CN111533656A - Synthesis method of tert-butyl 4-methoxy-3-oxobutyrate - Google Patents
Synthesis method of tert-butyl 4-methoxy-3-oxobutyrate Download PDFInfo
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- CN111533656A CN111533656A CN202010464096.2A CN202010464096A CN111533656A CN 111533656 A CN111533656 A CN 111533656A CN 202010464096 A CN202010464096 A CN 202010464096A CN 111533656 A CN111533656 A CN 111533656A
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- butyl
- methoxy
- oxobutyrate
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- LOFQPGJUYHMGIO-UHFFFAOYSA-N tert-butyl 4-methoxy-3-oxobutanoate Chemical compound COCC(=O)CC(=O)OC(C)(C)C LOFQPGJUYHMGIO-UHFFFAOYSA-N 0.000 title claims abstract description 46
- 238000001308 synthesis method Methods 0.000 title claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 33
- RMIODHQZRUFFFF-UHFFFAOYSA-N methoxyacetic acid Chemical compound COCC(O)=O RMIODHQZRUFFFF-UHFFFAOYSA-N 0.000 claims abstract description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 20
- -1 acyl imidazole Chemical compound 0.000 claims abstract description 17
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims abstract description 17
- NGGGZUAEOKRHMA-UHFFFAOYSA-N 3-[(2-methylpropan-2-yl)oxy]-3-oxopropanoic acid Chemical compound CC(C)(C)OC(=O)CC(O)=O NGGGZUAEOKRHMA-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000002904 solvent Substances 0.000 claims abstract description 12
- 239000007818 Grignard reagent Substances 0.000 claims abstract description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 10
- WXKNALUCQHFLLA-UHFFFAOYSA-M CC(C)(C)OC(=O)CC(=O)O[Mg] Chemical compound CC(C)(C)OC(=O)CC(=O)O[Mg] WXKNALUCQHFLLA-UHFFFAOYSA-M 0.000 claims abstract description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 36
- 238000000034 method Methods 0.000 claims description 22
- 239000000243 solution Substances 0.000 claims description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- 230000002194 synthesizing effect Effects 0.000 claims description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 18
- 239000012043 crude product Substances 0.000 claims description 12
- 239000012074 organic phase Substances 0.000 claims description 12
- 230000015572 biosynthetic process Effects 0.000 claims description 11
- 238000003786 synthesis reaction Methods 0.000 claims description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical class OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 11
- 239000003814 drug Substances 0.000 description 6
- 239000002994 raw material Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 125000002252 acyl group Chemical group 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- GRBMOFAYJFJXCG-UHFFFAOYSA-L magnesium;3-[(2-methylpropan-2-yl)oxy]-3-oxopropanoate Chemical compound [Mg+2].CC(C)(C)OC(=O)CC([O-])=O.CC(C)(C)OC(=O)CC([O-])=O GRBMOFAYJFJXCG-UHFFFAOYSA-L 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 230000000171 quenching effect Effects 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- ZPMWWAIBJJFPPQ-UHFFFAOYSA-N 2-ethoxyacetyl chloride Chemical compound CCOCC(Cl)=O ZPMWWAIBJJFPPQ-UHFFFAOYSA-N 0.000 description 1
- NGGGZUAEOKRHMA-UHFFFAOYSA-M 3-[(2-methylpropan-2-yl)oxy]-3-oxopropanoate Chemical compound CC(C)(C)OC(=O)CC([O-])=O NGGGZUAEOKRHMA-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- JAMFGQBENKSWOF-UHFFFAOYSA-N bromo(methoxy)methane Chemical compound COCBr JAMFGQBENKSWOF-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- QGBPKJFJAVDUNC-UHFFFAOYSA-N methyl 4-methoxy-3-oxobutanoate Chemical compound COCC(=O)CC(=O)OC QGBPKJFJAVDUNC-UHFFFAOYSA-N 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a synthesis method of tert-butyl 4-methoxy-3-oxobutyrate, which comprises the following steps: s1, reacting methoxyacetic acid with CDI at 0-20 ℃ under the protection of nitrogen to generate acyl imidazole; s2, dissolving mono-tert-butyl malonate in a solvent, dropwise adding an isopropyl Grignard reagent under an ice bath condition, and reacting at the temperature of-10-25 ℃ to generate magnesium mono-tert-butyl malonate; s3, dropping the solution after the S2 reaction into the solution after the S1 reaction, and reacting for 15-18 hours at 20-35 ℃ to generate the tert-butyl 4-methoxy-3-oxobutyrate. The synthesis method provided by the invention has the advantages of low cost, high efficiency and mild reaction conditions, and is suitable for large-scale industrial production.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a synthesis method of tert-butyl 4-methoxy-3-oxobutyrate.
