CN113443986A - Preparation method of intermediate for synthesizing 3-oxo-1-cyclobutanecarboxylic acid - Google Patents
Preparation method of intermediate for synthesizing 3-oxo-1-cyclobutanecarboxylic acid Download PDFInfo
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- 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
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Abstract
The invention discloses a preparation method of an intermediate 1, 1-bis (propyl-2-yl) 3, 3-dimethoxycyclobutane-1, 1-dicarboxylate (compound I) for synthesizing 3-oxo-1-cyclobutanecarboxylic acid, and particularly relates to an effective method for preparing 1, 1-bis (propyl-2-yl) 3, 3-dimethoxycyclobutane-1, 1-dicarboxylate (compound I) by using cyclization reaction: the potassium isopropoxide is selected as alkali, DMAc is selected as solvent, and the method plays a crucial role in the yield and purity of the final product.
Description
Technical Field
The invention relates to the field of synthesis of drug intermediates, in particular to a preparation method of an intermediate 1, 1-bis (propyl-2-yl) 3, 3-dimethoxycyclobutane-1, 1-dicarboxylate for synthesizing 3-oxo-1-cyclobutanecarboxylic acid.
Background
The 3-oxo-1-cyclobutanecarboxylic acid is a key intermediate for drug synthesis, can be used as an important molecular fragment for the synthesis of dozens of raw material drugs, such as an ACK1 antibody, an MDM2 antagonist, a JAK inhibitor, a CETP inhibitor, a kinase inhibitor, a PDE10 inhibitor, a thrombin inhibitor and is used in autoimmune chronic inflammation and antitumor drugs. Meanwhile, a series of compounds derived from the 3-oxo-1-cyclobutanecarboxylic acid also have wider application, for example, 3-difluorocyclobutylamine hydrochloride which is a key intermediate of an anticancer drug Ivosidenib for treating acute myeloid leukemia (R/R AML) is prepared by using the 3-oxo-1-cyclobutanecarboxylic acid as a starting material.
The literature reports that 3-oxo-1-cyclobutanecarboxylic acid can be prepared from 1, 1-bis (propyl-2-yl) 3, 3-dimethoxycyclobutane-1, 1-dicarboxylate (compound I) through a one-step hydrolysis reaction, and the reaction process is mature and stable. The synthesis process of the compound I has certain defects and needs to overcome more technical problems, so that the development of a new process capable of being amplified in a large scale has great significance.
The synthesis of compound I is described in international patent publication No. WO2007062308a 2:
the reaction was stirred at 140 ℃ for 24 hours using NaH as base and DMF as solvent. After the reaction is finished, the purification is performed through a Vigreux column, and after the rectification by using an air condenser, the secondary purification is performed through an Analogix silica gel column. The reported yield was 51% and no chemical purity was indicated.
Similar ring closure reactions are reported in specifications of WO2004082682A1/WO2009135842A1/WO2009114512/WO2013020993A 1; synlett, (11), 1827-; 2009/Synlett,25(3), 355-358; 2014 et al have reported similar methods. In the reaction process for preparing the compound I from the compound II and the compound III reported in the existing documents and patents, the reaction conditions are mostly that under the action of NaH, DMF is taken as a solvent, and the reported yield is about 50%. Patent CN105037130A discloses the preparation of compound I by ring closure of compound II and compound III using potassium tert-butoxide as base and DMF as solvent.
The inventor finds that the reaction condition has explosion and ignition risks by using NaH/DMF condition to prepare the compound I through experimental research; the reaction conversion rate is low, only 50-60%, the reaction compound II is incompletely converted (10-20% of residue), and the problem of blocking a condenser pipe is easily caused in the rectification process in large-scale production; NaH is used as alkali, the purification after the reaction is finished is inevitable, mineral oil impurities exist, meanwhile, a large amount of waste water containing DMF and sodium bromide is generated by post-treatment, and the three-waste treatment is difficult.
The inventor finds that potassium tert-butoxide is used as an alkali, ester exchange can occur between tert-butyl and isopropyl during the reaction process, about 10% of ester exchange byproducts are generated, the highest yield can only reach about 55-65%, and in addition, potassium tert-butoxide is used as an alkali, tarry impurities can be generated in a reaction system, and the reaction conversion rate is not high.
