CN102127032A - Method for synthesizing poly-substituted 5-acyl-2-imine thiazoline - Google Patents
Method for synthesizing poly-substituted 5-acyl-2-imine thiazoline Download PDFInfo
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- CN102127032A CN102127032A CN2011100233968A CN201110023396A CN102127032A CN 102127032 A CN102127032 A CN 102127032A CN 2011100233968 A CN2011100233968 A CN 2011100233968A CN 201110023396 A CN201110023396 A CN 201110023396A CN 102127032 A CN102127032 A CN 102127032A
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Abstract
The invention discloses a method for synthesizing poly-substituted 5-acyl-2-imine thiazoline, which belongs to the field of organic synthesis. The method comprises the following steps of: (a) making carbodiimide shown as a formula I react with acyl chloride shown as a formula II in an ether solvent I at the reaction temperature of between 25 DEG C and the boiling point of the ether solvent I; (b) making a terminal alkyne compound shown as a formula III react with an alkyl metal compound in an ether solvent II at the reaction temperature of between the freezing point of the ether solvent II and 0 DEG C, adding a sulfur simple substance for continually reacting and naturally raising the temperature to room temperature; (c) adding reaction liquid obtained in the step (a) into reaction liquid obtained in the step (b) and raising the reaction temperature to 60-100 DEG C; and (d) performing post-treatment on the reaction liquid to obtain the poly-substituted 5-acyl-2-imine thiazoline shown as a formula IV. The reaction formula is shown in the specifications. The method can be applied to the fields of pesticides, medicaments and the like.
Description
Technical field
The present invention relates to have the universal synthesis method of multiple substituent 5-acyl group-2-imines thiazoline derivative, belong to the organic synthesis field.
Background technology
Have multiple substituent 5-acyl group-2-imines thiazoline derivative and in agriculture production, have higher desinsection, antibacterial and weeding activity; secretion that simultaneously can the coordinate plant growth hormone; as promote the activity of taking root of plant cotyledon, be efficient, the environment amenable pesticide molecule of a class.5-acyl group-2-imines thiazoline derivative is lower to the toxicity of human body, so more application is also arranged in medicine, has higher biological activity, and kinase inhibiting activity that it had and platelet aggregation inhibitory activity make it become potential medicine lead compound.In the synthetic method of 5-acyl group-2-imines thiazoline derivative that present document provides, the synthetic difficulty of starting raw material is big, complex operation, and the substrate scope is subjected to bigger restriction.The present invention then provides a kind of and carries out the synthetic method from general industrial chemicals, the efficient height, and cost is low, compared with existent method, has bigger application prospect and value.
Summary of the invention
The purpose of this invention is to provide a kind of synthetic universal method of multiple substituent 5-acyl group-2-imines thiazoline derivative that has.Technical scheme of the present invention is as follows:
The method of a kind of synthetic polysubstituted 5-acyl group-2-imines thiazoline derivative may further comprise the steps:
A) acyl chlorides shown in carbodiimide shown in the formula I and the formula II is reacted in ether solvent one, temperature of reaction is between the boiling point of 25 ℃ and described ether solvent one;
B) terminal alkyne compound shown in the formula III and alkide are reacted in ether solvent two, temperature of reaction is between the zero pour of described ether solvent two and 0 ℃; Add sulphur simple substance and continue reaction, be warming up to room temperature naturally;
C) a) reaction solution is added to b) reaction solution in, temperature of reaction is risen to 60-100 ℃;
D) reaction solution obtains the polysubstituted 5-acyl group-2-imines thiazoline shown in the formula IV through aftertreatment.
The primitive reaction formula of above-mentioned reaction process 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 or the like.
R
3Expression:
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 or the like.
R
4Expression:
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 or the like.
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, promptly ether solvent one and ether solvent two can be alkyl oxide, aryl oxide or cyclic ethers, can be a kind of ether, also can be the mixtures of multiple ether, ether solvent commonly used is ether, tetrahydrofuran (THF), methyltetrahydrofuran etc. for example.This ether solvent useful commercial reagent is back to mazarine through sodium-benzophenone before using and steams and get final product.The moiety of described ether solvent one and ether solvent two can be identical, also can be different, and have no special requirements.
