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A kind of preparation method and application of 2-hydroxymethyl oxetane derivative

A technology of trimethylsilyl and phenyl, applied in the field of preparation of 2-hydroxymethyl oxetane derivatives, can solve problems such as being unsuitable for industrial production, uneconomical and environmentally friendly, and expensive catalysts

Active Publication Date: 2020-08-14
NANJING FURUN KAIDE BIOLOGICAL PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the third step of this route, tri-n-butyl methoxytin is used. This catalyst is relatively expensive, and the post-treatment is more troublesome, and the three wastes are high; and the last step requires high temperature 200°C heating reaction, which requires relatively high equipment requirements. Therefore, considering comprehensively, this route Not economical and environmentally friendly, not suitable for industrial production

Method used

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  • A kind of preparation method and application of 2-hydroxymethyl oxetane derivative
  • A kind of preparation method and application of 2-hydroxymethyl oxetane derivative
  • A kind of preparation method and application of 2-hydroxymethyl oxetane derivative

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040]

[0041] Preparation of Compound IV-1

[0042] Compound II-1 (400g, 3.30mol, 1.0e.q.), compound III-1 (480g, 8.26mol, 2.5e.q.) were dissolved in 1.5L ammonium chloride (320g) aqueous solution, and Zn powder (216.2g, 3.30mol, 1.0e.q.), control T1 H-NMR (400MHz, CDCl 3 ) δ (ppm) 1.24 (s, 6H), 2.24-2.26 (d, 2H), 5.11-5.18 (m, 2H), 5.86-5.93 (m, 1H).

[0043] Preparation of Compound V-1

[0044] Dissolve compound IV-1 (160.0g, 1.59mol, 1.0e.q.) in 2L of DCM, add m-CPBA (389.8g, 1.92mol, 1.2e.q.) in batches, exotherm, control T1 H-NMR (400MHz, CDCl3) δ (ppm) 1.33-1.35 (d, 6H), 1.55-1.60 (q, 1H), 1.81-1.86 (dd, 1H), 1.94 (s, 1H), 2.48-2.50 ( m, 1H), 2.80-2.82(t, 1H), 3.11-3.16(m, 1H).

[0045] Preparation of compound VI-1

[0046] NaH (31.43g, 0.78mol, 1.1e.q.) was dissolved in 400mL of THF, benzyl alcohol (100mL) was added dropwise under an ice-water bath, and after stirring for 30min, compound V-1 (83.0g, 0.71mol, 1.0e.q. ), after the dropwise addition, stirred at r...

Embodiment 2

[0052]

[0053] Preparation of Compound IV-2

[0054] Compound II-2 (100g, 0.74mol, 1.0e.q.), compound III-1 (133.5g, 1.11mol, 1.5e.q.) were dissolved in 1.0L aqueous solution, and Cu powder (94.04g, 1.48mol, 2.0e.q. ), control T<50°C, after the addition is complete, stir at room temperature for 3 h, filter, wash the filter cake with MTBE, extract the aqueous phase with MTBE, combine the organic phases, wash with 1L saturated brine, dry and concentrate to obtain compound IV-2 as 71.73 g of light yellow liquid, yield 55%.

[0055] Preparation of Compound V-2

[0056] Compound IV-2 (70g, 0.39mol, 1.0e.q.) was dissolved in 800mL of 1,4-dioxane, and tert-butanol peroxide (70.29g, 0.78mol, 2.0e.q.) was added in portions at -10°C , after the addition is complete, stir and react at room temperature for 16 hours, add 1L sodium thiosulfate (80g) aqueous solution, stir and react for 1 hour, filter and separate the liquids, wash the organic phase with saturated brine, dry over anhyd...

Embodiment 3

[0064]

[0065] Preparation of Compound IV-3

[0066] Compound II-3 (100g, 0.507mol, 1.0e.q.), compound III-3 (106.7g, 1.52mol, 3.0e.q.) were dissolved in 800L sodium acetate (80g) aqueous solution, and Mg powder (36.96g, 1.521 mol, 3.0e.q.), control T<50°C, after the addition, T=40°C and stir for 8h, filter, wash the filter cake with MTBE, extract the aqueous phase with MTBE, combine the organic phases, wash with 1L saturated brine, and dry Concentration gave 60.41 g of compound IV-3 as a light yellow liquid, with a yield of 63.3%. Preparation of Compound V-3

[0067] Dissolve IV-3 (60.0g, 0.318mol, 1.0e.q.) in 600mL of DCM solution, add carbamide peroxide (87.81g, 0.956mol, 3.0e.q.) in batches at 0°C, exotherm, control T<40°C , after the addition was completed, stirred and reacted at T=10°C for 16 h, added 1 L of sodium thiosulfate (100 g) aqueous solution, stirred and reacted for 1 h, filtered and separated, and the organic phase was washed with saturated brine, dried ...

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Abstract

The invention discloses a preparation method and application of a 2-hydroxymethyloxetane derivative. The method comprises the following steps that a compound II and a compound III are used as raw materials; Barbier reaction is performed to obtain a compound IV; olefinic bonds in the compound IV are cyclized and oxidized to obtain a compound V; under the alkaline condition, ring opening is performed to generate a compound VI; after ring closing reaction, a compound VII is obtained; finally, benzyl protecting groups are removed to obtain the 2-hydroxymethyloxetane derivative (the compound I).

Description

technical field [0001] The invention relates to the field of synthesis of pharmaceutical intermediates, in particular to a preparation method and application of a 2-hydroxymethyloxetane derivative. Background technique [0002] Oxetane compounds are an important class of pharmaceutical intermediates, which play an important role in drug research and development with their unique structures. Their unique ring-shaped rigid structures can increase the stability of drug molecule metabolism while maintaining or reducing Lipophilicity of drug molecules. 2-Hydroxymethyl oxetane derivatives are a class of oxetane compounds, which are important intermediates in pharmaceutical synthesis and can be used as small molecule fragments to prepare a HIV inhibitor Pyrrolopyridine derivatives can be used for drug regulation of protein kinases and treatment of anti-proliferative diseases; they can also be used for the synthesis of drugs such as γ-secretase inhibitors, so they have broad market...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D305/06C07D305/14
CPCC07D305/06C07D305/14Y02P20/55
Inventor 张雷亮徐峰
Owner NANJING FURUN KAIDE BIOLOGICAL PHARMA CO LTD
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