CN115286539B - Preparation method of guanfacine metabolite - Google Patents
Preparation method of guanfacine metabolite Download PDFInfo
- Publication number
- CN115286539B CN115286539B CN202210949019.5A CN202210949019A CN115286539B CN 115286539 B CN115286539 B CN 115286539B CN 202210949019 A CN202210949019 A CN 202210949019A CN 115286539 B CN115286539 B CN 115286539B
- Authority
- CN
- China
- Prior art keywords
- guanfacine
- intermediate product
- reaction
- metabolite
- preparing
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C277/08—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups of substituted guanidines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/51—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition
- C07C45/511—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups
- C07C45/513—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups the singly bound functional group being an etherified hydroxyl group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/16—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/10—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with ester groups or with a carbon-halogen bond
- C07C67/11—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with ester groups or with a carbon-halogen bond being mineral ester groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of guanfacine metabolites, which takes (methoxymethyl) triphenyl phosphorus chloride and 2, 6-dichloro-3-methoxybenzaldehyde as starting materials, and the guanfacine metabolites are synthesized through six steps of reactions. The whole process has reasonable design and strong operability, and can realize industrial production; the reagent used in the synthesis method is simple and easy to obtain; the prepared guanfacine metabolite has the purity of more than 98.5%, provides a test sample for guanfacine research, and has important research value in clinical pharmacokinetics research.
Description
Technical Field
The invention relates to the field of compound preparation, in particular to a preparation method of guanfacine metabolites.
Background
Guanfacine is a phenylacetylguanidine reagent developed by Shire corporation under the trade names chloracetamidine, chlorethylguanidine, and guanfacine. The chemical name is N-amidino-2- (2, 6-dichlorophenyl) acetamide, and the molecular weight is as follows: 246.09, the structural formula is:
guanidine Xin Chang is used as hydrochloride in the treatment of moderate to severe hypertension, and can be used singly or in combination with diuretics. FDA approved it for marketing in 2009 for the treatment of attention deficit and hyperactivity disorder in 6-l7 year old children and adolescents. The drug is a selective alpha 2 a-adrenergic receptor agonist, and the effective mechanism of action for treating attention deficit and hyperactivity disorder is not known. However, preclinical studies have found that guanfacine hydrochloride binds directly to receptors in the prefrontal cortex, whereas stimulation of postsynaptic alpha 2 a-receptors may produce effects that enhance working memory, reduce distraction, improve attention regulation, increase behavioral suppression, and enhance impulse control.
The guanfacine hydrochloride has fast and complete oral absorption, and the depressurization effect reaches the peak after oral administration for more than 24 hours. The half-life of oral administration is 21h, so that the medicine is easier to distribute to various tissues, and the medicine concentration in blood is lower, and the plasma protein binding rate is low. Most drugs are metabolized in the body, the major metabolite being the 3-hydroxy derivative and its oxidized thiol uric acid derivative, 80% of which is excreted via the kidneys.
Pharmacokinetics is a new technology developed over the last 40-50 years and plays an increasing role in the drug development process. More and more technologies are applied to the pharmaceutical metabolism, so that the period of drug development is shortened, the cost of drug development is reduced, and a new way is provided for new drug discovery.
At present, the synthesis method of the guanfacine metabolite has not been reported, and in order to comprehensively analyze and research clinical, pharmacological and pharmacokinetic properties and toxicology of guanfacine, it is necessary to design and develop a preparation method of the guanfacine metabolite on the basis of the prior art, and provide a reference substance for comprehensively analyzing and researching clinical, pharmacological, pharmacokinetic and toxicology properties of guanfacine.
Disclosure of Invention
The invention aims to: aiming at the defects and shortcomings of the prior art, the invention provides a preparation method of guanfacine metabolites, and the synthesis process has reasonable design and strong operability; the reagent used in the synthesis method is simple and easy to obtain; the purity of the guanfacine metabolite obtained by the reaction can reach more than 98.5 percent.
