CN104356139A - Synthetic method of nitidine chloride - Google Patents
Synthetic method of nitidine chloride Download PDFInfo
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- CN104356139A CN104356139A CN201410676737.5A CN201410676737A CN104356139A CN 104356139 A CN104356139 A CN 104356139A CN 201410676737 A CN201410676737 A CN 201410676737A CN 104356139 A CN104356139 A CN 104356139A
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- 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
Abstract
The invention discloses a synthetic method of nitidine chloride. The synthetic method comprises the following steps: 1) dissolving 3,4-dimethoxybenzoic acid in a first organic solvent, adding thionyl chloride to react, evaporating out the solvent from reactants to obtain an intermediate 1; 2) dissolving the intermediate 1 by use of the first organic solvent, adding 3,4-methylenedioxy naphthylamine, and performing nucleophilic substitution reaction to obtain an intermediate 2; 3) dissolving the intermediate 2 in the first organic solvent, adding boron trifluoride diethyl etherate and di(trifluoroacetoxyl) iodobenzene to react, removing the solvent from the reactants, performing column chromatography on obtained residues on silica gel to obtain an intermediate 3; 4) dissolving the intermediate 3 in a second organic solvent, and performing lithium aluminum hydride reduction, dehydration and dimethyl sulfate methylation under an atmosphere protection condition, and then treating with sodium chloride to obtain the target product nitidine chloride. The synthetic method disclosed by the invention is relatively simple in synthesis route and relatively high in yield of the target product and the yield is higher than 27%.
Description
Technical field
The present invention relates to medical art, be specifically related to a kind of synthetic method of nitidine chloride.
Background technology
Nitidine chloride (Nitidine Chloride, NC), structure, as shown in following formula I, is yellow or pistac needle crystal.Nitidine chloride is by a kind of benzene a pair of horses going side by side [c] phenanthridine alkaloid alkaloid extracted in the dry root of Rutaceae xanthoxylum Shinyleaf Pricklyash Root, all restraining effect is had to LEWIS lung cancer, human body nasopharyngeal carcinoma, liver cancer, chronic myelocytic leukemia, also effective to mouse Emhorn water cancer, hepatic ascites, therefore NC has good anti-tumor activity, there is very large development and application values.
At present, NC content in two sides crown skin, stem or leaf only reaches 0.2% ~ 0.3%, and the cost extracted from plant is higher, comparatively difficult for further transformation and optimization, also counteracts that the application of NC, therefore carries out complete synthesis extremely urgent to nitidine chloride.(the Tetra lett such as Kessar, 1974,26:2269-2270.) with 2-bromo-4,5-dimethoxy-benzoyl chloride and 2,3-methylenedioxy group naphthylamines is raw material, and synthesizing amide circularizes into the acid amides at Fourth Ring through lamp and high pressure mercury, again through reduction, dehydrogenation, methylating to obtain Shinyleaf Pricklyash Root alkali salt, concrete synthetic route is as follows:
In above-mentioned synthetic method, raw material 2-bromo-4,5-dimethoxy Benzoyl chloride is non-common raw material, and need with 3,4-dimethoxybenzoic acid or vanillin food grade,1000.000000ine mesh for Material synthesis, complex operation, side reaction is many, relates to Photocyclization in reaction, is unfavorable for suitability for industrialized production; When being wherein raw material with 3,4-dimethoxybenzoic acid, output is only 6.12% (US2013/253222), and is that raw material reaction needs 6 steps just can complete altogether with vanillin food grade,1000.000000ine mesh, overall yield not high (J Org Chem, 1942,7:354,355).
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of synthetic method of new nitidine chloride.The method synthetic route is more simple, and the yield of target product is higher.