Background
The drug is a very complex organic compound, and the corresponding synthetic process is a very time-consuming and long-term process, in other words, the drug cannot be synthesized in place at one time by only one reaction, but is synthesized in stages and steps, and the compounds which are generated at each stage in the synthetic process and do not reach the structural formula of the drug are collectively called medical intermediates. More than 2000 raw materials and intermediates matched with chemical industry are required in China every year, and the demand is more than 250 million tons. Therefore, the method has the advantages of improving the synthesis yield of important medical intermediates, simplifying the synthesis operation and reducing the cost, and plays a good role in promoting the development of medicine synthesis.
4-methoxy-3-oxobutyric acid tert-butyl ester is an important high-grade intermediate in medicine synthesis, and two main synthetic routes are as follows:
route 1
Firstly, methoxy acetic acid is converted into oxygen methoxy acetyl chloride, then tert-butyl acetate is reacted with LiHMDS low-temperature hydrogen and ethoxy acetyl chloride to generate the oxygen methoxy acetyl chloride, and the obtained product is finally purified by rectification.
Route 2
Bromomethyl methyl ether is used as a raw material to prepare a Grignard reagent which reacts with tert-butyl malonate at low temperature to generate a product, and the product is purified by rectification.
The two synthetic routes have extremely low yield, and the reaction conditions are harsh and cannot be industrially generated. Therefore, a method for synthesizing tert-butyl 4-methoxy-3-oxobutyrate, which has the advantages of simple production process, high yield, easiness in purification and suitability for industrialization, is urgently needed.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a method for synthesizing tert-butyl 4-methoxy-3-oxobutyrate, which adopts methoxyacetic acid and mono-tert-butyl malonate as raw materials to synthesize the tert-butyl 4-methoxy-3-oxobutyrate under mild conditions.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention provides a synthesis method of tert-butyl 4-methoxy-3-oxobutyrate, which comprises the following steps:
reacting methoxyacetic acid and CDI (N, N-carbonyl-diimidazole) at 0-20 ℃ for 1.5-3.5 hours under the protection of nitrogen to generate acyl imidazole;
dissolving mono-tert-butyl malonate in a solvent, then dropwise adding an isopropyl Grignard reagent, and reacting for 1-2 hours at the temperature of-10-25 ℃ to generate mono-tert-butyl malonate magnesium salt;
and step three, dripping the solution reacted in the step two into the solution reacted in the step one, and reacting for 15-18 hours at the temperature of 20-35 ℃ to generate the tert-butyl 4-methoxy-3-oxobutyrate.
Further, the solvent used in the reaction of step one is tetrahydrofuran or 2-methyltetrahydrofuran.
Further preferably, the solvent used in the reaction of step one is tetrahydrofuran.
Further, the specific operation process of the step one is as follows: dissolving methoxyacetic acid in tetrahydrofuran, adding CDI solid in batches at the temperature of 20 ℃ under ice bath condition, and reacting for 2 hours at the temperature of 20 ℃ under the protection of nitrogen after the addition is finished.
Further, in the first step, the molar ratio of the methoxyacetic acid to the CDI is 10: 11.
further, the molar ratio of the mono-tert-butyl malonate to the isopropyl grignard reagent in the second step is 1: 2.
Further, the molar ratio of methoxyacetic acid to mono-tert-butyl malonate was 1: 1.
Further, the reaction conditions in the second step were 0 ℃ and the reaction time was 1 hour.
Further, the reaction conditions in the third step were 20 ℃ and the reaction time was 16 hours.
Further, the third step further comprises the following steps:
s1, extracting and killing the reaction by using saturated citric acid aqueous solution, extracting by using ethyl acetate, and combining organic phases;
s2, washing the organic phase once with saturated saline, then drying with anhydrous sodium sulfate, filtering, desolventizing to obtain a crude product of the tert-butyl 4-methoxy-3-oxobutyrate;
s3, rectifying the crude product to obtain colorless liquid, namely the tert-butyl 4-methoxy-3-oxobutyrate.
Further, the temperature of the fraction in S3 was 80 ℃.
