CN106749173A - A kind of preparation method of pyrimidine bipyridyliumses compound - Google Patents
A kind of preparation method of pyrimidine bipyridyliumses compound Download PDFInfo
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- CN106749173A CN106749173A CN201611050403.2A CN201611050403A CN106749173A CN 106749173 A CN106749173 A CN 106749173A CN 201611050403 A CN201611050403 A CN 201611050403A CN 106749173 A CN106749173 A CN 106749173A
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- Prior art keywords
- pyridine
- pyrimidine
- bases
- amine
- cyclohexanol
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The invention belongs to organic synthesis field, specifically related to a kind of preparation method of pyrimidine bipyridyliumses compound, including A, the synthesis of 2 (methyl mercapto) 5 (base of pyridine 2) alcohol of pyrimidine 4, B, the synthesis of 4 chlorine 2 (methyl mercapto) 5 (base of pyridine 2) pyrimidines, C, (1R, 4R) the synthesis of 4 ((2 (methyl mercapto) 5 (base of the pyridine 2) base of pyrimidine 4) amine) cyclohexanol, D, (1R, 4R) four steps of synthesis of 4 ((2 (butylamine) 5 (base of the pyridine 2) base of pyrimidine 4) amine) cyclohexanol；The process route is using cyclization, chloro, halogen substitution, methyl mercapto substitution four-step reaction synthesis (1R, 4R) 4 ((2 (butylamine) 5 (base of the pyridine 2) base of pyrimidine 4) amine) cyclohexanol, synthesis step is few, easy to operate, equipment requirement is low, each step yield is higher.With process is simple, it is easy to the advantage of industrial-scale production and low cost.
Description
Technical field
Organic chemistry.
Background technology
It is specifically related to a kind of（One kind (1R, 4R) -4- ((2- (butylamine) -5- (pyridine -2- bases)-pyrimidine-4-yl) amine)
The synthetic method of cyclohexyl alcohol.
The content of the invention
It is specifically related to a kind of（One kind (1R, 4R) -4- ((2- (butylamine) -5- (pyridine -2- bases)-pyrimidine-4-yl) amine)
The synthetic method of cyclohexyl alcohol, including A, 2- (methyl mercapto) -5- (pyridine -2- bases) pyrimidine -4- alcohol synthesis, the chloro- 2- (first of B, 4-
Sulfenyl) -5- (pyridine -2- bases) pyrimidine synthesis, C, (1R, 4R) -4- ((2- (methyl mercapto) -5- (pyridine -2- bases)-pyrimidine -4-
Base) amine) cyclohexanol synthesis, D, (1R, 4R) -4- ((2- (butylamine) -5- (pyridine -2- bases)-pyrimidine-4-yl) amine) hexamethylene
Four steps of synthesis of alcohol；The process route using cyclization, chloro, halogen substitution, methyl mercapto substitution four-step reaction synthesis (1R,
4R) -4- ((2- (butylamine) -5- (pyridine -2- bases)-pyrimidine-4-yl) amine) cyclohexanol, synthesis step is few, easy to operate, equipment
It is required that low, each step yield is higher.With process is simple, it is easy to the advantage of industrial-scale production and low cost.
Fig. 1 synthetic technology route maps.
Claims (12)
1. the preparation method of one kind (trans) -4- ((2- (butylamine) -5- (pyridine -2- bases)-pyrimidine-4-yl) amine) cyclohexanol,
Characterized in that, its preparation process is comprised the following steps：
The synthesis of A, 2- (methyl mercapto) -5- (pyridine -2- bases) pyrimidine -4- alcohol：Methyl -3- ethyoxyls -2- (pyridine -2- bases) third
Olefin(e) acid liposoluble in solvent in the basic conditions with methyl isothiourea occur ring-closure reaction, obtain 2- (methyl mercapto) -5- (pyridine -
2- yls) pyrimidine -4- alcohol；
The synthesis of B, 4- chloro- 2- (methyl mercapto) -5- (pyridine -2- bases) pyrimidine：By above-mentioned 2- (methyl mercapto) -5- (pyridine -2- bases)
Pyrimidine -4- alcohol reacts with chlorinating agent, obtains hydroxyl chloro-product 4- chloro- 2- (methyl mercapto) -5- (pyridine -2- bases) pyrimidine；
The synthesis of C, (trans) -4- ((2- (methyl mercapto) -5- (pyridine -2- bases)-pyrimidine-4-yl) amine) cyclohexanol：By above-mentioned 4-
Chloro- 2- (methyl mercapto) -5- (pyridine -2- bases) pyrimidines are dissolved in solvent with (trans) -4- amido cyclohexanol, are sent out in the presence of alkali
Raw substitution reaction, obtains (1R, 4R) -4- ((2- (methyl mercapto) -5- (pyridine -2- bases)-pyrimidine-4-yl) amine) cyclohexanol；
The synthesis of D, (trans) -4- ((2- (butylamine) -5- (pyridine -2- bases)-pyrimidine-4-yl) amine) cyclohexanol：Will be above-mentioned (anti-
Formula) -4- ((2- (methyl mercapto) -5- (pyridine -2- bases)-pyrimidine-4-yl) amine) cyclohexanol is dissolved in solvent, generated under oxidizing condition
Intermediate sulfoxide（Sulfone）, be subsequently added n-butylamine occur substitution reaction, obtain (trans) -4- ((2- (butylamine) -5- (pyridine -
2- yls)-pyrimidine-4-yl) amine) cyclohexanol.
