CN110396080B - Vonoprazan fumarate metabolite and preparation method of deutero metabolite thereof - Google Patents
Vonoprazan fumarate metabolite and preparation method of deutero metabolite thereof Download PDFInfo
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- CN110396080B CN110396080B CN201810372201.2A CN201810372201A CN110396080B CN 110396080 B CN110396080 B CN 110396080B CN 201810372201 A CN201810372201 A CN 201810372201A CN 110396080 B CN110396080 B CN 110396080B
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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
- C07D207/32—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The invention relates to a Vonoprazan fumarate metabolite and a preparation method of a deuterogen thereof, belonging to the technical field of pharmacy. The preparation method comprises the step of introducing a proper protecting group to protect the phenolic hydroxyl of the intermediate so as to ensure the stability of the 3-pyridine sulfonyl in the deprotection process. The preparation method provided by the invention has the advantages of simplicity, convenience, low cost, high yield and the like, is easy to operate and control, and is suitable for industrial production.
Description
Technical Field
The invention relates to the field of pharmaceutical chemicals, and particularly relates to a vonoprazan fumarate metabolite and a preparation method of a deuterate thereof.
Background
The Vonoprazan fumarate tablet is a potassium ion competitive acid retarder (P-CAB) developed by Wutian pharmaceutical company in Japan, is firstly approved and marketed in Japan in 2014 12 months, is used for treating gastric Acid Related Diseases (ARDS) such as gastric ulcer, duodenal ulcer, erosive esophagitis and helicobacter pylori infection, and has stronger and more lasting gastric acid secretion inhibiting effect compared with the in vivo research of lansoprazole.
Metabolic impurities are important for researching the action mechanism of the drug in human body, and a biological analysis method for quantitatively analyzing main metabolites of the drug in human plasma has important significance for pharmacological research, safety evaluation of the metabolites and clarification of drug-drug interaction. LC/MS/MS analysis has become the standard practice for quantifying drug metabolites due to its high selectivity. Since a stable isotopic internal standard is more desirable for LC/MS analysis, the preparation of each metabolite and deuteron for use as an internal standard is of great significance. The preparation method of the compound shown in the formula VPZ-IMP-M4 is not reported in the prior art, and the corresponding intermediate is not disclosed in the prior art. Therefore, the preparation method of the vonoprazan fumarate metabolite and the deuteroid thereof has important significance.
Disclosure of Invention
Summary of The Invention
In a first aspect of the invention, the invention provides a preparation method of a vonoprazan fumarate metabolite compound shown as VPZ-IMP-M4; the preparation route is shown as the following formula:
wherein R is selected from one of tert-butyl dimethyl silicon base, trimethyl silicon base, tert-butyl diphenyl silicon base, triisopropyl silicon base, phenyl, formyl benzyl ester base and 4-methoxybenzyl.
The preparation method introduces a proper protecting group to protect the phenolic hydroxyl of M4-08 so as to ensure the stability of 3-pyridine sulfonyl in the deprotection process.
In a second aspect of the invention, a preparation method of a compound shown as a vonoprazan fumarate metabolism deuterogen compound VPZ-d4-M4 is provided; the preparation route is shown as the following formula:
wherein R is selected from one of tert-butyl dimethyl silicon base, trimethyl silicon base, tert-butyl diphenyl silicon base, triisopropyl silicon base, phenyl, formyl benzyl ester base and 4-methoxybenzyl.
The preparation method of the compound shown in the vonoprazan fumarate metabolism deuteroid formula VPZ-d4-M4 has the advantages of low cost, high yield, simple process, simple post-treatment, reduction of difficulty and danger of industrial operation, suitability for industrial production and the like.
In a third aspect of the invention, there is provided a compound represented by formula M4-05a, formula M4-05, formula M4-07a, formula M4-07, formula M4-08 and formula M4-06a as an intermediate for the above metabolites and metabolic deuterons; the structures of these intermediates are shown below:
wherein R is selected from one of tert-butyl dimethyl silicon base, trimethyl silicon base, tert-butyl diphenyl silicon base, triisopropyl silicon base, phenyl, formyl benzyl ester base and 4-methoxybenzyl.
The intermediate compound provided by the invention has high purity, and can be used for preparing the vonoprazan fumarate metabolite or the deuterogen thereof.
Definition of terms
The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.
It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.
