CN101643450B - Synthesis method for multi substituted 2, 3-dihydro-4(1H)-pyrimidin thionone - Google Patents
Synthesis method for multi substituted 2, 3-dihydro-4(1H)-pyrimidin thionone Download PDFInfo
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- CN101643450B CN101643450B CN 200910092120 CN200910092120A CN101643450B CN 101643450 B CN101643450 B CN 101643450B CN 200910092120 CN200910092120 CN 200910092120 CN 200910092120 A CN200910092120 A CN 200910092120A CN 101643450 B CN101643450 B CN 101643450B
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- NKUBPSGHXRYOAC-UHFFFAOYSA-N CC(C)N(C(C)(C)N1)C=C(c2c[s]cc2)C1=S Chemical compound CC(C)N(C(C)(C)N1)C=C(c2c[s]cc2)C1=S NKUBPSGHXRYOAC-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention discloses a synthesis method for multi substituted 2, 3-dihydro-4(1H)-pyrimidin thionone, belonging to the organic synthesis field. The method comprises the following steps of: (a) reacting end hydrocarbon compound and hydrocarbyl metal compound in ether solvent; reacting temperature being between the freezing point of the solvent and zero DEG C; (b) adding sulphur simple substance to continue the reaction and naturally warming up to the room temperature; (c) adding carbodiimide and rising the reaction temperature to be 60-100 DEG C; (6) postprocessing reaction liquid to obtain multi substituted 2, 3-dihydro-4(1H)-pyrimidin thionone. The method uses the end hydrocarbon compound and the carbodiimide to prepare 2, 3-dihydro-4(1H)-pyrimidin thionone derivative, has higher yield, is scientific and reasonable, has easily obtained raw materials, and has wide application range and high separation yield; and experimental facilities and operation are simple and practicable and convenient for being further developed and applied.
Description
Technical field
The present invention relates to have multiple substituent 2, the universal synthesis method of 3-dihydro-4 (1H)-pyrimidine thioketone derivative belongs to the organic synthesis field.
Background technology
Have multiple substituently 2,3-dihydro-pyrimidine thioketone derivative is the important synthetic precursor of medicine, is widely used in synthetic uracil medicine, and this compounds is also important organic synthesis molecule simultaneously.At present bibliographical information mostly is polysubstituted 2, the synthetic method of 3-dihydro-2 (1H)-pyrimidine thioketone, and the synthetic method of 2,3-dihydro-4 (1H)-pyrimidine thioketone derivative only has the only a few bibliographical information.Document provides in synthetic method, and the synthetic difficulty of starting raw material is large.The invention provides a kind of method of synthesizing from general industrial chemicals, efficient is high, and cost is low, compared with existing method, has larger application prospect and value.
Summary of the invention
The purpose of this invention is to provide a kind of synthetic have multiple substituent 2, the universal method of 3-dihydro-4 (1H)-pyrimidine thioketone derivative.Technical scheme of the present invention is as follows:
A kind of synthetic polysubstituted 2, the method for 3-dihydro-4 (1H)-pyrimidine thioketone derivative comprises the following steps:
A) the end hydrocarbon compound shown in formula I and alkide (RM) are reacted in ether solvent, temperature of reaction is between the zero pour of described solvent and 0 ℃;
B) add sulphur simple substance to continue reaction, naturally be warming up to room temperature;
C) add the carbodiimide shown in formula II, temperature of reaction is risen to 60-100 ℃;
D) reaction solution obtains polysubstituted 2 shown in formula III, 3-dihydro-4 (1H)-pyrimidine thioketone through aftertreatment.
Its primitive reaction formula is as follows:
Wherein:
R
1And R
2Can be the same or different, independently of one another expression:
Carbonatoms is 1-12 or more alkyl, such as: methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-..., undecyl, dodecyl, tridecyl ..., octadecyl etc., more preferably C1-6 alkyl, more preferably C1-4 alkyl;
Carbonatoms is the cycloalkyl of 3-6, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;
Carbonatoms is the aryl of 6-12, such as phenyl, xenyl, naphthyl etc.;
Or carbonatoms is the heterocyclic aryl of 2-5, such as thienyl, thiazolyl, pyridyl etc.
