CN116986986A - Synthesis method of 3-oxo-1-cyclobutanecarboxylic acid intermediate - Google Patents
Synthesis method of 3-oxo-1-cyclobutanecarboxylic acid intermediate Download PDFInfo
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- CN116986986A CN116986986A CN202310887877.6A CN202310887877A CN116986986A CN 116986986 A CN116986986 A CN 116986986A CN 202310887877 A CN202310887877 A CN 202310887877A CN 116986986 A CN116986986 A CN 116986986A
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- IENOFRJPUPTEMI-UHFFFAOYSA-N 3-oxocyclobutane-1-carboxylic acid Chemical compound OC(=O)C1CC(=O)C1 IENOFRJPUPTEMI-UHFFFAOYSA-N 0.000 title claims abstract description 28
- 238000001308 synthesis method Methods 0.000 title claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 85
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims abstract description 42
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims abstract description 41
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims abstract description 39
- 239000000543 intermediate Substances 0.000 claims abstract description 35
- CPAHOXOBYHMHDT-UHFFFAOYSA-N 1,3-dibromo-2,2-dimethoxypropane Chemical compound COC(CBr)(CBr)OC CPAHOXOBYHMHDT-UHFFFAOYSA-N 0.000 claims abstract description 19
- BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical compound COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 claims abstract description 19
- 229910000104 sodium hydride Inorganic materials 0.000 claims abstract description 19
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 15
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 15
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 14
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000012312 sodium hydride Substances 0.000 claims abstract description 13
- 238000010438 heat treatment Methods 0.000 claims description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 16
- 238000003756 stirring Methods 0.000 claims description 11
- 230000002194 synthesizing effect Effects 0.000 claims description 10
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 9
- 239000002480 mineral oil Substances 0.000 claims description 9
- 235000010446 mineral oil Nutrition 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 238000010791 quenching Methods 0.000 claims description 9
- 230000000171 quenching effect Effects 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 6
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 12
- 238000005809 transesterification reaction Methods 0.000 abstract description 5
- 239000003513 alkali Substances 0.000 abstract description 4
- 150000001875 compounds Chemical class 0.000 abstract description 3
- SZJMXTBKYMLPTJ-UHFFFAOYSA-N dipropan-2-yl 3,3-dimethoxycyclobutane-1,1-dicarboxylate Chemical compound COC1(OC)CC(C(=O)OC(C)C)(C(=O)OC(C)C)C1 SZJMXTBKYMLPTJ-UHFFFAOYSA-N 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 2
- 239000012450 pharmaceutical intermediate Substances 0.000 abstract description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 54
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Substances [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 238000001704 evaporation Methods 0.000 description 14
- 238000005406 washing Methods 0.000 description 14
- 239000007788 liquid Substances 0.000 description 11
- 239000002904 solvent Substances 0.000 description 10
- 239000000047 product Substances 0.000 description 9
- 239000012065 filter cake Substances 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 238000004321 preservation Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 238000004537 pulping Methods 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 6
- 239000012295 chemical reaction liquid Substances 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- QRVSDVDFJFKYKA-UHFFFAOYSA-N dipropan-2-yl propanedioate Chemical compound CC(C)OC(=O)CC(=O)OC(C)C QRVSDVDFJFKYKA-UHFFFAOYSA-N 0.000 description 2
- 150000002148 esters Chemical group 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000000630 rising effect Effects 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- WLXXTHPAORBNIG-UHFFFAOYSA-N (3,3-difluorocyclobutyl)azanium;chloride Chemical compound Cl.NC1CC(F)(F)C1 WLXXTHPAORBNIG-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- 102000012199 E3 ubiquitin-protein ligase Mdm2 Human genes 0.000 description 1
