CN107814737B - Deuterated telaprevir key intermediate and preparation method thereof - Google Patents

Deuterated telaprevir key intermediate and preparation method thereof Download PDF

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CN107814737B
CN107814737B CN201711120909.0A CN201711120909A CN107814737B CN 107814737 B CN107814737 B CN 107814737B CN 201711120909 A CN201711120909 A CN 201711120909A CN 107814737 B CN107814737 B CN 107814737B
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何大荣
许良志
胡志刚
杜小鹏
钱祝进
何勇
刘庄子
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Anhui Nature Pharmaceutical Co ltd
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Abstract

The invention discloses a deuterated telaprevir key intermediate, which has a structure shown as a formula (VII):

Description

Deuterated telaprevir key intermediate and preparation method thereof
Technical Field
The invention relates to the technical field of deuterated compounds, and in particular relates to a deuterated telaprevir key intermediate and a preparation method thereof.
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.
Figure BDA0001467311510000011
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, has an isotopic effect, and a key intermediate for preparing deuterated telaprevir and a preparation method thereof are not reported at present.
Disclosure of Invention
The invention aims to solve the technical problem of providing a deuterated telaprevir key intermediate for preparing deuterated telaprevir and a preparation method thereof.
The invention solves the technical problems through the following technical scheme:
on the one hand, the deuterated telaprevir key intermediate is provided, and has a structure shown as a formula (VII):
Figure BDA0001467311510000021
the preparation method of the deuterated telaprevir key intermediate comprises the following steps:
(1) 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);
Figure BDA0001467311510000022
(2) 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);
Figure BDA0001467311510000023
(3) 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);
Figure BDA0001467311510000024
(4) 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);
Figure BDA0001467311510000031
preferably, in the step (1), the cyclization and hydrolysis reaction process comprises adding a metal sodium block into methanol in batches, stirring until the metal sodium block disappears, adding ethyl hexadeuterobutyrate 4-chloride shown in the formula (II), heating and refluxing for 10-14 h, cooling to 20-30 ℃, adding a 30% sodium hydroxide aqueous solution, and reacting for 4-8 h.
Preferably, 1-3 g of metal sodium block, 8-12 g of ethyl hexadeutero-4-chlorobutyrate shown in the formula (II) and 15-20 g of 30% sodium hydroxide aqueous solution are added into every 10mL of methanol.
Preferably, in step (1), the extraction is at least 2 times with dichloromethane.
Preferably, in the step (2), 2-4 mL of benzyl alcohol, 10-13 mL of toluene, 3-5 g of diphenyl azide phosphate and 1-2 g of triethylamine are added to 1g of deuterated cyclopropylcarboxylic acid shown in the formula (III); and/or
The rearrangement reaction process is heating to reflux reaction for 4-6 h, and then cooling to 20-30 ℃.
Preferably, in the step (2), the reaction solution is washed by sequentially washing with 1mol/L hydrochloric acid, a saturated aqueous sodium carbonate solution and pure water.
Preferably, in the step (3), 80-120 mL of methanol, 8-12 mL of concentrated hydrochloric acid and 0.5-2 g of palladium carbon are added into every 10g of deuterated amide shown in the formula (IV); and/or
The time of the reduction reaction is 10-14 h.
Preferably, in the step (4), 1-2 g of amino acid methyl ester shown in the formula (VI) and 8-12 mL of methanol are added into every 1g of deuterated cyclopropylamine hydrochloride shown in the formula (V); and/or
The condensation reaction process comprises the steps of heating to reflux reaction for 40-60 hours, cooling to 20-30 ℃, and stirring for 1-3 hours.
Compared with the prior art, the invention has the following advantages: the cyclization and hydrolysis reaction adopts a one-pot method, so that the operation is simplified; the rearrangement reaction uses benzyl alcohol to replace common toluene as a solvent, directly obtains the deuterated amide shown in the formula (IV), can remove carbobenzoxy by hydrogenation under normal pressure, and is simple, convenient and feasible, the reaction route is reasonable in design, the preparation steps are simple and convenient to operate, and the reaction raw materials are easy to obtain.
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
The synthetic process is as follows:
Figure BDA0001467311510000041
(1) preparation of deuterated cyclopropylcarboxylic acid as shown in formula (III)
Adding 30mL of 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 a 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 for 2 times with dichloromethane, and concentrating to dryness to obtain yellow liquid 13.5g of deutero-cyclopropyl formic acid shown as a formula (III), wherein the yield is 83%. The yellow liquid is detected by mass spectrum and nuclear magnetic resonance, and the result is as follows:1H NMR(DMSO-d6,400MHz,ppm)δ13.05(s,br,1H).MS(ESI):m/z＝92[M+H]+. Because in the deuterated cyclopropylcarboxylic acid of the formula (III), the ring is on the propyl groupIs deuterated, so that the 5 atoms do not show peaks in nuclear magnetic hydrogen spectrum, and [ M + H [, H ]]+The peak on the mass spectrum was 92 instead of 87.
