CN103936666B - A kind of synthetic method of 2,4-dioxopiperidine - Google Patents
A kind of synthetic method of 2,4-dioxopiperidine Download PDFInfo
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
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Abstract
The invention discloses a kind of 2; 4-dioxopiperidine synthetic method; the method with malonic acid monomethyl ester and 3-aminopropanoate hydrochloride or 3-alanine carbethoxy hydrochloride for initial feed; take methylene dichloride as solvent, dicyclohexylcarbodiimide (DDC) is react under the condition of acid binding agent as dewatering agent, triethylamine; acidylate condensation product methyl-3-((3-methoxyl group-3-carbonyl propyl group) is amino)-3-carbonyl propionic acid ester; using salt as catalyzer in acidylate condensation reaction, this catalyst selectivity is good, side reaction is few, yield is higher.Then under the effect of sodium methylate, cyclization shortens 3-(methoxycarbonyl (methoxycarbonyl))-4-carbonyl-1 into, 4,5,6-tetrahydropyridine-2-alkyd sodium, then decarboxylation becomes 2 in hydrochloric acid system, 4-dioxopiperidine, in whole reaction, because methoxyl group is easily sloughed, reaction raw materials is easy to get, reaction conditions is gentle, operational safety and transformation efficiency is high.
Description
Technical field
The invention belongs to technical field of fine, be specifically related to a kind of synthetic method of medicine intermediate 2,4-dioxopiperidine.
Background technology
2,4-dioxopiperidine is a kind of important medicine intermediate, its derivative is widely used in the fields such as antibacterial, antitumor, as passed through 2, alosetron hydrochloride (AlosetronHydrochloride prepared by 4-dioxopiperidine, its chemistry by name 2,3,4,5-tetrahydrochysene-5-methyl-2-[(5-methyl isophthalic acid H-imidazol-4 yl) methyl]-1H-pyrido [4,3-b] indoles-1-keto hydrochloride), be a kind of effective, highly selective 5-HT3 receptor antagonist, be also the new drug that first of FDA approval is in recent years used for the treatment of the easy syndrome of intestines (IBS) simultaneously.Be colorless oil under 2,4-dioxopiperidine room temperature, molecular formula: C
5h
4nO
2it is a kind of newer medicine intermediate, existing synthesis technique is: take monoethyl malonate as raw material, utilize sulfur oxychloride for solvent, reflux obtains acyl chlorides, then with 3-alanine ethyl ester Reactive Synthesis, the raw materials used corrodibility of this technique is very strong, easy generation by product also makes product colour deepen, can to environment in suitability for industrialized production.
Summary of the invention
The object of this invention is to provide a kind of synthetic method of 2,4-dioxopiperidine, adopt raw material corrodibility very strong to solve existing technique, easily produce by product and the problem to environment.
Realizing technical scheme of the present invention is: a kind of synthetic method of 2,4-dioxopiperidine, comprises the steps:
(1) acidylate: add methylene dichloride in reaction flask, chemical compounds I is added under stirring, then acid binding agent triethylamine, saline catalyst, dewatering agent dicyclohexylcarbodiimide is added at 5-15 DEG C of temperature, keep temperature of reaction at 5-15 DEG C, be added dropwise to malonic acid monomethyl ester, and react 15-20h, end is reacted, washes, is distilled out compound ii;
(2) condensation: the compound ii of above-mentioned preparation is dissolved in toluene solution, under sodium methylate existence and reflux conditions, condensation obtains intermediate product B;
(3) decarboxylation: the intermediate product B decarboxylation that refluxes in hydrochloric acid system obtains 2,4-dioxopiperidine;
Above-claimed cpd I is: the one in 3-aminopropanoate hydrochloride or 3-alanine carbethoxy hydrochloride, and compound ii is methyl-3-((3-methoxyl group-3-carbonyl propyl group) is amino)-3-carbonyl propionic acid ester.
Preferably, described saline catalyst is selected from (2-(7-azo benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester), (one in 2-(7-azo benzotriazole)-tetramethyl-urea phosphofluoric acid ester or phosphofluoric acid benzotriazole-1-base-oxygen base tripyrrole alkyl phosphorus, its addition is the 5-7% of chemical compounds I quality.
Preferably, in described step (1), temperature of reaction is 5-15 DEG C, and the reaction times is 15-20h.
Preferably, described step (2) condensation detailed process is, under normal temperature, sodium methylate solid is added, by this mixture reflux 1-1.5h, after reacting completely in this reaction solution, reaction solution is cooled to 5-15 DEG C, filters to obtain intermediate product B, product is faint yellow solid powder.
