CN100497309C - Method for synthesizing heteroaryl thiosemicarbazone antineoplastic - Google Patents

Method for synthesizing heteroaryl thiosemicarbazone antineoplastic Download PDF

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CN100497309C
CN100497309C CNB2005100284803A CN200510028480A CN100497309C CN 100497309 C CN100497309 C CN 100497309C CN B2005100284803 A CNB2005100284803 A CN B2005100284803A CN 200510028480 A CN200510028480 A CN 200510028480A CN 100497309 C CN100497309 C CN 100497309C
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thiosemicarbazone
reaction
compound
imines
crude product
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CN1907970A (en
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谢立华
王小龙
高澍
齐铭
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Suzhou Homesun Pharmaceutical Co ltd
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JIAXING SANGDIYA LIANYOU PHARMACY CO Ltd
SHANGHAI UNITED PHARMATECH CO Ltd
SUNDIA MEDITECH (SHANGHAI) Co Ltd
Challenge Medical Sci & Tech (shanghai) Co Ltd
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Abstract

本发明公开了缩氨基硫脲类抗肿瘤药物的合成方法。本发明的合成路线短，纯化次数少，总产率高，原料易得，而且避免了产生刺激性强且剧毒的甲硫醇副产物。按本发明方法制备的产品质量能达到99.5%以上。The invention discloses a synthesis method of thiosemicarbazone antitumor drugs. The invention has the advantages of short synthesis route, less purification times, high total yield, easy-to-obtain raw materials, and avoids the production of highly irritating and highly toxic by-products of methyl mercaptan. The quality of the product prepared by the method of the invention can reach more than 99.5%.

Description

The synthetic method of heteroaryl thiosemicarbazone antineoplastic
Technical field
The present invention relates to the pharmaceutical chemistry technical field, be specifically related to the synthetic method of a kind of Heteraryl ring thiosemicarbazone kind compound and derivative thereof.
Background technology
The inventor discloses new (thiosemicarbazone) compound and derivative thereof and has reported that they are to external cancer strain and to the shown good antineoplastic activity that goes out of in animal body experiment once in last patent application (number of accepting 200510027600.8).Experimental result shows to have structure activity relationship very closely between the molecular structure of compound and its tumor-suppression activity in the last invention.
About synthesizing of (thiosemicarbazone) compound, in 200510027600.8 patent applications, summed up once used method (seeing reaction formula one) in the document, but also proposed another kind of method (seeing reaction formula two).But these two kinds of methods can not be synthesized all basic thioureas that contracts, and have the problem of the low purifying difficulty of productive rate in some compound synthetic in addition.
Synthesizing of reaction formula one heterocyclic aryl (thiosemicarbazone) compound
Figure C200510028480D00041
Synthesizing of reaction formula two heterocyclic aryl (thiosemicarbazone) compounds
Figure C200510028480D00042
Summary of the invention
Problem to be solved by this invention is to overcome above-mentioned weak point, further studies the synthetic method of heterocyclic aryl (thiosemicarbazone) compound.
Dike of the present invention has supplied a kind of method of new synthesizing heterocyclic aryl (thiosemicarbazone) compound; The committed step of this method is that the condensation reaction by imines and thiosemicarbazide obtains target compound (seeing reaction formula three).The imines that heterocyclic aryl replaces can obtain by corresponding Grignard reagent and the reaction of itrile group compound, and the crude product of imines can be directly used in condensation reaction.
Reaction formula three heterocyclic aryl (thiosemicarbazone) compound synthetic methods of the present invention
Being used for the synthetic chemical feedstocks overwhelming majority of the present invention can obtain by commercial sources.Wherein can not can prepare (R.Larock, Comprehensive OrganicTransformations, VCH Publishers, 1989) by the method for document by the thiosemicarbazide compound that purchase obtains.Those of ordinary skill in the art can be synthetic smoothly according to described explanation and method.