The inventor finds that DMF is used as a solvent, DMF is partially decomposed to generate formaldehyde, the formaldehyde reacts with diisopropyl malonate to generate a byproduct (compound V), the compound V is further subjected to deesterification at 140 ℃ to be converted into a compound VI and a compound VII, the two compounds are not easy to remove in the rectification process of products, glutaric acid impurities are generated in the production process of downstream products of 3-oxo-1-cyclobutanecarboxylic acid (compound IV), and the purification process needs recrystallization to obtain high-purity 3-oxo-1-cyclobutanecarboxylic acid, and the experiment finds that the product yield loss is 10-20%.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to overcome the defects in the prior art and provides an improved method for preparing 1, 1-bis (propyl-2-yl) 3, 3-dimethoxycyclobutane-1, 1-dicarboxylate (compound I), which has the advantages of easily available raw materials, simple and convenient operation, high product purity, high yield, total yield of over 80 percent and suitability for large-scale preparation.
The invention provides a preparation method of a compound I, which comprises the following steps:
DMAc is used as a solvent, the compound III reacts with potassium isopropoxide for a period of time, and then the compound II is added for reaction.
Preferably, the potassium isopropoxide is prepared by reacting isopropanol and potassium hydroxide in the presence of cycloalkane or an aromatic organic solvent; wherein the cycloalkane is selected from methylcyclohexane or cyclohexane; the aromatic organic solvent is selected from toluene, xylene, chlorobenzene or anisole;
preferably, in the preparation process of the potassium isopropoxide, cyclohexane is selected as the cycloalkane; toluene is selected as the aromatic organic solvent;
preferably, in the step of preparing the potassium isopropoxide, the molar ratio of the potassium hydroxide, the isopropanol and the cyclohexane is 1: 6-8: 2-3, and the reaction temperature is 60-80 ℃;
preferably, in the preparation step of the potassium isopropoxide, a water separator is used for water separation, and the water separation end point is the water content of the reaction system of 0.10-0.30%;
preferably, in the preparation step of the potassium isopropoxide, after the reaction is finished, distilling the solvent under normal pressure, stopping distilling when the temperature of a distillation system is reduced to 90-95 ℃, and preserving under the protection of inert gas after the solvent is removed;
preferably, the molar ratio of the compound II to the compound III to the potassium isopropoxide is 1: 2.2-3.
Preferably, the compound III firstly reacts with potassium isopropoxide, the reaction temperature ranges from 30 ℃ to 50 ℃, and the reaction time is 3-5 h;
preferably, in the process of adding the compound II, the compound II is added into the reaction system at one time, and an iodinating reagent is added at the same time, wherein the iodinating reagent is selected from potassium iodide or sodium iodide, and the reaction temperature range is 130-150 ℃.
Advantageous effects
According to the preparation method of the 1, 1-bis (propyl-2-yl) 3, 3-dimethoxycyclobutane-1, 1-dicarboxylate (compound I), the residual quantity of a starting material compound II at the end of reaction is reduced to 1-3%, the separation yield is up to 83%, potassium isopropoxide prepared by using potassium hydroxide and isopropanol is used as an alkali, and the production cost of DMAc as a solvent is greatly reduced (compared with the NaH/DMF condition and the potassium tert-butoxide/DMF condition in the prior art) (the cost of the NaH/DMF condition is 420 yuan/kg; the cost of the potassium tert-butoxide/DMF condition is 470 yuan/kg; and the cost of the potassium isopropoxide/DMAc condition is 245 yuan/kg); in addition, DMAc is used for replacing DMF as a solvent, so that the generation of a byproduct is effectively avoided, and the synthesis yield of a downstream product, namely 3-oxo-1-cyclobutanecarboxylic acid (compound IV) is indirectly improved.
Abbreviations for the reagents referred to in the specification are as follows:
DMAc: n, N-dimethylacetamide;
DMF: n, N-dimethylformamide;
Detailed Description
The present invention will be further illustrated by the following specific examples, which are carried out on the premise of the technical scheme of the present invention, and it should be understood that these examples are only for illustrating the present invention and are not intended to limit the scope of the present invention.