The technical scheme is as follows: the preparation method of the guanfacine metabolite is characterized by comprising the following steps of: comprising the following steps:
1) Suspending the reactant I- (methoxymethyl) triphenyl phosphorus chloride in tetrahydrofuran, adding alkali and stirring to obtain a reaction solution; dissolving 2, 6-dichloro-3-methoxybenzaldehyde in tetrahydrofuran, then adding the tetrahydrofuran into a reaction solution, and reacting to obtain an intermediate product II:
2) Dissolving the intermediate product II in an organic solvent, adding an acidic aqueous solution, and reacting to generate an intermediate product III:
3) Dissolving the intermediate product III in tetrahydrofuran and water, adding 2-methyl-2-butene, sodium chlorite and sodium dihydrogen phosphate, and reacting to obtain an intermediate product IV:
4) Dissolving the intermediate product IV in dimethylformamide, adding alkali and methyl iodide, and reacting to obtain an intermediate V:
5) Intermediate V is taken and dissolved in methylene dichloride to react with boron tribromide to obtain intermediate VI:
6) Intermediate VI is taken and dissolved in ethanol and reacted with guanidine to give the final product VII, the guanfacine metabolite:
wherein in the step 1), the molar use ratio of the (methoxymethyl) triphenyl phosphorus chloride, the alkali and the 2, 6-dichloro-3-methoxybenzaldehyde is 1:1:1-1:10:10, preferably 1:2:2; the base is potassium tert-butoxide, sodium tert-butoxide or butyllithium, preferably potassium tert-butoxide; the reaction temperature is-0.5 ℃, the reaction time is 1-24 h, and the reaction time is about 0 ℃ and is preferably 1-8 h.
In the step 1), after the reaction is finished, pouring the intermediate product II into water in an ice bath, spinning off tetrahydrofuran, extracting with ethyl acetate, combining organic layers, drying with anhydrous sodium sulfate, filtering and spinning to obtain a crude product.
Wherein in the step 2), the volume ratio of the intermediate product II to the acidic aqueous solution is 1:5-1:50, preferably 1:15-1:25; the acid is hydrochloric acid, sulfuric acid or phosphoric acid, preferably hydrochloric acid; the organic solvent is acetone, tetrahydrofuran or dioxane, preferably acetone; the reaction temperature is 58-62 ℃, the reaction time is 1-30 h, and the reaction is preferably about 60 ℃ for 1-15 h.
In the step 3), the molar use ratio of the intermediate product III to the 2-methyl-2-butene, sodium chlorite and sodium dihydrogen phosphate is 1:1:1-1:10:10:10, preferably 1:4:3:3.5-1:5:4:4.5; the reaction temperature is 0-50 ℃, the reaction time is 1-36 h, and the reaction is preferably carried out at 15-25 ℃ for 8-24 h.
Wherein in the step 4), the molar use ratio of the intermediate product IV to the alkali to the methyl iodide is 1:1:1-1:5:5, preferably 1:1.1:1.2-1:1.3:1.5; the base is cesium carbonate, potassium carbonate or sodium carbonate, preferably cesium carbonate; the reaction temperature is 0-80 ℃, the reaction time is 1-30 h, and the reaction is preferably carried out at 15-60 ℃ for 5-16 h.
Wherein in the step 5), the molar use ratio of the intermediate product V to the boron tribromide is 1:1-1:10, preferably 1:1.5-1:2.5; the reaction temperature is 0-40 ℃, the reaction time is 1-30 h, and the reaction is preferably carried out at 15-20 ℃ for 2-24 h.
Wherein in the step 6), the molar use ratio of the intermediate product VI to guanidine is 1:1-1:20, preferably 1:5-1:10; the guanidine is prepared by reacting guanidine hydrochloride with sodium ethoxide, wherein the molar dosage ratio of the hydrochloride to the sodium ethoxide is 1:1; the reaction temperature is 40-90 ℃, the reaction time is 1-30 h, and the reaction is preferably carried out at 80 ℃ for 5-15 h.