Preferably, described step (3) decarboxylation detailed process is, disposablely in the intermediate product B obtained adds hydrochloric acid, and then by this reaction solution reflux 2-3h, concentrated mother liquor, the finished product are separated out in cooling.
Preferably, in described step (1), methylene dichloride addition is 4-6 times of chemical compounds I quality, triethylamine addition is 1-2 times of chemical compounds I quality, and malonic acid monomethyl ester addition is 0.8-1 times of chemical compounds I quality, and addition is 0.8-1 times of chemical compounds I quality.
Preferably, in described step (2), toluene addition is 0.3 times of chemical compounds I quality, and sodium methylate addition is 2.5-3 times of chemical compounds I quality.
Preferably, in described step (3), hydrochloric acid addition is 2.5-4 times of chemical compounds I quality.
The reaction process chemical equation of the synthetic method of the present invention 2,4-dioxopiperidine is as follows:
Synthetic method of the present invention with malonic acid monomethyl ester and 3-aminopropanoate hydrochloride or 3-alanine carbethoxy hydrochloride for initial feed; acidylate condensation product compound ii; using salt as catalyzer in acidylate condensation reaction, this catalyst selectivity is good, side reaction is few, yield is higher.Then under the effect of sodium methylate, cyclization shortens 3-(methoxycarbonyl (methoxycarbonyl))-4-carbonyl-1 into, 4,5,6-tetrahydropyridine-2-alkyd sodium, then decarboxylation becomes 2 in hydrochloric acid system, 4-dioxopiperidine, in whole reaction, because methoxyl group is easily sloughed, reaction raw materials is easy to get, reaction conditions is gentle, operational safety and transformation efficiency is high.
Embodiment
In embodiment, material used is as follows: raw material one: malonic acid monomethyl ester, chemical compounds I: 3-aminopropanoate hydrochloride or 3-alanine carbethoxy hydrochloride, compound ii: methyl-3-((3-methoxyl group-3-carbonyl propyl group) is amino)-3-carbonyl propionic acid ester, dewatering agent: dicyclohexylcarbodiimide (DDC);
Salt acidylate condensation catalyst is as follows:
(2-(7-azo benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester) (writing a Chinese character in simplified form: HATU),
(2-(7-azo benzotriazole)-tetramethyl-urea phosphofluoric acid ester (writing a Chinese character in simplified form: HBTU)
Phosphofluoric acid benzotriazole-1-base-oxygen base tripyrrole alkyl phosphorus (writing a Chinese character in simplified form: PyBOP);
Intermediate product B:3-(methoxycarbonyl (methoxycarbonyl))-4-carbonyl-Isosorbide-5-Nitrae, 5,6-tetrahydropyridine-2-alkyd sodium.
Embodiment 1: chemical compounds I is 3-aminopropanoate hydrochloride,
(1) acidylate: add 150g methylene dichloride in reaction flask; under stirring; add 20g chemical compounds I; then the temperature in reaction flask is down to 10 DEG C, adds 35g triethylamine, after adding; control temperature is 10 DEG C; add DCC, 1.5gHATU of 17.6g raw material one, 25g successively, this mixture is kept stirring reaction 20h under 10 DEG C of conditions, reaction terminates.
Aftertreatment: first filter out the solid DCC in reaction solution, filtrate pH be 5 dilute hydrochloric acid wash, with anhydrous sodium sulfate drying, steam desolventize compound ii product is weak yellow liquid.
(2) condensation: the compound ii of above-mentioned preparation is dissolved in 60g toluene solution, under normal temperature, 6.8g sodium methylate solid is once added in this reaction solution, by this mixture reflux 1h, after reacting completely, reaction solution is cooled to 10 DEG C, filters to obtain intermediate product B, product is faint yellow solid powder.
(3) decarboxylation: the disposable hydrochloric acid 60g adding 1mol/L in the intermediate product B obtained, then by this reaction solution reflux 2h, after TLC detection reaction is complete, distillation and concentration mother liquor, white crystal 2,4-dioxopiperidine is separated out in cooling, drying is weighed as 10.3 grams, and productive rate is 61%.
Embodiment 2: catalyzer adopts HBTU, and chemical compounds I is 3-aminopropanoate hydrochloride,
(1) acidylate: add 120g methylene dichloride in reaction flask; under stirring; add 25g chemical compounds I; then the temperature in reaction flask is down to 8 DEG C, adds 30g triethylamine, after adding; control temperature is 8 DEG C; add 16g raw material one, 20gDCC, 1.4gHBTU successively, this mixture is kept stirring reaction 18h under 8 DEG C of conditions, reaction terminates.