The synthetic chemistry that is used to prepare (thiosemicarbazone) compound of the present invention transforms and the method for radical protection (going to protect) is known to those skilled in the art, specifically can be referring to R.Larock, ComprehensiveOrganic Transformations, VCH Publishers (1989); T.W.Green and P.G.M.Wuts, ProtectiveGroups in Organic Synthesis, 3rd Ed., John Wiley and Sons (1999), L.Fieser and M.Fieser, Fieser and Fieser ' s Reagents for Organic Synthesis, John Wiley and Sons (1994); And L.Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and follow-up works thereof.
Method of the present invention comprises the following steps:
(1) organic amine and dithiocarbonic anhydride, sodium chloroacetate are in aqueous sodium hydroxide solution, in 0～50 ℃ of reaction 2-40 hour, through being acidified to pH is that 1-4 generates amino monothioester, and the mol ratio of organic amine and dithiocarbonic anhydride, sodium chloroacetate and sodium hydroxide is that the 1:0.9-1.5:0.9-1.5:1.0-2.0. reaction yield is more than 90%.
(2) product of hydrazine hydrate and step (1) in 45-100 ℃ of reaction 2-20 hour, generates thiosemicarbazide in aqueous sodium hydroxide solution, and the product of hydrazine hydrate and step 1 and the mol ratio of sodium hydroxide are 1:0.5-2:0.5-2.Crude product can be used the organic solvent recrystallizing and refining; These organic solvents comprise methyl alcohol, ethanol, methylene dichloride, sherwood oil, ethyl acetate etc.
(3) imines of heterocyclic aryl replacement can pass through corresponding Grignard reagent or lithium reagent and itrile group compound reaction acquisition, and the crude product of imines can be directly used in condensation reaction.This reaction can be at ether, methyl tertiary butyl ether, and 1, the 2-glycol dimethyl ether carries out in the tetrahydrofuran (THF) equal solvent.Temperature of reaction can be in-50～60 ℃ of scopes.The mol ratio of Grignard reagent and itrile group compound can be between the 1:0.7-1.5.Reaction mixture after ammonium chloride, ammonium sulfate, ammonium acetate or the ammonium formiate aqueous solution are handled again through methylene dichloride, sherwood oil, or ethyl acetate extraction concentrates to such an extent that crude product can be directly used in next step.
(4) condensation reaction of imines and thiosemicarbazide can be at ether, methyl tertiary butyl ether, 1, the 2-glycol dimethyl ether, methylene dichloride in ethyl acetate or the tetrahydrofuran (THF), adds small amount of acid, such as exsiccant hydrogenchloride, acetic acid, or phenylformic acid got crude product in 2-40 hour in 0～50 ℃ of reaction, the mol ratio of imines and thiosemicarbazide is 1:0.7-2, and imines is 1:0-1.2 with the mol ratio of acid.Crude product can be used the organic solvent recrystallizing and refining; These organic solvents comprise methyl alcohol, ethanol, methylene dichloride, ethyl acetate, tetrahydrofuran (THF) or their mixture etc.Target product purity can reach 95-99.9% behind the recrystallization.
The present invention provides a kind of new method for the synthetic of heterocyclic aryl (thiosemicarbazone) compound, and can be used for heterocyclic aryl (thiosemicarbazone) compound and derivative thereof that synthetic original method can not prepare.Processing step route of the present invention is short, and the purifying number of times is few, the overall yield height, and raw material is easy to get, and has avoided producing the strong and hypertoxic thiomethyl alcohol by product of pungency.
Quality product by the inventive method preparation can reach more than 99.5%.
