CN109293567A - A kind of synthetic method of the bromo- 2- methylnicotinic acid ethyl ester of 5- - Google Patents
A kind of synthetic method of the bromo- 2- methylnicotinic acid ethyl ester of 5- Download PDFInfo
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- CN109293567A CN109293567A CN201811406212.4A CN201811406212A CN109293567A CN 109293567 A CN109293567 A CN 109293567A CN 201811406212 A CN201811406212 A CN 201811406212A CN 109293567 A CN109293567 A CN 109293567A
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- 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
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Abstract
The invention discloses a kind of synthetic methods of the bromo- 2- methylnicotinic acid ethyl ester of 5-, comprising the following steps: ethyl acetoacetate and alkali A are added in solvent B and carry out enolization；Intermediate III is added and DABCO is reacted；Ammonium acetate is added and carries out cyclization；Water quenching is added to go out, organic solvent C extraction；It removes organic solvent C and obtains crude product to be crystallized；Crude product to be crystallized is recrystallized into obtain the bromo- 2- methylnicotinic acid ethyl ester of 5-；The present invention is based on the 5- chloro-2-methyl ethyl nicotinate synthesis technology that Meck is developed, by changing reaction dissolvent and reducing reaction temperature, significantly improve the stability of intermediate III, so that reaction can smoothly obtain product, post-processing chromatographs process by recrystallization purifying, so as to avoid the column of time and effort consuming, and average yield reaches 70%, purity reaches 99.0% or more, is suitable for large-scale industrial production.
Description
Technical field
The present invention relates to technical field of organic synthesis, and in particular to a kind of synthetic method of the bromo- 2- methylnicotinic acid ethyl ester of 5-.
Background technique
As a kind of important medicine and industrial chemicals, the bromo- 2- methylnicotinic acid ethyl ester of 5- is widely used in pharmaceutical intermediate
Synthesis, structural formula are as follows:
Less about its synthesis report on document: patent EP1180514 in 2002 is from nitro malonaldehyde and amino crotonic acid
Ethyl ester sets out, and has synthesized the bromo- 2- methylnicotinic acid ethyl ester of 5- by three-step reaction, but the ring closure reaction yield of the first step is only
30%, and nitro malonaldehyde is explosive material, security risk is high when storing and using, therefore this synthetic route is unsuitable extensive
Industrialized production, synthetic reaction are as follows:
After its bromo elimination reaction will occur for patent US2017/15655 in 2017 from methacrylaldehyde, and 2- bromine third is made
Then olefine aldehydr occurs condensation reaction with 2- chloro ethyl acetoacetate, obtains target product with 7% yield.2- bromopropene aldehyde
Easily it polymerize, and condensation reaction yield is low, dopant species are more, purification difficult, it is difficult to amplify production, synthesis is anti-
It should be as follows:
Meck company in 2000 develops the synthesis technology of Formulas I analog 5- chloro-2-methyl ethyl nicotinate, mild condition,
Hundred kilograms of ranks can be amplified to；But its technique is applied in the synthesis of the bromo- 2- methylnicotinic acid ethyl ester (Formulas I) of 5-, cannot be smooth
To product, main reason is that the stability of Bromo-intermediates (formula III) is poorer than chloro thing (formula IV), strong acid, highly basic and
High temperature is easy to happen decomposition, and synthetic reaction is as follows:
Summary of the invention
The purpose of the present invention is to provide a kind of synthetic methods of the bromo- 2- methylnicotinic acid ethyl ester of 5-, to solve above-mentioned background
The problem of being proposed in technology.
To achieve the above object, the invention provides the following technical scheme:
A kind of synthetic method of the bromo- 2- methylnicotinic acid ethyl ester of 5-, which comprises the following steps:
1) ethyl acetoacetate and alkali A are added in solvent B and carry out enolization；Following reaction occurs:
2) intermediate III is added into step (1) and DABCO is reacted；Following reaction occurs:
3) ammonium acetate is added and carries out cyclization；Following reaction occurs:
4) water quenching is added to go out, organic solvent C extraction；
5) it removes organic solvent C and obtains crude product to be crystallized；
6) crude product to be crystallized is recrystallized into obtain the bromo- 2- methylnicotinic acid ethyl ester of 5-.
As a further solution of the present invention: step 1) the alkali A is potassium tert-butoxide, and quality used is ethyl acetoacetate
0.5-1.5 times.
As a further solution of the present invention: solvent B described in step 1) is including but not limited to dioxane, 2- first
One of base-tetrahydrofuran, tetrahydrofuran, glycol dimethyl ether, methyl tertiary butyl ether, ether, isopropyl ether ethers；Solvent B institute
It is not more than 50 times of ethyl acetoacetate quality with quality.
