CN113717100B - Preparation method of pefloxacin aldehyde 4-aryl thiosemicarbazide derivative - Google Patents
Preparation method of pefloxacin aldehyde 4-aryl thiosemicarbazide derivative Download PDFInfo
- Publication number
- CN113717100B CN113717100B CN202111180624.2A CN202111180624A CN113717100B CN 113717100 B CN113717100 B CN 113717100B CN 202111180624 A CN202111180624 A CN 202111180624A CN 113717100 B CN113717100 B CN 113717100B
- Authority
- CN
- China
- Prior art keywords
- formula
- compound
- preparation
- aryl
- aldehyde
- 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.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
Abstract
The invention relates to a preparation method of pefloxacin aldehyde 4-aryl thiosemicarbazide derivatives, which takes a compound shown in a formula 2 as a starting material, and the compounds are subjected to reduction, oxidation, condensation with the 4-aryl thiosemicarbazide derivatives, substitution and the likeThe pefloxacin aldehyde 4-aryl thiosemicarbazide derivative shown in the formula 1 is obtained. The invention provides a novel preparation method of a pefloxacin aldehyde 4-aryl thiosemicarbazide derivative, which has the advantages of mild reaction conditions, economic synthesis method, high product yield and suitability for commercial production.
Description
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a preparation method of pefloxacin aldehyde 4-aryl thiosemicarbazide derivatives.
Background
New drug innovation originates from the discovery of leads, and the construction of lead molecules based on the building-up of the dominant pharmacophore backbone is the most economical and effective strategy. Thiosemicarbazone derivatives constructed from aldehydes or ketones and thiosemicarbazones show wide pharmacological activity due to the fact that the thiosemicarbazone derivatives are easy to generate coordination compounds or chelation with macromolecules or metal ions. However, the aldehydes or ketones constituting the thiosemicarbazone molecule are mostly common benzene or heterocyclic aromatic aldehydes and ketones, and thiosemicarbazones formed from quinoline aldehydes, especially fluoroquinazolinone aldehydes, have not been reported at present. On the other hand, the quinoline dominant pharmacophore framework is not only an important structural unit of important natural product alkaloids, such as quinine and camptothecin, but also a pharmacophore framework of antibacterial fluoroquinolone drugs. Meanwhile, the water solubility of the fluoroquinolone medicines is increased due to the existence of hydrophilic piperazinyl, so that the bioavailability is improved. In particular, topoisomerase (TOPO), which is an action target of fluoroquinolone medicines, is also an important action target of antitumor medicines, and the antibacterial activity of the fluoroquinolone medicines can be converted into the antitumor activity. Therefore, fluoroquinolone C-3 carboxyl is converted into formyl to form corresponding fluoroquinolone C-3 aldehyde, and then the fluoroquinolone C-3 aldehyde is condensed with thiosemicarbazones, so that the splicing of a quinoline skeleton and thiosemicarbazone pharmacophores is realized, the activity superposition among different structure pharmacophores is expected to be achieved, and a fluoroquinolone candidate compound with anti-tumor activity is found.
The institution discovers a series of pefloxacin aldehyde-condensed 4-aryl thiosemicarbazide derivatives and carries out continuous research, wherein the compounds are shown as the following formula 1:
Disclosure of Invention
The invention provides a method for synthesizing a pefloxacin aldehyde 4-aryl thiosemicarbazide derivative shown as a formula 1, which specifically comprises the following steps:
(1) The compound of the formula 2 is reduced to obtain a compound of a formula 3, the compound of the formula 3 is oxidized to obtain a compound of a formula 4,
(2) The compound of formula 4 is reacted with the compound of formula 5 to obtain the compound of formula 6,
(3) Reacting the compound shown in the formula 6 with a compound shown in a formula 7 to obtain a compound shown in a formula 1,
wherein Ar is selected from benzene ring, substituted benzene ring, pyridine ring, furan ring or thiophene ring, and R is selected from C1-C6 alkyl.
Preferably, R is selected from methyl, ethyl or isopropyl.
Preferably, the reducing agent used in step (1) is borane dimethyl sulfide complex; the reducing agent may be used in an amount of 1.0 to 1.1 times, preferably 1.05 times, the molar amount of the compound of formula 2.
Preferably, the oxidizing agent used in step (1) is pyridinium chlorochromate; the amount of the oxidizing agent to be used may be 1.2 to 1.3 times, preferably 1.25 times, the molar amount of the compound of formula 2.
Preferably, the reaction solvent used in the reduction reaction in step (1) is selected from tetrahydrofuran, and the reaction temperature is selected from 0-20 ℃.
Preferably, the reduction reaction in step (1) is not subjected to post-treatment, and an oxidizing agent is directly added to carry out the oxidation reaction.
The compound 4-arylaminothiourea derivative of the formula 5 is synthesized by the following steps: the 4-aryl thiosemicarbazide derivative shown in the formula 5 can be obtained by condensing aromatic amine compounds and carbon disulfide into aryl ammonium dithiocarbamates, condensing with sodium chloroacetate to obtain S-carboxymethyl aryl sodium dithiocarbamates, carrying out substitution reaction with hydrazine hydrate, and carrying out post-treatment.