Table 1 has been enumerated heterocyclic aryl (thiosemicarbazone) compound and derivative thereof representative among the present invention
Table 1
Numbering The compound title Molecular formula (MF) Molten point (℃)
S00111 N, N-dimethyl-N '-[2-phenyl-2-(2-pyridyl)-1-azepine thiazolinyl]-thiocarbamide C 15H 16N 4S 124-126
S00112 N, N-dimethyl-N '-[2-(3-pyridyl)-2-(2-pyridyl)-1-azepine thiazolinyl]-thiocarbamide C 14H 15N 5S 154-156
S00114 N, N-dimethyl-N '-[2-(4-pyridyl)-2-(2-pyridyl)-1-azepine thiazolinyl]-thiocarbamide C 14H 15N 5S 187-189
S00115 N, N-dimethyl-N '-[2-(2-thienyl)-2-(2-pyridyl)-1-azepine thiazolinyl]-thiocarbamide C 13H 14N 4S 2 130-131
S00178 N-methyl-N-cyclopentyl-N '-[2,2-two (2-pyridyl)-1-azepine thiazolinyl]-thiocarbamide C 18H 21N 5S Do not detect
S00340 N, N-dimethyl-N '-[2-(4-trifluoromethyl-phenyl)-2-(2-thienyl)-1-azepine thiazolinyl]-thiocarbamide C 15H 14F 3N 3S 2 102-103
S00341 N, N-dimethyl-N '-[2-(2-thienyl)-2-(3-pyridyl)-1-azepine thiazolinyl]-thiocarbamide C 13H 14N 4S 2 119-121
The structural formula of above-claimed cpd is as follows:
Figure C200510028480D00071
The invention will be further described below in conjunction with specific embodiment.But be not limited in this.
Synthesizing of embodiment 1 2-pyridyl-phenyl imine
Tetrahydrofuran (THF) (200 milliliters) solution with 2-itrile group pyridine (104 grams, 1 mole) under the room temperature splashes in the freshly prepd phenyl grignard reagent (1.5 liters of ether-tetrahydrofuran solutions, 1 mole), and mixture stirred 5 hours.Aqueous ammonium chloride solution with 20% (600 milliliters) added the back restir 30 minutes, used ethyl acetate extraction (3 * 500 milliliters) then.Extraction liquid is concentrated into to do with the anhydrous sodium sulfate drying after-filtration and promptly gets product and can be directly used in next step (embodiment 7).
Synthesizing of embodiment 2 2-pyridyl-2-thienyl imines
As embodiment 1, with the reaction of newly formed 2-thienyl Grignard reagent (preparing with ordinary method) and 2-itrile group pyridine from the 2-bromothiophene get final product product (being directly used in embodiment 8).
Synthesizing of embodiment 3 2-pyridyl-3-pyridyl imines
Under-40 ℃, tetrahydrofuran (THF) (100 milliliters) solution of 2-bromopyridine (15.8 gram, 0.1 mole) is splashed in the hexane (60 milliliters) of butyllithium (0.1 mole) and tetrahydrofuran (THF) (140 milliliters) solution and stir 30 minutes generation 2-pyridyl lithium reagents.Tetrahydrofuran (THF) (200 milliliters) solution with 3-itrile group pyridine (10.4 grams, 0.1 mole) under the low temperature splashes in the freshly prepd 2-pyridyl lithium reagent, and mixture stirred 5 hours and slowly rose to room temperature.Aqueous ammonium chloride solution with 20% (600 milliliters) added the back restir 2 hours, used ethyl acetate extraction (3 * 500 milliliters) then.Extraction liquid is concentrated into to do with the anhydrous sodium sulfate drying after-filtration and promptly gets product and can be directly used in next step.
Synthesizing of embodiment 4 other imines
As embodiment 1 or 3, with newly formed aryl or heterocyclic aryl Grignard reagent or lithium reagent and aryl or the reaction of heterocyclic aryl formonitrile HCN get final product product (being directly used in embodiment 9-11).
Embodiment 5 N, N-dimethyl-N '-thiosemicarbazide synthetic
At room temperature, dithiocarbonic anhydride (3.8 grams, 50 mmoles) is splashed in the aqueous solution (50 milliliters) of sodium hydroxide (2.4 grams, 60 mmoles) and dimethyl amine (5.45 grams, 33% aqueous solution, 40 mmoles).Reactant stirred after 2 hours, dripped sodium chloroacetate (5.8 grams, the 50 mmoles) aqueous solution (30 milliliters) and continuation and stirred 20 hours.Reactant is acidified to pH=3 with rare HCl solution, with throw out filter 4.2 the gram intermediates.With this intermediate and sodium hydroxide (0.9 gram, 20 mmoles), hydrazine hydrate (2 milliliters, 85%) and water (12 milliliters) mix, and reflux 4 hours has solid to separate out after the cooling.After the filtration solids is dissolved in hot methylene dichloride, refilters and remove filter residue, concentrated filtrate obtains crude product, crude product recrystallization in ethanol is got pure product 0.8 gram again.