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 various reaction raw materials of table 1. or reagent
| Raw material or reagent | Carbodiimide | Acyl chlorides | Terminal alkyne compound | Alkide | Ether solvent | S 8 |
| Molar equivalent | 1 | 1-1.2 | 1-1.2 | 1-1.2 | Arbitrarily | 0.125-0.15 |
The inventive method is not particularly limited the ratio of terminal alkyne compound and ether solvent, as long as reaction solution is evenly stirred, the terminal alkyne compound of preferred 1mmol is dissolved in the ether solvent of volume greater than 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 with raw material to be as the criterion general 10-12 hour.
Steps d 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.
The normally simple reaction solution of aftertreatment concentrates, and the reaction solution concentration process can adopt methods such as air distillation, underpressure distillation, or for example concentrates with Rotary Evaporators.
In order to obtain more highly purified product, preferably the product after the aftertreatment is carried out purifying, described purge process can be made eluent with certain polar solvent, and the chromatographic column separation gets final product.Selected eluent has certain difference according to the opposed polarity of product.Generally speaking, to select volume ratio for use be sherwood oil to eluent: methylene dichloride=1: 1.The chromatographic column of using such as laboratory silicagel column commonly used or high performance liquid chromatography etc.
The present invention utilizes carbodiimide, acyl chlorides, terminal alkyne compound and elemental sulfur to prepare 5-acyl group-2-imines thiazoline derivative; productive rate is higher; synthetic method is scientific and reasonable, thereby provides one synthetic to have a universal method of multiple substituent 5-acyl group-2-imines thiazoline derivative.This 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 IVa (R
1=R
2=
iPr, R
3=4-CF
3-Ph, R
4=Ph) compound:
Under nitrogen protection, in the reaction tubes of the 20mL that the 3mL ether is housed, add 1mmol N, N '-DIC and 1mmol 4-trifluoromethyl benzoyl chloride, 25 ℃ of reaction 48h.Under nitrogen protection, in the reaction tubes of the 20mL that the 2mL ether is housed, add the 1mmol phenylacetylene, it is constant in-78 ℃ with temperature of reaction to adopt dry ice-propanone to bathe, and drips the 1mmol n-Butyl Lithium, adds afterreaction half an hour, adds 0.125mmol S
8, be warming up to 25 ℃ naturally, magnetic agitation reaction two hours.Above-mentioned two kinds of reaction solns are mixed, and 80 ℃ were reacted 10 hours.Reaction solution concentrates, the silicagel column decolouring separates, use sherwood oil: the mixed solvent of methylene dichloride=1: 1 is made eluent, obtain thiazoline derivative 3-sec.-propyl-2-sec.-propyl imido grpup-4-phenyl-2,3-thiazoline-5-thiazolinyl-(4-trifluoromethyl)-benzophenone 355mg (purity＞98%, yellow solid), isolated yield 82%.The nuclear magnetic data of this compound is as follows:
1H NMR (400MHz, CDCl
3, Me
4Si): δ 1.21 (d, J=6.2Hz, 6H, CH
3), 1.44 (d, J=6.8Hz, 6H, CH
3), 3.19 (m, 1H, CH), 3.89 (m, 1H, CH), 6.96-7.20 (m, 10H, CH);
13C NMR (100MHz, CDCl
3, Me
4Si): δ 18.99,22.97,51.21,56.59,112.57,127.24,127.64,128.11,129.30,129.47,129.89,130.71,139.13,150.19,151.24,187.69.
