[ CAS No. 77-09-8 ] {[proInfo.proName]}

Name: 77-09-8|3,3-Bis(4-hydroxyphenyl)isobenzofuran-1(3H)-one|99%
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Quality Control of [ 77-09-8 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 77-09-8 ]

SDS Specification

Alternatived Products of [ 77-09-8 ]

Product Details of [ 77-09-8 ]

CAS No. :	77-09-8	MDL No. :	MFCD00005913
Formula :	C₂₀H₁₄O₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	KJFMBFZCATUALV-UHFFFAOYSA-N
M.W :	318.32	Pubchem ID :	4764
Synonyms :	Phthalimetten

Calculated chemistry of [ 77-09-8 ]

Physicochemical Properties

Num. heavy atoms :	24
Num. arom. heavy atoms :	18
Fraction Csp3 :	0.05
Num. rotatable bonds :	2
Num. H-bond acceptors :	4.0
Num. H-bond donors :	2.0
Molar Refractivity :	88.67
TPSA :	66.76 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.53 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.13
Log Po/w (XLOGP3) :	2.41
Log Po/w (WLOGP) :	3.45
Log Po/w (MLOGP) :	3.05
Log Po/w (SILICOS-IT) :	3.85
Consensus Log Po/w :	2.98

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-3.75
Solubility :	0.056 mg/ml ; 0.000176 mol/l
Class :	Soluble
Log S (Ali) :	-3.45
Solubility :	0.112 mg/ml ; 0.000352 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-6.43
Solubility :	0.000118 mg/ml ; 0.000000372 mol/l
Class :	Poorly soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	2.86

Safety of [ 77-09-8 ]

Signal Word:	Danger	Class:	9
Precautionary Statements:	P201-P202-P280-P308+P313-P405-P501	UN#:	3077
Hazard Statements:	H340-H350-H361	Packing Group:	Ⅲ
GHS Pictogram:

Application In Synthesis of [ 77-09-8 ]

* 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 [ 77-09-8 ]
Downstream synthetic route of [ 77-09-8 ]

[ 77-09-8 ] Synthesis Path-Upstream 1~11

1
[ 85-44-9 ]
[ 108-95-2 ]
[ 77-09-8 ]

Yield	Reaction Conditions	Operation in experiment
90%	at 80℃; for 0.0833333 h;	500 mg of phthalic anhydride, 500 mg of phenol and 1 g of crude catalyst derived from Thlaspi (Example 1.1, 12N HCl) dehydrated at 110° C. for a few minutes are placed in a single-necked flask and heated at 80° C. for 5 minutes. (0510) After cooling down, the reaction mixture is diluted in 5 mL of a water/ethanol mixture. 1 mL of solution is taken then added to a 3M soda solution. (0511) In the case of phenolphthalein, the solution becomes pink immediately. (0512) After washing with ether, the phenolphthalein crystallizes easily.
89%	at 120℃; for 24 h; Inert atmosphere	Preparation of Phenolphthalein Using Zinc-Containing Ionic Liquid Catalyst Compositions.; In a 250 mL round bottom flask equipped with mechanical stirrer, thermometer, nitrogen inlet and reflux condenser, 10.0 g of phthalic anhydride (0.067 moles) and 15 g of ionic liquid catalyst composition (zinc chloride and 1-butyl-3-methyl-imidazolium) (60 wt. percent based on total weight of reactants) were charged to the round bottom flask followed by 14.3 g phenol (2.25 molar equivalents based on phthalic anhydride) and 1.9 g chlorosulphonic acid (0.2 molar equivalents based on phthalic anhydride), while maintaining the round bottom flask in a nitrogen atmosphere at 50 to 60° C. The reaction mixture was then heated with stirring at 120° C. (bath temperature). Over the course of the reaction (24 hours), the reaction mass progressively turned from orange to brownish orange to deep brown. After 24 hours, the reaction mixture comprising phenolphthalein was then quenched with 150 mL toluene. The viscous mass produced by the addition of toluene was stirred at 85° C. for about 30 min. The supernatant (containing the ionic liquid catalyst composition, toluene, and unreacted starting material) was decanted and the remaining viscous mass was then heated with 150 mL water and stirred at 85° C. for about 30 min. The solidified phenolphthalein was filtered while hot and washed until the supernatant was neutral with cold, distilled water to obtain crude phenolphthalein. The resulting brownish yellow solid was dried under vacuum at 100° C. overnight. The yield of crude phenolphthalein was 18.7 g (89 mol percent) and the purity was 96.08 wt. percent.
88%	at 140℃; for 48 h; Inert atmosphere	Example 1; Preparation of Phenolphthalein: A Procedure for the Preparation of phenolphthalein using metal oxide catalysts is as follows. In a 250 mL, round bottom flask equipped with mechanical stirrer, thermometer, nitrogen inlet, and reflux condenser, 18.5 g of phthalic anhydride and 27.6 g of phenol were charged, followed by 10.0 g of heterogeneous catalyst (tungstated zirconia) and 1.9 g of chlorosulphonic acid ("CSA"), while maintaining the round bottom flask in a nitrogen atmosphere at 50 to 60° C. This amounted to 2.25 molar equivalents of phenol with respect to the phthalic anhydride, and 17percent by weight loading of the catalyst.The reaction mixture was then heated with stirring at 140° C. (bath temperature). During the course of the reaction for 48 hours, the reaction mass progressively turned from orange to brownish orange to deep brown. The reaction product was then quenched (stopped) with a solvent (160 mL of methanol). The quenched mass comprising phenolphthalein (PP), unreacted phthalic anhydride (PA), and by-products was stirred at 85° C. for about 30 minutes. All organic compounds including the phenolphthalein dissolved in the methanol. The solution was then filtered to remove the solid catalyst as a residue and obtain a filtrate. The methanol was removed from the filtrate using a Rotovac.(R). evaporator, and the viscous mass was then heated with 160 mL of toluene solvent and stirred at 85° C. for 30 minutes. The toluene removed unreacted reactants and by-products. The solid, crude precipitate, which did not dissolve in the toluene, was filtered while hot and washed with hot water. The resulting brownish yellow solid was dried under vacuum at 100° C. overnight to obtain crude phenolphthalein. The isolated yield of crude phenolphthalein was 35.0 g (88 wt. percent, based on the phthalic anhydride), and the purity was 95.9percent, as determined by HPLC as described above.Phenolphthalein was prepared under the same conditions, except for using tungstated ceria and molybdenum on silica. The results of the various methods of preparing phenolphthalein are shown in Table 1 below, using the same analytical procedures as in Example 1. In Table 1, the "conversion" and "reaction yield" were determined just before quenching with methanol as described above. The "isolated yield" and "purity" in Table 1 refers to the crude phenolphthalein (after filtering and washing) according to the method described above.