Principle analysis:
the guanfacine metabolite (compound VII) is a main metabolite generated in the metabolic process of guanfacine, and the name of the guanfacine metabolite is 3-hydroxyguanfacine, and the chemical name is:
n-carbamidyl-2- (2, 6-dichloro-3-hydroxyphenyl) acrylamide, molecular weight of 262.09, molecular formula of C9H9Cl2N3O2, and structural formula as follows:
3-hydroxyguanfacine has one more hydroxyl structure than the bulk drug, and is synthesized by a metabolic method which is not available for chemical synthesis at present, and the synthetic route is as follows:
the beneficial effects are that: compared with the prior art, the invention has the following remarkable advantages: the synthesis process has reasonable design and strong operability; the reagent used in the synthesis method is simple and easy to obtain; the purity of the guanfacine metabolite obtained by the reaction can reach more than 98.5 percent. Through actual experimental operation, and HNMR and MS characterization of the obtained product, the corresponding metabolite can be obtained through verification. The guanfacine metabolite (compound VII) prepared by the invention provides a test sample for the research of guanfacine, and has important research value in clinical pharmacokinetics research.
Drawings
FIG. 1 is a nuclear magnetic pattern of intermediate II of the present invention;
FIG. 2 is a mass spectrum of intermediate III of the present invention;
FIG. 3 is a nuclear magnetic pattern of intermediate III of the present invention;
FIG. 4 is a mass spectrum of intermediate IV of the present invention;
FIG. 5 is a nuclear magnetic pattern of intermediate IV of the present invention;
FIG. 6 is a mass spectrum of intermediate V of the present invention;
FIG. 7 is a nuclear magnetic pattern of intermediate V of the present invention;
FIG. 8 is a mass spectrum of intermediate VI of the present invention;
FIG. 9 is a nuclear magnetic pattern of intermediate VI of the present invention;
FIG. 10 is a mass spectrum of the final product VII of the present invention;
FIG. 11 is a nuclear magnetic pattern of the final product VII of the present invention;
FIG. 12 is a liquid phase diagram of the final product VII of the present invention.
Detailed Description
The technical scheme of the invention is further described below with reference to the accompanying drawings and the specific embodiments.
Example 1:
reactant I was prepared from 2, 4-dichloroanisole according to WO2012/004378 patent method.
Preparation of intermediate II 133.76g of (methoxymethyl) triphenylphosphine chloride was suspended in 1.2L of tetrahydrofuran, 43.78g of potassium tert-butoxide was added under ice bath, and stirred under ice bath for 1 hour. 40g of 2, 6-dichloro-3-methoxybenzaldehyde is dissolved in THF and then added dropwise to the reaction solution, the mixture is stirred for 1 hour under ice bath, the reaction is completed, the reaction solution is poured into 1.5L of water under ice bath, most of tetrahydrofuran is swirled off, the mixture is extracted three times with 300mL of ethyl acetate, the organic layers are combined and then dried with anhydrous sodium sulfate, filtered and dried by a spin to obtain 85g of crude product, and 42g of brown oily intermediate II is separated by column chromatography, the yield is 92.36%, and the nuclear magnetism is shown in FIG. 1:
preparation of intermediate III by dissolving 42g of intermediate II in 1L of acetone, adding 840mL of 3M aqueous hydrochloric acid under ice bath, reacting for 1 hour at 60 ℃, ending the reaction, adding 500mL of water under ice bath, spinning most of the acetone, extracting three times with 300mL of ethyl acetate, combining organic layers, drying with anhydrous sodium sulfate, filtering, spinning to obtain 49g of crude product, and separating by column chromatography to obtain 38g of pale yellow solid intermediate III with a yield of 96.27%. Mass spectrum is shown in fig. 2, nuclear magnetism is shown in fig. 3:
