CN108191878B - Novel method for preparing summer alkali-free B - Google Patents
Novel method for preparing summer alkali-free B Download PDFInfo
- Publication number
- CN108191878B CN108191878B CN201810013594.8A CN201810013594A CN108191878B CN 108191878 B CN108191878 B CN 108191878B CN 201810013594 A CN201810013594 A CN 201810013594A CN 108191878 B CN108191878 B CN 108191878B
- Authority
- CN
- China
- Prior art keywords
- formula
- compound
- compound represented
- under
- contacting
- 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.)
- Expired - Fee Related
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention provides a method for preparing a natural compound xiawu alkali B. The method comprises the following steps: (i) contacting a compound represented by formula 4 with a compound represented by formula 5 under conditions suitable for carbon-carbon coupling to produce a compound represented by formula 3; thereafter (ii) cyclizing the compound represented by formula 3 with ammonium acetate under suitable conditions to produce compound 2; and (iii) reacting the compound shown in the formula 2 with paraformaldehyde under proper conditions to generate the compound of the formula 1, namely the xiawuweizi B.
Description
Technical Field
The invention relates to the field of medicinal chemistry, in particular to a method for preparing a xiawulkali B.
Background
Decumbent Corydalis B is one of the main alkaloid chemical components in decumbent Corydalis (dried tuber of Corydalis decumbens). Rhizoma corydalis Decumbentis has effects of lowering blood pressure, tranquilizing mind, relaxing muscles and tendons, activating collaterals, and relieving pain, and can be used for treating hypertension, apoplexy, rheumarthritis, ischialgia, etc.
At present, the preparation method of the xiawu alkali B is rarely reported, and the preparation method is still to be improved.
Disclosure of Invention
The present invention is directed to solving at least one of the problems of the prior art.
In one aspect of the present invention, a process for preparing a compound of formula 1 (i.e., xiawu base B) is provided.
According to an embodiment of the present invention, the method for preparing the compound represented by formula 1 comprises:
(i) contacting a compound of formula 4 with a compound of formula 5 under conditions suitable for carbon-carbon coupling to produce a compound of formula 3
(ii) Cyclizing the compound shown as the formula 3 with ammonium acetate under a suitable condition to generate the compound shown as the formula 2
(iii) Contacting the compound of formula 2 with paraformaldehyde under conditions suitable for carbon-hydrogen activation to produce the compound of formula 1 (i.e., xiawu base B).
The term "contacting" as used herein is to be understood broadly and can be any means that enables a chemical reaction of at least two reactants, such as mixing the two reactants under appropriate conditions.
Herein, a "compound of formula N" is also sometimes referred to herein as "compound N", where N is any integer from 1 to 10, e.g., "compound of formula 2" may also be referred to herein as "compound 2".
The terms "first," "second," and the like as used herein are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or implicit indication of the number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. In the description of the present invention, unless otherwise specified, "a plurality" means two or more unless explicitly defined otherwise.
By using the method according to the embodiment of the present invention, the compound represented by formula 1 can be efficiently prepared, i.e., the xiawuweizi B can be efficiently prepared.
According to the embodiment of the present invention, both the compound represented by formula 4 and the compound represented by formula 5 may be synthesized by chemical synthesis means. For example, according to one embodiment of the present invention, the compound represented by formula 4 is prepared by the following steps:
(i-1) contacting the compound represented by formula 8 with bromine to produce a compound represented by formula 7
(i-2) contacting the compound represented by the formula 7 with aluminum chloride and pyridine to produce a compound represented by the formula 6
(i-3) contacting the compound represented by formula 6 with dibromomethane to produce a compound represented by formula 4.
According to a specific embodiment of the present invention, the step of contacting the compound represented by formula 8 (i.e., isovanillin) with bromine to produce the compound represented by formula 7 comprises:
compound 8 (isovanillin, 3g, 19.7mmol) was dissolved in 20ml of glacial acetic acid under an argon atmosphere, and sodium acetate (3.2g, 39.4mmol) and reduced iron powder (110mg, 1.96mmol) were added. Then, a solution of bromine (1.1ml, 21.1mmol) in glacial acetic acid (5ml) was gradually added to the above reaction solution, and vigorously stirred at room temperature for 1 hour. . The progress of the reaction was monitored by TLC until compound 8 was completely reacted. The reaction solution was poured into 150ml of ice water and washed, and then filtered to give a nearly colorless precipitate, and the filter cake was washed with 30ml of ice water and then vacuum-dried at room temperature to give 3.4g of crude compound 7 as an off-white solid. Then, the residue was recrystallized from ethanol to obtain 2.1g of a light brown needle-like crystal solid compound 7.