84.2%

at 50 - 115℃; for 17 - 20 h;

Comparative Example A; In a 250 milliliter (mL) round bottom flask equipped with mechanical stirrer, thermometer, nitrogen inlet and reflux condenser, 18.5 gram (g) (0.124 mole) of phthalic anhydride and 9.99 g (0.073 mole) of zinc chloride were charged followed by 26.25 g (0.278 mole) phenol and 2.91 g (0.024 mole) chloro sulphonic acid, while maintaining the round bottom flask in nitrogen atmosphere at 50 to 60° C. The reaction mixture was then heated with stirring at 115° C. During the course of the reaction of 18 to 20 hours, the reaction mixture progressively turned from yellowish orange to brownish orange to deep brown while gaining viscosity. The reaction mixture was then treated with 250 mL hot water (50 to 90° C.). The treated mixture was stirred further for about 30 minutes at 80 to 85° C. The treated mixture was filtered while hot and washed with cold de-ionized water, then dried in an oven, resulting in a crude phenolphthalein material. The crude phenolphthalein material comprises 95 wt percent phenolphthalein based on the total weight of the material. The molar yield based on phthalic anhydride was 90percent.; Example 1; In a 250 mL round bottom flask equipped with mechanical stirrer, thermometer, nitrogen inlet and reflux condenser, 18.5 g (0.124 mole) of phthalic anhydride and 9.99 g (0.073 mole) of zinc chloride were charged followed by 26.25 g (0.278 mole) phenol and 2.91 g (0.024 mole) chlorosulphonic acid, while maintaining the round bottom flask in nitrogen atmosphere at 50 to 60° C. The reaction mixture was then heated with stirring at 115° C. for 18 to 20 hours. During the course of the reaction of 18 to 20 hours, the reaction mass progressively turned from yellowish orange to brownish orange to deep brown while gaining viscosity. The reaction mass was cooled to room temperature and a solvent system containing a mixture of methanol and toluene (10:90, v:v) was added and stirred for 1 hour at reflux. The viscous mass became very free and the product was filtered. Hot water (50 to 90° C.) was added and then the reaction mixture was heated at 80 to 85° C. for 30 minutes and then cooled to room temperature. The resulting brownish yellow solid was dried in an oven at 100° C., over night. The solid comprised 98 wt percent phenolphthalein based on the total weight of the solid as analyzed by HPLC. The molar yield based on phthalic anhydride was 85percent.; Comparative Example B; In a 500 mL four neck round bottom flask fitted with an overhead stirrer, a nitrogen gas inlet, thermowell, and a reflux condenser were placed 100.0 g (0.675 mole) of phthalic anhydride, 143.0 g (1.52 mole) of phenol, 55.20 g of zinc chloride (0.40 mole), and 15.73 g of chloro sulphonic acid (0.135 mole). A slow stream of nitrogen gas was continuously passed through the flask, and the reaction mixture was heated at 115° C. for 17 to 18 hours. The reaction mixture was allowed to cool to 50° C. then 900 mL of water was added to the reaction mixture followed by stirring for 2 hours at 85 to 90° C. The slurry formed was filtered out, washed with 100 mL water for 5 times until free from acid, and dried, resulting in crude phenolphthalein material. The yield of this process was 190.50 g (89 mol percent) based on the moles of phthalic anhydride. The crude phenolphthalein material comprised less than or equal to 95 wt percent phenolphthalein based on the total weight of the material.; Examples 21-23; 18.5 g (0.124 mole) of phthalic anhydride, 9.99 g (0.073 mole) of zinc chloride, 26.25 g (0.278 mole) phenol and 2.91 g (0.024 mole) chlorosulphonic acid were reacted under nitrogen at 110° C. for 18 hours. The reaction mass was cooled to 50 to 60° C. and a solvent system containing a mixture of methanol and toluene (10:90, v:v) was added in the amounts shown in Table 2. The resulting mixture is stirred at reflux temperature for 2 hours, and then cooled to 0 to 10° C. and maintained at 0 to 10° C. for 0.5 to 1.0 hour. In some examples the reaction mass was treated with the solvent system more than once as shown in Table 2. After filtering, the solid was washed with 300 mL of hot water (50 to 90° C., or more specifically, 70° C.), filtered and dried. Yields and purities are shown in Table 2. Yield is in mole percent based on the amount of phthalic anhydride. Purity is in wt percent based on the total weight of the solid material. These examples show that using a solvent system comprising a polar organic solvent is an efficient method to obtain high purity phenolphthalein in a simple and efficient manner.