preparation of intermediate IV 14g of intermediate III was dissolved in 280mL of tetrahydrofuran and 280mL of water, 17.93g of 2-methyl-2-butene, 21.67g of sodium chlorite and 26.84g of sodium dihydrogen phosphate were added and reacted for 18 hours at 15℃and after the reaction of the raw materials was completed, 150mL of saturated sodium thiosulfate solution was added under ice bath, pH=3-4 was adjusted with 1M HCl, extraction was performed three times with 100mL of ethyl acetate, washing was performed once with saturated sodium chloride solution, the organic layers were combined and dried with anhydrous sodium sulfate, filtered, dried by spin-drying and slurried with n-hexane to purify 13g of white solid intermediate IV with a yield of 86.54%. Mass spectra are shown in fig. 4, nuclear magnetism is shown in fig. 5:
preparation of intermediate V13 g of intermediate IV was dissolved in 130mL of dimethylformamide, 19.82g of cesium carbonate and 11.77g of methyl iodide were added and reacted for 15 hours at 25℃and the starting materials were reacted, 300mL of water was added, 100mL of ethyl acetate was extracted three times, washed once with saturated sodium chloride solution, the organic layers were combined and dried over anhydrous sodium sulfate, filtered and spin-dried to give 13g of brown oil V, yield: 94.37%. Mass spectrum is shown in fig. 6, nuclear magnetism is shown in fig. 7:
preparation of intermediate VI 13g of intermediate V was dissolved in 130mL of dichloromethane, 19.61g of boron tribromide was dissolved in dichloromethane, added dropwise to the reaction solution at-78℃and stirred at 15℃for 16 hours, and the reaction was completed. 300mL of saturated sodium bicarbonate solution is added under ice bath, 100mL of dichloromethane is extracted three times, 200mL of water is used for washing once, the organic layers are combined and then dried with anhydrous sodium sulfate, filtration and spin drying are carried out to obtain 13g of crude product, and 11g of white solid compound VI is obtained through column chromatography separation, and the yield is: 89.67%. Mass spectra are shown in fig. 8, nuclear magnetism is shown in fig. 9:
preparation of final product VII, namely, 79.61g of 20% sodium ethoxide ethanol solution is dissolved in 55mL of ethanol, 22.35g of guanidine hydrochloride is added under ice bath, stirring is carried out for 1h at 20 ℃, the reaction solution is filtered by suction, and the filtrate is collected for standby. 11g of intermediate VI was added to the previous filtrate and stirred at 80℃for 5 hours and then at room temperature for 15 hours, the starting materials were reacted. 100mL of water is added under ice bath, the pH value is firstly adjusted to be 2-3 by 1M hydrochloric acid solution, then the pH value is adjusted to be 7-8 by saturated sodium bicarbonate solution, the three times of extraction are performed by 300mL of ethyl acetate/methanol (9/1), the organic layers are combined, then dried by anhydrous sodium sulfate, filtered and spin-dried to obtain 11g of crude product, and 8g of off-white solid final product VII is obtained by crystallization and purification by methanol, and the yield is: 57.26%, HPLC:98.6%. Mass spectrum is shown in fig. 10, nuclear magnetism is shown in fig. 11, liquid phase is shown in fig. 12:
and (3) effect analysis: the synthesis process of the embodiment has reasonable design and strong operability; the reagent used in the synthesis method is simple and easy to obtain; the purity of the guanfacine metabolite obtained by the reaction can reach more than 98.5 percent. Through actual experimental operation, and HNMR and MS characterization of the obtained product, the corresponding metabolite can be obtained through verification.
Example 2:
reactant I was prepared from 2, 4-dichloroanisole according to WO2012/004378 patent method.