- 108050002772 E3 ubiquitin-protein ligase Mdm2 Proteins 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- 229940122245 Janus kinase inhibitor Drugs 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 101000712605 Theromyzon tessulatum Theromin Proteins 0.000 description 1
- 229940122388 Thrombin inhibitor Drugs 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- WIJZXSAJMHAVGX-DHLKQENFSA-N ivosidenib Chemical compound FC1=CN=CC(N([C@H](C(=O)NC2CC(F)(F)C2)C=2C(=CC=CC=2)Cl)C(=O)[C@H]2N(C(=O)CC2)C=2N=CC=C(C=2)C#N)=C1 WIJZXSAJMHAVGX-DHLKQENFSA-N 0.000 description 1
- 229950010738 ivosidenib Drugs 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- -1 patent CN105037130A Chemical compound 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 239000003868 thrombin inhibitor Substances 0.000 description 1
- 230000003313 weakening effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/03—Preparation of carboxylic acid esters by reacting an ester group with a hydroxy group
-
- 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
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to the technical field of synthesis of pharmaceutical intermediates, and discloses a synthesis method of a 3-oxo-1-cyclobutanecarboxylic acid intermediate, which comprises a first step and a second step which are sequentially carried out, wherein the first step is as follows: dimethyl malonate and 1, 3-dibromo-2, 2-dimethoxy propane are adopted as raw materials, and condensed under the conditions of sodium methoxide, DMAC and KI to prepare a four-membered ring, thus obtaining a compound C 1 The method comprises the steps of carrying out a first treatment on the surface of the Step two: by using compounds C 1 And (3) taking isopropanol as a raw material, and carrying out transesterification under the condition of sodium hydride to obtain a compound C, namely 3, 3-dimethoxy cyclobutane-1, 1-dicarboxylic acid diisopropyl ester. The invention adopts dimethyl malonate as a synthesis raw material and sodium methoxide as alkali, thereby not only improving the compound C 1 And is composed of the conversion rate of the compound C 1 The transesterification reaction can be carried out to obtain a high levelThe compound C with high yield and purity is easy to obtain raw materials, low in price, simple to operate and suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of synthesis of pharmaceutical intermediates, in particular to a synthesis method of a 3-oxo-1-cyclobutanecarboxylic acid intermediate.
Background
3-oxo-1-cyclobutanecarboxylic acid, english name 3-oxocyclobutane carboxylic acid, CAS 23761-23-1, and its molecular weight is small and structure is unique, so that it can be used as several downstream products, and can be used as an important medical intermediate for synthesizing several tens of raw medicines, such as ACKI antibody, MDM2 antagonist, JAK inhibitor, PDE10 inhibitor, kinase inhibitor and thrombin inhibitor. And a series of compounds derived therefrom have a variety of applications, such as the key intermediate 3, 3-difluorocyclobutylamine hydrochloride of the anticancer drug Ivosidenib, which is produced from 3-oxo-1-cyclobutanecarboxylic acid as starting material.
There are many documents reporting the synthesis of 3-oxo-1-cyclobutanecarboxylic acid, such as patent CN105037130A, patent CN111320535, document J.org.chem.1988,53,16,3841-3843, etc., and more mature processes. One of the main raw materials is diisopropyl 3, 3-dimethoxy-cyclobutane-1, 1-dicarboxylate (compound C). The synthesis process of the compound C still has the defects of low yield, high impurity content and high cost. Taking patent CN105037130A and patent WO2007062308A2 as examples, synthesizing the compound C by taking NaH as alkali and DMF as solvent, stirring at 140 ℃ for 24-48h, purifying by post-treatment, and distilling to obtain the product with the yield of about 50%. Similar four-membered ring forming reactions have been reported, for example, in patent WO2009114512A1, patent WO2013020993A1, patent US2009/233903, patent Synlett,2009,11,1827-1829, RSC Advances,2016,6,22737-22748, etc., and the reactions basically use NaH as a base and DMF as a solvent, and the yields are about 50%.
