CN113135848A - Preparation method of mercaptoalkenol ester compound - Google Patents
Preparation method of mercaptoalkenol ester compound Download PDFInfo
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- CN113135848A CN113135848A CN202110453696.3A CN202110453696A CN113135848A CN 113135848 A CN113135848 A CN 113135848A CN 202110453696 A CN202110453696 A CN 202110453696A CN 113135848 A CN113135848 A CN 113135848A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/02—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of thiols
- C07C319/06—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of thiols from sulfides, hydropolysulfides or polysulfides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/10—Systems containing only non-condensed rings with a five-membered ring the ring being unsaturated
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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Abstract
The invention discloses a preparation method of mercaptoalkenoic ester compounds, belonging to the field of organic chemistry synthesis and aiming at solving the problems of high risk of scale-up production and the like, the synthetic route provided by the invention comprises three steps of reactions: (1) mixing starting materials of 2-ketoformate compounds and Tf2O (trifluoromethanesulfonic anhydride) generates trifluoromethanesulfonyl protected enol intermediate 1 under the action of alkali and solvent A; (2) then carrying out substitution reaction with a thionation reagent to obtain an intermediate 2; (3) and then the intermediate 2 is deprotected under the action of a deprotection reagent to obtain a target product 3. The invention has the beneficial effects that: the method for preparing the mercaptoalkenoic ester compound has novel process, avoids using toxic gases such as hydrogen sulfide and the like, improves the effects of the overall safety, the environmental protection and the like of the process, is more suitable for large-scale production, and solves the industrial problem.
Description
Technical Field
The invention belongs to the field of organic chemical synthesis, and particularly relates to a preparation method for synthesizing a mercaptoalkenoic ester compound.
Background
The mercaptoenol ester compound is a key intermediate for preparing novel medicines such as septicemia and the like. The main route for synthesizing the substances is shown as the following formula, and hydrogen sulfide methanol solution with higher concentration needs to be prepared in the reaction process, and then hydrogen chloride is introduced into the reaction liquid. Although the synthesis scheme is simple and convenient, hydrogen sulfide has toxicity and foul smell, great potential safety hazard exists when a large amount of hydrogen sulfide is used, and hydrogen chloride gas has strong irritation.
In summary, the above defects make the safety control of the route difficult and the risk of scale-up production high. Therefore, the industry does not have a mature process for preparing the mercaptoenol ester compound (J.Phys. org. chem.2009,22, 1188-742; J.Med. chem.2005,48, 7457-7467).
Disclosure of Invention
In view of the above problems in the prior art, the present invention aims to provide a method for preparing mercaptoalkenoic ester compounds, which comprises the following steps.
The synthetic route is a three-step reaction, and the specific synthetic route and the reaction conditions are as follows:
(1) mixing starting materials of 2-ketoformate compounds and Tf2O (trifluoromethanesulfonic anhydride) generates trifluoromethanesulfonyl protected enol intermediate 1 under the action of alkali and solvent A;
among the required bases are sodium hydrogen (NaH), sodium bis (trimethylsilyl) amide (NaHMDS), Diisopropylethylamine (DIPEA), and preferably NaH.
Among them, the solvent A is dichloromethane or tetrahydrofuran, preferably dichloromethane.
The specific operation mode is as follows: adding alkali (such as sodium hydrogen 1.5-2.0 eq.) into a reaction container (such as a three-neck flask), adding a solvent A, replacing with nitrogen, dropwise adding 2-ketoformate compounds (1.0eq.) into the reaction container at 0-5 ℃, keeping the temperature and stirring to uniformly disperse, then continuously cooling to-60-70 ℃, and continuously dropwise adding Tf2O (1.3 to 1.6eq.) is added into the reaction solution (the dropping speed is controlled and the proper value is maintained)And (4) reaction temperature), continuously preserving heat and stirring after the dropwise addition is finished to uniformly disperse, then naturally heating to 25-30 ℃, and stirring for reaction. After the reaction is completed, saturated NaHCO is used again3And adjusting the pH value of the solution to 8-9. The layers were separated, and the resulting organic phase was dried over anhydrous sodium sulfate and concentrated to give intermediate 1.
(2) Then carrying out substitution reaction with a thionation reagent to obtain an intermediate 2;
among them, the required thioreagent is potassium thioacetate, 4-methoxybenzyl mercaptan, and 4-methoxybenzyl mercaptan is preferable.