Preparation of intermediate II 125.41g of (methoxymethyl) triphenylphosphine chloride was suspended in 750mL of tetrahydrofuran, 41.05g of potassium tert-butoxide was added under ice bath, and stirred under ice bath for 1 hour. 25g of 2, 6-dichloro-3-methoxybenzaldehyde is dissolved in THF and then added dropwise into the reaction solution, stirring is carried out for 1 hour under ice bath, the reaction is completed, the reaction solution is poured into 1L of water under ice bath, most of tetrahydrofuran is spirally removed, the mixture is extracted three times with 300mL of ethyl acetate, the organic layers are combined and then dried with anhydrous sodium sulfate, filtration and spin-drying are carried out, 55g of crude product is obtained, and 21g of brown oily intermediate II is obtained by column chromatography, wherein the yield is 73.89 percent:
preparation of intermediate III 21g of intermediate II was dissolved in 315mL of acetone, 315mL of 3M aqueous hydrochloric acid was added under ice bath, the reaction was completed for 10 hours at 60℃and 500mL of water was added under ice bath, most of the acetone was swirled off, extracted three times with 300mL of ethyl acetate, the organic layers were combined and dried over anhydrous sodium sulfate, filtered and dried by spin to give 20g of crude product, and 15g of pale yellow solid intermediate III was isolated by column chromatography in 76% yield:
preparation of intermediate IV 15g of intermediate III are dissolved in 300mL of tetrahydrofuran and 300mL of water, 21.61g of 2-methyl-2-butene, 27.09g of sodium chlorite and 32.86g of sodium dihydrogen phosphate are added to react for 8 hours at 15 ℃, 150mL of saturated sodium thiosulfate solution is added under ice bath, pH=3-4 is regulated by 1M HCl, 100mL of ethyl acetate is used for three times, the saturated sodium chloride solution is used for washing, the organic layers are combined and then dried by anhydrous sodium sulfate, filtered, dried by spin and then pulped by normal hexane to obtain 12g of white solid intermediate IV with the yield of 74.55 percent:
preparation of intermediate V12 g of intermediate IV was dissolved in 120mL of dimethylformamide, 19.96g of cesium carbonate and 11.77g of methyl iodide were added and reacted at 60℃for 5 hours, the starting materials were reacted completely, 300mL of water was added, 100mL of ethyl acetate was extracted three times, washed once with saturated sodium chloride solution, the organic layers were combined and dried over anhydrous sodium sulfate, filtered and spin-dried to give 10g of intermediate V as a brown oil, yield: 78.64%:
preparation of intermediate VI 10g of intermediate V was dissolved in 100mL of dichloromethane, 20.11g of boron tribromide was dissolved in dichloromethane, added dropwise to the reaction solution at-78℃and stirred at 20℃for 2 hours, and the reaction was completed. 300mL of saturated sodium bicarbonate solution is added under ice bath, 100mL of dichloromethane is extracted three times, 200mL of water is washed once again, the organic layers are combined and then dried with anhydrous sodium sulfate, the mixture is filtered, the mixture is dried by rotation to obtain 9g of crude product, and 7g of white solid intermediate product VI is obtained by column chromatography, and the yield is: 74.18%:
preparation of final product VII, namely, 75.99g of 20% sodium ethoxide ethanol solution is dissolved in 35mL of ethanol, 21.34g of guanidine hydrochloride is added under ice bath, stirring is carried out for 1h at 20 ℃, the reaction solution is filtered by suction, and the filtrate is collected for standby. 7g of intermediate VI was added to the previous filtrate and stirred at 80℃for 15 hours, the starting materials were reacted. 100mL of water was added under ice bath, pH=2-3 was adjusted with 1M hydrochloric acid solution, pH=7-8 was adjusted with saturated sodium bicarbonate solution, extraction was performed three times with 300mL of ethyl acetate/methanol (9/1), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried to give 9g of crude product, which was purified by crystallization with methanol to give 5g of off-white solid final product VII, yield: 56.24%, HPLC:98.5%:
example 3:
reactant I was prepared from 2, 4-dichloroanisole according to WO2012/004378 patent method.