Above-mentioned group can be substituted base and replace, and described substituting group can be common C1-4 alkyl or alkoxyl group, C4-6 cycloalkyl, halogen atom (F, Cl, Br, I), cyano group, nitro etc.
Especially, work as R
1Expression is during phenyl, and between its substituting group must be positioned at, position or contraposition, can not be the ortho position, the alkyl that replaces as contraposition, a position, alkoxyl group, halogen atom etc.
R
3And R
4Can be the same or different, independently of one another expression:
Hydrogen;
Carbonatoms is 1-12 or more alkyl, such as: methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-..., undecyl, dodecyl, tridecyl ..., octadecyl etc., more preferably C1-6 alkyl, more preferably C1-4 alkyl;
Carbonatoms is the cycloalkyl of 3-6, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;
Carbonatoms is the aryl of 6-12, such as phenyl, xenyl, naphthyl etc.;
Or carbonatoms is the heterocyclic aryl of 2-5, such as thienyl, thiazolyl, pyridyl etc.
Above-mentioned group can be substituted base and replace, and described substituting group can be common C1-4 alkyl or alkoxyl group, C4-6 cycloalkyl, halogen atom (F, Cl, Br, I), cyano group, nitro etc.
R
3And R
4Also can Cheng Huan, the ring carbon number is 4-6, as shown in embodiment 1 formula III a.
The preferred n-Butyl Lithium of alkide RM used in the present invention or tert-butyl lithium, useful commercial reagent need not special processing.
Ether solvent used in the present invention can be alkyl oxide, aryl oxide or cyclic ethers, can be a kind of ether, can be also the mixture of multiple ether, ether solvent commonly used such as ether, tetrahydrofuran (THF), methyltetrahydrofuran etc.This ether solvent useful commercial reagent is back to mazarine through sodium-benzophenone before using and steams and get final product.
The mol ratio preferable range of various reaction raw materials of the present invention or reagent is as shown in table 1:
The preferred molar ratio of the various reaction raw materials of table 1. or reagent
| Raw material or reagent | Terminal alkyne compound | Alkide | Ether solvent | S 8 | Carbodiimide |
| Molar equivalent | 1-1.2 | 1-1.2 | Arbitrarily | 0.125-0.15 | 1 |
The ratio of the inventive method opposite end hydrocarbon compound and ether solvent is not particularly limited, as long as can make the reaction solution uniform stirring, the end hydrocarbon compound of preferred 1mmol is dissolved in volume greater than the ether solvent of 2mL.
It is how much slightly different according to different raw materials that the inventive method respectively goes on foot the reaction times, detects to disappear to be as the criterion general 2-3 hour with raw material.
Step c of the present invention can adopt oil bath (for example silicone oil, paraffin wet goods) or other modes to heat, as long as maintain temperature of reaction.
Usually make with the following method reaction product is carried out aftertreatment: add entry or neutrality, weakly alkaline aqueous solution cancellation, water repeatedly extracts with organic solvent, merge organic phase, wash with saturated nacl aqueous solution, filter after adding desiccant dryness in the backward organic phase of separatory, the filtrate concentration process can adopt the methods such as air distillation, underpressure distillation, and is for example concentrated with Rotary Evaporators.
In order to obtain more highly purified product, preferably the product after aftertreatment is carried out purifying, described purge process can be made eluent with the solvent of certain polarity, and the chromatographic column separation gets final product.Selected eluent has different according to the opposed polarity of product.Generally, to select volume ratio be sherwood oil to eluent: methylene dichloride=2: 1 also adds the mixed solvent of 3% triethylamine.The chromatographic column of using silicagel column as commonly used in the laboratory or high performance liquid chromatography etc.
