CN112521370B - Radioisotope carbon-14labeled D-rabeprazole sodium and synthetic method thereof - Google Patents

Radioisotope carbon-14labeled D-rabeprazole sodium and synthetic method thereof Download PDF

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CN112521370B
CN112521370B CN202011494539.9A CN202011494539A CN112521370B CN 112521370 B CN112521370 B CN 112521370B CN 202011494539 A CN202011494539 A CN 202011494539A CN 112521370 B CN112521370 B CN 112521370B
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杨征敏
马双江
王国通
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Zhejiang aisuotuo Technology Co.,Ltd.
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Abstract

The invention provides a radioisotope carbon-14labeled D-rabeprazole sodium ((R) - (+) -2- { [4- (3-methoxypropoxy) -3-methylpyridin-2-yl)]Methanesulfinyl } -1H-benzo [ d,2-14C]Imidazole sodium), which provides a feasible, safe and economic method for the synthesis of the 2-position carbon-14 mark in the benzimidazole segment in the prazole drug molecule for the first time, and is characterized in that: the target product, namely the carbon-14labeled D-rabeprazole sodium, is obtained by taking the formic acid ester of the radioisotope carbon-14labeled carbonyl as a radioisotope raw material and carrying out cyclization, sulfo-substitution, chiral oxidation, salt formation and other reactions with o-phenylenediamine. The carbon-14labeled D-rabeprazole sodium can be used as a radioactive tracer, and is mainly used for pharmacokinetic researches such as absorption, distribution, metabolism and excretion (ADME) and the like in preclinical animal tests and clinical human body tests of the chiral D-rabeprazole sodium; meanwhile, the method of the invention provides reference for the preparation of the carbon-14-containing synthetic building block.

Description

Radioisotope carbon-14labeled D-rabeprazole sodium and synthetic method thereof
Technical Field
The invention belongs to the field of radiochemical synthesis, and particularly relates to radioisotope carbon-14labeled D-rabeprazole sodium ((R) - (+) -2- { [4- (3-methoxypropoxy) -3-methylpyridin-2-yl)]Methanesulfinyl } -1H-benzo [ d,2-14C]Imidazole sodium) is prepared.
Background
Rabeprazole sodium (English name: sodium rebeprazole, sodium pariprazole; Chinese name: 2- { [4- (3-methoxypropoxy) -3-methylpyridin-2-yl]Mesyl } -1H-benzimidazole sodium) is a novel class of Proton Pump Inhibitors (PPIs) that act by blocking the superficial layers of human gastric mucosal cells (H)+/K+) -secretion of ATPase enzyme thereby inhibiting gastric acid secretion. It can be used for treating gastric ulcer, duodenal ulcer, and anastomosisMouth ulcers, gastroesophageal reflux and Zollinger-Ellison syndrome.
The carbon-14labeled rabeprazole sodium radioactive isotope is a radioactive tracer necessary for researching the safety and the effectiveness of the rabeprazole sodium in preclinical animal tests and clinical human pharmacokinetics (tissue distribution, metabolite structure identification, mass balance and the like). In the carbon-14 pharmacokinetic research of the prazole medicine, an imidazole ring and pyridine-2-methylene with chemical stability and metabolic stability are often selected as marking positions. In the radiosynthesis of a drug in which imidazole ring carbon-14 is labeled with a prazole, the term14C]Carbon disulfide ([ 2 ]14C]CS2) As isotopic starting material (The preparation of14C,35S and 13C laboratory of spherical, compact radiopharmam, 1986,23(1): 21-33; synthesis of carbon-14 layered dispersed compact radiopharmams, 1988,25(8):891-900), but the preparation process of the raw material is complicated, the post-treatment is complicated, and the price is high. Further, the term14C]The boiling point of the carbon disulfide (about 46 ℃) is low, the carbon disulfide is very volatile in the experiment transfer operation process, and the human body is possibly caused by the fact that experimenters are carelessly sucked into the human body14And C, internal irradiation endangers the health of the body. In order to ensure the personal safety of experimenters, the subsequent radiosynthesis of the azole drugs at the sites is changed into ethyl (thiocarbonyl) produced by the international radioisotope carbon-14 manufacturing factory14C]Potassium xanthate (made of [ [ solution ] ])14C]Converted from carbon disulfide) or by14C]Thiourea is an isotope raw material, but the radioactive synthesis routes of the two raw materials are long, so that the price of the raw materials is extremely high, and finally, the cost of the radioactive synthesis of the prazole medicine is increased.
Although the racemic form of (R)/(S) -rabeprazole sodium is mainly used in the currently clinically used rabeprazole sodium, there are pharmacological and toxicological differences between the two optical isomers. The optical isomer (R) - (+) -rabeprazole sodium has significantly stronger drug effect than the racemes of (S) - (-) -rabeprazole sodium and (R)/(S) -rabeprazole sodium, so that the optical isomer (R) - (+) -rabeprazole sodium is developed again as a novel proton pump inhibitor.