Preparation of intermediate II 200.63g of (methoxymethyl) triphenylphosphine chloride was suspended in 900mL of tetrahydrofuran, 65.67g of potassium tert-butoxide was added in ice, and stirred in ice for 1 hour. 30g of 2, 6-dichloro-3-methoxybenzaldehyde is dissolved in THF and then added dropwise to the reaction solution, stirring is carried out for 8 hours under ice bath, the reaction is completed, the reaction solution is poured into 1.5L of water under ice bath, most of tetrahydrofuran is swirled off, extraction is carried out three times with 300mL of ethyl acetate, the organic layers are combined and then dried with anhydrous sodium sulfate, filtration and spin-drying are carried out to obtain 56g of crude product, and 27g of brown oily intermediate II is obtained by column chromatography, wherein the yield is 79.17 percent:
preparation of intermediate III 27g of intermediate II was dissolved in 675mL of acetone, 675mL of 3M aqueous hydrochloric acid was added under ice bath, the reaction was completed for 15 hours at 60℃and 500mL of water was added under ice bath, most of the acetone was swirled off, extracted three times with 300mL of ethyl acetate, the organic layers were combined and dried over anhydrous sodium sulfate, filtered and dried by spin to give 28g of crude product, which was isolated by column chromatography to give 21g of intermediate III as a pale yellow solid in 82.76% yield.
Preparation of intermediate IV 21g of intermediate III was dissolved in 420mL of tetrahydrofuran and 420mL of water, 33.61g of 2-methyl-2-butene, 43.35g of sodium chlorite and 51.76g of sodium dihydrogen phosphate were added, the reaction was completed for 24 hours at 25℃and 300mL of saturated sodium thiosulfate solution was added under ice bath, pH=3-4 was adjusted with 1M HCl, 100mL of ethyl acetate was used for three times, the saturated sodium chloride solution was used for washing, the organic layers were combined and dried with anhydrous sodium sulfate, filtered, dried by spin-drying and slurried with n-hexane to give 17g of intermediate IV as a white solid in 75.44% yield:
preparation of intermediate V17 g of intermediate IV was dissolved in 170mL of dimethylformamide, 30.63g of cesium carbonate and 19.25g of methyl iodide were added and reacted for 10 hours at 25℃and the starting materials were reacted, 300mL of water was added, 100mL of ethyl acetate was extracted three times, washed once with saturated sodium chloride solution, the organic layers were combined and dried over anhydrous sodium sulfate, filtered and spin-dried to give 13g of intermediate V as a brown oil, yield: 72.16%:
preparation of intermediate VI 13g of intermediate V was dissolved in 130mL of dichloromethane, 32.69g of boron tribromide was dissolved in dichloromethane, added dropwise to the reaction solution at-78℃and stirred at 15℃for 24 hours, and the reaction was completed. 300mL of saturated sodium bicarbonate solution is added under ice bath, 100mL of dichloromethane is extracted three times, 200mL of water is washed once again, the organic layers are combined and then dried with anhydrous sodium sulfate, filtration and spin drying are carried out to obtain 11g of crude product, and 9g of white solid intermediate product VI is obtained through column chromatography, and the yield is: 73.36%.
Preparation of final product VII, namely, 130.28g of 20% sodium ethoxide ethanol solution is dissolved in 90mL of ethanol, 36.58g of guanidine hydrochloride is added under ice bath, stirring is carried out for 1h at 20 ℃, the reaction solution is filtered by suction, and the filtrate is collected for standby. 9g of intermediate VI was added to the previous filtrate and stirred at 80℃for 15 hours, the starting materials were reacted. 100mL of water was added under ice bath, pH=2-3 was adjusted with 1M hydrochloric acid solution, pH=7-8 was adjusted with saturated sodium bicarbonate solution, extraction was performed three times with 300mL of ethyl acetate/methanol (9/1), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried to give 11g of crude product, which was purified by crystallization with methanol to give 8g of white solid final product VII, yield: 69.99%, HPLC:98.9%.