According to a specific embodiment of the present invention, the step of contacting the compound represented by formula 7 with aluminum chloride and pyridine to produce the compound represented by formula 6 comprises:
compound 7(1.5g, 6.5mmol) was dissolved in 40ml of dichloromethane under argon and aluminium chloride (4.4g, 32.5mmol) was added slowly in portions. Thereafter, pyridine (10.5ml, 129.8mmol) was gradually added to the above reaction solution, and the reaction was refluxed in an oil bath at 45 ℃ for 30 hours. The progress of the reaction was monitored by TLC until compound 7 was completely reacted. And (3) cooling the reaction liquid to room temperature, adjusting the pH value of the reaction liquid to 1 by using 6M hydrochloric acid, performing rotary removal on dichloromethane under reduced pressure, re-dissolving the crude product by using diethyl ether, washing the diethyl ether layer by using 1M dilute hydrochloric acid and saturated salt water respectively, drying the diethyl ether layer by using anhydrous sodium sulfate, performing rotary drying to obtain a crude product, and recrystallizing the crude product by using ethyl acetate/n-hexane to obtain 1.3g of a solid compound 6.
According to a specific embodiment of the present invention, the step of contacting the compound represented by formula 6 with dibromomethane to produce a compound represented by formula 4 comprises:
compound 6(200mg, 0..92mmol) was dissolved in 8ml of N, N-dimethylformamide under an argon atmosphere, and potassium fluoride (0.27g, 4.61mmol) was added thereto and stirred for 15 minutes. Thereafter, dibromomethane (71. mu.l, 1.01mmol) was added to the above reaction solution, and the reaction solution was heated in an oil bath at 115 ℃ for 2 hours. The progress of the reaction was monitored by TLC until compound 6 was completely reacted. After the reaction mixture was cooled to room temperature, the reaction mixture was poured into water, extracted with ether three times, the organic phases were combined, washed with water and saturated brine once each, the ether layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to give a crude product, and the crude product was purified by flash silica gel column (petroleum ether: ethyl acetate 100: 1) to give 181.2mg of solid compound 4.
Thus, the compound represented by formula 4 can be efficiently prepared.
On the other hand, according to an embodiment of the present invention, the compound represented by formula 5 may be prepared by the following steps:
(i-4) contacting the compound represented by formula 10 with trimethylsilylacetylene to produce the compound represented by formula 9
(i-5) removing the trimethylsilyl protecting group from the compound shown in the formula 9 under the action of tetrabutylammonium fluoride to generate the compound shown in the formula 5.
According to a specific embodiment of the present invention, the step of contacting the compound represented by formula 10 (i.e., 4-bromopiperonyl ring) with trimethylsilylacetylene to produce the compound represented by formula 9 comprises:
compound 10 (4-bromopiperonyl ring, 5g, 24.9mmol) was dissolved in 30ml of triethylamine under an argon atmosphere, and palladium tetratriphenylphosphine (462mg, 0.4mmol) and cuprous iodide (52mg, 0.27mmol) were added. Thereafter, trimethylsilylacetylene (4.4g, 44.8mmol) was gradually added to the above reaction solution, and reacted for 5 hours under heating in an oil bath at 70 ℃. The progress of the reaction was monitored by TLC until compound 10 was substantially reacted. Filtering the reaction by using kieselguhr, washing insoluble substances by using a small amount of ethyl acetate, drying the filtrate by spinning, redissolving the filtrate by using ethyl acetate, washing the redissolved filtrate by using saturated ammonium chloride and saturated saline solution, drying an ethyl acetate layer by using anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography on silica gel (petroleum ether elution) to give 4.8g of the compound 9 as a colorless oil.