Example 1
Preparation of compound I:
sequentially adding isopropanol (2300g), potassium hydroxide (280.0g) and cyclohexane (1100g) into a 5000mL four-neck flask, stirring and heating to 70-80 ℃, refluxing and dividing water through a rectifying tower (phi ring glass filler, tower height 500mm), and detecting that the water content of liquid in the reaction flask is 0.10-0.30% as a water dividing terminal point; heating and normal pressure to evaporate the mixed solvent of cyclohexane and isopropanol, stopping distillation when the distillation is less and the temperature in the kettle rises to 93-95 ℃, and cooling to room temperature under the protection of nitrogen; and packaging the potassium isopropoxide and isopropanol solution for later use, and detecting the content of the potassium isopropoxide by 30.0 percent.
Under the protection of nitrogen in a 5000mL four-neck flask, sequentially adding a compound III (718.6g,3.82mol, 2.5eq.) and N, N-dimethylacetamide (1116.0g), controlling the reaction liquid to be 30-50 ℃, dropwise adding a prepared 30.0% potassium isopropoxide solution (1250.0g, 3.82mol, 2.5eq.), dropwise adding 1/3, beginning to precipitate a large amount of white solid, keeping the temperature to be 40-50 ℃, and stirring for reaction for 4 hours; after the incubation is finished, the compound II (400.0g, 1.53mol,1.0eq.), potassium iodide (20.0g) are added in one portion, and the reaction is stirred until the addition is finished, in order to 1E1.5h, heating to 135-145 ℃ for heat preservation reaction (in the heating process, a large amount of isopropanol is evaporated, and a water separator and a condensation pipe are required to recover the isopropanol); preserving the temperature to be 135-145 ℃ and reacting for 22-24 h; after the reaction is finished, evaporating DMAc under reduced pressure, adding 800mL of toluene, stirring for 1h, filtering, and collecting filtrate; washing the filter cake twice with toluene (1600mL), combining toluene mother liquor, adding water for washing, stirring for 10min, standing for layering, separating out a toluene layer, discarding a water layer, and evaporating the toluene by an organic phase water pump under reduced pressure. And (3) carrying out reduced pressure rectification on the residual liquid at the pressure of 100-150 Pa, collecting the fraction at 85-94 ℃, and obtaining 363.1g of a colorless liquid of the compound I, wherein the yield is 82.4% and the purity is 98.5%.1HNMR(400MHz，CDCl3)(ppm)：5.06～5.03(m，2H)，3.14(s，6H)，2.68(s，4H)，1.23(s，6H)，1.22(s，6H)。
Example 2
Preparation of compound I:
sequentially adding isopropanol (330g), potassium hydroxide (28.0g) and toluene (300g) into a 1000mL four-neck flask, stirring and heating to 70-80 ℃, refluxing and dividing water through a rectifying tower (phi ring glass filler, tower height 500mm), and detecting that the water content of liquid in the reaction bottle is 0.10-0.30% as a water dividing end point; heating and normal pressure to evaporate the mixed solvent of the toluene and the isopropanol, stopping distillation when the distillation is less and the temperature in the kettle rises to 93-95 ℃, and cooling to room temperature under the protection of nitrogen; and packaging the potassium isopropoxide and isopropanol solution for later use, and detecting the content of the potassium isopropoxide by 30.0 percent.