Since NaH/DMF is at risk of explosion when reacting at high temperature, its conversion rate is usually only about 50%, and 10% -20% of raw material B remains, the melting point of raw material B is low (65 ℃) and can cause the blockage of the rectifying tower during rectifying C. On the basis of this, patent reports that potassium tert-butoxide (patent CN105037130 a) is used instead of NaH, however, potassium tert-butoxide has the disadvantages of high price and easy transesterification, and DMF is also easy to decompose at high temperature to generate formaldehyde, thereby generating impurities with raw material B.
Disclosure of Invention
In order to solve the technical problems, the invention provides a synthesis method of a 3-oxo-1-cyclobutanecarboxylic acid intermediate, which is used for obtaining a compound C with high yield and high purity through a novel synthesis reaction route.
The aim of the invention is realized by the following technical scheme: a synthesis method of a 3-oxo-1-cyclobutanecarboxylic acid intermediate, which comprises a first step and a second step which are sequentially carried out, wherein the reaction equation is as follows:
step one:
step two:
dimethyl malonate (compound A) and 1, 3-dibromo-2, 2-dimethoxy propane (compound B) are used as starting materials, four-membered rings are prepared by condensation under alkaline conditions, and isopropyl alcohol is used for transesterification to obtain 3, 3-dimethoxy cyclobutane-1, 1-dicarboxylic acid diisopropyl ester. Compared with the prior art, the invention adopts sodium methoxide to replace NaH, potassium tert-butoxide and other alkalis, the alkalinity of the sodium methoxide is weaker than that of the potassium tert-butoxide, the side reaction caused by strong alkalinity is avoided, the conversion rate of the reaction is improved, and in addition, the space of the sodium methoxide is smaller, and the sodium methoxide is easier to participate in hydrogen extraction of dimethyl malonate, therebyPromote the reaction, and finally effectively reduce the material cost. Secondly, diisopropyl malonate is replaced by dimethyl malonate, isopropyl is changed into methyl, and the space resistance of a reaction site is effectively reduced, so that the diisopropyl malonate can still maintain higher conversion rate under the condition of alkali alkalinity weakening, and an intermediate product C can be obtained with the yield of 80 percent or more 1 . The second step then gives compound C in 95% and above yield by transesterification in extremely high yields. Through a new reaction route, the compound C with high yield and high purity is obtained, and the production cost is greatly reduced (the cost of a NaH/DMF system is 410 yuan/kg; the cost of a potassium tert-butoxide/DMF system is 465 yuan/kg, and the cost of a sodium methoxide/dimethyl malonate/DMAC system is 220 yuan/kg).
Preferably, the first step includes: mixing dimethyl malonate, DMAC and sodium methoxide, performing a first heating reaction, adding 1, 3-dibromo-2, 2-dimethoxypropane and KI, performing a second heating reaction, and performing post-treatment I after the reaction is finished to obtain a compound C 1 。
Preferably, the first temperature rising reaction is to raise the temperature to 60-70 ℃ and keep the temperature for 2-3 hours under stirring.
Preferably, the second temperature rising reaction is to raise the temperature to 140-160 ℃ for 24-28 h.
Preferably, the molar ratio of the dimethyl malonate to the 1, 3-dibromo-2, 2-dimethoxypropane is 2.0-2.8: 1.
preferably, the molar ratio of the sodium methoxide to the 1, 3-dibromo-2, 2-dimethoxypropane is 2.0 to 2.8; the dosage of the KI is 4-6% of the mass of the 1, 3-dibromo-2, 2-dimethoxy propane.
Preferably, the post-treatment I is: the DMAC is distilled off under reduced pressure, toluene is added, the mixture is stirred and pulped, the filtrate is collected after filtration, the filter cake is washed by toluene, the toluene is combined for two times, and the solvent is distilled off under reduced pressure after being concentrated and dried.
Preferably, the second step includes: compound C 1 Mixing with isopropanol, nitrogen displacing, adding sodium hydride dissolved in mineral oil, heating to react, and reactingAdding saturated ammonium chloride solution to quench the reaction, and then carrying out post-treatment II to obtain the compound C.
