CN118084942B - Preparation method of methylated SMTP-7 - Google Patents

Preparation method of methylated SMTP-7 Download PDF

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CN118084942B
CN118084942B CN202410508590.2A CN202410508590A CN118084942B CN 118084942 B CN118084942 B CN 118084942B CN 202410508590 A CN202410508590 A CN 202410508590A CN 118084942 B CN118084942 B CN 118084942B
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CN118084942A (en
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乔创
许坤华
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Shenzhen Chuangyuan Biomedical Technology Co ltd
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Abstract

The invention discloses a preparation method of methylation SMTP-7, which is characterized in that from commercially available 3, 5-dimethoxy methyl benzoate, a pyran ring is constructed through a key step of sodium borohydride catalyzed reductive amination cyclization, suzuki coupling connection of a side chain and vanadium catalyzed oxidative cyclization reaction, so that the preparation of methylation SMTP-7 g can be conveniently realized in a laboratory; methylated SMTP-7 is taken as a precursor compound of a natural product SMTP-7, and provides good synthetic thought and solution for the total synthesis of SMTP-7. The method has the advantages of simple synthetic route, simple operation and higher yield, and the used reagents are all common reagents and can be prepared on a large scale.

Description

Preparation method of methylated SMTP-7
Technical Field
The invention belongs to the technical field of heterocyclic compound synthesis, and particularly relates to a preparation method of methylated SMTP-7.
Background
SMTP-7 (Stachybotry microspore triprenyl phenol-7, CAS: 733805-92-0), the hydromyces microsporidian triallylphenol-7 was extracted from mould (Stachybotry smicrospora) on a special cast leaf on the Okinawa county surface island in 2000. It is a small molecule trypsin activator, similar in structure to vitamin E. It can decompose thrombus through a new action mechanism and inhibit local inflammation of thrombus. In addition, SMTP-7 has anti-tumor angiogenesis activity, antioxidant activity and tissue regeneration promoting activity. Plasminogen is a plasmin precursor and can be activated to produce plasmin. This is a protease that hydrolyzes many proteins, including thrombin-sensitive proteins. After binding to plasminogen, SMTP-7 changes its molecular conformation making it more susceptible to activation by plasminogen activator. Thus, SMTP-7 does not have the function of activating plasminogen itself, but makes the activation process easier. The unique combination of SMTP-7 makes it possible to be the best thrombolytic drug for the treatment of Acute Ischemic Stroke (AIS) (J. Antibiot,2000,53 (3): 241-247).
In Japanese Sho university, itanjo et al, JP7381035B2, 2020, synthesized a series of useful intermediates of Pre-SMTP and SMTP analogs, and envisaged that the reverse synthetic analysis of SMTP-7 could be derived from condensation of Pre-SMTP and L-ornithine, wherein Pre-SMTP could be derived from the simple and readily available compound methyl 3, 5-dimethoxybenzoate, via a ten-step synthesis, but the complete synthesis of SMTP-7 was not reported in this patent.
The main mode of SMTP-7 is to add L-ornithine from a mould (Stachybotrys microspora) for biosynthesis and purification, and the complete synthesis of SMTP-7 and methylated SMTP-7 has not been reported in the literature or patent. The methylated SMTP-7 can be used as a precursor compound for synthesizing SMTP-7, has important research value on the total synthesis of the active natural product SMTP-7, and can provide a synthesis idea and solution for synthesizing SMTP-7.
Disclosure of Invention
In order to overcome the defects and shortcomings in the prior art, the invention aims to provide a preparation method of methylated SMTP-7.
