stirred in n-Hepatne (720 ml). The solid was isolated by filtration and dried to give 79 g of the title compound (VIII).Efficiency: 32.91 %Purity by HPLC: 99.5%Chiral purity: 98.1%
		ExampIe-3: Preparation of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid compound of formula-7:Methanolic sodium methoxide solution (33 grams) was added to the solution of L-proline methyl ester hydrochloride (30.38 grams) in methanol (28 ml), stirred for 15 minutes at 25-35C then filtered to remove the unwanted solid. The solvent from the reaction mixture was distilled off under reduced pressure at 6O0C. The solution of 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid compound of formula-6 (50 grams) in methyltertiarybutylether (530 ml) was added to the above residue. The reaction mixture was heated to reflux temperature (55-60C), stirred for 45 minutes and then cooled to 25-35C and further stirred for 30 minutes. The solid separated was filtered off and washed with MTBE. Water (220 ml) was added to the filtrate and pH was adjusted to 1.2 with hydrochloric acid. The aqueous and organic layers were separated and then aqueous layer extracted with MTBE. The total organic layer washed with water and then distilled off the solvent completely under reduced pressure at 60C. Toluene (100 ml) was added to the residue, heated to reflux temperature for 15 minutes then cooled to 25-350C and stirred for 45 minutes. The obtained solid was filtered off and washed with toluene then dried at 50-600C to get the title compound. Yield: 17 grams M.R: 118-1220C. S.O.R: + 26 (C= 0.5; MeOH)
	With (R)-1-phenyl-ethyl-amine; In chloroform; at 40℃; for 0.5h;Product distribution / selectivity;	Preparation of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid R(+)-phenyl ethyl amine (11.12 grams) was added to a solution of 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid (25 grams) and chloroform (25 ml) at 40 C. and stirred for 30 minutes. The reaction mixture was cooled, and the solid obtained was filtered and washed with chloroform. Ethyl acetate (50 ml) and water (50 ml) was added to the obtained solid and then the reaction mixture was acidified with concentrated hydrochloric acid. The layers were separated and the aqueous layer extracted with ethyl acetate. The solvent from combined organic layer was distilled off completely under reduced pressure at below 60 C. The obtained residue was dissolved in toluene (30 ml) at 60-70 C. and then cooled to 25-30 C. The solid was filtered, washed with toluene and then dried to get the title compound.Yield: 5.5 grams; S.O.R: +28.32
	With sodium methylate; L-proline methyl ester monohydrochloride; In methanol; tert-butyl methyl ether; at 25 - 60℃; for 1.25h;Reflux;Product distribution / selectivity;	Preparation of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid compound of formula-7 Methanolic sodium methoxide solution (33 grams) was added to the solution of L-proline methyl ester hydrochloride (30.38 grams) in methanol (28 ml), stirred for 15 minutes at 25-35 C. then filtered to remove the unwanted solid. The solvent from the reaction mixture was distilled off under reduced pressure at 60 C. The solution of 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid compound of formula-6 (50 grams) in methyltertiarybutylether (530 ml) was added to the above residue. The reaction mixture was heated to reflux temperature (55-60 C.), stirred for 45 minutes and then cooled to 25-35 C. and further stirred for 30 minutes. The solid separated was filtered off and washed with MTBE. Water (220 ml) was added to the filtrate and pH was adjusted to 1.2 with hydrochloric acid. The aqueous and organic layers were separated and then aqueous layer extracted with MTBE. The total organic layer washed with water and then distilled off the solvent completely under reduced pressure at 60 C. Toluene (100 ml) was added to the residue, heated to reflux temperature for 15 minutes then cooled to 25-35 C. and stirred for 45 minutes. The obtained solid was filtered off and washed with toluene then dried at 50-60 C. to get the title compound.Yield: 17 gramsM.R: 118-122 C.S.O.R: +26 (C=0.5; MeOH)

Reference： [1]Patent: JP2017/128528,2017,A .Location in patent: Paragraph 0005; 0041; 0042; 0045; 0046
[2]Patent: WO2012/17441,2012,A1 .Location in patent: Page/Page column 11-12
[3]Patent: CN104098462,2017,B .Location in patent: Paragraph 0009; 0028; 0029; 0031
[4]Patent: JP5700378,2015,B2 .Location in patent: Paragraph 0071; 0072
[5]Patent: WO2013/57468,2013,A1 .Location in patent: Page/Page column 23-24
[6]Journal of Medicinal Chemistry,1999,vol. 42,p. 3026 - 3032
[7]Patent: WO2010/70658,2010,A2 .Location in patent: Page/Page column 19
[8]Patent: US2011/263854,2011,A1 .Location in patent: Page/Page column 10
[9]Patent: US2011/263854,2011,A1 .Location in patent: Page/Page column 8
[10]Patent: WO2014/1511,2014,A1
[11]Patent: WO2014/1511,2014,A1
[12]Patent: KR2016/39907,2016,A
[13]Patent: CN110437063,2019,A