Reference： [1] Tetrahedron Letters, 2009, vol. 50, # 46, p. 6261 - 6263
[2] Catalysis Today, 2012, vol. 189, # 1, p. 111 - 116
[3] Patent: US9149796, 2015, B2, . Location in patent: Page/Page column 41
[4] Patent: US2010/81831, 2010, A1, . Location in patent: Page/Page column 6
[5] Patent: US2010/81828, 2010, A1, . Location in patent: Page/Page column 6-7
[6] Patent: US2008/177091, 2008, A1, . Location in patent: Page/Page column 3-5
[7] Chemical Papers, 2011, vol. 65, # 4, p. 504 - 509
[8] Justus Liebigs Annalen der Chemie, 1880, vol. 202, p. 56,63
[9] Journal of the Chemical Society, 1920, vol. 117, p. 215
[10] Journal of the American Chemical Society, 1924, vol. 46, p. 2495
[11] Die Fabrikation pharmazeutischer und chemisch-technischer Produkte <Berlin 1931>, S. 235,
[12] Chemiker-Zeitung, Chemische Apparatur, 1927, vol. 51, p. 84[13] Chem. Zentralbl., 1927, vol. 98, # I, p. 1523
[14] Z. chim. Promysl., 1924, vol. 1, # 4, p. 26[15] Chem. Zentralbl., 1926, vol. 97, # II, p. 753
[16] Journal of the Chemical Society, 1920, vol. 117, p. 215
[17] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 14, p. 719
[18] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 14, p. 719
[19] Journal of the Chemical Society, 1921, vol. 119, p. 851
[20] Justus Liebigs Annalen der Chemie, 1880, vol. 202, p. 56,63
[21] Patent: US2522939, 1949, ,
[22] Patent: US2522939, 1949, ,
[23] Journal of Medicinal Chemistry, 1999, vol. 42, # 12, p. 2112 - 2124
[24] Patent: US2010/81829, 2010, A1, . Location in patent: Page/Page column 7-8
[25] Chem. Zentralbl., 1929, vol. 100, # I, p. 2156
[26] Patent: EP2769765, 2014, A1, . Location in patent: Page/Page column
[27] Patent: US2015/376224, 2015, A1, . Location in patent: Paragraph 0717-0721
[28] Patent: WO2018/13623, 2018, A1, . Location in patent: Paragraph 0064
[29] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 14, p. 720
[30] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 14, p. 720