The method of the invention, is synthesized by following synthetic route for starting raw material with 3,4-dimethoxybenzoic acid:
The synthetic method of nitidine chloride of the present invention, specifically comprises the following steps:
1) get 3,4-dimethoxybenzoic acid to be dissolved in the first organic solvent, add thionyl chloride and react, reactant steams and desolventizes, and obtains intermediate 1 (acyl chlorides);
2) by intermediate 1 with adding 3,4-methylenedioxy group naphthylamines after the first organic solvent dissolution, nucleo philic substitution reaction obtains intermediate 2 (acid amides);
3) getting intermediate 2 is dissolved in the first organic solvent, add boron trifluoride diethyl etherate and two (trifluoroacetyl oxygen base) iodobenzene (i.e. two (trifluoroacetyl oxygen base) iodobenzene, be abbreviated as PIFA) react, reactant is except desolventizing, silica gel column chromatography on gained residue, obtains intermediate 3 (oxyterihanine);
4) getting intermediate 3 is dissolved in the second organic solvent, through lithium aluminium hydride reduction, dehydration and dimethyl sulfate methylation of ester, again through sodium-chlor process, namely obtain target product nitidine chloride under atmosphere protection condition.
Above-mentioned synthetic method, the first described organic solvent is generally methylene dichloride or chloroform, and the consumption of described first organic solvent is advisable can dissolve the raw material participating in reaction; The second described organic solvent is generally anhydrous tetrahydro furan, anhydrous diethyl ether or anhydrous methanol, and the consumption of described second organic solvent is advisable can dissolve the raw material participating in reaction.
The step 1 of above-mentioned synthetic method) in, the mol ratio of 3,4-dimethoxybenzoic acid and thionyl chloride is stoichiometric ratio, is generally 1:2 ~ 5; Described 3, the reaction of 4-dimethoxybenzoic acid and thionyl chloride is carried out usually under 20 ~ 80 DEG C of conditions, and reaction preferably adopts the mode of heating or backflow to carry out, and whether reaction can adopt thin-layer chromatography tracing detection completely, under above-mentioned qualifications, reaction is to completely approximately needing 12 ~ 48h.
The step 2 of above-mentioned synthetic method) in, nucleophilic substitution reaction preferably carries out under 0 ~ 10 DEG C of condition.This step specifically comprises: by intermediate 1 with after the first organic solvent dissolution, 3 are added under 0 ~ 10 DEG C of condition, (pyridine or triethylamine are used as acid binding agent for 4-methylenedioxy group naphthylamines and pyridine or triethylamine, its consumption is same as the prior art), under above-mentioned condition, react (whether reaction can adopt thin-layer chromatography tracing detection completely again, under above-mentioned qualifications, reaction is to completely approximately needing 24 ~ 48h), in reaction process, adularescent solid is separated out, suction filtration, washing (adopts anhydrous methanol usually, dehydrated alcohol or acetonitrile wash), namely intermediate 2 is obtained.In order to improve the purity of intermediate 2 further, intermediate 2 anhydrous methanol of acquisition, dehydrated alcohol or acetonitrile can also be carried out recrystallization.In this step, intermediate 1 and 3,4-methylenedioxy group naphthylamines mol ratio are preferably 1 ~ 2:1.For avoiding reaction too violent, preferably will enter 3,4-methylenedioxy group naphthylamines and adding in batches.
The step 3 of above-mentioned synthetic method) in, the mol ratio of intermediate 2, boron trifluoride diethyl etherate and two (trifluoroacetyl oxygen base) iodobenzene is preferably 1:0.5 ~ 1:1 ~ 2, is more preferably 1:0.6:1.3; Above-mentioned reaction is preferably carried out under 10 ~ 60 DEG C of conditions, and whether reaction can adopt thin-layer chromatography tracing detection completely, and under above-mentioned qualifications, reaction is to completely approximately needing 1 ~ 5h.In this step, on gained residue during silica gel column chromatography, preferably with being the mixed solvent wash-out that the sherwood oil of 2 ~ 10:1 and ethyl acetate form by volume ratio, more preferably adopting by volume ratio is the mixed solvent wash-out that the sherwood oil of 2 ~ 6:1 and ethyl acetate form; Elutriant solvent evaporated, obtains intermediate 3.
