[ CAS No. 16859-59-9 ]

Name: 16859-59-9|3-Hydroxyisobenzofuran-1(3H)-one|97%
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Product Details of [ 16859-59-9 ]

CAS No. :	16859-59-9	MDL No. :	MFCD00956142
Formula :	C₈H₆O₃	Boiling Point :	362.6°C at 760 mmHg
Linear Structure Formula :	-	InChI Key :	N/A
M.W :	150.13 g/mol	Pubchem ID :	3804259
Synonyms :

Safety of [ 16859-59-9 ]

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

Application In Synthesis of [ 16859-59-9 ]

Upstream synthesis route of [ 16859-59-9 ]
Downstream synthetic route of [ 16859-59-9 ]

[ 16859-59-9 ] Synthesis Path-Upstream 1~4

1
[ 16859-59-9 ]
[ 143-33-9 ]
[ 20361-09-5 ]

Reference： [1] Journal of Heterocyclic Chemistry, 1987, vol. 24, p. 877

2
[ 16859-59-9 ]
[ 868-85-9 ]
[ 61260-15-9 ]

Yield	Reaction Conditions	Operation in experiment
95%	With sodium methylate In methanol at 0 - 20℃; for 1 h;	Dimethyl phosphite (11 g, 0.1 mol) at 0 ° CAdd dropwise to a solution of sodium methoxide in methanol (100 ml).Then 2-carboxy benzaldehyde (10.5g, 0.05mol)Add to the reaction system,The entire process temperature is controlled below 5 °C.Thereafter, the mixture was heated to room temperature for 1 hour.Methanesulfonic acid (10.6 g, 0.11 mol) was added.The reaction solution was concentrated and washed with water and chloroform.The organic layers were combined and dried over anhydrous NaSO4.Concentrated to:3-oxo-1,3-dihydroxy-isobenzofuran-1-phosphate dimethyl ester (16 g),The yield was 95percent.

Reference： [1] Patent: CN108191770, 2018, A, . Location in patent: Paragraph 0048; 0050-0052

3
[ 16859-59-9 ]
[ 124-41-4 ]
[ 868-85-9 ]
[ 61260-15-9 ]

Yield	Reaction Conditions	Operation in experiment
95%	Stage #1: at 0 - 20℃; for 1 h; Stage #2: With methanesulfonic acid In methanol	Dimethyl phosphite (22.0 g, 0.2 mol) was added drop-wise to a solution of sodium methoxide (43.0 g) in methanol (100 ml) at 0oC. 2- Carboxybenzaldehyde (21.0 g, 0.1 mol) was then added portion-wise to the reaction mixture as a slurry in methanol (40 ml), with the temperature kept below 5oC. The resulting pale yellow solution was warmed to 20oC over 1 hour. Methanesulphonic acid (21.2 g, 0.22 mol) was added to the reaction drop-wise and the resulting white suspension was evaporated in vacuo. The white residue was quenched with water and extracted into chloroform (3 x 100 ml). The combined organic extracts were washed with water (2 x 100 ml), dried over MGSO4, and evaporated in vacuo to yield (3-OXO-1, 3-dihydro-isobenzofuran-1-yl) phosphonic acid dimethyl ester as a white solid (32.0 g, 95 percent, 95 percent purity). This was then used without further purification in the next stage

Reference： [1] Patent: WO2004/80976, 2004, A1, . Location in patent: Page 46

4
[ 16859-59-9 ]
[ 763114-26-7 ]

Reference： [1] Patent: CN108794405, 2018, A,

[ 16859-59-9 ] Synthesis Path-Downstream 1~25

1
[ 4122-57-0 ]
[ 16859-59-9 ]

Yield	Reaction Conditions	Operation in experiment
	With water; toluene-4-sulfonic acid In dimethylsulfoxide-d6; chloroform-d1 at 30℃; half-time life;

Reference： [1]Wulff, Guenter; Wolf, Gabriele [Chemische Berichte, 1986, vol. 119, # 6, p. 1876 - 1889]

2
[ 67-56-1 ]
[ 16859-59-9 ]
[ 4122-57-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	Heating;
	With toluene-4-sulfonic acid In dimethylsulfoxide-d6; chloroform-d1 at 30℃; half-time life;

