CN112094219A - Method for preparing intermediate of potassium ion competitive retarder - Google Patents

Method for preparing intermediate of potassium ion competitive retarder Download PDF

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CN112094219A
CN112094219A CN202010948975.2A CN202010948975A CN112094219A CN 112094219 A CN112094219 A CN 112094219A CN 202010948975 A CN202010948975 A CN 202010948975A CN 112094219 A CN112094219 A CN 112094219A
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benzyl
methoxybenzyl
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CN112094219B (en
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黄志宁
周章涛
叶伟平
费安杰
米成根
杨曼欣
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Guangdong Raffles Pharmatech Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/30—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and unsaturated

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Abstract

A method for synthesizing a key intermediate compound 1 of a novel potassium ion competitive retarder fexuprazan belongs to the field of synthesis of medical intermediates. The invention aims to solve the problems of high preparation cost, low yield and the like of the compound 1, further improve the productivity and reduce the production cost. The method takes 2, 4-difluorobenzylamine as a raw material, and sequentially carries out condensation reaction, benzyl protection, cyclization under alkaline conditions, methylation, deprotection and the like to obtain a target product. The method for synthesizing the compound 1 adopts a novel process route, has the yield of more than 50 percent, and has the characteristics of novel route, mild reaction condition, low cost and the like.