Claims (8)
1. A method for preparing a guanfacine metabolite, which is characterized by comprising the following steps: comprising the following steps:
1) Suspending the reactant I- (methoxymethyl) triphenyl phosphorus chloride in tetrahydrofuran, adding alkali and stirring to obtain a reaction solution; dissolving 2, 6-dichloro-3-methoxybenzaldehyde in tetrahydrofuran, then adding the tetrahydrofuran into a reaction solution, and reacting to obtain an intermediate product II:
2) Dissolving the intermediate product II in an organic solvent, adding an acidic aqueous solution, and reacting to generate an intermediate product III:
3) Dissolving the intermediate product III in tetrahydrofuran and water, adding 2-methyl-2-butene, sodium chlorite and sodium dihydrogen phosphate, and reacting to obtain an intermediate product IV:
4) Dissolving the intermediate product IV in dimethylformamide, adding alkali and methyl iodide, and reacting to obtain an intermediate V:
5) Intermediate V is taken and dissolved in methylene dichloride to react with boron tribromide to obtain intermediate VI:
6) Intermediate VI is taken and dissolved in ethanol and reacted with guanidine to give the final product VII, the guanfacine metabolite:
2. the method for preparing the guanfacine metabolite according to claim 1, wherein: in the step 1), the molar use ratio of the (methoxymethyl) triphenyl phosphorus chloride, the alkali and the 2, 6-dichloro-3-methoxybenzaldehyde is 1:1:1-1:10:10; the alkali is potassium tert-butoxide, sodium tert-butoxide or butyllithium, the reaction temperature is-0.5 ℃, and the reaction time is 1-24 h.
3. The method for preparing the guanfacine metabolite according to claim 1, wherein: in the step 1), after the reaction is finished, pouring the intermediate product II into water in an ice bath, spinning off tetrahydrofuran, extracting with ethyl acetate, combining organic layers, drying with anhydrous sodium sulfate, filtering and spinning to obtain a crude product.
4. The method for preparing the guanfacine metabolite according to claim 1, wherein: in the step 2), the volume ratio of the intermediate product II to the acidic aqueous solution is 1:5-1:50; the acid is hydrochloric acid, sulfuric acid or phosphoric acid, the organic solvent is acetone, tetrahydrofuran or dioxane, the reaction temperature is 58-62 ℃, and the reaction time is 1-30 h.
5. The method for preparing the guanfacine metabolite according to claim 1, wherein: in the step 3), the molar use ratio of the intermediate product III to the 2-methyl-2-butene, sodium chlorite and sodium dihydrogen phosphate is 1:1:1-1:10:10:10; the reaction temperature is 0-50 ℃, and the reaction time is 1-36 h.
6. The method for preparing the guanfacine metabolite according to claim 1, wherein: in the step 4), the molar dosage ratio of the intermediate product IV to the alkali to the methyl iodide is 1:1:1-1:5:5; the alkali is cesium carbonate, potassium carbonate or sodium carbonate, the reaction temperature is 0-80 ℃, and the reaction time is 1-30 h.
7. The method for preparing the guanfacine metabolite according to claim 1, wherein: in the step 5), the molar use ratio of the intermediate product V to the boron tribromide is 1:1-1:10; the reaction temperature is 0-40 ℃ and the reaction time is 1-30 h.
8. The method for preparing the guanfacine metabolite according to claim 1, wherein: in the step 6), the molar dosage ratio of the intermediate product VI to guanidine is 1:1-1:20; the guanidine is prepared by reacting guanidine hydrochloride with sodium ethoxide; the reaction temperature is 40-90 ℃ and the reaction time is 1-30 h.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210949019.5A CN115286539B (en) | 2022-08-09 | 2022-08-09 | Preparation method of guanfacine metabolite |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210949019.5A CN115286539B (en) | 2022-08-09 | 2022-08-09 | Preparation method of guanfacine metabolite |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115286539A CN115286539A (en) | 2022-11-04 |
| CN115286539B true CN115286539B (en) | 2023-08-18 |
Family
ID=83827631