By adopting the technical scheme, compared with the prior art, the invention has the following technical effects:
in the invention, methoxy ethyl and mono-tert-butyl malonate are adopted as raw materials, the raw materials are easy to obtain and cheap, flammable and explosive reagents are not used in the whole synthesis process, the reaction condition temperature is mild, the post-treatment is less, and the yield is high.
Detailed Description
The invention provides a synthesis method of tert-butyl 4-methoxy-3-oxobutyrate, which comprises the following steps:
reacting methoxyacetic acid and CDI (N, N-carbonyl-diimidazole) at 0-30 ℃ for 1.5-3.5 hours under the protection of nitrogen to generate acyl imidazole;
dissolving mono-tert-butyl malonate in a solvent, dropwise adding an isopropyl Grignard agent under an ice bath condition, and reacting at the temperature of-10-30 ℃ to generate a magnesium salt of mono-tert-butyl malonate;
and step three, dripping the solution reacted in the step two into the solution reacted in the step one, and reacting for 15-18 hours at the temperature of 10-40 ℃ to generate the tert-butyl 4-methoxy-3-oxobutyrate after finishing dripping.
The specific operation process of the step one is as follows: dissolving the methoxyacetic acid in the tetrahydrofuran, adding the CDI solid in batches at the temperature of 20 ℃ under ice bath condition, and reacting for 2 hours at 20 ℃ under the protection of nitrogen after the addition is finished.
In a preferred embodiment of the present invention, the solvent used in the reaction of step one is tetrahydrofuran or 2-methyltetrahydrofuran, more preferably tetrahydrofuran.
In a preferred embodiment of the invention, the molar ratio of methoxyacetic acid to CDI in step one is 10: 11; in the second step, the molar ratio of the mono-tert-butyl malonate to the isopropyl grignard reagent is 1: 2; the molar ratio of the methoxy acetic acid to the mono-tert-butyl malonate is 1: 1.
in a preferred embodiment of the present invention, the reaction conditions of step two are 0 ℃ and the reaction time is 1 hour; the reaction condition of the third step is 20 ℃, and the reaction time is 16 hours.
In a preferred embodiment of the present invention, step three further includes the following steps:
s1, extracting and killing the reaction by using saturated citric acid aqueous solution, extracting by using ethyl acetate, and combining organic phases;
s2, washing the organic phase once with saturated saline, then drying with anhydrous sodium sulfate, filtering, and desolventizing to obtain the crude product of the tert-butyl 4-methoxy-3-oxobutyrate;
s3, rectifying the crude product to obtain colorless liquid, namely the tert-butyl 4-methoxy-3-oxobutyrate.
In a preferred embodiment of the present invention, the temperature of the fraction in S3 is 80 ℃.
The present invention will be described in detail and specifically with reference to the following examples to facilitate better understanding of the present invention, but the following examples do not limit the scope of the present invention.
Example 1
This example provides a preferred method for the synthesis of tert-butyl 4-methoxy-3-oxobutyrate, with reference to the following synthetic route, comprising the steps of:
step one, synthesizing methoxyacetic acid acyl imidazole:
9g (0.1mol) of methoxyacetic acid is dissolved in 90ml of tetrahydrofuran, CDI solid (17.8g, 0.11mol) is added in batches at the temperature of 20 ℃ under ice bath condition, and after the addition is finished, the solution is reacted for 2.5 hours at the temperature of 0 ℃ under the protection of nitrogen, and the solution 1 is obtained and directly enters the next reaction without any treatment.
Step two, synthesizing a malonic acid mono-tert-butyl ester magnesium salt:
dissolving mono-tert-butyl malonate (16g, 0.1mol) in 80ml of tetrahydrofuran, dropwise adding 8ml (0.2mol) of isopropyl Grignard reagent (2M tetrahydrofuran solution) at the temperature of-10 ℃ in an ice bath, and reacting for 2 hours at the temperature of-10 ℃ after dropwise adding is finished, namely directly carrying out the next reaction on the solvent 2 without any treatment.
Step three, synthesizing tert-butyl 4-methoxy-3-oxobutyrate:
dropwise adding the solution 2 obtained in the step two into the solution 1 obtained in the step one under the condition of ice bath temperature control of 25 ℃, reacting for 18 hours at 20 ℃, extracting and quenching the reaction by using saturated citric acid aqueous solution, extracting by using ethyl acetate (3 x 150ml), combining organic phases, washing the organic phases once by using saturated salt water, drying by using anhydrous sodium sulfate, filtering, desolventizing to obtain a crude product of the tert-butyl 4-methoxy-3-oxobutyrate, and rectifying the crude product to obtain 14.5g of the tert-butyl 4-methoxy-3-oxobutyrate. Wherein the temperature of the distillate was 80 ℃.
The finally obtained 4-methoxy-3-oxobutanoic acid tert-butyl ester was a colorless liquid, yield 77.3%.
Example 2
This example provides a preferred method for the synthesis of tert-butyl 4-methoxy-3-oxobutyrate, with reference to the following synthetic route, comprising the steps of:
step one, synthesizing methoxyacetic acid acyl imidazole:
9g (0.1mol) of methoxyacetic acid is dissolved in 90ml of tetrahydrofuran, CDI solid (17.8g, 0.11mol) is added in batches at the temperature of 20 ℃ under ice bath condition, and after the addition is finished, the solution is reacted for 2 hours at the temperature of 20 ℃ under the protection of nitrogen, and the solution 1 is obtained and directly enters the next reaction without any treatment.
Step two, synthesizing a malonic acid mono-tert-butyl ester magnesium salt:
dissolving mono-tert-butyl malonate (16g, 0.1mol) in 80ml of tetrahydrofuran, dropwise adding 8ml (0.2mol) of isopropyl Grignard reagent (2M tetrahydrofuran solution) at the temperature of 0 ℃ in an ice bath, and reacting for 1 hour at the temperature of 0 ℃ after dropwise adding is finished, namely, directly carrying out the next reaction on the solvent 2 without any treatment.
Step three, synthesizing tert-butyl 4-methoxy-3-oxobutyrate:
dropwise adding the solution 2 obtained in the step two into the solution 1 obtained in the step one under the condition of ice bath temperature control of 20 ℃, reacting at room temperature for 16 hours after dropwise adding, performing extraction and quenching reaction by using saturated citric acid aqueous solution, extracting by using ethyl acetate (3 x 150ml), combining organic phases, washing the organic phases once by using saturated salt water, drying by using anhydrous sodium sulfate, filtering, performing desolventizing to obtain a crude product of the tert-butyl 4-methoxy-3-oxobutyrate, and rectifying the crude product to obtain 15.0g of the tert-butyl 4-methoxy-3-oxobutyrate. Wherein the temperature of the distillate was 80 ℃.
The finally obtained 4-methoxy-3-oxobutanoic acid tert-butyl ester is colorless liquid, and the yield is 80%.
Example 3
This example provides a preferred method for the synthesis of tert-butyl 4-methoxy-3-oxobutyrate, with reference to the following synthetic route, comprising the steps of:
step one, synthesizing methoxyacetic acid acyl imidazole:
9g (0.1mol) of methoxyacetic acid is dissolved in 90ml of tetrahydrofuran, CDI solid (17.8g, 0.11mol) is added in batches at the temperature of 30 ℃ under ice bath condition, and after the addition is finished, the solution is reacted for 1.5 hours at the temperature of 20 ℃ under the protection of nitrogen, and the solution 1 is obtained and directly enters the next reaction without any treatment.
Step two, synthesizing a malonic acid mono-tert-butyl ester magnesium salt:
dissolving mono-tert-butyl malonate (16g, 0.1mol) in 80ml of tetrahydrofuran, dropwise adding 8ml (0.2mol) of isopropyl Grignard reagent (2M tetrahydrofuran solution) at the temperature of 25 ℃ in an ice bath, and reacting for 1 hour at the temperature of 25 ℃ after dropwise adding is finished, namely, directly carrying out the next reaction on the solvent 2 without any treatment.
Step three, synthesizing tert-butyl 4-methoxy-3-oxobutyrate:
and (3) dropwise adding the solution 2 obtained in the step two into the solution 1 obtained in the step one under the condition of ice bath temperature control of 35 ℃, reacting for 15 hours at 30 ℃, extracting and quenching the reaction by using saturated citric acid aqueous solution, extracting by using ethyl acetate (3 x 150ml), combining organic phases, washing the organic phases once by using saturated salt water, drying by using anhydrous sodium sulfate, filtering, desolventizing to obtain a crude product of the tert-butyl 4-methoxy-3-oxobutyrate, and rectifying the crude product to obtain 13g of the tert-butyl 4-methoxy-3-oxobutyrate. Wherein the temperature of the distillate was 80 ℃.
The finally obtained 4-methoxy-3-oxobutanoic acid tert-butyl ester was a colorless liquid, with a yield of 69.3%.