The following definitions as used herein should be applied unless otherwise indicated. For the purposes of the present invention, the chemical elements are in accordance with the CAS version of the periodic Table of elements, and the 75 th version of the handbook of chemistry and Physics, 1994. The term "comprising" or "comprises" is open-ended, i.e. comprising what is specified in the present invention, but not excluding other aspects.
The term "TBS" denotes tert-butyldimethylsilane; the term "TMS" means trimethylsilane; the term "TBDPS" means t-butyl diphenylsilane; the term "TIPS" means triisopropylsilane; the term "Bn" denotes phenyl; the term "Cbz" denotes formyl benzyl ester; the term "PMB" denotes 4-methoxybenzyl; the term "NaH" means sodium hydride; the term "STAB" denotes sodium triacetoxyborohydride; the term "LDA" denotes lithium diisopropylamide; the term "NaBH4"represents sodium borohydride; the term "NBS" denotes N-bromosuccinimide; the term "DIPEA" means diisopropylethylamine; the term "DMAP" denotes dimethylaminopyridine; the term "DBU" denotes 1, 8-diazabicyclo [5.4.0]Undec-7-ene.
Detailed Description
In a first aspect, the invention provides a process for the preparation of a vonoprazan fumarate metabolite of a compound represented by the formula VPZ-IMP-M4; the preparation route is as follows:
wherein R is selected from one of tert-butyl dimethyl silicon base, trimethyl silicon base, tert-butyl diphenyl silicon base, triisopropyl silicon base, phenyl, formyl benzyl ester base and 4-methoxybenzyl.
In some embodiments, a compound of formula M4-07 is reacted with chlorosulfonic acid in the presence of an organic solvent and a base to provide a compound of formula VPZ-IMP-M4.
In some embodiments, the organic solvent is dichloromethane, dichloroethane, ethyl acetate or 1, 4-dioxane, preferably dichloromethane. .
In some embodiments, the base is an organic base or an inorganic base.
In some embodiments, the base is DBU, DIPEA, or triethylamine.
In some embodiments, the compound of formula M4-07 is performed at a temperature of-10 ℃ to 10 ℃, or at a temperature of-5 ℃ to 5 ℃.
In some embodiments, the reaction time is 1 hour to 3 hours, or 2 hours.
In some embodiments, a compound represented by M4-07a is reacted in an organic solvent and a deprotection reagent to provide a compound represented by M4-07.
In some embodiments, the organic solvent is dichloromethane, dichloroethane, ethyl acetate or 1, 4-dioxane, preferably dichloromethane. .
In some embodiments, the deprotection reagent is tetrabutylammonium fluoride (TBAF).
In some embodiments, the reaction temperature is from 20 ℃ to 30 ℃.
In some embodiments, the reaction time is from 1 hour to 4 hours, or from 2 hours to 3 hours.
In some embodiments, a reductive amination reaction of a compound of formula M4-06a in an organic solvent affords a compound of formula M4-07 a.
In some embodiments, a compound of formula M4-06a is reacted with a solution of methylamine.
In some embodiments, the organic solvent is dichloromethane, dichloroethane, ethyl acetate or 1, 4-dioxane, preferably dichloromethane. .
In some embodiments, the reducing agent is selected from at least one of sodium hydride, sodium triacetoxyborohydride, lithium diisopropylamide, or sodium borohydride.
In some embodiments, the reaction temperature is from 20 ℃ to 30 ℃.
In some embodiments, the reaction time is 1 hour to 3 hours, or 2 hours, or 1 hour.
In a second aspect, the invention provides a preparation method of a vonoprazan fumarate metabolism deuteroid compound shown as formula VPZ-d4-M4, and the preparation route is shown as follows:
wherein R is selected from one of tert-butyl dimethyl silicon base, trimethyl silicon base, tert-butyl diphenyl silicon base, triisopropyl silicon base, phenyl, formyl benzyl ester base and 4-methoxybenzyl.
In some embodiments, a compound of formula M4-05 is reacted with chlorosulfonic acid in the presence of an organic solvent and a base to provide a compound of formula VPZ-d 4-M4.
In some embodiments, the organic solvent is dichloromethane, dichloroethane, ethyl acetate or 1, 4-dioxane, preferably dichloromethane.
In some embodiments, the base is an organic base or an inorganic base.
In some embodiments, the base is triethylamine.
In some embodiments, the reaction temperature is from 0 ℃ to 30 ℃, or from 10 ℃ to 20 ℃.