The present invention utilizes end hydrocarbon compound and carbodiimide to prepare 2,3-dihydro-4 (1H)-pyrimidine thioketone derivative, productive rate is higher, and synthetic method is scientific and reasonable, thereby provide one synthetic have multiple substituent 2, the universal method of 3-dihydro-4 (1H)-pyrimidine thioketone derivative.The method raw material is easy to get, and is applied widely, high isolated yield, and experimental installation and operation is simple is convenient to further Application and Development.
Embodiment
Further describe the present invention below in conjunction with embodiment, but the scope that does not limit the present invention in any way.
Embodiment 1---preparation formula IIIa (R
1=Ph, R
2=Cy, R
3+ R
4=Cy) compound:
Add the 1mmol phenylacetylene in the reaction tubes of the 20mL that the 2ml ether is housed under nitrogen protection, adopt dry ice-propanone to bathe temperature of reaction is constant in-78 ℃, drip the 1mmol n-Butyl Lithium, add afterreaction half an hour, add 0.125mmol S
8, naturally be warming up to 25 ℃, magnetic agitation reaction two hours.Add 1mmolN, N '-dicyclohexylcarbodiimide rises to 80 ℃ of reactions six hours.Add the shrend reaction of going out, water dichloromethane extraction three times, merge organic phase, wash with saturated nacl aqueous solution, add anhydrous magnesium sulfate in the backward organic phase of separatory, dry 30 minutes, normal pressure filters, filtrate is concentrated, and the silicagel column decolouring separates, and uses sherwood oil: methylene dichloride=2: 1 and the mixed solvent that adds 3% (weight percent) triethylamine are as eluent, obtain pyrimidine thioketone derivative 1-cyclohexyl-3-phenyl-4-sulfo--1,5-diaza-spiro [5.5] 10 one-2-alkene 252mg (purity＞98%, yellow solid), isolated yield 74%.The nuclear magnetic data of this compound is as follows:
1HNMR (300MHz, CDCl
3, Me
4Si, 25 ℃): δ=1.32-1.87 (m, 18H, CH
2), 2.26-2.32 (m, 2H, CH
2), 3.24-3.33 (m, 1H, CH), 6.88 (s, 1H, CH), 6.88-6.99 (m, 1H, CH), 7.30-7.34 (m, 3H, CH), 7.47-7.49 (m, 1H, CH), 7.48 (br, 1H, NH);
13C NMR (75MHz, CDCl
3, Me
4Si, 25 ℃): δ=21.12 (2CH
2), 24.44 (1CH
2), 24.88 (1CH
2), 25.86 (2CH
2), 32.58 (2CH
2), 34.69 (2CH
2), 55.57 (1CH), 73.46 (1quat.C), 113.42 (1quat.C), 126.04 (1CH), 127.60 (2CH), 129.67 (2CH), 138.44 (1quat.C), 138.66 (1CH), 185.19 (1quat.C).