Reference： [1]Benderradji, Farah; Nechab, Malek; Einhorn, Cathy; Einhorn, Jacques [Synlett, 2006, # 13, p. 2035 - 2038]
[2]Wulff, Guenter; Wolf, Gabriele [Chemische Berichte, 1986, vol. 119, # 6, p. 1876 - 1889]

3
[ 109-65-9 ]
[ 16859-59-9 ]
[ 3413-15-8 ]

Yield	Reaction Conditions	Operation in experiment
87.4%		General procedure: To a suspension of magnesium (6.0 equiv) and catalytic amounts of I2 in anhydrous THF (12 mL) was added the appropriate 1-bromoalkane (5.0 equiv) under argon atmosphere until the Grignard reaction had started. After addition was completed, the reaction mixture was refluxed for 2 h and allowed to cool to room temperature. Subsequently, the prepared Grignard solution was added dropwise to a solution of 4 (300 mg, 1.998 mmol) at -5C. The resulting reaction mixture was stirred at room temperature for 5 h. The mixture was quenched with 3N HCl to pH=2 at 0C and stirred for another 1 h at room temperature. The solution was extracted with ethyl acetate (15 mL×3). The combined organic layers were washed with 10% K2CO3 aqueous solution (10 mL×3) and brine (10 mL×2), dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The resulting residue was purified by column chromatography to give intermediates 5a-d as oils. 3-butylisobenzofuran-1(3H)-one (5a) It was synthesized from 1-bromobutane. Elution with petroleum ether/ethyl acetate (40:1) afforded 5a as brown oils. 87.4% Yield; 1H NMR (400 MHz, CDCl3) delta 7.90 (d, 1H, J = 7.6 Hz, Ar-H), 7.67 (t, 1H, J = 7.6 Hz, Ar-H), 7.53 (t, 1H, J = 7.6 Hz, Ar-H), 7.44 (d, 1H, J = 7.6 Hz, Ar-H), 5.48 (dd, 1H, J1 = 7.6 Hz, J2 = 4.0 Hz, CH), 2.08-2.01 (m, 1H, 1/2 × CH2), 1.80-1.72 (m, 1H, 1/2 × CH2), 1.52-1.33 (m, 4H, 2 × CH2), 0.91 (t, 3H, J = 7.2 Hz, CH3).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 718 - 722
[2]Tetrahedron,1988,vol. 44,p. 2903

4
[ 693-03-8 ]
[ 16859-59-9 ]
[ 3413-15-8 ]

Reference： [1]Tetrahedron Letters,1984,vol. 25,p. 3453 - 3456

5
[ 16859-59-9 ]
[ 3027-13-2 ]
[ 78673-51-5 ]

Reference： [1]Australian Journal of Chemistry,1980,vol. 33,p. 2699 - 2715

6
[ 16859-59-9 ]
[ 143-33-9 ]
[ 18807-71-1 ]
[ 80262-85-7 ]

Reference： [1]Journal of Organic Chemistry,1982,vol. 47,p. 886 - 888

7
[ 16859-59-9 ]
[ 143-33-9 ]
[ 20361-09-5 ]

Reference： [1]Journal of Heterocyclic Chemistry,1987,vol. 24,p. 877

8
[ 99275-30-6 ]
[ 4122-57-0 ]
[ 16859-59-9 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride In methanol; water for 72h; Ambient temperature;

Reference： [1]Sloan; Koch [Journal of Heterocyclic Chemistry, 1985, vol. 22, # 2, p. 429 - 432]

9
[ 99275-29-3 ]
[ 4122-57-0 ]
[ 16859-59-9 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride In methanol; water for 72h; Ambient temperature;

Reference： [1]Sloan; Koch [Journal of Heterocyclic Chemistry, 1985, vol. 22, # 2, p. 429 - 432]

10
[ 99275-28-2 ]
[ 4122-57-0 ]
[ 16859-59-9 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride In methanol; water for 72h; Ambient temperature;

Reference： [1]Sloan; Koch [Journal of Heterocyclic Chemistry, 1985, vol. 22, # 2, p. 429 - 432]

11
[ 186581-53-3 ]
[ 16859-59-9 ]
[ 1077-79-8 ]
[ 164992-12-5 ]

Reference： [1]Synthesis,1995,p. 431 - 434
[2]Synthesis,1995,p. 431 - 434

12
[ 16859-59-9 ]
[ 42858-60-6 ]
3-(4-carboxy-2-hydroxy-6-oxo-1-cyclohexen-1-yl)-3H-isobenzofuran-1-one [ No CAS ]

Reference： [1]Tetrahedron,2007,vol. 63,p. 11781 - 11792

13
[ 16859-59-9 ]
[ 4122-57-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: dmap / dichloromethane / 5 h / -30 °C 2: dichloromethane / 24 h / -30 °C

Reference： [1]Niedek, Dominik; Schuler, Sören M.M.; Eschmann, Christian; Wende, Raffael C.; Seitz, Alexander; Keul, Felix; Schreiner, Peter R. [Synthesis, 2017, vol. 49, # 2, p. 371 - 382]

14
[ 16859-59-9 ]
[ 541-88-8 ]
(±)-3-phthalideyl chloroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With dmap; triethylamine In dichloromethane at 20℃;	Synthesis of 2a-i through Acylation of (±)-3-Hydroxyphthalides; General Procedure A General procedure: 2-Formylbenzoic acid (1a; 1.0 equiv) and DMAP (0.1 equiv) were dis-solved in CH2Cl2 (0.15 M), producing a colorless clear solution. Thedesired carboxylic anhydride (2.0 equiv) and triethylamine (1.0equiv) were subsequently added and the reaction mixture was stirredat r.t. until complete conversion of the starting material was achieved(monitored by TLC). The solvent was removed under reduced pres-sure and the crude products were purified by column chromatogra-phy (n-hexane/EtOAc, 2:1).

Reference： [1]Niedek, Dominik; Schuler, Sören M.M.; Eschmann, Christian; Wende, Raffael C.; Seitz, Alexander; Keul, Felix; Schreiner, Peter R. [Synthesis, 2017, vol. 49, # 2, p. 371 - 382]

15
[ 16859-59-9 ]
[ 623-68-7 ]
3-oxo-1,3-dihydro-1-isobenzofuranyl crotonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With dmap; triethylamine In dichloromethane at 20℃;	Synthesis of 2a-i through Acylation of (±)-3-Hydroxyphthalides; General Procedure A General procedure: 2-Formylbenzoic acid (1a; 1.0 equiv) and DMAP (0.1 equiv) were dis-solved in CH2Cl2 (0.15 M), producing a colorless clear solution. Thedesired carboxylic anhydride (2.0 equiv) and triethylamine (1.0equiv) were subsequently added and the reaction mixture was stirredat r.t. until complete conversion of the starting material was achieved(monitored by TLC). The solvent was removed under reduced pres-sure and the crude products were purified by column chromatogra-phy (n-hexane/EtOAc, 2:1).

Reference： [1]Niedek, Dominik; Schuler, Sören M.M.; Eschmann, Christian; Wende, Raffael C.; Seitz, Alexander; Keul, Felix; Schreiner, Peter R. [Synthesis, 2017, vol. 49, # 2, p. 371 - 382]

16
[ 16859-59-9 ]
[ 13831-30-6 ]
(±)-3-phthalideyl acetoxyacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40%	With dmap; diisopropyl-carbodiimide; In dichloromethane; at 20℃; for 18h;	General procedure: 2-Formylbenzoic acid (1a; 1.0 equiv) and DMAP (0.1 equiv) were dissolved in CH2Cl2 (0.15 M), producing a colorless clear solution. Thedesired carboxylic anhydride was formed in situ by adding carboxylic acid (4.0 equiv) and carbodiimide (2.0 equiv). The reaction mixturewas stirred at r.t. for 18 h, while the corresponding urea was formed as a pale-yellow precipitate. The reaction was monitored by TLC.Upon complete conversion of the starting material, the precipitatedurea was filtered off and the solvent was removed under reduced pressure. The crude products were purified by column chromatogra-phy (n-hexane/EtOAc, 2:1).

Reference： [1]Synthesis,2017,vol. 49,p. 371 - 382

17
[ 16859-59-9 ]
[ 13831-30-6 ]
(S)-3-phthalideyl acetoxyacetate [ No CAS ]
(R)-3-phthalideyl acetoxyacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: Carboxylic acid (4.0 equiv) and DIC (2.0 equiv) were dissolved eitherin n-hexane or chlorobenzene (0.15 M) and cooled to -10 C. Afterstirring for 12 h at -10 C, 2-formylbenzoic acid (1a; 1.0 equiv) and(+)-cinchonine (4a; 0.1 equiv) were added and the mixture wasstirred at -10 C until the starting material was consumed, which wasmonitored by TLC (up to 48 h). The reaction was quenched by addi-tion of an excess of MeOH. The resulting mixture was stirred for 15-30 min at -10 C, then the solvent was removed under reduced pres-sure and the products were purified by column chromatography.

Reference： [1]Synthesis,2017,vol. 49,p. 371 - 382

18
[ 16859-59-9 ]
[ 2450-71-7 ]
[ 132456-42-9 ]

Yield	Reaction Conditions	Operation in experiment
79%	Stage #1: 3-hydroxy-1(3H)-isobenzofuranone With thionyl chloride at 100℃; for 4h; Stage #2: Propargylamine In dichloromethane at 0 - 20℃; for 24h;	Synthesis of (±)-Isoindolinones 12a-d; General Procedure G General procedure: 2-Formylbenzoic acid (1a; 1.0 equiv) was heated at reflux in SOCl2 (5-10 equiv) for 4 h at 100 °C. The remaining SOCl2 was removed in vacu-um and the obtained solid was dissolved in CH2Cl2 (10 mL). The mix-ture was cooled to 0 °C and the desired primary amine (2.0 equiv)was slowly added. The solution was stirred for 24 h at r.t. then thereaction mixture was diluted with EtOAc (70 mL), washed with citricacid (0.5 M), sat. aq Na2CO3 solution, and brine. The organic layer wasdried over MgSO4 and the solvent was removed under reduced pres-sure. The obtained products were used without further purification.

Reference： [1]Niedek, Dominik; Schuler, Sören M.M.; Eschmann, Christian; Wende, Raffael C.; Seitz, Alexander; Keul, Felix; Schreiner, Peter R. [Synthesis, 2017, vol. 49, # 2, p. 371 - 382]

19
[ 16859-59-9 ]
[ 108-24-7 ]
[ 30645-26-2 ]

Yield	Reaction Conditions	Operation in experiment
87%	With dmap; triethylamine In dichloromethane at 20℃;	Synthesis of 2a-i through Acylation of (±)-3-Hydroxyphthalides; General Procedure A General procedure: 2-Formylbenzoic acid (1a; 1.0 equiv) and DMAP (0.1 equiv) were dis-solved in CH2Cl2 (0.15 M), producing a colorless clear solution. Thedesired carboxylic anhydride (2.0 equiv) and triethylamine (1.0equiv) were subsequently added and the reaction mixture was stirredat r.t. until complete conversion of the starting material was achieved(monitored by TLC). The solvent was removed under reduced pres-sure and the crude products were purified by column chromatogra-phy (n-hexane/EtOAc, 2:1).

Reference： [1]Niedek, Dominik; Schuler, Sören M.M.; Eschmann, Christian; Wende, Raffael C.; Seitz, Alexander; Keul, Felix; Schreiner, Peter R. [Synthesis, 2017, vol. 49, # 2, p. 371 - 382]

20
[ 106-31-0 ]
[ 16859-59-9 ]
[ 108761-29-1 ]

Yield	Reaction Conditions	Operation in experiment
83%	With dmap; triethylamine In dichloromethane at 20℃;	Synthesis of 2a-i through Acylation of (±)-3-Hydroxyphthalides; General Procedure A General procedure: 2-Formylbenzoic acid (1a; 1.0 equiv) and DMAP (0.1 equiv) were dis-solved in CH2Cl2 (0.15 M), producing a colorless clear solution. Thedesired carboxylic anhydride (2.0 equiv) and triethylamine (1.0equiv) were subsequently added and the reaction mixture was stirredat r.t. until complete conversion of the starting material was achieved(monitored by TLC). The solvent was removed under reduced pres-sure and the crude products were purified by column chromatogra-phy (n-hexane/EtOAc, 2:1).

