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Synthesis method of 1H-pyrazolo (4, 3-b) pyridine-3-carboxylic acid ethyl ester and 6-bromine-substituted compound thereof

A compound, the technology of ethyl acetoacetate, which is applied in the field of synthesis of pharmaceutical intermediates, can solve the problems of preparation without literature reports, and achieve the effects of increased yield, simplified post-processing, and simple operation

Inactive Publication Date: 2013-02-06
PHARMABLOCK SCIENCES (NANJING) INC
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] There is no literature report on the preparation of ethyl 6-bromo-1H-pyrazol[4,3-b]pyridine-3-carboxylate (Compound I-2)

Method used

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  • Synthesis method of 1H-pyrazolo (4, 3-b) pyridine-3-carboxylic acid ethyl ester and 6-bromine-substituted compound thereof
  • Synthesis method of 1H-pyrazolo (4, 3-b) pyridine-3-carboxylic acid ethyl ester and 6-bromine-substituted compound thereof
  • Synthesis method of 1H-pyrazolo (4, 3-b) pyridine-3-carboxylic acid ethyl ester and 6-bromine-substituted compound thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Synthesis of compound IV-1:

[0027]

[0028] A solution of 17% sodium ethoxide (EtONa) (514.7 g, 1.286 mol, 1.0 eq.) in ethanol (EtOH) was added to a 5 L four-necked flask, and 700 mL of EtOH was added. After cooling down in an ice bath, a solution of ethyl acetoacetate (167.5 g, 1.286 mol, 1.0 eq.) in EtOH (725 mL) was added dropwise to the reaction flask, and after the addition was complete, it was raised to room temperature and stirred for 30 min. Then, a solution of compound II-1 (204.25 g, 1.29 mol, 1.0 eq.) in THF (1250 mL) was added dropwise under ice-bath conditions. After the dropwise addition, the temperature was raised to reflux and reacted for 10 h. After the reaction was complete, the reaction solution was concentrated and poured into ice water. Extracted with EA, anhydrous Na 2 SO 4 The organic phase is dried. Concentrated under reduced pressure to obtain 227.7 g of compound IV-1 as a red oil, with a yield of 84.0%. 1 H NMR (400MHz, CDCl 3 ) δ (p...

Embodiment 2

[0036] Synthesis of compound IV-1:

[0037]

[0038] A solution of compound II-1 (204.25g, 1.29mol, 1.0eq.) in tetrahydrofuran (THF) (750mL) was added to a 5L four-necked flask, and NaH (60%) (128.4g, 3.22mol, 2.5eq. ), stirred at room temperature for 1 h after the addition, and added a THF (525 mL) solution of ethyl acetoacetate (418.7 g, 3.21 mol, 2.5 eq.) dropwise into the reaction flask. After the reaction was complete, the reaction solution was concentrated and poured into ice water. Extracted with EA, anhydrous Na 2 SO 4 The organic phase is dried. Concentration gave 248.1 g of compound IV-1 as a red oil, with a yield of 91.5%. 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 8.80 (q, J = 1.52Hz, J = 3.20Hz, 1H), 8.44 (q, J = 1.52Hz, J = 6.76Hz, 1H), 7.48 (q, J = 4.76Hz, J = 3.52Hz, 1H), 4.34(s, 2H), 4.18-4.24(q, J=7.12Hz, 2H), 1.27(t, J=7.12Hz, 3H).

[0039] Synthesis of compound V-1:

[0040]

[0041] In a 2L single-necked bottle, 80.0g of compound IV-1 was completely d...

Embodiment 3

[0046] Synthesis of compound IV-2:

[0047]

[0048] Add 17% EtONa (51.47g, 0.1286mol, 1.0eq.) in EtOH solution to a 1L four-neck flask, and then add 70mL EtOH. After cooling down in an ice bath, a solution of ethyl acetoacetate (16.75 g, 0.1286 mol, 1.0 eq.) in EtOH (72.5 mL) was added dropwise to the reaction flask, and after the addition was complete, it was raised to room temperature and stirred for 30 min. Then, a solution of compound II-2 (30.63 g, 1.29 mol, 1.0 eq.) in THF (125 mL) was added dropwise under ice-bath conditions. After the dropwise addition, the temperature was raised to reflux and reacted for 10 h. After the reaction was complete, the reaction solution was concentrated and poured into ice water. Extracted with EA, anhydrous Na 2 SO 4 The organic phase is dried. Concentration under reduced pressure gave 31.32 g of compound IV-2 as a red oil, with a yield of 84.0%. 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 8.86 (s, 1H), 8.04 (s, 1H), 8.59 (s, 1H), 4.30 (s,...

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Abstract

The invention relates to the field of synthesis of pharmaceutical intermediates and specifically relates to a preparation method of 1H-pyrazolo (4, 3-b) pyridine-3-carboxylic acid ethyl ester and 6-bromo-1H-pyrazolo (4, 3-b) pyridine-3-carboxylic acid ethyl ester. The preparation method is characterized by using an intermediate (V) and sodium nitrite as key intermediates for preparing a variety of kinase inhibitors to perform reaction under acidic conditions. The preparation method disclosed by the invention has the advantages of mild reaction conditions, simplicity and convenience in operation, simplicity in post-treatment and high yield.

Description

technical field [0001] The present invention relates to the field of synthesis of pharmaceutical intermediates, in particular to ethyl 1H-pyrazol[4,3-b]pyridine-3-carboxylate and 6-bromo-1H-pyrazol[4,3-b]pyridine-3- Preparation method of ethyl carboxylate. Background technique [0002] 1H-pyrazolo[4,3-b]pyridine-3-carboxylate ethyl ester and 6-bromo-substituted compounds are important drug intermediates, and many reported kinase inhibitors use this as the key intermediate. [0003] For ethyl 1H-pyrazol[4,3-b]pyridine-3-carboxylate (compound I-1), the synthesis method of the intermediate of this compound (compound V-1) reported in patent WO2003027111 is as follows: [0004] [0005] Reagents and conditions: (a) NaH, dimethyl sulfoxide (DMSO), yield: 70%; (b) LiCl, DMSO, H 2 O, yield: 92%; (c) Pd / C, H 2 , Yield: 94%. [0006] There is no literature report on the preparation of ethyl 6-bromo-1H-pyrazolo[4,3-b]pyridine-3-carboxylate (compound I-2). Contents of the inven...

Claims

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Application Information

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IPC IPC(8): C07D471/04
Inventor 朱经纬毛俊杨民民吴希罕
Owner PHARMABLOCK SCIENCES (NANJING) INC
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