CN110386889B - Synthesis method of NSC128981 - Google Patents
Synthesis method of NSC128981 Download PDFInfo
- Publication number
- CN110386889B CN110386889B CN201910581529.XA CN201910581529A CN110386889B CN 110386889 B CN110386889 B CN 110386889B CN 201910581529 A CN201910581529 A CN 201910581529A CN 110386889 B CN110386889 B CN 110386889B
- Authority
- CN
- China
- Prior art keywords
- naphthoquinone
- amino
- reaction
- nsc128981
- iii
- 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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
- C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
Abstract
The invention discloses a method for synthesizing NSC128981, wherein the structure of NSC128981 is shown in a formula (I), and the method comprises the following steps: performing amination reaction on the naphthoquinone (II) to obtain 2-amino-1, 4-naphthoquinone (III); carrying out p-chlorobenzenethiolation reaction on the 2-amino-1, 4-naphthoquinone (III) to obtain 2-amino-3-p-chlorobenzenethiol-1, 4-naphthoquinone (IV); adding an acetylation reagent into 2-amino-3-p-chlorobenzenethiol-1, 4-naphthoquinone (IV) under an acidic condition for acetylation reaction to obtain NSC128981(I), wherein the reaction formula is as follows:
Description
Technical Field
The invention relates to a synthetic method of a bioactive molecule NSC 128981.
Background
Many natural products have a quinone structural backbone, and the quinone structure is widely associated with many biological activities. More than 100 kinds of 1, 4-naphthoquinones are separated from natural products, and many of them have a biocidal effect. 1, 4-naphthoquinone having amino group or substituted amino group at 2-position is receiving wide attention and has been subjected to activity tests for tuberculosis resistance, malaria resistance, bacteria resistance, tumor resistance, insect killing, and weed control. On the other hand, molecules with substituted thio groups in their structure also have a wide range of biological activities. NSC128981 is an important heterocyclic compound of 1, 4-naphthoquinone derivatives, and the structure of the heterocyclic compound is shown as a formula I. The skeleton of NSC128981 has potential application value in drugs with biological activity. For example, NSC128981 exhibits inhibitory activity against Cdc25B bispecific protein phosphatase ([1] Lavecchia, A.; Cosconti, S.; Limongelli, V.; Novellino, E.ChemMedChem 2006,1,540.[2] Lazo, J.S.; Nemoto, K.; Pestell, K.E.; Cooley, K.; Southwick, E.C.; Mitchell, D.A.; Furey, W.; Gussio, R.; Zaharevitz, D.W.; Joo, B.; Wipf, P.mol. Pharmacol.2002,61,720.). NSC128981 has the following structure:
for the chemical synthesis of NSC128981, it has been reported (Clark, n.g. pesticide.sci.1985, 16,23.) that synthetic route 1 is as follows: naphthoquinone is taken as an initial raw material, and a target product is obtained by sequentially carrying out ortho-dichloro, amination, mercaptan substitution and acetyl protection amination reactions.
Route 1
Scheme 2 is as follows: naphthoquinone is taken as an initial raw material, and a target product is obtained by sequentially carrying out ortho-dichloro reaction, amination reaction, acetyl protection amination reaction and mercaptan substitution reaction.
Route 2
However, in these synthetic methods, it is necessary to introduce a chlorine atom into the reaction site and then perform SN2-substituted introduction of a sulfenyl functional group, the route has the defects of complicated steps, higher cost, and incapability of avoiding environmental pollution or high requirements on reaction equipment caused by using a toxic or corrosive chlorinated reagent, and reports that a substrate hydrocarbon oxidation coupling reaction is directly carried out under the action of an oxidant and a sulfur source by using a 2-amino-1, 4-naphthoquinone compound (III) as a raw material and the sulfenyl functional group is introduced in one step to synthesize NSC128981 are not seen.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a simple synthesis method of NSC 128981.