As a further solution of the present invention: quality used in the step 2) intermediate III is ethyl acetoacetate quality
3-4 times；Quality used in DABCO is 0.5-1.0 times of ethyl acetoacetate quality；Reaction temperature is subzero 78-5 DEG C, the reaction time
4-6h。
As a further solution of the present invention: step 2) reaction temperature is subzero 10-0 DEG C.
As a further solution of the present invention: ammonium acetate quality used in step 3) is 1-2 times of ethyl acetoacetate quality；Instead
Answering temperature is 55-65 DEG C, reaction time 15-17h.
As a further solution of the present invention: water used in step 4) is that quality is 25-30 times of ethyl acetoacetate quality
Ice water；Organic solvent C is the MTBE that quality is 6.5-7.5 times of ethyl acetoacetate quality.
As a further solution of the present invention: the step 6) recrystallization temperature is subzero 30-100 DEG C.
As a further solution of the present invention: recrystallization solvent used in step 6) is esters, ketone, ethers, halogenated hydrocarbons, alcohol
The mixture of one or more of class, alkanes, recrystallization solvent quality used are not more than 40 times of crude product quality to be crystallized.
As a further solution of the present invention: the esters include but is not limited to ethyl acetate and propyl acetate；The ketone
Class includes but is not limited to acetone and butanone；The ethers includes but is not limited to dioxane, 2- methyl-tetrahydro furans, tetrahydro furan
It mutters and glycol dimethyl ether；The halogenated hydrocarbons includes but is not limited to methylene chloride and chlorobenzene；The alcohols includes but is not limited to first
Alcohol, ethyl alcohol, normal propyl alcohol and isopropanol；The alkanes include but is not limited to pentane, n-hexane and normal heptane.
Compared with prior art, the beneficial effects of the present invention are: with the 5- chloro-2-methyl ethyl nicotinate synthesis of Meck exploitation
Based on technique, by changing reaction dissolvent and reducing reaction temperature, the stability of intermediate III is significantly improved, to make
Must react can smoothly obtain product, and post-processing chromatographs process by recrystallization purifying, so as to avoid the column of time and effort consuming, average
Yield reaches 70%, and purity reaches 99.0% or more, is suitable for large-scale industrial production.
Detailed description of the invention
Fig. 1 is the liquid chromatogram for the bromo- 2- methylnicotinic acid ethyl ester of 5- that embodiment 1 synthesizes；
Fig. 2 is the hydrogen nuclear magnetic resonance spectrogram for the bromo- 2- methylnicotinic acid ethyl ester of 5- that comparative example 1 synthesizes；
Fig. 3 is the liquid chromatogram for the bromo- 2- methylnicotinic acid ethyl ester of 5- that comparative example 3 synthesizes.
Specific embodiment
The technical solution of the patent is explained in further detail With reference to embodiment.
Embodiment 1
Ethyl acetoacetate (7.0 grams) and dioxane (140 grams) are added in the three-necked flask of 250mL, it will under ice salt bath
System temperature is down to -10 DEG C, sequentially adds potassium tert-butoxide (6.4 grams), intermediate III (23.8 grams) and DABCO (6.1 grams), stirs
It mixes 5 hours, is added ammonium acetate (10.0 grams), be warming up to 60 DEG C and react 16 hours, TLC, which is monitored to reaction, to be terminated.Reaction solution is down to
Room temperature is poured into ice water (200 grams), is added MTBE (50 grams), and 1 small layered is stirred, and (50 grams) of water phase MTBE are extracted once, is had
Machine is added to the drying 1 hour of (20 grams) of anhydrous sodium sulfate.Filtering, Rotary Evaporators concentration, the normal heptane (30.0 of residue heat
Gram) after dissolution, be cooled to -20 DEG C, stir 1 hour, filtering is dried under reduced pressure to obtain the bromo- 2- methylnicotinic acid ethyl ester of 5-, white solid
7.8 grams, yield 60.0%, purity 99.4% (is shown in Table 1).
