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Structure of 1088994-20-0

Chemical Structure| 1088994-20-0

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Product Details of [ 1088994-20-0 ]

CAS No. :1088994-20-0
Formula : C13H12N2O2
M.W : 228.25
SMILES Code : COC(=O)C1=C(C=CC(C)=C1)C1=NC=CC=N1
MDL No. :MFCD23135805

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Application In Synthesis of [ 1088994-20-0 ]

* 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 [ 1088994-20-0 ]
  • Downstream synthetic route of [ 1088994-20-0 ]

[ 1088994-20-0 ] Synthesis Path-Upstream   1~1

  • 1
  • [ 1088994-20-0 ]
  • [ 1088994-22-2 ]
YieldReaction ConditionsOperation in experiment
97%
Stage #1: With sodium hydroxide; water In 2-methyltetrahydrofuran at 72℃; for 1.5 h;
Stage #2: at 7 - 10℃;
5-Methyl-2-pyrimidin-2-ylbenzoic acid (E-4)A solution of Ejψ from the previous step was charged to a visually clean 100 L flask through an in-line filter, concentrated and solvent switched to 2-MeTHF (-15 L). To this solution was added water (20 L) and then sodium hydroxide (10N) (2.60 L, 26.0 mol). After the <n="47"/>addition the reaction turned red and the heat source was set to 720C. The mixture was aged at this temperature for 1.5 hours after which complete conversion was observed by HPLC analysis. The reaction was cooled and transferred to a 50 L extractor. The flask was rinsed with 4 L of water and 10 L of MTBE which was added to the stirring mixture in the extractor. The layers were cut, and the aqueous phase was washed twice with 10 L of MTBE. The aqueous layer was then re-introduced into the reactor (100 L) through an in-line filter for the acidification. 2.3L of 12 N HCl was added slowly to the cold mixture which causes an exotherm from 7 to 10°C. This caused a beige precipitate to form (pH = 1). This precipitate was filtered. The beige filter cake was washed twice with 3 mL/g of cold water. Then the cake was washed with 3 mL/g of cold 15percent MTBE/Heptane and 15percent PhMe/Heptane. Finally it was washed with 1.5 mL/g of room temperature MTBE and twice with room temperature 3 mL/g Heptane. The solid was then dried under a stream of N2 for 2 days to provide E-4 as a light beige powder (2.15 kg, 10.04 mol, 97 percent yield). HPLC analysis reveals the product to be 99.2percent purity. Heavy metal analysis revealed 264ppm of Pd and 19.7ppm of Fe. Data for Ej4: 1H NMR (500 MHz, DMSOd6): 12.65 (s, 1 H); 8.85-8.82 (m, 2 H); 7.78 (dd, J = 7.89, 2.34 Hz, 1 H); 7.49-7.37 (m, 3 H); 2.40 (s, 3 H).
97%
Stage #1: With water; sodium hydroxide In 2-methyltetrahydrofuran at 72℃; for 1.5 h;
Stage #2: With hydrogenchloride In water
5-Methyl-2-pyrimidin-2-ylbenzoic acid (B-4) A solution of B1I from the previous step was charged to a visually clean 100 L flask through an in-line filler, concentrated and solvent switched to 2-MeTHF (-15 L). To this solution was added water (20 L) and then sodium hydroxide (10 N) (2.60 L, 26.0 mol). After the addition the reaction turned red and the heat source was set to 72 0C. The mixture was aged at this temperature for 1.5 h after which complete conversion was observed by HPLC analysis. The reaction was cooled and transferred to a 50 L extractor. The flask was rinsed with 4 L of water and 10 L of MTBE which was added to the stirring mixture in the extractor. The layers were cut, and the aqueous phase was washed twice with 10 L of MTBE. The aqueous layer was then reintroduced into the reactor (100 L) through an in-line filter for the acidification. 2.3 L of 12 N HCl was added slowly to the cold mixture which causes an exotherm from 7 to 10 0C. This caused a beige precipitate to form (pH = 1). This precipitate was filtered. The beige filter cake <n="32"/>was washed twice with 3 mL/g of cold water. Then the cake was washed with 3 mL/g of cold 15percent MTBE/Heptane and 15percent PhMe/Heptane. Finally it was washed with 1.5 mL/g of room temperature MTBE and twice with room temperature 3 mL/g Heptane. The solid was then dried under a stream of N2 for 2 days to provide B-4 as a light beige powder (2.15 kg, 10.04 mol, 97 percent yield). HPLC analysis reveals the product to be 99.2percent purity. Heavy metal analysis revealed 264ppm of Pd and 19.7ppm of Fe. Data for B^: lH NMR (500 MHz, DMSO-d6): 12.65 (s, 1 H); 8.85-8.82 (m, 2 H); 7.78 (dd, J - 7.89, 2.34 Hz, 1 H); 7.49-7.37 (m, 3 H); 2.40 (s, 3 H).
65% With water; sodium hydroxide In 2-methyltetrahydrofuran at 72℃; To a solution of methyl 5-methyl-2-(pyrimidin-2-yl)benzoate (p60, 231 mg, 1.01 mmol) in 2-Me-THF (4 mL) water (2.5 mL) and sodium hydroxide solution (10 N) (1.25 mL) were added. The reaction turned red, the mixture was heated to 72°C and stirred at that temperature overnight. The reaction was gone to completion; therefore it was cooled down to RT and transferred to an extractor washing with water and diethyl ether. The layers were separated and the aqueous phase was back-extracted twice with diethyl ether. The aqueous layer was acidified with HCI (12 N). A precipitated was formed, that was filtered washing with water and dried affording 5-methyl-2-(pyrimidin-2-yl)benzoic acid (p61 , 140 mg, y= 65percent) as white solid. MS (mlz): 214.0 [MH]+.
59.98 g With water; sodium hydroxide In tetrahydrofuran at 70℃; for 4 h; Methyl 5-methyl-2-(pyrimidin-2-yl)benzoate (86.1 g; 377 mmol) are dissolved in THF (350 ml) followed by the addition of water (350 ml) and aq. NaOH (190 ml; 4M). The reaction mixture is heated to 70°C for 4 hours. The organic solvent is distilled off under reduced pressure andthe aq. phase is extracted with DCM. Then the aq. phase is cooled to 0°C and the pH is adjusted to pH = 1 by careful addition of aq. 2M hydrochloric acid solution which results in the formation of a suspension. The solid is filtered off and dried at high vacuum to give 59.98 g of the title compound as a beige solid; tR [mm] = 0.58; [M+H] = 215.14.

References: [1] Organic Process Research and Development, 2013, vol. 17, # 1, p. 61 - 68.
[2] Patent: WO2008/147518, 2008, A1, . Location in patent: Page/Page column 43; 45-46.
[3] Patent: WO2009/143033, 2009, A1, . Location in patent: Page/Page column 30-31.
[4] Patent: CN105461699, 2016, A, . Location in patent: Paragraph 0754; 0755; 0756; 0757; 0758; 0759.
[5] Patent: WO2019/43407, 2019, A1, . Location in patent: Page/Page column 90.
[6] Patent: WO2015/83094, 2015, A1, . Location in patent: Page/Page column 19.
 

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