CN113527081B - Preparation method of 3-oxocyclobutanecarboxylic acid - Google Patents
Preparation method of 3-oxocyclobutanecarboxylic acid Download PDFInfo
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- CN113527081B CN113527081B CN202111006581.6A CN202111006581A CN113527081B CN 113527081 B CN113527081 B CN 113527081B CN 202111006581 A CN202111006581 A CN 202111006581A CN 113527081 B CN113527081 B CN 113527081B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/377—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
- C07C51/38—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups by decarboxylation
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- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/48—Preparation of compounds having groups
- C07C41/50—Preparation of compounds having groups by reactions producing groups
- C07C41/56—Preparation of compounds having groups by reactions producing groups by condensation of aldehydes, paraformaldehyde, or ketones
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/373—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of functional groups containing oxygen only in doubly bound form
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- 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
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Abstract
The invention discloses a preparation method of 3-oxocyclobutanecarboxylic acid, belonging to the technical field of synthesis of medical intermediates. 1, 3-dihydroxyacetone is used as a raw material, and is condensed with trimethyl orthoformate to protect ketone to obtain 2, 2-dimethoxy-1, 3-propanediol, and then the ketone is subjected to mitsunobu reaction with malonate to obtain 3, 3-dimethylcyclobutyl-1, 1-dicarboxylic diester, and then the diester is hydrolyzed, decarboxylated and deprotected under acidic conditions to obtain 3-oxocyclobutanecarboxylic acid. The method has the advantages of high yield, common and easily-obtained raw materials, simple and convenient process and industrial amplification prospect.
Description
Technical Field
The invention relates to a preparation method of 3-oxocyclobutanecarboxylic acid, belonging to the technical field of synthesis of medical intermediates.
Background
3-oxocyclobutanecarboxylic acid, english name: 3-oxocylo butane carboxylic acid, CAS:23761-23-1, which is a raw material for synthesizing many antiviral drugs and important organic intermediates, and is widely used in the fields of chemistry, chemical engineering, medicine, etc.
The 3-oxocyclobutanecarboxylic acid is a key raw material for drug synthesis, a drug intermediate is very important for the development of new drug research and development, and the drug intermediate is a chemical product with high technological density, high added value and specific application. The 3-oxocyclobutanecarboxylic acid can be used in platinum group drugs, wherein cyclobutane has special biological activity, carboxyl can be condensed with different polypeptides, amino acids and azacyclic nucleosides to obtain different drug intermediates, and the drugs can be used in autoimmune diseases and antitumor drugs such as kinase inhibitors and antagonists.
The key step is the synthesis of 3, 3-dimethylcyclobutyl-1, 1-dicarboxylic acid diisopropyl ester. Wherein the yield of US2009/233903,2009, A1 is 56.32%, 1, 3-dibromo-2, 2-dimethoxypropane and diisopropyl malonate are adopted to react with sodium hydride at 70 ℃, and the ring is closed by refluxing at 140 ℃ in DMF solvent for 48 hours. The method adopts a DMF and NaH system, so that the explosion risk exists, and the energy consumption is high during the high-temperature long-time reaction.
Therefore, it is necessary to develop a suitable synthesis method, which avoids the adoption of high temperature, reduces the reaction time, has high yield, mild reaction conditions, a safe and stable reaction route, and is suitable for industrial scale-up production.
Disclosure of Invention
In order to meet the industrial requirement, the invention discloses a preparation method of 3-oxocyclobutanecarboxylic acid, which takes 1, 3-dihydroxyacetone as a raw material, condenses with trimethyl orthoformate to protect ketone to obtain 2, 2-dimethoxy-1, 3-propanediol, and then reacts with malonic diester in a triphenyl phosphorus/azodicarboxylate system to obtain 3, 3-dimethylcyclobutyl-1, 1-dicarboxylic diisopropyl ester. Followed by hydrolysis, decarboxylation and deprotection under acidic conditions to give the 3-oxocyclobutanecarboxylic acid.