Comparative example 1
The yield of the 4-methoxy-3-oxobutyl tert-butyl butyrate synthesized by the comparative example according to the synthetic route 1 in the background technology is 15% -25%, and meanwhile, the industrial production cannot be carried out under severe reaction conditions (low temperature).
Comparative example 2
The yield of the tert-butyl 4-methoxy-3-oxobutyrate synthesized according to the synthetic route 1 in the background technology is 35% -40%, the generated by-product methyl 4-methoxyacetoacetate line cannot be controlled, so that the purification of the product is difficult, and meanwhile, the industrial production cannot be carried out under severe reaction conditions (low temperature of-78 ℃).
In conclusion, the synthesis method provided by the invention has the advantages of simple production process, high yield, easiness in purification and suitability for industrialization.
The embodiments of the present invention have been described in detail, but the embodiments are merely examples, and the present invention is not limited to the embodiments described above. Any equivalent modifications and substitutions to those skilled in the art are also within the scope of the present invention. Accordingly, equivalent changes and modifications made without departing from the spirit and scope of the present invention should be covered by the present invention.
Claims (10)
1. The synthesis method of tert-butyl 4-methoxy-3-oxobutyrate is characterized by comprising the following steps of:
reacting methoxyacetic acid and CDI at 0-20 ℃ for 1.5-3.5 hours under the protection of nitrogen to generate acyl imidazole;
dissolving mono-tert-butyl malonate in a solvent, then dropwise adding an isopropyl Grignard reagent, and reacting for 1-2 hours at the temperature of-10-25 ℃ to generate mono-tert-butyl malonate magnesium salt;
and step three, dripping the solution obtained after the reaction in the step two into the solution obtained after the reaction in the step one, and reacting for 15-18 hours at the temperature of 20-35 ℃ to generate the tert-butyl 4-methoxy-3-oxobutyrate.
2. The method for synthesizing tert-butyl 4-methoxy-3-oxobutyrate according to claim 1, wherein the solvent used in the reaction in the first step is tetrahydrofuran or 2-methyltetrahydrofuran.
3. The method for synthesizing tert-butyl 4-methoxy-3-oxobutyrate according to claim 2, wherein the solvent used in the reaction in the first step is tetrahydrofuran.
4. The method for synthesizing tert-butyl 4-methoxy-3-oxobutyrate according to claim 3, wherein the specific operation process in the first step is as follows: dissolving the methoxyacetic acid in the tetrahydrofuran, adding the CDI solid in batches at the temperature of 20 ℃ under ice bath condition, and reacting for 2 hours at 20 ℃ under the protection of nitrogen after the addition is finished.
5. The method for synthesizing tert-butyl 4-methoxy-3-oxobutyrate according to claim 1, characterized in that the molar ratio of methoxyacetic acid to CDI in step one is 10: 11.
6. the method for synthesizing tert-butyl 4-methoxy-3-oxobutyrate according to claim 1, wherein the molar ratio of mono-tert-butyl malonate to isopropyl grignard reagent in step two is 1: 2.
7. the process for the synthesis of tert-butyl 4-methoxy-3-oxobutyrate according to claim 1, characterized in that the molar ratio of methoxyacetic acid to mono-tert-butyl malonate is 1: 1.
8. the method for synthesizing tert-butyl 4-methoxy-3-oxobutyrate according to claim 1, wherein the reaction conditions in step two are 0 ℃ and the reaction time is 1 hour; the reaction condition of the third step is 20 ℃, and the reaction time is 16 hours.
9. The method for synthesizing tert-butyl 4-methoxy-3-oxobutyrate according to claim 1, wherein the third step further comprises the following steps:
s1, extracting and killing the reaction by using saturated citric acid aqueous solution, extracting by using ethyl acetate, and combining organic phases;
s2, washing the organic phase once with saturated saline, then drying with anhydrous sodium sulfate, filtering, and desolventizing to obtain the crude product of the tert-butyl 4-methoxy-3-oxobutyrate;
s3, rectifying the crude product to obtain colorless liquid, namely the tert-butyl 4-methoxy-3-oxobutyrate.
10. The process for the synthesis of tert-butyl 4-methoxy-3-oxobutyrate according to claim 9, characterized in that the temperature of the fraction in S3 is 80 ℃.
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| CN113773200A (en) * | 2021-09-14 | 2021-12-10 | 郑州猫眼农业科技有限公司 | Preparation method of mono-tert-butyl glutarate |
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