In some embodiments, the reaction time is from 1 hour to 4 hours, or from 2 hours to 3 hours.
In some embodiments, deprotection of a compound of formula M4-05a by concentrated HCl affords a compound of formula M4-05.
In some embodiments, the deprotection reaction temperature is from 0 ℃ to 30 ℃.
In some embodiments, a reductive amination reaction of a compound of formula M4-06a in an organic solvent affords a compound of formula M4-05 a.
In some embodiments, a compound of formula M4-06a is reacted with deuterated methylamine hydrochloride to give a compound of formula M4-05 a.
In some embodiments, the reducing agent is sodium deuteride boron.
In some embodiments, the reaction temperature is from 10 ℃ to 40 ℃, or from 20 ℃ to 30 ℃.
In some embodiments, the compounds of formula M4-06a are prepared by the following route:
wherein R is selected from one of tert-butyldimethylsilane, trimethylsilane, tert-butyldiphenylsilane, triisopropylsilane, phenyl, formyl benzyl ester or 4-methoxybenzyl.
In some embodiments, a compound of formula M4-08a is reacted with 3-pyridinesulfonyl chloride in an organic solvent in the presence of a base to provide a compound of formula M4-06 a.
In some embodiments, the base is an organic base or an inorganic base.
In some embodiments, the base is DBU, DMAP, DIPEA or triethylamine, preferably DIPEA.
In some embodiments, a compound of formula M4-08 is reacted with a halide R-X in an organic solvent in the presence of a base to provide a compound of formula M4-08a, wherein X is F, Cl, Br or I.
In some embodiments, the base is DBU, DMAP, DIPEA or triethylamine, preferably DBU.
In some embodiments, the compound of formula M4-04 is catalytically reduced under the influence of hydrogen to provide a compound of formula M4-08.
In some embodiments, the catalyst for the catalytic reduction reaction is selected from at least one of raney nickel or palladium on carbon.
In some embodiments, the compounds of formula M4-04 are prepared as follows:
in some embodiments, the compound of formula M4-03 is reacted with Pd/C and hydrogen to obtain a compound of formula M4-04.
In some embodiments, a compound of formula M4-02 is reacted with a chlorinating agent to provide a compound of formula M4-03.
In some embodiments, the chlorinating reagent is hydrochloric acid, TMSCl, oxalyl chloride, thionyl chloride or sulfuryl chloride, preferably oxalyl chloride.
In some embodiments, a compound of formula M4-01 is reacted with malononitrile to give a compound of formula M4-02.
In some embodiments, a compound of formula M4-00 is reacted with a brominating agent to provide a compound of formula M4-01.
In some embodiments, the brominating reagent is bromine, N-bromosuccinimide (NBS), or dibromohydantoin, preferably bromine.
In the invention, a vonoprazan fumarate metabolite and a preparation method of a deutero metabolite thereof can be shown as the following reaction formula:
wherein R is selected from one of tert-butyl dimethyl silicon base, trimethyl silicon base, tert-butyl diphenyl silicon base, triisopropyl silicon base, phenyl, formyl benzyl ester base and 4-methoxybenzyl.
Those skilled in the art, under the concept of the present invention, can properly adjust the reaction conditions according to the disclosure, such as selecting other proper reaction solvents, adjusting the reaction temperature, properly prolonging the reaction time to obtain better reaction effect, etc.
Compared with the prior art, the technical scheme provided by the invention has the following advantages:
1. in the process of removing protective group R, the stability of 3-pyridine sulfonyl is good, and the preparation method provided by the invention has the advantages of simplicity, low cost, high yield and the like, is easy to operate and control, has stable process and is suitable for industrial production.
2. The preparation method of the compound shown in the vonoprazan fumarate metabolism deuteroid formula VPZ-d4-M4 has the advantages of low cost, high yield, simple process, simple post-treatment, reduction of difficulty and danger of industrial operation, suitability for industrial production and the like.
3. The intermediate compound provided by the invention has high purity, and can be used for preparing the vonoprazan fumarate metabolite or the deuterogen thereof.
Detailed Description
In order to make the technical solution of the present invention better understood by those skilled in the art, the present invention exemplarily provides a part of preparation examples, and the following further discloses some non-limiting examples to further explain the present invention in detail.
