Category: ethers-buliding-blocks

Some common heterocyclic compound, 5961-59-1, name is 4-Methoxy-N-methylaniline, molecular formula is C8H11NO, 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. Recommanded Product: 4-Methoxy-N-methylaniline

HATU (1.5 g, 4.0 mmol) was added to a stirred solution of 4-methoxy-N-methylaniline mg, 3.64 mmol) and (S)-2-((tert-butoxycarbonyl)amino)-3-phenylpropanoic acid (1.06 g, 4.0 mmol) in DMF (20 mL) and DIPEA (1.3 mL, 7.3 mmol) and the reaction mixture was stirred at rt for 4h. The reaction was concentrated and the residual crude oil was partitioned between EtOAc (-60 mL) and 1/2 sat. NaHCC (aq) (-60 mL). The organic component was washed with brine (-40 mL), dried (MgS04), filtered, concentrated and purified using a Biotage Horizon (80 g SiC , 10-40% EtOAc/hexanes) to yield Intermediate JB-1 (1.34 g) as a clear amber viscous oil. LC-MS retention time = 3.17 min; m/z = 385.3 [M+H]+. (Column: Phenonenex-Luna C18 2.0 x 50mm 3 muiotaeta. Solvent A = 95% Water:5% Acetonitrile: 10 mM NH4OAc. Solvent B = 5% Water:95% Acetonitrile: 10 mM NH4OAc. Flow Rate = 0.8 mL/min. Start % B = 0. Final % B = 100. Gradient Time = 4 min. Wavelength = 220). NMR (400 MHz, CDCh) delta 7.25 – 7.20 (m, 3H), 7.03 – 6.64 (m, 6H), 5.20 (d, J=8.8 Hz, 1H), 4.53 (app q, J=7.4 Hz, 1H), 3.83 (s, 3H), 3.18 (s, 3H), 2.89 (dd, J=13.1, 7.5 Hz, 1H), 2.71 (dd, J=13.1, 6.5 Hz, 1H), 1.39 (s, 9H).

These compound has a wide range of applications. It is believed that with the continuous development of the source of the synthetic route 5961-59-1, its application will become more common.

Reference:
Patent; BRISTOL-MYERS SQUIBB COMPANY; BENDER, John A.; GENTLES, Robert G.; PENDRI, Annapurna; WANG, Alan Xiangdong; MEANWELL, Nicholas A.; BENO, Brett R.; FRIDELL, Robert A.; BELEMA, Makonen; NGUYEN, Van N.; YANG, Zhong; WANG, Gan; KUMARAVEL, Selvakumar; THANGATHIRUPATHY, Srinivasan; BORA, Rajesh Onkardas; HOLEHATTI, Shilpa Maheshwarappa; METTU, Mallikarjuna Rao; PANDA, Manoranjan; (319 pag.)WO2016/172424; (2016); 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 101-55-3 as follows. HPLC of Formula: C12H9BrO

(1) Grignard reagent: first in a 1000mL three-necked flask, Add 600mLTHF and 200g 4 – Bromodiphenyl ether stirred solution, spare. Then in a 2000mL three-necked flask was added 21.5g of magnesium, 20 mL THF, one small Iodine, 20mL of prepared 4-bromo-diphenyl ether in THF was added dropwise, and after the initiation of heating, the remaining 4-bromo-diphenyl ether in THF was added dropwise at 30-35 C. After the addition, the mixture was incubated at 30-35 C Stirred for 1 hour, The flask was cooled to -30 C with liquid nitrogen until ready for use. (2) Borated: In the above format liquid, 100.1 g of trimethyl borate 600 mL THF solution was slowly added dropwise, Dropping process to maintain -40 ~ -30 the following, After dropping the mixture was allowed to warm to room temperature, 400 ml of 10% hydrochloric acid was added dropwise and refluxed for 1 hour. After distilling off the THF, 500 ml of cold water was added and the mixture was stirred for 30 minutes, cooled, crystallized and separated, 154.1 g of 4-phenoxybenzeneboronic acid were obtained, The yield is 90%. (3) Purification: In a 1 L three-necked flask were added 154.1 g of wet crude 4-phenoxybenzeneboronic acid, Add 200 mL of toluene to dissolve, desolvate, cool, crystallize and centrifuge to obtain 137 g of 4-phenoxybenzeneboronic acid product in a yield of 80%

According to the analysis of related databases, 101-55-3, the application of this compound in the production field has become more and more popular.