Synthesizing of the thiosemicarbazide that embodiment 6 replaces
As embodiment 5, with other amine replace dimethyl amine reaction get final product the thiosemicarbazide (referring to embodiment 10) that replaces of required target intermediate.
Embodiment 7 N, N-dimethyl-N '-[2-phenyl-2-(2-pyridyl)-1-azepine thiazolinyl]-thiocarbamide synthetic
2-pyridyl-phenyl imine (0.9 gram, 5 mmoles) and N, N-dimethyl-N '-thiosemicarbazide (0.6 gram, 5 mmoles) mixes in methylene dichloride (10 milliliters) lining, and stirring adds the dry saturated HCl diethyl ether solution of 0.15ml down and at room temperature stirs and spend the night.After thin layer plate chromatography (TLC) demonstration reacts completely reaction mixture is concentrated into dried.The gained solid promptly gets purified product (1.0 grams, 70% productive rate), fusing point 124-126 ℃ behind the ethyl alcohol recrystallization secondary. show that through the detection of high performance liquid phase chromaticness combined instrument purity is higher than 99%, mass-to-charge ratio is 284.9[M+1] .300 million nuclear-magnetism results are as follows: 14.46ppm (S, 1H), 8.75 (m, 1H), 7.79 (m, 1H), 7.56-7.59 (m, 2H), 7.26-7.41 (m, 5H), 3.44 ﹠amp; 3.46 (S, 6H).
Embodiment 8 N, N-dimethyl-N '-[2-(2-thienyl)-2-(2-pyridyl)-1-azepine thiazolinyl]-thiocarbamide synthetic
Make the pure product of 1.24 grams, 86% productive rate as embodiment 7 from 2-pyridyl-2-thienyl imines (0.95 gram, 5 mmoles), fusing point 130-131 ℃. detect through high performance liquid phase chromaticness combined instrument and to show that purity is higher than 99%, mass-to-charge ratio is 289.0[M-1] .300 million nuclear-magnetism results are as follows: 14.2ppm (S, 0.56H), 13.15 (S, 0.44H), 8.76-8.83 (m, 1H), and 7.68-7.90 (m, 3H), 7.25-7.45 (m, 2H), 7.0-7.20 (m, 1H), 3.44 (S, 6H).
Embodiment 9 N, N-dimethyl-N '-[2-(2-thienyl)-2-(3-pyridyl)-1-azepine thiazolinyl]-thiocarbamide synthetic
Make the pure product of 1.0 grams, 69% productive rate as embodiment 7 from 2-pyridyl-3-thienyl imines (0.95 gram, 5 mmoles), fusing point 119-121 ℃. detect through high performance liquid phase chromaticness combined instrument and to show that purity is higher than 95%, mass-to-charge ratio is 291.0[M+1] .300 million nuclear-magnetism results are as follows: 14.2ppm (S, 0.56H), 13.15 (S, 0.44H), 8.76-8.83 (m, 1H), and 7.68-7.90 (m, 3H), 7.25-7.45 (m, 2H), 7.0-7.20 (m, 1H), 3.44 (S, 6H).
Synthesizing of embodiment 10 N-methyl-N-cyclopentyl-N '-[2,2-two (2-pyridyl)-1-azepine thiazolinyl]-thiocarbamide
Make from two (2-pyridyl) imines and N-methyl-N-cyclopentyl-N '-thiosemicarbazide as embodiment 7,75% productive rate shows that through the detection of high performance liquid phase chromaticness combined instrument purity is higher than 95%, and mass-to-charge ratio is 340.0[M+1].
Embodiment 11 N, N-dimethyl-N '-[2-(4-trifluoromethyl-phenyl)-2-(2-thienyl)-1-azepine thiazolinyl]-thiocarbamide synthetic
As embodiment 7 from 2-(4-trifluoromethyl-phenyl)-2-(2-thienyl) imines and N, N-dimethyl-N '-thiosemicarbazide makes, 77% productive rate, fusing point 102-103 ℃. show that through the detection of high performance liquid phase chromaticness combined instrument purity is higher than 95%, mass-to-charge ratio is 358[M+1] .300 million nuclear-magnetism results are as follows: 3.19-3.39ppm (3s, 6H), and 6.74-8.25 (m, 7H).