The invention relates to a preparation method of 3-oxocyclobutanecarboxylic acid, which comprises the following steps:
the first step is as follows: adding 1, 3-dihydroxyacetone and trimethyl orthoformate into a methanol solution, adding a catalyst for reaction, and carrying out reduced pressure distillation to obtain 2, 2-dimethoxy-1, 3-propanediol;
the second step is that: under the protection of nitrogen, dissolving triphenylphosphine, malonic diester and alkali in an organic solvent, dropwise adding 2, 2-dimethoxy-1, 3-propanediol, adding azodicarboxylate, heating for reaction, and performing aftertreatment to obtain 3, 3-dimethoxycyclobutane-1, 1-dicarboxylic diester;
the third step: 3, 3-dimethoxycyclobutane-1, 1-dicarboxylic acid diester is mixed with a phase transfer catalyst in hydrochloric acid and heated under reflux, followed by recrystallization to give 3-oxocyclobutanecarboxylic acid.
Further, in the technical scheme, the catalyst in the first step is selected from p-toluenesulfonic acid, and the using amount of the p-toluenesulfonic acid is 1-3% of the weight of the raw materials.
Furthermore, in the technical scheme, the molar ratio of the 1, 3-dihydroxyacetone to the trimethyl orthoformate is 1.5-2.0.
Further, in the above technical solution, in the second step, the organic solvent is selected from anhydrous tetrahydrofuran or 1, 4-dioxane, and the azodicarboxylate is selected from diisopropyl azodicarboxylate or diethyl azodicarboxylate; the malonic diester is selected from diisopropyl malonate or diethyl malonate.
Further, in the above technical scheme, in the second step, the molar ratio of the 2, 2-dimethoxy-1, 3-propanediol, malonic diester, triphenylphosphine and azodicarboxylate is 1:1.01-1.05:2.1-2.3:2.1-2.3.
Further, in the above technical scheme, in the second step, the base is selected from triethylamine, diisopropylethylamine, t-BuOK or DBU.
Further, in the above technical scheme, in the second step, the reaction temperature is-5 to 50 ℃.
Furthermore, in the above technical scheme, in the second step, the crude product is dissolved in n-heptane or petroleum ether by the post-treatment, and a by-product triphenyl phosphine oxide can be removed by filtering in a sand core funnel which is paved with a small amount of silica gel in advance. The color and purity of the intermediate in the second step are greatly improved.
Further, in the above technical solution, in the third step, the phase transfer catalyst is selected from methyltrioctylammonium chloride, and the reaction temperature is selected from 70-80 ℃.
Further, in the above technical scheme, in the third step, the reaction process maintains pH =1.5-2.0; the recrystallization is selected from toluene and n-heptane mixing ratio 2:1, purifying the crude product.
Advantageous effects of the invention
The method has the advantages of easily obtained raw materials and simple operation, and the second step selects a better solvent and quickly passes through a small amount of silica gel, so that the quality and the color of the product are improved, and by-products of the triphenyl phosphine oxide and pigments with large polarity are effectively removed. And in the third step, a methyl trioctyl ammonium chloride phase transfer catalyst is added, so that the reaction time is greatly shortened, and a reagent which is easy to self-ignite, easy to explode and strong in nucleophilicity, such as sodium hydride, is avoided. The process has industrial amplification prospect.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The invention is further illustrated by the following specific examples. These examples are to be construed as merely illustrative and not limitative of the remainder of the disclosure in any way whatsoever. After reading the description of the invention, one skilled in the art can make various changes and modifications to the invention, and such equivalent changes and modifications also fall into the scope of the invention defined by the claims.