In the literature newspaperIn the lane, the imidazole ring carbon-14 markers of the prazole drugs are all racemates. A method for synthesizing the imidazole ring carbon-14 marker of rabeprazole sodium was reported by Tagami K et al in 1993 (Synthesis of14C-lamellar sodium pariprazole (E3810), J laboratory Compound Radiopharm,1993,33(9):849-14C]The carbon disulfide is an isotope raw material, the method still has high safety risk to operators, the isotope raw material cost is high, and the marker is a racemate and cannot be used for pharmacokinetic research of the optical isomer (R) - (+) -rabeprazole sodium. Although the target substance of the present patent can be obtained by chiral resolution of racemate, at least half of radioactive substances must be lost by chiral resolution, and sulfoxide, which is the target substance, is easily oxidized by air and degenerates during resolution. Therefore, the invention should be developed.
Disclosure of Invention
In view of the above, in order to find a synthetic route of an imidazole ring carbon-14 marker of an optical isomer (R) - (+) -rabeprazole sodium with lower isotope raw material cost, easy self-preparation and high safety, the present application firstly provides an imidazole ring carbon-14 marker of an optical isomer (R) - (+) -rabeprazole sodium isotopically labeled at different carbon positions, and the present invention provides a radioisotope carbon-14labeled d-rabeprazole sodium, which is characterized in that: the radioisotope carbon-14 labeling site is positioned on the 2-carbon atom of the imidazole ring in the dextral rabeprazole sodium molecule, and the structural formula is as follows:
Figure BDA0002841732550000021
the invention has the beneficial effects that:
the carbon-14labeled D-rabeprazole sodium can be used as a radioactive tracer, and is mainly used for pharmacokinetic researches such as absorption, distribution, metabolism and excretion (ADME) and the like in preclinical animal tests and clinical human body tests of the chiral D-rabeprazole sodium.
The invention also provides a synthetic method of the radioisotope carbon-14labeled D-rabeprazole sodium, which is characterized by comprising the following steps:
s1: under the protection of inert gas and under the acidic condition, o-phenylenediamine and [ carbonyl-14C]The formate reacts in a low-boiling point alcohol solvent at a temperature of between 10 ℃ below zero and 150 ℃, and after the reaction is finished, benzo [ d,2-14C]Imidazole;
s2: under the protection of inert gas and at a reaction temperature of 50-250 ℃, the benzo [ d,2-14C]Imidazole and sulfur powder react in a high-boiling point aprotic organic solvent, and 2-mercaptobenzo [ d,2-14C]Imidazole;
s3: reacting the 2-mercaptobenzo [ d,2-14C]Imidazole, 2-chloromethyl-4- (3-methoxy propoxy) -3-methylpyridine hydrochloride and alkali are stirred in a polar organic solvent for 3-20 hours until the reaction is finished; then adding water to the reaction mixture to precipitate the product, filtering, washing with water and vacuum drying at room temperature to obtain 2- { [4- (3-methoxypropoxy) -3-methylpyridin-2-yl]Methylthio } -1H-benzo [ d,2-14C]Imidazole;
s4: the 2- { [4- (3-methoxypropoxy) -3-methylpyridin-2-yl group is reacted at a reaction temperature of 10-100 DEG C]Methylthio } -1H-benzo [ d,2-14C]Imidazole, L- (+) -diethyl tartrate (abbreviated as L-DET) and tetraisopropyl titanate (abbreviated as TIPT) are stirred for 0.5 to 6 hours in a mixed solution of an aprotic solvent and water; then adjusting the reaction temperature to-10-35 ℃, sequentially adding N, N-diisopropylethylamine (abbreviated as DIPEA) and cumene hydroperoxide (abbreviated as CHP) into the reaction system, and keeping the reaction temperature of-10-35 ℃ for 12-36 hours to finish the reaction; after quenching reaction, sequentially adding an alkaline aqueous solution and a fat-soluble solvent into the reaction mixture; separating to obtain a water phase, adding acid to adjust the pH of the water phase to 10-11 to precipitate a product, filtering the precipitate, and drying the precipitate in vacuum at room temperature to obtain (R) - (+) -2- { [4- (3-methoxypropoxy) -3-methylpyridin-2-yl]Methanesulfinyl } -1H-benzo [ d,2-14C]Imidazole;
s5: under the protection of inert gas and at room temperature, the (R) - (+) -2- { [4- (3-methoxypropoxy) -3-methylpyridin-2-yl]Methanesulfinyl } -1H-benzo [ d,2-14C]Of imidazole with sodium hydroxideStirring the low molecular weight alcohol solution for 0.5-3 h, and concentrating to obtain a target substance of carbon-14labeled D-rabeprazole sodium ((R) - (+) -2- { [4- (3-methoxy propoxy) -3-methylpyridin-2-yl)]Methanesulfinyl } -1H-benzo [ d,2-14C]Sodium imidazole).
The invention has the beneficial effects that:
the radioisotope raw material [ carbonyl-14C]The formate is easy to be used as the raw material of radioactive isotope from common source14C]The barium carbonate is prepared by itself, and the links of isotope raw material import and export are omitted, so that the cost is low and the research and development period is short; carbonyl-14C]The formate is high-boiling point viscous substance or solid, is extremely difficult to volatilize, and cannot cause the problem of experimenters14C, internal irradiation, so that the problem of safety risk of experimental operation does not exist; the carbon-14 marker of the optical isomer (R) - (+) -rabeprazole sodium with high optical purity is obtained by adopting a chiral oxidation synthesis method, the optical purity meets the requirements of a pharmacological test, chiral resolution is not required, and the radiochemical yield of a target object is high.