The specific operation mode is as follows: sodium hydrogen (1.2 to 1.5eq.) is added into a reaction vessel (such as a three-neck flask), and a solvent A is added for nitrogen replacement. And (3) reacting at 0-5 ℃, dropwise adding a thionizing agent (1.0eq.) and stirring at a constant temperature to uniformly disperse. Then, dropwise adding the intermediate 1(1.0eq.) into the reaction liquid (controlling the dropwise adding speed and maintaining the appropriate temperature), simultaneously preserving the temperature and stirring at 0-5 ℃, after the dropwise adding is finished, then stirring at room temperature for 8h, and after the reaction is finished, then adding saturated NaHCO3And adjusting the pH value of the solution to 8-9. Then, the resulting solution was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate 2.
(3) And then the intermediate 2 is deprotected under the action of a deprotection reagent to obtain a target product 3.
Among the desired deprotecting reagents are trifluoroacetic acid, 2, 3-dichloro-5, 6-dicyan-p-benzoquinone (DDQ) and cerium ammonium sulfate (CAN), preferably trifluoroacetic acid (TFA).
The specific operation mode is as follows: adding the intermediate 2(1.0eq.) into a reaction vessel (such as a three-neck flask), replacing with nitrogen, adding a deprotection reagent (6.0eq.), and stirring the reaction at 40-50 ℃; after the reaction is finished, the final product 3 is obtained through vacuum rectification.
4-methoxybenzyl mercaptan is used as a thioreagent, trifluoroacetic acid is used as a deprotection reagent, and the reaction route is shown as follows:
the invention has the beneficial effects that: the method for preparing the mercaptoalkenoic ester compound has novel process, avoids using toxic gases such as hydrogen sulfide and the like, improves the effects of the overall safety, the environmental protection and the like of the process, is more suitable for large-scale production, and solves the industrial problem.
Detailed Description
The present disclosure will be further explained and illustrated with reference to the following embodiments.
Example 1
(1) Synthesis of ethyl 2- (trifluoromethylsulfonyloxy) cyclohex-1-enecarboxylate (intermediate 1a, 122135-83-5)
In a 500mL three-necked flask, 60% sodium hydrogen (3.5g, 1.5eq.) was added, 200mL of methylene chloride was added, and nitrogen gas was replaced three times. Reacting at 0-5 ℃, dropwise adding 2-cyclohexanone ethyl formate (10.0g, 1.0eq.), keeping the temperature and stirring for 10min, then continuously cooling to-70 ℃, and dropwise adding Tf2O (24.3g, 1.5eq.) is added into the reaction solution (the dropping speed is controlled), the temperature is kept and the stirring is carried out for 15 minutes, and then the temperature is naturally raised to 25 ℃ and the stirring is carried out overnight; then saturated NaHCO was added3The pH of the solution is adjusted to 8-9, and the organic phase is dried over anhydrous sodium sulfate and concentrated to obtain an intermediate 1a (15.6g, 90.0% yield).
(2) Synthesis of ethyl 2- (4-methoxythiophenol) cyclohex-1-enecarboxylate (intermediate 2a)
In a 500mL three-necked flask, 60% sodium hydrogen (1.90g, 1.2eq.) was added, 120mL of methylene chloride was added, and nitrogen gas was replaced three times. Reacting at 0-5 ℃, dropwise adding 4-methoxybenzyl mercaptan (6.1g, 1.0eq.) and stirring for 10 minutes under heat preservation. Then, the intermediate 1a (12.0g, 1.0eq.) was added dropwise to the reaction mixture (the dropping rate was controlled), the mixture was stirred for 15 minutes while maintaining the temperature, then the mixture was naturally warmed to room temperature and stirred for 8 hours, and then anhydrous sodium sulfate was added to dry, and after filtration, the mixture was concentrated to obtain an intermediate 2a (11.4g, 93.4% yield).
(3) Synthesis of 2-mercaptocyclohexenecarboxylic acid ethyl ester (target product 3a)
To a 100mL three-necked flask, intermediate 2a (11.0g, 1.0eq.) was added and replaced with nitrogen three times. After addition of trifluoroacetic acid (24.5g, 6.0eq.) the reaction was left to stir at 50 ℃ for 6 h. After the reaction, the reaction mixture was concentrated under reduced pressure to remove volatile components, and then distilled under high vacuum and reduced pressure to obtain the final product 3a (6.0g, 90% yield).