Under the protection of nitrogen in a 1000mL four-neck flask, sequentially adding a compound III (71.9g,0.382mol, 2.5eq.) and N, N-dimethylacetamide (112.0g), controlling the reaction liquid to be 30-50 ℃, dropwise adding a prepared 30.0% potassium isopropoxide solution (125.0g, 0.382mol, 2.5eq.), dropwise adding 1/3 to precipitate a large amount of white solid, and stirring and reacting for 4 hours at the temperature of 40-50 ℃ after dropwise adding; after the heat preservation is finished, adding the compound II (40.0g, 0.153mol,1.0eq.) and sodium iodide (2.0g) at one time, stirring and reacting for 1-1.5 h after the addition is finished, heating to 135-145 ℃ for heat preservation reaction (the isopropanol is evaporated in large quantity in the heating process, and the connection is neededRecycling isopropanol by a water separator and a condensation pipe); preserving the temperature to be 135-145 ℃ and reacting for 22-24 h; after the reaction is finished, evaporating DMAc under reduced pressure, adding 40mL of toluene, stirring for 1h, filtering, and collecting filtrate; washing the filter cake twice with toluene (80mL), combining toluene mother liquor, adding water for washing, stirring for 10min, standing for layering, separating out a toluene layer, discarding a water layer, and evaporating the toluene by an organic phase water pump under reduced pressure. And (3) carrying out reduced pressure rectification on the residual liquid at the pressure of 100-150 Pa, collecting the fraction at 85-94 ℃, and obtaining 33.3g of a compound I which is a colorless liquid, wherein the yield is 75.7%, and the purity is 98.3%.1HNMR(400MHz，CDCl3)(ppm)：5.06～5.03(m，2H)，3.14(s，6H)，2.68(s，4H)，1.23(s，6H)，1.22(s，6H)。
This example was carried out in accordance with the preparation of compound I of example 1, using different starting materials and the results obtained are given in table 1 below.
TABLE 1
Claims (9)
1. A process for the preparation of compound I, comprising:
taking N, N-dimethylacetamide as a solvent, reacting the compound III with potassium isopropoxide, and then adding the compound II for reaction.
2. The method of claim 1, wherein: the potassium isopropoxide is prepared by the reaction of isopropanol and potassium hydroxide in the presence of cycloalkane or aromatic organic solvent; wherein the cycloalkane is selected from methylcyclohexane or cyclohexane; the aromatic organic solvent is selected from toluene, xylene, chlorobenzene or anisole.
3. The method of claim 2, wherein: in the preparation process of potassium isopropoxide, if cycloalkane is added, cyclohexane is selected; if aromatic organic solvent is added, toluene is selected.
4. The production method according to claim 2 or claim 3, characterized in that: in the preparation step of the potassium isopropoxide, the molar ratio of the potassium hydroxide, the isopropanol and the cyclohexane is 1: 6-8: 2-3, and the reaction temperature is 60-80 ℃.
5. The method of claim 4, wherein: in the preparation step of the potassium isopropoxide, a water separator is used for water separation, and the water content of the reaction system is 0.1-0.3% as the water separation end point.
6. The method of claim 5, wherein: in the preparation step of the potassium isopropoxide, after the reaction is finished, distilling under normal pressure to remove the solvent, stopping distilling when the temperature of a distillation system is reduced to 90-95 ℃, and preserving under the protection of inert gas after the solvent is removed.
7. The production method according to claim 1 or claim 2, characterized in that: the molar ratio of the compound II to the compound III to the potassium isopropoxide is 1: 2.2-3.
8. The method of claim 7, wherein: the reaction temperature of the compound III and potassium isopropoxide ranges from 30 ℃ to 50 ℃, and the reaction time is 3-5 h.
9. The method of claim 1, wherein: and (3) adding a compound II, namely adding the compound II into a reaction system at one time, and simultaneously adding an iodinating reagent, wherein the iodinating reagent is selected from potassium iodide or sodium iodide, and the reaction temperature range is 130-150 ℃.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114163323A (en) * | 2021-12-13 | 2022-03-11 | 大连双硼医药化工有限公司 | Synthetic method of 3-oxocyclobutanecarboxylic acid |
| CN118530108A (en) * | 2024-07-26 | 2024-08-23 | 中节能万润股份有限公司 | Preparation method of 3-oxo-cyclobutanecarboxylic acid |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114163323A (en) * | 2021-12-13 | 2022-03-11 | 大连双硼医药化工有限公司 | Synthetic method of 3-oxocyclobutanecarboxylic acid |
| CN114163323B (en) * | 2021-12-13 | 2024-03-26 | 大连双硼医药化工有限公司 | Synthesis method of 3-oxo-cyclobutanecarboxylic acid |
| CN118530108A (en) * | 2024-07-26 | 2024-08-23 | 中节能万润股份有限公司 | Preparation method of 3-oxo-cyclobutanecarboxylic acid |
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