The step 4 of above-mentioned synthetic method) in, the mol ratio of described intermediate 3 and lithium aluminum hydride is generally 1:3 ~ 5, described in add lithium aluminum hydride and carry out reducing and follow-up processed is all carry out under 20 ~ 50 DEG C of conditions.Particularly; intermediate 3 is being dissolved in after in the second organic solvent; add lithium aluminum hydride under atmosphere protection condition to reduce under 20 ~ 50 DEG C of conditions; reaction end (whether reaction can adopt thin-layer chromatography tracing detection completely) afterwards gained reactant uses hydrochloric acid (HCl content is the hydrochloric acid of 10 ~ 30%) to carry out processed usually; then filter; filtrate thin up; yellow mercury oxide is had (to be the product after dehydration; i.e. Dihydronitidine) separate out, collect yellow mercury oxide as the methylated raw material of next step methyl-sulfate.
The step 4 of above-mentioned synthetic method) in, described dimethyl sulfate methylation of ester is by through lithium aluminium hydride reduction, product (i.e. above-mentioned yellow mercury oxide Dihydronitidine) after dehydration is dissolved in the solvent (being preferably made up of with the volume percent of 70 ~ 100%:0 ~ 30% oil of mirbane and dimethylbenzene) be made up of with the volume percent of 50 ~ 100%:0 ~ 50% oil of mirbane and dimethylbenzene, react under 150 ~ 200 DEG C of conditions (whether reaction can adopt thin-layer chromatography tracing detection completely), ether or tetrahydrofuran (THF) is added after reactant cooling, there is brown color Precipitation, isolate precipitation, obtain sulfation nitidine, as the raw material of next step sodium-chlor process.The consumption of described methyl-sulfate is preferably 2 ~ 5 times of intermediate 3 amount of substance.In this step, described atmosphere protection normally carries out under nitrogen or other rare gas element are as the atmosphere protection such as argon gas or helium condition.
The step 4 of above-mentioned synthetic method) in, described sodium-chlor process (is reacted reacting through the methylated product of methyl-sulfate (i.e. sulfation nitidine) and sodium chloride aqueous solution usually at 20 ~ 40 DEG C, preferably carry out at ambient temperature, reaction time be Precipitation completely, be generally 3 ~ 20min), there is pale yellow precipitate to separate out, collect this pale yellow precipitate, be nitidine chloride.The consumption of wherein said sodium-chlor is generally 5 ~ 20 times of intermediate 3 amount of substance, after determining the consumption of sodium-chlor, with water, namely sodium-chlor dissolving is obtained sodium chloride aqueous solution, the concentration of described sodium chloride aqueous solution is not exquisite especially, is normally mixed with the sodium chloride aqueous solution of 5 ~ 20% (quality).
Compared with prior art, the inventive method is with 3,4-dimethoxybenzoic acid for starting raw material, and synthetic route is more simple, and the yield of target product is higher, and total recovery can reach more than 27%.
Embodiment
Below in conjunction with specific embodiment, the present invention is described in further detail, and to understand content of the present invention better, but the present invention is not limited to following examples.
Embodiment 1
1) synthesis of intermediate 1:
By 0.98g 3,4-dimethoxybenzoic acid (5.4mmol) thermosol in 40mL methylene dichloride, then add 0.78mL SOCl
2(10.8mmol) reflux 4h at 40 DEG C.Solvent evaporated, obtains white solid, is intermediate 1, productive rate 100%.