Embodiment 2---preparation formula IVb (R
1=R
2=Cy, R
3=3-MeO-Ph, R
4=3-thienyl) compound:
Under nitrogen protection, in the reaction tubes of the 20mL that the 4mL ether is housed, add 1mmol N, N '-dicyclohexylcarbodiimide and 1.2mmol 3-methoxy benzoyl chloride, 25 ℃ of reaction 48h.Under nitrogen protection, in the reaction tubes of the 20mL that the 3mL tetrahydrofuran (THF) is housed, add 1mmol 3-thienyl acetylene, drip the 1mmol n-Butyl Lithiums, add afterreaction half an hour, add 0.15mmol S at-78 ℃
8, be warming up to about 25 ℃ magnetic agitation reaction two hours.Above-mentioned two kinds of reaction solns are mixed, and 80 ℃ were reacted 10 hours.Reaction solution concentrates, the silicagel column decolouring separates, use sherwood oil: the mixed solvent of methylene dichloride=1: 1 is made eluent, obtain straight product 3-cyclohexyl-2-cyclohexyl imido grpup-4-phenyl-2,3-thiazoline-5-thiazolinyl-(4-methoxyl group)-benzophenone 347mg (purity＞98%, yellow solid), isolated yield 75%.The nuclear magnetic data of this compound is as follows:
1H NMR (400MHz, CDCl
3, Me
4Si): δ 0.83-1.15 (m, 4H, CH
2), 1.37-1.59 (m, 8H, CH
2), 1.71-1.82 (m, 6H, CH
2), 2.17 (s, 3H, CH
3), 2.73-2.80 (m, 2H, CH
2), 2.90-2.96 (m, 1H, CH), 3.43-3.51 (m, 1H, CH), 6.87-7.19 (m, 7H, CH);
13C NMR (75MHz, CDCl
3, Me
4Si): δ 21.42,24.72, and 25.42,26.45,26.49,28.78,33.18,60.08,64.23,114.16,125.22,126.69,127.93 (2CH), 128.68,128.77,130.56,131.30,137.23,139.33,145.55,151.46,188.53.
Embodiment 3---preparation formula IVc (R
1=R
2Cy, R
3=2-thienyl, R
4=4-Me-Ph) compound:
With embodiment 1, aftertreatment is identical substantially for synthetic route.This synthetic raw material that sets out is the 4-methylbenzene acetylene of 1.1mmol, the N of 1mmol, N '-dicyclohexylcarbodiimide, 1.1mmol 2-thiophene acyl chlorides, use the 1mmol n-Butyl Lithium, obtain straight product 3-cyclohexyl-2-cyclohexyl imido grpup-4-(4-methyl)-phenyl-2,3-thiazoline-5-thiazolinyl-(2-thienyl)-ketone 333mg (purity＞98%, yellow solid), isolated yield 72%.The nuclear magnetic data of this compound is as follows:
1H NMR (400MHz, CDCl
3, Me
4Si): δ 0.83-1.80 (m, 18H, CH
2), 2.35 (s, 3H, CH
3), 2.71-2.80 (m, 2H, CH
2), 2.91-2.96 (m, 1H, CH), 3.48-3.56 (m, 1H, CH), 6.82-7.40 (m, 7H, CH);
13C NMR (75MHz, CDCl
3, Me
4Si): δ 21.36,24.24,24.98,25.95,25.99,28.09,32.73,59.17,63.77,108.43,127.00,128.65,128.96,129.21,131.28,131.52,139.27,144.65,150.71,150.75,177.39.
Embodiment 4---preparation formula IVd (R
1=Cy, R
2=Ph, R
3=4-CF
3-Ph, R
4=cyclohexenyl) compound:
With embodiment 1, aftertreatment is identical substantially for synthetic route.This synthetic raw material that sets out is the cyclohexenyl acetylene of 1mmol, the 1-cyclohexyl 3-phenyl carbons diimine of 1mmol, the 4-trifluoromethyl benzoyl chloride of 1mmol, use the 1.2mmol tert-butyl lithium, obtain straight product 316mg (purity＞98%, yellow solid), isolated yield 62%.The nuclear magnetic data of this compound is as follows:
1HNMR (400MHz, CDCl
3, Me
4Si): δ 0.84-2.01 (m, 16H, CH
2), 2.79-2.99 (m, 2H, CH
2), 3.63-3.72 (m, 1H, CH), 5.69 (s, 1H, CH), 7.01-7.62 (m, 9H, CH);
13C NMR (75MHz, CDCl
3, Me
4Si): δ 20.50,21.80, and 24.89,25.10,26.34,26.50,28.18,28.85,28.94,60.48,111.85,120.81,123.64,123.67 (q, J
C-F=270.1Hz), 124.88 (q, J
C-F=3.7Hz), 127.57,128.10,129.56,131.88 (q, J
C-F=32.3Hz), and 135.77,144.05,150.90,153.57,155.73,186.84.