Preferably, in S1, the [ carbonyl-14C]Formates include, but are not limited to [ carbonyl-14C]Ethyl formate, [ carbonyl-14C]Cyclohexyl formate, [ carbonyl-14C]Tert-butyl formate, [ carbonyl-14C]Benzyl formate; the low boiling point alcohol solvent includes but is not limited to methanol, ethanol, ethylene glycol.
Preferably, in S2, the high-boiling aprotic organic solvent includes, but is not limited to, diphenyl ether, N-methylpyrrolidone.
Preferably, in S3, the base includes, but is not limited to, sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate; the polar organic solvent includes, but is not limited to, methanol, ethanol, acetonitrile.
Preferably, in S4, the aprotic solvent includes, but is not limited to, benzene, toluene; the fat-soluble solvent includes but is not limited to ethyl acetate, dichloromethane, methyl isobutyl ketone.
Preferably, in S5, the low molecular weight alcohol solution includes, but is not limited to, methanol, ethanol.
The invention also provides a carbon-14-containing synthetic building block synthesized according to the synthesis method.
Drawings
FIG. 1 shows the structure of carbon-14labeled D-rabeprazole sodium of the present invention.
FIG. 2 is a synthetic route diagram of the present invention.
FIG. 3 is a benzo [ d,2-14C]Nuclear magnetic resonance hydrogen spectrum of imidazole.
FIG. 4 is a scheme showing 2-mercaptobenzo [ d,2-14C]Nuclear magnetic resonance hydrogen spectrum of imidazole.
FIG. 5 is a drawing of the radioactive intermediate 2- { [4- (3-methoxypropoxy) -3-methylpyridin-2-yl ] of the present invention]Methylthio } -1H-benzo [ d,2-14C]Nuclear magnetic resonance hydrogen spectrum of imidazole.
FIG. 6 is a scheme showing the radioactive intermediate of the present invention, (R) - (+) -2- { [4- (3-methoxypropoxy) -3-methylpyridin-2-yl group]Methanesulfinyl } -1H-benzo [ d,2-14C]Nuclear magnetic resonance hydrogen spectrum of imidazole.
FIG. 7 is a nuclear magnetic resonance hydrogen spectrum of carbon-14labeled D-rabeprazole sodium.
Detailed Description
The embodiments of the present invention are described below with reference to specific embodiments, and other advantages and effects of the present invention will be easily understood by those skilled in the art from the disclosure of the present specification. The invention is capable of other and different embodiments and of being practiced or of being carried out in various ways, and its several details are capable of modification in various respects, all without departing from the spirit and scope of the present invention.
Example 1:
referring to FIG. 2, o-phenylenediamine (1,65mg,0.6mmol) was added to a dry reaction tube under argon atmosphere and replaced with argon three times; ethylene glycol (1.5mL) was added and concentrated sulfuric acid (0.1mL, 98%) and [ carbonyl-14C]A solution of 4-phenyl benzyl formate (0.5mmol,50mCi/mmol) in ethylene glycol (2 mL); the reaction was completed after stirring the reaction in an oil bath at 150 ℃ for 12 hours. At room temperature, using saturated sodium carbonate to regulate pH value of reaction system to alkalinity, separating ethyl acetate/water, drying ethyl acetate phase, suction filtering and concentratingCondensing and stirring the sample, and carrying out column chromatography (normal hexane/ethyl acetate: 20/1) to obtain a radioactive intermediate benzo [ d,2-14C]Imidazole (2,51mg, radiochemical yield 85%).1H NMR(400MHz,DMSO-d6)δ:12.43(s,1H),8.18(s,1H),7.62–7.52(m,2H),7.20–7.13(m,2H).ESI-MS m/z:119[M+H]+,121[M+2+H]+(see FIG. 3).
Under the protection of argon, benzo [ d,2-14C]Imidazole (2,51mg) and sulfur powder (20mg) were added to a dry reaction tube, and replaced with argon gas three times; injecting N-methylpyrrolidone (2mL), placing the reaction tube in a 250 ℃ oil bath, stirring for 3h, and finishing the reaction; after TLC monitors that the raw materials are completely consumed, the reaction is stopped, and the reaction tube is taken out and cooled to room temperature; 1mL of water was added to the reaction mixture, and the pH of the mixture was adjusted to 4 with diluted hydrochloric acid. Extracting with ethyl acetate (2mL) for 3 times, separating, drying ethyl acetate phase with anhydrous sodium sulfate, filtering, and concentrating to obtain crude product of 2-mercaptobenzo [ d,2-14C]Imidazole (3,60mg, radiochemical yield 90%) was used directly in the next reaction.1H NMR(400MHz,DMSO-d6)δ:12.47(s,2H),7.15–7.06(m,4H).ESI-MS m/z:151[M+H]+,153[M+2+H]+(see FIG. 4).