Preferably, the compound C 1 And isopropyl alcohol in a molar ratio of 1:6 to 6.4.
Preferably, the molar ratio of the sodium hydride to the isopropanol is 2.2-3.0: 1.
preferably, the temperature-rising reaction is carried out for 24-28 hours after the temperature is raised to 140-160 ℃.
Preferably, the post-treatment ii is: the product was extracted with ethyl acetate, washed with water, concentrated, and then subjected to rectification under reduced pressure.
Compared with the prior art, the invention has the following beneficial effects:
(1) Sodium methoxide is used as alkali, so that the compound C can be improved 1 The conversion rate of the catalyst is lower, and the raw material cost is lower;
(2) Dimethyl malonate is used as a synthesis raw material, the steric hindrance of a reaction site is effectively reduced, and the compound C can be obtained with higher yield under the action of sodium methoxide with lower alkalinity 1 And is composed of compound C 1 The ester exchange reaction can be carried out to obtain the compound C with higher yield;
(2) The compound C synthesis route with high yield and high purity can be obtained through the mutual synergistic coordination of the raw materials, the raw materials of the process route are easy to obtain, the price is low, the operation is simple, and the process route is suitable for industrial production.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of a compound C obtained in example 1 of the present invention.
Detailed Description
The technical scheme of the present invention is described below by using specific examples, but the scope of the present invention is not limited thereto:
a synthesis method of a 3-oxo-1-cyclobutanecarboxylic acid intermediate, which has the following reaction equation:
step one:mixing dimethyl malonate, DMAC and sodium methoxide, heating to 60-70 ℃, stirring, preserving heat for 2-3 h, adding 1, 3-dibromo-2, 2-dimethoxy propane and KI, heating to 140-160 ℃ for reaction for 24-28 h, evaporating DMAC under reduced pressure after the reaction is finished, adding toluene, stirring and pulping, filtering, collecting filtrate, washing filter cake with toluene, combining toluene of two times, concentrating, evaporating solvent under reduced pressure to obtain a compound C 1 . Wherein the molar ratio of the dimethyl malonate to the 1, 3-dibromo-2, 2-dimethoxy propane is 2.0-2.8: 1, a step of; the molar ratio of the sodium methoxide to the 1, 3-dibromo-2, 2-dimethoxy propane is 2.0-2.8; the dosage of the KI is 4-6% of the 1, 3-dibromo-2, 2-dimethoxy propane.
Step two: compound C 1 Mixing with isopropanol, performing nitrogen substitution, adding sodium hydride dissolved in mineral oil, heating to 140-160 ℃ for reaction for 24-28 h, adding saturated ammonium chloride solution after the reaction is finished for quenching reaction, extracting a product with ethyl acetate, washing with water, concentrating, and performing vacuum rectification to obtain a compound C. Wherein the compound C 1 And isopropyl alcohol in a molar ratio of 1:6 to 6.4; the molar ratio of the sodium hydride to the isopropanol is 2.2-3.0: 1.
example 1
Synthesis of 3-oxo-1-cyclobutanecarboxylic acid intermediate (Compound C):
step 1: 150mL of DMAC, 25.2g of dimethyl malonate and 24.8g of sodium methoxide are sequentially added into a 500mL reaction bottle at room temperature, the temperature is raised to 60 ℃, 50g of 1, 3-dibromo-2, 2-dimethoxypropane and 2.5g of potassium iodide are added into the reaction bottle after 3h of heat preservation, and the temperature is raised to 150 ℃ and then the temperature is maintained for 24h; after the reaction is finished, evaporating DMAC under reduced pressure, adding 250mL of toluene, stirring and pulping for 3 hours, filtering, washing a filter cake with 250mL of toluene, combining the filtrates, and evaporating the solvent under reduced pressure to obtain an intermediate C 1 45.8g of pale yellow liquid; step 2: 45.8g of intermediate C were added sequentially to a 500mL reaction flask at room temperature 1 74mL of isopropanol, 15.9g of 60wt% sodium hydride dissolved in mineral oil is slowly added into a reaction bottle after nitrogen replacement, then the temperature is raised to 65 ℃ for reaction for 4 hours, 150mL of saturated ammonium chloride solution is added into the reaction solution after the reaction is finished for quenching reaction, and 100mL of acetic acid is used as a productEthyl ester is extracted for 3 times, washing is carried out for 1 time by 50mL of water, the organic phase is concentrated and dried, then decompression rectification is carried out, the pressure is 100-120 Pa, the fraction at 86-93 ℃ is collected, and 44.1g of colorless liquid is obtained.