Its synthetic route are as follows:
Embodiment 2
Ethyl acetoacetate (7.0 grams) and 2- methyltetrahydrofuran (70 grams), ice salt bath are added in the three-necked flask of 250mL
It is lower that system temperature is down to -8 DEG C, potassium tert-butoxide (3.5 grams), intermediate III (21.0 grams) and DABCO (3.5 grams) are sequentially added,
Stirring 4 hours is added ammonium acetate (7.0 grams), is warming up to 55 DEG C and reacts 15 hours, TLC, which is monitored to reaction, to be terminated.Reaction solution is down to
Room temperature is poured into ice water (180 grams), is added MTBE (46 grams), and 1 small layered is stirred, and (46 grams) of water phase MTBE are extracted once, is had
Machine is added to the drying 1 hour of (20 grams) of anhydrous sodium sulfate.Filtering, Rotary Evaporators concentration, the normal heptane (20.0 of residue heat
Gram) after dissolution, be cooled to 0 DEG C, stir 1 hour, filtering is dried under reduced pressure to obtain the bromo- 2- methylnicotinic acid ethyl ester of 5-, white solid
6.4 grams, yield 49.0%.
Embodiment 3
Ethyl acetoacetate (7.0 grams) and tetrahydrofuran (210 grams) are added in the three-necked flask of 250mL, it will under ice salt bath
System temperature is down to -6 DEG C, sequentially adds potassium tert-butoxide (7.0 grams), intermediate III (22.5 grams) and DABCO (4.5 grams), stirring
It 4 hours, is added ammonium acetate (9.0 grams), is warming up to 57 DEG C and reacts 16 hours, TLC, which is monitored to reaction, to be terminated.Reaction solution is down to room
Temperature is poured into ice water (180 grams), is added MTBE (48 grams), and 1 small layered is stirred, and (46 grams) of water phase MTBE are extracted once, organic
It is added to the drying 1 hour of (20 grams) of anhydrous sodium sulfate.Filtering, Rotary Evaporators concentration, the normal heptane (25.0 of residue heat
Gram) after dissolution, rise to 20 DEG C, stir 1 hour, filtering is dried under reduced pressure to obtain the bromo- 2- methylnicotinic acid ethyl ester of 5-, white solid 6.4
Gram, yield 49.0%.
Embodiment 4
Ethyl acetoacetate (7.0 grams) and dioxane (280 grams) are added in the three-necked flask of 250mL, it will under ice salt bath
System temperature is down to -4 DEG C, sequentially adds potassium tert-butoxide (10.0 grams), intermediate III (24.0 grams) and DABCO (5.5 grams), stirs
It mixes 5 hours, is added ammonium acetate (12 grams), be warming up to 62 DEG C and react 16 hours, TLC, which is monitored to reaction, to be terminated.Reaction solution is down to room
Temperature is poured into ice water (205 grams), is added MTBE (51 grams), and 1 small layered is stirred, and (51 grams) of water phase MTBE are extracted once, organic
It is added to the drying 1 hour of (20 grams) of anhydrous sodium sulfate.Filtering, Rotary Evaporators concentration, the normal heptane (35.0 of residue heat
Gram) after dissolution, be warming up to 40 DEG C, stir 1 hour, filtering is dried under reduced pressure to obtain the bromo- 2- methylnicotinic acid ethyl ester of 5-, white solid
6.5 grams, yield 50.1%.
Embodiment 5
Ethyl acetoacetate (7.0 grams) and tetrahydrofuran (340 grams) are added in the three-necked flask of 250mL, it will under ice salt bath
System temperature is down to -2 DEG C, sequentially adds potassium tert-butoxide (10.5 grams), intermediate III (28.0 grams) and DABCO (7.0 grams), stirs
It mixes 5 hours, is added ammonium acetate (14.0 grams), be warming up to 65 DEG C and react 17 hours, TLC, which is monitored to reaction, to be terminated.Reaction solution is down to
Room temperature is poured into ice water (210 grams), is added MTBE (52 grams), and 1 small layered is stirred, and (52 grams) of water phase MTBE are extracted once, is had
Machine is added to the drying 1 hour of (20 grams) of anhydrous sodium sulfate.Filtering, Rotary Evaporators concentration, the normal heptane (40.0 of residue heat
Gram) after dissolution, be warming up to 80 DEG C, stir 1 hour, filtering is dried under reduced pressure to obtain the bromo- 2- methylnicotinic acid ethyl ester of 5-, white solid
5.6 grams, yield 43.2%.
Comparative example 1
Methacrylaldehyde (3.6 grams) are added in the three-necked flask of referenced patent US2017/15655:1L, are added water (100 milliliters),
After stirring and dissolving, it is cooled to 0 DEG C, bromine (10.6 grams) slowly are added dropwise, keep the temperature 1 hour after dripping off, methylene chloride extraction (50 is added
Milliliter).Merge organic phase, successively uses saturated sodium-chloride water solution (10 milliliters) and water washing, (5 grams) dryings of anhydrous sodium sulfate
Organic phase.Filtering, Rotary Evaporators concentration, obtains the bromo- methacrylaldehyde of 2- (6.0 grams), which is weak yellow liquid, puts at 0 DEG C
It is unstable when setting, it can gradually become foaming solid.Therefore the bromo- methacrylaldehyde of 2- obtained directly carries out next without purifying
Step reaction.