3
[ 178306-52-0 ]
[ 178306-51-9 ]

Reference： [1]European Journal of Organic Chemistry,2006,p. 4573 - 4577

4
[ 178306-52-0 ]
[ 204268-09-7 ]

Reference： [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 3026 - 3032
[2]Organic Process Research and Development,2001,vol. 5,p. 16 - 22

5
[ 178306-52-0 ]
[ 204268-10-0 ]

Reference： [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 3026 - 3032
[2]Organic Process Research and Development,2001,vol. 5,p. 16 - 22

6
[ 178306-52-0 ]
Feloprentan [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 3026 - 3032

7
2-methylsulfonyl-4,5-dimethylthiazole [ No CAS ]
[ 178306-52-0 ]
(S)-2-(4,5-dimethylthiazol-2-yloxy)-3-methoxy-3,3-diphenylpropionic acid [ No CAS ]

Reference： [1]Patent: US6358983,2002,B1 .Location in patent: Example 5

Yield	Reaction Conditions	Operation in experiment
35%		Example 10 S-2-Hydroxy-3-methoxy-3,3-diphenylpropionic acid (racemate resolution with L-proline methyl ester) 148.8 g of a 30% strength methanolic sodium methanolate solution (0.826 mol) were added dropwise to 240 g of a 57% strength methanolic L-proline methyl ester hydrochloride solution (0.826 mol) at room temperature, and 2.4 l of MTB and 225 g (0.826 mol) of 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid were added. After 2680 ml of MTB/methanol mixture had been distilled out with simultaneous dropwise addition of 2.4 l of MTB, the mixture was slowly cooled to room temperature, the crystals (R-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid x L-proline methyl ester) were filtered off with suction, and the solid was washed with 150 ml of MTB. The filtrate was concentrated by distilling out 1.5 l of MTB, and 1.0 l of water was added. The pH was adjusted to 1.2 with concentrated hydrochloric acid at room temperature and, after stirring and phase separation, the aqueous phase was separated off and extracted with 0.4 l of MTB. The combined organic phases were extracted with 0.4 l of water. The residue after the MTB had been stripped off was dissolved in 650 ml of toluene under reflux, and the product was crystallized by seeding and slow cooling. Filtration with suction, washing with toluene and drying in a vacuum oven resulted in 78.7 g of S-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid (yield 35% based on the racemate). Chiral HPLC: 100% pure; HPLC: 99.8%
35%		Example 11 S-2-Hydroxy-3-methoxy-3,3-diphenylpropionic acid (racemate resolution with (S)-1-(4-nitrophenyl)ethylamine) 30.5 g (0.184 mol) of (S)-1-(4-nitrophenyl)ethylamine were added to 100 g (0.368 mol) of 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid in 750 ml of acetone and 750 ml of MTB under reflux, the mixture was seeded, boiled under reflux for one hour and slowly cooled to room temperature for crystallization. The crystals (S-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid x (S)-1-(4-nitrophenyl)ethylamine) were filtered off with suction and washed with MTB. The residue was suspended in 500 ml of water and 350 ml of MTB and then the pH was adjusted to 1.2 with concentrated hydrochloric acid at room temperature, and, after stirring and phase separation, the aqueous phase was separated off and extracted with 150 ml of MTB. The combined organic phases were extracted with 100 ml of water. 370 ml of MTB were distilled out and then 390 ml of n-heptane were added under reflux, and the mixture was slowly cooled to room temperature while the product crystallized. Filtration with suction, washing with n-heptane and drying in a vacuum oven resulted in 35.0 g of S-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid (yield 35% based on the racemate). Chiral HPLC: 100% pure; HPLC: 99.8%
35%		EXAMPLE 10 S-2-Hydroxy-3-methoxy-3,3-diphenylpropionic acid (racemate resolution with L-proline methyl ester) 148.8 g of a 30% strength methanolic sodium methanolate solution (0.826 mol) were added dropwise to 240 g of a 57% strength methanolic L-proline methyl ester hydrochloride solution (0.826 mol) at room temperature, and 2.4 l of MTB and 225 g (0.826 mol) of 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid were added. After 2680 mol of MTB/methanol mixture had been distilled out with simultaneous dropwise addition of 2.4 l of MTB, the mixture was slowly cooled to room temperature, the crystals (R-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid*L-proline methyl ester) were filtered off with suction, and the solid was washed with 150 ml of MTB. The filtrate was concentrated by distilling out 1.5 l of MTB, and 1.0 l of water was added. The pH was adjusted to 1.2 with concentrated hydrochloric acid at room temperature and, after stirring and phase separation, the aqueous phase was separated off and extracted with 0.4 l of MTB. The combined organic phases were extracted with 0.4 l of water. The residue after the MTB had been stripped off was dissolved in 650 ml of toluene under reflux, and the product was crystallized by seeding and slow cooling. Filtration with suction, washing with toluene and drying in a vacuum oven resulted in 78.7 g of S-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid (yield 35% based on the racemate). Chiral HPLC: 100% pure HPLC: 99.8%

