CN107880097B - Preparation method of deuterated telaprevir - Google Patents
Preparation method of deuterated telaprevir Download PDFInfo
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- CN107880097B CN107880097B CN201711120621.3A CN201711120621A CN107880097B CN 107880097 B CN107880097 B CN 107880097B CN 201711120621 A CN201711120621 A CN 201711120621A CN 107880097 B CN107880097 B CN 107880097B
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Abstract
The invention discloses a preparation method of deuterated telaprevir, which comprises the following steps: (1) carrying out condensation reaction on a deuterated compound and a telaprevir intermediate, washing reaction liquid, and separating liquid to obtain an organic phase containing another deuterated compound; (2) adding tetramethylpiperidine oxide and a sodium bicarbonate aqueous solution into the organic phase containing the other deuterated compound, cooling, slowly dropwise adding a sodium hypochlorite aqueous solution, carrying out an oxidation reaction, separating liquid, washing the organic phase, concentrating under reduced pressure, slowly dropwise adding ethyl acetate at 20-30 ℃ to precipitate a solid, filtering, washing a filter cake with ethyl acetate, and drying under reduced pressure to obtain deuterated telaprevir. The invention has the advantages that: the preparation raw materials are easy to obtain, the preparation steps are simple and convenient to operate, the route design is reasonable, and the deuterium atoms on the initial raw materials can be reserved in the end product of the deuterated telaprevir.
Description
Technical Field
The invention relates to the technical field of deuterated compounds, and in particular relates to a preparation method of deuterated telaprevir.
Background
Telaprevir (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-carboxamides of formula C36H53N7O6The molecular weight is 679.85, and the structure is shown in the following formula.
Telaprevir is a drug for treating chronic hepatitis C. Deuterium is a hydrogen isotope existing in nature, namely, common medicines all contain trace amounts of deuterium isotope elements. Deuterium is non-toxic and non-radioactive, is safe to human bodies, and C-D bonds are more stable (6-9 times) than C-H bonds, in other words, after hydrogen is replaced by deuterium, metabolic sites can be sealed, the half-life period of the drug is prolonged, and meanwhile pharmacological activity is not influenced (the shape difference between H and D is small). The deuterated telaprevir is a compound obtained by isotopic replacement of telaprevir, and has an isotopic effect, but the preparation method of the deuterated telaprevir is not reported at present.
Disclosure of Invention
The invention aims to solve the technical problem of providing a preparation method of deuterated telaprevir with simple steps.
The invention solves the technical problems through the following technical scheme:
a preparation method of deuterated telaprevir comprises the following steps:
(1) carrying out condensation reaction on a deuterated compound shown as a formula (VII) and a telaprevir intermediate shown as a formula (VIII), washing reaction liquid, and separating liquid to obtain an organic phase containing the deuterated compound shown as a formula (IX);
(2) adding tetramethylpiperidine oxide and a sodium bicarbonate aqueous solution into the organic phase containing the deuterated compound shown in the formula (IX), cooling, slowly dropwise adding a sodium hypochlorite aqueous solution, carrying out an oxidation reaction, separating, washing the organic phase, carrying out reduced pressure concentration, slowly dropwise adding ethyl acetate at 20-30 ℃ to precipitate a solid, filtering, washing a filter cake with ethyl acetate, and carrying out reduced pressure drying to obtain deuterated telaprevir shown in the formula (I);
preferably, the deuterated compound shown in the formula (VII) is prepared by cyclization, hydrolysis, rearrangement, reduction and acylation of ethyl hexadeuterated 4-chlorobutyrate. More preferably, it is prepared by the following process:
(a1) performing cyclization and hydrolysis reaction on ethyl hexahydro-4-chlorobutyrate shown in a formula (II) and sodium hydroxide under the action of sodium methoxide, adjusting the pH to 3 after concentration, and concentrating to dryness after extraction to obtain deuterated cyclopropyl formic acid shown in a formula (III);
(a2) carrying out rearrangement reaction on deuterated cyclopropyl formic acid, benzyl alcohol, toluene, diphenyl azide phosphate and triethylamine shown in the formula (III), washing reaction liquid, concentrating an organic phase, and carrying out column chromatography purification to obtain deuterated amide shown in the formula (IV);
(a3) adding hydrogen into deuterated amide shown in formula (IV), methanol, concentrated hydrochloric acid and palladium-carbon at 20-30 ℃ under normal pressure for reduction reaction, filtering, and concentrating the filtrate to dryness to obtain deuterated cyclopropylamine hydrochloride shown in formula (V);
(a4) carrying out condensation reaction on deuterated cyclopropylamine hydrochloride shown in a formula (V), amino acid methyl ester shown in a formula (VI) and methanol, filtering, and washing a filter cake with the methanol to obtain a deuterated compound shown in a formula (VII).
