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Preparation method of alfentanil and sufentan and compounds used for preparation of sufentanil and alfentan

A compound and methylation technology, applied in the field of sufentanil compound and preparation of alfentanil, can solve the problems of safety, harsh reaction conditions, cumbersome operation, etc.

Inactive Publication Date: 2017-01-18
NHWA PHARMA CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] There are many methods for the synthesis of alfentanil and sufentanil at present, however, the existing methods of synthesizing alfentanil and sufentanil all use highly toxic cyanide and Explosive sodium azide and highly toxic cyanide are also used in the synthesis of sufentanil, and Pd / C and H2 are used for debenzylation, all of which have potential safety hazards
That is to say, the existing method for synthesizing alfentanil and sufentanil has harsh reaction conditions and great safety problems, and the reaction route is long and complicated to operate, which is unfavorable for industrialized production
[0008] Thereby, the synthetic method of current alfentanil and sufentanil all needs to be improved

Method used

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  • Preparation method of alfentanil and sufentan and compounds used for preparation of sufentanil and alfentan
  • Preparation method of alfentanil and sufentan and compounds used for preparation of sufentanil and alfentan
  • Preparation method of alfentanil and sufentan and compounds used for preparation of sufentanil and alfentan

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preparation example Construction

[0079] (1) According to the method for preparing the compound shown in the formula V described above, prepare the compound shown in the formula V or the oxalate of the compound shown in the formula V;

[0080] (2) contacting ethyl isocyanate with azidotrimethylsilyl to obtain 4-ethyl-1H-tetrazol-5-one;

[0081] (3) contacting 4-ethyl-1H-tetrazol-5-one with 1.4-dihaloalkane so as to obtain the compound shown in formula XII; and

[0082] (4) making the compound shown in formula V or the oxalate salt of the compound shown in formula V condense with the compound shown in formula XII, so as to obtain the compound shown in the formula VI,

[0083]

[0084] Wherein, the group Z in formula XII is halogen.

[0085] According to the embodiments of the present invention, the method can be used to conveniently, efficiently and safely prepare the compound shown in the formula VI, which is the intermediate product of alfentanil synthesis, and then, the compound shown in the formula VI c...

Embodiment 1

[0178] Example 1 Preparation of 4-anilino-1-tert-butoxycarbonyl-piperidine-4-carboxylic acid (compound shown in formula I)

[0179]

[0180] Aniline (20g, 215mmol), sodium hydroxide (30g, 750mmol), and N-Boc piperidone (90g, 452mmol) were added to a three-necked flask filled with tetrahydrofuran (1200ml), cooled to 0°C, and slowly added dropwise with chloroform (90 g, 75 mmol). After the dropwise addition, the reaction solution was a yellow transparent liquid, and the reaction was maintained at 0° C. for 1 h. Then, react at room temperature for 12h. Post-treatment: Stand still to produce precipitation, filter with suction, dissolve the filter cake in water (400ml), extract impurities 2 times with an appropriate amount of ether, adjust the pH value of the aqueous phase to 3, and use ethyl acetate (100ml / time, 3 times) ) to extract the product, wash the organic phase twice with water, dry over anhydrous magnesium sulfate, filter, and concentrate to obtain a yellow oil, add ...

Embodiment 2

[0182] Embodiment 2 prepares the compound shown in formula II

[0183] 1. Preparation of methyl 1-BOC-4-phenylaminopiperidine-4-carboxylate

[0184]

[0185] Add 4-phenylamino-1-tert-butoxycarbonyl-piperidine-4-carboxylic acid (16g, 50mmol) into a reaction flask filled with N,N-dimethylformamide (150ml), stir at room temperature to dissolve, Then potassium carbonate (21g, 152mmol) was added, stirred at room temperature for 0.5h, the reaction solution became turbid, then methyl iodide (15g, 106mmol) was added, stirred at room temperature for 12h. Post-processing: add water (300ml) to the reaction solution, separate out oil, extract with ether (100ml / time, 3 times), wash with water, dry over anhydrous magnesium sulfate, filter, concentrate to get yellow oil, add n-hexane ( 100ml) was stirred and beaten to obtain 14.5 g of a milky white solid, with a yield of 87%, an HPLC purity of 99.1%, and a melting point of 92-93°C.

[0186] 1H NMR (400MHz, CDCl3) δ7.21–7.10 (m, 2H), 6.7...

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Abstract

The invention discloses a preparation method of alfentanil and sufentan and compounds used for preparation of sufentanil and alfentan. Specifically, the method for preparation of a compound shown as formula V includes: carrying out BOC reaction on a compound shown as formula IV to obtain the compound shown as formula V in the specification. The method can conveniently, efficiently and safely prepare an intermediate product for synthesis of alfentanil and sufentan, i.e. the compound shown as formula V. And then, the compound shown as formula V can be effectively used for preparation of alfentanil and sufentan.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis. Specifically, the present invention relates to a preparation method of alfentanil and sufentanil and compounds used for preparing alfentanil and sufentanil. Background technique [0002] The analgesic drugs alfentanil (ALFENTANIL) and sufentanil (Sufentan), which act on the mu opioid receptor, are short-acting and strong analgesics, which were launched in the United States in 1983 and 1984, respectively. [0003] The structure of alfentanil is as follows: [0004] [0005] The structure of sufentanil is as follows: [0006] [0007] There are many methods for the synthesis of alfentanil and sufentanil at present, however, the existing methods of synthesizing alfentanil and sufentanil all use highly toxic cyanide and Explosive sodium azide and highly toxic cyanide are also used in the synthesis of sufentanil, and Pd / C and H2 are used to remove benzylation, all of which have pot...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/58C07D401/06C07D409/06C07D211/66
CPCC07D211/58C07D211/66C07D401/06C07D409/06Y02P20/55
Inventor 杨相平王超王辉辛建创李春明李瑞芳
Owner NHWA PHARMA CORPORATION