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210949019.5A Active CN115286539B (en) | 2022-08-09 | 2022-08-09 | Preparation method of guanfacine metabolite |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115286539B (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009155156A1 (en) * | 2008-06-18 | 2009-12-23 | Merck & Co., Inc. | Inhibitors of janus kinases |
| CN102887838A (en) * | 2012-10-29 | 2013-01-23 | 河南中帅医药科技发展有限公司 | Preparation method of guanfacine hydrochloride |
| WO2021144439A1 (en) * | 2020-01-17 | 2021-07-22 | Grünenthal GmbH | Quinoxaline derivatives |
| WO2022117678A1 (en) * | 2020-12-03 | 2022-06-09 | UCB Biopharma SRL | Octahydroisoquinolinyl derivatives |
-
2022
- 2022-08-09 CN CN202210949019.5A patent/CN115286539B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009155156A1 (en) * | 2008-06-18 | 2009-12-23 | Merck & Co., Inc. | Inhibitors of janus kinases |
| CN102887838A (en) * | 2012-10-29 | 2013-01-23 | 河南中帅医药科技发展有限公司 | Preparation method of guanfacine hydrochloride |
| WO2021144439A1 (en) * | 2020-01-17 | 2021-07-22 | Grünenthal GmbH | Quinoxaline derivatives |
| WO2022117678A1 (en) * | 2020-12-03 | 2022-06-09 | UCB Biopharma SRL | Octahydroisoquinolinyl derivatives |
Non-Patent Citations (1)
| Title |
|---|
| Metabolite profiling of guanfacine in plasma and urine of healthy Japanese subjects after oral administration of guanfacine extended-release tablets;Yuji Inoue et al.;Biopharmaceutics & Drug Disposition;第40卷;282-293 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN115286539A (en) | 2022-11-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101772494B (en) | 4-pyrimidinesulfamide derivative | |
| CN108017583A (en) | A kind of preparation method for winning U.S. | |
| CN104418807A (en) | Preparation method of 2-ethoxyl-1-[[2'-(hydroxyl amidino)-biphenylyl]-4-yl]methyl-1H-benzimidazole-7-carboxylic acid and ester derivatives thereof | |
| CN111848607B (en) | Novel BCL-2/BCL-XL inhibitor, pharmaceutical composition and application | |
| CN113233975B (en) | Preparation method of bevacizidine acid | |
| CN115286539B (en) | Preparation method of guanfacine metabolite | |
| CN111646971B (en) | Method for synthesizing 4- (hydroxymethyl) -5-methyl- [1,3] dioxol-2-one | |
| CN102267983B (en) | Sym-triazine derivative compounds containing sym-tetrazine rings and preparation method thereof | |
| CN116143599A (en) | Preparation method of high-purity pentoxifylline intermediate | |
| CN113861066B (en) | Deuterated fluvoxamine maleate and synthesis method thereof | |
| CN102807504B (en) | Method for synthesizing salicylamide | |
| CN110229111B (en) | Ambroxol impurity and preparation method and application thereof | |
| CN106749195A (en) | A kind of olmesartan medoxomil intermediate impurities synthesis, the method for identification | |
| CN103467449A (en) | Piperidine derivative, and preparation method and application thereof in preparation of halofuginone | |
| CN114874132B (en) | Preparation method of recombinant human receptor protein FKBP12 ligand | |
| CN112047942A (en) | Synthesis method of 7-fluoroimidazo [1,2-A ] pyridine | |
| CN101935317B (en) | Synthesizing method of 2-methyl-7-(substituted pyrimidine-4-amino)-4-(substituted piperazine-1-base) piperidine-1-base) isoindoline-1-ketone and intermediate thereof | |
| CN113480549B (en) | Imidazo [1,2-a ] pyrimidine compound and preparation method thereof | |
| CN109384771B (en) | Olmesartan medoxomil related impurities and preparation method thereof | |
| CN111100080B (en) | Preparation method of letrozole | |
| CN109734702B (en) | Method for preparing rupatadine fumarate by adopting micro-channel reaction device | |
| CN101121710A (en) | Method for synthesizing chemiluminescent substance acridinum ester DMAE.NHS | |
| CN106467515A (en) | The application with field of medicaments for the one class 6- pyridine benzimidazole indole derivativeses and preparation method thereof | |
| CN102924415A (en) | 7-methoxycoumarin-3-carboxylic acid compound and preparation method thereof | |
| CN105111217A (en) | Method for synthesizing isoindole dihyroquinazoline derivative |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |