Category: indolines-derivatives

These common heterocyclic compound, 3339-73-9, name is 3-(1,3-Dioxoisoindolin-2-yl)propanoic acid, its traditional synthetic route has been very mature, but the traditional synthetic route has various shortcomings, such as complicated route, low yield, poor purity, etc, below Introduce a new synthetic route. Safety of 3-(1,3-Dioxoisoindolin-2-yl)propanoic acid

Step-1: 3-(1,3-dioxoisoindolin-2-yl)-N’-(2-methoxyacetyl)propanehydrazide Oxalyl chloride (27.47 g, 0.216 mol) was added slowly to an ice-cooled solution of 3-(1,3-dioxoisoindolin-2-yl)propanoic acid (15.80 g, 0.072 mol) in DCM (250 mL) followed by catalytic DMF (0.5 mL). The reaction mixture was stirred at room temperature for 1 h and volatiles were removed completely under vacuum to obtain the intermediate acid chloride as a yellow solid. A solution of 2-methoxyacetohydrazide (2, 9.01 g, 0.086 mol) in DCM (50 mL) was added to a solution of this acid chloride in DCM (200 mL) at 0 C. followed by triethylamine (60.5 g, 0.597 mol). The resultant reaction mixture was stirred at room temperature for 1 h. The resulting yellow suspension was quenched onto crushed ice (200 mL). Separated organic layer was washed with water (2×200 mL), brine (150 mL) and concentrated under vacuum to afford crude product (5 g). The aqueous layer which also contains desired product was concentrated under reduced pressure to afford a solid residue. The crude residue was dried and extracted sequentially with THF (1000 mL), acetone (300 mL) and acetonitrile (400 mL). The combined organic layer was concentrated to obtain yellow semisolid (37 g) which was combined with solid residue (5 g) from organic layer and was used in the next reaction without purification. LC-MS [M+H]+ 306.1 m/z.

The synthetic route of 3-(1,3-Dioxoisoindolin-2-yl)propanoic acid has been constantly updated, and we look forward to future research findings.

Reference:
Patent; PROTEOSTASIS TEHRAPEUTICS, INC.; Bastos, Cecilia M.; Munoz, Benito; Tait, Bradley; (48 pag.)US2017/1993; (2017); A1;,
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Researchers who often do experiments know that organic synthesis is a process of preparing more complex target molecules from simple raw materials through one or more chemical reactions. Generally, it requires fewer steps, and cheap raw materials. 552330-86-6, name is 5-Bromoisoindolin-1-one, A new synthetic method of this compound is introduced below., Recommanded Product: 552330-86-6

5-Bromoisoindolin-1-one (10 g, 47.16 mmol) and sodium ethanethiolate (9.92 g, 117.90mmol) were mixed together in DMF (100 mL) and the reaction heated to 100 C for 20mm. The reaction was cooled to rt, poured into water (100 mL) and the product extractedwith EtOAc (3 x 200 mL). The combined organic extracts were washed with brine (4 x 50mL). LCMS indicated product in the aqueous washings, and consequently they werecombined and extracted with EtOAc (4 x 50 mL). The organic extracts were combined, dried using a phase separator cartridge and concentrated in vacuo. The solid obtained was dried under high vacuum overnight. 5-(Ethylthio)isoindolin-1-one (8.68 g, 95%) was obtained as a yellow solid. The material was used in the next step without furtherpurification.LC/MS: m/zrr 194 [M+H]. ?H NMR (500 MHz, DMSO-d6) i5 1.27 (t, 3H), 3.06 (q, 2H), 4.33 (s, 2H), 7.36 (dd, 1H), 7.47 – 7.48 (m, 1H), 7.57 (d, 1H), 8.45 (s, 1H).

The basis of chemical reaction formula synthesis, the synthesis route is composed of some specific reactions and combined according to certain logical thinking. We look forward to the emergence of more reaction modes in the future.

Reference:
Patent; ASTRAZENECA AB; LEVER, Sarah; NARJES, Frank; OLSSON, Roine, Ingemar; VON BERG, Stefan; (124 pag.)WO2018/229155; (2018); A1;,
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Reference of 5181-35-1, In the chemical reaction process, reaction time, type of solvent, can easily affect the result of the reaction, thereby determining the yield and properties of the reaction product. An updated downstream synthesis route of 5181-35-1 as follows.