2. one kind (trans) -4- ((2- (butylamine) -5- (pyridine -2- bases)-pyrimidine-4-yl) according to claim 1
Amine) cyclohexanol preparation method, it is characterised in that：Solvent described in step A is selected from ethanol, methyl alcohol, water, n-butanol, N, N- bis-
One or more in NMF, dimethyl sulfoxide；Alkali in the step A is selected from triethylamine, diisopropyl ethyl amine, carbon
Sour potassium, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide, cesium carbonate, cesium fluoride, sodium methoxide.
3. one kind (trans) -4- ((2- (butylamine) -5- (pyridine -2- bases)-pyrimidine-4-yl) according to claim 1
Amine) cyclohexanol preparation method, it is characterised in that：Methyl -3- ethyoxyls -2- (pyridine -2- bases) acrylic acid described in step A
The ratio between mole of fat and methyl isothiourea is 1:1.05~5；Methyl -3- ethyoxyls -2- (pyridine -2- bases) acrylates with
The ratio between mole of alkali is 1:1.05~5；Reaction temperature is in room temperature to solvent reflux temperature；Reaction time range 5-75 hours.
4. one kind (trans) -4- ((2- (butylamine) -5- (pyridine -2- bases)-pyrimidine-4-yl) according to claim 1
Amine) cyclohexanol preparation method, it is characterised in that：Solvent described in step B is selected from chloralkane, sulfoxide type solvents, aromatic hydrocarbons
One or more in solvent and amide solvent；Chlorinating agent described in step B is selected from POCl3, phosphorus trichloride, pentachloro-
Change phosphorus, thionyl chloride, oxalyl chloride；Reaction temperature 25oC~150 oC；Reaction time range 5-72 hours.
5. one kind (trans) -4- ((2- (butylamine) -5- (pyridine -2- bases)-pyrimidine-4-yl) according to claim 1
Amine) cyclohexanol preparation method, it is characterised in that：2- (methyl mercapto) -5- (pyridine -2- bases) pyrimidine -4- alcohol described in step B is anti-
It is 0.1~2 mol/L to answer concentration；The ratio between mole of 2- (methyl mercapto) -5- (pyridine -2- bases) pyrimidine -4- alcohol and chlorinating agent
It is 1:1.05~5.
6. one kind (trans) -4- ((2- (butylamine) -5- (pyridine -2- bases)-pyrimidine-4-yl) according to claim 1
Amine) cyclohexanol preparation method, it is characterised in that：Solvent described in step C is selected from halogenated hydrocarbon solvent, alcohols solvent, aromatic hydrocarbons
One or more in class solvent and esters solvent；Alkali described in step C is selected from triethylamine, diisopropyl ethyl amine, carbon
Sour potassium, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide, cesium carbonate, cesium fluoride, sodium methoxide；Reaction temperature room temperature is to solvent refluxing temperature
Degree；Reaction time range 1-30 hours.
7. one kind (trans) -4- ((2- (butylamine) -5- (pyridine -2- bases)-pyrimidine-4-yl) according to claim 1
Amine) cyclohexanol preparation method, it is characterised in that：4- chloro- 2- (methyl mercapto) -5- (pyridine -2- bases) pyrimidines described in step C with
The ratio between (trans) -4- amido cyclohexanol moles are 1:1.2~5；4- chloro- 2- (methyl mercapto) -5- (pyridine -2- bases) pyrimidines and alkali
The ratio between mole is 1:1.2~5；The chloro- 2- of 4- (methyl mercapto) -5- (pyridine -2- bases) the pyrimidine reaction density is 0.1~2
mol/L。
8. one kind (trans) -4- ((2- (butylamine) -5- (pyridine -2- bases)-pyrimidine-4-yl) according to claim 1
Amine) cyclohexanol preparation method, it is characterised in that：The step D includes two-step reaction：
（1）The dissolving of (trans) -4- ((2- (methyl mercapto) -5- (pyridine -2- bases)-pyrimidine-4-yl) amine) cyclohexanol exists in a solvent
There is oxidation reaction in the presence of oxidant, obtain corresponding sulfoxide（Sulfone）Intermediate；
（2）Sulfoxide（Sulfone）With n-butylamine in the presence of alkali, there is substitution reaction and obtain (trans) -4- ((2- (butylamine) -5-
(pyridine -2- bases)-pyrimidine-4-yl) amine) cyclohexanol.