At room temperature by the bromo- methacrylaldehyde of 2- (6.0 grams), ammonium acetate (71.8 grams), (25.7 grams) of 2- ethyl chloroacetate dissolutions
It in acetic acid (40 milliliters), stirs 48 hours at room temperature, TLC shows that raw material disappears.Ice water (400 milliliters) quenching reaction is added,
Water phase ethyl acetate (100 milliliters * 3 times) extraction.Merge organic phase, successively with saturated sodium-chloride water solution (10 milliliters) and
Water washing, (5 grams) of anhydrous sodium sulfate dry organic phases.Filtering, Rotary Evaporators concentration, obtains crude product, flash column chromatography,
Eluent: ethyl acetate/petroleum ether=1:8 obtains 2.8 grams of white solid, yield 7.2%.
Its synthetic route are as follows:
Comparative example 2
With reference to Meck company technique, chloro thing is prepared: ethyl acetoacetate (7.0 grams) are added in the three-necked flask of 250mL
With tetrahydrofuran (140 milliliters), system temperature is down to -10 DEG C under ice salt bath.It is added potassium tert-butoxide (6.4 grams), is warming up to 20
Compound IV (20.7 grams) and bicyclic [2,2, the 2] octane (6.1 grams) of-two nitrine of Isosorbide-5-Nitrae are sequentially added after DEG C, stirring rises after 1 hour
Temperature continues stirring 3 hours to 45 DEG C, is added ammonium acetate (10.0 grams), is warming up to 60 DEG C and reacts 16 hours, TLC is monitored to reaction
Terminate.Reaction solution is down to room temperature, pours into ice water (200 milliliters), is added MTBE (50 milliliters), stirs 1 small layered, water phase
(50 milliliters) of MTBE are extracted once, organic to be added to the drying 1 hour of (20 grams) of anhydrous sodium sulfate.Filtering, Rotary Evaporators concentration,
Residue is recrystallized with (50.0 grams) of normal heptane, obtains chloro thing V, and 7.0 grams of white solid, yield 65.0%, synthetic route
Are as follows:
Comparative example 3
With reference to Meck company technique, bromo-derivative is prepared: ethyl acetoacetate (7.0 grams) are added in the three-necked flask of 250mL
With tetrahydrofuran (140 milliliters), system temperature is down to -10 DEG C under ice salt bath.It is added potassium tert-butoxide (6.4 grams), is warming up to 20
Compound IV (20.7 grams) and bicyclic [2,2, the 2] octane (6.1 grams) of-two nitrine of Isosorbide-5-Nitrae are sequentially added after DEG C, stirring rises after 1 hour
Temperature continues stirring 3 hours to 45 DEG C, is added ammonium acetate (10.0 grams), is warming up to 60 DEG C and reacts 16 hours, TLC is monitored to reaction
Terminate.Reaction solution is down to room temperature, pours into ice water (200 milliliters), is added MTBE (50 milliliters), stirs 1 small layered, water phase
(50 milliliters) of MTBE are extracted once, organic to be added to the drying 1 hour of (20 grams) of anhydrous sodium sulfate.Filtering, Rotary Evaporators concentration,
Residue is recrystallized with (50.0 grams) of normal heptane, obtains chloro thing V, and 1.2 grams of white solid, yield 9.1%, purity 98.5%
(being shown in Table 2), synthetic route are as follows:
The purity table of the bromo- 2- methylnicotinic acid ethyl ester of 5- of 1 embodiment 1 of table synthesis
The purity table of the bromo- 2- methylnicotinic acid ethyl ester of 5- of 2 comparative example 3 of table synthesis
The yield table of the different synthetic method synthesis bromo- 2- methylnicotinic acid ethyl esters of 5- of table 3
| Project | Product | Yield |
| Embodiment 1 | Bromo-derivative | 60.0% |
| Embodiment 2 | Bromo-derivative | 49.0% |
| Embodiment 3 | Bromo-derivative | 49.0% |
| Embodiment 4 | Bromo-derivative | 50.1% |
| Embodiment 5 | Bromo-derivative | 43.2% |
| Comparative example 1 | Bromo-derivative | 7.2% |
| Comparative example 2 | Chloro thing | 65.0% |
| Comparative example 3 | Bromo-derivative | 9.1% |
The product yield that the synthesis technology of 1-5 of the embodiment of the present invention obtains as can be seen from Table 3 is bright 40.0% or more
The aobvious yield higher than current method comparative example 1 and comparative example 3, purifying process of the present invention is simple, obtains product purity height.