2) synthesis of intermediate 2:
Get above-mentioned 1.12g intermediate 1 and be dissolved in 40mL methylene dichloride, add 2.8mL pyridine and 1g 3,4-methylenedioxy group aniline (3,4-methylenedioxy group aniline is divided into 3 batches and adds in 10min) at 0 DEG C wherein, then react 24h under 5 DEG C of conditions.In reaction process, adularescent solid is separated out, suction filtration, absolute ethanol washing, and then obtains white needle-like crystals with dehydrated alcohol recrystallization, is intermediate 2, productive rate 47.5%, fusing point 235-236 DEG C.FAB-MS m/z:352([M+H]
+)；
1H NMR(DMSO-d
6)δ:10.15(s,1H,NH),7.78-7.59(m,3H,ArH),7.37(dd,J＝5.4,1.2Hz,3H,ArH),7.20(s,1H,ArH),7.11(d,J＝8.5Hz,1H,ArH),6.14(s,2H,-CH
2),3.86(s,6H,-OCH
3)；
13CNMR(DMSO-d6,100MHz)，165.94,152.10,148.81,148.03,133.96,131.49,127.03,125.85,124.41,123.30,121.60,111.50,104.32,101.80,100.19,56.12.
3) synthesis of intermediate 3:
1mmol intermediate 2 is dissolved in 60mL methylene dichloride, adds 0.56g PIFA solid and 0.1mL boron trifluoride diethyl etherate, under 10 DEG C of conditions, react 3h.After reaction terminates, drained by solvent, carry out column chromatography for separation, elutriant solvent evaporated with petrol ether/ethyl acetate (volume ratio is for 4:1) for eluent, obtain intermediate 3, productive rate is 12%.m.p.235-236℃；
1H NMR(CDCl
3)δ:8.37(s,1H,ArH),8.28(s,2H,ArH),8.14～7.98(m,2H,ArH),7.84(t,J＝7.4Hz,1H,ArH),7.66～7.53(m,4H,ArH),7.48(dd,J＝15.9,8.5Hz,2H,ArH),6.67(d,J＝2.1Hz,1H,ArH),3.84(s,3H,-OCH
3),2.53(s,3H,-CH
3).
4) synthesis of nitidine chloride:
4.1) 0.1g intermediate 3 is dissolved in 10mL anhydrous tetrahydro furan, under nitrogen protection, adds 0.06gLiAlH
43h is reacted under room temperature condition, after reaction terminates, reactant 2mol/L hydrochloric acid processed, filters insolubles, 10mL distilled water is added in gained filtrate, there is yellow mercury oxide to separate out, be Dihydronitidine, this precipitation is used 95% ethyl alcohol recrystallization again, obtain yellow needle-like crystals 0.06g, productive rate 60%;
4.2) get the above-mentioned yellow needle-like crystals of 0.06g and be placed in the solvent be made up of 4mL oil of mirbane and 2mL dimethylbenzene, add the methyl-sulfate of 200 μ L, 7min is reacted under 180 DEG C of conditions, ether is added wherein to there being brown color Precipitation after reactant cooling, suction filtration, filter residue anhydrous methanol recrystallization obtains sulfation nitidine, productive rate 70%;
4.3) getting 0.1mmol sulfation nitidine joins in the sodium chloride solution of 5mL 8w/w%, and stirring at room temperature reaction 30min, has pale yellow precipitate to separate out, isolate this pale yellow precipitate and be target product nitidine chloride, productive rate 80%,
1h NMR (DMSO-d
6) δ: 9.98 (s, 1H, CH=N), 8.68 (s, 1H, ArH), 8.62 (d, J=7.4Hz, 1H, ArH), 8.20 (d, J=7.4Hz, 1H, ArH), 8.18 (d, J=7.4Hz, ArH), 8.17 (d, J=8.5Hz, 2H, ArH), 7.54 (d, J=8.5Hz, 1H, ArH), 6.27 (s, 2H ,-O-CH
2-O-, 4.99 (s, 3H, N-CH
3), 4.29 (s, 3H ,-OCH
3), 4.14 (s, 3H ,-OCH
3). fusing point 272 ~ 275 DEG C, basically identical with literature value 275 ~ 276 DEG C, be same compound (developping agent: chloroform: methyl alcohol=9:1) by TLC method and reference substance (Chun You bio tech ltd, Shanghai) comparison.