9. one kind (trans) -4- ((2- (butylamine) -5- (pyridine -2- bases)-pyrimidine-4-yl) according to claim 1
Amine) cyclohexanol preparation method, it is characterised in that：The step of step D（1）Solvent to be selected from alcohols solvent, sulfoxide type molten
Agent and amide solvent；The step of step D（1）Oxidant be selected from metachloroperbenzoic acid, Oxone, IBX, hydrogen peroxide；
Reaction temperature 25oC~100oC；0.5~6 hour reaction time.
10. one kind (trans) -4- ((2- (butylamine) -5- (pyridine -2- bases)-pyrimidine-4-yl) according to claim 1
Amine) cyclohexanol preparation method, it is characterised in that：The step of step D（1）(trans) -4- ((2- (methyl mercapto) -5- (pyrroles
Pyridine -2- bases)-pyrimidine-4-yl) amine) the ratio between the mole of cyclohexanol and oxidant is 1:1.5~5；(trans)-the 4- ((2-
(methyl mercapto) -5- (pyridine -2- bases)-pyrimidine-4-yl) amine) cyclohexanol reaction density be 0.1~2 mol/L.
11. one kind (trans) -4- ((2- (butylamine) -5- (pyridine -2- bases)-pyrimidine-4-yl) according to claim 1
Amine) cyclohexanol preparation method, it is characterised in that：The step of step D（2）Solvent to be selected from alcohols solvent, sulfoxide type molten
Agent and amide solvent；The step of step D（2）Alkali be selected from be selected from triethylamine, diisopropyl ethyl amine, potassium carbonate, carbon
Sour sodium, potassium tert-butoxide, sodium tert-butoxide, cesium carbonate, cesium fluoride, sodium methoxide；Reaction temperature 50oC~150oC；；Reaction time range
1-30 hours.
12. one kind (trans) -4- ((2- (butylamine) -5- (pyridine -2- bases)-pyrimidine-4-yl) according to claim 1
Amine) cyclohexanol preparation method, it is characterised in that：The step of step D（2）(trans) -4- ((2- (methyl mercapto) -5-
(pyridine -2- bases)-pyrimidine-4-yl) amine) the ratio between the mole of cyclohexanol and n-butylamine is 1:1.5~5；(the trans) -4-
The ratio between mole of ((2- (methyl mercapto) -5- (pyridine -2- bases)-pyrimidine-4-yl) amine) cyclohexanol and alkali is 1:1.5~5；It is described
(trans) -4- ((2- (methyl mercapto) -5- (pyridine -2- bases)-pyrimidine-4-yl) amine) cyclohexanol reaction density is 0.1~2 mol/
L。
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1183099A (en) * | 1995-05-03 | 1998-05-27 | 沃尼尔·朗伯公司 | Pyrido (2, 3 -d) pyrimidines for inbibiting protein tyrosine kinase mediated cellular proliferation |
| CN104302627A (en) * | 2012-05-22 | 2015-01-21 | 北卡罗来纳大学教堂山分校 | Pyrimidine compounds for the treatment of cancer |
-
2016
- 2016-11-25 CN CN201611050403.2A patent/CN106749173A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1183099A (en) * | 1995-05-03 | 1998-05-27 | 沃尼尔·朗伯公司 | Pyrido (2, 3 -d) pyrimidines for inbibiting protein tyrosine kinase mediated cellular proliferation |
| CN104302627A (en) * | 2012-05-22 | 2015-01-21 | 北卡罗来纳大学教堂山分校 | Pyrimidine compounds for the treatment of cancer |
Non-Patent Citations (1)
| Title |
|---|
| ZHANG WEIHE等: ""Pseudo-Cyclization through Intramolecular Hydrogen Bond Enables Discovery of Pyridine Substituted Pyrimidines as New Mer Kinase Inhibitors"", 《J. MED. CHEM.》 * |
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