Example 2
(1) Synthesis of ethyl 2- (trifluoromethylsulfonyloxy) cyclopent-1-enecarboxylate (intermediate 1b, 122539-74-6)
In a 500mL three-necked flask, 60% sodium hydrogen (3.5g, 1.5eq.) was added, 200mL of methylene chloride was added, and nitrogen gas was replaced three times. Reacting at 0-5 ℃, dropwise adding 2-cyclopentanone ethyl formate (9.2g, 1.0eq.), stirring for 10min under heat preservation, then continuously cooling to-70 ℃, and continuously dropwise adding Tf2O (24.9g, 1.5eq.) is added into the reaction solution (the dropping speed is controlled), the temperature is kept and the stirring is carried out for 15 minutes, and then the temperature is naturally raised to 25 ℃ and the stirring is carried out overnight; then saturated NaHCO was added3The pH of the solution is adjusted to 8-9, and the organic phase is dried over anhydrous sodium sulfate and concentrated to obtain an intermediate 1b (14.9g, 88.0% yield).
(2) Synthesis of ethyl 2- (4-methoxythiophenol) cyclopent-1-enecarboxylate (intermediate 2b)
In a 500mL three-necked flask, 60% sodium hydrogen (1.67g, 1.2eq.) was added, 120mL of methylene chloride was added, and nitrogen gas was replaced three times. Reacting at 0-5 ℃, dropwise adding 4-methoxybenzyl mercaptan (5.35g, 1.0eq.) and stirring for 10 minutes under heat preservation. Then, the intermediate 1b (10.0g, 1.0eq.) was added dropwise to the reaction mixture (the dropping rate was controlled), and the mixture was stirred for 15 minutes while maintaining the temperature, and then stirred for 5 hours while naturally warming to room temperature. Then dried over anhydrous sodium sulfate, filtered and concentrated to give intermediate 2b (9.1g, 90.2% yield).
(3) Synthesis of ethyl 2-mercaptocyclopentenecarboxylate (target product 3b)
To a 100mL three-necked flask, intermediate 2b (5.0g, 1.0eq.) was added and replaced with nitrogen three times. After the addition of trifluoroacetic acid (11.7g, 6.0eq.) the reaction was left to stir at 50 ℃ for 6 h. After the reaction, the reaction mixture was concentrated under reduced pressure to remove volatile components, and then distilled under high vacuum and reduced pressure to obtain the final product 3b (2.5g, 85% yield).
Example 3
(1) Synthesis of ethyl 2- (trifluoromethylsulfonyloxy) cyclohept-1-enecarboxylate (intermediate 1c, 122539-74-6)
In a 500mL three-necked flask, 60% sodium hydrogen (3.3g, 1.5eq.) was added, 200mL of methylene chloride was added, and nitrogen gas was replaced three times. Reacting at 0-5 ℃, dropwise adding 2-cycloheptanone ethyl formate (10.1g, 1.0eq.), keeping the temperature and stirring for 10min, then continuously cooling to-70 ℃, and continuously dropwise adding Tf2O (23.2g, 1.5eq.) is added into the reaction solution (the dropping speed is controlled), the temperature is kept and the stirring is carried out for 15 minutes, and then the temperature is naturally raised to 25 ℃ and the stirring is carried out overnight; then saturated NaHCO was added3The solution was adjusted to pH and the organic phase was dried over anhydrous sodium sulfate and concentrated to give intermediate 1c (14.7g, 85.0% yield).
(2) Synthesis of ethyl 2- (4-methoxythiophenol) cyclohepta-1-enecarboxylate (intermediate 2c)
In a 500mL three-necked flask, 60% sodium hydrogen (1.5g, 1.2eq.) was added, 120mL of methylene chloride was added, and nitrogen gas was replaced three times. Reacting at 0-5 ℃, dropwise adding 4-methoxybenzyl mercaptan (4.88g, 1.0eq.) and stirring for 10 minutes under heat preservation. Then, the intermediate 1c (10.0g, 1.0eq.) was added dropwise to the reaction mixture (the dropping rate was controlled), and the mixture was stirred for 15 minutes while maintaining the temperature, and then stirred for 5 hours while naturally warming to room temperature. Then dried over anhydrous sodium sulfate, filtered and concentrated to give intermediate 2c (8.9g, 88% yield).
