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Preparation method of deuterated telaprevir

A technology of telaprevir and telaprevir, which is applied in the field of preparation of deuterated telaprevir, can solve problems such as unreported preparation methods of deuterated telaprevir, and achieves the effects of reasonable route design and simple and convenient preparation steps.

Active Publication Date: 2018-04-06
合肥诺全医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

And deuterated telaprevir is the compound after telaprevir isotope replacement, has isotope effect, but the preparation method about deuterated telaprevir is not reported at present

Method used

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  • Preparation method of deuterated telaprevir
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  • Preparation method of deuterated telaprevir

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Embodiment 1 Preparation of the deuterated compound shown in formula (VII)

[0033] The synthesis process is as follows:

[0034]

[0035] Add 30mL of methanol to the reaction flask, add 5.5g of sodium metal in batches, stir until the sodium block disappears to obtain sodium methylate (NaOMe), then add 28g of hexadeuterio ethyl 4-chlorobutyrate shown in formula (II) , heated and refluxed for 12 hours, lowered to 20-30 ° C, added 50 g of 30% sodium hydroxide aqueous solution, reacted for 6 hours, concentrated, adjusted pH to 3 with concentrated hydrochloric acid, extracted twice with dichloromethane, concentrated to dryness, and obtained yellow Liquid 13.5g, yield 83%. Add 3.6 g of the above yellow liquid, 10 mL of benzyl alcohol (PhCH 2 OH), 40mL of toluene, 13g of diphenylphosphoryl azide (DPPA) and 4.8g of triethylamine (TEA), heated to reflux for 5 hours, cooled to 20-30°C, and the reaction solution was sequentially filled with 1mol / L (1N) After washing with hy...

Embodiment 2

[0037] The synthesis process is as follows:

[0038]

[0039] (1) Preparation of an organic phase comprising a deuterated compound as shown in formula (IX)

[0040] Add 210mL of dichloromethane to the reaction flask, cool down to 0~5°C, add 35g telaprevir intermediate shown in formula (VIII), 8.8g 4-hydroxybenzotriazole (HBOt), 12.4g 1 -(3-Dimethylaminopropyl)-3-ethylcarbimide (EDCI), stir and mix, then add 14.4g of the deuterated compound shown in formula (VII), slowly add 12.9mL of N- Methylmorpholine was naturally heated to 20-30°C for 8 hours, and the reaction liquid was washed with water, 1N hydrochloric acid, and 5% sodium bicarbonate in sequence, and the organic phase was directly put into the next reaction after liquid separation.

[0041] (2) preparation of deuterated telaprevir as shown in formula (I)

[0042] Add 0.75g tetramethylpiperidine oxide (TEMPO) and 120g 7% sodium bicarbonate aqueous solution into the organic phase prepared in Example 2, cool to 0-5°C,...

Embodiment 3

[0044] (1) Preparation of an organic phase comprising a deuterated compound as shown in formula (IX)

[0045] Add 210mL of dichloromethane to the reaction flask, cool down to 0-5°C, add 31.5g telaprevir intermediate shown in formula (VIII), 6.3g 4-hydroxybenzotriazole (HBOt), 10.5g 1-(3-Dimethylaminopropyl)-3-ethylcarboimide (EDCI), stirred and mixed, then added 12.2g of the deuterated compound shown in formula (VII), slowly added dropwise 12.9mL N -Methylmorpholine, naturally heated to 20-30°C for 6 hours, the reaction solution was washed with water, 1N hydrochloric acid, and 5% sodium bicarbonate in sequence, and the organic phase was directly put into the next reaction after liquid separation.

[0046] (2) preparation of deuterated telaprevir as shown in formula (I)

[0047] Add 0.75g tetramethylpiperidine oxide (TEMPO) and 120g 7% sodium bicarbonate aqueous solution into the organic phase prepared in Example 2, cool to 0-5°C, slowly add 70g 10-13% sodium hypochlorite aque...

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Abstract

The invention discloses a preparation method of deuterated telaprevir. The preparation method comprises the following steps: (1) carrying out a condensation reaction on a deuterated compound and a telaprevir intermediate, washing a reaction liquid, and separating the liquid to obtain an organic phase containing the other deuterated compound; and (2) adding 2,2,6,6-tetramethylpiperidinooxy and a sodium bicarbonate water solution into the organic phase containing the other deuterated compound, carrying out cooling, then, slowly and dropwise adding a sodium hypochlorite water solution to carry out an oxidation reaction, separating the liquid, then, washing the organic phase, carrying out reduced pressure concentration, then, slowly and dropwise adding ethyl acetate at 20-30 DEG C to separatea solid, carrying out filtration, then, washing a filter cake by using ethyl acetate, and carrying out reduced pressure drying to obtain deuterated telaprevir. The preparation method has the advantages that preparation raw materials are available, the preparation steps are simple and convenient to operate, the route design is reasonable, and deuterated telaprevir serving as a final product can retain deuterium atoms on starting raw materials.

Description

technical field [0001] The present invention relates to the technical field of deuterated compounds, more specifically to a preparation method of deuterated telaprevir. Background technique [0002] Telaprevir, chemical name (1S,3aR,6aS)-(2S)-2-cyclohexyl-N-(carbonylpyrazine)-glycyl-3-methyl-L-valyl -N-(1S)-1-[(cyclopropylamino)-oxoacetyl]butyl-octahydrocyclopenta[c]pyrrole-1-carboxamide, the molecular formula is C 36 h 53 N 7 o 6 , the molecular weight is 679.85, and the structure is shown in the following formula. [0003] [0004] Telaprevir is a drug used to treat chronic hepatitis C. Deuterium is a hydrogen isotope that exists in nature, which means that common medicines contain trace amounts of deuterium isotope. Deuterium is non-toxic, non-radioactive, and safe to the human body, and the C-D bond is more stable (6-9 times) than the C-H bond. In other words, after replacing hydrogen with deuterium, it may close the metabolic site and prolong the drug half-life...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/06C07K1/02
CPCC07K7/06
Inventor 胡志刚许良志何大荣杜小鹏钱祝进何勇刘庄子
Owner 合肥诺全医药有限公司
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