Example 1
45g (0.5 mol) of 1, 3-dihydroxyacetone, 4.5g of anhydrous p-toluenesulfonic acid and 500mL of methanol are placed in a reaction flask under the protection of nitrogen. Heating to 35 ℃, dropwise adding 79.6g (0.75 mol) of trimethyl orthoformate, refluxing and stirring for 4 hours after dropwise adding is finished, detecting color development of phosphomolybdic acid by TLC (thin layer chromatography) without raw material residue, adding a polymerization inhibitor, changing into a normal pressure distillation device, and distilling most of methanol. Finally, the front fraction is distilled under reduced pressure at 65-80 ℃, and the colorless oily substance 2, 2-dimethoxy-1, 3-propanediol 59g is obtained by reduced pressure distillation at 88-97 ℃ (-0.095 to-0.098 Mpa), GC 98.8 percent and the yield is 86.7 percent. 1 H NMR(400MHz,CDCl3)δ:4.12(s,2H),3.78-3.75(m,4H),3.29(s,6H).
Example 2
173.2g (0.66 mol) of triphenylphosphine, 40.9g (0.3 mol) of 2, 2-dimethoxy-1, 3-propanediol, 59.3g (0.315 mol) of diisopropyl malonate, and 800mL of anhydrous tetrahydrofuran were charged into a reaction flask under a nitrogen atmosphere, cooled to 0 ℃ and added with 45.5g (0.45 mol) of triethylamine, stirred for 30 minutes, followed by adding DIAD 133 dropwise.4g (0.66 mol), followed by heating to 50 ℃ for 6 hours. Adding ammonium chloride aqueous solution for quenching, layering, extracting an aqueous phase by using n-heptane, combining organic phases, concentrating under reduced pressure, replacing by n-heptane, separating out a large amount of solids, filtering in a sand core funnel paved with a small amount of silica gel in advance, leaching for multiple times by using n-heptane, and concentrating a filtrate under reduced pressure until no liquid flows to obtain 71.9g of crude product of diisopropyl 3, 3-dimethoxycyclobutane-1, 1-dicarboxylate, wherein the yield is 83.1 percent and GC is 96.9 percent. 1 HNMR(400MHz,CDCl3):5.06-5.04(m,2H),3.20(s,6H),2.70(m,4H),1.24-1.20(m,12H).
Example 3
173.2g (0.66 mol) of triphenylphosphine, 40.9g (0.3 mol) of 2, 2-dimethoxy-1, 3-propanediol, 50.5g (0.315 mol) of diethyl malonate and 800mL1, 4-dioxane were charged into a reaction flask under nitrogen protection, the temperature was reduced to 0 ℃ and 40.4g (0.45 mol) of potassium tert-butoxide was added in portions, and after completion of the addition, stirring was carried out at room temperature for 1.5 hours, followed by dropwise addition of 115g (0.66 mol) of DEAD. The reaction was then allowed to warm to 50 ℃ for 4 hours. Added to ice water and adjusted pH =6-7 with acetic acid. Layering, extracting a water phase by using n-heptane, combining organic phases, concentrating under reduced pressure, replacing the n-heptane, separating out a large amount of solid, filtering in a sand core funnel paved with a small amount of silica gel in advance, leaching with the n-heptane for multiple times, and concentrating the filtrate under reduced pressure until no flow exists to obtain 57.7g of crude product 3, 3-dimethoxycyclobutane-1, 1-dicarboxylic acid diethyl ester, wherein the yield is 73.9 percent and GC is 97.3 percent. 1 HNMR(400MHz,CDCl3):4.15-4.12(m,4H),3.30(s,6H),2.82(m,4H),1.20-1.18(m,6H).
Example 4
Under the protection of nitrogen, 57.7g (0.2 mol) of 3, 3-dimethoxycyclobutane-1, 1-dicarboxylic acid diisopropyl ester and 219mL of 20% hydrochloric acid were put into a reaction flask and mixed, 5.8g of methyltrioctylammonium chloride was added, the temperature was raised to 75 ℃ and the reaction was carried out for 12 hours,adding 20% sodium carbonate to adjust pH =2.0-2.5, adding ethyl acetate to extract, separating layers, extracting the aqueous phase with ethyl acetate, combining organic phases, concentrating under reduced pressure to remove the solvent, adding 80mL of toluene and 40mL of n-heptane to recrystallize to obtain 19.6g of 3-oxocyclobutanecarboxylic acid with yield of 85.9%, GC:99.6 percent. 1 HNMR(400MHz,CDCl3):12.15(s,1H),3.37-3.28(m,5H).