Description

Method for preparing intermediate of potassium ion competitive retarder
Technical Field
The invention belongs to the field of organic chemical synthesis of medical intermediates, and particularly relates to a method for synthesizing a key intermediate of a novel potassium ion competitive retarder fexuprazan.
Background
Erosive esophagitis is a common disease of the digestive system, mostly caused by acid reflux or bile reflux. At present, the main medicines aiming at the disease on the market comprise pantoprazole, ranitidine, famotidine, omeprazole, esomeprazole and the like. Among them, esomeprazole has the best therapeutic effect.
The korean Daewoong pharmaceutical company recently published the phase III clinical data of a novel gastroesophageal reflux disease drug fexurrazan, which is a novel potassium competitive blocker, for the first time in 2020 weeks of Digestive Disease (DDW), confirming that fexurrazan has a significant effect of inhibiting gastric acid secretion and is even superior to esomeprazole in relieving heartburn and other non-specific symptoms. It is worth mentioning that the fexuparzan digest was rated as a TOP 10% digest for all posters selected by the American Gastroenterology Association (AGA) and was selected as an outstanding poster for display during DDW.
Since fexuparzan is very expected to become a globally-popular drug in the next market of antacid secretion, the synthesis of the intermediate thereof will become one of important research subjects.
Wherein, the 4-methoxy pyrrole derivative (the structure is shown as the following) is a key middle of fexuperazan, and the fexuperazan bulk drug can be obtained by the structure through sulfonylation, reduction, oxidation and reductive amination.
Figure BDA0002676278660000011
Structural formula of fexuparzan key intermediate compound 1
Patent US20200181079a1 discloses a preparation method of fexuprazan key intermediate compound I, and the specific route is as follows:
Figure BDA0002676278660000021
the starting materials for this route are relatively expensive; although the route is short, the yield in the pyrrole ring formation and methylation steps is low, and the demand of the pharmaceutical industry is difficult to meet.
Disclosure of Invention
Aiming at the characteristics of expensive materials, low yield and the like of the existing synthetic route, the invention provides a novel method for preparing the compound 1.
The present invention provides a process for preparing compound 1, the process comprising: 2, 4-difluorobenzylamine is taken as a raw material, and a compound 1 is obtained through condensation reaction, benzyl protection, cyclization under alkaline conditions, methylation and deprotection, wherein the reaction process is shown in the following synthetic route,
Figure BDA0002676278660000031
wherein R is an organic substituent group; preferably, R is benzyl or substituted benzyl.
According to one embodiment of the invention, the method comprises the steps of:
s1, 2, 4-difluorobenzylamine is used as a raw material, dimethyl malonate and a condensing agent are condensed, and the compound shown in the formula 2 is obtained.
S2, under the action of alkali, the compound shown in the formula 2 and benzyl bromide are subjected to substitution reaction to obtain the compound shown in the formula 3.
S3, under the action of alkali, cyclizing the compound shown in the formula 3 to obtain a compound shown in a formula 4;
s4, under the action of alkali, methylating the compound shown in the formula 4 and a methylating agent to obtain a compound shown in the formula 5;
s5 and the compound represented by formula 5 were deprotected further to obtain compound 1.
According to an embodiment of the present invention, in the above synthetic scheme, R is any one of benzyl, 4-methoxybenzyl, 4-methylbenzyl, 2-methoxybenzyl, 2, 4-dimethoxybenzyl; when R is a benzyl group, it is preferred because of its low cost.
According to an embodiment of the present invention, in step S1, the condensing agent includes one of triethyl orthoformate, trimethyl orthoformate, and N, N-dimethylformamide dimethyl acetal, which is preferable because the reaction efficiency is high when N, N-dimethylformamide dimethyl acetal is used as the condensing agent; preferably, in step S1, the molar ratio of the 2, 4-difluorobenzylamine to the dimethyl malonate to the condensing agent is 0.8 to 1.2: 1.8-2.2: 1, more preferably 0.9 to 1.1: 1.9-2.1: 1, more preferably 1.1: 2.0: 1.
according to one embodiment of the present invention, in step S2, the base includes an inorganic base and an organic base; wherein the inorganic base comprises potassium carbonate, sodium carbonate, cesium carbonate, which is preferred because of its high activity; the organic base comprises triethylamine, N-diisopropylethylamine and 1, 8-diazabicycloundecen-7-ene; preferably, the molar ratio of the compound represented by formula 2 to benzyl bromide is 1: 1.0 to 2.0, more preferably 1: 1.0 to 1.5, more preferably 1: 1.05.