Compared with the prior art, the preparation method has the advantages of mild reaction conditions, economic synthesis method, high product purity and yield, and suitability for commercial production.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to specific examples. The following examples are merely illustrative of the present invention and should not be construed as limiting the scope of the invention.
Example 1
Adding 29.77g of the compound shown in the formula 21 into 600ml of tetrahydrofuran, stirring for dissolving, introducing nitrogen for protection, cooling to about 10 ℃, controlling the temperature to be 0-20 ℃, dropwise adding 7.97g of borane dimethyl sulfide complex, and keeping the temperature for reaction for 8-9 hours. After the reaction, 10ml of water is slowly added, and the reaction solvent is recovered by decompression concentration, so that the residue is the compound shown in the formula 3. A small amount of the compound of formula 3 was taken and subjected to mass spectrometry, MS: ESI, M/z:256.05 (100.0%), 258.04 (32.1%), M + H + 。
Example 2
29.77g of the compound of formula 21 was added to 600ml of tetrahydrofuranStirring for dissolving, introducing nitrogen for protection, cooling to about 10 ℃, dropwise adding 7.97g of borane dimethyl sulfide complex at the temperature of 0-20 ℃, and reacting for 8-9 hours under the condition of heat preservation. And after the reaction is finished, adding 26.95g of pyridinium chlorochromate, stirring for reaction for 5-6 hours, recovering the solvent under reduced pressure after the reaction is finished, adding 100ml of water into the residue, extracting twice with 100ml of dichloromethane, drying the organic layer with anhydrous sodium sulfate, concentrating under reduced pressure until the organic layer is dried to obtain a crude compound of the formula 4, and recrystallizing and purifying the crude compound of the formula 4 with isopropanol to obtain 22.58g of the compound of the formula 4. 1 HNMR(400MHz,d 6 DMSO):1.46(t,3H),4.52(q,2H),8.94(s,1H),7.02(d,1H),7.34(d,1H),10.4(d,1H)。MS:ESI,m/z,254.03(100.0％),256.03(32.1％),M+H + 。
Example 3
The compound of formula 4 (25.37 g) was added to absolute ethanol (500 ml), 4- (4-methylphenyl) thiosemicarbazide represented by formula 51 (18.13 g) was added, the mixture was refluxed for 6 hours, the solvent was distilled off under reduced pressure, and the remaining solid was recrystallized from a DMF-ethanol (V: V = 4) mixed solvent to give 35.14g of the compound of formula 61.
MS:ESI,m/z,417.09,M+H + ；HNMR(400MHz,DMSOd 6 )：11.73(s,1H,CH＝N),9.82(s,1H,NH),8.91(s,1H,2-H),8.45(s,1H,NH),7.81～7.03(m,6H,Ph-H、5-H and8-H),4.56(q,2H,1-NCH 2 ),2.26(s,3H,),1.41(t,3H)。
Example 4
After 41.69g of the compound of formula 61 was added to 500ml of DMSO, 20.0g of N-methylpiperazine was added, and the mixture was heated to 30 to 35 ℃ to react for 1 hour, the reaction mixture was washed with 5L of water, filtered, and the filter cake was washed with a small amount of ethanol and then recrystallized from a DMF-ethanol (V: V = 5) mixed solvent to obtain 42.78g of the compound of formula 11 as a pale yellow crystal. Liquid phase detection, area normalization purity 99.1%.
MS:ESI,m/z,481.21,M+H + ；HNMR(400MHz,DMSOd 6 )：11.72(s,1H,CH＝N),9.81(s,1H,NH),8.93(s,1H,2-H),8.46(s,1H,NH),7.86～7.07(m,6H,Ph-H、5-H and8-H),4.57(q,2H,1-NCH 2 ),3.27(t,4H，piperazine-H)，2.54(t,4H，piperazine-H)，2.21(s,3H,)，2.27(s,3H,)，1.42(t,3H)。
Claims (7)
1. A process for the preparation of a compound of formula 1, comprising the steps of,
(1) The compound of the formula 2 is reduced to obtain a compound of a formula 3, the compound of the formula 3 is oxidized to obtain a compound of a formula 4,
(2) The compound of formula 4 is reacted with the compound of formula 5 to obtain the compound of formula 6,
(3) Reacting the compound shown in the formula 6 with a compound shown in a formula 7 to obtain a compound shown in a formula 1,
wherein Ar is selected from benzene ring, substituted benzene ring, pyridine ring, furan ring or thiophene ring, and R is selected from C1-C6 alkyl.
2. The process according to claim 1, wherein the reducing agent used in step (1) is borane dimethylsulfide complex.
3. The process of claim 1, wherein the oxidizing agent used in step (1) is pyridinium chlorochromate.
4. The method of claim 1, wherein R is selected from methyl, ethyl, or isopropyl.
5. The method according to claim 1, wherein the solvent for the reduction reaction in step (1) is selected from tetrahydrofuran.