According to an embodiment of the present invention, the step of contacting the compound represented by formula 9 with tetrabutylammonium fluoride to produce the compound represented by formula 5 comprises:
compound 9(5g, 22.9mmol) was dissolved in 80ml of tetrahydrofuran under an argon atmosphere, and tetrabutylammonium fluoride (722mg, 2.29mmol) was added to the solution to conduct a reaction at room temperature for 0.5 hour. The progress of the reaction was monitored by TLC until compound 9 was substantially reacted. The reaction was concentrated under reduced pressure to remove tetrahydrofuran by rotary evaporation, and the residue was redissolved with diethyl ether, washed with 1M dilute hydrochloric acid and saturated brine, the diethyl ether layer was dried over anhydrous sodium sulfate, and the crude solvent was removed under reduced pressure. The crude product was purified by flash column chromatography on silica gel (petroleum ether elution) to give 2.9g of the compound 5 as a colorless oil.
According to an embodiment of the present invention, after synthesizing the compounds represented by formula 4 and formula 5, respectively, the compound represented by formula 4 and the compound represented by formula 5 may be subjected to carbon-carbon coupling to obtain compound 3. The compound 3 is contacted with ammonium acetate to obtain a compound 2, and the compound 2 is further contacted with paraformaldehyde to obtain a compound 1, namely the xiawu alkali B comprises:
compound 4(1g, 4.37mmol) was dissolved in 20ml of tetrahydrofuran under an argon atmosphere, and bis-triphenylphosphine palladium dichloride (0.22mmol) and triethylamine (1.82ml, 13.11mmol) were added and stirred at room temperature for 10 minutes. Then, compound 5(958mg, 6.66mmol) and cuprous iodide (41.6mg, 0.22mmol) were added to the above reaction solution, and reacted for 3 hours under heating in an oil bath at 70 ℃. The progress of the reaction was monitored by TLC until compound 4 was substantially reacted. Filtering the reaction solution by using kieselguhr, washing insoluble substances by using a small amount of ethyl acetate, drying the filtrate by spinning, redissolving by using ethyl acetate, washing by using saturated ammonium chloride and saturated salt water, drying an ethyl acetate layer by using anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography on silica gel to give 913mg of compound 3 as a yellow solid.
Compound 3(1g, 3.4mmol) was dissolved in 10ml of t-butanol under an argon atmosphere, and silver nitrate (57.8mg, 0.34mmol) and ammonium acetate (393.1mg, 5.1mmol) were added to react at room temperature. The progress of the reaction was monitored by TLC until compound 3 was substantially reacted. The reaction was quenched by the addition of sodium bicarbonate (1.14g, 13.6mmol) and continued at room temperature for 4 hours. Filtering the reaction by using kieselguhr, washing insoluble substances by using a small amount of ethyl acetate, drying the filtrate by spinning, redissolving the filtrate by using ethyl acetate, washing the redissolved filtrate by using saturated ammonium chloride and saturated saline solution, drying an ethyl acetate layer by using anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography on silica gel to give 650mg of compound 2 as a yellow solid.
In a sealed tube under argon protection, compound 2(50mg, 0.17mmol) was dissolved in 1ml of tetrahydrofuran, and zinc bromide (19.2mg, 0.085mmol), ruthenium trichloride (4.3mg, 0.017mmol) and paraformaldehyde (25.6mg, 0.85mmol) were added to the solution, followed by addition of dimethylzinc (0.6ml, 0.6mmol, 1M in toluene) and reaction at 60 ℃ for 24 hours. Diluting the reaction solution with a small amount of ethyl acetate, washing with saturated ammonium chloride and saturated brine, drying the ethyl acetate layer with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography on silica gel to give 37.6mg of white solid compound 1, xiawu base B.
In conclusion, the method according to the embodiment of the present invention can be used to synthesize the xiawu alkali B efficiently. Thus, in accordance with embodiments of the present invention, the present invention provides a more elegant method for preparing xiawu base B to overcome at least one of the disadvantages of the prior art. According to the method provided by the embodiment of the invention, the compound shown in the mother ring structural formula 2 is synthesized by using the simple and easily available compound 8 and compound 10 as starting materials. Then, by applying the idea of hydrocarbon activation, using paraformaldehyde with low price and safety as a hydrocarbon activation attacking reagent for introducing hydroxymethyl, and using ruthenium trichloride which is relatively simple and easy to obtain as a catalyst, reacting in tetrahydrofuran or 1, 2-dichloroethane to generate a compound shown in formula 1, namely the summer alkali-free B. Compared with the prior art, according to the method provided by the embodiment of the invention, all raw materials are simple and easy to obtain, the yield is greatly improved, the reaction conditions are mild, the production cost is reduced, and the method is suitable for industrial production.
Advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.
Detailed Description
The following embodiments of the present invention are described in detail, and it should be noted that the following embodiments are exemplary only, and are not to be construed as limiting the present invention. In addition, all reagents used in the following examples are commercially available or can be synthesized according to methods herein or known, and are readily available to those skilled in the art for reaction conditions not listed, if not explicitly stated.
General procedure
The synthetic route is as follows:
a process for preparing xiawuweizi B, comprising the steps of:
step 1) reacting a compound (isovanillin) shown in a formula 8 with bromine in a solvent under the catalysis of reduced iron powder to obtain a compound 7;
step 2) reacting a compound shown as a formula 7 with pyridine in a solvent under the catalysis of aluminum chloride to obtain a compound 6;
step 3) reacting the compound shown as the formula 6 with dibromomethane in a solvent under the catalysis of potassium fluoride to obtain a compound 4;
step 4) reacting the compound shown in the formula 10 with trimethylsilyl acetylene in a solvent under the catalysis of palladium tetratriphenylphosphine to obtain a compound 9;
step 5) reacting the compound shown in the formula 9 with tetrabutylammonium fluoride in a solvent to obtain a compound 5;
step 6) reacting the compound shown in the formula 4 with the compound shown in the formula 5 in a solvent under the catalysis of bis (triphenylphosphine) palladium dichloride to obtain a compound 3;
step 7) reacting the compound shown in the formula 3 with ammonium acetate in a solvent under the catalysis of silver nitrate to obtain a compound 2;
and step 8) reacting the compound shown in the formula 2 with paraformaldehyde in a solvent under the catalysis of ruthenium trichloride to obtain a compound 1, namely the summer alkali-free B.
Example 1
Compound 8 (isovanillin, 3g, 19.7mmol) was dissolved in 20ml of glacial acetic acid under an argon atmosphere, and sodium acetate (3.2g, 39.4mmol) and reduced iron powder (110mg, 1.96mmol) were added. Then, a solution of bromine (1.1ml, 21.1mmol) in glacial acetic acid (5ml) was gradually added to the above reaction solution, and vigorously stirred at room temperature for 1 hour. . The progress of the reaction was monitored by TLC until compound 8 was completely reacted. The reaction solution was poured into 150ml of ice water and washed, and then filtered to give a nearly colorless precipitate, and the filter cake was washed with 30ml of ice water and then vacuum-dried at room temperature to give 3.4g of crude compound 7 as an off-white solid. Then, the resulting mixture was recrystallized from ethanol to obtain 2.1g of a light brown needle-like crystal solid compound 7, which was then subjected to the next reaction without further purification.
Example 2
Compound 7(1.5g, 6.5mmol) was dissolved in 40ml of dichloromethane under argon and aluminium chloride (4.4g, 32.5mmol) was added slowly in portions. Thereafter, pyridine (10.5ml, 129.8mmol) was gradually added to the above reaction solution, and the reaction was refluxed in an oil bath at 45 ℃ for 30 hours. The progress of the reaction was monitored by TLC until compound 7 was completely reacted. And (3) cooling the reaction liquid to room temperature, adjusting the pH value of the reaction liquid to 1 by using 6M hydrochloric acid, performing rotary removal on dichloromethane under reduced pressure, re-dissolving the crude product by using diethyl ether, washing the diethyl ether layer by using 1M dilute hydrochloric acid and saturated salt water respectively, drying the diethyl ether layer by using anhydrous sodium sulfate, performing rotary drying to obtain the crude product, and performing recrystallization on the crude product by using ethyl acetate/n-hexane to obtain 1.3g of a solid compound 6 with the yield of 96%.