(3) Synthesis of ethyl 2-mercaptocycloheptenecarboxylate (target product 3c)
To a 100mL three-necked flask, intermediate 2c (5.0g, 1.0eq.) was added and replaced with nitrogen three times. After the addition of trifluoroacetic acid (10.7g, 6.0eq.) the reaction was left to stir at 50 ℃ for 6 h. After the reaction, the reaction mixture was concentrated under reduced pressure to remove volatile components, and then distilled under high vacuum and reduced pressure to obtain the final product 3c (2.8g, 91.0% yield).
Claims (7)
1. The preparation method of the mercaptoalkenol ester compound is characterized by comprising the following steps:
(1) adding alkali and a solvent into a reaction container, replacing with nitrogen, dropwise adding 2-ketoformate compounds at a temperature of 0-5 ℃, keeping the temperature and stirring to uniformly disperse, then continuously cooling to-60-70 ℃, and dropwise adding Tf2O, continuing to keep the temperature and stir after the dropwise addition is finished to enable the mixture to be uniformly dispersed, then naturally heating to 25-30 ℃, stirring for reaction, adjusting the pH to 8-9 after the reaction is finished, then separating liquid, drying an organic phase, and concentrating to obtain an intermediate 1;
(2) adding alkali and a solvent into a reaction container, replacing with nitrogen, dropwise adding a thioreagent at a controlled temperature of 0-5 ℃, keeping the temperature and stirring to uniformly disperse, then dropwise adding the intermediate 1, keeping the temperature and stirring at 0-5 ℃, stirring at room temperature after the dropwise adding is finished until the reaction is finished, adjusting the pH to 8-9 after the reaction is finished, separating liquid, drying an organic phase, and concentrating to obtain an intermediate 2;
(3) and adding the intermediate 2 into a reaction container, performing nitrogen displacement, adding a deprotection reagent, placing the reaction in a temperature range of 40-50 ℃, stirring until the reaction is finished, and performing reduced pressure rectification to obtain a final product 3.
2. The process for preparing mercaptoalkenoic acid esters according to claim 1 wherein in step (1) the base is sodium hydrogen, sodium bis (trimethylsilyl) amide and/or diisopropylethylamine.
3. The process for producing mercaptoalkenoic ester according to claim 1 wherein the solvent in steps (1) and (2) is dichloromethane, tetrahydrofuran.
4. The process for preparing mercaptoalkenoic esters according to claim 1 wherein the pH adjustment in steps (1) and (2) is effected by saturated NaHCO3And (3) solution.
5. The process for producing mercaptoalkenoic ester according to claim 1 wherein the drying in steps (1) and (2) is carried out using anhydrous sodium sulfate.
6. The method of claim 1, wherein the thionating agent in step (2) is potassium thioacetate or 4-methoxybenzyl mercaptan.
7. The method of claim 1, wherein the deprotection reagent in step (3) is trifluoroacetic acid, 2, 3-dichloro-5, 6-dicyan-p-benzoquinone and/or cerium ammonium sulfate.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113636960A (en) * | 2021-08-24 | 2021-11-12 | 上海皓元医药股份有限公司 | Preparation method of 2- (chlorosulfonyl) cyclohexane-1-ethyl olefin formate derivative |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106413402A (en) * | 2014-03-13 | 2017-02-15 | 美国印第安纳大学研究和技术公司 | Hepatitis b core protein allosteric modulators |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106413402A (en) * | 2014-03-13 | 2017-02-15 | 美国印第安纳大学研究和技术公司 | Hepatitis b core protein allosteric modulators |
Non-Patent Citations (2)
| Title |
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| MASAMI YAMADA ET AL.: "Discovery of novel and potent small-molecule inhibitors of NO and cytokine production as antisepsis agents：synthesis and biological activitity of alkyl 6-（N-Substituted sulfamoyl）cyclohex-1-ene-1-carboxylate", 《J.MED.CHEM.》 * |
| SHIGEKI ISOMURA ET AL.: "Synthesis Properties，and Reactivity ofcocaine benzoylthio ester possessing the cocaine absolute configuration", 《JACS》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113636960A (en) * | 2021-08-24 | 2021-11-12 | 上海皓元医药股份有限公司 | Preparation method of 2- (chlorosulfonyl) cyclohexane-1-ethyl olefin formate derivative |
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