2
[ 85-44-9 ]
[ 95-48-7 ]
[ 108-95-2 ]
[ 77-09-8 ]
[ 854-76-2 ]
[ 596-27-0 ]

Reference： [1] Russian Journal of Applied Chemistry, 2015, vol. 88, # 4, p. 711 - 718[2] Zh. Prikl. Khim. (S.-Peterburg, Russ. Fed.), 2015, vol. 88, # 4, p. 665 - 672,8

3
[ 83-44-3 ]
[ 37777-96-1 ]
[ 77-09-8 ]

Reference： [1] Chemistry and Physics of Lipids, 2011, vol. 164, # 2, p. 99 - 105

4
[ 128-13-2 ]
[ 137078-96-7 ]
[ 77-09-8 ]

Reference： [1] Chemistry and Physics of Lipids, 2011, vol. 164, # 2, p. 99 - 105

5
[ 85-57-4 ]
[ 108-95-2 ]
[ 77-09-8 ]

Reference： [1] Journal of the American Chemical Society, 1917, vol. 39, p. 680
[2] Journal of the American Chemical Society, 1924, vol. 46, p. 2495
[3] Bl. Acad. Sci. Agra Oudh, 1933, vol. 2, p. 253,255

6
[ 85-44-9 ]
[ 108-95-2 ]
[ 77-09-8 ]
[ 596-24-7 ]

Reference： [1] Justus Liebigs Annalen der Chemie, 1882, vol. 212, p. 349
[2] Chemische Berichte, 1891, vol. 24, p. 1414,2600[3] Chemische Berichte, 1893, vol. 26, p. 205
[4] Chemische Berichte, 1871, vol. 4, p. 659[5] Chemische Berichte, 1876, vol. 9, p. 1233
[6] Justus Liebigs Annalen der Chemie, 1880, vol. 202, p. 56,63

7
[ 62625-15-4 ]
[ 77-09-8 ]

Reference： [1] Bioscience, Biotechnology and Biochemistry, 2011, vol. 75, # 1, p. 89 - 94

8
[ 88-99-3 ]
[ 108-95-2 ]
[ 77-09-8 ]

Reference： [1] Z. chim. Promysl., 1924, vol. 1, # 4, p. 26[2] Chem. Zentralbl., 1926, vol. 97, # II, p. 753
[3] Journal of the Chemical Society, 1920, vol. 117, p. 215

9
[ 509-77-3 ]
[ 77-09-8 ]

Reference： [1] Chemische Berichte, 1879, vol. 12, p. 644[2] Justus Liebigs Annalen der Chemie, 1880, vol. 202, p. 52

10
[ 84755-69-1 ]
[ 77-09-8 ]

Reference： [1] Chemical and Pharmaceutical Bulletin, 1990, vol. 38, # 1, p. 159 - 163

11
[ 77-09-8 ]
[ 1255-69-2 ]
[ 1552-42-7 ]

Reference： [1] Patent: US4595768, 1986, A,

[ 77-09-8 ] Synthesis Path-Downstream 1~61

1
[ 85-44-9 ]
[ 108-95-2 ]
[ 77-09-8 ]