Embodiment 2---preparation formula IIIb (R
1=OMe, R
2=
iPr, R
3=R
4=Me) compound:
Add 1mmol 4-methoxyl group-phenylacetylene in the reaction tubes of the 20mL that the 3ml tetrahydrofuran (THF) is housed under nitrogen protection, drip n-Butyl Lithiums at-78 ℃, add afterreaction half an hour, add 0.15mmol S
8, be warming up to 25 ℃ of left and right, magnetic agitation reaction two hours.Add 1mmol N, N '-DIC rises to 100 ℃ of reactions four hours.Add the shrend reaction of going out under zero degree, water dichloromethane extraction three times, merge organic phase, wash with saturated nacl aqueous solution, add anhydrous magnesium sulfate in the backward organic phase of separatory, dry 30 minutes, normal pressure filters, and filtrate is concentrated, and the silicagel column decolouring separates, use sherwood oil: methylene dichloride=2: 1 and the mixed solvent that adds 3% triethylamine are as eluent, obtain straight product 1-sec.-propyl-2,2-dimethyl-5-(4-methoxyl group-phenyl)-2,3-dihydro-4 (1H)-pyrimidine thioketone 0.191g (purity＞98%, yellow solid), isolated yield 66%.The nuclear magnetic data of this compound is as follows:
1H NMR (300MHz, CDCl
3, Me
4Si, 25 ℃): δ=1.30 (d, J=6.9Hz, 6H, CH
3), 1.60 (s, 6H, CH
3), 3.62-3.71 (m, 1H, CH), 3.81 (s, CH
3), 6.78 (s, CH), 6.88 (d, J=8.7Hz, 2H, CH), 7.38 (d, J=8.7Hz, 2H, CH), 7.59 (br, 1H, NH);
13C NMR (75 MHz, CDCl
3, Me
4Si, 25 ℃): δ=23.96 (2CH
3), 25.88 (2CH
3), 47.68 (1CH), 55.21 (1CH
3), 72.29 (1quat.C), 112.96 (1quat.C), 113.20 (1CH), 130.98 (1CH), 131.05 (1quat.C), 137.36 (1CH), 158.12 (1quat.C), 185.99 (1quat.C).
Embodiment 3---preparation formula IIIc (R
1=Pr, R
2=
iPr, R
3=R
4=Me) compound:
With embodiment 2, aftertreatment is identical substantially for synthetic route.This synthetic raw material that sets out is the 1-pentyne of 1.2mmol, obtains straight product 1-sec.-propyl-2,2-dimethyl-5-n-propyl-2,3-dihydro-4 (1H)-pyrimidine thioketone 187mg (purity＞98%, yellow solid), isolated yield 83%.The nuclear magnetic data of this compound is as follows:
1H NMR (300MHz, CDCl
3, Me
4Si, 25 ℃): δ=0.91 (t, J=7.2Hz, 3H, CH
3), 1.27 (d, J=6.6Hz, 6H, CH
3), 1.48-1.58 (m, 2H, CH
2), 1.54 (s, 6H, CH
3), 2.37-2.49 (m, 2H, CH
2), 3.58-3.67 (m, 1H, CH), 6.54 (s, 3H, CH), 8.03 (br, 1H, NH);
13C NMR (75MHz, CDCl
3, Me
4Si, 25 ℃): δ=13.30 (1CH
3), 22.80 (1CH
2), 23.62 (2CH
3), 24.95 (2CH
3), 32.72 (1CH
2), 46.88 (1CH), 71.50 (1quat.C), 110.05 (1quat.C), 135.98 (1CH), 185.65 (1quat.C).
Embodiment 4---preparation formula IIId (R
1=Thiophenyl, R
2=
iPr, R
3=R
4=Me) compound:
With embodiment 2, aftertreatment is identical substantially for synthetic route.This synthetic raw material that sets out is 3-thiophene acetylene, uses the 1.2mmol tert-butyl lithium.Obtain straight product 141mg (purity＞98%, yellow solid), isolated yield 53%.The nuclear magnetic data of this compound is as follows:
1H NMR (300MHz, CDCl
3, Me
4Si, 25 ℃): δ=1.32 (d, J=6.9Hz, 6H, CH
3), 1.60 (s, 6H, CH
3), 3.64-3.73 (m, 1H, CH), 6.91 (s, CH), 7.26 (br, 1H, CH), 7.38-7.40 (m, 2H, CH), 7.52 (br, 1H, NH);
13C NMR (75MHz, CDCl
3, Me
4Si, 25 ℃): δ=24.01 (2CH
3), 25.95 (2CH
3), 47.90 (1CH), 72.22 (1quat.C), 121.06 (1CH), 123.81 (1CH), 129.29 (1CH), 129.32 (1quat.C), 137.70 (1CH), 138.57 (1quat.C), 185.52 (1quat.C).
Embodiment 5---preparation formula IIIe (R
1=Ph, R
2=Ph, R
3=H, R
4=Ph) compound:
With embodiment 2, aftertreatment is identical substantially for synthetic route.This synthetic carbodiimide that uses is N-phenyl-N-3-thiophene acetylene, and the straight product that obtains at last is 140mg (purity＞98%, yellow solid), isolated yield 53%.