The technical scheme of the invention is summarized as follows:
a method for synthesizing NSC128981, wherein the structure of NSC128981 is shown in formula I, comprises the following steps:
a) performing amination reaction on the naphthoquinone II to obtain 2-amino-1, 4-naphthoquinone III;
b) carrying out p-chlorobenzenethiolation reaction on the 2-amino-1, 4-naphthoquinone III to obtain 2-amino-3-p-chlorobenzenethiol-1, 4-naphthoquinone IV;
c) adding an acetylation reagent into 2-amino-3-p-chlorobenzenethiol-1, 4-naphthoquinone IV to perform acetylation reaction under an acidic condition to obtain NSC128981I, wherein the reaction formula is as follows:
step a) is preferably: and (2) performing amination reaction on the naphthoquinone II and an acetic acid acidified sodium azide aqueous solution in a mixed solvent to obtain the 2-amino-1, 4-naphthoquinone III.
The volume ratio of the mixed solvent is 1: 4 water and tetrahydrofuran.
Step b) is preferably: adding mixed solution obtained by reacting the di-p-chlorophenyl disulfide and dichloroiodobenzene in an organic solvent into organic solution of 2-amino-1, 4-naphthoquinone (III) to carry out p-chlorophenylation reaction to obtain 2-amino-3-p-chlorophenylthio-1, 4-naphthoquinone (IV).
The organic solvent is N, N-dimethylformamide or anhydrous acetonitrile.
Step c) is preferably: dissolving 2-amino-3-p-chlorobenzenethiol-1, 4-naphthoquinone IV in acetic anhydride, adding trifluoroacetic acid, and performing acetylation reaction at 60 deg.C to obtain NSC 128981I.
The method has the advantages of simple steps, cheap and easily obtained raw materials, relatively ideal yield, relatively low product purity and high cost, and the like.
Detailed Description
Sodium azide 97 commercially available+% of sodium azide.
The di-p-chlorophenyl disulfide was a commercially available analytically pure di-p-chlorophenyl disulfide.
Tetrahydrofuran (THF), N-Dimethylformamide (DMF), anhydrous acetonitrile, acetic acid, acetic anhydride and trifluoroacetic acid were commercially available analytical purifiers.
The oxidant required in the examples, dichloroiodobenzene, was prepared for reference (Zhao, x. -f.; Zhang, c. synthesis 2007,2007,551.)
The present invention will be further described with reference to the following examples.
Example 1
Preparation of 2-amino-1, 4-naphthoquinone III
Sodium azide (1mmol,1.25g) was dissolved in 3mL of water and acidified with 1mL of acetic acid. 1, 4-naphthoquinone was added to 20mL of a mixture of Tetrahydrofuran (THF) and water (THF/H)2O ═ 4:1), and the acidified aqueous sodium azide solution was added to the above 1, 4-naphthoquinone solution, followed by stirring at room temperature until TLC showed complete reaction of the substrate. Spin-drying the organic phase, adding ethyl acetate to extract the aqueous phase three times, combining the organic phases, washing the organic phase with sodium hydroxide and brine respectively, adding anhydrous sodium sulfate to dry, adding the organic phase into column silica gel to evaporate, and separating by column chromatography (ethyl acetate: petroleum ether ═ 50:50) to obtain 0.96g of red solid III, wherein the yield is 96%. The melting point was 204 ℃ and 205 ℃.1HNMR(600MHz,DMSO)δ7.99–7.95(m,1H),7.95–7.90(m,1H),7.82(td,J＝7.5,1.1Hz,1H),7.72(td,J＝7.5,1.1Hz,1H),7.55–6.95(br,2H),5.85(s,1H).13C NMR(151MHz,DMSO)δ181.9,181.7,150.3,134.6,133.1,132.0,130.4,125.7,125.2,102.2.