(2) Preparation of deuterated amides as shown in formula (IV)
3.6g of deuterated cyclopropylcarboxylic acid shown in formula (III) and 10mL of benzyl alcohol (PhCH) are added into a reaction flask2OH), 40mL of toluene, 13g of azido diphenyl phosphate (DPPA) and 4.8g of Triethylamine (TEA), heating to reflux and react for 5 hours, cooling to 20-30 ℃, washing the reaction solution with 1mol/L (1N) of hydrochloric acid, saturated sodium carbonate aqueous solution and pure water in sequence, concentrating the organic phase to dryness, and purifying by column chromatography to obtain 5g of deuterated amide shown in formula (IV), wherein the yield is 64%. The yellow liquid is detected by mass spectrum and nuclear magnetic resonance, and the result is as follows: 1H NMR (CDCl3,400MHz):7.38-7.28(5H, M),5.12(2H, br.s),5.00(1H, br.s.) MS (ESI): M/z ═ 197[ M + H ] M + H]+. Since 5 hydrogen atoms on the cyclopropyl group are deuterated in the deuterated amide represented by the formula (IV), the 5 atoms do not show peaks in the nuclear magnetic hydrogen spectrum, and [ M + H ]]+Peaks in the mass spectrum were 197 instead of 192.
(3) Preparation of deuterated compounds represented by formula (VII)
Adding 20g of deuterated amide shown in the formula (IV), 200mL of methanol, 20mL of concentrated hydrochloric acid and 2g of 10% palladium carbon (Pd/C) into an eggplant-shaped bottle, carrying out hydrogenation reaction for 12 hours at 20-30 ℃ under normal pressure, filtering, and concentrating the filtrate to dryness to obtain 9.5g of light yellow solid deuterated cyclopropylamine hydrochloride shown in the formula (V), wherein the yield is 95%. Adding 14.8g of the light yellow solid, 16.1g of amino acid methyl ester (VI) and 160mL of methanol into a reaction bottle, heating to reflux for 48 hours, cooling to 20-30 ℃, stirring for 2 hours, filtering, and washing a filter cake with 60mL of methanol to obtain 18.3g of a white solid deuterated compound shown as the formula (VII) with the yield of 81%. The white solid was detected by mass spectrometry and nuclear magnetic resonance and the results were as follows:1H-NMR(DMSO-d6,400MHz/ppm)：δ＝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 as the formula (VII) has 5 hydrogen atoms on the cyclopropyl group which are deuterated, so that no peak is generated at the corresponding position on a nuclear magnetic resonance hydrogen spectrum, and [ M + H ]]+The peak on the mass spectrum was 228 instead of 223.
Example 2
(1) Preparation of deuterated cyclopropylcarboxylic acid as shown in formula (III)
Adding 30mL of methanol into a reaction bottle, adding 3g of metallic sodium in batches, stirring until sodium blocks disappear to obtain sodium methoxide (NaOMe), adding 24g of ethyl hexadeutero-4-chlorobutyrate shown as a formula (II), heating and refluxing for 10 hours, cooling to 20-30 ℃, adding 50g of 30% sodium hydroxide aqueous solution, reacting for 4 hours, concentrating, adjusting the pH to 3 by using concentrated hydrochloric acid, extracting for 2 times by using dichloromethane, and concentrating to dryness to obtain a yellow liquid 10.1g of deutero-cyclopropyl formic acid shown as a formula (III), wherein the yield is 75%. The yellow liquid is detected by mass spectrum and nuclear magnetic resonance, and the result is as follows:1H NMR(DMSO-d6,400MHz,ppm)δ13.05(s,br,1H).MS(ESI):m/z＝92[M+H]+. Since 5 hydrogen atoms on the cyclopropyl group are deuterated in the deuterated cyclopropylcarboxylic acid represented by formula (III), the 5 atoms do not show peaks in the nuclear magnetic hydrogen spectrum, and [ M + H ]]+The peak on the mass spectrum was 92 instead of 87.