Embodiment 2
Repeat the method for embodiment 1, just revise as follows:
1, by step 1) in methylene chloride used be revised as chloroform, react 48h under reaction conditions being revised as 30 DEG C of conditions;
2, by step 2) in methylene chloride used be revised as chloroform, react 12h under reaction conditions being revised as 10 DEG C of conditions;
3, by step 3) in reaction conditions be revised as 50 DEG C of conditions under react 1h;
4, by step 4.1) in solvent anhydrous tetrahydro furan used be revised as anhydrous diethyl ether; By step 4.2) in reaction conditions be revised as 200 DEG C of conditions under react 3min, simultaneously by step 4.2) in the used solvent be made up of 4mL oil of mirbane and 2mL dimethylbenzene be revised as 6mL oil of mirbane.
The final product productive rate 22% that this enforcement is obtained, fusing point 272 ~ 275 DEG C, basically identical with literature value 275-276 DEG C, be same compound (developping agent: chloroform: methyl alcohol=9:1) by TLC method and reference substance (Chun You bio tech ltd, Shanghai) comparison.
Embodiment 3
Repeat the method for embodiment 1, just revise as follows:
1, by step 3) in the mixed solvent of wash-out to change to by volume ratio be that the sherwood oil of 10:1 and ethyl acetate form;
2, by step 3) in reaction conditions be revised as 60 DEG C of conditions under react 1h;
3, by step 4.2) in reaction conditions be revised as 150 DEG C of conditions under react 15min, and ether is wherein changed to tetrahydrofuran (THF).
The final product productive rate 20% that this enforcement is obtained, fusing point 272 ~ 275 DEG C, basically identical with literature value 275-276 DEG C, be same compound (developping agent: chloroform: methyl alcohol=9:1) by TLC method and reference substance (Chun You bio tech ltd, Shanghai) comparison.
Claims (10)
1. a synthetic method for nitidine chloride, comprises the following steps:
1) get 3,4-dimethoxybenzoic acid to be dissolved in the first organic solvent, add thionyl chloride and react, reactant steams and desolventizes, and obtains intermediate 1;
2) by intermediate 1 with adding 3,4-methylenedioxy group naphthylamines after the first organic solvent dissolution, nucleo philic substitution reaction obtains intermediate 2;
3) get intermediate 2 to be dissolved in the first organic solvent, add boron trifluoride diethyl etherate and two (trifluoroacetyl oxygen base) iodobenzene and react, reactant is except desolventizing, and silica gel column chromatography on gained residue, obtains intermediate 3;
4) getting intermediate 3 is dissolved in the second organic solvent, through lithium aluminium hydride reduction, dehydration and dimethyl sulfate methylation of ester, again through sodium-chlor process, namely obtain target product nitidine chloride under atmosphere protection condition.
2. synthetic method according to claim 1, is characterized in that: the first described organic solvent is methylene dichloride or chloroform.
3. synthetic method according to claim 1, is characterized in that: step 1) in, react and carry out under 20 ~ 80 DEG C of conditions.
4. synthetic method according to claim 1, is characterized in that: step 2) in, nucleophilic substitution reaction carries out under 0 ~ 10 DEG C of condition.
5. synthetic method according to claim 1, is characterized in that: step 3) in, react and carry out under 10 ~ 60 DEG C of conditions.
6. synthetic method according to claim 1, is characterized in that: step 3) in, on gained residue during silica gel column chromatography, with by volume ratio being the mixed solvent wash-out that the sherwood oil of 2 ~ 10:1 and ethyl acetate form.
7. synthetic method according to claim 1, is characterized in that: the second described organic solvent is anhydrous tetrahydro furan, anhydrous diethyl ether or anhydrous methanol.