The reagents used in the present invention are either commercially available or can be prepared by the methods described herein.
mL means mL, g means g, H means H, min means min, DEG C means centigrade, N means mol/liter, 1H NMR means nuclear magnetic hydrogen spectrum, MS means mass spectrum, HPLC means high performance liquid chromatography, CDCl3Deuterated chloroform, DMSO-d6Refers to deuterated dimethyl sulfoxide.
EXAMPLE 1 preparation of intermediate M4-01
Adding M4-00(100.00g) and dioxane (900ml) into a 2L reaction bottle, cooling to 0 ℃, dropwise adding a mixed solution of bromine (35ml) and DCM (500ml), heating to 15 ℃ for reaction, sampling for 5h, carrying out HPLC detection, and stopping the reaction until the reaction of the raw materials is complete. Concentrating the reaction solution to dryness, adding 1, 2-dichloroethane, refluxing at 85 ℃ for 1h, cooling to 0 ℃, performing suction filtration, and drying the filter cake in vacuum to obtain 102g of solid, wherein the yield is 67.5%, and the HPLC purity is 95.21%.
EXAMPLE 2 preparation of M4-02 intermediate
Adding M4-01(50.00g), malononitrile (15.53g) and EA (500ml) into a 1L reaction bottle, cooling to 0 ℃, dropwise adding DIPEA (33.30g), carrying out heat preservation reaction, sampling for 23h, carrying out HPLC detection until the reaction of the raw materials is complete, and stopping the reaction. The reaction mixture was washed with water (50ml), and the organic phase was concentrated under reduced pressure to give 60.00g of a black oil (containing a portion of the solvent) which was used directly in the next reaction.
EXAMPLE 3 preparation of M4-03 intermediate
M4-02(60.00g) and THF (360ml) were added to a 1L reaction flask, oxalyl chloride (42.00g) was added, the temperature was raised to 50 ℃ for reaction, and 4h sampling HPLC was performed until the reaction was complete, and the reaction was stopped. Concentrating under reduced pressure to obtain black oil, adding EA (200ml), 5% NaHCO3The solution (150ml) was washed with brine (150ml) and the organic phase was concentrated under reduced pressure to give a black oil. Purifying by silica gel column chromatography (eluent EA: DCM ═ 1:20), and purifying by successive pulping with EA to obtain 6.12g of gray yellow solid, with two-step total yield of 14.1% and HPLC purity of 97.49%.
EXAMPLE 4 preparation of M4-04 intermediate
M4-03(5.00g), Pd/C (1.00g), DIPEA (3.55g) and EtOH (50ml) were added to a 250ml reaction flask, H2And (5) replacing, heating to 70 ℃ for reaction, sampling for 8h, detecting by HPLC (high performance liquid chromatography) until the reaction of the raw materials is complete, and stopping the reaction. Filtering, washing filter cake with EtOH (5ml multiplied by 2), decompressing and concentrating filtrate to remove EtOH, adding EA (40ml) and water (40ml), adjusting pH to 6-7, separating liquid, extracting water phase with EA (30ml multiplied by 2), combining organic phases, using anhydrous Na2SO4Drying to obtain 3.98g of solid, the yield is 93.2%, and the HPLC purity is 94.90%.
EXAMPLE 5 preparation of M4-08 intermediate
M4-04(3.95g), Raney nickel (1.98g), DMAc (30ml), HCOOH (22ml) and water (9ml) were added to a 250ml reaction flask, H2And (5) replacing, heating to 50 ℃ for reaction, sampling for 17h, detecting by HPLC (high performance liquid chromatography) until the reaction of the raw materials is complete, and stopping the reaction. Suction filtration was carried out, the filter cake was washed with DMAc (100 ml. times.3), and water (100ml), saturated Na2CO3The solution was adjusted to pH 6-7, extracted with EA (100 ml. times.3), the organic phase was washed with saturated brine (100 ml. times.3), and the organic phase was concentrated to give a black oil. Purification by column chromatography on silica gel (eluent EA: n-hexane: 1:5 to 1:1) to give 2.45g of gray solid, yield 61.1%, HPLC purity 98.82%
EXAMPLE 6 preparation of intermediate M4-08a
M4-08(1.98g), DBU (2.03g) and DCM (36ml) were added to a 100ml reaction flask, TBSCl (1.98g) was added dropwise thereto by cooling to 0 ℃ and sampling was carried out for 2h by HPLC until the reaction of the starting materials was completed, and the reaction was stopped. The reaction mixture was washed with water (35 ml. times.2), and the organic phase was concentrated under reduced pressure to give M4-08a as a brown oil (3.64 g). Purification by column chromatography on silica gel (eluent DCM containing 0.1% TEA) gave 2.23g of an off-white solid in 72.3% yield and 97.50% HPLC purity.
