CN103304535A - Azide and preparation method thereof - Google Patents
Azide and preparation method thereof Download PDFInfo
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- CN103304535A CN103304535A CN2013102513642A CN201310251364A CN103304535A CN 103304535 A CN103304535 A CN 103304535A CN 2013102513642 A CN2013102513642 A CN 2013102513642A CN 201310251364 A CN201310251364 A CN 201310251364A CN 103304535 A CN103304535 A CN 103304535A
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Abstract
The invention discloses an azide and a preparation method thereof. The azide (I) can be used as a key raw material for preparing medicines with a 1,2,3-triazole structure, such as ticagrelor. The preparation method for the azide comprises the following step of: performing azidation reaction on an amino compound (II) and an azidation reagent (III) to obtain the azide (I). The preparation method is moderate in conditions, safe and environmentally-friendly, high in chemical yield, and especially capable of keeping the original absolute configuration and chiral purity.
Description
Technical field
The invention belongs to organic synthesis highway route design and bulk drug thereof and intermediate preparation technical field, particularly a kind of new triazo-compound and preparation method thereof.
Background technology
1,2,3-triazole is important three nitrogen virtue heterocycle, owing to easily form hydrogen bond, coordinate bond etc., can bring into play multiple non-covalent interaction, thereby be widely used in polytype functional moleculars such as constructing macromolecular material, new catalyst, medicine and supramolecule medicine thereof.In recent years, especially at field of medicaments, 1,2, the female ring of 3-triazole is widely used in designing the novel drugs molecule, existing multiplely so far contains 1,2, the compound of the female ring of 3-triazole enters clinical experiment or has been used for clinically, relates to a plurality of treatments fields such as antibacterium, antimycotic, tuberculosis, antiviral, antitumor, anticoagulation and other cardiovascular disorder.
For card Gray (Ticagrelor) be by Astrazeneca AB research and development a kind of novel, have optionally small molecules anticoagulant, also be the oral P2Y12 adenosine diphosphate (ADP) of first reversible mating type receptor antagonist.The platelet aggregation that ADP is caused has the obvious suppression effect, can effectively improve acute coronary patient's symptom.Analyze the molecular structure for card Gray, as can be seen, one of its core texture is exactly and 1,2 of Mi Dingbing ring [4,5-d] the female ring of 3-triazole.
Disclosed preparation document for card Gray, although operational path and preparation method are varied, its core methed all is to grind the various improvement of doing on the technical foundation Astrazeneca AB former.Sum up these synthetic routes and method, find that its great majority are with three intermediate (A, B and C) be starting raw material, formerly make up on the basis of pyrimidine ring (intermediate A), by the amino nitrosification on the pyrimidine ring, form 1,2 with another ortho position amino (C provides by intermediate) again, the female ring structure of 3-triazole prepares then for card Gray.
Up to the present, Shang Weijian has and makes up earlier 1,2,3-triazole, make up again [4,5] thereby and the pyrimidine ring preparation for card Gray's method.If can realize this design, for the preparation of simplifying this compounds, improve the quality of products and yield can produce breakthrough surely.For this reason, the present invention at first designs and has prepared and makes up the female ring of 1,2,3-triazole necessary starting raw material, i.e. triazo-compound or derivatives thereof.
Summary of the invention
The objective of the invention is to the synthetic theory according to Green Chemistry, a kind of novel triazo-compound and preparation method thereof is provided, this preparation method is easy, economy and environmental protection, chiral purity and chemical yield are all higher, can be used for containing 1,2,3, the bulk drug of the female ring structure of-triazole is as the suitability for industrialized production for card Gray etc.
To achieve these goals, main technical schemes provided by the present invention is as follows: a kind of triazo-compound is characterized in that its chemical structure is alkoxy substituted-2 suc as formula the 1-shown in (I), 3-fork acetone protection o-dihydroxy-4-azido-pentamethylene:
In addition, the present invention also provides following attached technical scheme:
The preparation method of described triazo-compound comprises the steps: by aminocompound (II) and azide reagent (III) azido reaction to take place, and obtains triazo-compound (I).
Substituent R in the described triazo-compound (I) is end the ester group [(CH of the cycloalkyl of alkynyl group, a 3-10 carbon atom of the alkenyl of alkyl, a 2-6 carbon atom of hydrogen (H), a 1-6 carbon atom and 2-6 carbon atom or aryl or heterocyclic radical, a 1-5 carbon atom (n=1-5)
2)
nCO
2R
1] or end the alkoxyl group [(CH of 1-5 carbon atom (n=1-5)
2)
nOR
2]
Be end the ester group [(CH of 1-5 carbon atom (n=1-5) when substituent R
2)
nCO
2R
1] time, its R
1Be the alkyl of 1-6 carbon atom or aryl or the substituted aryl of 6-12 carbon atom.
