Month: June 2021

Some common heterocyclic compound, 651734-54-2, name is 2,6-Difluoro-3,5-dimethoxyaniline, molecular formula is C8H9F2NO2, 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. HPLC of Formula: C8H9F2NO2

Example 1233-{ 13-(2,6-difluoro-3,5-dimethoxyphenyl)-2,8-dioxo-2,3,4,7,8,9-hexahydro-1H- pyrrolo j3?,2?:5,6j pyrido 14,3-d jpyrimidin-1-ylj methyl}benzonitrile Step 1: N-[(4-chloro-1-{[2-(trimethylsilyl)ethoxyJmethyl}-JH-pyrrolo[2, 3-bJpyridin-5- yl)methylJ-2, 6-dijluoro-3 , 5-dimethoxyaniline To a solution of sodium triacetoxyborohydride (6.2 g, 29 mmol) in trifluoroacetic acid (10.0 mL, 1.30E2 mmol) at 0 C was added a solution of 2,6-difluoro-3,5-dimethoxyaniline (1.52 g, 8.03 mmol) in methylene chloride (10 mL), followed by a solution of 4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl} -1 H-pyrrolo[2,3 -b]pyridine-5 -carbaldehyde (Example 106, Step 1: 2.27 g, 7.30 mmol) in methylene chloride (40 mL, 700 mmol). The reaction mixture was stirred at 0 C for 1 h then poured into a cold aqueous solution of NaHCO3 and then extracted with methylene chloride. The organic phase was washed with brine then dried over Na2SO4 and concentrated. The residue was purified by flash chromatography eluted with 0 to40 % EtOAc in DCM to give the desired product as a yellow oil which solidified on standing (3.32 g, 94 %). LC-MS calculated for C22H29C1F2N3O3Si (M+H) mlz: 484.2; found: 484.1.

These compound has a wide range of applications. It is believed that with the continuous development of the source of the synthetic route 651734-54-2, its application will become more common.

Reference:
Patent; INCYTE CORPORATION; WU, Liangxing; ZHANG, Colin; HE, Chunhong; SUN, Yaping; LU, Liang; QIAN, Ding-Quan; XU, Meizhong; ZHUO, Jincong; YAO, Wenqing; WO2014/7951; (2014); A2;,
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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. 41365-75-7, name is 1-Amino-3,3-diethoxypropane, A new synthetic method of this compound is introduced below., COA of Formula: C7H17NO2

/V./V-Diisopropylethylamine (3.397 mL, 19.5 mmol) followed by 3,3-diethoxypropan-l- amine (3.154 mL, 19.5 mmol) were added to a solution of 4-chloro-l-fluoro-2- nitrobenzene (1.765 mL, 15 mmol), in iPrOH (35 mL) and heated at 80 C for 4.5 h. After cooling to rt, the reaction mixture was diluted with EtOAc (100 mL), washed successively with LLO (acidified to -pH 6 with 0.01 M aqueous HC1, 4x) and brine (1 x, 100 mL each), dried (MgS04) and the solvent removed under reduced pressure to afford the crude product as an orange solid (4.308 g, 97%). ‘H NMR (400 MHz, CDCls): d 8.29 (br s, 1H), 8.17 (d, J = 2.6 Hz, 1H), 7.37 (ddd, J = 9.2, 2.6, 0.6 Hz, 1H), 6.83 (d, J = 9.2 Hz, 1H), 4.65 (t, J = 5.0 Hz, 1H), 3.76-3.65 (m, 2H), 3.59-3.49 (m, 2H), 3.44-3.37 (m, 2H), 2.07-2.01 (m, 2H), 1.24 (t, J = 7.0 Hz, 6H). LRMS (ESI+) m/z 324.9 [M+Na]+

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; REVIRAL LIMITED; GOOD, James; (48 pag.)WO2019/122928; (2019); A1;,
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These common heterocyclic compound, 89282-70-2, name is 2-Methoxy-2-methylpropan-1-amine, 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. HPLC of Formula: C5H13NO

The following Examples were prepared according to Method 5 (Example 54) above using 8-chloro-A/-(2-methoxy-4-(1 -methyl-1 H-pyrazol-4-yl)phenyl)pyrido[3,4- d]pyrimidin-2-amine (Example 94) and the appropriate amine as described. Where the amine hydrochloride was used, triethylamine (190uL, 0.373 mmol) was also added to the reaction. The crude reaction residues were purified as above or according to one of the following methods: Method A: Silica gel column chromatography eluting with 0-5% or 0-10% MeOH in DCM. Method B: Silica gel column chromatography eluting with 0-5% MeOH in EtOAc. Method C: Silica gel column chromatography eluting with 0-70% EtOAc in cyclohexane followed by reverse phase preparative HPLC eluting with 10-90% MeOH in water (0.1% formic acid).

The synthetic route of 2-Methoxy-2-methylpropan-1-amine has been constantly updated, and we look forward to future research findings.

Reference:
Patent; CANCER RESEARCH TECHNOLOGY LIMITED; HOELDER, Swen; BLAGG, Julian; SOLANKI, Savade; WOODWARD, Hannah; NAUD, Sebastian; BAVETSIAS, Vassilios; SHELDRAKE, Peter; INNOCENTI, Paolo; CHEUNG, Jack; ATRASH, Butrus; WO2014/37750; (2014); A1;,
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Reference of 2674-34-2, 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 2674-34-2 as follows.

Into a 200-mL three-neck flask were put 8.9 g (30 mmol) of 1,4-dibromo-2,5-dimethoxybenzene, 10 g (72 mmol) of 2-fluorophenylboronic acid, 15 mL of toluene, 15 mL of diethylene glycol dimethyl ether (diglyme), and 60 mL of a sodium carbonate aqueous solution (2.0 mol/L). This mixture was degassed by being stirred while the pressure in the flask was reduced. After the degassing, the atmosphere in the flask was replaced with nitrogen, and the mixture was heated to 80 C. To this mixture was added 0.69 g (0.60 mmol) of tetrakis(triphenylphosphine)palladium(0), and the mixture was stirred at the same temperature for 2 hours. The mixture was cooled down to room temperature and degassed again under reduced pressure. Then, the atmosphere in the flask was replaced with nitrogen, and the mixture was heated to 80 C. After the heating, 0.69 g (0.60 mmol) of tetrakis(triphenylphosphine)palladium(0) was added to this mixture, and the mixture was heated at the same temperature for 5 hours. After the heating, 2.0 g (14 mmol) of 2-fluorophenylboronic acid was added to this mixture, and the mixture was further stirred at the same temperature for 3 hours. After the heating, the mixture was cooled down to the room temperature and degassed under reduced pressure. Then, the atmosphere in the flask was replaced with nitrogen. This mixture was heated to 80 C., 0.64 g (0.55 mmol) of tetrakis(triphenylphosphine)palladium(0) and 3.0 g (21 mmol) of 2-fluorophenylboronic acid were added to the mixture, and the mixture was stirred at the same temperature for 2 hours. After the stirring, the mixture was cooled down to the room temperature, and the mixture was separated into an organic layer and an aqueous layer. The obtained aqueous layer was subjected to extraction with toluene three times, the extracted solution and the organic layer were combined, and this mixture was washed with saturated saline and dried with anhydrous magnesium sulfate. The obtained mixture was gravity-filtered, and then the obtained filtrate was concentrated to give a compound. The obtained compound was recrystallized with toluene to give 2.5 g of a target. The compound obtained by the concentration of the filtrate was purified by column chromatography (a developing solvent: a mixed solvent of hexane and ethyl acetate in a ratio of 30:1) to give 0.3 g of a target. The targets were 2.8 g in total, and the yield was 29%. A synthesis scheme of the above synthesis method is shown in (A-1) below.

According to the analysis of related databases, 2674-34-2, the application of this compound in the production field has become more and more popular.

Reference:
Patent; Semiconductor Energy Laboratory Co., Ltd.; Kawakami, Sachiko; Ishiguro, Yoshimi; Takahashi, Tatsuyoshi; Hamada, Takao; Seo, Hiromi; Seo, Satoshi; (113 pag.)US9997725; (2018); B2;,
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Synthetic Route of 38380-85-7, As we all know, there are many different methods for the synthesis of a compound, and people can choose the synthesis method that suits their own laboratory according to the actual situation. 38380-85-7 name is 1-Bromo-4-cyclopropoxybenzene, This compound is widely used in many fields, so it is necessary to find a new synthetic route. The downstream synthesis method of this compound is introduced below.

General procedure: A mixture of 2,4-dibromothiazole (Compound 8A) (3.9 g, 16 mmol), 3,4- dichlorophenylboronic acid (3.05 g, 16 mol), Pd(dppf)C12 (0.7 g, 0.87 mmol), and cesium carbonate (15 g, 46 mmol) in DME (120 mL) and water (10 mL) was heated at reflux under nitrogen overnight. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (200 mL x 2). The combined extracts were washed with water (200 mL) and brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 10% v/v) to yield Compound 8B. LC-MS (ESI) m/z: 308 [M+H]t

At the same time, in my other blogs, there are other synthetic methods of this type of compound, 1-Bromo-4-cyclopropoxybenzene, and friends who are interested can also refer to it.

Reference:
Patent; BIOMARIN PHARMACEUTICAL INC.; WANG, Bing; CHAO, Qi; (737 pag.)WO2019/133770; (2019); A2;,
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Electric Literature of 651734-54-2, A common heterocyclic compound, 651734-54-2, name is 2,6-Difluoro-3,5-dimethoxyaniline, molecular formula is C8H9F2NO2, 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.

To a 2-L reactor equipped with a thermocouple, a nitrogen inlet and mechanical stirrer were charged AOV-dimethyl formamide (450 mL, 425 g), 4-chloro-2-(morpholinomethyl)-l- (phenylsulfonyl)- 1 //-pyrrolo|2.3-6 |pyridine-5-carbaldehyde (30.0 g, 71.45 mmol) and 2,6- difluoro-3,5-dimethoxyanihne (14.2 g, 75.0 mmol). To this suspension (internal temperature 20 C) was added chlorotrimethylsilane (19.4 g, 22. 7 mL, 179 mmol) dropwise in 10 min at room temperature (internal temperature 20-23 C). The suspension changed into a solution in 5 min after the chlorotrimethylsilane addition. The solution was stirred at room temperature for 1.5 h before cooled to 0-5 C with ice-bath. Borane-THF complex in THF (1.0 M, 71.4 mL, 71.4 mmol, 64.2 g, 1.0 eq.) was added dropwise via additional funnel over 30 min while maintaining temperature at 0-5 C. After addition, the mixture was stirred for 4 h. Water (150 g, 150 mL) was added under ice-bath cooling in 20 min, followed by slow addition of ammonium hydroxide solution (28% N, 15.3 g, 17 ml, 252 mmol, 3.53 eq.) to pH 9-10 while maintaining the temperature below 10 C. More water (250 mL, 250 g) was added through the additional funnel. The slurry was stirred for 30 min and the solids were collected by filtration. The wet cake was washed with water (90 g x 2, 90 ml x 2) and heptane (61.6 g x2, 90 ml x 2). The product w as suction dried overnight to give the desired product LG-((4- chloro-2-(morphohnomethyl)-l-(phenylsulfonyl)-li/-pyrrolo[2,3-Z>]pyridin-5-yl)methyl)-2,6- difluoro-3,5-dimethoxyaniline (41.6 g, 96% yield): LCMS calculated for C27H28ClF2N405S[M+H]+: 593.10; Found: 593.1 ; NMR (400 MHz, DMSO-d6) 5 8.36 (m, 2H), 8.28 (s, 1H), 7.72 (m, 1H), 7.63 (m, 2H), 6.78 (s, 1H), 6.29 (m, 1H), 5.82 (m, 1H), 4.58 (m, 2H), 3.91 (s, 2H), 3.76 (s, 6H), 3.56 (m, 4H), 2.47 (m, 4H).

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; INCYTE CORPORATION; BURN, Timothy C.; LIU, Phillip C.; FRIETZE, William; JIA, Zhongjiang; TAO, Ming; WANG, Dengjin; ZHOU, Jiacheng; LI, Qun; (262 pag.)WO2019/213544; (2019); A2;,
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These common heterocyclic compound, 10541-78-3, name is 2-Methoxy-N-methylaniline, 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. HPLC of Formula: C8H11NO

To a stirring dichloromethane (40 mL) solution containing 5-bromo-4- chloro-2-hydroxybenzoic acid (2.0 g, 8.0 mmol), were added triethylamine (2.2 mL, 16.0 mmol), HATU (4.5 g, 12 mmol) and 2-methoxyl-N-methylaniline (1.19 g, 8.7 mmol). The mixture was stirred at rt for 16 hrs and water was added. The organic layer was separated, washed with NaHCO3, dried over Na2SO4, filtered and concentrated. The residue was purified via silica gel flash column chromatography eluting with 20% ethyl acetate in hexane to afford 5-bromo-4-chloro-2-hydroxy-N-(2- methoxy-phenyl)-N-methyl-benzamide (300 mg). MS [M+H]+: 371.9; tR = 2.60 min (method 1)Alternatively, a mixture of 5-bromo-4-chloro-2-hydroxybenzoic acid (5 g, 19.9 mmol), 2-methoxy-N-methyaniline (3.13g, 22.9 mmol) and P2O5 (5.36g, 37. 8 mmol) in anhydrous xylene was heated at 60 0C for 2 hrs and then refluxed for 17 hrs. The mixture was concentrated and purified via silica gel flash column chromatography eluted with ethyl acetate in hexane (20%) to give 5-bromo-4-chloro-2-hydroxy-N-(2- methoxy-phenyl)-N-methyl-benzamide (3.3 g).