Compound 6, grey solid, mp 181-,1H NMR(400MHz,DMSO-d6)δ11.04(brs,1H),10.06(s,1H),9.62(brs,1H),7.31(d,J＝8.4Hz,1H),6.92(d,J＝8.4Hz,1H)。
example 3
Compound 6(200mg, 0.92mmol) was dissolved in 8ml of N, N-dimethylformamide under an argon atmosphere, and potassium fluoride (0.27g, 4.61mmol) was added thereto and stirred for 15 minutes. Thereafter, dibromomethane (71. mu.l, 1.01mmol) was added to the above reaction solution, and the reaction solution was heated in an oil bath at 115 ℃ for 2 hours. The progress of the reaction was monitored by TLC until compound 6 was completely reacted. After the reaction solution was cooled to room temperature, the reaction solution was poured into water, extracted with ether three times, the organic phases were combined, washed with water and saturated brine once each, the ether layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to give a crude product, which was purified by flash silica gel column (petroleum ether: ethyl acetate 100: 1) to give 181.2mg of solid compound 4 with a yield of 86%.
Compound 4, white solid, mp 130-,1H NMR(400MHz,DMSO-d6)δ9.99(s,1H),7.51(d,J＝8.0Hz,1H),7.12(d,J＝8.0Hz,1H),6.28(s,2H)。
example 4
Compound 10 (4-bromopiperonyl ring, 5g, 24.9mmol) was dissolved in 30ml of triethylamine under an argon atmosphere, and palladium tetratriphenylphosphine (462mg, 0.4mmol) and cuprous iodide (52mg, 0.27mmol) were added. Thereafter, trimethylsilylacetylene (4.4g, 44.8mmol) was gradually added to the above reaction solution, and reacted for 5 hours under heating in an oil bath at 70 ℃. The progress of the reaction was monitored by TLC until compound 10 was substantially reacted. Filtering the reaction by using kieselguhr, washing insoluble substances by using a small amount of ethyl acetate, drying the filtrate by spinning, redissolving the filtrate by using ethyl acetate, washing the redissolved filtrate by using saturated ammonium chloride and saturated saline solution, drying an ethyl acetate layer by using anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography on silica gel (petroleum ether elution) to give 4.8g of 9 as a colorless oil with a yield of 90%.
Example 5
Compound 9(5g, 22.9mmol) was dissolved in 80ml of tetrahydrofuran under an argon atmosphere, and tetrabutylammonium fluoride (722mg, 2.29mmol) was added to the solution to conduct a reaction at room temperature for 0.5 hour. The progress of the reaction was monitored by TLC until compound 9 was substantially reacted. The reaction was concentrated under reduced pressure to remove tetrahydrofuran by rotary evaporation, and the residue was redissolved with diethyl ether, washed with 1M dilute hydrochloric acid and saturated brine, the diethyl ether layer was dried over anhydrous sodium sulfate, and the crude solvent was removed under reduced pressure. The crude product was purified by flash column chromatography on silica gel (petroleum ether elution) to yield 2.9g of 5 as a colorless oil with a yield of 86%.
Example 6
Compound 4(1g, 4.37mmol) was dissolved in 20ml of tetrahydrofuran under an argon atmosphere, and bis-triphenylphosphine palladium dichloride (0.22mmol) and triethylamine (1.82ml, 13.11mmol) were added and stirred at room temperature for 10 minutes. Then, compound 5(958mg, 6.66mmol) and cuprous iodide (41.6mg, 0.22mmol) were added to the above reaction solution, and reacted for 3 hours under heating in an oil bath at 70 ℃. The progress of the reaction was monitored by TLC until compound 4 was substantially reacted. Filtering the reaction solution by using kieselguhr, washing insoluble substances by using a small amount of ethyl acetate, drying the filtrate by spinning, redissolving by using ethyl acetate, washing by using saturated ammonium chloride and saturated salt water, drying an ethyl acetate layer by using anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a crude product. The crude product was purified by flash silica gel column to give 913mg of compound 3 as a yellow solid in 71% yield.
Compound 3, yellow solid, mp168-170 deg.c,1H NMR(400MHz,DMSO-d6)δ10.19(s,1H),7.52(d,J＝8.4Hz,1H),7.18-7.10(m,3H),7.00(d,J＝8.4Hz,1H),6.29(s,2H),6.11(s,2H)；13CNMR(100MHz,DMSO-d6)δ189.26,152.10,149.47,148.50,147.47,129.69,126.66,125.72,114.71,111.03,108.88,108.51,105.36,103.09,101.70,98.87,78.37；HRMS(ESI):m/zcalcd forC17H10O5Na[M+Na]+:317.0420；found:317.0422。
example 7
Compound 3(1g, 3.4mmol) was dissolved in 10ml of t-butanol under an argon atmosphere, and silver nitrate (57.8mg, 0.34mmol) and ammonium acetate (393.1mg, 5.1mmol) were added to react at room temperature. The progress of the reaction was monitored by TLC until compound 3 was substantially reacted. The reaction was quenched by the addition of sodium bicarbonate (1.14g, 13.6mmol) and continued at room temperature for 4 hours. Filtering the reaction by using kieselguhr, washing insoluble substances by using a small amount of ethyl acetate, drying the filtrate by spinning, redissolving the filtrate by using ethyl acetate, washing the redissolved filtrate by using saturated ammonium chloride and saturated saline solution, drying an ethyl acetate layer by using anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography on silica gel to give 650mg of compound 2 as a yellow solid in 65.2% yield.
Compound 2, yellow solid, mp160-162 deg.c,1H NMR(400MHz,DMSO-d6)δ9.27(s,1H),7.98(s,1H),7.82-7.73(m,3H),7.44(d,J＝8.4Hz,1H),7.03(d,J＝8.4Hz,1H),6.33(s,2H),6.09(s,2H)；13C NMR(150MHz,DMSO-d6)δ152.59,149.20,147.94,147.89,146.93,139.88,132.96,123.57,122.96,121.74,120.71,111.48,108.44,106.69,106.51,102.43,101.27；HRMS(ESI):m/z calcd forC17H12NO4[M+H]+:294.0761；found:294.0763。
example 8
In a sealed tube under argon protection, compound 2(50mg, 0.17mmol) was dissolved in 1ml of tetrahydrofuran, and zinc bromide (19.2mg, 0.085mmol), ruthenium trichloride (4.3mg, 0.017mmol) and paraformaldehyde (25.6mg, 0.85mmol) were added to the solution, followed by addition of dimethylzinc (0.6ml, 0.6mmol, 1M in toluene) and reaction at 60 ℃ for 24 hours. Diluting the reaction solution with a small amount of ethyl acetate, washing with saturated ammonium chloride and saturated brine, drying the ethyl acetate layer with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a crude product. The crude product was purified by flash silica gel column to give 37.6mg of white solid compound 1, xiawu base B, in 68.4% yield.
Compound 1, white solid, mp 224-,1H NMR(400MHz,DMSO-d6)δ9.30(s,1H),7.88(s,1H),7.81(d,J＝8.6Hz,1H),7.50(d,J＝8.6Hz,1H),7.20(d,J＝8.0Hz,1H),6.98(d,J＝8.0Hz,1H),6.33(s,2H),6.12(s,2H),5.52(t,J＝5.6Hz,1H),4.42(d,J＝5.6Hz,2H)；13CNMR(100MHz,DMSO-d6)δ152.1,151.0,147.2,147.1,146.6,139.8,134.5,124.0,123.2,123.2,121.6,121.3,119.1,111.1,107.6,102.6,101.3,55.0；HRMS(ESI):m/z calcdforC18H13NO5Na[M+Na]+:346.0686；found:346.0688。
in the description herein, references to the description of the terms "one embodiment," "some embodiments," "an illustrative embodiment," "an example," "a specific example," "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above do not necessarily refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.
While embodiments of the invention have been shown and described, it will be understood by those of ordinary skill in the art that: various changes, modifications, substitutions and alterations can be made to the embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the claims and their equivalents.
Claims (11)
1. A process for preparing a summer alkali-free B of formula 1,
it is characterized by comprising:
(i) contacting a compound of formula 4 with a compound of formula 5 under conditions suitable for carbon-carbon coupling to produce a compound of formula 3
(ii) Cyclizing the compound shown as the formula 3 with ammonium acetate under a suitable condition to generate the compound shown as the formula 2
；
(iii) Contacting the compound shown in the formula 2 with paraformaldehyde under the condition suitable for carbon-hydrogen activation to generate the compound shown in the formula 1, namely the xiawulkane B.
2. The method of claim 1, further comprising the following steps for preparing a compound represented by formula 4:
(i-1) contacting the compound represented by formula 8 with bromine to produce a compound represented by formula 7
(i-2) contacting the compound represented by the formula 7 with aluminum chloride and pyridine to produce a compound represented by the formula 6
(i-3) contacting the compound represented by formula 6 with dibromomethane to produce a compound represented by formula 4.
3. The method according to claim 2, wherein in step (i-1), the following step is further included for preparing the compound represented by formula 7:
under the protection of argon, the compound shown in the formula 8, sodium acetate and reduced iron powder are mixed in glacial acetic acid, then a glacial acetic acid solution of bromine is dropwise added to the reaction solution under an ice bath, and then the reaction solution is moved to room temperature for reaction for 1 hour.
4. The method according to claim 2, wherein in step (i-2), the following step is further included for preparing the compound represented by formula 6:
dispersing the compound shown in the formula 7 with dichloromethane under the protection of argon, slowly adding aluminum chloride solid into the mixture, gradually adding pyridine, and moving to 45 DEGoC refluxing reaction for 45 hours.
5. The method according to claim 2, wherein in step (i-3), the following step is further included for preparing the compound represented by formula 4:
dispersing the compound shown in the formula 6 by using N, N-dimethylformamide under the protection of argon, slowly adding potassium fluoride solid into the mixture in sequence, gradually adding dibromomethane, and moving to 115 DEG CoC, heating and reacting for 2 hours.
6. The method of claim 1, further comprising the following steps of preparing a compound represented by 5:
(i-4) contacting the compound represented by formula 10 with trimethylsilylacetylene to produce the compound represented by formula 9
(i-5) removing the trimethylsilyl protecting group from the compound shown in the formula 9 under the action of tetrabutylammonium fluoride to generate the compound shown in the formula 5.
7. The method according to claim 6, wherein in step (i-4), the following step is further included for preparing the compound represented by formula 9:
under the protection of argon, dispersing the compound shown in the formula 10 by triethylamine, sequentially adding palladium tetratriphenylphosphine and cuprous iodide, then adding trimethylsilyl acetylene, and moving to 70 DEGoC, heating and reacting for 5 hours.
8. The method according to claim 6, wherein in step (i-5), the following step is further included for preparing the compound represented by formula 5:
the compound of formula 9 was dispersed in tetrahydrofuran under argon, tetrabutylammonium fluoride was added thereto, and the mixture was allowed to stand at room temperature and stirred for 0.5 hour.
9. The method of claim 1, wherein in step (i), contacting the compound of formula 4 with the compound of formula 5 further comprises:
under the protection of argon, dispersing the compound shown in the formula 4 and the compound shown in the formula 5 by triethylamine, sequentially adding palladium tetratriphenylphosphine and cuprous iodide into the mixture, and moving the mixture to 70 DEG CoC the reaction was stirred in an oil bath for 5 hours.
10. The method of claim 1, wherein in step (ii), contacting the compound of formula 3 with ammonium acetate further comprises:
under the protection of argon, the compound shown in the formula 3 is dispersed by tert-butyl alcohol, ammonium acetate and silver nitrate are sequentially added into the mixture, and then the mixture is moved to room temperature and stirred for reaction overnight.
11. The method of claim 1, wherein in step (iii), contacting the compound of formula 2 with paraformaldehyde further comprises:
under the protection of argon, dissolving a compound shown in a formula 2, paraformaldehyde, zinc bromide and a metal catalyst in a first solvent, adding alkali, and stirring for 24 hours;
optionally, the metal catalyst is a manganese metal catalyst or a ruthenium metal catalyst, and the metal catalyst is manganese (I) pentacarbonyl bromide, ruthenium trichloride trihydrate (III), ruthenium trichloride (III), and dichlorobis (4-methylisopropylphenyl) ruthenium (II);
optionally, the first solvent is at least one of a halogenated hydrocarbon organic solvent and an ether organic solvent, the halogenated hydrocarbon organic solvent is 1, 2-dichloroethane, and the ether organic solvent is tetrahydrofuran;
optionally, the base is at least one selected from organic bases and inorganic bases, the organic bases are dimethyl zinc, potassium tert-butoxide and potassium acetate, and the inorganic bases are sodium hydroxide and cesium carbonate;
