Hydroxylamine synthesis method

A synthesis method, hydroxylamine technology, applied in organic chemistry methods, chemical instruments and methods, and the formation/introduction of functional groups, etc., can solve the problems of cost, toxicity, and purification that is not suitable for high volume, increase project cost, and difficult to purify.

Active Publication Date: 2013-09-18
乐威医药(天津)有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The first step of the Mitsunobu reaction product requires column separation and purification, and the yield is only 56.3%. The low yield and column separation and purification greatly increase the project cost
In addition, the reaction produces a toxic by-product, triphenoxyphos, and the disposal of toxic waste can be a problem
Due to the cost and toxicity of this step reaction, it is not suitable for large-scale
The second step is the hydrazinolysis reaction of methylhydrazine. Toxic methylhydrazine will remain in the product, which makes purification difficult.
Therefore, although this route is very short, it is not suitable for large-scale production due to its cost, toxicity and purification problems.

Method used

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preparation example Construction

[0072] The present invention relates to the synthetic method of hydroxylamine, comprises the following steps:

[0073] (A) First, in the presence of an acid-binding agent, the alcohol reacts with an alkylsulfonyl halide to generate a sulfonate;

[0074] (B) then reacting the sulfonic acid ester obtained in step (A) with N-hydroxyl cyclic imide in the presence of a base to generate an alkylated product of N-hydroxyl cyclic imide;

[0075] (C) reacting the alkylated product obtained in step (B) with an aminolysis reagent or a hydrazinolysis reagent to obtain hydroxylamine.

[0076] In a preferred embodiment, the present invention relates to a synthetic method of hydroxylamine, comprising the following steps:

[0077] (A) Step 1, in the presence of an acid-binding agent, the alcohol represented by Chemical Formula 1 reacts with the alkylsulfonyl halide of Chemical Formula 5 to generate a sulfonate represented by Chemical Formula 2,

[0078]

[0079] (B) step 2, in the presen...

Embodiment 1

[0149]

[0150] step 1:

[0151] Add raw material 1a (47g, 0.4mol, 1eq), triethylamine (51.8g, 0.51mol, 1.28eq), MTBE (400ml) into a 1L reaction flask, drop MsCl (50.4g , 0.44mol, 1.1eq). After dropping, stir at room temperature for 2 hours to stop the reaction. The organic phase was sequentially washed with saturated NaHCO 3 washed, washed with saturated brine, dried and concentrated to obtain the product (83.3 g, 0.4 mol) with a yield of 100%.

[0152] 1 H NMR (CDCl 3 ): 4.33(t, 2H); 3.63(t, 2H); 3.06(s, 3H); 1.20(s, 9H).

[0153] Step 2:

[0154] N-hydroxyphthalimide (3.46g, 0.021mol, 1eq), 2a (5g, 0.025mol, 1.2eq), sodium bicarbonate (2.139g, 0.025mol, 1.2eq), DMF (15ml) were added to In a 50ml reaction bottle, set the temperature at 80°C and react for 24 hours. The temperature was lowered, and the ice-water mixture (10V) was poured into the reaction solution. A solid was precipitated, and the solid was filtered, washed and dried to obtain the product (3.5g0.01...

Embodiment 2

[0160]

[0161] step 1:

[0162] The preparation method is the same as 2a, and the yield is 96%.

[0163] LC-MS: 155.4 (M + ).

[0164] 1 H NMR (CDCl 3 ): 4.23(t, 2H), 3.03(s, 3H), 1.75(m, 2H), 1.45(m, 2H), 0.95(t, 3H).

[0165] Step 2:

[0166] The preparation method is the same as 3a, and the yield is 65.9%.

[0167] LC-MS: 220.46 (M+1).

[0168] 1 H NMR: (CDCl 3 ): 7.83 (d, 2H); 7.76 (d, 2H); 4.25 (d, 2H); 1.77 (m, 2H); 1.50 (m, 2H); 0.98 (m, 3H).

[0169] Step 3:

[0170] The preparation method is the same as 4a, release the pressure, add EA / HCl solution directly after filtration to form a salt. The resulting solid was filtered and the product yield was 93%. 1 H NMR (D 2 O): 4.0 (t, 3H); 1.64 (t, 3H); 1.37 (m, 3H); 0.90 (t, 3H).

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Abstract

The invention relates to a hydroxylamine synthesis method. The hydroxylamine synthesis method comprises the following steps: (A) enabling alcohol to react with alkyl sulfonyl halide in the presence of an acid-binding agent to obtain sulphonate; (B) enabling the obtained sulphonate in the step (A) to react with N-hydroxycyclodiimide in the presence of alkali to generate alkylate of the N-hydroxycyclodiimide; and (C) enabling the alkylate obtained in the step (B) to react with an aminolysis reagent or a hydrazinolysis reagent to obtain the hydroxylamine. The method is high in yield and suitable for large-scale industrial hydroxylamine synthesis.

Description

technical field [0001] The present invention relates to the synthesis method of hydroxylamine, especially the industrial scale synthesis method of hydroxylamine. Background technique [0002] N-(2-hydroxyethoxy)amide is a key functional group in many emerging anti-tumor drug molecules (US2009124595, WO2008055236, US2008125437, US2009275606, WO2009097578), the most representative of which is the MEK enzyme inhibitor AZD6244, the drug It has entered the second clinical phase (WO2007076245A2). The introduction of N-(2-hydroxyethoxy)amide functional group is obtained by condensation of O-ethylhydroxylamine protected by hydroxyl with carboxylic acid, and then deprotected under acidic conditions, as shown in Scheme1. As for the protecting group R, there are two kinds in the literature, one is vinyl and the other is tert-butyl, and these two kinds of hydroxylamines are respectively prepared from the corresponding protected ethylene glycol. Vinyl-protected ethylene glycol, due to ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07B43/00C07C239/20
CPCY02P20/55
Inventor 曹洪庆杨光
Owner 乐威医药(天津)有限公司
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