Yield	Reaction Conditions	Operation in experiment
90%	With mixed metal catalyst derived from Thlaspi; at 80℃; for 0.0833333h;	500 mg of phthalic anhydride, 500 mg of phenol and 1 g of crude catalyst derived from Thlaspi (Example 1.1, 12N HCl) dehydrated at 110 C. for a few minutes are placed in a single-necked flask and heated at 80 C. for 5 minutes. (0510) After cooling down, the reaction mixture is diluted in 5 mL of a water/ethanol mixture. 1 mL of solution is taken then added to a 3M soda solution. (0511) In the case of phenolphthalein, the solution becomes pink immediately. (0512) After washing with ether, the phenolphthalein crystallizes easily.
89.00%	chlorosulfonic acid; at 120℃; for 24h;Inert atmosphere;Product distribution / selectivity;	Preparation of Phenolphthalein Using Zinc-Containing Ionic Liquid Catalyst Compositions.; In a 250 mL round bottom flask equipped with mechanical stirrer, thermometer, nitrogen inlet and reflux condenser, 10.0 g of phthalic anhydride (0.067 moles) and 15 g of ionic liquid catalyst composition (zinc chloride and 1-butyl-3-methyl-imidazolium) (60 wt. % based on total weight of reactants) were charged to the round bottom flask followed by 14.3 g phenol (2.25 molar equivalents based on phthalic anhydride) and 1.9 g chlorosulphonic acid (0.2 molar equivalents based on phthalic anhydride), while maintaining the round bottom flask in a nitrogen atmosphere at 50 to 60 C. The reaction mixture was then heated with stirring at 120 C. (bath temperature). Over the course of the reaction (24 hours), the reaction mass progressively turned from orange to brownish orange to deep brown. After 24 hours, the reaction mixture comprising phenolphthalein was then quenched with 150 mL toluene. The viscous mass produced by the addition of toluene was stirred at 85 C. for about 30 min. The supernatant (containing the ionic liquid catalyst composition, toluene, and unreacted starting material) was decanted and the remaining viscous mass was then heated with 150 mL water and stirred at 85 C. for about 30 min. The solidified phenolphthalein was filtered while hot and washed until the supernatant was neutral with cold, distilled water to obtain crude phenolphthalein. The resulting brownish yellow solid was dried under vacuum at 100 C. overnight. The yield of crude phenolphthalein was 18.7 g (89 mol %) and the purity was 96.08 wt. %.
88%	With chlorosulfonic acid;15 wt.% tungsten oxide on zirconia; at 140℃; for 48h;Inert atmosphere;Product distribution / selectivity;	Example 1; Preparation of Phenolphthalein: A Procedure for the Preparation of phenolphthalein using metal oxide catalysts is as follows. In a 250 mL, round bottom flask equipped with mechanical stirrer, thermometer, nitrogen inlet, and reflux condenser, 18.5 g of phthalic anhydride and 27.6 g of phenol were charged, followed by 10.0 g of heterogeneous catalyst (tungstated zirconia) and 1.9 g of chlorosulphonic acid (?CSA?), while maintaining the round bottom flask in a nitrogen atmosphere at 50 to 60 C. This amounted to 2.25 molar equivalents of phenol with respect to the phthalic anhydride, and 17% by weight loading of the catalyst.The reaction mixture was then heated with stirring at 140 C. (bath temperature). During the course of the reaction for 48 hours, the reaction mass progressively turned from orange to brownish orange to deep brown. The reaction product was then quenched (stopped) with a solvent (160 mL of methanol). The quenched mass comprising phenolphthalein (PP), unreacted phthalic anhydride (PA), and by-products was stirred at 85 C. for about 30 minutes. All organic compounds including the phenolphthalein dissolved in the methanol. The solution was then filtered to remove the solid catalyst as a residue and obtain a filtrate. The methanol was removed from the filtrate using a Rotovac evaporator, and the viscous mass was then heated with 160 mL of toluene solvent and stirred at 85 C. for 30 minutes. The toluene removed unreacted reactants and by-products. The solid, crude precipitate, which did not dissolve in the toluene, was filtered while hot and washed with hot water. The resulting brownish yellow solid was dried under vacuum at 100 C. overnight to obtain crude phenolphthalein. The isolated yield of crude phenolphthalein was 35.0 g (88 wt. %, based on the phthalic anhydride), and the purity was 95.9%, as determined by HPLC as described above.Phenolphthalein was prepared under the same conditions, except for using tungstated ceria and molybdenum on silica. The results of the various methods of preparing phenolphthalein are shown in Table 1 below, using the same analytical procedures as in Example 1. In Table 1, the ?conversion? and ?reaction yield? were determined just before quenching with methanol as described above. The ?isolated yield? and ?purity? in Table 1 refers to the crude phenolphthalein (after filtering and washing) according to the method described above.