35%

EXAMPLE 11 S-2-Hydroxy-3-methoxy-3,3-diphenylpropionic acid (racemate resolution with (S)-1-(4-nitrophenyl)ethylamine) 30.5 g (0.184 mol) of (S)-1-(4-nitrophenyl)ethylamine were added to 100 g (0.368 mol) of 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid in 750 ml of acetone and 750 ml of MTB under reflux, the mixture was seeded, boiled under reflux for one hour and slowly cooled to room temperature for crystallization. The crystals (S-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid*(S)-1(4-nitrophenyl)ethylamine) were filtered off with suction and washed with MTB. The residue was suspended in 500 ml of water and 350 ml of MTB and then the pH was adjusted to 1.2 with concentrated hydrochloric acid at room temperature, and, after stirring and phase separation, the aqueous phase was separated off and extracted with 150 ml of MTB. The combined organic phases were extracted with 100 ml of water. 370 ml of MTB were distilled out and then 390 ml of n-heptane were added under reflux, and the mixture was slowly cooled to room temperature while the product crystallized. Filtration with suction, washing with n-heptane and drying in a vacuum oven resulted in 35.0 g of S-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid (yield 35% based on the racemate). Chiral HPLC: 100% pure HPLC: 99.8%

9
[ 75-64-9 ]
[ 178306-52-0 ]
[ 1231755-36-4 ]

Yield	Reaction Conditions	Operation in experiment
	In ethyl acetate; at 25 - 30℃; for 0.75h;	Example-23: Preparation of <strong>[178306-52-0](S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid</strong>:The title compound was prepared in a similar manner to example-4 except that 8.89 grams of R(+)-phenyl ethyl amine was used instead of 11.85 grams of R(+)-phenyl ethylamine. Yield: 6.0 grams; S.O.R: + 27.0 Example-24: Preparation of tertiary butyl amine salt of (S)-2-hydroxy-3-methoxy- 3,3-diphenylpropionic acid:A solution of tertiary butyl amine (1.61 grams) in ethyl acetate (5 ml) was added to a solution of <strong>[178306-52-0](S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid</strong> (5 grams) in ethyl acetate (20 ml) at 25-30C and stirred for 45 minutes. The solid formed was filtered, washed with ethyl acetate and then dried to get the title compound Yield: 6.5 grams M.R: 210-2160C Purity by HPLC: 99.77 %

Reference： [1]Patent: WO2010/70658,2010,A2 .Location in patent: Page/Page column 26
[2]Patent: US2011/263854,2011,A1 .Location in patent: Page/Page column 10

10
[ 35144-22-0 ]
[ 178306-52-0 ]
ambrisentan [ No CAS ]

Yield	Reaction Conditions	Operation 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%

Reference： [1]Patent: JP2017/128528,2017,A .Location in patent: Paragraph 0005; 0047
[2]Patent: KR2016/39907,2016,A .Location in patent: Paragraph 0113; 0114; 0116; 0117
[3]Patent: WO2010/70658,2010,A2 .Location in patent: Page/Page column 24
[4]Patent: WO2011/114338,2011,A1 .Location in patent: Page/Page column 8-9
[5]Patent: US2011/263854,2011,A1 .Location in patent: Page/Page column 10
[6]Patent: EP2476670,2012,A1 .Location in patent: Page/Page column 4
[7]Patent: US2013/60031,2013,A1 .Location in patent: Paragraph 0057; 0058; 0059

11
[ 67-56-1 ]
[ 178306-52-0 ]
[ 177036-78-1 ]

