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Preparation method of 7,9-dioxo-2,6-aza-spiro[3.5]nona-2-tert-butyl formate and intermediate thereof

A technology of trimethylsilyl and trimethylsilyl, which is applied in the field of pharmaceutical intermediate synthesis, can solve the problems of low total yield, lack of feasibility of large-scale preparation, and high cost of raw materials, and achieves cheap and easy raw materials. The effect of easy operation and availability of raw materials

Active Publication Date: 2013-02-20
SHANDONG DIAI BIOTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The above-mentioned method prepares compound I from compound VIII through IX, X, XI, and the synthesis method of this report has the following disadvantages: the cost of raw materials is high; b, c two-step intermediates need to be purified by column chromatography, and the total yield is lower than 40%. Not feasible for large-scale preparation

Method used

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  • Preparation method of 7,9-dioxo-2,6-aza-spiro[3.5]nona-2-tert-butyl formate and intermediate thereof
  • Preparation method of 7,9-dioxo-2,6-aza-spiro[3.5]nona-2-tert-butyl formate and intermediate thereof
  • Preparation method of 7,9-dioxo-2,6-aza-spiro[3.5]nona-2-tert-butyl formate and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Synthesis of compound III

[0026]

[0027] Preparation of LiHMDS solution: Hexamethyldisilazane (96.84 g, 0.6 mol, 1.5 eq.) was dissolved in 360 mL THF. Under the protection of nitrogen, the temperature was lowered to -20°C, and 2.5M butyllithium (240mL, 0.6mol, 1.5eq.) was added dropwise. After dropping, keep warm at -10°C for 1h. Compound II (72.88 g, 0.4 mol, 1.0 eq.) was dissolved in 800 mL THF. Under nitrogen protection, the temperature was lowered to -78°C, and the prepared LiHMDS solution was added dropwise. After dripping and keeping warm for 2h, ethyl chloroformate (43.3g, 0.40mol, 1.0eq.) was added dropwise. After dropping, the reaction solution was acidified with 0.5N HCl, and then extracted with EA. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated to obtain 85.9 g of compound III as a white solid, yield: 95.0%. 1 HNMR (400MHz, DMSO-d 6 ) δ (ppm) 7.77 (s, 1H), 4.34 (d, 2H), 4.00 (br, 2H), 1.39...

Embodiment 2

[0035] Synthesis of compound III

[0036]

[0037] Preparation of LiHMDS solution: Hexamethyldisilazane (193.6 g, 1.2 mol, 3.0 eq.) was dissolved in 360 mL THF. Under the protection of nitrogen, the temperature was lowered to -20°C, and 2.5M butyllithium (480mL, 1.2mol, 3.0eq.) was added dropwise. After dropping, keep warm at -10°C for 1.5h. Compound II (72.88 g, 0.4 mol, 1.0 eq.) was dissolved in 800 mL THF. Under nitrogen protection, the temperature was lowered to -70°C, and the prepared LiHMDS solution was added dropwise. After dripping and keeping warm for 2h, ethyl chloroformate (86.6g, 0.8mol, 2.0eq.) was added dropwise. After dropping, the reaction solution was acidified with 0.5N HCl, and then extracted with EA. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated to obtain 84.5 g of compound III as a white solid, yield: 93.5%. 1 HNMR (400MHz, DMSO-d 6 ) δ (ppm) 7.77 (s, 1H), 4.34 (d, 2H), 4.00 (br, 2H), 1.3...

Embodiment 3

[0045] Synthesis of compound III

[0046]

[0047] Compound II (72.88 g, 0.4 mol, 1.0 eq.) was dissolved in 1 L of diethyl ether. Under nitrogen protection, the temperature was lowered to -80°C, and lithium diisopropylamide (LDA) (800 mL, 1.6 mol, 4.0 eq., 2.0 mol / L) was added dropwise. After dripping and keeping warm for 3h, ethyl chloroformate (129.9g, 1.2mol, 3.0eq.) was added dropwise. After dropping, the reaction solution was acidified with 0.5N HCl, and then extracted with EA. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated to obtain 81.7 g of compound III as a white solid, yield: 90.5%. 1 HNMR (400MHz, DMSO-d 6 ) δ (ppm) 7.77 (s, 1H), 4.34 (d, 2H), 4.00 (br, 2H), 1.39 (s, 1H).

[0048] Synthesis of Compound IV

[0049]

[0050] Compound III (32.4g, 0.143mol, 1.0eq.) was dissolved in 180mL THF, and Cs was added in batches under a water bath 2 CO 3 (46.6g, 0.143mol, 1.0eq.), followed by dropwise additi...

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Abstract

The invention relates to the field of medicine intermediate synthesis, and particularly relates to a preparation method of 7,9-dioxo-2,6-aza-spiro[3.5]nona-2-tert-butyl formate (VII) and an intermediate (I) thereof. The method is characterized by comprising the following steps of: enabling the raw material 1-Boc-3-cyanoazetidine to react with ethyl chloroformate and then with methyl iodide; and finally performing reduction reaction to obtain the intermediate (I). The invention also discloses a preparation method for preparing the compound (VII) by taking the 1-Boc-3-cyanoazetidine as the raw material. According to the preparation method provided by the invention, the raw material is cheap and easily available, the reaction conditions are relatively mild, the yield is high, the total yield of the compound VII can reach about 72.0%, and the yield of the compound I is 90%. The raw material is cheap, the after-treatment is simple, and the method is easy to operate and suitable for large-scale preparation.

Description

technical field [0001] The invention relates to the field of synthesis of pharmaceutical intermediates, in particular to a preparation method of tert-butyl 7,9-dioxo-2,6-aza-spiro[3.5]nonan-2-carboxylate and its intermediate. Background technique [0002] 7,9-dioxo-2,6-aza-spiro[3.5]nonan-2-carboxylate tert-butyl ester (VII) is an important drug intermediate, a variety of reported MK2 inhibitors or inhibit TNF activity Therapeutic drugs all use this as a key intermediate. WO2009 / 010488 reports a class of derivatives of tetracyclic lactams, pharmaceutical compositions containing these compounds and the use of these compounds as MK2 inhibitors or for treating diseases related to TNF activity. [0003] For the preparation of tert-butyl 7,9-dioxo-2,6-aza-spiro[3.5]nonan-2-carboxylate (VII), a synthetic method is reported in patent WO2009 / 010488: [0004] [0005] Reagents and yields: (a) NaOH / H 2 O, EtOH; (b) triethylamine (NEt 3 ), tetrahydrofuran (THF), isobutyl chlorof...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D205/04C07D471/10
Inventor 曹莹杨民民罗飞周西朋吴希罕
Owner SHANDONG DIAI BIOTECH CO LTD
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