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Preparation method of intermediate compound for preparing naratriptan

A technology of naratriptan and compounds, which is applied in the field of synthesis of pharmaceutical intermediates, can solve problems such as high cost, harsh reaction conditions, and inapplicability to large-scale production, and achieve the effects of avoiding waste, reducing production costs, and avoiding separation and purification steps

Pending Publication Date: 2021-12-21
SHANGHAI BOC CHEM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0015] In view of the above-mentioned shortcoming of prior art, the object of the present invention is to provide a kind of preparation method of intermediate compound for the preparation of naratriptan, for solving the important intermediate synthetic compound of naratriptan in the prior art The reaction conditions in the existing method are harsh, the cost is high, and it is not suitable for large-scale production

Method used

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  • Preparation method of intermediate compound for preparing naratriptan
  • Preparation method of intermediate compound for preparing naratriptan
  • Preparation method of intermediate compound for preparing naratriptan

Examples

Experimental program
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Embodiment 1

[0085] This embodiment is as figure 1 Synthetic route shown: Preparation of intermediate compound II.

[0086] Add compound I (12kg, 61.2mol), dichloromethane (60L), triethylamine (7.4kg, 73.5mol) in the mechanically stirred 100L reactor, drop Boc anhydride (16kg, 73.5mol) at room temperature, Reaction 12h. Dilute hydrochloric acid (1M, 24L) was added dropwise into the reaction solution. After liquid separation, saturated sodium bicarbonate solution (24L) was added to the organic phase and stirred for 10 min. %. Figure 7 H of the compound of formula II for the structure prepared in the present embodiment 1 - NMR spectrum.

[0087] Figure 8 It is the HPLC spectrogram of the compound of the structure such as formula II prepared in the embodiment.

Embodiment 2

[0089] This embodiment is as figure 2 The synthetic route shown: the preparation of the compound of formula III.

[0090]Add compound II (8kg, 27mol), aqueous sodium vinylsulfonate (14.8kg, 28.4mol), triethylamine (4.1kg, 40.5mol), triphenylphosphine (629g, 2.4 mol), acetonitrile (64L), palladium acetate (48.5g, 0.22mol), reacted for 12 hours at 70-80°C under the protection of argon, and added water (96L) to the reaction solution at room temperature, and then used 80L×2 ethyl acetate The ester was washed twice and the aqueous phase was retained. The aqueous phase was acidified to pH 3 with 1mol / L hydrochloric acid, then extracted with 80L×4 dichloromethane, and the combined dichloromethane was concentrated in vacuo to obtain a compound with the structure shown in formula III , directly submitted to the next step without further purification.

Embodiment 3

[0092] This embodiment is as image 3 The synthetic route shown: the preparation of the compound of formula IV.

[0093] Add compound III (2.39kg, 7.4mol) and tetrahydrofuran (8L) to a mechanically stirred 20L reactor, add thionyl chloride (1.1kg, 8.9mol) at 10-20°C, and react for 3h at 40-50°C after dropping , the reaction solution dropped to room temperature and was directly cast into the next step.

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Abstract

The invention provides a preparation method of an intermediate compound for preparing naratriptan. The preparation method comprises the step of reacting a compound with a structure shown in a formula VI with hydrogen to obtain an intermediate compound with a structure shown in a formula VII. According to the preparation method provided by the invention, a high-quality intermediate compound can be obtained, the intermediate does not need to be separated and purified by using a silica gel column, tedious post-treatment operation is also not needed, tedious separation and purification steps are avoided, waste of raw materials is also avoided, the production cost is reduced, and the preparation method is more suitable for industrial production.

Description

technical field [0001] The invention relates to the field of synthesis of pharmaceutical intermediates, in particular to a preparation method of an intermediate compound for the preparation of naratriptan. Background technique [0002] Naratriptan (English name Naratriptan, also known as AmeNaramig), chemical name is M-methyl-3-(1-methyl-4-piperidinyl)-1,4-indole-5-ethylsulfonamide , its structural formula is as follows: [0003] [0004] Its synthetic route is as follows: [0005] [0006] Naratriptan is the second-generation triptan anti-migraine drug developed by Glaxo Chengkang. For this related symptom, Intermediate VII has a high market value. [0007] The published information shows that the synthesis route of naratriptan can be divided into two categories. One of the major categories is the formation of ethylsulfonamide derivatives substituted by benzene rings first, followed by indole ring closure and condensation with N-methylpiperidone. There is no comm...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/08
CPCC07D209/08Y02P20/55
Inventor 郭伟张鹏飞李尚立
Owner SHANGHAI BOC CHEM CO LTD