The aim of the invention is achieved by the following technical scheme:
the preparation method of the methylated SMTP-7 comprises the following synthetic route:
The step 1 specifically includes: the compound 2, lewis acid and 1, 1-dichloro dimethyl ether react in methylene dichloride solution for 1 to 2 hours to obtain a compound 3;
the step 2 specifically comprises the following steps: lewis acid and the compound 3 react in dichloromethane solution for 1 to 2 hours to obtain a compound 4;
The step 3 specifically comprises the following steps: the compound 4, lewis acid and N-iodosuccinimide react in dichloromethane solution for 1 to 2 hours to obtain a compound 5;
The step 4 specifically comprises the following steps: reacting the compound 5 and the compound 5a (L-ornithine tert-butyl ester, CAS: 195320-40-2) in dichloromethane solution for 1-2 hours to obtain a compound 6;
The step 5 specifically comprises the following steps: reacting the compound 6 with a reducing agent in a dichloromethane/methanol solution for 1-2 hours to obtain a compound 7;
The step 6 specifically comprises the following steps: reacting the compound 7, alkali and halogenated ether in dichloromethane solution for 1-2 hours to obtain a compound 8;
The step 7 specifically comprises the following steps: heating compound 8, compound 8a (farnesyl borate, CAS: 1268820-35-4), alkali and palladium catalyst in N, N-dimethylformamide solution for 8-14 hours to obtain compound 9;
the step 8 specifically comprises the following steps: reacting the compound 9 with acid in dichloromethane solution for 2-6 hours to obtain a compound 10;
the step 9 specifically comprises the following steps: the compound 10, the vanadium catalyst, the oxidant and the organic acid are reacted in methylene dichloride solution for 1 to 2 hours to obtain the compound 1, namely the methylated SMTP-7.
Preferably, the lewis acid in step 1 is any one of aluminum trichloride, aluminum tribromide and titanium tetrachloride, and more preferably titanium tetrachloride.
Preferably, the lewis acid in step 2 is any one of aluminum trichloride, boron tribromide, and boron trichloride, and more preferably aluminum trichloride.
Preferably, the lewis acid in step 3 is any one of aluminum trichloride, aluminum tribromide and titanium tetrachloride, and more preferably aluminum trichloride.
Preferably, the reducing agent in step 5 is any one of sodium borohydride, sodium borohydride acetate, sodium cyanoborohydride, and lithium aluminum hydride, and more preferably sodium borohydride.
Preferably, the base in step 6 is any one of triethylamine, N-diisopropylethylamine, pyridine, 2, 6-lutidine, imidazole, and 4-dimethylaminopyridine, and more preferably N, N-diisopropylethylamine.
Preferably, the halogenated ether in step 6 is any one of bromomethyl ether and chloromethyl ether, and more preferably bromomethyl ether.
Preferably, the base in step 7 is any one of cesium carbonate, cesium fluoride, potassium tert-butoxide, and sodium tert-butoxide, and more preferably cesium fluoride.
Preferably, the palladium catalyst in step 7 is any one of [1,1 '-bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex, tris (dibenzylideneacetone) dipalladium, bis (dibenzylideneacetone) palladium, tetrakis (triphenylphosphine) palladium, more preferably [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex.
Preferably, the acid in step 8 is any one of hydrochloric acid, p-toluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid and acetic acid, and more preferably hydrochloric acid.
Preferably, the vanadium catalyst in step 9 is any one of vanadyl acetylacetonate and triisopropoxy vanadium oxide, and more preferably triisopropoxy vanadium oxide.
Preferably, the oxidizing agent in step 9 is any one of hydrogen peroxide, tert-butyl hydroperoxide, cumene hydroperoxide, and m-chloroperoxybenzoic acid, and more preferably tert-butyl hydroperoxide.
Preferably, the organic acid in step 9 is any one of p-toluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid and acetic acid, and more preferably trifluoroacetic acid.
Compared with the prior art, the invention has the following advantages and effects:
(1) The method has the advantages of simple synthetic route, simple operation and higher yield, and the used reagents are all common reagents and can be prepared on a large scale.
(2) According to the invention, a pyran ring is constructed by starting from commercially available 3, 5-dimethoxy methyl benzoate and through a key step of sodium borohydride catalyzed reductive amination cyclization, suzuki coupling connection of a side chain and vanadium catalyzed oxidative cyclization reaction, the preparation of methylated SMTP-7 g level can be conveniently realized in a laboratory; methylated SMTP-7 is taken as a precursor compound of a natural product SMTP-7, and provides good synthetic thought and solution for the total synthesis of SMTP-7.
Drawings
In order to more clearly illustrate the embodiments of the invention or the technical solutions in the prior art, the drawings that are required in the embodiments or the description of the prior art will be briefly described, it being obvious that the drawings in the following description are only some embodiments of the invention, and that other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a synthetic route for the methylation of SMTP-7 according to an embodiment of the invention.