Yield	Reaction Conditions	Operation in experiment
	hydrogenchloride; at 25 - 35℃; for 48h;	Example 6 to 9: preparation of <strong>[178306-52-0](S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid</strong> methyl ester compound of formula-8a:The title compound <strong>[178306-52-0](S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid</strong> methyl ester has been prepared in analogues manner to example-5 using the appropriate amount starting material, methanol and catalyst in the ratio which are mentioned in the following table.
	With toluene-4-sulfonic acid; at 25 - 35℃; for 48h;Product distribution / selectivity;	Preparation of <strong>[178306-52-0](S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid</strong> methyl ester compound of formula-8a Paratoluene sulfonic acid (7.9 grams) was added to a mixture of S-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid compound of formula-7 (50 grams) and methanol (150 ml) at. 25-35 C. then stirred for 48 hours at 25-35 C. The reaction mixture was quenched with cooled water (200 ml) and methylene chloride (150 ml) was added to it. The aqueous and organic layers were separated and aqueous layer was extracted with methylene chloride. The organic layer combined, washed with sodium bicarbonate solution and the solvent from the organic layer distilled off under reduced pressure at 55 C. Cyclohexane (50 ml) was added to the above residue and stirred at 30 minutes at 45-50 C. The reaction mixture was initially cooled to 25-30 C. and then to -5 to 0 C. The reaction mixture was stirred for 60 minutes at -5 to 0 C. The obtained solid was filtered and washed with chilled cyclohexane. The solid was dried at 25-35 C. to get the title compound. The PXRD, IR and DSC of the obtained solid compound were similar to the crystalline form-I of formula-8a.Yield: 35 grams; M.R: 58-60 C.S.O.R: +39.3 (C=0.5; MeOH)Purity: 98.5% by HPLC

Reference： [1]Patent: WO2010/70658,2010,A2 .Location in patent: Page/Page column 20
[2]Patent: US2011/263854,2011,A1 .Location in patent: Page/Page column 8

12
[ 119-61-9 ]
[ 178306-52-0 ]

Reference： [1]Patent: US2011/263854,2011,A1
[2]Patent: WO2012/17441,2012,A1
[3]Patent: KR2016/39907,2016,A
[4]Patent: JP2017/128528,2017,A

13
[ 178306-52-0 ]
ambrisentan [ No CAS ]

Reference： [1]Patent: US2011/263854,2011,A1
[2]Patent: WO2013/57468,2013,A1
[3]Patent: CN109705042,2019,A

14
[ 178306-52-0 ]
[ 171714-84-4 ]

Reference： [1]Patent: US2011/263854,2011,A1
[2]Patent: WO2013/57468,2013,A1

15
[ 178306-52-0 ]
[ 1106685-61-3 ]

Reference： [1]Patent: US2011/263854,2011,A1
[2]Patent: WO2013/57468,2013,A1

16
[ 178306-52-0 ]
[ 1231755-51-3 ]

Reference： [1]Patent: US2011/263854,2011,A1
[2]Patent: US2011/263854,2011,A1

17
[ 178306-47-3 ]
[ 178306-52-0 ]

Reference： [1]Patent: US2011/263854,2011,A1
[2]Patent: KR2016/39907,2016,A
[3]Patent: JP2017/128528,2017,A

18
[ 76527-25-8 ]
[ 178306-52-0 ]

Reference： [1]Patent: WO2012/17441,2012,A1
[2]Patent: KR2016/39907,2016,A
[3]Patent: CN106699626,2017,A
[4]Patent: JP2017/128528,2017,A

19
[ 178306-52-0 ]
[ 1231755-49-9 ]

Reference： [1]Patent: EP2476670,2012,A1

20
[ 178306-52-0 ]
[ 1386342-70-6 ]

Reference： [1]Patent: EP2476670,2012,A1

21
[ 178306-52-0 ]
[ 1386915-48-5 ]

Reference： [1]Patent: EP2476670,2012,A1

22
[ 178306-52-0 ]
[ 177036-79-2 ]

Reference： [1]Patent: WO2013/57468,2013,A1

23
[ 178306-52-0 ]
BSF 420627 [ No CAS ]

Reference： [1]Organic Process Research and Development,2001,vol. 5,p. 16 - 22

24
[ 178306-52-0 ]
[ 177036-78-1 ]

Reference： [1]Organic Process Research and Development,2001,vol. 5,p. 16 - 22

25
2C₁₆H₁₆O₄*C₅H₁₁NO₂ [ No CAS ]
[ 178306-52-0 ]

Yield	Reaction Conditions	Operation in experiment
95%	In tert-butyl methyl ether; water; at 20℃; for 0.5h;	To a round-bottom flask equipped with magnetic stirrer containing Form I (98% ee) (200 mg, 0.30 mmol) was added a mixture of water/TBME (1 :1 ) (10 ml_). The resulting mixture was stirred at room temperature for 30 minutes. After phase separation, the aqueous phase was separated off and extracted with TBME (3 x 5 ml_). The combined organic extracts were washed with water (10 ml_), dried (MgSO4) and distilled under vacuum to yield (S)-2- hydroxy-3-methoxy-3,3-diphenylpropanoic acid as a white solid (157 mg, 95% yield, 99% ee).