Claims (6)

1. the synthetic method of a (thiosemicarbazone) compound is characterized in that this method comprises the following steps:
1) prepare amino monothioester: organic amine and dithiocarbonic anhydride, sodium chloroacetate in 0～50 ℃ of reaction 2-40 hour, are that 1-4 generates amino monothioester through being acidified to pH in aqueous sodium hydroxide solution;
2) preparation thiosemicarbazide: the product of hydrazine hydrate and step 1 in 45-100 ℃ of reaction 2-20 hour, generates thiosemicarbazide in aqueous sodium hydroxide solution;
3) preparation imines: the imines that heterocyclic aryl replaces can pass through corresponding Grignard reagent or lithium reagent and the reaction of itrile group compound and obtain, and is directly used in down the step condensation reaction;
4) condensation reaction: the condensation of imines and thiosemicarbazide is under acidic conditions, in ether, methyl tertiary butyl ether, 1,0～50 ℃ of reaction got crude product in 2-40 hour in 2-glycol dimethyl ether, methylene dichloride, ethyl acetate or the tetrahydrofuran solvent, and crude product obtains the thiosemicarbazone compound with the organic solvent recrystallizing and refining.
2. the synthetic method of a kind of (thiosemicarbazone) compound according to claim 1 is characterized in that the molar ratio of the middle organic amine of wherein said step (1) and dithiocarbonic anhydride, sodium chloroacetate and sodium hydroxide is 1:0.9-1.5:0.9-1.5:1.0-2.0.
3. the synthetic method of a kind of (thiosemicarbazone) compound according to claim 1, it is characterized in that the middle hydrazine hydrate of wherein said step (2) and the product of step 1 and the molar ratio of sodium hydroxide are 1:0.5-2:0.5-2, crude product organic solvent recrystallizing and refining, this organic solvent are methyl alcohol, ethanol, methylene dichloride, sherwood oil or ethyl acetate.
4. the synthetic method of a kind of (thiosemicarbazone) compound according to claim 1, it is characterized in that wherein said step (3) reaction is at ether, methyl tertiary butyl ether, 1, carry out in 2-glycol dimethyl ether or the tetrahydrofuran solvent, temperature of reaction is-50～60 ℃; The mol ratio of Grignard reagent or lithium reagent and itrile group compound is 1:0.7-1.5; Reaction mixture is handled through ammonium chloride, ammonium sulfate, ammonium acetate or the ammonium formiate aqueous solution, behind methylene dichloride, sherwood oil or ethyl acetate extraction, concentrate again crude product.
5. the method for condensing of a (thiosemicarbazone) compound, it is characterized in that this method is at ether, methyl tertiary butyl ether, 1, in 2-glycol dimethyl ether, methylene dichloride, ethyl acetate or the tetrahydrofuran solvent, with imines and thiosemicarbazide, carry out condensation in 2-40 hour in 0～50 ℃ of reaction and make crude product, obtain (thiosemicarbazone) compound with the organic solvent crystallization then.
6. the synthetic method of a kind of (thiosemicarbazone) compound according to claim 5, the mol ratio that it is characterized in that wherein said imines and thiosemicarbazide is 1:0.7-2; Imines is 1:0-1.2 with the mol ratio of acid, and acid is exsiccant hydrogenchloride, acetic acid or phenylformic acid; The organic solvent of crude product during with the organic solvent recrystallizing and refining is included as methyl alcohol, ethanol, methylene dichloride, ethyl acetate, tetrahydrofuran (THF) or their mixture.
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EP2318406B1 (en) 2008-07-17 2016-01-27 Critical Outcome Technologies, Inc. Thiosemicarbazone inhibitor compounds and cancer treatment methods
EP2552915B1 (en) 2010-04-01 2017-07-19 Critical Outcome Technologies Inc. Compounds for the treatment of hiv
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CN104177288B (en) * 2013-05-23 2020-05-01 中国人民解放军军事医学科学院毒物药物研究所 Selenourea derivatives, pharmaceutical compositions and uses thereof

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