8. synthetic method according to claim 1, is characterized in that: step 4) in, add that lithium aluminum hydride carries out reducing, processed is carried out under 20 ~ 50 DEG C of conditions.
9. synthetic method according to claim 1, it is characterized in that: step 4) in, described dimethyl sulfate methylation of ester is dissolved in the solvent be made up of with the volume percent of 50 ~ 100%:0 ~ 50% oil of mirbane and dimethylbenzene by the product after lithium aluminium hydride reduction, dehydration, react under 150 ~ 200 DEG C of conditions, ether or tetrahydrofuran (THF) is added after reactant cooling, there is Precipitation, isolate precipitation, obtain sulfation nitidine.
10. synthetic method according to claim 1, is characterized in that: step 4) in, described sodium-chlor process is reacted through the methylated product of methyl-sulfate and sodium chloride aqueous solution, has Precipitation, collect this precipitation, be nitidine chloride.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109369772A (en) * | 2018-12-19 | 2019-02-22 | 桂林理工大学 | A kind of synthetic method and antitumor application thereof of phenanthridines class nitidine derivative |
Citations (3)
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|---|---|---|---|---|
| US3912740A (en) * | 1974-02-28 | 1975-10-14 | Us Health | Method for the preparation of oxygenated benzo{8 c{9 phenanthridine compounds |
| CN101061121A (en) * | 2004-11-17 | 2007-10-24 | 日本化药株式会社 | Method for producing benzo[c]phenanthridine derivative |
| CN102887904A (en) * | 2012-10-10 | 2013-01-23 | 广西师范大学 | 2,3-dioxyethyl-5-methyl-8,9-dimethoxy benzophenanthridine derivative, and preparation method and application thereof |
-
2014
- 2014-11-21 CN CN201410676737.5A patent/CN104356139B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3912740A (en) * | 1974-02-28 | 1975-10-14 | Us Health | Method for the preparation of oxygenated benzo{8 c{9 phenanthridine compounds |
| CN101061121A (en) * | 2004-11-17 | 2007-10-24 | 日本化药株式会社 | Method for producing benzo[c]phenanthridine derivative |
| CN102887904A (en) * | 2012-10-10 | 2013-01-23 | 广西师范大学 | 2,3-dioxyethyl-5-methyl-8,9-dimethoxy benzophenanthridine derivative, and preparation method and application thereof |
Non-Patent Citations (3)
| Title |
|---|
| SATINDER V. KESSAR，等: "Benzyne Cyclization Route to Benzo[ c Iphenanthridine Alkaloids.Synthesis of Chelerythrine, Decarine, and Nitidine", 《J. ORG. CHEM.》, vol. 53, no. 8, 30 April 1988 (1988-04-30), pages 1708 - 1713, XP055296020, DOI: doi:10.1021/jo00243a020 * |
| SV KESSAR，等: "Studies in synthetic photochemistry-I synthesis of naphthaphenanthridine alkaloids", 《TETRAHEDRON LETTERS》, vol. 15, no. 26, 17 May 1974 (1974-05-17), pages 2269 - 2270 * |
| TAKESHI NAKANISHI，等: "Synthesis and Cytotoxic Activities of a New Benzo[c]phenanthridine Alkaloid，7-Hydroxynitidine, and Some 9-Oxygenated Benzo[c]phenanthridine Derivatives", 《ORGANIC LETTERS》, vol. 1, no. 7, 9 April 1999 (1999-04-09), pages 985 - 988, XP055295951, DOI: doi:10.1021/ol990775g * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109369772A (en) * | 2018-12-19 | 2019-02-22 | 桂林理工大学 | A kind of synthetic method and antitumor application thereof of phenanthridines class nitidine derivative |
| CN109369772B (en) * | 2018-12-19 | 2021-01-05 | 桂林理工大学 | Synthetic method and anti-tumor application of phenanthridine nitidine derivatives |
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