Reference： [1]Patent: WO2014/1511,2014,A1 .Location in patent: Page/Page column 24

26
2C₁₆H₁₆O₄*C₅H₁₁NO₂ [ No CAS ]
[ 72-18-4 ]
[ 178306-52-0 ]

Yield	Reaction Conditions	Operation in experiment
97%; 100%	In ethyl acetate; at 80℃; for 3h;	180 mg, 0.27 mmol) was added AcOEt (3.6 ml_). The resulting suspension was stirred at 80 C (bath temperature) for 3 hours. The solid was filtered with a sintered funnel (porosity 4), washed with hot AcOEt (1 ml_) and dried under vacuum at room temperature. L-valine was obtained as a white powder (31 mg, 97% yield). The filtrate was washed with water (1 .5 mL), dried (MgSO4) and distilled under vacuum to yield (S)-2-hydroxy-3-methoxy-3,3- diphenylpropanoic acid as a white solid (quantitative yield, 97% ee)

Reference： [1]Patent: WO2014/1511,2014,A1 .Location in patent: Page/Page column 24

27
[ 42882-31-5 ]
[ 178306-51-9 ]
[ 178306-52-0 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; tert-butyl methyl ether; water;	(a) Resolution using (S)-(-)-1-(1-Naphthyl)ethyl amine To a stirred solution of 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid (compound VII; 240 gms/0.88 moles) in a mixture of tert-butyl methyl ether (1.2 lit) and methanol (1.2 lit) was added (S)-(-)-1-(1-Naphthyl) ethyl amine (82.8 gms/0.484 moles). The reaction mass was further stirred for 1 hour at 25-30 C. The solid was isolated by filtration, washed with tert-butyl methyl ether (500 ml) and dried. The solid was stirred in a mixture of distilled water (1.2 lit) and tert-butyl methyl ether (1.2 lit) and cooled to 10-15 C. The reaction mass was acidified with conc. HCl and stirred for 30 minutes. The organic phase was separated; aqueous phase was extracted with tert-butyl methyl ether (1.0 lit). The organic phases were combined together, washed with brine, and concentrated under vacuum at 25-30 C. The residue was stirred in n-Hepatne (720 ml). The solid was isolated by filtration and dried to give 79 g of the title compound (VIII). Efficiency: 32.91% Purity by HPLC: 99.5% Chiral purity: 98.1%

Reference： [1]Patent: US2014/256004,2014,A1 .Location in patent: Page/Page column

28
[ 42142-15-4 ]
[ 4187-53-5 ]
[ 178306-51-9 ]
[ 178306-52-0 ]

Yield	Reaction Conditions	Operation in experiment
	In n-heptane; tert-butyl methyl ether; water;	(b) Resolution using (S)-1-(4-nitrophenyl)ethyl amine To a stirred solution of 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid (compound VII; 240 gms/0.88 moles) in tert-butyl methyl ether (1.2 lit) was added S-1-(4-nitro phenyl)ethyl amine (73.5 gms/0.44 moles) at 45-50 C. The reaction mass was further stirred for 1 hour at 45-50 C., cooled to 25-30 C. and stirred for 1 hour. The solid was isolated by filtration, washed with tert-butyl methyl ether (500 ml) and dried. The solid was stirred in a mixture of distilled water (1.2 lit) and tert-butyl methyl ether (1.2 lit) and cooled to 10-15 C. The reaction mass was acidified with conc. HCl and stirred for 30 minutes. The organic phase was separated; aqueous phase was extracted with tert-butyl methyl ether (1.0 lit). The organic phases were combined together, washed with brine, dried on sodium sulphate and concentrated under vacuum at 25-30 C. The residue was stirred in n-Heptane (720 ml). The solid was isolated by filtration, and dried to give 66 g of the title compound (VIII). Efficiency: 27.5% Purity by HPLC: 99.78% Chiral purity: 99.9%

Reference： [1]Patent: US2014/256004,2014,A1 .Location in patent: Page/Page column

29
[ 178306-52-0 ]
[ 1431363-04-0 ]

Reference： [1]Patent: US2014/256004,2014,A1
[2]Patent: US2014/256004,2014,A1

30
[ 178306-52-0 ]
[ 178306-47-3 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium methylate; dimethyl sulfate; In water; N,N-dimethyl-formamide;	EXAMPLE 9 Preparation of (S)-methyl-2-hydroxy-3-methoxy-3,3-diphenylpropionate (compound IV from compound VIII; R'=methyl) Stirred (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid (compound VIII; 79 gms/0.290 moles) in dimethyl formamide (790 ml) under nitrogen and cooled to 5 C. Sodium methoxide (17.3 gms/0.320 moles) was added followed by slow addition of dimethyl sulfate (54.81 gms/0.44 moles) under nitrogen. The reaction mass was further stirred for 3 hours at 25-28 C. and quenched in DI water (2.4 lit). The reaction mass was extracted with ethyl acetate (3*790.0 ml), washed with water and distilled completely under vacuum below 50 C. to obtain 79 gms of the title compound (IV). Efficiency: 95.11%