according to one embodiment of the present invention, in step S3, the base includes sodium bis (trimethylsilyl) amide, lithium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, lithium N, N-diisopropylamide; preferably, the molar ratio of the compound represented by formula 3 to the base is 1: 1.5 to 3.0, more preferably 1: 1.5-2.5, more preferably 1: 2.1.
according to one embodiment of the present invention, in step S4, the alkali includes sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride; the methylating agent comprises dimethyl sulfate and methyl iodide.
Provided herein are compounds represented by the following formula 2
Figure BDA0002676278660000041
Provided herein is the use of compound 2 as described above for the preparation of compound 3.
Provided herein is a compound represented by the following formula 3, wherein R is benzyl, 4-methoxybenzyl, 4-methylbenzyl, 2-methoxybenzyl, or 2, 4-dimethoxybenzyl; preferably, R is benzyl.
Figure BDA0002676278660000042
Provided herein is the use of compound 3 as described above for the preparation of compound 4.
Provided herein are compounds represented by the following formula 4, wherein R is benzyl, 4-methoxybenzyl, 4-methylbenzyl, 2-methoxybenzyl, 2, 4-dimethoxybenzyl; preferably, R is benzyl.
Figure BDA0002676278660000051
Provided herein is the use of compound 4 as described above for the preparation of compound 5.
Provided herein are compounds represented by the following formula 5, wherein R is benzyl, 4-methoxybenzyl, 4-methylbenzyl, 2-methoxybenzyl, 2, 4-dimethoxybenzyl; preferably, R is benzyl.
Figure BDA0002676278660000052
Provided herein is the use of compound 5 as described above for the preparation of compound 1.
Compared with the prior art, the invention has the following advantages:
1. the method for preparing the compound 1 has the characteristics of novel process route, novel intermediates of formula 2, formula 3, formula 4 and formula 5, total yield of more than 50 percent (for comparison, the yield of the route disclosed by the patent US20200181079A1 is 25 percent), relatively mild reaction conditions and the like.
2. The synthetic route of the invention has the advantages of easily obtained used raw materials, lower cost (reduced by more than half compared with the existing route), no special operation process, low requirement on equipment and suitability for large-scale industrial production.
Detailed Description
The following detailed description of the preferred embodiments of the present invention is provided to enable those skilled in the art to more clearly understand the advantages and features of the present invention and to clearly define the scope of the present invention.
Example 1:
Figure BDA0002676278660000061
1. synthesis of Compound 2
66.7 g of malonic acid dimethyl ester and 60.1 g of N, N-dimethylformamide dimethyl acetal are added into a 500ml reaction bottle, the temperature is increased to 70 ℃ for reaction for 2 hours, the reaction bottle is cooled to room temperature, 65 g of 2, 4-difluorobenzylamine is added, the temperature is increased to 70 ℃ for further reaction for 2 hours. Cooling to room temperature, adding 500ml of water and 500ml of ethyl acetate, stirring for 10 minutes, standing for layering, washing an organic phase with saturated saline solution, drying with anhydrous sulfuric acid, concentrating under reduced pressure to remove the solvent, adding n-heptane into a residue, pulping, filtering, and drying to obtain 111.1 g of compound 2, wherein the yield is 85.8%, and the white solid is obtained.
1H-NMR(400MHz，d6-DMSO):9.40(br,1H),8.14-8.18-(m,1H),7.42-7.49(m,1H),7.27-7.32(m,1H),7.12-7.17(m,1H),4.64(d,2H),3.64(d,3H),3.60(d,3H)；ESI-MS:m/z 286.14[M+1]
2. Synthesis of Compound 3A
In a 250 ml reaction flask were added 15 g of compound 2, 21 g of potassium carbonate powder, 150 ml of N, N-dimethylformamide, 9.0 g of benzyl bromide, and the mixture was heated to 60 ℃ under nitrogen atmosphere for 2 hours. Cooled to room temperature, 150 ml of water were added and extracted twice with ethyl acetate. The combined organic phases were washed successively with water, saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 18.1 g of compound 3A in 91.5% yield as a pale yellow oil which was used directly in the next reaction.
1H-NMR(400MHz，d6-DMSO):7.80(s,1H),7.19-7.37(m,6H),7.10(m,2H),4.51(br,4H),3.57(s,3H),3.34(s,3H)；ESI-MS:m/z 376.20[M+1]
3. Synthesis of Compound 4A
18.1 g of the compound of formula 3A, 180 ml of tetrahydrofuran are added into a 500ml reaction flask and cooled to-10 ℃ under the protection of nitrogen (the temperature can be controlled between-30 ℃ and 20 ℃, the temperature is reduced, and the selectivity of the reaction is improved). 50.6 ml of 2M sodium bis (trimethylsilyl) amide solution are added dropwise under controlled temperature. After the dropwise addition, the reaction solution was transferred to an aqueous citric acid solution to quench. After standing, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 14.4 g of compound 4A in 86.8% yield as an oil, which was used directly in the next reaction.