optionally, stirring at a temperature of 0-100 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810013594.8A CN108191878B (en) | 2018-01-05 | 2018-01-05 | Novel method for preparing summer alkali-free B |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810013594.8A CN108191878B (en) | 2018-01-05 | 2018-01-05 | Novel method for preparing summer alkali-free B |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108191878A CN108191878A (en) | 2018-06-22 |
| CN108191878B true CN108191878B (en) | 2020-05-15 |
Family
ID=62588012
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810013594.8A Expired - Fee Related CN108191878B (en) | 2018-01-05 | 2018-01-05 | Novel method for preparing summer alkali-free B |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108191878B (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103356752A (en) * | 2013-08-02 | 2013-10-23 | 江西天施康中药股份有限公司 | Corydalisdecumbens(Thunb.)Pers. injection and preparation method thereof |
-
2018
- 2018-01-05 CN CN201810013594.8A patent/CN108191878B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103356752A (en) * | 2013-08-02 | 2013-10-23 | 江西天施康中药股份有限公司 | Corydalisdecumbens(Thunb.)Pers. injection and preparation method thereof |
Non-Patent Citations (3)
| Title |
|---|
| A room-temperature protocol to access isoquinolines through Ag(I) catalysed annulation of o-(1-alkynyl)arylaldehydes and ketones with NH4OAc: elaboration to berberine and palmatine;Virsinha Reddy等;《Org. Biomol. Chem.》;20150209;第13卷(第12期);第3732-3741页，尤其第3732页左栏，Table 2 * |
| Exploratory, Mechanistic, and Synthetic Aspects of Silylarene-Iminium Salt SET Photochemistry. Studies of Diradical Cyclization Processes and Applications to Protoberberine Alkaloid Synthesis;Ginny Dai-Ho等;《J. Org. Chem.》;19881231;第53卷(第21期);第5113-5127页，尤其Scheme VIII，第5124页左栏第3段 * |
| Synthesis of Isoquinolines and Pyridines by the Palladiu Copper-Catalyzed Coupling and Cyclization of Terminal Acetylenes and Unsaturated Imines: The Total Synthesis of Decumbenine B;Kevin R. Roesch等;《J. Org. Chem.》;20011212;第67卷(第1期);第86-94页，尤其Scheme 7，第94页左栏至右栏首段 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108191878A (en) | 2018-06-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5221544B2 (en) | Processes and intermediates for preparing integrase inhibitors | |
| CA2698245C (en) | Process and intermediates for preparing integrase inhibitors | |
| EP2880017B1 (en) | Process and intermediates for preparing integrase inhibitors | |
| JPS62149695A (en) | Selective methylation of erythromycin a derivative | |
| JP7500102B2 (en) | Intermediate for synthesizing camptothecin derivatives, production method thereof and use thereof | |
| CN112174989B (en) | Preparation method of clenbuterol | |
| CN108191878B (en) | Novel method for preparing summer alkali-free B | |
| JP7144873B2 (en) | Method for producing sugammadex sodium salt | |
| JP7227925B2 (en) | Method for producing 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate | |
| CN113045496B (en) | Method for selectively synthesizing dihydrophenanthridine or phenanthridine compounds | |
| CN114163380A (en) | Alavazepam intermediate, preparation method and application thereof | |
| CN113861167A (en) | Preparation method of Voranolan fumarate | |
| CN106957318B (en) | Condensed polycyclic indoline compound, preparation method, pharmaceutical composition and application thereof | |
| CN113372281A (en) | Synthetic method of metronidazole | |
| CN114605320B (en) | Synthesis method of 5-nitro-6-methylnicotinic acid ethyl ester | |
| CN111196750B (en) | Preparation method of benzyl iodide and derivatives thereof | |
| EP1539751B1 (en) | Process for the preparation of imidazo(1,2-a)pyridine-3-acetamides | |
| CN109970596B (en) | Method for preparing 1, 1-diiodo olefin derivative through N-propynamide trifunctional reaction | |
| JP7424115B2 (en) | Method for producing ester compounds | |
| JP2662162B2 (en) | Method for producing 3-alkylpyrrole | |
| JP6975107B2 (en) | A method for purifying 4-halocyclohexane-1-carboxylic acid and a method for producing a product containing 4-halocyclohexane-1-carboxylic acid. | |
| CN108558878B (en) | Synthesis process of quinoline and derivatives thereof | |
| JP2001513797A (en) | Preparation of phosphonium compounds as intermediates of glycine antagonists | |
| JP2706554B2 (en) | 4-trifluoromethylaniline derivative and method for producing the same | |
| CN115925720A (en) | Quinoline cyclobutane compound and synthesis method thereof |
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 | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20200515 Termination date: 20220105 |