Aftertreatment: first filter out the solid DCC in reaction solution, filtrate pH be 5 dilute hydrochloric acid wash, with anhydrous sodium sulfate drying, steam desolventize to obtain 30.6g compound ii, product is weak yellow liquid.
(2) condensation: the compound ii of above-mentioned preparation is dissolved in 62.5g toluene solution, under normal temperature, 6.0g sodium methylate solid is once added in this reaction solution, by this mixture reflux 1.5h, after reacting completely, reaction solution is cooled to 8 DEG C, filters to obtain intermediate product B, product is faint yellow solid powder.
(3) decarboxylation: the disposable hydrochloric acid 62.5g adding 1mol/L in the intermediate product B obtained, then by this reaction solution reflux 3h, after TLC detection reaction is complete, distillation and concentration mother liquor, white crystal 2,4-dioxopiperidine is separated out in cooling, drying is weighed as 9.6 grams, and calculating productive rate is 57%.
Embodiment 3 catalyzer adopts pyBOP, and chemical compounds I is 3-aminopropanoate hydrochloride,
(1) acidylate: add 100g methylene dichloride in reaction flask; under stirring; add 20g chemical compounds I; then the temperature in reaction flask is down to 5 DEG C, adds 37.5g triethylamine, after adding; control temperature is 5 DEG C; add the pyBOP of 20g raw material one, 16gDCC, 1.25g successively, this mixture is kept stirring reaction 18h under 5 DEG C of conditions, reaction terminates.
Aftertreatment: first filter out the solid DCC in reaction solution, filtrate pH be 5 dilute hydrochloric acid wash, with anhydrous sodium sulfate drying, steam desolventize to obtain 32.1g compound ii, product is weak yellow liquid.
(2) condensation: the compound ii of above-mentioned preparation is dissolved in 75g toluene solution, under normal temperature, 7.5g sodium methylate solid is once added in this reaction solution, by this mixture reflux 1.2h, after reacting completely, reaction solution is cooled to 5 DEG C, filters to obtain intermediate product B, product is faint yellow solid powder.
(3) decarboxylation: the disposable hydrochloric acid 75g adding 1mol/L in the intermediate product B obtained, then by this reaction solution reflux 2.5h, after TLC detection reaction is complete, distillation and concentration mother liquor, white crystal 2,4-dioxopiperidine is separated out in cooling, drying is weighed as 10.6 grams, and calculating productive rate is 63%.
Embodiment 4: chemical compounds I is 3-aminopropanoate hydrochloride,
(1) acidylate: add 80g methylene dichloride in reaction flask; under stirring; add 20g chemical compounds I; then the temperature in reaction flask is down to 15 DEG C, adds 40g triethylamine, after adding; control temperature is 15 DEG C; add the HATU of DCC, 1.0g of 25g raw material one, 25g successively, this mixture is kept stirring reaction 20h under 15 DEG C of conditions, reaction terminates.
Aftertreatment: first filter out the solid DCC in reaction solution, filtrate pH be 5 dilute hydrochloric acid wash, with anhydrous sodium sulfate drying, steam desolventize compound ii product is weak yellow liquid.
(2) condensation: the compound ii of above-mentioned preparation is dissolved in 40g toluene solution, under normal temperature, 6.0g sodium methylate solid is once added in this reaction solution, by this mixture reflux 1.5h, after reacting completely, reaction solution is cooled to 15 DEG C, filters to obtain intermediate product B, product is faint yellow solid powder.
(3) decarboxylation: the disposable hydrochloric acid 80g adding 1mol/L in the intermediate product B obtained, then by this reaction solution reflux 3h, after TLC detection reaction is complete, distillation and concentration mother liquor, white crystal 2,4-dioxopiperidine is separated out in cooling, drying is weighed as 10.8 grams, and calculating productive rate is 64%.
Embodiment 5: chemical compounds I is 3-alanine carbethoxy hydrochloride,
(1) acidylate: add 100g methylene dichloride in reaction flask; under stirring; add 20g chemical compounds I; then the temperature in reaction flask is down to 10 DEG C, adds 25g triethylamine, after adding; control temperature is 10 DEG C; add DCC, 1.5gHATU of 17.6g raw material one, 25g successively, this mixture is kept stirring reaction 20h under 10 DEG C of conditions, reaction terminates.
Aftertreatment: first filter out the solid DCC in reaction solution, filtrate pH be 5 dilute hydrochloric acid wash, with anhydrous sodium sulfate drying, steam desolventize compound ii product is weak yellow liquid.
(2) condensation: the compound ii of above-mentioned preparation is dissolved in 50g toluene solution, under normal temperature, 6.0g sodium methylate solid is once added in this reaction solution, by this mixture reflux 1h, after reacting completely, reaction solution is cooled to 10 DEG C, filters to obtain intermediate product B, product is faint yellow solid powder.