Claims (7)
- One kind polysubstituted 2, the synthetic method of 3-dihydro-4 (1H)-pyrimidine thioketone is characterized in that, comprises the following steps:A) the end hydrocarbon compound shown in formula I and alkide are reacted in ether solvent, temperature of reaction is between the zero pour of described solvent and 0 ℃;B) add sulphur simple substance to continue reaction, naturally be warming up to room temperature;C) add the carbodiimide shown in formula II, temperature of reaction is risen to 60-100 ℃;D) reaction solution obtains polysubstituted 2 shown in formula III through aftertreatment, 3-dihydro-4 (1H)-pyrimidine thioketone,
Wherein, R 1And R 2Expression independently of one another replaces or non-substituted C 1-12Alkyl, C 3-6Cycloalkyl, C 6-12Aryl or C 2-12Heterocyclic aryl; R 3And R 4Represent independently of one another hydrogen, replacement or non-substituted C 1-12Alkyl, C 6-12Aryl or C 2-5Heterocyclic aryl, R 3And R 4Can become C 4-6Ring; Described substituting group is C1-4 alkyl or alkoxyl group, C4-6 cycloalkyl, halogen atom, cyano group and nitro. - 2. synthetic method as claimed in claim 1, is characterized in that, described alkide is n-Butyl Lithium or tert-butyl lithium.
- 3. synthetic method as claimed in claim 1, is characterized in that, described ether solvent is selected from: alkyl oxide, aryl oxide or cyclic ethers or their mixture.
- 4. synthetic method as claimed in claim 3, is characterized in that, described ether solvent is ether, tetrahydrofuran (THF), methyltetrahydrofuran or their mixture.
- 5. synthetic method as claimed in claim 1, is characterized in that, described end hydrocarbon compound, and alkide, the molar equivalent of sulphur simple substance and carbodiimide is than being (1-1.2): (1-1.2): (0.125-0.15): 1.
- 6. synthetic method as claimed in claim 1, it is characterized in that, described aftertreatment comprises: add entry or neutrality, weak alkaline aqueous solution cancellation, water repeatedly extracts with organic solvent, merge organic phase, with saturated nacl aqueous solution washing, filter concentrated filtrate after adding desiccant dryness in the backward organic phase of separatory.
- 7. synthetic method as claimed in claim 1, is characterized in that, by chromatographic column separation and purification product, eluent is that volume ratio is sherwood oil and the methylene dichloride mixed solvent of 2:1, and wherein adding weight percent is 3% triethylamine.
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Non-Patent Citations (6)
| Title |
|---|
| C. Oliver Kappe.Biologically active dihydropyrimidones of the Biginelli-type — a literature survey.《European Journal of Medicinal Chemistry》.2000,第35卷第1043-1052页. * |
| José Barluenga, et al..Cycloaddition of Unactivated 2-Aza-1,3-dienes with Heterocumulenes: A Convenient Route to the Synthesis of 1,3-Difunctionalized Compounds.《J. CHEM. SOC. PERKIN TRANS. I》.1988,第1739-1744页. * |
| JoséBarluenga et al..Cycloaddition of Unactivated 2-Aza-1 |
| Mithun Ashok, et al..Convenient one pot synthesis of some novel derivatives of thiazolo[2,3-b]dihydropyrimidinone possessing 4-methylthiophenyl moiety and evaluation of their antibacterial and antifungal activities.《European Journal of Medicinal Chemistry》.2006,第42卷第380-385页. * |
| MithunAshok et al..Convenient one pot synthesis of some novel derivatives of thiazolo[2 |
| Thomas U. Mayer, et al..Small Molecule Inhibitor of Mitotic Spindle Bipolarity Identified in a Phenotype-Based Screen.《SCIENCE》.1999,第286卷第971-974页. * |
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