Reference： [1]Niedek, Dominik; Schuler, Sören M.M.; Eschmann, Christian; Wende, Raffael C.; Seitz, Alexander; Keul, Felix; Schreiner, Peter R. [Synthesis, 2017, vol. 49, # 2, p. 371 - 382]

21
[ 16859-59-9 ]
[ 97-72-3 ]
(±)-3-phthalideyl 2-methylpropionate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With dmap; triethylamine In dichloromethane at 20℃;	Synthesis of 2a-i through Acylation of (±)-3-Hydroxyphthalides; General Procedure A General procedure: 2-Formylbenzoic acid (1a; 1.0 equiv) and DMAP (0.1 equiv) were dis-solved in CH2Cl2 (0.15 M), producing a colorless clear solution. Thedesired carboxylic anhydride (2.0 equiv) and triethylamine (1.0equiv) were subsequently added and the reaction mixture was stirredat r.t. until complete conversion of the starting material was achieved(monitored by TLC). The solvent was removed under reduced pres-sure and the crude products were purified by column chromatogra-phy (n-hexane/EtOAc, 2:1).

Reference： [1]Niedek, Dominik; Schuler, Sören M.M.; Eschmann, Christian; Wende, Raffael C.; Seitz, Alexander; Keul, Felix; Schreiner, Peter R. [Synthesis, 2017, vol. 49, # 2, p. 371 - 382]

22
[ 6940-49-4 ]
[ 16859-59-9 ]

Yield	Reaction Conditions	Operation in experiment
99.2%	With lithium hydroxide monohydrate at 100℃; for 3h;	1 Example 1: Preparation of 3-hydroxyisobenzofuran-1(3H)-one (compound 2) Add 3-bromophthalide (30g, 0.14mol) into the round bottom flask,Using water (100 mL) as solvent, the reaction was refluxed at 100°C for 3 hours. TLC monitored the completion of the reaction. The reaction liquid was cooled in an ice bath to precipitate a solid, filtered with suction, washed with water, and dried to obtain 20.97 g of a white solid (compound 2) with a yield of 99.2%.
86%	With lithium hydroxide monohydrate; potassium hydroxide for 2h; Reflux;
83.4%	With lithium hydroxide monohydrate Reflux;	3-hydroxyisobenzofuran-1(3H)-one (4) 3-bromoisobenzofuran-1(3H)-one (3.7 g, 17.368 mmol) was heated to reflux in water (35 mL) for 2 h, then the mixture was cooled to room temperature for overnight. The white solid formed was collected by filtration, washed with water, and dried to afford intermediate 4, 83.4% yield; mp: 97-98°C. (lit.3 97-98°C).

	With lithium hydroxide monohydrate for 1h; Reflux;
	With lithium hydroxide monohydrate at 100℃; for 2h;

Reference： [1]Current Patent Assignee: CHINA PHARMACEUTICAL UNIVERSITY - CN113264884, 2021, A Location in patent: Paragraph 0034-0037
[2]Ortega, María J.; Parra-Torrejón, Belén; Cano-Cano, Fátima; Gómez-Jaramillo, Laura; González-Montelongo, M. Carmen; Zubía, Eva [Pharmaceuticals, 2022, vol. 15, # 5]
[3]Qiang, Xiaoming; Li, Yan; Yang, Xia; Luo, Li; Xu, Rui; Zheng, Yunxiaozhu; Cao, Zhongcheng; Tan, Zhenghuai; Deng, Yong [Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 4, p. 718 - 722]
[4]Zhou, Muxing; Gridneva, Tatiana; Zhang, Zhenfeng; He, Ende; Liu, Yangang; Zhang, Wanbin [Angewandte Chemie - International Edition, 2021, vol. 60, # 3, p. 1641 - 1645][Angew. Chem., 2021, vol. 133, # 3, p. 1665 - 1669,5]
[5]Chen, Li; Lei, Zhichao; Sun, Jianbo; Sun, Xiaona; Wang, Yujin; Yue, Shasha [European Journal of Medicinal Chemistry, 2022, vol. 234]

23
[ 16859-59-9 ]
[ 868-85-9 ]
[ 61260-15-9 ]