Under the cooling of ice bath, 2-mercaptobenzo [ d,2-14C]Adding potassium carbonate (136mg) into a methanol (2mL) solution of imidazole (3,60mg), and stirring for 0.5 h; 2-chloromethyl-4- (3-methoxypropoxy) -3-methylpyridine hydrochloride (4) was then added and the resulting mixture was stirred at room temperature for a further 16 h. To the reaction mixture was added 4mL of water to precipitate the product. The resulting solid was collected by filtration, washed with water and dried under vacuum at room temperature to give the radioactive intermediate 2- { [4- (3-methoxypropoxy) -3-methylpyridin-2-yl]Methylthio } -1H-benzo [ d,2-14C]Imidazole (5,115mg, radiochemical yield 87%).1H NMR(400MHz,DMSO-d6)δ:12.58(s,1H),8.22(d,J＝5.6Hz,1H),7.50(s,1H),7.37(s,1H),7.11(dd,J＝5.9,2.9Hz,2H),6.93(d,J＝5.7Hz,1H),4.68(s,2H),4.09(t,J＝6.2Hz,2H),3.47(t,J＝6.2Hz,2H),3.23(s,3H),2.20(s,3H),1.93～1.96(m,2H).ESI-MS m/z:344[M+H]+,346[M+2+H]+(see FIG. 5).
To the stirred intermediate 2- { [4- (3-methoxypropoxy) -3-methylpyridine at 100 deg.C-2-yl]Methylthio } -1H-benzo [ d,2-14C]To a suspension of imidazole (5,115mg) in toluene (2mL) were added water (3mg), diethyl L- (+) -tartrate (abbreviated as L-DET; 103mg) and tetraisopropyl titanate (abbreviated as TIPT; 76mg) in this order, and the mixture was stirred at a constant temperature for 20 min. The temperature of the reaction system is reduced to 0-10 ℃, N-diisopropylethylamine (22mg) and cumene hydroperoxide (76mg, content 80%) are added, and the mixture is stirred for 18 hours at 10 ℃. After the reaction was completed, the reaction was quenched by adding an equivalent amount of an aqueous solution of sodium thiosulfate (0.5mL), stirred for 0.5h, filtered to remove unreacted starting compounds, the filter cake was washed with toluene (3mL), the filtrate was collected, extracted 3 times with 12.5% aqueous ammonia, and the aqueous ammonia phases were combined. The aqueous ammonia phase was washed 3 times with methyl isobutyl ketone, the aqueous ammonia phase was collected and filtered through an organic filter (0.45 μm). And (4) cooling by using an ice bath, dropwise adding 10% acetic acid until the ammonia water phase is turbid, and rapidly stirring for 2 hours until a white solid is separated out. Filtering, rinsing the filter cake to neutrality with pure water, collecting the filter cake, and vacuum drying at room temperature overnight to obtain the radioactive intermediate (R) - (+) -2- { [4- (3-methoxypropoxy) -3-methylpyridin-2-yl]Methanesulfinyl } -1H-benzo [ d,2-14C]Imidazole (6,90mg, radiochemical yield 75%).1H NMR(400MHz,DMSO-d6)δ:13.55(s,1H),8.19(d,J＝5.6Hz,1H),7.63(s,2H),7.29(s,2H),6.94(d,J＝5.7Hz,1H),4.73(m,2H),4.08(t,J＝6.2Hz,2H),3.46(t,J＝6.2Hz,2H),3.22(s,3H),2.12(s,3H),1.98～1.93(m,2H).ESI-MS m/z:360[M+H]+,362[M+2+H]+(see FIG. 6).
To the ice-cold intermediate (R) - (+) -2- { [4- (3-methoxypropoxy) -3-methylpyridin-2-yl]Methanesulfinyl } -1H-benzo [ d,2-14C]NaOH is added into the methanol solution of imidazole (6), the mixture is stirred for 0.5h and concentrated to obtain the target product, namely the carbon-14labeled D-rabeprazole sodium (90mg, radiochemical yield 95%), please refer to figure 1. The chemical purity of the target product carbon-14 marked dextro-rabeprazole sodium is more than 98 percent, the chiral purity is more than 98 percent, and the radiochemical purity is more than 99 percent by adopting the conventional method (J Label Compound radiopharm.2018,61(11): 812-.1H NMR(400MHz,DMSO-d6)δ:13.56(s,1H),8.19(d,J＝5.6Hz,1H),7.63(s,2H),7.30(s,2H),6.94(d,J＝5.7Hz,1H),4.73(m,2H),4.08(t,J＝6.2Hz,2H),3.46(t,J＝6.2Hz,2H),3.21(s,3H),2.12(s,3H),1.97～1.93(m,2H).ESI-MS m/z:360[M-Na+2H]+,362[M-Na+2H+2]+(see FIG. 7).
Example 2:
under the protection of argon, o-phenylenediamine (1,65mg,0.6mmol) is added into a dry reaction tube, and argon is replaced for three times; methanol (1.5mL) was added, and concentrated sulfuric acid (0.1mL, 98%) and [ carbonyl-14C]A solution of ethyl formate (0.5mmol,1mCi/mmol) in methanol (2 mL); the reaction is finished after stirring and reacting for 8 hours in a bath solution at the temperature of minus 10 ℃. After conventional post-treatment (same as example 1) and column chromatography (n-hexane/ethyl acetate 20/1), the radioactive intermediate benzo [ d,2-14C]Imidazole (2,53mg, radiochemical yield 88%).
Under the protection of argon, benzo [ d,2-14C]Imidazole (2,51mg) and sulfur powder (20mg) were added to a dry reaction tube, and replaced with argon gas three times; diphenyl ether (2mL) was injected and the reaction tube was stirred in a 50 ℃ oil bath for 72h to complete the reaction. After conventional post-treatment (same as example 1), crude 2-mercaptobenzo [ d,2-14C]Imidazole (3,23mg, radiochemical yield 34%) was used directly in the next reaction.