Example 2
Preparation of 2-amino-3-p-chlorophenylthio-1, 4-naphthoquinone IV
Di-p-chlorophenyl disulfide (p-Cl-C)6H4SSC6H4-Cl-p) (0.6mmol,172mg) was dissolved in 2mLN, N-Dimethylformamide (DMF) (or anhydrous acetonitrile) and dichloroiodobenzene (PhICl) was added in one portion2) (0.6mmol,165mg) and stirred at room temperature for 10min, added to a solution of 2-amino-1, 4-naphthoquinone III (1.0mmol,173mg) in DMF (or anhydrous acetonitrile) -and reacted at room temperature for 30min until TLC indicated complete reaction of the substrate. Diluting the reaction solution with dichloromethane, extracting with water and dichloromethane three times, combining the organic phases, washing the organic phases with saturated solution of sodium bicarbonate brine respectively,anhydrous sodium sulfate was added thereto, the organic phase was dried over silica gel, and column chromatography (dichloromethane: petroleum ether ═ 2: 1) was performed to obtain an orange solid IV 290mg with a yield of 92%. The melting point was 212-213 ℃.1H NMR(600MHz,DMSO)δ8.04(d,J＝7.5Hz,1H),8.00(d,J＝7.6Hz,1H),7.91(s,1H),7.85(t,J＝7.3Hz,1H),7.77(t,J＝7.4Hz,1H),7.70(s,1H),7.29(d,J＝8.5Hz,2H),7.23(d,J＝8.5Hz,2H).13C NMR(151MHz,DMSO)δ180.0,178.3,153.9,135.5,134.9,133.4,132.5,130.5,129.6,128.7,128.0,126.1,101.6.
Example 3
Preparation of NSC128981I
2-amino-3-p-chlorobenzenethiol-1, 4-naphthoquinone IV (0.32mmol,100mg) was dissolved in 2mL of acetic anhydride, trifluoroacetic acid (2.68mmol,200uL) was added in one portion, and the reaction was carried out at 60 ℃ for 10min until TLC indicated complete reaction of the substrate. Stopping heating, cooling to room temperature, extracting with water and ethyl acetate for three times, combining organic phases, washing the organic phases with brine, adding anhydrous sodium sulfate for drying, adding silica gel into the organic phases for drying by evaporation, and separating by column chromatography (dichloromethane: petroleum ether: 3:1) to obtain a red solid I96 mg, wherein the yield is 85%, and the melting point is 222-.1H NMR(600MHz,CDCl3)δ8.11–8.08(m,1H),8.03(s,1H),8.02–8.00(m,1H),7.79–7.66(m,2H),7.31–7.27(m,2H),7.26–7.20(m,2H),2.10(s,3H).13C NMR(151MHz,CDCl3)δ180.6,179.7,166.9,138.4,135.7,134.6,133.90,133.85,133.0,132.7,132.1,130.4,129.0,127.4,126.8,23.8.
The above description is only a part of the embodiments of the present invention, and is not intended to limit the present invention in any way, and all simple modifications, equivalent changes and modifications made to the above embodiments according to the technical spirit of the present invention are within the technical scope of the present invention.
Claims (5)
1. A method for synthesizing NSC128981, wherein the structure of NSC128981 is shown in formula (I), is characterized by comprising the following steps:
a) performing amination reaction on the naphthoquinone (II) to obtain 2-amino-1, 4-naphthoquinone (III);
b) adding mixed solution obtained by reacting di-p-chlorophenyl disulfide and dichloroiodobenzene in an organic solvent into organic solution of 2-amino-1, 4-naphthoquinone (III) to perform p-chlorophenylation reaction to obtain 2-amino-3-p-chlorophenylene-1, 4-naphthoquinone (IV);
c) adding an acetylation reagent into 2-amino-3-p-chlorobenzenethiol-1, 4-naphthoquinone (IV) under an acidic condition for acetylation reaction to obtain NSC128981(I), wherein the reaction formula is as follows:
2. the synthesis method according to claim 1, characterized in that step a) is: and (3) performing amination reaction on the naphthoquinone (II) and an acetic acid acidified sodium azide aqueous solution in a mixed solvent to obtain the 2-amino-1, 4-naphthoquinone (III).
3. The synthesis process according to claim 2, characterized in that the mixed solvent consists of, by volume, 1: 4 water and tetrahydrofuran.
4. The synthesis method according to claim 1, wherein the organic solvent is N, N-dimethylformamide or anhydrous acetonitrile.