Preferably, in the step (1), the condensation reaction comprises the steps of adding the telaprevir intermediate shown in the formula (VIII), 4-hydroxybenzotriazole and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide into cooled dichloromethane, uniformly mixing, adding the deuterated compound shown in the formula (VII), slowly dropwise adding N-methylmorpholine, and naturally heating to 20-30 ℃ for reaction for 6-10 hours.
Preferably, the temperature of the cooled dichloromethane is 0-5 ℃.
Preferably, 15-20 g of telaprevir intermediate shown as a formula (VIII), 3-5 g of 4-hydroxybenzotriazole, 5-7 g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide and 6-8 g of deuterated compound shown as a formula (VII) are added into every 100m of L dichloromethane.
Preferably, the washing of the reaction solution is performed by sequentially washing with water, 1N hydrochloric acid and 5% sodium bicarbonate.
Preferably, in the step (2), the mass fraction of the sodium bicarbonate aqueous solution is 7%, and the mass fraction of the sodium hypochlorite aqueous solution is 10-13%.
Preferably, the organic phase is washed with water, a 1% aqueous sodium sulfite solution and water in this order.
Preferably, in the step (2), the temperature is reduced to 0-5 ℃; the temperature of the reduced pressure drying is 40-50 ℃.
Preferably, the time of the oxidation reaction is 0.5-2 h.
Compared with the prior art, the invention has the following advantages: the preparation raw materials are easy to obtain, the preparation steps are simple and convenient to operate, the route design is reasonable, and the deuterium atoms on the initial raw materials can be reserved in the end product of the deuterated telaprevir.
Drawings
Figure 1 is a nuclear magnetic resonance hydrogen spectrum of deuterated telaprevir;
figure 2 is a mass spectrum of deuterated telaprevir;
fig. 3 is a partial enlarged view of the deuterated telaprevir spectrogram shown in fig. 2.
Detailed Description
The following examples are given for the detailed implementation and specific operation of the present invention, but the scope of the present invention is not limited to the following examples.
All chemicals were commercially available chemicals.
Example 1 preparation of deuterated Compounds represented by formula (VII)
The synthetic process is as follows:
adding 30m of L methanol into a reaction bottle, adding 5.5g of metallic sodium in batches, stirring until sodium blocks disappear to obtain sodium methoxide (NaOMe), adding 28g of ethyl hexadeutero-4-chlorobutyrate shown as the formula (II), heating and refluxing for 12 hours, cooling to 20-30 ℃, adding 50g of 30% sodium hydroxide aqueous solution, reacting for 6 hours, concentrating, adjusting the pH to 3 with concentrated hydrochloric acid, extracting with dichloromethane for 2 times, concentrating to dryness to obtain 13.5g of yellow liquid, wherein the yield is 83%, adding 3.6g of the yellow liquid and 10m of L benzyl alcohol (PhCH L) into the reaction bottle2OH), 40m L toluene, 13g azido-diphenylphosphateEster (DPPA) and 4.8g Triethylamine (TEA) are heated to reflux reaction for 5 hours, the reaction solution is cooled to 20-30 ℃, 1 mol/L (1N) hydrochloric acid, a saturated sodium carbonate aqueous solution and pure water are sequentially used for washing, an organic phase is concentrated to be dry, column chromatography purification is carried out to obtain 5g of deuterated amide shown in formula (IV), the yield is 64%, 20g of deuterated amide shown in formula (IV), 200m L methanol, 20m L concentrated hydrochloric acid and 2g of 10% palladium-carbon (Pd/C) are added into an eggplant-shaped bottle, hydrogenation reaction is carried out for 12 hours at 20-30 ℃ under normal pressure, filtration is carried out, filtrate is concentrated to be dry, 9.5g of light yellow solid is obtained, the yield is 95%, 14.8g of light yellow solid, 16.1g of amino acid methyl ester (VI) and 160m L methanol are added into the reaction bottle, the temperature is raised to reflux reaction for 48 hours, the temperature is reduced to 20-30 ℃, the mass spectrum is stirred for 2 hours, the filtration is carried out, washing is carried out by 60m L methanol, the white solid shown in formula (VII), the like), and the yield is 18.3g of the nuclear magnetic resonance compound, the:1H-NMR(DMSO-d6,400MHz/ppm)：＝0.87(3H,t),1.25-1.51(4H,m),3.40(1H,bs),4.23(1H,bs),6.28(1H,bs),8.05(4H,bs).MS(ESI):m/z＝228[M+H]+. The deuterated compound shown in the formula (VII) has no peak at the corresponding position on the hydrogen spectrum of nuclear magnetic resonance because 5 hydrogen atoms on the cyclopropyl group are deuterated; also therefore, [ M + H ]]+The peak on the mass spectrum was 228 instead of 223.
Example 2
The synthetic process is as follows:
(1) preparation of organic phase comprising deuterated compound represented by formula (IX)
Adding 210m of L dichloromethane into a reaction bottle, cooling to 0-5 ℃, adding 35g of telaprevir intermediate shown in formula (VIII), 8.8g of 4-hydroxybenzotriazole (HBOt) and 12.4g of 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDCI), stirring and mixing, adding 14.4g of deuterated compound shown in formula (VII), slowly dropwise adding 12.9m of L N-methylmorpholine, naturally heating to 20-30 ℃ for reacting for 8 hours, washing reaction liquid with water, 1N hydrochloric acid and 5% sodium bicarbonate in sequence, and directly adding an organic phase after liquid separation into the next reaction.
(2) Preparation of deuterated telaprevir as shown in formula (I)
Adding 0.75g of tetramethylpiperidine oxide (TEMPO) and 120g of 7% sodium bicarbonate aqueous solution into the organic phase prepared in the example 2, cooling to 0-5 ℃, slowly dropwise adding 70g of 10-13% sodium hypochlorite aqueous solution, reacting at 0-5 ℃ for 1 hour after dropwise adding, separating, washing the organic phase with 150m L water, 150m L1% sodium sulfite aqueous solution and 150m L water in sequence, concentrating the organic phase under reduced pressure to 60m L, slowly dropwise adding 120m L ethyl acetate at 20-30 ℃ to separate out a solid, washing the filter cake with 120m L ethyl acetate after filtering, drying under reduced pressure at 40 ℃ to obtain 36.8g of deuterated telaprevir as shown in the formula (I), wherein the yield is 79%, and detecting the solid by mass spectrometry and nuclear magnetic resonance, wherein the results are as follows:1H-NMR(CDCl3,400MHz/ppm)：＝9.40(1H,s),8.77(1H,d),8.57(1H,s),8.30(1H,d),7.65-7.60(2H,m),7.23(1H,s),5.51(1H,t),4.80-4.69(2H,m),4.62(1H,s),3.86(1H,t),3.66(1H,dd),2.90-2.78(2H,m),1.93-0.89(33H,m).MS(ESI):m/z＝685[M+H]+. The hydrogen spectrum of nuclear magnetic resonance is shown in figure 1, and the mass spectrum is shown in figures 2 and 3. The deuterated telaprevir as shown in the formula (I) has 5 hydrogen atoms on the cyclopropyl group deuterated, so that the [ M + H ] is]+Peaks in the mass spectrum at 685 instead of 680.
Example 3
(1) Preparation of organic phase comprising deuterated compound represented by formula (IX)
Adding 210m of L dichloromethane into a reaction bottle, cooling to 0-5 ℃, adding 31.5g of telaprevir intermediate shown in formula (VIII), 6.3g of 4-hydroxybenzotriazole (HBOt) and 10.5g of 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDCI), stirring and mixing, adding 12.2g of deuterated compound shown in formula (VII), slowly dropwise adding 12.9m of L N-methylmorpholine, naturally heating to 20-30 ℃ for reacting for 6 hours, washing reaction liquid with water, 1N hydrochloric acid and 5% sodium bicarbonate in sequence, and directly adding an organic phase after liquid separation into the next reaction.
(2) Preparation of deuterated telaprevir as shown in formula (I)
0.75g of tetramethylpiperidine oxide (TEMPO) and 120g of 7% aqueous sodium hydrogencarbonate solution were added to the mixtureThe temperature of the organic phase prepared in the example 2 is reduced to 0-5 ℃, 70g of 10-13% sodium hypochlorite aqueous solution is slowly dripped, the organic phase reacts for 0.5 hour at 0-5 ℃ after dripping is finished, liquid separation is carried out, the organic phase is sequentially washed by 150m L water, 150m L1% sodium sulfite aqueous solution and 150m L water, the organic phase is subjected to pressure concentration to 60m L, 120m L ethyl acetate is slowly dripped at 20-30 ℃ to separate out solid, the filter cake is washed by 120m L ethyl acetate after filtration, and the solid is dried under reduced pressure at 50 ℃ to obtain 25.8g of solid deuterated telaprevir shown in the formula (I), the yield is 60%, the solid is detected by mass spectrometry and nuclear magnetic resonance, and the results are as follows:1H-NMR(CDCl3,400MHz/ppm)：＝9.40(1H,s),8.77(1H,d),8.57(1H,s),8.30(1H,d),7.65-7.60(2H,m),7.23(1H,s),5.51(1H,t),4.80-4.69(2H,m),4.62(1H,s),3.86(1H,t),3.66(1H,dd),2.90-2.78(2H,m),1.93-0.89(33H,m).MS(ESI):m/z＝685[M+H]+。
example 4
(1) Preparation of organic phase comprising deuterated compound represented by formula (IX)
Adding 210m of L dichloromethane into a reaction bottle, cooling to 0-5 ℃, adding 42g of telaprevir intermediate shown in formula (VIII), 10.5g of 4-hydroxybenzotriazole (HBOt) and 14.7g of 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDCI), stirring and mixing, adding 16.8g of deuterated compound shown in formula (VII), slowly dropwise adding 12.9m of L N-methylmorpholine, naturally heating to 20-30 ℃ for reaction for 10 hours, washing reaction liquid with water, 1N hydrochloric acid and 5% sodium bicarbonate in sequence, and directly adding an organic phase after liquid separation into the next reaction.
(2) Preparation of deuterated telaprevir as shown in formula (I)
Adding 0.75g of tetramethylpiperidine oxide (TEMPO) and 120g of 7% sodium bicarbonate aqueous solution into the organic phase prepared in the example 2, cooling to 0-5 ℃, slowly dropwise adding 70g of 10-13% sodium hypochlorite aqueous solution, reacting for 2 hours at 0-5 ℃ after dropwise adding, separating liquid, sequentially washing the organic phase with 150m L water, 150m L1% sodium sulfite aqueous solution and 150m L water, concentrating the organic phase under reduced pressure to 60m L, slowly dropwise adding 120m L ethyl acetate at 20-30 ℃ to separate out solid, washing the filter cake with 120m L ethyl acetate after filtering, and drying under reduced pressure at 45 ℃ to obtain 30.5g of solid deuterated tera shown in the formula (I)Yield of pyrrosia leaf is 72%. The solid was detected by mass spectrometry and nuclear magnetic resonance and the results were as follows:1H-NMR(CDCl3,400MHz/ppm)：＝9.40(1H,s),8.77(1H,d),8.57(1H,s),8.30(1H,d),7.65-7.60(2H,m),7.23(1H,s),5.51(1H,t),4.80-4.69(2H,m),4.62(1H,s),3.86(1H,t),3.66(1H,dd),2.90-2.78(2H,m),1.93-0.89(33H,m).MS(ESI):m/z＝685[M+H]+。
the above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.
Claims (8)
1. A preparation method of deuterated telaprevir is characterized by comprising the following steps:
(1) carrying out condensation reaction on a deuterated compound shown as a formula (VII) and a telaprevir intermediate shown as a formula (VIII), washing reaction liquid, and separating liquid to obtain an organic phase containing the deuterated compound shown as a formula (IX);
(2) adding tetramethylpiperidine oxide and a sodium bicarbonate aqueous solution into the organic phase containing the deuterated compound shown in the formula (IX), cooling, slowly dropwise adding a sodium hypochlorite aqueous solution, carrying out an oxidation reaction, separating, washing the organic phase, carrying out reduced pressure concentration, slowly dropwise adding ethyl acetate at 20-30 ℃ to precipitate a solid, filtering, washing a filter cake with ethyl acetate, and carrying out reduced pressure drying to obtain deuterated telaprevir shown in the formula (I); the mass fraction of the sodium bicarbonate aqueous solution is 7%, and the mass fraction of the sodium hypochlorite aqueous solution is 10-13%
The deuterated compound shown in the formula (VII) is prepared by cyclization, hydrolysis, rearrangement, reduction and acylation of ethyl hexadeuterated 4-chlorobutyrate.
2. The preparation method of deuterated telaprevir according to claim 1, wherein in the step (1), the condensation reaction comprises the steps of adding a telaprevir intermediate shown in formula (VIII), 4-hydroxybenzotriazole and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide into cooled dichloromethane, uniformly mixing, adding a deuterated compound shown in formula (VII), slowly dropwise adding N-methylmorpholine, and naturally heating to 20-30 ℃ for reacting for 6-10 hours;
3. the method of claim 2, wherein the temperature of the cooled dichloromethane is 0-5 ℃.
4. The preparation method of deuterated telaprevir according to claim 3, wherein 15-20 g of telaprevir intermediate shown in formula (VIII), 3-5 g of 4-hydroxybenzotriazole, 5-7 g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide and 6-8 g of deuterated compound shown in formula (VII) are added into every 100m of L dichloromethane.
5. The method of preparing deuterated telaprevir according to claim 1, wherein in step (1), the reaction solution is washed with water, 1N hydrochloric acid and 5% sodium bicarbonate in sequence.
6. The process for preparing deuterated telaprevir according to claim 1, wherein in step (2), the organic phase is washed sequentially with water, a 1% aqueous sodium sulfite solution and water.
7. The preparation method of deuterated telaprevir according to claim 1, wherein in step (2), the temperature is reduced to 0-5 ℃; the temperature of the reduced pressure drying is 40-50 ℃.
8. The method for preparing deuterated telaprevir according to claim 1, wherein in step (2), the time for the oxidation reaction is 0.5-2 h.
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