84.2 - 90%	chlorosulfonic acid; zinc(II) chloride; at 50 - 115℃; for 17 - 20h;Product distribution / selectivity;	Comparative Example A; In a 250 milliliter (mL) round bottom flask equipped with mechanical stirrer, thermometer, nitrogen inlet and reflux condenser, 18.5 gram (g) (0.124 mole) of phthalic anhydride and 9.99 g (0.073 mole) of zinc chloride were charged followed by 26.25 g (0.278 mole) phenol and 2.91 g (0.024 mole) chloro sulphonic acid, while maintaining the round bottom flask in nitrogen atmosphere at 50 to 60 C. The reaction mixture was then heated with stirring at 115 C. During the course of the reaction of 18 to 20 hours, the reaction mixture progressively turned from yellowish orange to brownish orange to deep brown while gaining viscosity. The reaction mixture was then treated with 250 mL hot water (50 to 90 C.). The treated mixture was stirred further for about 30 minutes at 80 to 85 C. The treated mixture was filtered while hot and washed with cold de-ionized water, then dried in an oven, resulting in a crude phenolphthalein material. The crude phenolphthalein material comprises 95 wt % phenolphthalein based on the total weight of the material. The molar yield based on phthalic anhydride was 90%.; Example 1; In a 250 mL round bottom flask equipped with mechanical stirrer, thermometer, nitrogen inlet and reflux condenser, 18.5 g (0.124 mole) of phthalic anhydride and 9.99 g (0.073 mole) of zinc chloride were charged followed by 26.25 g (0.278 mole) phenol and 2.91 g (0.024 mole) chlorosulphonic acid, while maintaining the round bottom flask in nitrogen atmosphere at 50 to 60 C. The reaction mixture was then heated with stirring at 115 C. for 18 to 20 hours. During the course of the reaction of 18 to 20 hours, the reaction mass progressively turned from yellowish orange to brownish orange to deep brown while gaining viscosity. The reaction mass was cooled to room temperature and a solvent system containing a mixture of methanol and toluene (10:90, v:v) was added and stirred for 1 hour at reflux. The viscous mass became very free and the product was filtered. Hot water (50 to 90 C.) was added and then the reaction mixture was heated at 80 to 85 C. for 30 minutes and then cooled to room temperature. The resulting brownish yellow solid was dried in an oven at 100 C., over night. The solid comprised 98 wt % phenolphthalein based on the total weight of the solid as analyzed by HPLC. The molar yield based on phthalic anhydride was 85%.; Comparative Example B; In a 500 mL four neck round bottom flask fitted with an overhead stirrer, a nitrogen gas inlet, thermowell, and a reflux condenser were placed 100.0 g (0.675 mole) of phthalic anhydride, 143.0 g (1.52 mole) of phenol, 55.20 g of zinc chloride (0.40 mole), and 15.73 g of chloro sulphonic acid (0.135 mole). A slow stream of nitrogen gas was continuously passed through the flask, and the reaction mixture was heated at 115 C. for 17 to 18 hours. The reaction mixture was allowed to cool to 50 C. then 900 mL of water was added to the reaction mixture followed by stirring for 2 hours at 85 to 90 C. The slurry formed was filtered out, washed with 100 mL water for 5 times until free from acid, and dried, resulting in crude phenolphthalein material. The yield of this process was 190.50 g (89 mol %) based on the moles of phthalic anhydride. The crude phenolphthalein material comprised less than or equal to 95 wt % phenolphthalein based on the total weight of the material.; Examples 21-23; 18.5 g (0.124 mole) of phthalic anhydride, 9.99 g (0.073 mole) of zinc chloride, 26.25 g (0.278 mole) phenol and 2.91 g (0.024 mole) chlorosulphonic acid were reacted under nitrogen at 110 C. for 18 hours. The reaction mass was cooled to 50 to 60 C. and a solvent system containing a mixture of methanol and toluene (10:90, v:v) was added in the amounts shown in Table 2. The resulting mixture is stirred at reflux temperature for 2 hours, and then cooled to 0 to 10 C. and maintained at 0 to 10 C. for 0.5 to 1.0 hour. In some examples the reaction mass was treated with the solvent system more than once as shown in Table 2. After filtering, the solid was washed with 300 mL of hot water (50 to 90 C., or more specifically, 70 C.), filtered and dried. Yields and purities are shown in Table 2. Yield is in mole percent based on the amount of phthalic anhydride. Purity is in wt % based on the total weight of the solid material. These examples show that using a solvent system comprising a polar organic solvent is an efficient method to obtain high purity phenolphthalein in a simple and efficient manner.
	chlorosulfonic acid; at 140℃; for 48h;Inert atmosphere;Product distribution / selectivity;	Example 1 Preparation of Phenolphthalein.; In a 250-ml round bottom flask equipped with mechanical stirrer, thermometer, nitrogen inlet and reflux condenser, 18.5 g of phthalic anhydride and 27.6 g of phenol were charged, followed by 10.0 g of supported heteropolyacid catalyst (silicotungstic acid in Sample 1) and 1.9 g chlorosulphonic acid, while maintaining the round bottom flask in a nitrogen atmosphere at 50 to 60 C. This amounted to 1 molar equivalent of phenolphthalein, 2.25 molar equivalents of phenol with respect to the phthalic anhydride, and 17% by weight loading of the catalyst.The reaction mixture was then heated with stirring at 140 C. (bath temperature). During the course of the reaction for 48 hours, the reaction mass progressively turned from orange to brownish orange to deep brown. The reaction product was then quenched with a solvent, 160 mL of methanol. The quenched mass comprising phenolphthalein, unreacted phthalic anhydride, and by-products was stirred at 85 C. for about 30 min. The solution was then filtered to remove solid catalyst as a residue and to obtain a filtrate containing the phenolphthalein. The methanol was removed from the filtrate using a Rotovac evaporator, and the viscous mass was then heated with 160 mL of toluene, and stirred at 85 C. for 30 min. The precipitated solid (precipitated phenolphthalein) was filtered while hot and washed with hot water. The resulting brownish yellow solid was dried under vacuum at 100 C. overnight to obtain crude phenolphthalein. The yield of crude phenolphthalein was 35.0 g (88% by weight of the crude phenolphthalein). The purity was 95.88%, as determined by HPLC.Phenolphthalein was also prepared using the above procedure and 15 wt. tungstophosphoric acid/zirconia, 15 wt. % tungstophosphoric acid/titania, and 15 wt. % wt. % tungstophosphoric acid/22.4 wt. % ZrO2 on 62.6 wt. % SBA-15 zeolite. The results are shown in Table 1.
	With hydrogenchloride; In ethanol; water;	- phenolphthalein 500 mg of phthalic anhydride, 500 mg of phenol and 1 g of crude catalyst derived from Thlaspi (Example 1.1, 12N HCl) dehydrated at 110C for a few minutes are placed in a single-necked flask and heated at 80C for 5 minutes. After cooling down, the reaction mixture is diluted in 5 mL of a water/ethanol mixture. 1 mL of solution is taken then added to a 3M soda solution. In the case of phenolphthalein, the solution becomes pink immediately. After washing with ether, the phenolphthalein crystallizes easily.
	With hydrogenchloride; In water; at 80℃; for 0.0833333h;	500mg of phthalic anhydride, 500mg of phenol and1 g of crude catalyst derived from Thiaspi (ReferenceExample 1.1, 12N HC1) dehydrated at 1100 C. for a fewminutes are placed in a single-necked flask and heated at 80C. for 5 minutes.After cooling down, the reaction mixture is dilutedinS mL of a water/ethanol mixture. 1 mL of solution is takenthen added to a 3M soda solution.In the case ofphenolphthalein, the solution becomes pink immediately.After washing with ether, the phenolphthalein crystallizes easily.
	With chlorosulfonic acid; zinc(II) chloride;	A process for production of PPPBP is optionally a two-step process, where the first step is making PP in a batch reactor with a cycle time of 15-20 hours (hrs). Phthalic anhydride is reacted with phenol in the presence of ZnCl2 as a catalyst and chloro sulfonic acid (CSA) as a co-catalyst. The purification and isolation of phenolphthalein is also performed batch-wise where the phenolphthalein reaction mass is cooled to 65C and partially dissolved in methanol-water mixture to make the reaction mass flow. The reaction mass is then transferred to another vessel and completely dissolved in a 90% methanol in water, and further treated with activated charcoal and sodium bisulfite. The slurry reaction mass is then filtered to remove the charcoal and collected in a separate vessel. The reaction mass is then boiled away to evaporate more than 50% of the solvent and then cooled to induce to precipitation of the phenolphthalein. The slurry is then separated for solid isolation using multiple centrifuge batches. The product is washed in a centrifuge with hot water and dried in batches.