5. The synthesis method according to claim 1, characterized in that step c) is: dissolving 2-amino-3-p-chlorobenzenethiol-1, 4-naphthoquinone (IV) in acetic anhydride, adding trifluoroacetic acid, and performing acetylation reaction at 60 deg.C to obtain NSC128981 (I).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910581529.XA CN110386889B (en) | 2019-06-29 | 2019-06-29 | Synthesis method of NSC128981 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910581529.XA CN110386889B (en) | 2019-06-29 | 2019-06-29 | Synthesis method of NSC128981 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110386889A CN110386889A (en) | 2019-10-29 |
| CN110386889B true CN110386889B (en) | 2021-03-16 |
Family
ID=68285973
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910581529.XA Expired - Fee Related CN110386889B (en) | 2019-06-29 | 2019-06-29 | Synthesis method of NSC128981 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110386889B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114213361B (en) * | 2021-12-30 | 2023-08-25 | 遵义医科大学珠海校区 | Preparation method of thiamine 1, 4-naphthoquinone compound |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1050146C (en) * | 1997-07-11 | 2000-03-08 | 南开大学戈德防伪技术公司 | Molecular distinguishing type solid phase anti-counterfeit tech. |
-
2019
- 2019-06-29 CN CN201910581529.XA patent/CN110386889B/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN110386889A (en) | 2019-10-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP2835376B1 (en) | New synthesis process of antiparasitic drug selamectin | |
| ES2413480T3 (en) | Method to produce L-biopterin | |
| CN105294653A (en) | Preparation technology for vonoprazan fumarate | |
| Bukownik et al. | Synthetic receptors. 3, 6-Anhydro-7-benzenesulfonamido-1, 7-dideoxy-4, 5-O-isopropylidene-D-altro-hept-1-ynitol: A useful component for the preparation of chiral water-soluble cyclophanes based on carbohydrate precursors | |
| CN110386889B (en) | Synthesis method of NSC128981 | |
| CN106946972B (en) | A kind of ursolic acid derivative with anti-tumor activity and preparation method thereof | |
| CN105949118B (en) | A kind of preparation method of 2- aryl quinoline derivatives | |
| CN107033210B (en) | A kind of preparation method of fulvestrant and its intermediate | |
| To et al. | Divergent reactivity of an indole glucosinolate yields Lossen or Neber rearrangement products: the phytoalexin rapalexin A or a unique β-D-glucopyranose fused heterocycle | |
| CN110511193A (en) | A kind of α -one thioamide analog compound and its synthetic method | |
| Ghorbani-Choghamarani et al. | Versatile and efficient conversion of thiols into disulfides by poly (4-vinylpyridinium tribromide) as reusable oxidizing polymer | |
| CN115093372A (en) | Synthesis method of imidazole derivative | |
| CN106866608B (en) | A kind of preparation method of fluoro -3,4- dihydrocoumarin derivative | |
| CN108033948A (en) | A kind of preparation of De Lasha stars and its intermediate | |
| CN108440466B (en) | 5-aryl-3- (2-sulfamate-5-substituted benzylidene) butenolide compound and preparation method and application thereof | |
| CN109438414B (en) | Method for preparing benzo 1, 3-oxathiane-4-ketone | |
| CN108299466B (en) | Improved dolutegravir synthesis method | |
| RU2479588C1 (en) | Method of producing sodium salt of 3-sulphate betulinic acid | |
| CN112939922A (en) | Synthesis method of 1-cyano-6-methylsulfonyl-7-nitro-9H-xanthene-9-ketone | |
| CN107151239B (en) | A method of synthesis α -1,3- dithiane replaces aldehyde compound | |
| CN105399790A (en) | Synthesis method of 3-ketone-4-androstene-17 beta carboxylic acid | |
| CN109574904A (en) | A kind of trifluoromethyl substituted-dihydro Benzazole compounds and preparation method thereof | |
| CN108191828A (en) | A kind of synthetic method of lenalidomide metabolin | |
| Syvret et al. | Selective fluorination of an aryl triazolinone herbicide intermediate | |
| CN104829412B (en) | Method of preparing 1,3,5-triphenylbenzene with [beta]-methylchalcone as raw material |
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 |
Granted publication date: 20210316 Termination date: 20210629 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |