CN104557686A - Synthesis method for pyridinone compound - Google Patents
Synthesis method for pyridinone compound Download PDFInfo
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- CN104557686A CN104557686A CN201410829432.3A CN201410829432A CN104557686A CN 104557686 A CN104557686 A CN 104557686A CN 201410829432 A CN201410829432 A CN 201410829432A CN 104557686 A CN104557686 A CN 104557686A
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- compound
- methyl
- synthetic method
- pyridine compounds
- alkyl group
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- 0 CN**[*+]=C=C Chemical compound CN**[*+]=C=C 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/803—Processes of preparation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
Abstract
The invention relates to the field of synthesis of organic compounds, in particular to a synthesis method for a pyridinone compound. The synthesis method comprises the following steps: (a) reacting a raw material with halogenated hydrocarbon to obtain a compound intermediate under an alkaline condition; (b) conducting condensation on the compound intermediate obtained in step (a) and an amine compound to obtain the pyridinone compound. The synthesis method is short in process route, high in yield, easy to operate and harmless.
Description
Technical field
The present invention relates to organic compound synthesis field, be specifically related to a kind of synthetic method of pyridine compounds.
Background technology
Dolutegravir is by GlaxoSmithKline PLC (GlaxoSmithKline, the anti-HIV-1 infection medicine of the ViiV Healthcare HIV specialized company exploitation GSK) under house flag, commodity are called Tivicay, use its sodium salt clinically, formulation is 50 mg thin membrane coated tablets, obtains U.S. FDA approval listing on August 12nd, 2013.Below be the sodium salt structure of Dolutegravir and Cabotegravir respectively.
Dolutegravir is hiv integrase inhibitor, and it can stop viral DNA chain to shift to host DNA.Compared with replacing lattice Wei (elvitegravir) with existing hiv integrase inhibitor Merck (raltegravir), dust, this Drug safety improves.Such as, WO2006116764 protects compound structure, and WO2010011819 protects its prodrug forms, and WO2010068262, WO2010068253, WO2012018065 preparation technology to Dolutegravir protects.And Intermediates pyridinones is the key of synthesis Dolutegravir and Cabotegravir.In WO2011119566A1; with 4-methoxyl group methyl aceto acetate for raw material; with N, N-dimethyl-1,1-dimethoxy-ethylamine is obtained by reacting 3-(dimethylamino)-2 [(methoxyl group) ethanoyl]-2-methyl acrylate; again with 1; 1-dimethoxy-ethylamine synthetic compound 1, (MOR, wherein R is alkyl; M is alkali metal cation, preferred lithium ion) to obtain pyridone 3(with compound 2 under condition as follows).
But this technological process is comparatively complicated, and step is various, the 3rd step needs to use the alcohol alkali cpds such as lithium methoxide, and not easily preserve, price is more expensive, and the reaction times is longer, is unfavorable for suitability for industrialized production.
Summary of the invention
The object of the invention is for the deficiencies in the prior art, the synthetic method that a kind of step is simple, efficient, environmental friendliness, economy are applicable to the pyridine compounds of suitability for industrialized production is provided.
Technical problem to be solved by this invention is achieved by the following technical programs:
A synthetic method for pyridine compounds, comprises the steps:
A () is by Compound I and halohydrocarbon R
3x reacts obtained Compound II per in the basic conditions;
B step (a) gained Compound II per and aminated compounds III can be obtained described pyridine compounds IV by condensation by ();
Wherein, X is chlorine, bromine or iodine; R
1for H, carboxyl or low alkyl group ester group; R
2for low alkyl group or aryl; R
3for low alkyl group; R
4for H or low alkyl group.
Further, described R
1for H, carboxyl or low alkyl group ester group; R
2for methyl, ethyl or benzyl; R
3for methyl; R
4for methyl or ethyl.
Further, described R
1for methoxycarbonyl; R
2for methyl; R
3for methyl; R
4for methyl.
Further, described Compound I and halohydrocarbon R
3the mol ratio of X is 1:1.2 ~ 1.5.
Further, the mol ratio of described Compound II per and aminated compounds III is 1:1.5 ~ 2.
Alkaline matter used in step (a) is that the alkali that the art is commonly used all can realize the present invention, as sodium bicarbonate, and the materials such as saleratus.
The present invention has following beneficial effect:
Operational path in the present invention is short, and yield is high, simple to operate without hazardness.
Embodiment
Below in conjunction with embodiment, the present invention will be described in detail, and embodiment is only the preferred embodiment of the present invention, is not limitation of the invention.
The experimental technique used in following embodiment if no special instructions, is ordinary method.
Material used in following embodiment, reagent etc., if no special instructions, all can obtain from commercial channels.
embodiment 1
A synthetic method for pyridine compounds, comprises the steps:
A 214g Compound I is dissolved in 1L N-Methyl pyrrolidone by (), add 168g NaHCO
3with 170g CH
3i, 40 DEG C of stirring reaction 6h, then cool, add 2M HCl solution and 20% sodium chloride solution, crystallize out, filter, wash with water, be drying to obtain compound
194g (yield is 85%).
B () is by 114g compound
and 105g2,2-dimethoxy-ethylamine mixes, be added in the middle of 650mL ethanol, stir and be warming up to back flow reaction to terminating, cooling, add 200mL water and 400mL ethyl acetate, after layering, aqueous layer with ethyl acetate washes twice, and merges organic layer, after dried over mgso, then obtain target product after underpressure distillation solvent
129g (yield 82%).ESI-MS [M+H]
+ 316.0，1H NMR (300 MHz, DMSO) δ 15.4 (s, 1 H)，8.22 (s, 1 H), 4.90-4.80 (m, 1 H), 3.88 (s, 3H), 3.78 (s, 3H), 3.74 (d, J = 5.0 Hz, 2H), 3.60 (s, 6H)。
embodiment 2
A synthetic method for pyridine compounds, comprises the steps:
A 246g Compound I is dissolved in 1L N-Methyl pyrrolidone by (), add 168gNaHCO
3and 170gCH
3i, 40 DEG C of stirring reaction 6h, then cool, add 2M HCl solution, be extracted with ethyl acetate rear with saturated NaCl solution washing organic layer, after underpressure distillation ethyl acetate, obtain compound
197g (yield is 76%).
B () is by 130g compound
with the mixing of 77g 2,2-dihydroxyl ethamine, add 650mL ethanol, stir and be warming up to back flow reaction to terminating, cooling, add 200mL water and 400mL ethyl acetate, after layering, aqueous layer with ethyl acetate washes twice, merge organic layer, after dried over mgso, then obtain target product after underpressure distillation solvent
115g (yield 72%).ESI-MS [M+H]
+ 320.1，1H NMR (300 MHz, DMSO) δ 7.62 (d, J = 7.5 Hz, 1 H), 7.42-7.30 (m, 5H), 6.33 (d, J = 6.0 Hz, 2H), 6.29 (d, J = 7.5 Hz, 1 H), 5.08 (s, 2H), 4.95-4.85 (m, 1 H), 3.80 (s, 3H), 3.74 (d, J = 5.1 Hz, 2H)。
embodiment 3
A synthetic method for pyridine compounds, comprises the steps:
A 170g Compound I is dissolved in 1L N-Methyl pyrrolidone by (), add 168gNaHCO
3with 170g CH
3i, 40 DEG C of stirring reaction 6h, then cool, add 2M HCl solution, be extracted with ethyl acetate rear with saturated NaCl solution washing organic layer, after underpressure distillation ethyl acetate, obtain compound
151g (yield is 82%).
B () is by 92g compound
and 105g2,2-dimethoxy-ethylamine mixes, add 500mL ethanol, stir and be warming up to back flow reaction to terminating, cooling, add 200mL water and 400mL ethyl acetate, after layering, aqueous layer with ethyl acetate washes twice, and merges organic layer, after dried over mgso, then obtain target product after underpressure distillation solvent
122g yield 90%).ESI-MS [M+H]
+ 272.1，1H NMR (300 MHz, DMSO) δ 7.66 (d, J = 7.3 Hz, 1 H), 6.21 (d, J = 7.3 Hz, 1 H), 4.90-4.82 (m, 1 H), 3.88 (s, 3H), 3.80 (s, 3H), 3.76 (d, J = 4.8 Hz, 2H), 3.59 (s, 6H)。
embodiment 4
A synthetic method for pyridine compounds, comprises the steps:
A Compound I is dissolved in 1L N-Methyl pyrrolidone by (), add 168gNaHCO
3with 170g CH
3i, 40 DEG C of stirring reaction 6h, then cool, add 2M HCl solution, be extracted with ethyl acetate rear with saturated NaCl solution washing organic layer, after underpressure distillation ethyl acetate, obtain compound
210g (yield is 87%).
B () is by 121g compound
with 105g 2,2-dimethoxy-ethylamine mixes, add 500mL ethanol, stir and be warming up to back flow reaction to terminating, cooling, add 200mL water and 400mL ethyl acetate, after layering, aqueous layer with ethyl acetate washes twice, and merges organic layer, after dried over mgso, then obtain target product after underpressure distillation solvent
148g (yield 90%).ESI-MS [M+H]
+ 330.1，1H NMR (300 MHz, DMSO) δ 8.14 (s, 1 H), 4.90-4.80 (m, 1 H), 3.88 (s, 3H), 3.82 (s, 3H), 3.78 (s, 3H), 3.74 (d, J = 5.0 Hz, 2H), 3.60 (s, 6H)。
The above embodiment only have expressed embodiments of the present invention; it describes comparatively concrete and detailed; but therefore can not be interpreted as the restriction to the scope of the claims of the present invention; in every case the technical scheme adopting the form of equivalent replacement or equivalent transformation to obtain, all should drop within protection scope of the present invention.
Claims (5)
1. a synthetic method for pyridine compounds, is characterized in that comprising the steps:
A () is by Compound I and halohydrocarbon R
3x reacts obtained Compound II per in the basic conditions;
B step (a) gained Compound II per and aminated compounds III can be obtained described pyridine compounds IV by condensation by ();
Wherein, X is chlorine, bromine or iodine; R
1for H, carboxyl or low alkyl group ester group; R
2for low alkyl group or aryl; R
3for low alkyl group; R
4for H or low alkyl group.
2. the synthetic method of a kind of pyridine compounds according to claim 1, is characterized in that, described R
1for H, carboxyl or low alkyl group ester group; R
2for methyl, ethyl or benzyl; R
3for methyl; R
4for methyl or ethyl.
3. the synthetic method of a kind of pyridine compounds according to claim 2, is characterized in that, described R
1for methoxycarbonyl; R
2for methyl; R
3for methyl; R
4for methyl.
4. the synthetic method of a kind of pyridine compounds according to claim 1, is characterized in that, described Compound I and halohydrocarbon R
3the mol ratio of X is 1:1.2 ~ 1.5.
5. the synthetic method of a kind of pyridine compounds according to claim 1, is characterized in that, the mol ratio of described Compound II per and aminated compounds III is 1:1.5 ~ 2.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410829432.3A CN104557686A (en) | 2014-12-29 | 2014-12-29 | Synthesis method for pyridinone compound |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410829432.3A CN104557686A (en) | 2014-12-29 | 2014-12-29 | Synthesis method for pyridinone compound |
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ID=53074863
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110294705A (en) * | 2019-07-25 | 2019-10-01 | 浙江沙星科技有限公司 | A kind of synthetic method of Du Lutewei key intermediate |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010068262A1 (en) * | 2008-12-11 | 2010-06-17 | Glaxosmithkline Llc | Processes and intermediates for carbamoylpyridone hiv integrase inhibitors |
| CN102933080A (en) * | 2010-03-23 | 2013-02-13 | Viiv保健公司 | Process for preparing carbamoylpridone derivatives and intermediates |
| CN103154004A (en) * | 2010-08-05 | 2013-06-12 | 盐野义制药株式会社 | Process for preparing compound having HIV integrase inhibitory activity |
-
2014
- 2014-12-29 CN CN201410829432.3A patent/CN104557686A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010068262A1 (en) * | 2008-12-11 | 2010-06-17 | Glaxosmithkline Llc | Processes and intermediates for carbamoylpyridone hiv integrase inhibitors |
| CN102933080A (en) * | 2010-03-23 | 2013-02-13 | Viiv保健公司 | Process for preparing carbamoylpridone derivatives and intermediates |
| CN103154004A (en) * | 2010-08-05 | 2013-06-12 | 盐野义制药株式会社 | Process for preparing compound having HIV integrase inhibitory activity |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110294705A (en) * | 2019-07-25 | 2019-10-01 | 浙江沙星科技有限公司 | A kind of synthetic method of Du Lutewei key intermediate |
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Effective date of registration: 20160818 Address after: No. 5, science and technology innovation road, Dayawan science and Technology Innovation Zone, Huizhou, Guangdong Applicant after: Raffles Guangdong Pharmaceutical Technology Co. Ltd. Address before: 516001, 5, science and Technology Innovation Park, Dayawan District, Guangdong, Huizhou Applicant before: Xu Junye |
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| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20150429 |
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