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[5]Patent: US2010/81828,2010,A1 .Location in patent: Page/Page column 6-7
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[8]Journal of Heterocyclic Chemistry,2019,vol. 56,p. 2811 - 2821
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[10]Journal of the Chemical Society,1920,vol. 117,p. 215
[11],1924,vol. 1,p. 26
    Chemisches Zentralblatt,1926,vol. 97,p. 753
[12]Journal of the Chemical Society,1920,vol. 117,p. 215
[13]Journal of the Chemical Society,1921,vol. 119,p. 851
[14]Justus Liebigs Annalen der Chemie,1880,vol. 202,p. 56,63
[15]Patent: US2522939,1949,
[16]Patent: US2522939,1949,
[17]Journal of Medicinal Chemistry,1999,vol. 42,p. 2112 - 2124
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[19]Chemisches Zentralblatt,1929,vol. 100,p. 2156
[20]Patent: EP2769765,2014,A1 .Location in patent: Page/Page column
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2
[ 623-11-0 ]
[ 77-09-8 ]
[ 85-57-4 ]
[ 88-99-3 ]

Reference： [1]Journal of the American Chemical Society,1943,vol. 65,p. 2097

3
[ 85-57-4 ]
[ 108-95-2 ]
[ 77-09-8 ]

Reference： [1]Journal of the American Chemical Society,1917,vol. 39,p. 680
[2]Journal of the American Chemical Society,1924,vol. 46,p. 2495
[3],1933,vol. 2,p. 253,255

4
[ 77-09-8 ]
[ 100-44-7 ]
[ 128102-98-7 ]

Reference： [1]Tetrahedron,1990,vol. 46,p. 967 - 978

5
[ 77-09-8 ]
[ 76-62-0 ]