Under the cooling of ice bath, 2-mercaptobenzo [ d,2-14C]Adding sodium carbonate (105mg) into imidazole (3,60mg) solution in acetonitrile (2mL), and stirring for 0.5 h; 2-chloromethyl-4- (3-methoxypropoxy) -3-methylpyridine hydrochloride (4) was then added and the resulting mixture was stirred at room temperature for a further 13 h. Conventional work-up (same procedure as in example 1) and column chromatography gave the radioactive intermediate 2- { [4- (3-methoxypropoxy) -3-methylpyridin-2-yl]Methylthio } -1H-benzo [ d,2-14C]Imidazole (5,107mg, radiochemical yield 81%).
To the stirred intermediate 2- { [4- (3-methoxypropoxy) -3-methylpyridin-2-yl at 20 deg.C]Methylthio } -1H-benzo [ d,2-14C]To a suspension of imidazole (5,115mg) in benzene (2mL) were added water (3mg), diethyl L- (+) -tartrate (abbreviated as L-DET; 103mg) and tetraisopropyl titanate (abbreviated as TIPT; 76mg) in this order, and the mixture was stirred at a constant temperature for 5 hours. The temperature of the reaction system is reduced to 0-10 ℃, N-diisopropylethylamine (22mg) and cumene hydroperoxide (76mg, content 80%) are added, and the mixture is stirred for 8 hours at 50 ℃. Completion of the reactionThe reaction was quenched by the addition of an equivalent amount of aqueous sodium thiosulfate (0.5mL), stirred for 0.5h, filtered to remove unreacted starting compound, the filter cake was washed with benzene (3mL), the filtrate was collected, extracted 3 times with 12.5% aqueous ammonia, and the aqueous ammonia phases were combined. The aqueous ammonia phase was washed 3 times with dichloromethane, the aqueous ammonia phase was collected and filtered through an organic filter (0.45 μm). And (4) cooling by using an ice bath, dropwise adding 10% acetic acid until the ammonia water phase is turbid, and rapidly stirring for 2 hours until a white solid is separated out. Filtering, rinsing the filter cake to neutrality with pure water, collecting the filter cake, and vacuum drying at room temperature overnight to obtain the radioactive intermediate (R) - (+) -2- { [4- (3-methoxypropoxy) -3-methylpyridin-2-yl]Methanesulfinyl } -1H-benzo [ d,2-14C]Imidazole (6,79mg, radiochemical yield 66%).
To the ice-cold intermediate (R) - (+) -2- { [4- (3-methoxypropoxy) -3-methylpyridin-2-yl]Methanesulfinyl } -1H-benzo [ d,2-14C]NaOH is added into the ethanol solution of imidazole (6), the mixture is stirred for 0.5h, and the target product, namely the carbon-14labeled D-rabeprazole sodium (82mg, radiochemical yield 86%) is obtained by concentration, please refer to figure 1. The chemical purity of the target product carbon-14 marked dextro-rabeprazole sodium is more than 98 percent, the chiral purity is more than 98 percent, and the radiochemical purity is more than 99 percent by adopting the conventional method (J Label Compound radiopharm.2018,61(11): 812-.
Example 3:
under the protection of argon, o-phenylenediamine (1,65mg,0.6mmol) is added into a dry reaction tube, and argon is replaced for three times; cyclohexanol (1.5mL) was added, and concentrated sulfuric acid (0.1mL, 98%) and [ carbonyl-14C]A solution of cyclohexyl formate (0.5mmol,1mCi/mmol) in cyclohexanol (2 mL); the reaction was completed after stirring the reaction in an oil bath at 80 ℃ for 13 hours. After conventional post-treatment (same as example 1) and column chromatography (n-hexane/ethyl acetate 20/1), the radioactive intermediate benzo [ d,2-14C]Imidazole (2,49mg, radiochemical yield 81%).
Under the protection of argon, benzo [ d,2-14C]Imidazole (2,51mg) and sulfur powder (20mg) were added to a dry reaction tube, and replaced with argon gas three times; dimethyl sulfoxide (2mL) was injected, and the reaction tube was stirred in a 50 ℃ oil bath for 20h to complete the reaction. After conventional post-treatment (same as example 1), crude 2-mercaptobenzo [ d,2 ] is obtained-14C]Imidazole (3,18mg, radiochemical yield 26%).
Under the cooling of ice bath, 2-mercaptobenzo [ d,2-14C]Adding sodium bicarbonate (105mg) into ethanol (2mL) solution of imidazole (3,60mg), and stirring for 0.5 h; 2-chloromethyl-4- (3-methoxypropoxy) -3-methylpyridine hydrochloride (4) was then added and the resulting mixture was stirred at room temperature for a further 13 h. Conventional work-up (same procedure as in example 1) and column chromatography gave the radioactive intermediate 2- { [4- (3-methoxypropoxy) -3-methylpyridin-2-yl]Methylthio } -1H-benzo [ d,2-14C]Imidazole (5,107mg, radiochemical yield 81%).