6. The method according to claim 1, wherein the reduction reaction temperature in step (1) is selected from 0 to 20 ℃.
7. The method of claim 1, wherein the reduction reaction in step (1) is carried out without post-treatment by directly adding an oxidizing agent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111180624.2A CN113717100B (en) | 2021-10-11 | 2021-10-11 | Preparation method of pefloxacin aldehyde 4-aryl thiosemicarbazide derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111180624.2A CN113717100B (en) | 2021-10-11 | 2021-10-11 | Preparation method of pefloxacin aldehyde 4-aryl thiosemicarbazide derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113717100A CN113717100A (en) | 2021-11-30 |
| CN113717100B true CN113717100B (en) | 2023-03-17 |
Family
ID=78685824
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111180624.2A Active CN113717100B (en) | 2021-10-11 | 2021-10-11 | Preparation method of pefloxacin aldehyde 4-aryl thiosemicarbazide derivative |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113717100B (en) |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100309871B1 (en) * | 1999-02-24 | 2001-10-29 | 윤종용 | Process for Preparing (-)Pyridobenzoxazine Carboxylic Acid Derivatives |
| US20090023925A1 (en) * | 2007-06-28 | 2009-01-22 | Wyeth | N'-(2-halobenzylidene)sulfonylhydrazides as intermediates in the manufacture of arylsulfonylindazoles |
| EP2451790A4 (en) * | 2009-07-07 | 2012-12-26 | Anthem Biosciences Private Ltd | Histone deacetylase inhibitors |
| TW201319063A (en) * | 2011-10-04 | 2013-05-16 | Yakult Honsha Kk | Medicinal agent comprising thiazolidine derivative or salt thereof as active ingredient |
| CN106699656B (en) * | 2016-12-26 | 2019-09-24 | 郑州工业应用技术学院 | Pefloxacin aldehyde contracting 4- arylamino thiourea derivatives and its preparation method and application |
-
2021
- 2021-10-11 CN CN202111180624.2A patent/CN113717100B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN113717100A (en) | 2021-11-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2581835C (en) | Process for the preparation of 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-n-methylpyridine-2-carboxamide | |
| CA3115570C (en) | Process for the preparation of a pde4 inhibitor | |
| US9115158B2 (en) | Thionating agent | |
| CN113717100B (en) | Preparation method of pefloxacin aldehyde 4-aryl thiosemicarbazide derivative | |
| US20170145001A1 (en) | Processes for preparing brexpiprazole | |
| JPS6046104B2 (en) | Method for producing butene derivatives | |
| JP4408578B2 (en) | 3- (1-Hydroxy-pentylidene) -5-nitro-3H-benzofuran-2-one, production method thereof and use thereof | |
| Coşkun et al. | Synthesis of 2-aryl-1, 2, 3, 4-tetrahydroquinazolin-1-ols and their conversion to 7-aryl-9H-6-oxa-5, 8-diaza-benzocycloheptenes | |
| CA2395407C (en) | Method for producing 4-(heteroaryl-methyl)-1(2h)-phthalazinones | |
| EP2582690B1 (en) | Process for preparation of 2, 3-diaryl-5-substituted pyridines and their intermediates | |
| Elgemeie et al. | Activated nitriles in heterocyclic synthesis: A novel synthetic route to furyl-and thienyl-substituted pyridine derivatives | |
| TW202102477A (en) | Production method of quinolinecarboxamide derivative or production intermediate thereof | |
| JPH07113017B2 (en) | Method for reducing carbonyl-containing acridine derivative | |
| JP2001261653A5 (en) | ||
| Elgemeie et al. | Novel synthesis of N-amino-2-pyridones and cycloalkane ringfused pyridines containing benzothiazole moiety | |
| CN108558878B (en) | Synthesis process of quinoline and derivatives thereof | |
| CN113278007B (en) | Synthetic method of 2-hydroxy-indole-3-ketone compound | |
| CN114380743B (en) | Method for introducing trifluoromethylthio into nitrogen-containing compound | |
| CN110423215B (en) | Chalcone pyridine salt and preparation method and application thereof | |
| CN108558751B (en) | Synthesis process of 3-nitroquinoline derivative | |
| JPS6365675B2 (en) | ||
| KR100300880B1 (en) | Method of Making 2-Aminothioxanthone | |
| Yue et al. | Synthesis, Crystal Structure and Antitumor Activity of Novel 5-Chloro-β-carboline Derivatives | |
| CN111718301A (en) | Synthetic method of quinazolinone derivative | |
| RU2310653C1 (en) | METHOD FOR PREPARING DERIVATIVES OF 2-METHYL-5-(5-METHYL-2-FURYL)-4,10-DIHYDRO-3H-PYRIDAZINO[1,6-b]ISOQUINOLINE-10-ONE (VARIANTS) |
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 |