Reference:
Patent; Bengbu Zhong Shi Chemical Co., Ltd.; Yang Qing; Liu Hongqiang; Zhao Shimin; Xu Jianxiao; (5 pag.)CN105820184; (2016); A;,
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Electric Literature of 2062-98-8, A common heterocyclic compound, 2062-98-8, name is Perfluoro(2-methyl-3-oxahexanoyl) fluoride, molecular formula is C6F12O2, 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.

EXAMPLE 2: Example for preparation of CF3CF2CF2OCF (CF3) CF2OCOCF (CF3) OCF2CF2CF3 (1b) (fluorination step)[0090] Compound (3b) (200.0 g) obtained in Example 1, was dissolved in CF3CF2CF2OCF(CF3)COF (hereinafter referred to as compound (4b), 1000.0 g). On the other hand, into a 3000 mL autoclave made of nickel, NaF powder (260.5 g) was. put, and compound (4b) (2000.0 g) was added, followed by stirring and cooling to -10 DEG C. After supplying nitrogen gas for 1 hour, fluorine gas diluted to 20% with nitrogen gas, was supplied at a flow rate of 22.59 L/hr for 1 hour, and while supplying it at the same flow rate, the above fractional solution was injected over a period of 60 hours. [0091] Then, while supplying fluorine gas diluted to 20% with nitrogen gas, while maintaining the above flow rate, 20 mL of a solution of compound (4b) in benzene (0.01 g/mL) was injected, the outlet valve of the autoclave was closed, and when the pressure became 0.12 MPa, the inlet valve of the autoclave was closed, followed by stirring for 1 hour. Further, such an operation was repeated 4 times during a period until the temperature rose from -10 DEG C to room temperature and thereafter 5 times at room temperature. During the period, benzene was supplied in a total of 1.800 g, and compound (4b) was injected in a total of 281.0 g. Thereafter, nitrogen gas was supplied for 2 hours, and the reaction mixture was taken out by decantation. The obtained crude liquid was concentrated by an evaporator, and the product was quantified by <19>F-NMR, whereby it contained CF3CF2CF2OCF (CF3) CF2OCOCF (CF3) OCF2CF2CF3 (compound (1b)) in a yield of 69%. A part of the crude liquid was taken and distilled under reduced pressure to obtain compound (1b) . The boiling point of compound (1b) was from 46 to 51 DEG C/5.2 kPa.; EXAMPLE 3: Example for preparation of compound (1b) by a continuous process[0092] Using compound (2b) (75.5 g, 0.640 mol) and compound (1b) obtained in Example 2 (213.1 g, 0.321 mol), the reaction was carried out in the same manner as in Example 1 to obtain compound (3b) (amount: 272.4 g, 0.634 mol). The yield of compound (3b) as quantified by <1>H-NMR, was 99%. Then, the compound (3b) was reacted with fluorine in the same manner as in Example 2 to obtain compound (1b) (amount: 294.0 g, 0.44 mol). The same operation was repeated to finally obtain 3000 g of compound (1b).

The synthetic route of 2062-98-8 has been constantly updated, and we look forward to future research findings.