To the stirred intermediate 2- { [4- (3-methoxypropoxy) -3-methylpyridin-2-yl at 20 deg.C]Methylthio } -1H-benzo [ d,2-14C]To a suspension of imidazole (5,115mg) in benzene (2mL) were added water (3mg), diethyl L- (+) -tartrate (abbreviated as L-DET; 103mg) and tetraisopropyl titanate (abbreviated as TIPT; 76mg) in this order, and the mixture was stirred at a constant temperature for 5 hours. The temperature of the reaction system is reduced to 0-10 ℃, N-diisopropylethylamine (22mg) and cumene hydroperoxide (76mg, content 80%) are added, and the mixture is stirred for 8 hours at 50 ℃. After the reaction was completed, the reaction was quenched by adding an equivalent amount of an aqueous solution of sodium thiosulfate (0.5mL), stirred for 0.5h, filtered to remove unreacted starting compounds, the filter cake was washed with benzene (3mL), the filtrate was collected, extracted 3 times with 12.5% aqueous ammonia, and the aqueous ammonia phases were combined. The aqueous ammonia phase was washed 3 times with ethyl acetate, the aqueous ammonia phase was collected and filtered through an organic filter (0.45 μm). And (4) cooling by using an ice bath, dropwise adding 10% acetic acid until the ammonia water phase is turbid, and rapidly stirring for 2 hours until a white solid is separated out. Filtering, rinsing the filter cake to neutrality with pure water, collecting the filter cake, and vacuum drying at room temperature overnight to obtain the radioactive intermediate (R) - (+) -2- { [4- (3-methoxypropoxy) -3-methylpyridin-2-yl]Methanesulfinyl } -1H-benzo [ d,2-14C]Imidazole (6,79mg, radiochemical yield 66%).
To the ice-cold intermediate (R) - (+) -2- { [4- (3-methoxypropoxy) -3-methylpyridin-2-yl]Methanesulfinyl } -1H-benzo [ d,2-14C]NaOH is added into the ethanol solution of imidazole (6), the mixture is stirred for 0.5h, and the target product, namely the carbon-14labeled D-rabeprazole sodium (82mg, radiochemical yield 86%) is obtained by concentration, please refer to figure 1. By a conventional method (J Label)Compd radiopharm.2018,61(11): 812-819) analysis shows that the chemical purity of the target product carbon-14 marked D-rabeprazole sodium is more than 98%, the chiral purity is more than 98% and the radiochemical purity is more than 99%.
Example 4:
under the protection of argon, o-phenylenediamine (1,65mg,0.6mmol) is added into a dry reaction tube, and argon is replaced for three times; ethanol (1.5mL) was added, and concentrated sulfuric acid (0.1mL, 98%) and [ carbonyl-14C]A solution of tert-butyl formate (0.5mmol,1mCi/mmol) in ethanol (2 mL); the reaction was completed after stirring the reaction in an oil bath at 70 ℃ for 16 h. Obtaining the radioactive intermediate benzo [ d,2-14C]Imidazole (2,52mg, radiochemical yield 85%).
Under the protection of argon, benzo [ d,2-14C]Imidazole (2,51mg) and sulfur powder (20mg) were added to a dry reaction tube, and replaced with argon gas three times; diphenyl ether (2mL) was injected and the reaction tube was stirred in a 50 ℃ oil bath for 20h to complete the reaction. After conventional post-treatment (same as example 1), crude 2-mercaptobenzo [ d,2-14C]Imidazole (3,18mg, radiochemical yield 26%).
Under the cooling of ice bath, 2-mercaptobenzo [ d,2-14C]Cesium carbonate (105mg) was added to a solution of imidazole (3,60mg) in acetonitrile (2mL), and stirred for 0.5 h; 2-chloromethyl-4- (3-methoxypropoxy) -3-methylpyridine hydrochloride (4) was then added and the resulting mixture was stirred at room temperature for a further 13 h. Conventional work-up (same procedure as in example 1) and column chromatography gave the radioactive intermediate 2- { [4- (3-methoxypropoxy) -3-methylpyridin-2-yl]Methylthio } -1H-benzo [ d,2-14C]Imidazole (5,107mg, radiochemical yield 81%).
To the stirred intermediate 2- { [4- (3-methoxypropoxy) -3-methylpyridin-2-yl at 20 deg.C]Methylthio } -1H-benzo [ d,2-14C]To a suspension of imidazole (5,115mg) in benzene (2mL) were added water (3mg), diethyl L- (+) -tartrate (abbreviated as L-DET; 103mg) and tetraisopropyl titanate (abbreviated as TIPT; 76mg) in this order, and the mixture was stirred at a constant temperature for 5 hours. Reducing the temperature of the reaction system to 0-10 ℃, adding N, N-diisopropylethylamine (22mg) and cumene hydroperoxide (76mg, content 80%) into the reaction system, and heating the reaction system at 50 DEG CStirring for 8 h. After the reaction was completed, the reaction was quenched by adding an equivalent amount of an aqueous solution of sodium thiosulfate (0.5mL), stirred for 0.5h, filtered to remove unreacted starting compounds, the filter cake was washed with benzene (3mL), the filtrate was collected, extracted 3 times with 12.5% aqueous ammonia, and the aqueous ammonia phases were combined. The aqueous ammonia phase was washed 3 times with dichloromethane, the aqueous ammonia phase was collected and filtered through an organic filter (0.45 μm). And (4) cooling by using an ice bath, dropwise adding 10% acetic acid until the ammonia water phase is turbid, and rapidly stirring for 2 hours until a white solid is separated out. Filtering, rinsing the filter cake to neutrality with pure water, collecting the filter cake, and vacuum drying at room temperature overnight to obtain the radioactive intermediate (R) - (+) -2- { [4- (3-methoxypropoxy) -3-methylpyridin-2-yl]Methanesulfinyl } -1H-benzo [ d,2-14C]Imidazole (6,79mg, radiochemical yield 66%).