To a solution of 2-(2-bromoethoxy)isoindoline- l,3-dione (20 g, 7.4 mmol prepared according to the procedure described in step 1 of preparation 10) and 5-methyl- lH-tetrazole (6.22 g, 7.4 mmol) in dimethylformamide (100 ml) was added cesium carbonate (24.13 g, 7.4 mmol) in a lot wise under stirring at 25-30 C. After 16 hours, completion of the reaction was confirmed by performing the thin layer chromatography using mixture of chloroform and methanol as solvent. The resulted reaction mixture was filtered and the filtrate was slowly poured into chilled water (700 ml) under stirring. After 30 minutes of stirring, the reaction mixture was extracted with ethyl acetate (200 ml and 100 ml). The combined organic layer was washed with brine (100 ml). The organic layer was dried on sodium sulfate and concentrated on rota vapour to provide 18 g of the crude product. The two regio isomers were separated by using column chromatography using mixture of acetone and hexane as an eluent. The upper spot isolated at 15-25% concentration of acetone in hexane yielded 7.0 g of non-polar isomer 2-[2-(5-methyl-2H-tetrazol-2-yl)ethoxy]-lH-isoindole-l,3(2H)-dione. The lower spot isolated at 25-40% concentration of acetone in hexane yielded 3.8 g of polar isomer 2-[2-(5-methyl-lH-tetrazol-l-yl)ethoxy]-lH-isoindole-l,3(2H)-dione. (10.8 g, 53 % yield). Analysis: Mass: 274.2 (M+l); for Molecular weight: 273 and Molecular formula: C12H11N5O3.

According to the analysis of related databases, 5181-35-1, the application of this compound in the production field has become more and more popular.

Reference:
Patent; WOCKHARDT LIMITED; TADIPARTHI, Ravikumar; PATIL, Vijaykumar Jagdishwar; DEKHANE, Deepak; SHAIKH, Mohammad Usman; BIRAJDAR, Satish; DOND, Bharat; PATEL, Mahesh Vithalbhai; (100 pag.)WO2017/81615; (2017); A1;,
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897957-06-1, name is 6-Bromo-1-methylindolin-2-one, belongs to indolines-derivatives compound, is considered to be a conventional heterocyclic compound, which is widely used in drug synthesis. The chemical synthesis route is as follows. Computed Properties of C9H8BrNO

Step 3: Synthesis of Intermediate R7 [0295] To I-4.2 (32.0 g, 142 mmol) in anhydrous dioxane (400 mL) is added R3 (54.4 g, 241 mmol) and potassium acetate (41.6 g, 424 mmol). The mixture is purged with Argon, [1,1?-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) as a comple× with dichloromethane (11.2 g, 14 mmol) is added and the mixture is heated to 90 C. for 2 h. The reaction mixture is diluted with ethyl acetate and water, the organic layer is washed with water, dried over MgSO4 and concentrated. The residue is purified via flash chromatography (cyclohexane/EA=70:30). Yield 72%, m/z 274 [M+H]+, rt 0.67 min, LC-MS Method V011_S01

The synthetic route of 897957-06-1 has been constantly updated, and we look forward to future research findings.

Reference:
Patent; BOEHRINGER INGELHEIM INTERNATIONAL GMBH; ANDERSKEWITZ, Ralf; GRUNDL, Marc; MORSCHHAEUSER, Gerd; OOST, Thorsten; PAUTSCH, Alexander; US2014/275114; (2014); A1;,
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Electric Literature of 1504-06-9,Some common heterocyclic compound, 1504-06-9, name is 3-Methyloxindole, molecular formula is C9H9NO, traditional synthetic route has been very mature, but the traditional synthetic route has various shortcomings, such as complicated route, low yield, poor purity, etc, below Introduce a new synthetic route.

Step 2: Preparation of 3-methyl-3-(pyrimidin-5-ylmethyl)-l,3-dihydro-2H-indol-2-onePyrimidin-5-ylmethanol (510 mg, 4.63 mmol) in tetrahydrofuran (8 mL) at room temperature was treated with sodium hydride (185 mg, 4.63 mmol) and stirred for 5 minutes, p-Toluenesulfonyl chloride (883 mg, 4.63 mmol) was added, and the resulting mixture stirred for one hour to form pyrimidin-5-ylmethyl 4-methylbenzenesulfonate. In a separate flask 3- methyloxindole (682 mg, 4.63 mmol) and JV,iV-dimethylethylenediamine (1.538 mL, 10.19 mmol) in tetrahydrofuran (16 mL) were cooled to -78 0C and treated dropwise with n-butyllithium (2.5M in hexanes, 4.08 mL, 10.2 mmol). The mixture was allowed to warm to 0 0C and stirred for 15 minutes. The mixture was recooled to -78 C. To this mixture was added the tetrahydrofuran solution of pyrimidin-5-ylmethyl 4-methylbenzenesulfonate via cannula; the resulting reaction mixture was allowed to warm to room temperature and was stirred for 18 hours. Water (50 mL) was added, and the mixture extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel Biotage 25S, eluting with 0-100% ethyl acetate/hexane to afford 3-methyl-3-(pyrimidin-5-ylmethyl)-l,3-dihydro-2H- indol-2-one as a white solid.1H NMR (CDCl3): delta 8.97 (s, 1 H), 8.29 (s, 2 H), 7.88 (br s, 1 H), 7.25 (d, 1 H, J = 7.3 Hz), 7.20 (m, 1 H), 7.1 1 (m, 1 H), 6.74 (d, 1 H, J = 7.8 Hz), 3.20 (d, 1 H, J – 13.5 Hz), 3.0 (d, 1 H, J – 13.5 Hz), 1.57 (s, 3H) MS: m/e 240.19 (M + H)+

These compound has a wide range of applications. It is believed that with the continuous development of the source of the synthetic route 3-Methyloxindole, its application will become more common.