It is obvious to a person skilled in the art that invention is not limited to the details of the above exemplary embodiments, Er Qie
In the case where without departing substantially from spirit or essential attributes of the invention, the present invention can be realized in other specific forms.Therefore, no matter
From the point of view of which point, the present embodiments are to be considered as illustrative and not restrictive, and the scope of the present invention is by appended power
Benefit requires rather than above description limits, it is intended that all by what is fallen within the meaning and scope of the equivalent elements of the claims
Variation is included within the present invention.
In addition, it should be understood that although this specification is described in terms of embodiments, but not each embodiment is only wrapped
Containing an independent technical solution, this description of the specification is merely for the sake of clarity, and those skilled in the art should
It considers the specification as a whole, the technical solutions in the various embodiments may also be suitably combined, forms those skilled in the art
The other embodiments being understood that.
Claims (10)
1. a kind of synthetic method of the bromo- 2- methylnicotinic acid ethyl ester of 5-, which comprises the following steps:
1) ethyl acetoacetate and alkali A are added in solvent B and carry out enolization；
2) intermediate III is added into step (1) and DABCO is reacted；
3) ammonium acetate is added and carries out cyclization；
4) water quenching is added to go out, organic solvent C extraction；
5) it removes organic solvent C and obtains crude product to be crystallized；
Crude product to be crystallized is recrystallized into obtain the bromo- 2- methylnicotinic acid ethyl ester of 5-.
2. synthetic method as described in claim 1, which is characterized in that alkali A described in step 1) is potassium tert-butoxide, quality used
It is 0.5-1.5 times of ethyl acetoacetate.
3. synthetic method as described in claim 1, which is characterized in that solvent B described in step 1) is to include but is not limited to
One of dioxane, 2- methyl-tetrahydro furans, tetrahydrofuran, glycol dimethyl ether, methyl tertiary butyl ether, ether, isopropyl ether
Ethers；Quality used in solvent B is not more than 50 times of ethyl acetoacetate quality.
4. synthetic method as described in claim 1, which is characterized in that step 2) the intermediate III structural formula are as follows:
Quality used is 3-4 times of ethyl acetoacetate quality；Quality used in DABCO is 0.5-1.0 times of ethyl acetoacetate quality；
Reaction temperature is subzero 78-5 DEG C, reaction time 4-6h.
5. synthetic method as described in claim 4, which is characterized in that reaction temperature is subzero 10-0 DEG C.
6. synthetic method as described in claim 1, which is characterized in that ammonium acetate quality used in step 3) is acetoacetate second
1-2 times of ester quality；Reaction temperature is 55-65 DEG C, reaction time 15-17h.
7. synthetic method as described in claim 1, which is characterized in that water used in step 4) is that quality is ethyl acetoacetate
25-30 times of quality of ice water；Organic solvent C is the MTBE that quality is 6.5-7.5 times of ethyl acetoacetate quality.
8. synthetic method as described in claim 1, which is characterized in that recrystallization temperature described in step 6) is subzero 30-100
℃。
9. synthetic method as described in claim 1, which is characterized in that recrystallization solvent used in step 6) be esters, ketone,
The mixture of one or more of ethers, halogenated hydrocarbons, alcohols, alkanes, recrystallization solvent quality used is no more than to be crystallized
40 times of crude product quality.
10. synthetic method as described in claim 8, which is characterized in that the esters include but is not limited to ethyl acetate and
Propyl acetate；The ketone includes but is not limited to acetone and butanone；The ethers includes but is not limited to dioxane, 2- methyl-
Tetrahydrofuran, tetrahydrofuran and glycol dimethyl ether；The halogenated hydrocarbons includes but is not limited to methylene chloride and chlorobenzene；The alcohols
Including but not limited to methanol, ethyl alcohol, normal propyl alcohol and isopropanol；The alkanes include but is not limited to pentane, n-hexane and just
Heptane.
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| EP0388620A1 (en) * | 1989-03-21 | 1990-09-26 | American Cyanamid Company | Process for the preparation of o-carboxypyridyl- and o-carboxyquinolylimidazolinones |
| EP1180514A1 (en) * | 1999-04-09 | 2002-02-20 | Meiji Seika Kaisha Ltd. | Nitrogen-containing heterocyclic compounds and benamide compounds and drugs containing the same |
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| CN103562200A (en) * | 2011-05-26 | 2014-02-05 | 伊莱利利公司 | Novel imidazole derivatives useful for the treatment of arthritis |
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