EXAMPLE 7 preparation of intermediate M4-06a
M4-08a (2.35g) from example 6, DMAP (0.36g), DIPEA (1.90g) and DCM (35ml) were added to a 100ml reaction flask and stirred at 25. + -. 5 ℃; dropwise adding 3-pyridine sulfonyl chloride (1.96g is dissolved in 5ml of DCM), carrying out heat preservation reaction after the dropwise adding is finished, starting HPLC for 1h, controlling until the raw materials are completely reacted, and stopping the reaction. The reaction mixture was washed with water (40 ml. times.2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give M4-06a as a brown-red oil (3.68 g). Purifying by silica gel column chromatography (eluent containing 0.1% TEA in DCM), and concentrating the target at 35 deg.C under reduced pressure to obtain light yellow solid 2.80g, yield 82.6%, and HPLC purity 97.40%
EXAMPLE 8 preparation of intermediate M4-07a
M4-06a (2.15g) obtained in example 7, a methylamine solution (1.93g) and DCM (40ml) were charged into a 100ml reaction flask, stirred at 25. + -. 5 ℃ for 1h, then added with sodium triacetoxyborohydride (1.16g), and reacted for 1h while maintaining the temperature, sampled and HPLC-detected until the reaction of the starting materials was completed, and the reaction was stopped. The reaction mixture was washed with water (40 ml. times.2), the organic phase was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to give M4-07a as an off-white solid (4.47 g). Purifying by silica gel column chromatography (eluent EA), concentrating at 30 deg.C under reduced pressure to obtain light brown oil 1.47g, yield 66.2%, and HPLC purity 96.95%
EXAMPLE 9 preparation of intermediate M4-07
M4-07a (1.70g), TBAF (5.4ml) and DCM (12ml) from example 8 were added to a 50ml reaction flask and stirred at 25. + -. 5 ℃. Sampling was started at 2h and HPLC was detected until the reaction of the starting materials was complete. After the reaction is finished, concentrating under reduced pressure until 5-10 ml of the solution remains. Purified by silica gel column chromatography (MeOH: DCM ═ 1:10), concentrated to dryness to give 2.93g of oil (containing a portion of solvent) which was used directly in the next reaction.
EXAMPLE 10 preparation of the metabolite VPZ-IMP-M4
M4-07(2.93g), DBU (1.36g) and DCM (15ml) were added to a 50ml reaction flask and the temperature was reduced to-5 ℃ with stirring. ClSO3H (0.48g) and DCM (5ml) were mixed and added dropwise to the reaction mixture, the reaction was incubated and HPLC was started for 2H until the starting material was almost completely reacted. The reaction was quenched and concentrated under reduced pressure to remove DCM. The remaining oil was purified by column chromatography on silica gel eluting with MeOH: DCM 1:20, the resulting impure sample was separated on a thin prep plate, developing MeOH: EA 1:5, and the product was concentrated at 25 ℃ to give 0.61g of metabolite VPZ-IMP-M4, with a two-step overall yield of 38.6% and HPLC purity 98.57%.
Example 11 preparation of the Metabolic deuteron VPZ-d4-M4
M4-06a (1.41g), a solution of triethylamine (0.62g) in 3ml of DCM, DCM (12ml) and deuterated methylamine hydrochloride (0.43g) were added to a reaction flask, stirred at 30 ℃ for 4h, 15ml of water was added, the aqueous phase was extracted with 10ml of DCM, the layers were separated, the organic phases were combined and concentrated to dryness under reduced pressure. 15ml of absolute methanol is added, the temperature is reduced to 0 ℃, boron deuteride sodium (0.077g) is added, sampling is started for 1h, HPLC detection is carried out until the reaction of the raw materials is complete, and the reaction is stopped. Adding concentrated hydrochloric acid (1.69g) at 0 deg.C, heating to 30 deg.C, reacting for 2h, adding 1.01g concentrated hydrochloric acid, reacting for 1h, and detecting by HPLC until the intermediate reaction is complete. Concentration under reduced pressure gave a blue solid, which was stirred for 0.5h with 15ml of anhydrous methanol and 2.00g of TEA, and concentrated to dryness under reduced pressure to give a black oil. Purifying by silica gel column chromatography, and concentrating under reduced pressure at 30 deg.C to obtain M4-05 black oily substance 1.28g, which can be directly used in the next reaction. .