Reference:
Patent; MERCK & CO., INC.; WO2009/45386; (2009); A1;,
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Researchers who often do experiments know that organic synthesis is a process of preparing more complex target molecules from simple raw materials through one or more chemical reactions. Generally, it requires fewer steps, and cheap raw materials. 769965-95-9, name is 5′-Fluorospiro[cyclopropane-1,3′-indolin]-2′-one, A new synthetic method of this compound is introduced below., SDS of cas: 769965-95-9

Example 2.5Trans-2-chloro-N-{-4-((5′-fluoro-2′-oxospiro[cyclopropane-1 ,3′-indoline]-1 yl)methyl)cyctohexyl}-5-(trifluoromethyl)benzamide 5′-Fluorospiro[cyclopropane-1 ,3′-indolin]-2′-one (Intermediate H) {67 mg, 0.378 mmol) in dry D F (3 ml) was treated with NaH {60% in mineral oil) (15.12 mg, 0.378 mmol) under N2 and the contents left stirring for ~10 mins. After this time, trans- methanesulfonic acid 4-{2-chloro-5-trifluoromethyl-benzoylamino)-cyclohexyl methyl ester (Intermediate C) (105 mg, 0.253 mmol) was added and the solution heated to 70C for 2.5 h. After cooling to RT overnight, the mixture was diluted with EtOAc/H20 (40 ml) and transferred to a separating funnel. The organic layer was separated and washed with brine, dried (MgS04), and concentrated in vacuo to give a light brown oil. The crude oil was chromatographed on silica eluting with a gradient of 0%-30% EtOAc/iso-hexane follwed by an isocratic gradient of 30% EtOAc/iso-hexane to afford the title compound as a white solid; LC-MS Rt= 1.36 mins; [M+H]+ 495.3; Method = 2minl_C_30_v002. 1H NMR (400 MHz, CDCI3). delta 7.90 (1H, s), 7.55 (1 H, d), 7.50 (1H, d), 6.95 (1H, m), 6.80 (1 H, m), 6.60 (1H, m), 5.95 (1 H, d), 4.0 (1H, m), 3.65 (2H, d), 2.20 (2H, m), 1.85 (5H, m), 1.55 (2H, m), 1.25 (4H, m).

The basis of chemical reaction formula synthesis, the synthesis route is composed of some specific reactions and combined according to certain logical thinking. We look forward to the emergence of more reaction modes in the future.

Reference:
Patent; ATKINSON Benjamin; BEATTIE David; CULSHAW Andrew James; DEVEREUX Nicholas James; MCKENNA Jeffrey; DALE James; WO2011/92293; (2011); A1;,
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Reference of 3484-35-3,Some common heterocyclic compound, 3484-35-3, name is 5-Methylindolin-2-one, molecular formula is C9H9NO, traditional synthetic route has been very mature, but the traditional synthetic route has various shortcomings, such as complicated route, low yield, poor purity, etc, below Introduce a new synthetic route.

General procedure: To a one-neck round-bottom flask equipped with magnetic stirringwas added 6-chloro-2-indolinone (2a, 1.00 g, 6.0 mmol),vinamidinium salt 324 (2.02 g, 12.0 mmol), Et3N (1.82 g, 18.0mmol), and DMF (10 mL). The mixture was stirred for 20 h atr.t., after the reaction was complete (monitored by TLC,EtOAc/MeOH = 20:1), 30 mL EtOAc and 30 mL water was added,then the aqueous layer was extracted with 30 mL EtOAc. Thecombined EtOAc layer was washed with sat. NaCl solution (15mL) and water (15 mL) then dried over Na2SO4. After filteringthe desiccant, the solvent was concentrated under vacuum to avolume of about 5 mL. The mixture was titrated with 15 mL nhexaneto give a yellow precipitant, the solid was filtered, anddried under vacuum to give 4a (1.34 g, yield 88%), a yellowpowder, which was used in the next step without further purification;mp > 250 C.

The synthetic route of 3484-35-3 has been constantly updated, and we look forward to future research findings.