To the ice-cold intermediate (R) - (+) -2- { [4- (3-methoxypropoxy) -3-methylpyridin-2-yl]Methanesulfinyl } -1H-benzo [ d,2-14C]NaOH is added into the ethanol solution of imidazole (6), the mixture is stirred for 0.5h, and the target product, namely the carbon-14labeled D-rabeprazole sodium (82mg, radiochemical yield 86%) is obtained by concentration, please refer to figure 1. The chemical purity of the target product carbon-14 marked dextro-rabeprazole sodium is more than 98 percent, the chiral purity is more than 98 percent, and the radiochemical purity is more than 99 percent by adopting the conventional method (J Label Compound radiopharm.2018,61(11): 812-.
Example 5:
under the protection of argon, o-phenylenediamine (1,65mg,0.6mmol) is added into a dry reaction tube, and argon is replaced for three times; methanol (1.5mL) was added, and concentrated sulfuric acid (0.1mL, 98%) and [ carbonyl-14C]Benzyl formate (0.5mmol,1mCi/mmol) in methanol (2 mL); the reaction is finished after stirring and reacting for 8 hours in a bath solution at the temperature of minus 10 ℃. After conventional post-treatment (same as example 1) and column chromatography (n-hexane/ethyl acetate 20/1), the radioactive intermediate benzo [ d,2-14C]Imidazole (2,47mg, radiochemical yield 78%).
Under the protection of argon, benzo [ d,2-14C]Imidazole (2,51mg) and sulfur powder (20mg) were added to a dry reaction tube, and replaced with argon gas three times; diphenyl ether (2mL) was injected and the reaction tube was stirred in a 50 ℃ oil bath for 72h to complete the reaction. After conventional post-treatment (same treatment as in example 1), crude 2-mercapto group is obtainedBenzo [ d,2-14C]Imidazole (3,23mg, radiochemical yield 34%) was used directly in the next reaction.
Under the cooling of ice bath, 2-mercaptobenzo [ d,2-14C]Adding sodium carbonate (105mg) into ethanol (2mL) solution of imidazole (3,60mg), and stirring for 0.5 h; 2-chloromethyl-4- (3-methoxypropoxy) -3-methylpyridine hydrochloride (4) was then added and the resulting mixture was stirred at room temperature for a further 13 h. Conventional work-up (same procedure as in example 1) and column chromatography gave the radioactive intermediate 2- { [4- (3-methoxypropoxy) -3-methylpyridin-2-yl]Methylthio } -1H-benzo [ d,2-14C]Imidazole (5,98mg, radiochemical yield 74%).
To the stirred intermediate 2- { [4- (3-methoxypropoxy) -3-methylpyridin-2-yl at 20 deg.C]Methylthio } -1H-benzo [ d,2-14C]To a suspension of imidazole (5,115mg) in benzene (2mL) were added water (3mg), diethyl L- (+) -tartrate (abbreviated as L-DET; 103mg) and tetraisopropyl titanate (abbreviated as TIPT; 76mg) in this order, and the mixture was stirred at a constant temperature for 5 hours. The temperature of the reaction system is reduced to 0-10 ℃, N-diisopropylethylamine (22mg) and cumene hydroperoxide (76mg, content 80%) are added, and the mixture is stirred for 8 hours at 50 ℃. After the reaction was completed, the reaction was quenched by adding an equivalent amount of an aqueous solution of sodium thiosulfate (0.5mL), stirred for 0.5h, filtered to remove unreacted starting compounds, the filter cake was washed with benzene (3mL), the filtrate was collected, extracted 3 times with 12.5% aqueous ammonia, and the aqueous ammonia phases were combined. The aqueous ammonia phase was washed 3 times with dichloromethane, the aqueous ammonia phase was collected and filtered through an organic filter (0.45 μm). And (4) cooling by using an ice bath, dropwise adding 10% acetic acid until the ammonia water phase is turbid, and rapidly stirring for 2 hours until a white solid is separated out. Filtering, rinsing the filter cake to neutrality with pure water, collecting the filter cake, and vacuum drying at room temperature overnight to obtain the radioactive intermediate (R) - (+) -2- { [4- (3-methoxypropoxy) -3-methylpyridin-2-yl]Methanesulfinyl } -1H-benzo [ d,2-14C]Imidazole (6,65mg, radiochemical yield 54%).
To the ice-cold intermediate (R) - (+) -2- { [4- (3-methoxypropoxy) -3-methylpyridin-2-yl]Methanesulfinyl } -1H-benzo [ d,2-14C]Adding NaOH into the ethanol solution of imidazole (6), stirring for 0.5h, concentrating to obtain the target product D-rabeprazole sodium (82mg, radiochemical yield 86%) marked by carbon-14Fig. 1 is a drawing. The chemical purity of the target product carbon-14 marked dextro-rabeprazole sodium is more than 98 percent, the chiral purity is more than 98 percent, and the radiochemical purity is more than 99 percent by adopting the conventional method (J Label Compound radiopharm.2018,61(11): 812-.
The invention also provides a carbon-14-containing synthetic building block, wherein the carbon-14-containing component can be selected from any one of the embodiments, but is not limited to the embodiments.
Many modifications may be made by one of ordinary skill in the art in light of the above teachings. Therefore, it is intended that the invention not be limited to the particular details of the embodiments disclosed, but that the invention will include all embodiments falling within the scope of the appended claims.

Claims (4)

1. A synthetic method of radioisotope carbon-14labeled D-rabeprazole sodium is characterized by comprising the following steps:
s1: under the protection of inert gas and under the acidic condition, o-phenylenediamine and [ carbonyl-14C]Reacting formate in a low-boiling-point alcohol solvent at-10-150 ℃, adjusting the pH of a reaction system to be alkaline by using saturated sodium carbonate after the reaction is finished, separating ethyl acetate/water, drying an ethyl acetate phase, performing suction filtration, concentrating and mixing samples, and performing column chromatography to obtain the benzo [ b ], [ 2 ]d, 2-14C]Imidazole, wherein the low-boiling-point alcohol solvent is selected from methanol, ethanol, glycol and cyclohexanol;
s2: under the protection of inert gas and at the reaction temperature of 50-250 ℃, the benzo [ alpha ], [ alpha ] is reacted with a catalyst, and [ alpha ], [ alpha ] is preparedd, 2-14C]Imidazole and sulfur powder react in a high-boiling point aprotic organic solvent, a reaction tube is taken out and cooled to room temperature, 1mL of water is added into reaction liquid, diluted hydrochloric acid is added to adjust the pH value of the mixture to 4, 2mL of ethyl acetate is used for extraction for 3 times, liquid separation is carried out, an ethyl acetate phase is dried by anhydrous sodium sulfate, and the 2-mercaptobenzo [ 2 ], [ is prepared by column chromatography after suction filtration and concentrationd, 2-14C]Imidazole, the high boiling point aprotic organic solvent is selected from diphenyl ether,N-methylpyrrolidone, dimethyl sulfoxide;
s3: reacting the 2-mercaptobenzo [ 2 ] at a reaction temperature of 0 to 50 DEG Cd, 2-14C]Imidazole, 2-chloromethylStirring the base-4- (3-methoxy propoxy) -3-methylpyridine hydrochloride and alkali in a polar organic solvent for 3-20 hours until the reaction is finished; then adding water to the reaction mixture to precipitate the product, filtering, washing with water and vacuum drying at room temperature to obtain 2- { [4- (3-methoxypropoxy) -3-methylpyridin-2-yl]Methylthio } -1H-benzo [ 2 ]d, 2-14C]Imidazole;
s4: the 2- { [4- (3-methoxypropoxy) -3-methylpyridin-2-yl group is reacted at a reaction temperature of 10-100 DEG C]Methylthio } -1H-benzo [ 2 ]d, 2-14C]Imidazole, imidazole,L- (+) -tartaric acid diethyl ester (abbreviated toL-DET) and tetraisopropyl titanate (abbreviated as TIPT) are stirred for 0.5-6 h in a mixed solution of an aprotic solvent and water; then adjusting the reaction temperature to-10-35 ℃, and sequentially adding the mixture into the reaction systemN,NDiisopropylethylamine (abbreviated as DIPEA) and cumene hydroperoxide (abbreviated as CHP), and the reaction is finished after the reaction temperature of-10-35 ℃ is kept for 12-36 h; after quenching reaction, sequentially adding an alkaline aqueous solution and a fat-soluble solvent into the reaction mixture; separating the solution to obtain a water phase, adding acid to adjust the pH of the water phase to 10-11 to precipitate a product, filtering the precipitate, and drying the precipitate in vacuum at room temperature to obtain (A)R) - (+) -2- { [4- (3-Methoxypropoxy) -3-methylpyridin-2-yl]Methanesulfinyl } -1H-benzo [ 2 ]d, 2-14C]Imidazole, the fat-soluble solvent is selected from ethyl acetate, dichloromethane and methyl isobutyl ketone;
s5: under the protection of inert gas and at room temperature, the mixture of (A) and (B)R) - (+) -2- { [4- (3-Methoxypropoxy) -3-methylpyridin-2-yl]Methanesulfinyl } -1H-benzo [ 2 ]d, 2-14C]Stirring the imidazole and sodium hydroxide solution with low molecular weight alcohol for 0.5-3 h, and concentrating to obtain a target substance (carbon-14 labeled D-rabeprazole sodium ((R))R) - (+) -2- { [4- (3-Methoxypropoxy) -3-methylpyridin-2-yl]Methanesulfinyl } -1H-benzo [ 2 ]d, 2-14C]Sodium imidazolium) and the low molecular weight alcohol solution is selected from methanol and ethanol.
2. The method of synthesis according to claim 1, characterized in that: in S1, the [ carbonyl-14C]The formate is selected from [ carbonyl-14C]Benzoic acid benzyl ester, [ carbonyl-14C]Ethyl formate, [ carbonyl-14C]Cyclohexyl formate, [ carbonyl-14C]Tert-butyl formate, [ carbonyl-14C]And (3) benzyl formate.
3. The method of synthesis according to claim 1, characterized in that: in S3, the base is selected from sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate; the polar organic solvent is selected from methanol, ethanol and acetonitrile.
4. The method of synthesis according to claim 1, characterized in that: in S4, the aprotic solvent is selected from benzene, toluene.
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