Adding black oily matter M4-05(1.28g), TEA (2.13g) and DCM (6ml) into a 100ml reaction bottle, stirring at 30 deg.C, partially dissolving, cooling to 0 deg.C, and adding ClSO dropwise3A solution of H (0.72g) in DCM (8ml) was raised to 30 ℃ for reaction and HPLC started 17H to detect essentially complete reaction of the starting material. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain 2.70g of a concentrate. Separating with chromatographic column, concentrating under reduced pressure to remove acetonitrile, and lyophilizing the rest water phase to obtain grey solid metabolic deuterode VPZ-d4-M4 of 460mg, with total yield of 33.7% calculated by M4-06a and HPLC purity of 97.54%.
While the methods of the present invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications of the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of the present invention within the context, spirit and scope of the invention. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to those skilled in the art are deemed to be included within the invention.
Claims (8)
1. A process for the preparation of a compound of formula VPZ-IMP-M4, the scheme being as follows:
wherein R is selected from one of tert-butyl dimethyl silicon base, trimethyl silicon base, tert-butyl diphenyl silicon base and triisopropyl silicon base; reacting the compound shown as the formula M4-07 with chlorosulfonic acid in the presence of an organic solvent and a base to obtain the compound shown as the formula VPZ-IMP-M4, wherein the reaction time is 1 hour to 3 hours.
2. The method according to claim 1, wherein the compound represented by formula M4-06a is subjected to reductive amination in an organic solvent to obtain a compound represented by formula M4-07a, wherein the reducing agent is at least one selected from sodium hydride, sodium triacetoxyborohydride, lithium diisopropylamide and sodium borohydride.
3. A process for the preparation of a compound of formula VPZ-d4-M4, the scheme being as follows:
wherein R is selected from one of tert-butyl dimethyl silicon base, trimethyl silicon base, tert-butyl diphenyl silicon base and triisopropyl silicon base; reacting a compound shown as a formula M4-05 with chlorosulfonic acid in the presence of an organic solvent and a base to obtain a compound shown as a formula VPZ-d 4-M4; the reaction time is 1 hour to 4 hours.
4. The method of claim 3, wherein the compound of formula M4-06a is subjected to reductive amination in an organic solvent to obtain the compound of formula M4-05a, wherein the reducing agent is sodium deuteride.
5. The process according to any one of claims 1 or 3, wherein the general scheme for the preparation of the compound of formula M4-06a is as follows:
wherein R is selected from one of tert-butyl dimethyl silicon base, trimethyl silicon base, tert-butyl diphenyl silicon base and triisopropyl silicon base.
6. The method according to claim 5, wherein the compound of formula M4-08a is reacted with 3-pyridinesulfonyl chloride in an organic solvent in the presence of a base to obtain a compound of formula M4-06 a.
7. The process according to claim 5, wherein the compound of formula M4-08 is reacted with a halide R-X in an organic solvent in the presence of a base to give a compound of formula M4-08 a; wherein X is F, Cl, Br or I.
8. The preparation method of claim 5, wherein the compound represented by the formula M4-04 is catalytically reduced under the action of hydrogen in the presence of a catalyst to obtain the compound represented by the formula M4-08, wherein the catalyst is at least one of Raney nickel or palladium on carbon.
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| CN102421753A (en) * | 2009-02-25 | 2012-04-18 | 武田药品工业株式会社 | Process for producing pyrrole compound |
| CN104327051A (en) * | 2014-10-13 | 2015-02-04 | 成都盛迪医药有限公司 | Crystal form of fumarate of pyrrole derivative |
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| CN102421753A (en) * | 2009-02-25 | 2012-04-18 | 武田药品工业株式会社 | Process for producing pyrrole compound |
| CN104327051A (en) * | 2014-10-13 | 2015-02-04 | 成都盛迪医药有限公司 | Crystal form of fumarate of pyrrole derivative |
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| In vitro metabolism of TAK-438, vonoprazan fumarate, a novel potassium-competitive acid blocker;Hitomi Yamasaki等;《Xenobiotica》;20160712;1-8 * |
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