The synthetic route of 2-Methoxy-N-methylaniline has been constantly updated, and we look forward to future research findings.

Reference:
Patent; NEUROCRINE BIOSCIENCES, INC.; WO2008/124610; (2008); A1;,
Ether – Wikipedia,
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7664-66-6, name is 4-Isopropoxyaniline, belongs to ethers-buliding-blocks compound, is considered to be a conventional heterocyclic compound, which is widely used in drug synthesis. The chemical synthesis route is as follows. HPLC of Formula: C9H13NO

To a solution of 4-isopropoxyaniline (9.06 g, 60.0 mmol) in CH2Cl2 (120 mL) and pyridine (30 mL) was added 4-nitrophenyl chloroformate (10.9 g, 54.0 mmol) portionwise with stirring over ~1 min with brief ice-bath cooling. After stirring at room temperature for 1 h, the homogeneous solution was diluted with CH2Cl2 (300 mL) and washed with 0.6 M HCl (1*750 mL) and 0.025 M HCl (1*1 L). The organic layer was dried (Na2SO4) and concentrated to give the title compound as a light violet-white solid (16.64 g, 98%). 1H NMR (CDCl3) delta 8.31-8.25 (m, 2H), 7.42-7.32 (m, 4H), 7.25-7.20 (m, 2H), 6.93 (br s, 1H), 2.90 (sep, J=6.9 Hz, 1H), 1.24 (d, J=6.9 Hz, 6H). LC/MS (ESI) calcd for C16H17N2O5 (MH)+ 317.1, found 633.2 (2 MH)+.

The synthetic route of 7664-66-6 has been constantly updated, and we look forward to future research findings.

Reference:
Patent; Baumann, Christian Andrew; Gaul, Michael David; US2006/281700; (2006); A1;,
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Reference of 33170-72-8, 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 33170-72-8 as follows.

2-Bromo-1,1-dimethoxypropane (2a) (18 g, 98.34 mmol) was dissolved in chloroform (100 mL), trifluoroacetic acid (67.28 g, 590.03 mmol) was added and reacted at room temperature for 4 hours. The reaction solution was added with dichloromethane (30 mL) and water (15 mL), and the layers were extracted.The organic phase was washed with saturated brine (100 mL x 4), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure at 30 C to give the title compound 2b as a yellow liquid (5 g, 37% yield).

According to the analysis of related databases, 33170-72-8, the application of this compound in the production field has become more and more popular.

Reference:
Patent; Sichuan Hai Sike Pharmaceutical Co., Ltd.; Wei Yonggang; Qiu Guanpeng; Lei Bolin; Li Yao; Wang Song; Zhu Guozhi; (39 pag.)CN106279128; (2017); A;,
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These common heterocyclic compound, 50742-37-5, name is (3-Phenoxyphenyl)methanamine, 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-Phenoxyphenyl)methanamine

To a solution of 3-phenoxybenzylamine described in Preparation Example 4 (33mg, 0.167mmol) and benzothiazole-6-carboxylic acid (30mg, 0.167mmol) in tetrahydrofuran (1 mL) were added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (89mg, 0.20mmol) and triethylamine (28mul, 0.20mmol), and the solution was stirred at room temperature for 17 hours. The solvent was evaporated, the residue was purified by NH silica gel column chromatography (hexane : ethyl acetate), and the title compound (37mg, 62%) was obtained as a colorless oil. 1H-NMR Spectrum (CDCl3) delta(ppm) : 4.68(2H, d, J=6.0Hz), 6.50(1H, brs), 6.94(1H, dd, J=2.0, 8.0Hz), 7.02-7.04(3H, m), 7.11-7.15(2H, m), 7.31-7.37(3H, m), 7.88(1H, dd, J=1.6, 8.8Hz), 8.18(1H, d, J=8.8Hz), 8.49(1H, d, J=1.6Hz), 9.13(1H, s).

The synthetic route of (3-Phenoxyphenyl)methanamine has been constantly updated, and we look forward to future research findings.

Reference:
Patent; Eisai Co., Ltd.; EP1669348; (2006); A1;,
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