Example 5
Under the protection of nitrogen, 52.1g (0.2 mol) of diethyl 3, 3-dimethoxycyclobutane-1, 1-dicarboxylate and 219mL of 20% hydrochloric acid were added into a reaction flask, mixed, 5.2g of methyltrioctylammonium chloride was added, the temperature was raised to 75 ℃, reaction was carried out for 14 hours, 20% sodium carbonate was added to adjust pH =2.0-2.5, ethyl acetate was added for extraction, layers were separated, the aqueous phase was extracted with ethyl acetate, the organic phase was concentrated under reduced pressure to remove the solvent, 80mL of toluene and 40mL of n-heptane were added for recrystallization to obtain 18.7g of 3-oxocyclobutanecarboxylic acid, the yield was 82.1%, GC:99.7 percent.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered as the technical solutions and the inventive concepts of the present invention within the technical scope of the present invention.
Claims (6)
1. A method for preparing 3-oxocyclobutanecarboxylic acid, which is characterized by comprising the following steps:
the first step is as follows: adding 1, 3-dihydroxyacetone and trimethyl orthoformate into a methanol solution, adding a catalyst for reaction, and carrying out reduced pressure distillation to obtain 2, 2-dimethoxy-1, 3-propanediol;
the second step is that: under the protection of nitrogen, dissolving triphenylphosphine, malonic diester and alkali in an organic solvent, dropwise adding 2, 2-dimethoxy-1, 3-propanediol, adding azodicarboxylate, heating to 50 ℃ for reaction, and performing aftertreatment to obtain 3, 3-dimethoxycyclobutane-1, 1-dicarboxylic diester; the organic solvent is selected from anhydrous tetrahydrofuran or 1, 4-dioxane, and the azodicarboxylic acid ester is selected from diisopropyl azodicarboxylate or diethyl azodicarboxylate; the malonic diester is selected from diisopropyl malonate or diethyl malonate; the base is selected from triethylamine, diisopropylethylamine, t-BuOK or DBU;
the third step: 3, 3-dimethoxycyclobutane-1, 1-dicarboxylic acid diester and methyltrioctylammonium chloride were mixed in hydrochloric acid and heated under reflux, followed by recrystallization to give 3-oxocyclobutanecarboxylic acid.
2. The method for producing 3-oxocyclobutanecarboxylic acid according to claim 1, characterized in that: in the first step, the catalyst is selected from p-toluenesulfonic acid, and the dosage of the catalyst is 1-3% of the weight of the raw materials.
3. The process for producing 3-oxocyclobutanecarboxylic acid according to claim 1, characterized in that: the molar ratio of the 1, 3-dihydroxyacetone to the trimethyl orthoformate is 1.5-2.0.
4. The method for producing 3-oxocyclobutanecarboxylic acid according to claim 1, characterized in that: in the second step, the molar ratio of 2, 2-dimethoxy-1, 3-propanediol, malonic diester, triphenylphosphine and azodicarboxylate is 1.01-1.05.
5. The process for producing 3-oxocyclobutanecarboxylic acid according to claim 1, characterized in that: in the third step, the reaction temperature is selected from 70-80 ℃.
6. The process for producing 3-oxocyclobutanecarboxylic acid according to claim 1, characterized in that: in the third step, the reaction process keeps pH =1.5-2.0; recrystallization the crude product was purified using toluene and n-heptane in a mixing ratio of 2.
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| CN109988126B (en) * | 2017-12-29 | 2023-05-16 | 南京富润凯德生物医药有限公司 | 3-amino-oxetane derivative and preparation method and application thereof |
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