As shown in FIG. 1, the 1H-NMR (400 MHz, DMSO-d6, ppm) of this compound C was 4.99 to 4.87 (m, 2H), 3.04 (s, 6H), 2.57 (s, 4H), and 1.18 to 1.17 (d, 12H).
Example 2
Synthesis of 3-oxo-1-cyclobutanecarboxylic acid intermediate (Compound C):
step 1: 600mL of DMAC, 100.9g of dimethyl malonate and 99.0g of sodium methoxide are sequentially added into a 2000mL of reaction bottle at room temperature, the temperature is raised to 60 ℃,200 g of 1, 3-dibromo-2, 2-dimethoxypropane and 10g of potassium iodide are added into the reaction bottle after heat preservation for 3 hours, and the temperature is raised to 150 ℃ and then the heat preservation is carried out for 24 hours; after the reaction is finished, evaporating DMAC under reduced pressure, adding 1000mL of toluene, stirring and pulping for 3 hours, filtering, washing a filter cake with 1000mL of toluene, combining the filtrates, and evaporating the solvent under reduced pressure to obtain an intermediate C 1 177.8g of pale yellow liquid;
step 2: 177.8g of intermediate C were added sequentially to a 500mL reaction flask at room temperature 1 288mL of isopropanol, displacing nitrogen, slowly adding 61.9g of 60wt% sodium hydride dissolved in mineral oil into a reaction bottle, then heating to 65 ℃ for reaction for 4 hours, adding 576mL of saturated ammonium chloride solution into the reaction liquid after the reaction is finished for quenching reaction, extracting the product with 389mL of ethyl acetate for 3 times, washing with 195mL of water for 1 time, concentrating an organic phase, concentrating and drying, and then rectifying under reduced pressure, wherein the pressure is 100-120 Pa, and collecting a fraction at 86-93 ℃ to obtain 172.0g of a colorless liquid of a compound C.
Example 3
Synthesis of 3-oxo-1-cyclobutanecarboxylic acid intermediate (Compound C):
step 1: 300mL of DMAC, 141.2g of dimethyl malonate and 57.7g of sodium methoxide are sequentially added into a 1000mL of reaction bottle at room temperature, the temperature is raised to 60 ℃, 100.0g of 1, 3-dibromo-2, 2-dimethoxypropane and 5.0g of potassium iodide are added into the reaction bottle after 3h of heat preservation, and the temperature is raised to 150 ℃ and then the temperature is maintained for 24h; after the reaction is finished, evaporating DMAC under reduced pressure, adding 500mL of toluene, stirring and pulping for 3 hours, filtering, washing a filter cake with 500mL of toluene, combining the filtrates, and evaporating the solvent under reduced pressure to obtain an intermediateC 1 84.1g of pale yellow liquid;
step 2: 84.1g of intermediate C were added sequentially to 1000mL reaction flask at room temperature 1 132mL of isopropanol, replacing nitrogen, slowly adding 28.4g of 60wt% sodium hydride dissolved in mineral oil into a reaction bottle, heating to 65 ℃ for reaction for 4 hours, adding 300mL of saturated ammonium chloride solution into the reaction liquid after the reaction is finished for quenching reaction, extracting the product with 200mL of ethyl acetate for 3 times, washing with 100mL of water for 1 time, concentrating an organic phase, concentrating and drying, performing vacuum rectification under the pressure of 100-120 Pa, and collecting a fraction at 86-93 ℃ to obtain 78.7g of compound C as colorless liquid.