Reference： [1]Patent: US2014/256004,2014,A1 .Location in patent: Page/Page column

31
[ 178306-52-0 ]
(S)-methyl-2-(4,6-dimethylpyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionate [ No CAS ]

Reference： [1]Patent: US2014/256004,2014,A1

32
[ 178306-52-0 ]
ambrisentan [ No CAS ]

Reference： [1]Patent: US2014/256004,2014,A1

33
[ 178306-52-0 ]
[ 178306-46-2 ]

Reference： [1]Patent: US2014/256004,2014,A1

34
[ 67-56-1 ]
[ 53884-87-0 ]
[ 178306-52-0 ]

Yield	Reaction Conditions	Operation in experiment
27 g		After dissolving 230 g of diphenyl-2,3-epoxypropionic acid in 600 mL of methanol at room temperature, 5.7 g of p-toluenesulfonic acid was added and the mixture was stirred at 20-25 C for 0.5 h. Reflux, and then dropping 10% sodium hydroxide 800 mL, after the end of reflux stirring 1.5 h, methanol concentration after adding 90 ml of water, placed in ice bath stirring 0.5 h after filtration, solid and then washed with cold water, 60 C Blast dry. The resulting solid was mixed with 60 ml of ethanol and 30 ml of petroleum ether for 1 h, filtered, and dried in vacuo at room temperature to give about 160 g of a white solid. The results of the HPLC test of sodium 2-hydroxy-3-methoxy-3,3-diphenylpropionate are shown in Table 1 and Fig. 100 gSyntheticSodium 2-hydroxy-3-methoxy-3,3-diphenylpropionate was addedMethyl tert-butyl ether(MTB, 2000 ml) and methanol (40 ml), and then 56.lg of L-proline methyl ester hydrochloride (0.34 mol) was added and the mixture was stirred at room temperature for 6 h. After standing, the filtrate was filtered, Water, with 6N hydrochloric acid to adjust rho Eta = 1-2. The organic layer was separated and washed with MTB (400 ml). The combined organic layer was washed with 800 ml of water and saturated NaCl. 500 ml and allowed to stand overnight. The solid was filtered, ca. 27 g.

Reference： [1]Patent: CN105801404,2016,A .Location in patent: Paragraph 0021; 0022; 0023

35
(S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid L-prolinamide salt [ No CAS ]
[ 178306-52-0 ]

Yield	Reaction Conditions	Operation in experiment
95%	With hydrogenchloride; In diethyl ether; water;pH 2.0;	(S) -2-hydroxy-3-methoxy-3,3-diphenylpropionic acid L-prolineamide salt was suspended in 300 ml of a mixed solvent of ether: H2O = 1: 1, Suspended in 300 ml of a mixed solvent, and adjusted to pH 2 with 3N HCl aqueous solution.The organic layer was separated, dried, filtered and distilled under reduced pressure to obtain 40 g of the (S) -2-hydroxy-3-methoxy-3,3-diphenylpropionic acid (yield: 95%) (ee = 100%).

Reference： [1]Patent: KR2016/39907,2016,A .Location in patent: Paragraph 0111; 0112

36
sodium 2-hydroxyl-3-methoxy-3,3-diphenylpropionate [ No CAS ]
[ 178306-52-0 ]