Yield	Reaction Conditions	Operation in experiment
95%	With sodium methoxide In methanol at 0 - 20℃; for 1h;	1 Dimethyl phosphite (11 g, 0.1 mol) at 0 ° CAdd dropwise to a solution of sodium methoxide in methanol (100 ml).Then 2-carboxy benzaldehyde (10.5g, 0.05mol)Add to the reaction system,The entire process temperature is controlled below 5 °C.Thereafter, the mixture was heated to room temperature for 1 hour.Methanesulfonic acid (10.6 g, 0.11 mol) was added.The reaction solution was concentrated and washed with water and chloroform.The organic layers were combined and dried over anhydrous NaSO4.Concentrated to:3-oxo-1,3-dihydroxy-isobenzofuran-1-phosphate dimethyl ester (16 g),The yield was 95%.
93%	With methanesulfonic acid; triethylamine In dichloromethane for 0.5h;	1 Example 1 Combine 20 g (133 mmol) o-carboxybenzaldehyde, 17.5 g (173 mmol) of triethylamine and 200 mL of dichloromethane were added to a three-necked flask and mixed and stirred, then 19.1 g (173 mmol) of dimethyl phosphite were added, and the reaction was stirred at room temperature for 4 h. TLC monitored the reaction to complete. 17.9 g (186 mmol) of methanesulfonic acid was added dropwise, stirred for 30 min, TLC monitored that the reaction was complete, the reaction solution was concentrated to dryness, water was added to make a slurry for 2 hours, and then filtered to dryness. Then be beaten with petroleum ether to obtain 30 g of a white solid with a yield of 93%, which is (3-oxo-1,3-dihydroisobenzofuran-1-yl) dimethyl phosphate
89.3%	Stage #1: Dimethyl phosphite With sodium methoxide In methanol at 0℃; for 0.166667h; Stage #2: 1,3-dihydro-3-oxo-1-isobenzofuranol In methanol at 0 - 25℃; for 1h;

85%	In dichloromethane at 100℃; for 0.416667h;	1.1 Example 1 (1) 3-hydroxyisobenzofuran-1(3H)-one (0.033 mol) in dichloromethane (50 mL) in a microchannel reaction apparatusAnd a solution of dimethyl phosphite (0.091 mol) in dichloromethane (50 mL) was pumped from the pump A1 pump B2 into the first mixing valve 3, the flow rate of the pump A1 was 0.18 mL/min, and the flow rate of the pump B2 was 0.026 mL/ Min. After thorough mixing, the first microreactor 4 was introduced. The volume of the first microreactor 4 was 40 mL, and the reaction residence time was 25 min. The reaction temperature is 100 ° C,The reaction liquid is collected in the first separation device 5,The first separating device 5 is a container for water and dichloromethane.Simple extraction and liquid separation(3-oxo-1,3-dihydroisobenzofuran-1-yl) dimethyl phosphateThe effluent of (Compound 1) had a yield of 85%.
84%	Stage #1: 1,3-dihydro-3-oxo-1-isobenzofuranol; Dimethyl phosphite With sodium methoxide In methanol at 0 - 20℃; for 1h; Stage #2: With methanesulfonic acid In methanol for 0.5h;	1 Example 1: Synthesis of Intermediate One Add 11.0 g of dimethyl phosphite, 6.5 g of sodium methoxide, and 100 mL of methanol into a 250 mL three-necked flask, and cool to 0-5 degrees Celsius in an ice bath. Add 7.5 g of SM1 in batches, and control the internal temperature to not exceed 10 degrees Celsius. After reacting for 1 hour at room temperature, 12.5 g of methanesulfonic acid was added dropwise. After dropping, stirring was continued for 0.5 hours. The methanol was distilled off under reduced pressure. 150 mL of water was added and extracted twice with 100 mL of dichloromethane. The organic layers were combined and used Drying with anhydrous magnesium sulfate for 0.5 hours and filtering, the filtrate was distilled under reduced pressure to obtain 10.2 g of white solid, with a yield of 84%. The liquid chromatogram is shown in Figure 1. The area normalization method is used to analyze the main peak purity of 99.03%.
	Stage #1: Dimethyl phosphite With sodium tert-pentylate In 2-methyltetrahydrofuran at 30℃; for 0.25h; Stage #2: 1,3-dihydro-3-oxo-1-isobenzofuranol In 2-methyltetrahydrofuran	1.1; 2.1 Step 1: Synthesis of (R/Z)-3-(3-chloro-4-fluorobenzylidene)isobenzofuran-1(3H)-one (compound formula Ia) Under mechanical stirring, add dimethyl phosphite 16.5kg (1.5eq, 150mol), sodium tert-amylate 16.5kg (1.5eq, 150mol) and methyltetrahydrofuran 150L to the there-necked flask, and react at 30°C for 15min; 15.0 kg (1.0 eq, 100 mol) of o-carboxybenzaldehyde was added, and after the reaction was completed, the mixture was washed with 75 L of water and 75 L of 20% potassium bicarbonate solution in turn. Separation, adding 15.8kg (1.0eq, 100mol) of 3-chloro-4-fluorobenzaldehyde to the organic phase, then adding 12.1kg (1.2eq, 120mol) of triethylamine dropwise, stirring at 50°C for 6h, filtering, and drying at 50°C 25.6kg of white solid was obtained, That is, compound formula Ia (there are two cis-trans isomers in a ratio of about 2:5), the yield is 93.23%, and the purity is 99.85%.