(2) Preparation of deuterated amides as shown in formula (IV)
3.6g of deuterated cyclopropylcarboxylic acid shown in formula (III) and 7.2mL of benzyl alcohol (PhCH) are added into a reaction flask2OH), 36mL of toluene, 10.8g of azido diphenyl phosphate (DPPA) and 3.6g of Triethylamine (TEA), heating to reflux reaction for 4 hours, cooling to 20-30 ℃, washing the reaction solution with 1mol/L (1N) of hydrochloric acid, saturated sodium carbonate aqueous solution and pure water in sequence, concentrating the organic phase to dryness, and purifying by column chromatography to obtain 3.8g of deuterated amide shown in formula (IV), wherein the yield is 60%. The yellow liquid is detected by mass spectrum and nuclear magnetic resonance, and the result is as follows: 1H NMR (CDCl3,400MHz):7.38-7.28(5H, M),5.12(2H, br.s),5.00(1H, br.s.) MS (ESI): M/z ═ 197[ M + H ] M + H]+. Since 5 hydrogen atoms on the cyclopropyl group are deuterated in the deuterated amide represented by the formula (IV), the 5 atoms do not show peaks in the nuclear magnetic hydrogen spectrum, and [ M + H ]]+Peaks in the mass spectrum were 197 instead of 192.
(3) Preparation of deuterated compounds represented by formula (VII)
Adding 20g of deuterated acyl shown as the formula (IV) into an eggplant-shaped bottleAmine, 160mL of methanol, 16mL of concentrated hydrochloric acid and 1g of 10% palladium on carbon (Pd/C) are subjected to hydrogenation reaction at 20-30 ℃ under normal pressure for 10 hours, the reaction product is filtered, the filtrate is concentrated to dryness, and 7.5g of light yellow solid deuterated cyclopropylamine hydrochloride shown as the formula (V) is obtained, wherein the yield is 85%. Adding 14.8g of the light yellow solid, 14.8g of amino acid methyl ester (VI) and 120mL of methanol into a reaction bottle, heating to reflux for 40 hours, cooling to 20-30 ℃, stirring for 1 hour, filtering, and washing a filter cake with 60mL of methanol to obtain 15.8g of a white solid deuterated compound shown as the formula (VII), wherein the yield is 76%. The white solid was detected by mass spectrometry and nuclear magnetic resonance and the results were as follows:1H-NMR(DMSO-d6,400MHz/ppm)：δ＝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 as the formula (VII) has 5 hydrogen atoms on the cyclopropyl group which are deuterated, so that no peak is generated at the corresponding position on a nuclear magnetic resonance hydrogen spectrum, and [ M + H ]]+The peak on the mass spectrum was 228 instead of 223.
Example 3
(1) Preparation of deuterated cyclopropylcarboxylic acid as shown in formula (III)
Adding 30mL of methanol into a reaction bottle, adding 9g of metallic sodium in batches, stirring until sodium blocks disappear to obtain sodium methoxide (NaOMe), adding 36g of ethyl hexadeutero-4-chlorobutyrate shown as a formula (II), heating and refluxing for 14 hours, cooling to 20-30 ℃, adding 50g of 30% sodium hydroxide aqueous solution, reacting for 8 hours, concentrating, adjusting the pH to 3 by using concentrated hydrochloric acid, extracting for 2 times by using dichloromethane, and concentrating to dryness to obtain 12g of deuterated cyclopropyl formic acid shown as a formula (III) as a yellow liquid, wherein the yield is 78%. The yellow liquid is detected by mass spectrum and nuclear magnetic resonance, and the result is as follows:1H NMR(DMSO-d6,400MHz,ppm)δ13.05(s,br,1H).MS(ESI):m/z＝92[M+H]+. Since 5 hydrogen atoms on the cyclopropyl group are deuterated in the deuterated cyclopropylcarboxylic acid represented by formula (III), the 5 atoms do not show peaks in the nuclear magnetic hydrogen spectrum, and [ M + H ]]+The peak on the mass spectrum was 92 instead of 87.
(2) Preparation of deuterated amides as shown in formula (IV)
3.6g of deuterated cyclopropyl as shown in the formula (III) is added into a reaction bottleBenzoic acid, 14.4mL benzyl alcohol (PhCH)2OH), 46.8mL of toluene, 18g of azido diphenyl phosphate (DPPA) and 7.2g of Triethylamine (TEA), heating to reflux reaction for 6 hours, cooling to 20-30 ℃, washing the reaction solution with 1mol/L (1N) of hydrochloric acid, saturated sodium carbonate aqueous solution and pure water in sequence, concentrating the organic phase to dryness, and purifying by column chromatography to obtain 4.5g of deuterated amide shown in formula (IV), wherein the yield is 57%. The yellow liquid is detected by mass spectrum and nuclear magnetic resonance, and the result is as follows: 1H NMR (CDCl3,400MHz):7.38-7.28(5H, M),5.12(2H, br.s),5.00(1H, br.s.) MS (ESI): M/z ═ 197[ M + H ] M + H]+. Since 5 hydrogen atoms on the cyclopropyl group are deuterated in the deuterated amide represented by the formula (IV), the 5 atoms do not show peaks in the nuclear magnetic hydrogen spectrum, and [ M + H ]]+Peaks in the mass spectrum were 197 instead of 192.