FIG. 2 is a nuclear magnetic resonance spectrum of compound 10 synthesized in the example of the present invention.
FIG. 3 is a nuclear magnetic resonance spectrum of methylated SMTP-7 synthesized according to the example of the present invention.
Detailed Description
Embodiments of the present invention will now be described more fully hereinafter with reference to the accompanying examples, in which some, but not all embodiments of the invention are shown. The following description of at least one exemplary embodiment is merely exemplary in nature and is in no way intended to limit the invention, its application, or uses. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The reagents or apparatus used in the present invention are conventional products commercially available without identifying the manufacturer. For process parameters not specifically noted, reference may be made to conventional techniques.
Examples
As shown in fig. 1, the present embodiment provides a preparation method of methylated SMTP-7, comprising the following steps:
Step 1: compound 2 (3, 5-dimethoxybenzoate, 19.6g,100 mmol) was dissolved in 500mL of dichloromethane solution, titanium tetrachloride (32.2 g,170 mmol) and 1, 1-dichlorodimethyl ether (15.5 g,135 mmol) were slowly added dropwise respectively at 0deg.C, the dropwise addition was then transferred to room temperature and stirring was continued for 1 hour, then 1M hydrochloric acid was added for quenching, dichloromethane extraction, brine washing, drying and concentration gave compound 3 (22 g,98mmol, yield 98%) as a yellow solid after purification of the crude product by silica gel column.
Step 2: aluminum trichloride (40 g,300 mmol) was weighed and dissolved in 300mL of dichloromethane solution, a dichloromethane solution of compound 3 (22 g of compound 3 was slowly added dropwise at 0 ℃ in 200mL of dichloromethane to prepare), then the reaction flask was heated to 45 ℃ to react for 2 hours, after TLC detection reaction was completed, ice water quenching was added, dichloromethane extraction, drying and concentration were carried out to obtain a crude product, and a yellow solid, namely compound 4 (16 g, yield 78%) was obtained after purification by silica gel column.
Step 3: compound 4 (10.0 g,47.6 mmol) was dissolved in 250mL of dichloromethane, aluminum trichloride (6.4 g,47.6 mmol) and N-iodosuccinimide (11.8 g,52.4 mmol) were added separately at 0deg.C, and after 2 hours at room temperature, ice water quench was added, dichloromethane extraction, drying, concentration gave a crude product, and recrystallization with dichloromethane gave compound 5 (14 g, yield 87%) as a brown solid.
Step 4: compound 5 (4.9 g,14.5 mmol) was dissolved in 70mL of dichloromethane, compound 5a (L-ornithine tert-butyl ester, CAS:195320-40-2,1.4g,7.3 mmol) was added with stirring at room temperature and stirring was continued for 2 hours, and after completion of the reaction of the starting materials by TLC, the dichloromethane solution of compound 6 was used directly in the next step without work-up and purification.
Step 5: 70mL of methanol is added to a dichloromethane solution of the compound 6 and cooled in an ice-water bath, sodium borohydride (0.82 g,21.7 mmol) is slowly added and then the reaction is continued for 1 hour at room temperature, 60mL of water and 15mL of acetic acid are added to a spin-dry solvent after the TLC detection of the complete reaction of the compound 6, the reaction is carried out at 90 ℃ for 1 hour and then cooled to room temperature, saturated sodium bicarbonate solution is quenched, ethyl acetate is used for extraction, an organic phase is respectively washed with saturated sodium bicarbonate solution and saline solution, 6g of light brown solid is obtained after concentration, namely a crude product of the compound 7, and the product is obtained after LCMS detection [ C 27H30I2N2O8+H]+: 764.8, and can be directly used for the next step without purification.
Step 6: crude compound 7 (6 g,7.8 mmol) was dissolved in 80mL of dry dichloromethane and placed in an ice-water bath for cooling, N-diisopropylethylamine (3.0 g,23.5 mmol) and bromomethyl ether (1.96 g,15.7 mmol) were added dropwise slowly with a syringe, respectively, and stirring was continued at room temperature for 2 hours; after completion of the reaction by TLC, ice-water quench was added, extraction was performed with dichloromethane, and the combined organic phases were washed with saturated brine, dried and concentrated, and purified by silica gel column to give compound 8 (2.9 g,3.4mmol, total yield of three steps 4 to 6 was 47%) as a yellow solid, which was measured by LCMS [ C 31H38I2N2O10+H]+: 852.9.
Step 7: compound 8 (2.9 g,3.4 mmol) and compound 8a (farnesyl borate, CAS:1268820-35-4,4.5g,13.6 mmol) were dissolved in 34mL of dry N, N-dimethylformamide and filled with nitrogen, and [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (0.55 g) and cesium fluoride (2.6 g,17.0 mmol) were added to the nitrogen stream, respectively, and stirred for 14 hours at 50℃and cooled to room temperature, quenched with water, extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried and concentrated to give compound 9 (2.0 g,2.0 mmol) as a yellow viscous liquid after purification by a silica gel column, yield 58%).
Step 8: compound 9 (2.0 g,2.0 mmol) was dissolved in 20mL of anhydrous dichloromethane, HCl (4mL,4N in dioxane) was slowly added dropwise at 0deg.C, and then the reaction was continued at room temperature for 4 hours; after completion of the TLC detection, the solvent was dried, quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate, the combined organic phases were washed with saturated brine, dried and concentrated, and purified by silica gel column to give compound 10 (1.8 g,1.9mmol, yield 95%) as a yellow foamy solid;
FIG. 2 is a nuclear magnetic resonance spectrum of Compound 10 .1H NMR (600 MHz, CDCl3) δ 6.96 (s, 1H), 6.95 (s, 1H), 5.29 – 5.21 (m, 2H), 5.20 – 5.13 (m, 1H), 5.10 – 5.03 (m, 3H), 4.95 – 4.89 (m, 1H), 4.52 (d, J = 16.7 Hz, 1H), 4.31 – 4.18 (m, 3H), 3.82 (s, 6H), 3.60 (t, J = 7.0 Hz, 2H), 3.52 – 3.42 (m, 4H), 2.29 – 2.23 (m, 1H), 2.18 – 2.13 (m, 1H), 2.12 – 1.92 (m, 14H), 1.81 (s, 6H), 1.78 – 1.70 (m, 3H), 1.67 (s, 3H), 1.66 (s, 3H), 1.63 (s, 3H), 1.60 (s, 3H), 1.57 (s, 6H), 1.38 (s, 9H).
Step 9: compound 10 (1.8 g,1.9 mmol) was dissolved in 20mL of dry dichloromethane and filled with nitrogen followed by addition of vanadium triisopropoxide (15.5 mg), stirred for 5 min, then t-butylhydroperoxide (4.9 mmol,0.92mL,5-6M in decane) was added by syringe and stirred for 30 min; trifluoroacetic acid (0.06 mL,0.8 mmol) was then added via syringe and the reaction was continued for 2 hours, after completion of the reaction the solvent was spun dry and purified by silica gel column to give a pale yellow foamy solid as compound 1, methylated SMTP-7 (0.74 g,0.76mmol, 40% yield) as determined by LCMS [ C 57H80N2O10+H]+:953.5.
FIG. 3 is a nuclear magnetic resonance spectrum of Compound 1 .1HNMR (400 MHz, CDCl3) δ 6.89 (s, 1H), 6.85 (s, 1H), 5.15 – 5.02 (m, 3H), 5.00 – 4.90 (m, 1H), 4.49 (t, J = 16.6 Hz, 1H), 4.31 – 4.15 (m, 3H), 3.97 – 3.88 (m, 1H), 3.84 (s, 6H), 3.72 – 3.49 (m, 2H), 3.01 – 2.84 (m, 2H), 2.82 – 2.60 (m, 2H), 2.25 – 1.82 (m, 20H), 1.66 (s, 3H), 1.65 (s, 6H), 1.58 (s, 3H), 1.56 (s, 6H), 1.43 (s, 6H), 1.42 (s, 9H).
The final product compound 1 has correct structure through nuclear magnetic spectrum verification, which shows that the invention successfully synthesizes the methylation SMTP-7.
According to the invention, a pyran ring is constructed by starting from commercially available 3, 5-dimethoxy methyl benzoate and through a key step of sodium borohydride catalyzed reductive amination cyclization, suzuki coupling connection of a side chain and vanadium catalyzed oxidative cyclization reaction, the preparation of methylated SMTP-7 g level can be conveniently realized in a laboratory; methylated SMTP-7 is taken as a precursor compound of a natural product SMTP-7, and provides good synthetic thought and solution for the total synthesis of SMTP-7. Meanwhile, the synthesis route is simple, the operation is simple, the yield is high, and all the used reagents are common reagents and can be prepared on a large scale.
The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.

Claims (6)

1. A preparation method of methylated SMTP-7 is characterized by comprising the following synthetic route:
The step 1 specifically includes: the compound 2, lewis acid and 1, 1-dichloro dimethyl ether react in methylene dichloride solution for 1 to 2 hours to obtain a compound 3;
the step 2 specifically comprises the following steps: lewis acid and the compound 3 react in dichloromethane solution for 1 to 2 hours to obtain a compound 4;
The step 3 specifically comprises the following steps: the compound 4, lewis acid and N-iodosuccinimide react in dichloromethane solution for 1 to 2 hours to obtain a compound 5;
The step 4 specifically comprises the following steps: reacting the compound 5 and the compound 5a in dichloromethane solution for 1-2 hours to obtain a compound 6;
The step 5 specifically comprises the following steps: reacting the compound 6 with a reducing agent in a dichloromethane/methanol solution for 1-2 hours to obtain a compound 7;
The step 6 specifically comprises the following steps: reacting the compound 7, alkali and halogenated ether in dichloromethane solution for 1-2 hours to obtain a compound 8;
the step 7 specifically comprises the following steps: heating compound 8, compound 8a, alkali and palladium catalyst in N, N-dimethylformamide solution for 8-14 hours to obtain compound 9;
the step 8 specifically comprises the following steps: reacting the compound 9 with acid in dichloromethane solution for 2-6 hours to obtain a compound 10;
the step 9 specifically comprises the following steps: reacting the compound 10, a vanadium catalyst, an oxidant and an organic acid in a dichloromethane solution for 1-2 hours to obtain a compound 1, namely methylated SMTP-7;
the reducing agent in the step 5 is any one of sodium borohydride, sodium borohydride acetate, sodium cyanoborohydride and lithium aluminum hydride;
The alkali in the step 7 is any one of cesium carbonate, cesium fluoride, potassium tert-butoxide and sodium tert-butoxide; the palladium catalyst is any one of [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex, tris (dibenzylideneacetone) dipalladium, bis (dibenzylideneacetone) palladium and tetrakis (triphenylphosphine) palladium;
The vanadium catalyst in the step 9 is any one of vanadyl acetylacetonate and triisopropoxy vanadium oxide; the oxidant is any one of hydrogen peroxide, tert-butyl hydroperoxide, cumene hydroperoxide and m-chloroperoxybenzoic acid; the organic acid is any one of p-toluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid and acetic acid.
2. The method for producing methylated SMTP-7 according to claim 1, wherein the Lewis acid in step 1 is any one of aluminum trichloride, aluminum tribromide and titanium tetrachloride.
3. The method for producing methylated SMTP-7 according to claim 1, wherein the Lewis acid in step 2 is any one of aluminum trichloride, boron tribromide and boron trichloride.
4. The method for producing methylated SMTP-7 according to claim 1, wherein the Lewis acid in step 3 is any one of aluminum trichloride, aluminum tribromide and titanium tetrachloride.
5. The method for producing methylated SMTP-7 according to claim 1, wherein the base in step 6 is any one of triethylamine, N-diisopropylethylamine, pyridine, 2, 6-lutidine, imidazole, 4-dimethylaminopyridine; the halogenated ether is any one of bromomethyl ether and chloromethyl methyl ether.
6. The method for producing methylated SMTP-7 according to claim 1, wherein the acid in step 8 is any one of hydrochloric acid, p-toluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, and acetic acid.
CN202410508590.2A 2024-04-26 2024-04-26 Preparation method of methylated SMTP-7 Active CN118084942B (en)

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JP7381035B2 (en) * 2018-11-02 2023-11-15 学校法人昭和大学 Production intermediates of SMTP group or SMTP-7 and chemical production methods thereof
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WO2023221797A1 (en) * 2022-05-18 2023-11-23 四川科伦博泰生物医药股份有限公司 Heterocyclic compound, preparation method therefor and application thereof
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