1H-NMR(400MHz，d6-DMSO):7.85(s,1H),7.48(s,1H),7.18-7.31(m,5H),7.07(m,1H),6.82(m,2H),4.98(s,2H),3.73(s,3H)；ESI-MS:m/z 344.16[M+1]
4. Synthesis of Compound 5A
14.4 g of the compound of formula 4A and 140 ml of methanol are added into a 250 ml reaction bottle, then 1.85 g of sodium hydroxide solution in 10 ml of methanol is added dropwise, 10.6 g of dimethyl sulfate is added after the dropwise addition, and the reaction is carried out for 5 to 10 hours at room temperature. After the reaction, acetic acid was added to neutralize the reaction solution, and the solution was concentrated to remove methanol. Ethyl acetate and water were added, the mixture was allowed to stand for separation, and the organic layer was washed with water and saturated brine in this order, dried over anhydrous sodium sulfate, concentrated, and the residue was crystallized from ethyl acetate and n-heptane to give 13.4 g of compound 5A in 89.4% yield as a pale yellow solid.
1H-NMR(400MHz，d6-DMSO):7.59(s,1H),7.20-7.32(m,5H),7.11(m,1H),6.85(m,2H),4.98(s,2H),3.72(s,3H),3.61(s,3H)；ESI-MS:m/z 358.17[M+1]
5. Synthesis of Compound 1
Adding 10 g of compound 5A, 100 ml of methanol and 1 g of 10% palladium carbon into a 200 ml hydrogenation kettle, sealing the reaction kettle, replacing with nitrogen, and hydrogenating for 10 hours at 50-60 ℃ and 0.4-0.5 MPa. After cooling, displacement with nitrogen, filtration, concentration of the filtrate under reduced pressure and recrystallization of the residue with ethyl acetate and n-heptane, 6.8 g of compound I are obtained, yield 91%, pale yellow solid.
1H-NMR(400MHz，CDCl3):8.77(s,1H),8.12(m,1H),7.30(d,1H),6.95(t,1H),6.88(t,1H),3.87(s,3H),3.85(s,3H)；ESI-MS:m/z 268.08[M+1]
Example 2:
Figure BDA0002676278660000081
1. synthesis of Compound 2
50.8 g of dimethyl malonate, 74.1 g of trimethyl orthoformate and 71.3 g of acetic anhydride are added into a 500mL reaction bottle, heated to 100 ℃ for reaction for 2 hours, cooled to room temperature, added with 50 g of 2, 4-difluorobenzylamine, heated to 90 ℃ for further reaction for 2 hours. Cooling to room temperature, adding 500ml of water and 500ml of ethyl acetate, stirring for 10 minutes, standing for layering, washing the organic phase with sodium bicarbonate solution and saturated saline solution in turn, drying with anhydrous sulfuric acid, and concentrating under reduced pressure. The residue was slurried with n-heptane, filtered and dried to give 83.9 g of compound 2 in 84.2% yield as a white solid.
2. Synthesis of Compound 3B
In a 500ml reaction flask were added 20 g of Compound 2, 45.7 g of cesium carbonate powder, 200 ml of N, N-dimethylformamide, and 11.5 g of 4-methoxybenzyl chloride, and the mixture was heated to 80 ℃ under nitrogen atmosphere for reaction for 2 hours. After cooling to room temperature, 200 ml of water were added, followed by extraction twice with ethyl acetate. The combined organic phases were washed successively with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 24.9 g of compound 3B, 87.6% yield, as a pale yellow oil, which was used directly in the next reaction.
3. Synthesis of Compound 4B
A500 ml reaction flask was charged with 24.9 g of the compound of formula 3B, 249 ml of tetrahydrofuran and cooled to-10 ℃ under nitrogen. 64.5 ml of a 2M solution of sodium bis (trimethylsilyl) amide are added dropwise at controlled temperature. After the dropwise addition, the reaction solution was quenched in an aqueous citric acid solution. After standing, the organic layer was separated, and the aqueous layer was extracted once with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 20.3 g of compound 4B in 88.4% yield as a pale yellow oil, which was used directly in the next reaction.
4. Synthesis of Compound 5B
20.3 g of the compound of formula 4B, 200 ml of acetone and 15 g of potassium carbonate powder are added into a 500ml reaction bottle, the temperature is raised to reflux, 10.3 g of dimethyl sulfate is dripped, and the reaction is carried out for 3 hours under the condition of heat preservation. After the reaction, the temperature was lowered to room temperature, and the solid was removed by filtration. After the filtrate was concentrated, ethyl acetate was added, washed twice with water, the organic layer was dried over anhydrous sodium sulfate, concentrated, and the residue was slurried with n-heptane to give 20.2 g of compound 5B in 96% yield as a pale yellow solid.
5. Synthesis of Compound 1
In a 500ml reaction flask were charged 10 g of compound 5B, 100 ml of acetonitrile, 50 ml of water, 56 g of ceric ammonium nitrate, and reacted at room temperature for 12 hours. 100 ml of water and 100 ml of ethyl acetate are added. The mixture was allowed to stand for separation, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with water and saturated brine in this order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product of Compound 1. The crude product was crystallized from ethyl acetate and n-heptane to give 6.1 g of compound 1 in 85.6% yield as a pale yellow solid.

Claims (15)

1. A process for preparing compound 1, the process comprising: the compound 1 is obtained by taking 2, 4-difluorobenzylamine as a raw material and performing condensation reaction, benzyl protection, cyclization under alkaline conditions, methylation and deprotection, wherein the reaction process is shown in the following synthetic route:
Figure FDA0002676278650000011
wherein R is an organic substituent group; preferably, R is benzyl or substituted benzyl.
2. Method according to claim 1, characterized in that it comprises the following steps:
s1, condensing 2, 4-difluorobenzylamine serving as a raw material with dimethyl malonate and a condensing agent to obtain a compound shown as a formula 2;
s2, under the action of alkali, carrying out substitution reaction on the compound shown in the formula 2 and benzyl bromide to obtain a compound shown in a formula 3;
s3, cyclizing the compound shown in the formula 3 under the action of alkali to obtain a compound shown in a formula 4;
s4, methylating the compound shown in the formula 4 with a methylating agent under the action of alkali to obtain a compound shown in the formula 5;
s5 and the compound represented by formula 5 were deprotected further to obtain compound 1.
3. The method according to claim 1 or 2,
r is benzyl, 4-methoxybenzyl, 4-methylbenzyl, 2-methoxybenzyl or 2, 4-dimethoxybenzyl;
preferably, R is benzyl.
4. The method as claimed in claim 2, wherein in step S1, the condensing agent includes at least one of triethyl orthoformate, N-dimethylformamide dimethyl acetal;
preferably, the condensing agent is N, N-dimethylformamide dimethyl acetal;
preferably, in step S1, the molar ratio of the 2, 4-difluorobenzylamine to the dimethyl malonate to the condensing agent is 0.8 to 1.2: 1.8-2.2: 1, more preferably 0.9 to 1.1: 1.9-2.1: 1, more preferably 1.1: 2.0: 1.
5. the method of claim 2, wherein in step S2, the base comprises an inorganic base and an organic base;
preferably, the inorganic base comprises at least one of potassium carbonate, sodium carbonate and cesium carbonate; the organic base comprises at least one of triethylamine, N-diisopropylethylamine and 1, 8-diazabicycloundecen-7-ene;
preferably, the base is cesium carbonate.
Preferably, the molar ratio of the compound represented by formula 2 to benzyl bromide is 1: 1.0 to 2.0, more preferably 1: 1.0 to 1.5, more preferably 1: 1.05.
6. the method of claim 2, wherein in step S3, the base comprises at least one of sodium bis (trimethylsilyl) amide, lithium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, and lithium N, N-diisopropylamide;
preferably, the base is sodium bis (trimethylsilyl) amide.
Preferably, the molar ratio of the compound represented by formula 3 to the base is 1: 1.5 to 3.0, more preferably 1: 1.5-2.5, more preferably 1: 2.1.
7. the method of claim 2, wherein in step S4, the alkali comprises at least one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and sodium hydride; the methylating agent comprises at least one of dimethyl sulfate and methyl iodide.
Preferably, the base is potassium carbonate and the methylating agent is dimethyl sulfate.
8. A compound represented by the following formula 2,
Figure FDA0002676278650000031
9. use of a compound according to claim 8 for the preparation of compound 3, said compound 3 having the structure shown in formula 3 below:
Figure FDA0002676278650000032
10. a compound having a structure represented by the following formula 3, wherein R is benzyl, 4-methoxybenzyl, 4-methylbenzyl, 2-methoxybenzyl or 2, 4-dimethoxybenzyl; preferably, R is a benzyl group,
Figure FDA0002676278650000041
11. use of a compound according to claim 10 for the preparation of compound 4, said compound 4 having the structure shown in formula 4 below:
Figure FDA0002676278650000042
12. a compound having a structure represented by the following formula 4, wherein R is benzyl, 4-methoxybenzyl, 4-methylbenzyl, 2-methoxybenzyl or 2, 4-dimethoxybenzyl; preferably, R is a benzyl group,
Figure FDA0002676278650000043
13. use of a compound according to claim 12 for the preparation of compound 5, said compound 5 having the structure shown in formula 5 below:
Figure FDA0002676278650000051
14. a compound having a structure represented by the following formula 5, wherein R is benzyl, 4-methoxybenzyl, 4-methylbenzyl, 2-methoxybenzyl, 2, 4-dimethoxybenzyl; preferably, R is a benzyl group,
Figure FDA0002676278650000052
15. use of a compound according to claim 14 for the preparation of compound 1, said compound 1 having the structure shown in formula 1 below:
Figure FDA0002676278650000053
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CN115772110A (en) * 2022-12-19 2023-03-10 沈阳药科大学 Method for preparing potassium ion competitive retarder non-surazan intermediate
WO2024221786A1 (en) * 2023-04-28 2024-10-31 诚达药业股份有限公司 4-methoxypyrrole derivative and synthesis method therefor

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