Yield	Reaction Conditions	Operation in experiment
96%	With sulfuric acid; cis-(2-(1H-imidazol-2-yl)pyridine)-(2-(imidazol-2-yl)pyridine)dioxidovanadate(V) tris(aqua); dihydrogen peroxide; potassium bromide; In methanol; water; at 20℃; for 0.5h;pH 2 - 3;	General procedure: Compound 1 (10.0 mg, 0.0125 mmol) and phenol/aniline-like compound (1.00 mmol)were dissolved in CH3OH:H2O (3:1, 4.0 mL). To this mixture, KBr (360 mg, 3.05 mmol) wasadded, followed by 30% H2O2 (2.0 mL), added dropwise with constant stirring. The pH ofthe solution was adjusted to 2-3 by dropwise addition of 50% H2SO4 solution. The reactionmixture was stirred for 0.5-2 h at room temperature. After the reaction was complete,by monitoring TLC, the reaction mixture was concentrated. Ethyl acetate was usedto extract the residual product. The results of the conversions are listed in Table 2.

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[4]Carbohydrate Research,1989,vol. 192,p. 103 - 110

6
[ 7664-93-9 ]
[ 77-09-8 ]
[ 605-32-3 ]
[ 129-43-1 ]

Reference： [1]Chemische Berichte,1874,vol. 7,p. 972

7
[ 77-09-8 ]
[ 81-90-3 ]

Yield	Reaction Conditions	Operation in experiment
94%	With palladium 10% on activated carbon; W(OTf)6; hydrogen; acetic acid; at 50℃; under 760.051 Torr; for 12h;	Specific methods are as follows: propiolactone was added (0.36g, 5mmol), palladium on carbon (10%, 26.5mg, 0.025mmol, 0.5mol%) in the reactor and W (OTf)6(107.8mg, 0.1mmol, 2mol%). A hydrogen balloon connected to the top of the reactor, and the reactor was purged with hydrogen gas atmosphere. Hydrogen atmosphere at normal pressure, the reaction was stirred at 135 deg.] C after 12h, detected by gas, gamma- valerolactone complete conversion of starting material, and only n-valeric acid. The method carried out as follows completion of the hydrogenation reaction of the ring-opening reaction system separation, to obtain the desired product n-valeric acid: The reaction was completed reaction mixture was dissolved with methylene chloride, filtered to remove the palladium on carbon catalyst and W (OTf)699% yield measured propionic acid, purity of the product was 99%. NMR data for the product using the embodiment of the present invention is the NMR identified the product as follows:The specific reaction procedure and operation method were the same as in Example 27 except that the substrate used was 2 mmol and lmL of acetic acid was added as a solvent at a reaction temperature of 50 C in 94% yield and 99% purity. The product was subjected to nuclear magnetic identification using the manner described in the present invention, and the NMR data of the product were as follows
26.3 mg		First, 20.0 grams (g) (0.06283 moles) <strong>[77-09-8]phenolphthalein</strong> (lib), 28.42 g (0.71060 moles) solid NaOH, and 200 milliliters (mL) of distilled water were charged into a round bottom flask, fitted with an overhead stirrer and stirred for 30 minutes. To the dark purple color solution formed, zinc dust (22.9 g, 0.3380 moles) was added. The reaction mixture was stirred at room temperature for 1 hour (hr), then heated to 60C and maintained at this temperature until a gray suspension (due to unreacted Zn dust) formed. The suspension was filtered while hot and washed with water (about 20 mL). The filtrate was acidified with 33% aqueous hydrochloric acid (65 g, 1.780 moles) to pH 3. The resulting off-white precipitate was filtered and washed with 50 mL water. The off-white solid was dried in vacuum to yield 26.3 g (HPLC purity about 95% and LC purity 97%) of dihydro<strong>[77-09-8]phenolphthalein</strong> (Illb) as an off-white solid. [0052] The product was confirmed by LC-Ms, found M/Z: 320.0; M+l peak: 321.34, Molecular weight (Mol. wt): 320.34 grams/mole. IR spectroscopy: FTIR (cm"1): 1658 (C=0), 1497 (quaternary carbon), 1600 (aromatic), 1547-1610 and 1386-1441 (COOH/COO ), 3353 (Ar- OH).

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[4]Patent: WO2017/182983,2017,A1 .Location in patent: Paragraph 0050-0052

8
[ 77-09-8 ]
[ 342-25-6 ]
polymer; monomer(s): 2,4\-difluorobenzophenone; 3,3-bis(4\-hydroxyphenyl)phthalide [ No CAS ]