(3) decarboxylation: the disposable hydrochloric acid 50g adding 1mol/L in the intermediate product B obtained, then by this reaction solution reflux 3h, after TLC detection reaction is complete, distillation and concentration mother liquor, white crystal 2,4-dioxopiperidine is separated out in cooling, drying is weighed as 7.5 grams, and calculating productive rate is 45%.
Structural Identification has been carried out to intermediate product of the present invention and final product,
Claims (6)
1. the synthetic method of a dioxopiperidine, is characterized in that it comprises the steps:
(1) acidylate: add methylene dichloride in reaction flask, chemical compounds I is added under stirring, then acid binding agent triethylamine, saline catalyst, dewatering agent dicyclohexylcarbodiimide is added at 5-15 DEG C of temperature, keep temperature of reaction at 5-15 DEG C, be added dropwise to malonic acid monomethyl ester, and react 15-20h, end is reacted, washes, is distilled out compound ii;
(2) condensation: be dissolved in toluene solution by the compound ii of above-mentioned preparation, under sodium methylate existence and reflux conditions, condensation obtains intermediate product B, and intermediate product B is
;
(3) decarboxylation: the intermediate product B decarboxylation that refluxes in hydrochloric acid system obtains 2,4-dioxopiperidine;
Above-claimed cpd I is: the one in 3-aminopropanoate hydrochloride or 3-alanine carbethoxy hydrochloride, compound ii is
;
Described saline catalyst is selected from (2-(7-azo benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester), (one in 2-(7-azo benzotriazole)-tetramethyl-urea phosphofluoric acid ester or phosphofluoric acid benzotriazole-1-base-oxygen base tripyrrole alkyl phosphorus, its addition is the 5-7% of chemical compounds I quality.
2. one 2 as claimed in claim 1, the synthetic method of 4-dioxopiperidine, it is characterized in that: described step (2) condensation detailed process is, under normal temperature, in this reaction solution, add sodium methylate solid, by this mixture reflux 1-1.5h, after reacting completely, reaction solution is cooled to 5-15 DEG C, filters to obtain intermediate product B, product is faint yellow solid powder.
3. the synthetic method of a kind of 2,4-dioxopiperidine as claimed in claim 1 or 2, is characterized in that: described step (3) decarboxylation detailed process is, disposablely in the intermediate product B obtained add hydrochloric acid, then by this reaction solution reflux 2-3h, concentrated mother liquor, the finished product are separated out in cooling.
4. one 2 as claimed in claim 3, the synthetic method of 4-dioxopiperidine, it is characterized in that: in described step (1), methylene dichloride addition is 4-6 times of chemical compounds I quality, triethylamine addition is 1-2 times of chemical compounds I quality, malonic acid monomethyl ester addition is 0.8-1 times of chemical compounds I quality, and the addition of dewatering agent dicyclohexylcarbodiimide is 0.8-1 times of chemical compounds I quality.
5. the synthetic method of a kind of 2,4-dioxopiperidine as claimed in claim 4, is characterized in that: in described step (2), toluene addition is 0.3 times of chemical compounds I quality, sodium methylate addition is 2.5-3 times of chemical compounds I quality.
6. the synthetic method of a kind of 2,4-dioxopiperidine as claimed in claim 5, is characterized in that: in described step (3), hydrochloric acid addition is 2.5-4 times of chemical compounds I quality.
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| Bu-2313, A NEW ANTIBIOTIC COMPLEX ACTIVE AGAINST ANAEROBES III. SEMI-SYNTHESIS OF Bu-2313 A AND B, AND THEIR ANALOGS;SOICHIRO TODA, et al.;《THE JOURNAL OF ANTIBIOTICS》;19800229;第XXXIII卷(第2期);173-181 * |
| Extending the Scope of the Aza-Fischer Synthesis of 4- and 6-Azaindoles;David Thomae, et al.;《Eur. J. Org. Chem.》;20131231;3328–3336 * |
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Effective date of registration: 20180314 Address after: 730020 Chengguan District, Lanzhou City, Gansu Province, Chengping No. 1 Patentee after: Lanzhou High-Tech Chemical Company Address before: 730000 Chengguan District, Lanzhou City, Gansu Province, Chengping No. 1 Patentee before: Gansu Research Institute of Chemical Industry |
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Address after: 730000 No. 3, Nanchang Road, Chengguan District, Gansu, Lanzhou Patentee after: Lanzhou Fine Chemical Co.,Ltd. Address before: 730020, 1, Gucheng Ping, Chengguan District, Gansu, Lanzhou Patentee before: LANZHOU HIGH-TECH CHEMICAL Co. |