Be end the alkoxyl group [(CH of 1-5 carbon atom (n=1-5) when substituent R
2)
nOR
2] time, its R
2Trityl group, THP trtrahydropyranyl or substituted-tetrahydro pyranyl or carbalkoxy for alkynyl group, benzyl or substituted benzyl, TMS, trityl group or the replacement of the alkenyl of the alkyl of hydrogen (H), a 1-6 carbon atom, a 2-6 carbon atom and 2-6 carbon atom.
Four latent chiral carbon atoms in the described triazo-compound (I) can be respectively single R configuration, single S configuration or its raceme.
The raw material ammonia based compound (II) of described azido reaction and the molar ratio of azide reagent (III) are 1: 1-5, preferred 1:1.2-1.8.
Described azide reagent (III) is sodium azide, hydrazoic acid, imidazoles sulfonyl azide (ImSO
2N
3), fluoroform sulfonyl azide (TfN
3), p-toluene sulfonyt azide (TsN
3), sulfonyloxy methyl nitrine (MsN
3) or trimethyl silicane nitrine (TMSN
3).
The employed alkali promotor of described azido reaction is sodium hydride, sodium methylate, sodium ethylate, sodium tert-butoxide, potassium tert.-butoxide, salt of wormwood, triethylamine (TEA), pyridine, 2,6-lutidine, 4-Dimethylamino pyridine (DMAP), N-methylmorpholine (NMM), N-ethylmorpholine (NEM), diisopropylethylamine (DIEA), 1,5-diazabicylo [4.3.0]-ninth of the ten Heavenly Stems-5-alkene (DBN), 1,8-diazabicyclo [5.4.0]-11-7-alkene (DBU) or 1,4-diazabicylo [2.2.2] octane (DABCO).
The catalyzer that described azido reaction can be selected to use is cupric chloride, nickelous chloride, cobaltous chloride (II), zinc chloride, copper sulfate, single nickel salt, the inferior cobalt (II) of sulfuric acid or zinc sulfate.
The employed solvent of described azido reaction is methylene dichloride, trichloromethane, 1,2-ethylene dichloride, toluene, acetonitrile, tetrahydrofuran (THF), methyl alcohol, ethanol, Virahol, 1,2-dioxane or tetrahydrofuran (THF).
Than prior art, triazo-compound involved in the present invention and preparation method thereof, its advantage mainly is that the preparation method is simple, the gentle easily control of reaction conditions, product yield and chiral purity height can be used for 1, the female ring of 2,3-triazole and derivative thereof are as the preparation for card Gray etc.
Embodiment
Embodiment one:
In reaction flask, add [3aR-(3a α, 4 α, 6 α, 6a α)]-and 6-amino-2,2-dimethyl-tetrahydrochysene-4H-cyclopenta-1,3-dioxane penta-4-alcohol (II) (1.73g, 10mmol), salt of wormwood (2.76g, 20mmol), (32mg 2%eq) and anhydrous methanol 25mL, adds imidazoles sulfonyl azide (III) (2.1g under 0 ℃ and the nitrogen atmosphere to copper sulfate, methanol solution 12mmol), stirring at room was reacted 5 hours, and the TLC detection reaction is finished.Concentrating under reduced pressure, residue gets [3aR-(3a α, 4 α, 6 α, 6a α)]-6-azido--2,2-dimethyl-tetrahydrochysene-4H-cyclopenta-1,3-dioxane penta-4-alcohol (I) 1.8g, yield 90.4% with normal hexane and re-crystallizing in ethyl acetate.
Embodiment two:
In reaction flask, add [3aR-(3a α, 4 α, 6 α, 6a α)] ethanol (II) (2.17g-[6-amino-2,2-dimethyl-tetrahydrochysene-4H-cyclopenta-1,3-dioxane penta-4-oxygen base], 10mmol), salt of wormwood (2.76g, 20mmol), (32mg 2%eq) and acetonitrile 25mL, adds fluoroform sulfonyl azide (III) (2.1g under 0 ℃ and the nitrogen atmosphere to copper sulfate, acetonitrile solution 12mmol), stirring at room was reacted 3 hours, and the TLC detection reaction is finished.Concentrating under reduced pressure, residue gets [3aR-(3a α, 4 α, 6 α, 6a α)]-[6-azido--2,2-dimethyl-tetrahydrochysene-4H-cyclopenta-1,3-dioxane penta-4-oxygen base] ethanol (I) 2.25g, yield 92.6% with normal hexane and re-crystallizing in ethyl acetate.
Embodiment three:
In reaction flask, add [3aR-(3a α, 4 α, 6 α, 6a α)] methyl acetate (II) (2.45g-[6-amino-2,2-dimethyl-tetrahydrochysene-4H-cyclopenta-1,3-dioxane penta-4-oxygen base], 10mmol) with dry tetrahydrofuran (THF) 30mL, be cooled to the tetrahydrofuran solution and p-toluene sulfonyt azide (III) (3.0g, tetrahydrofuran solution 15mmol) that drip sodium hydride (6g, 60% mineral oil) under 0 ℃ and the nitrogen atmosphere successively.After dropwising, be warming up to room temperature, stirring reaction 30 hours, the TLC detection reaction is finished.With methyl alcohol cancellation reaction, in the impouring water, hydrochloric acid is regulated pH to slightly acidic, ethyl acetate extraction 3 times, anhydrous sodium sulfate drying under the ice bath.Be evaporated to driedly, normal hexane/re-crystallizing in ethyl acetate gets off-white color solid [3aR-(3a α, 4 α, 6 α, 6a α)]-[6-azido--2,2-dimethyl-tetrahydrochysene-4H-cyclopenta-1,3-dioxane penta-4-oxygen base] methyl acetate (I) 2.3g, yield 85.2%.
It is pointed out that above-mentioned preferred embodiment only is explanation technical conceive of the present invention and characteristics, its purpose is to allow the personage who is familiar with this technology can understand content of the present invention and enforcement according to this, can not limit protection scope of the present invention with this.All equivalences that spirit is done according to the present invention change or modify, and all should be encompassed within protection scope of the present invention.
Claims (10)
1. a triazo-compound (I) is characterized in that its chemical structure is that 1-is alkoxy substituted-2,3-fork acetone protection o-dihydroxy-4-azido-pentamethylene.
2. according to the preparation method of the described triazo-compound of claim 1, it is characterized in that it comprises the steps: with aminocompound (II) and azide reagent (III) azido reaction to take place, and obtains described triazo-compound (I).
3. according to the preparation method of the described triazo-compound of claim 2, it is characterized in that: the substituent R in the described triazo-compound (I) is end the ester group [(CH of the cycloalkyl of alkynyl group, a 3-10 carbon atom of the alkenyl of alkyl, a 2-6 carbon atom of hydrogen (H), a 1-6 carbon atom and 2-6 carbon atom or aryl or heterocyclic radical, a 1-5 carbon atom (n=1-5)
2)
nCO
2R
1] or end the alkoxyl group [(CH of 1-5 carbon atom (n=1-5)
2)
nOR
2].
4. according to the preparation method of the described triazo-compound of claim 3, it is characterized in that: be end the ester group [(CH of 1-5 carbon atom (n=1-5) when described substituent R
2)
nCO
2R
1] time, its R
1Be the alkyl of 1-6 carbon atom or aryl or the substituted aryl of 6-10 carbon atom.
5. according to the preparation method of the described triazo-compound of claim 3, it is characterized in that: be end the alkoxyl group [(CH of 1-5 carbon atom (n=1-5) when described substituent R
2)
nOR
2] time, its R
2Trityl group, THP trtrahydropyranyl or substituted-tetrahydro pyranyl or carbalkoxy for alkynyl group, benzyl or substituted benzyl, TMS, trityl group or the replacement of sharp 2-6 the carbon atom of alkenyl of the alkyl of hydrogen (H), a 1-6 carbon atom, a 2-6 carbon atom.
6. according to the described triazo-compound of claim 1, it is characterized in that: four latent chiral carbon atoms in the described triazo-compound (I) can be respectively single R configuration, single S configuration or its raceme.
7. according to the preparation method of the described triazo-compound of claim 2, it is characterized in that: the raw material ammonia based compound (II) of described azido reaction and the molar ratio of azide reagent (III) are 1: 1-5.
8. according to the preparation method of the described triazo-compound of claim 2 (I), it is characterized in that: described azide reagent (III) is sodium azide, hydrazoic acid, imidazoles sulfonyl azide, fluoroform sulfonyl azide, p-toluene sulfonyt azide, sulfonyloxy methyl nitrine or trimethyl silicane nitrine.
9. according to the preparation method of the described triazo-compound of claim 2, it is characterized in that: the employed alkali promotor of described azido reaction is sodium hydride, sodium methylate, sodium ethylate, sodium tert-butoxide, potassium tert.-butoxide, salt of wormwood, triethylamine, pyridine, 2,6-lutidine, 4-Dimethylamino pyridine, N-methylmorpholine, N-ethylmorpholine, diisopropylethylamine, 1,5-diazabicylo [4.3.0]-ninth of the ten Heavenly Stems-5-alkene, 1,8-diazabicyclo [5.4.0]-11-7-alkene or 1,4-diazabicylo [2.2.2] octane.
10. according to the preparation method of the described triazo-compound of claim 2, it is characterized in that: the catalyzer that described azido reaction can be selected to use is cupric chloride, nickelous chloride, cobaltous chloride (II), zinc chloride, copper sulfate, single nickel salt, the inferior cobalt (II) of sulfuric acid or zinc sulfate; The employed solvent of described azido reaction is methylene dichloride, trichloromethane, 1,2-ethylene dichloride, toluene, acetonitrile, tetrahydrofuran (THF), methyl alcohol, ethanol, Virahol, 1,2-dioxane or tetrahydrofuran (THF).
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310251364.2A CN103304535B (en) | 2013-06-24 | 2013-06-24 | Azide and preparation method thereof |
| PCT/CN2014/079228 WO2014206187A1 (en) | 2013-06-24 | 2014-06-05 | Preparation method of ticagrelor and intermediates thereof |
| US14/975,785 US9604991B2 (en) | 2013-06-24 | 2015-12-20 | Preparation method of ticagrelor and intermediates thereof |
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|---|---|---|---|
| CN201310251364.2A CN103304535B (en) | 2013-06-24 | 2013-06-24 | Azide and preparation method thereof |
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| CN103304535B CN103304535B (en) | 2015-03-11 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014206187A1 (en) * | 2013-06-24 | 2014-12-31 | 苏州明锐医药科技有限公司 | Preparation method of ticagrelor and intermediates thereof |
| CN104311495A (en) * | 2014-10-23 | 2015-01-28 | 西北大学 | Method for synthesizing NH-1,2,3-triazole |
| TWI746568B (en) * | 2016-06-23 | 2021-11-21 | 美商陶氏全球科技有限責任公司 | Production of sulfonyl azide anhydride |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102924457A (en) * | 2011-08-12 | 2013-02-13 | 上海恒瑞医药有限公司 | Triazolopyrimidine derivatives, preparation method and uses thereof |
-
2013
- 2013-06-24 CN CN201310251364.2A patent/CN103304535B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102924457A (en) * | 2011-08-12 | 2013-02-13 | 上海恒瑞医药有限公司 | Triazolopyrimidine derivatives, preparation method and uses thereof |
Non-Patent Citations (1)
| Title |
|---|
| FARKAS, FREDERIC, ET AL.: "1,4-Addition of azide to trans-diepoxycyclopentane with solvent participation", 《TETRAHEDRON》, vol. 48, no. 1, 31 December 1992 (1992-12-31), pages 103 - 110, XP026645771, DOI: doi:10.1016/S0040-4020(01)80582-2 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014206187A1 (en) * | 2013-06-24 | 2014-12-31 | 苏州明锐医药科技有限公司 | Preparation method of ticagrelor and intermediates thereof |
| US9604991B2 (en) | 2013-06-24 | 2017-03-28 | Suzhou Miracpharma Technology Co., Ltd. | Preparation method of ticagrelor and intermediates thereof |
| CN104311495A (en) * | 2014-10-23 | 2015-01-28 | 西北大学 | Method for synthesizing NH-1,2,3-triazole |
| CN104311495B (en) * | 2014-10-23 | 2017-04-12 | 西北大学 | Method for synthesizing NH-1,2,3-triazole |
| TWI746568B (en) * | 2016-06-23 | 2021-11-21 | 美商陶氏全球科技有限責任公司 | Production of sulfonyl azide anhydride |
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|---|---|
| CN103304535B (en) | 2015-03-11 |
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Effective date of registration: 20200102 Address after: 221700 Xuzhou City, Jiangsu Province, Fengxian County Liang Zhai village dike Village Patentee after: Xuzhou Feiyun foam products limited liability company Address before: 215000 Jiangsu Province, Suzhou City Industrial Park Commercial Plaza Building 1 room 1305 Lianfeng Co-patentee before: Xu Xuenong Patentee before: Suzhou Mingyue Medical Technology Co., Ltd. |