Reference:
Patent; ASAHI GLASS COMPANY LTD.; EP1352892; (2003); 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. 41864-45-3, name is 4,5-Dimethoxy-2-methylaniline, A new synthetic method of this compound is introduced below., Recommanded Product: 41864-45-3

EXAMPLE 157 4-(4,5-Dimethoxy-2-methylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 4,5-dimethoxy-2-methylaniline (48 mg, 0.290 mmol) similar to Example 117 and isolated as a red solid (8 mg, 11%). 1H NMR (CDCl3): 9.69 (s, 1H), 8.74-8.68 (m, 2H), 7.56 (s, 1H), 7.43-7.39 (m, 1H), 6.84 (s, 1H), 6.83 (s, 1H), 6.46 (s, 1H), 3.94 (s, 3H), 3.86 (s, 3H), 2.23 (s, 3H).

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; Cytovia, Inc.; US2003/69239; (2003); A1;,
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Adding a certain compound to certain chemical reactions, such as: 393-15-7, name is 4-Methoxy-3-(trifluoromethyl)aniline, belongs to ethers-buliding-blocks 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 393-15-7, category: ethers-buliding-blocks

4-Methoxy-3-trifluoromethyl-phenylamine (5 g, 26 mmol) in 12 mL water was cooled to -5 degrees C (Ice/Methanol bath). Conc. HCl was added dropwise (7 ml), and the reaction mixture was stirred for five minutes. A solution of NaNO2 (2.0 g, 29 mmol) dissolved in 3 ml water was added dropwise over 10 minutes, and the reaction mixture was tirred for 30 min. Sodium acetate (1.8 g, 22 mmol) was then added, and stirring was continued at -5 degrees C. In a separate flask, ethyl alpha-acetoacetate (4.55 g, 29 mmol) in 20 ml absolute ethanol was stirred, and KOH (1.6 g, 29 mmol) dissolved in 3 ml water was added, followed by ice (30 g). The resulting diazonium salt was added quickly to the reaction mixture, rinsing in with 5 ml EtOH, and the reaction mixture was stirred at zero degrees C for 3.5 hours, then stored at -10 C) for 16 hours. The reaction mixture was warmed to room temperature and extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. Solvent was removed under reduced pressure to leave a liquid residue. In a separate flask 100 ml EtOH and 21 ml acetyl chloride were mixed, with cooling in an ice bath, then heated to 70 degrees C. The liquid residue was added via pipette over 15 minutes to the acetyl chloride solution. This reaction mixture was heated to reflux for 2.5 hours, cooled, evaporated under reduced pressure. The residue was purified by colunm chromatography (10% ethyl acetate/hexane) to give 3.0 g 5-Methoxy-3-methyl-6-trifluoromethyl-1H-indole-2-carboxylic acid ethyl ester, 38% as a white solid. and triturated with diethyl ether to give 5-Methoxy-3-methyl-6-trifluoromethyl-1H-indole-2-carboxylic acid ethyl ester (1.0 g) as a white solid, and 5-Methoxy-3-methyl-4-trifluoromethyl-1H-indole-2-carboxylic acid ethyl ester (14% ) as a white solid.

At the same time, in my other blogs, there are other synthetic methods of this type of compound, 4-Methoxy-3-(trifluoromethyl)aniline, and friends who are interested can also refer to it.

Reference:
Patent; Roche Palo Alto LLC; US2005/209260; (2005); A1;,
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Application of 6443-69-2,Some common heterocyclic compound, 6443-69-2, name is 1,2,3-Trimethoxy-5-methylbenzene, molecular formula is C10H14O3, 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: BF3¡¤Et2O was slowly added dropwise, to a stirred solution of polyhydroxy or polymethoxy phenols and alkyl alchol in dioxane at 0C. After the addition was completed, the stirring was continued for 3h at room temperature. The mixture was poured water and extracted with EtOAc. The organic layer was dried over Na2SO4 and filtered. The solvent was evaporated under reduced pressure. The crude was chromatographed on silica gel.

These compound has a wide range of applications. It is believed that with the continuous development of the source of the synthetic route 1,2,3-Trimethoxy-5-methylbenzene, its application will become more common.

Reference:
Article; Kamauchi, Hitoshi; Oda, Takumi; Horiuchi, Kanayo; Takao, Koichi; Sugita, Yoshiaki; Bioorganic and Medicinal Chemistry; vol. 28; 1; (2020);,
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Each compound has different characteristics, and only by selecting the characteristics of the compound suitable for a specific situation can the compound be applied on a large scale. 109-85-3, name is 2-Methoxyethylamine, This compound has unique chemical properties. The synthetic route is as follows., Quality Control of 2-Methoxyethylamine

[00580] To a solution of Example 116a (528 mg, 3.0 mmol) and Example 116b (450 mg, 6.0 mmol) in DMSO (4 mL) was added NN-diisopropylethylamine (780 mg, 6.0 mmol). The mixture was heated at 135C for 4 h. The reaction mixture was cooled to r.t., diluted with H20 (20 mL), and then extracted with EtOAc (100 mL). The organic layer was dried over Na2S04, filtered and concentrated under reduced pressure to give the desired product Example 116c (620 mg, yield 90%) as a white solid. LCMS [M+l] + = 230.9/232.9.

Chemical properties determine the actual use. Each compound has specific chemical properties and uses. We look forward to more synthetic routes in the future to expand reaction routes of 109-85-3.

Reference:
Patent; FRONTHERA U.S. PHARMACEUTICALS LLC; JIN, Bohan; DONG, Qing; HUNG, Gene; (214 pag.)WO2019/51265; (2019); 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 59557-91-4 as follows. name: 4-Bromo-2-methoxyaniline

Step 1: To a solution of 4-bromo-2-methoxyaniline (2.0 g, 9.9 mmol) in MeCN (50 mL) was added para-toluenesulfonic acid (5.1 g, 27 mmol). The resulting mixture was cooled in an ice water bath. A solution of NaNO2 (1.36 g, 19.7 mmol) and KI (4.11 g, 24.8 mmol) in water (50 mL) was then added, and the resulting mixture was stirred for 5 min. The mixture was then removed from the ice water bath. Once consumption of starting material was observed, the reaction mixture was partitioned between water and EtOAc. The organic phase was concentrated and the resulting crude residue was purified by silica gel chromatography to afford 4-bromo-1-iodo-2-methoxybenzene

According to the analysis of related databases, 59557-91-4, the application of this compound in the production field has become more and more popular.

Reference:
Patent; Gilead Scientific Systems, Inc.; Cory, Kevin S; Doo, Jimin; Farrand, Julie; Guerrero, Juan A; Katana, Ashley A; Cato, Daryl; Laisaweed, Scott I; Lee, Jiayao; Lingco, John O; Nicolaus, May; Notte, Gregory; Phyen, Hyeoung-Jung; Sangy, Michael; Sumit, Arun C; Adam J, Surayyah; Stephens, Cork L; Venkatraman, Chandrasekar; Watkins, William J; Yang, Jong Yu; Jabloki, Jeff; Jifel, Shiela; Ro, Jennifer; Lee, Sung H; Jao, Chung Dong; Grove, Jeffery; Su, Jianjun; Blomgren, Peter; Mitchell, Scott A; Shyung, Jin Ming; Chandrasekar, Jayaraman; (460 pag.)KR2016/37198; (2016); A;,
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Adding a certain compound to certain chemical reactions, such as: 588-96-5, name is p-Bromophenetole, belongs to ethers-buliding-blocks 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 588-96-5, SDS of cas: 588-96-5

Preparation Example 6 Synthesis of 1-(benzyloxy)-2-bromo-4-(4-ethoxybenzyl)benzene; Benzyl bromide (3.1 mL, 0.026 mol) was added to a mixture of 3-bromo-4-hydroxybenzaldehyde (5.0 g, 0.025 mol), tetrabutylammonium iodide (0.92 g, 2.5 mmol), potassium carbonate (6.9 g, 0.050 mol) and N,N-dimethylformamide (70 mL) at room temperature and stirred for 2.5 hours. An ice-water mixture (100 mL) was poured to the reaction mixture and the resultant solution was stirred for one hour. A resulting precipitate was filtered and dried to obtain 4-benzyloxy-3-bromobenzaldehyde (7.1 g, 98%) as a pale yellow powder. Then, 1.6 M n-butyllithium hexane solution (22.9 mL) was added to a mixture of 4-bromophenetole (7.3 g, 0.037 mol) and tetrahydrofuran (70 mL) at -78C. After stirred for 0.5 hours, 4-benzyloxy-3-bromobenzaldehyde (7.0 g, 0.024 mol) in a tetrahydrofuran (70 mL) solution was added and further stirred for 15 minutes, and the reaction mixture was warmed to room temperature. After the reaction mixture was added with a saturated ammonium chloride aqueous solution and extracted with ethyl acetate, the organic phase was washed with brine and dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain colorless oily [4-(benzyloxy)-3-bromophenyl](4-ethoxyphenyl)methanol (8.7 g, 86%). Then, Et3SiH (6.7 mL, 0.042 mol) and BF3¡¤Et2O (2.7 mL, 0.021 mol) were added sequentially to a chloroform (90 mL) solution of [4-(benzyloxy)-3-bromophenyl](4-ethoxyphenyl)methanol (8.7 g, 0.021 mol) at -15C. After stirred for one hour, the reaction mixture was warmed to room temperature. After the reaction mixture was added with a saturated sodium carbonate aqueous solution and extracted with chloroform, the organic layer was washed with brine and dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain a colorless oily title compound (8.8 g, quant). 1H NMR (300 MHz, CHLOROFORM-d) delta ppm 1.40 (t, J=7.0 Hz, 3 H) 3.82 (s, 2 H) 4.00 (q, J=7.0 Hz, 2 H) 5.12 (s, 2 H) 6.78 – 6.87 (m, 3 H) 6.98 – 7.10 (m, 3 H) 7.27 – 7.50 (m, 6 H).

In the field of chemistry, the synthetic routes of compounds are constantly being developed and updated. I will also mention this compound in other articles, p-Bromophenetole, other downstream synthetic routes, hurry up and to see.

Reference:
Patent; TAISHO PHARMACEUTICAL CO., LTD; EP1845095; (2007); A1;,
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171290-52-1, name is 3,5-Dimethoxyphenylacetylene, 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. name: 3,5-Dimethoxyphenylacetylene

A mixture of (S)-3-(5-amino-3-bromo-4-cyano-1H-pyrazol-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester 7c (5 g, 14.1 mmol), cuprous iodide (0.6 g, 2.8 mmol), triethylamine (9 mL), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (2 g, 2.8 mmol) and N,N-dimethylformamide (150 mL) was heated to 80 C. under argon, and then 1-ethynyl-3,5-dimethoxybenzene (14 g, 84.5 mmol) was added in portions, next stirred for 2 hours, and then cooled to room temperature, poured the reaction solution into water, extracted with ethyl acetate (200 mL*3); next the organic phases were combined and dried over anhydrous sodium sulfate, the desiccant was removed by filtering, and the reaction system was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/1), so as to obtain the title product (S)-3-(5-amino-4-cyano-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester 7d (5 g, brown oil), and the yield was 81%. MS m/z (ESI): 382[M+1-56]

The synthetic route of 171290-52-1 has been constantly updated, and we look forward to future research findings.

Reference:
Patent; BEIJING INNOCARE PHARMA TECH CO., LTD.; Chen, Xiangyang; Gao, Yingxiang; Kong, Norman Xianglong; (59 pag.)US2019/210997; (2019); A1;,
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