Reference:
Article; Tian, Shaixiao; Mao, Yu; Jiang, Yongjun; Xu, Guangyu; Synlett; vol. 29; 7; (2018); p. 949 – 953;,
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Researchers who often do experiments know that organic synthesis is a process of preparing more complex target molecules from simple raw materials through one or more chemical reactions. Generally, it requires fewer steps, and cheap raw materials. 5394-18-3, name is 2-(4-Bromobutyl)isoindoline-1,3-dione, A new synthetic method of this compound is introduced below., Computed Properties of C12H12BrNO2

a) A solution of imidazole (13.6 g) in dry DMF (50 ml) was added dropwise to a stirred suspension of sodium hydride (8.0 g, 60% dispersion in oil) in dry DMF (250 ml) at ambient temperature under nitrogen for 2.5 hours. A slurry of N-(4-bromobutyl)phthalimide (53.6 g) in dry DMF (80 ml) was added and the mixture heated at 95 C. for 16 hours. The solvent was evaporated off under vacuum and the residue was extracted with hot toluene. The combined toluene extracts were evaporated to dryness and the residue triturated with ether and dried to give N-[4-(imidazol-1-yl)butyl]phthalimide, m.p. 76-79 C.

The basis of chemical reaction formula synthesis, the synthesis route is composed of some specific reactions and combined according to certain logical thinking. We look forward to the emergence of more reaction modes in the future.

Reference:
Patent; The Boots Company PLC; US5547972; (1996); A;,
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Adding a certain compound to certain chemical reactions, such as: 89-40-7, name is 5-Nitroisoindoline-1,3-dione, belongs to indolines-derivatives compound, can increase the reaction rate and produce products with better performance than those obtained under traditional synthetic methods. Here is a downstream synthesis route of the compound 89-40-7, COA of Formula: C8H4N2O4

4-Nitrophthalimide (LOOGR) was taken into a hydrogenation kettle and dissolved using 700ML of dimethylformamide. 5% PALLADIUM/CARBON (LOGR, 50% wet) was added to the solution and hydrogenated initially at 20-30C under 20-40psi. After the exothermic nature of the reaction was over, hydrogen pressure was increased to 40-60psi and the temperature to 40-50C. After the hydrogenation was over the reaction mixture was filtered while hot and the catalyst removed by filtration. Dimethylformamide was removed from the filtrate under reduced pressure at 60-80C. Water (500ML) was added to the residue and the mixture stirred for 30MIN. The product was isolated by filtration and dried at 60-70C to get 80gr (95%) of yellow crystalline solid of 4- aminophthalimide. Melting point: 294-5C.

At the same time, in my other blogs, there are other synthetic methods of this type of compound, 5-Nitroisoindoline-1,3-dione, and friends who are interested can also refer to it.

Reference:
Patent; NATCO PHARMA LIMITED; VENKAIAH CHOWDARY, Nannapaneni; WO2004/43919; (2004); A1;,
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In the chemical reaction process, reaction time, type of solvent, can easily affect the result of the reaction, thereby determining the yield and properties of the reaction product. An updated downstream synthesis route of 60434-13-1 as follows. HPLC of Formula: C9H6ClNO2

General procedure: To a stirred solution of isatin 6 (20 mmol) in dry DMF (30 mL), K2CO3 (30 mmol) wasadded and stirred for 10 min. 7 (24 mmol) was added dropwise to the reaction mixture. Thereaction mixture was then stirred at room temperature overnight. Ice water was added and theprecipitate produced which was collected by filtration. Orange solid 8 was obtained afterdried by vacuum. Solid 8 was then dissolved in NH2NH2H2O (20 mL) and the reaction mixture washeated to 130 oC. After 3 h, the reaction was cooled and diluted with EtOAc. The aqueouslayer was extracted with EtOAc. The combined organic layer was washed with saturatedaqueous NaHCO3, brine, dried over anhydrous Na2SO4 and concentrated under reducedpressure. The residue 9 was used directly without purified. To a suspension of NaH in THF, N-substitued oxoindole 9 was added by portion in 0 oC.after stirred for 10 minutes, correspond isocyanate was added by potions. The mixture wascontinue stirred overnight. It was quenched by 1M HCl to adjust the PH to 2~5 and thendiluted with EtOAc. The water layer was extracted with EtOAc. The combined organic layerwas washed with water, brine, dried over anhydrous Na2SO4 and concentrated under reducedpressure. The residue was purified by column chromatography on silica gel. (PE/EA = 5/1) togive compound 1a-1r as a white solid.

According to the analysis of related databases, 60434-13-1, the application of this compound in the production field has become more and more popular.

Reference:
Article; Chen, Hui; Liu, Hui; Zhao, Si-Han; Cheng, Shao-Bing; Xu, Xiao-Ying; Yuan, Wei-Cheng; Zhang, Xiao-Mei; Synlett; vol. 30; 9; (2019); p. 1067 – 1072;,
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