Example 4
Synthesis of 3-oxo-1-cyclobutanecarboxylic acid intermediate (Compound C):
step 1: 300mL of DMAC, 100.9g of dimethyl malonate (2.0 eq) and 41.2g of sodium methoxide are sequentially added into a 1000mL reaction bottle at room temperature, the temperature is raised to 60 ℃, after 3h of heat preservation, 100.0g of 1, 3-dibromo-2, 2-dimethoxypropane and 5.0g of potassium iodide are added into the reaction bottle, after 140 ℃ of heat preservation, the temperature is raised for 24h; after the reaction is finished, evaporating DMAC under reduced pressure, adding 500mL of toluene, stirring and pulping for 3 hours, filtering, washing a filter cake with 500mL of toluene, combining the filtrates, and evaporating the solvent under reduced pressure to obtain an intermediate C 1 78.4g of pale yellow liquid;
step 2: to a 1000mL reaction flask was added, in order, 78.4g of intermediate C at room temperature 1 125mL of isopropanol, replacing nitrogen, slowly adding 26.9g of 60wt% sodium hydride dissolved in mineral oil into a reaction bottle, heating to 65 ℃ for reaction for 4 hours, adding 300mL of saturated ammonium chloride solution into the reaction liquid after the reaction is finished for quenching reaction, extracting the product with 200mL of ethyl acetate for 3 times, washing with 100mL of water for 1 time, concentrating an organic phase, concentrating and drying, performing vacuum rectification under the pressure of 100-120 Pa, and collecting a fraction at 86-93 ℃ to obtain 75.5g of compound C as colorless liquid.
Example 5
Synthesis of 3-oxo-1-cyclobutanecarboxylic acid intermediate (Compound C):
step 1: 150mL of LDMAC, 25.2g of dimethyl malonate and 24.8g of sodium methoxide are sequentially added into a 500mL reaction flask at room temperature, the temperature is raised to 60 ℃, and 50g of the mixture is added into the reaction flask after 3h of heat preservation1, 3-dibromo-2, 2-dimethoxy propane and 2.5g potassium iodide, and preserving heat for 28h after heating to 160 ℃; after the reaction is finished, evaporating DMAC under reduced pressure, adding 250mL of toluene, stirring and pulping for 3 hours, filtering, washing a filter cake with 250mL of toluene, combining the filtrates, and evaporating the solvent under reduced pressure to obtain an intermediate C 1 41.5g of pale yellow liquid; step 2: 41.5g of intermediate C were added sequentially to 500mL reaction flask at room temperature 1 65mL of isopropanol, replacing nitrogen, slowly adding 14.0g of 60wt% sodium hydride dissolved in mineral oil into a reaction bottle, heating to 65 ℃ for reaction for 4 hours, adding 150mL of saturated ammonium chloride solution into the reaction liquid after the reaction is finished for quenching reaction, extracting the product with 100mL of ethyl acetate for 3 times, washing with 50mL of water for 1 time, concentrating an organic phase, concentrating and drying, performing vacuum rectification under 100-120 Pa, and collecting a fraction at 86-93 ℃ to obtain 39.0g of compound C as colorless liquid.
Example 6
Synthesis of 3-oxo-1-cyclobutanecarboxylic acid intermediate (Compound C):
step 1: 150mL of DMAC, 25.2g of dimethyl malonate and 24.8g of sodium methoxide are sequentially added into a 500mL reaction bottle at room temperature, the temperature is raised to 70 ℃, 50g of 1, 3-dibromo-2, 2-dimethoxypropane and 2.5g of potassium iodide are added into the reaction bottle after heat preservation for 2 hours, and the temperature is raised to 140 ℃ and then the heat preservation is carried out for 28 hours; after the reaction is finished, evaporating DMAC under reduced pressure, adding 250mL of toluene, stirring and pulping for 3 hours, filtering, washing a filter cake with 250mL of toluene, combining the filtrates, and evaporating the solvent under reduced pressure to obtain an intermediate C 1 38.5g of pale yellow liquid; step 2: to a 500mL reaction flask was added, in order, 38.5g of intermediate C at room temperature 1 59mL of isopropanol, replacing nitrogen, slowly adding 12.7g of 60wt% sodium hydride dissolved in mineral oil into a reaction bottle, heating to 65 ℃ for reaction for 4 hours, adding 150mL of saturated ammonium chloride solution into the reaction liquid after the reaction is finished for quenching reaction, extracting the product with 100mL of ethyl acetate for 3 times, washing with 50mL of water for 1 time, concentrating an organic phase, concentrating and drying, performing vacuum rectification under 100-120 Pa, and collecting a fraction at 86-93 ℃ to obtain 36.0g of compound C.
TABLE 1
The foregoing description is only of the preferred embodiments of the present invention, and is not intended to limit the scope of the invention, but rather is intended to cover any equivalents of the structures disclosed herein or modifications in the equivalent processes, or any application of the structures disclosed herein, directly or indirectly, in other related arts.
Claims (10)
1. A synthesis method of a 3-oxo-1-cyclobutanecarboxylic acid intermediate, which is characterized by comprising a first step and a second step which are sequentially carried out, wherein the reaction equation is as follows:
step one:
step two:
2. the method for synthesizing 3-oxo-1-cyclobutanecarboxylic acid intermediate according to claim 1, wherein the first step comprises: mixing dimethyl malonate, DMAC and sodium methoxide, performing a first heating reaction, adding 1, 3-dibromo-2, 2-dimethoxypropane and KI, performing a second heating reaction, and performing post-treatment I after the reaction is finished to obtain a compound C 1 。
3. The method for synthesizing 3-oxo-1-cyclobutanecarboxylic acid intermediate according to claim 2, wherein the first heating reaction is to heat up to 60-70 ℃ and stir and keep the temperature for 2-3 h.
4. The method for synthesizing 3-oxo-1-cyclobutanecarboxylic acid intermediate according to claim 2, wherein the second heating reaction is to raise the temperature to 140-160 ℃ for 24-28 h.
5. The method for synthesizing a 3-oxo-1-cyclobutanecarboxylic acid intermediate according to any one of claims 2 to 4, wherein the molar ratio of dimethyl malonate to 1, 3-dibromo-2, 2-dimethoxypropane is from 2.0 to 2.8:1.
6. the method for synthesizing 3-oxo-1-cyclobutanecarboxylic acid intermediate according to any one of claims 2 to 4, wherein the molar ratio of sodium methoxide to 1, 3-dibromo-2, 2-dimethoxypropane is from 2.0 to 2.8; the dosage of the KI is 4-6% of the mass of the 1, 3-dibromo-2, 2-dimethoxy propane.
7. The method for synthesizing 3-oxo-1-cyclobutanecarboxylic acid intermediate according to claim 2, wherein the second step comprises: compound C 1 Mixing with isopropanol, performing nitrogen substitution, adding sodium hydride dissolved in mineral oil, performing heating reaction, adding saturated ammonium chloride solution after the reaction is finished for quenching reaction, and performing aftertreatment II to obtain a compound C.
8. A process for the synthesis of 3-oxo-1-cyclobutanecarboxylic acid intermediates according to claim 1 or 7, wherein compound C 1 And isopropyl alcohol in a molar ratio of 1:6 to 6.4.
9. The method for synthesizing 3-oxo-1-cyclobutanecarboxylic acid intermediate according to claim 1 or 7, wherein the molar ratio of sodium hydride to isopropyl alcohol is 2.2 to 3.0:1.
10. the method for synthesizing 3-oxo-1-cyclobutanecarboxylic acid intermediate as claimed in claim 7, wherein the temperature-raising reaction is to raise the temperature to 140-160 ℃ for 24-28 h.
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