Embodiment 5---preparation formula IVe (R
1=R
2=2-pyridyl, R
3=
nPr, R
4=Ph) compound:
With embodiment 1, aftertreatment is identical substantially for synthetic route.The synthetic raw material that sets out is the phenylacetylene of 1mmol, the N of 1mmol, N '-two (2-pyridyl) carbodiimide, the n-butyryl chloride of 1mmol uses the 1.2mmol n-Butyl Lithium, and the straight product that obtains at last is 269mg (purity＞98%, yellow solid), isolated yield 67%.
Claims (7)
1. the synthetic method of polysubstituted 5-acyl group-2-imines thiazoline is characterized in that, comprises the following steps:
A) acyl chlorides shown in carbodiimide shown in the formula I and the formula II is reacted in ether solvent one, temperature of reaction is between the boiling point of 25 ℃ and described ether solvent one;
B) terminal alkyne compound shown in the formula III and alkide are reacted in ether solvent two, temperature of reaction is between the zero pour of described ether solvent two and 0 ℃; Add sulphur simple substance and continue reaction, be warming up to room temperature naturally;
C) a) reaction solution is added to b) reaction solution in, temperature of reaction is risen to 60-100 ℃;
D) reaction solution obtains the polysubstituted 5-acyl group-2-imines thiazoline shown in the formula IV through aftertreatment;
Wherein, R
1, R
2, R
3And R
4The C of expression replacement independently of one another or non-replacement
1-12Alkyl, C
3-6Cycloalkyl, C
6-12Aryl or C
2-5Heterocyclic aryl.
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 one and ether solvent two are selected from independently of one another: 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 one and ether solvent two are selected from independently of one another: ether, tetrahydrofuran (THF), methyltetrahydrofuran or their mixture.
5. synthetic method as claimed in claim 1 is characterized in that, described carbodiimide, and acyl chlorides, terminal alkyne compound, alkide, the molar equivalent ratio of sulphur simple substance is 1: (1-1.2): (1-1.2): (1-1.2): (0.125-0.15).
6. synthetic method as claimed in claim 1 is characterized in that, described aftertreatment comprises that reaction solution concentrates, and concentration process adopts air distillation, underpressure distillation or evaporates with Rotary Evaporators.
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 1: 1 sherwood oil and a methylene dichloride mixed solvent.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103232406A (en) * | 2013-04-26 | 2013-08-07 | 北京大学 | 1, 3-thiazole derivative |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1097007A (en) * | 1992-12-04 | 1995-01-04 | 住友化学工业株式会社 | Prepare the method for 2-iminothiazoline derivatives and the method for its middle product of preparation |
| WO2007122241A1 (en) * | 2006-04-26 | 2007-11-01 | Glaxo Group Limited | Compounds which potentiate ampa receptor and uses thereof in medicine |
| CN101768134A (en) * | 2009-12-31 | 2010-07-07 | 浙江医药高等专科学校 | 2-imido-3-(substituted phenyl)-4-methyl-5-acetyl-4-thiazoline and synthesis method thereof |
-
2011
- 2011-01-20 CN CN 201110023396 patent/CN102127032B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1097007A (en) * | 1992-12-04 | 1995-01-04 | 住友化学工业株式会社 | Prepare the method for 2-iminothiazoline derivatives and the method for its middle product of preparation |
| WO2007122241A1 (en) * | 2006-04-26 | 2007-11-01 | Glaxo Group Limited | Compounds which potentiate ampa receptor and uses thereof in medicine |
| CN101768134A (en) * | 2009-12-31 | 2010-07-07 | 浙江医药高等专科学校 | 2-imido-3-(substituted phenyl)-4-methyl-5-acetyl-4-thiazoline and synthesis method thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103232406A (en) * | 2013-04-26 | 2013-08-07 | 北京大学 | 1, 3-thiazole derivative |
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