Yield	Reaction Conditions	Operation in experiment
9.1%	With L-proline methyl ester monohydrochloride; In methanol; tert-butyl methyl ether; at 20℃; for 6h;	100g of 2-hydroxyl-3-methoxy-3, 3-sodium diphenyl propionate is added into the methyl tert-butyl ether (MTB, 2000 ml) and methanol (40 ml), and then added the 56.1g L-Proline Methyl Ester hydrochloride (0.34 mol), stirring at room temperature for 6h, standing, crystallization, filtration, the filter cake and the filtrate are treated separately. into the filtrate added 400 ml of water, with 6N hydrochloric acid adjust pH=1~2. The organic layer is separated and the aqueous layer is extracted with MuTB (400 ml), the organic layers are combined, the organic layer is washed with 800 ml of water, saturated NaCl solution, dried over anhydrous sodium sulfate, concentrated, and then re-crystallized from 80 ml of ethyl acetate and 500 ml of cyclohexane, stand still overnight. Filter and then obtained S-2-hydroxyl-3-methoxy-3, 3-diphenylpropionic acid 27.0g, yield 29.2%. Filter cake 61.4g is R-2-hydroxyl-3-methoxy-3, 3-diphenylpropionic acid-L-proline methyl ester salt, into this added 300mL of water and 300mL of methyl t-butyl ether, 0.3 g of p-toluenesulfonic acid monohydrate, heated at reflux for 10 hours, add 6mol / L hydrochloric acid 26mL, solution pH=1 ~ 2, liquid, the organic phase is collected, concentrated under reduced pressure, and dissolved in 80mL of ethanol, add water 100mL, add drops of 10% sodium hydroxide solution 56mL, a large amount of white solid precipitation, the mixture is stirred under ice bath for 0.5h and filtered, dry at 60 C. The resulting solid is stirred with 60 ml of ethanol and 120 ml of petroleum ether for 1 h, filter, dry at 60 C, and then obtained white solid about 33.1g. the recovered 2-hydroxyl-3-methoxy-3, 3-diphenylpropionate is added into methyl tert-butyl ether (MTB, 650 ml) and methanol (130 ml), and then added 18. 6g L-Proline methyl ester hydrochloride, stirring at room temperature for 6h, standing, crystallization, filtration, into the filtrate added 130 ml of water, with 6N hydrochloric acid adjust pH=1~2. Separating the organic layer, the aqueous layer is extracted with MuTB (300 ml), the organic layers are combined, saturated NaCl solution, dried over anhydrous sodium sulfate, concentrated, and then re-crystallized from ethyl acetate and cyclohexane, stand still overnight. Filter solids S-2-hydroxyl-3-methoxy-3, 3-diphenylpropionic acid, approximately 8.4g, yield 9.1% (Based on the first charge of 2-hydroxyl-3-methoxy-3, 3-sodium diphenyl propionate).

Reference： [1]Patent: CN106699626,2017,A .Location in patent: Paragraph 0028; 0031; 0032; 0033; 0034

37
potassium 2-hydroxy-3-methoxy-3,3-diphenylpropionate [ No CAS ]
[ 178306-52-0 ]

Yield	Reaction Conditions	Operation in experiment
9.3%	With L-proline methyl ester monohydrochloride; In methanol; tert-butyl methyl ether; at 20℃; for 6h;	A solution of 106 g of potassium 2-hydroxy-3-methoxy-3,3-diphenylpropionate was added to methyl tert-butyl ether (MTB, 2000 ml)And methanol (40 ml)Then 56.1 g of L-proline methyl ester hydrochloride (0.34 mol) was added, Room temperature stirring 6h, Standing, crystallization, filtration, filter cake and filtrate were treated. The filtrate was added with 400 ml of water, and the pH was adjusted to 1 to 2 with 6N hydrochloric acid. The organic layer was separated and extracted with MTB (400 ml). The organic layers were combined, washed with 800 ml of water and saturated NaCl solution. The organic layer was dried over anhydrous sodium sulfate, concentrated, and recrystallized from 80 ml of ethyl acetate and 500 ml of cyclohexane , Put it overnight. And 28.3 g of S-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid was obtained in a yield of 30.6%. 59.2 g of the cake was R-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid-L-proline methyl ester salt,Add 200mL of water and 1000mL of ether, 1mol / L sulfuric acid 0.2mL, heated to reflux for 8 hours, Add 5mol / L sulfuric acid 13.5mL, adjust the solution pH = 1 ~ 2, liquid separation, the organic phase, concentrated under reduced pressure, add methanol dissolved 80mL, add water 100mL, dropping 10% potassium hydroxide solution 69ml, a large number of white solid precipitation, Ice bath for 0.5h after the filter, 60 blast drying. The resulting solid was stirred with 60 ml of ethanol and 120 ml of petroleum ether for 1 h, filtered and dried at 60 C with blowing to give 33.2 g of a white solid. The recovered 2-hydroxy-3-methoxy-3,3-diphenylpropionate was added to methyl tert-butyl ether (MTB, 650 ml) and methanol (130 ml), followed by the addition of 17.6 g of L-proline methyl ester hydrochloride, stirring at room temperature for 6h, after crystallization of static separation, the filtrate by adding 130ml of water, with 6N hydrochloric acid to adjust the pH = 1 ~ 2. The organic layer was separated and extracted with MTB (300 ml). The organic layers were washed with the organic layer and the saturated NaCl solution. The organic layer was dried over anhydrous sodium sulfate and concentrated. The crystals were recrystallized from ethyl acetate and cyclohexane and allowed to stand overnight. A solution of 8.6 g of solid S-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid in a yield of 9.3% (2-hydroxy-3-methoxy- - diphenylpropionic acid potassium).

Reference： [1]Patent: CN106699626,2017,A .Location in patent: Paragraph 0035; 0038; 0039; 0040; 0041

38
[ 3886-69-9 ]
[ 178306-52-0 ]
[ 1231755-40-0 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; tert-butyl methyl ether; at 10 - 30℃;Industrial scale;	The embodiment of the implementation process see the separation of the process;The specific process includes split 1 and split 2 two parts:Split 1: as in Example 1Split 2: Split 1 (see Example 1) to give 3.81 kg of material, dry methanol (18 L),Methyl tert-butyl ether (18L) was added to a 100L reactor,(R) - (+) - alpha-phenylethylamine (1.51 kg) was dropped at 10 to 30 C,After completion of the dropwise addition, the reaction was stirred for 3 to 4 hours at 10 to 30 C and filtered. The filter cake was washed once with methyl tert-butyl ether (4L) and dried to give 4.75 kg in 124.7% yield.HPLC Purity: 99.83%, Chiral Purity: 99.9%.

Reference： [1]Patent: CN104098462,2017,B .Location in patent: Paragraph 0009; 0034-0037; 0041

39
[ 100-39-0 ]
[ 178306-52-0 ]
[ 224455-84-9 ]

Yield	Reaction Conditions	Operation in experiment
		Add 3L of N,N-dimethylformamide to a 5L three-necked flask. Add 300 g of the compound of formula II and stir to dissolve; Add 457g of anhydrous potassium carbonate and stir for 10min. Then add 188g of benzyl bromide, Heat to 30 ~ 35 C temperature control stirring reaction for 2h, TLC tracking monitored the disappearance of spots to the compound of formula II, The reaction solution of the compound of the formula IIIa is directly introduced into the next step without treatment.

Reference： [1]Patent: CN109705042,2019,A .Location in patent: Paragraph 0048-0052

40
[ 100-39-0 ]
[ 178306-52-0 ]
C₂₉H₂₈N₂O₄ [ No CAS ]

Reference： [1]Patent: CN109705042,2019,A

41
3-methoxy-2-((p-toluenesulfonyl)oxy)-3,3-diphenylpropionic acid [ No CAS ]
[ 178306-52-0 ]

Yield	Reaction Conditions	Operation in experiment
89.7%	With methanol; sodium hydroxide; In water; at 0℃; for 24h;	Take the 3-methoxy-2-((p-toluenesulfonyl) oxy) -3,3-diphenylpropionic acid 21.3 (0.05mol) obtained in the previous step and add it to 100ml of methanol, add 10ml of purified water, and ice-water bath The temperature was controlled at 0 C, and 3.6 g (0.09mol) of sodium hydroxide was slowly added. The temperature of the ice-water bath was controlled at 0 C for 24 hours. After the reaction was completed, 200 ml of water was added. Extract 100ml of ethyl acetate, separate the organic layer, wash the organic layer with 100ml of saturated brine, concentrate under reduced pressure to dryness, add 30ml of ethyl acetate and 150ml of cyclohexane, heat to reflux, cool to 5-10 C and crystallize.Vacuum dried(S) 12.2g of 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid,The yield was 89.7%. HPLC test showed that the S configuration content was 84%.

Reference： [1]Patent: CN110437063,2019,A .Location in patent: Paragraph 0029; 0031

42
3-methoxy-2-((methanesulfonyl)oxy)-3,3-diphenylpropionic acid [ No CAS ]
[ 178306-52-0 ]

Yield	Reaction Conditions	Operation in experiment
13.2 g	With water; sodium hydroxide; In methanol; at 0℃; for 24h;	Take the 3-methoxy-2-((methanesulfonyl) oxy) -3,3-diphenylpropanoic acid 17.5 (0.05 mol) obtained in the previous step and add it to 100 ml of methanol. Add 10 ml of purified water. At 0 C, slowly add 3.6g (0.09mol) of sodium hydroxide, and control the temperature in an ice-water bath at 0 C for 24 hours. After the reaction is complete, add 200ml of water, adjust the pH == 5 6 with 0.1mol / L hydrochloric acid, and then add acetic acid. Extract 100 ml of ethyl acetate, separate the organic layer, wash the organic layer with 100 ml of saturated brine, concentrate under reduced pressure to dryness, add 26 ml of ethyl acetate and 130 ml of cyclohexane, heat to reflux, cool to 5-10 C, crystallize, filter, and vacuum After drying, 13.2 g of (S) -2-hydroxy-3-methoxy-3,3-diphenylpropanoic acid was obtained with a yield of 97.0%. HPLC detection showed that the S configuration content was 85%.

Reference： [1]Patent: CN110437063,2019,A .Location in patent: Paragraph 0020; 0022; 0023; 0025; 0026; 0028

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[ 178306-52-0 ] Synthesis Path-Upstream 1~9

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