(3) Preparation of deuterated compounds represented by formula (VII)
Adding 20g of deuterated amide shown as the formula (IV), 240mL of methanol, 24mL of concentrated hydrochloric acid and 4g of 10% palladium carbon (Pd/C) into an eggplant-shaped bottle, carrying out hydrogenation reaction for 14 hours at 20-30 ℃ under normal pressure, filtering, and concentrating the filtrate to dryness to obtain 9.0g of light yellow solid deuterated cyclopropylamine hydrochloride shown as the formula (V), wherein the yield is 89%. Adding 14.8g of the light yellow solid, 29.6g of amino acid methyl ester (VI) and 177mL of methanol into a reaction bottle, heating to reflux for reaction for 60 hours, cooling to 20-30 ℃, stirring for 3 hours, filtering, and washing a filter cake with 60mL of methanol to obtain 17.9g of a deuterated compound shown as a white solid in a formula (VII), wherein the yield is 72%. The white solid was detected by mass spectrometry and nuclear magnetic resonance and the results were as follows:1H-NMR(DMSO-d6,400MHz/ppm)：δ＝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 as the formula (VII) has 5 hydrogen atoms on the cyclopropyl group which are deuterated, so that no peak is generated at the corresponding position on a nuclear magnetic resonance hydrogen spectrum, and [ M + H ]]+The peak on the mass spectrum was 228 instead of 223.
The deuterated compound shown in the formula (VII) can be used for preparing deuterated telaprevir.
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 a deuterated telaprevir key intermediate is characterized in that the deuterated telaprevir key intermediate has a structure shown in a formula (VII):
Figure FDA0002263298050000011
the preparation method of the deuterated telaprevir key intermediate comprises the following steps:
(1) 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);
Figure FDA0002263298050000012
(2) 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);
Figure FDA0002263298050000013
(3) 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);
Figure FDA0002263298050000014
(4) 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);
Figure FDA0002263298050000021
2. the preparation method of the deuterated telaprevir key intermediate as claimed in claim 1, wherein in the step (1), the cyclization and hydrolysis reaction comprises the steps of adding metal sodium blocks into methanol in batches, stirring until the metal sodium blocks disappear, adding ethyl hexa-deuterated 4-chlorobutyrate as shown in formula (II), heating and refluxing for 10-14 h, cooling to 20-30 ℃, adding 30% sodium hydroxide aqueous solution, and reacting for 4-8 h.
3. The preparation method of the deuterated telaprevir key intermediate as claimed in claim 1, wherein 1-3 g of metallic sodium block, 8-12 g of ethyl hexadeuterated 4-chlorobutyrate as shown in formula (II) and 15-20 g of 30% sodium hydroxide aqueous solution are added into every 10mL of methanol.
4. The preparation method of the deuterated telaprevir key intermediate as claimed in claim 1, wherein in step (1), the extraction is at least 2 times with dichloromethane.
5. The preparation method of the deuterated telaprevir key intermediate as claimed in claim 1, wherein in the step (2), 2-4 mL of benzyl alcohol, 10-13 mL of toluene, 3-5 g of diphenyl azide phosphate and 1-2 g of triethylamine are added to 1g of deuterated cyclopropylcarboxylic acid as shown in formula (III); and/or
The rearrangement reaction process is heating to reflux reaction for 4-6 h, and then cooling to 20-30 ℃.
6. The method for preparing the deuterated telaprevir key intermediate as claimed in claim 1, wherein in the step (2), the reaction solution is washed by sequentially using 1mol/L hydrochloric acid, saturated aqueous sodium carbonate solution and pure water.
7. The preparation method of the deuterated telaprevir key intermediate as claimed in claim 1, wherein in the step (3), 80-120 mL of methanol, 8-12 mL of concentrated hydrochloric acid and 0.5-2 g of palladium carbon are added to every 10g of deuterated amide as shown in formula (IV); and/or
The time of the reduction reaction is 10-14 h.
8. The preparation method of the deuterated telaprevir key intermediate as claimed in claim 1, wherein in the step (4), 1-2 g of amino acid methyl ester as shown in formula (VI) and 8-12 mL of methanol are added to 1g of deuterated cyclopropylamine hydrochloride as shown in formula (V); and/or
The condensation reaction process comprises the steps of heating to reflux reaction for 40-60 hours, cooling to 20-30 ℃, and stirring for 1-3 hours.
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