Reference： [1]Current Patent Assignee: SICHUAN UNIVERSITY - CN108191770, 2018, A Location in patent: Paragraph 0048; 0050-0052
[2]Current Patent Assignee: NANJING HUAGUAN BIOTECHNOLOGY - CN112624981, 2021, A Location in patent: Paragraph 0005; 0012
[3]Chang, Xinyue; Huang, Wenhai; Liang, Meihao; Ma, Zhen; Shen, Zhengrong; Wang, Zunyuan; Zeng, Shenxin; Zhang, Chixiao; Zhang, Zhimin [Journal of Enzyme Inhibition and Medicinal Chemistry, 2020, vol. 35, # 1, p. 1606 - 1615]
[4]Current Patent Assignee: NANJING TECH UNIVERSITY - CN108794405, 2018, A Location in patent: Paragraph 0036; 0037; 0042; 0046; 0050; 0053; 0056; 0061
[5]Current Patent Assignee: NANJING YEWIN PHARMACENTICAL - CN112979557, 2021, A Location in patent: Paragraph 0016
[6]Current Patent Assignee: JIANGXI QINGFENG PHARMACEUTICAL CO LTD - CN114276301, 2022, A Location in patent: Paragraph 0085-0090; 0097-0099

24
[ 16859-59-9 ]
[ 763114-25-6 ]

Reference： [1]Patent: CN108794405,2018,A

25
[ 16859-59-9 ]
[ 138555-58-5 ]
(S)-3-oxo-1,3-dihydroisobenzofuran-1-yl 3-(2-bromophenyl)propanoate [ No CAS ]
3-oxo-1,3-dihydroisobenzofuran-1-yl 3-(2-bromophenyl)propanoate [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2020,vol. 59,p. 3859 - 3863
Angew. Chem.,2020,vol. 132,p. 3887 - 3891,5

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6-Methylisobenzofuran-1(3H)-one

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[ 23405-32-5 ]

Methyl 1-oxo-1,3-dihydroisobenzofuran-5-carboxylate

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[ 54120-64-8 ]

5-Methylisobenzofuran-1(3H)-one

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Ethyl 4-methylbenzoate

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tert-Butyl 4-(hydroxymethyl)benzoate

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2,3-Dihydroxypropyl benzoate

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Bis(2-hydroxyethyl) phthalate

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5-Hydroxyisobenzofuran-1,3-dione

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Related Parent Nucleus of
[ 16859-59-9 ]

Benzofurans

[ 87-41-2 ]

Isobenzofuran-1(3H)-one

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6-Methylisobenzofuran-1(3H)-one

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Ghs Precautionary Statements

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
{[ item.p_purity ]}	{[ item.pr_size ]}	{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]}	{[ getRatePrice(item.pr_usd, 1,1) ]}	{[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]}	{[ item.pr_usastock ]}	Inquiry -	{[ item.pr_chinastock ]}	Inquiry -

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 16859-59-9 ]

Quality Control of [ 16859-59-9 ]

Related Doc. of [ 16859-59-9 ]

Product Details of [ 16859-59-9 ]

Safety of [ 16859-59-9 ]

Application In Synthesis of [ 16859-59-9 ]

[ 16859-59-9 ] Synthesis Path-Upstream 1~4

[ 16859-59-9 ] Synthesis Path-Downstream 1~25

Related Functional Groups of [ 16859-59-9 ]

Esters

Alcohols

Related Parent Nucleus of [ 16859-59-9 ]

Benzofurans

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 16859-59-9 ]

Related Parent Nucleus of
[ 16859-59-9 ]