CN112521282A - Bepaidic acid intermediate and synthesis method thereof - Google Patents
Bepaidic acid intermediate and synthesis method thereof Download PDFInfo
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- 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
- C07C67/313—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of doubly bound oxygen containing functional groups, e.g. carboxyl groups
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Abstract
The invention provides a method for synthesizing a pipadienoic acid intermediate 7-chloro-2, 2-dimethyl heptanoate by isobutyrate and 1-bromo-5-chloropentane, and further used for synthesizing pipadienoic acid.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a pipadiric acid intermediate and a preparation method thereof.
Background
Bempedic acid (Bempedoic acid) is a novel lipid-regulated small-molecule drug developed by American Imperion Therapeutic company, the action targets of the Bempedonic acid are liver adenosine triphosphate lyase (ACL) and adenosine monophosphate activated protein kinase (AMPK), and compared with the statin drugs widely used clinically at present, the Bempedonic acid (Bempedoic acid) has the advantages of better tolerance and can be used for treating LDL-C which cannot be controlled by the existing method when being combined with the statin drugs.
Bemoparic acid CAS RN: 738606-46-7, having the chemical name 8-hydroxy-2, 2,14, 14-tetramethylpentadecanedioic acid and having the following structural formula:
in the prior art, the synthesis route of the bipartite acid is not many, the 7-bromo-2, 2-dimethylheptanoic acid ethyl ester is a key intermediate in the preparation process of the bipartite acid, and the intermediate and the bipartite acid are generally prepared by the following method:
the process reported in WO2008034119A1 and EP034271A1, etc. for synthesizing ethyl 7-bromo-2, 2-dimethylheptanoate using 1, 5-dibromopentane and ethyl isobutyrate and lithium diisopropylamide as a base is not high in yield. Ralf Mueller, et al (J.Med.chem.2004,47, 6082-. In CN202010673615.6, continuous-flow microreactor is adopted to synthesize ethyl 7-bromo-2, 2-dimethylheptanoate, and although yield of more than 80% can be obtained, the method is not suitable for large-scale production.
The reaction routes all adopt 1, 5-dibromopentane as a raw material for reaction, and if the reaction conditions are not well controlled, a large amount of disubstituted byproducts shown below are inevitably generated, thereby influencing the synthesis yield,
in summary, there are various problems in the existing preparation method of the besmead acid intermediate, and in order to improve the production efficiency, yield and purity of the intermediate and the final product, the preparation method needs to be improved.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a novel synthesis method of a bipeda acid intermediate 7-chloro-2, 2-dimethyl heptanoate and bipeda acid, and the preparation method has the advantages of simple reaction route, low byproduct content, high yield and purity and easy industrialization.
The invention also provides a prepetidic acid intermediate compound, namely 7-chloro-2, 2-dimethylheptanoate, and application thereof in synthesizing prepetidic acid.
The purpose of the invention is realized by the following technical scheme:
a synthesis method of a betadienoic acid intermediate 7-chloro-2, 2-dimethyl heptanoate comprises the steps of reacting isobutyrate and 1-bromo-5-chloropentane in a solvent under alkaline conditions to generate the 7-chloro-2, 2-dimethyl heptanoate,
r is selected from alkyl and aryl, said alkyl is further selected from C1-C8 alkyl or cycloalkyl and branched alkyl or cycloalkyl such as methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like; the aryl is further selected from C6-C12 aryl and substituted aryl, such as benzene and naphthalene.
Further wherein the base is selected from the group consisting of Lithium Diisopropylamide (LDA), n-butyllithium, t-butyllithium, lithium bis (trimethylsilyl) amide (LiHMDS), sodium methoxide, sodium t-butoxide, potassium t-butoxide, sodium ethoxide, potassium ethoxide, sodium hydrogen, and the like, preferably Lithium Diisopropylamide (LDA).
Further, the reaction solvent is selected from aprotic solvents, preferably tetrahydrofuran and toluene.
Further, the reaction temperature is-70-30 ℃.
Further, the molar ratio of the compound 1, 1a to the base is 1:0.5-2:0.5-2, preferably 1:1:0.8-1.2: 1-1.2.
Further, the post-treatment is to pour the mixture into water after the reaction is finished, extract the mixture by an organic solvent, take an organic phase, wash, dry and distill the organic phase to obtain a target product, wherein the organic solvent is selected from ethyl acetate, methyl tert-butyl ether and the like.
Further, the reaction of the step is carried out according to the following steps: slowly dripping alkali into the solvent, cooling to-70-30 ℃, slowly adding isobutyrate and 1-bromo-5-chloropentane, heating to room temperature for reaction, pouring into water after the reaction is detected, extracting by using an organic solvent, taking an organic phase, washing, drying and distilling to obtain a target product.
The invention provides a preparation method of 8-isocyanic acid-2, 2,14, 14-tetramethyl-8-p-acetyl pentadiene diester for synthesizing pipadiric acid, which comprises the step of generating 7-chloro-2, 2-dimethyl heptanoate by isobutyrate and 1-bromo-5-chloropentane under alkaline conditions.
R is selected from alkyl and aryl
Further, the preparation of 2a is carried out in the presence of a strong base selected from sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, potassium ethoxide, sodium hydrogen, a phase transfer catalyst selected from TBAI, TBAB, TBAC, crown ether, etc.
Further, the reaction temperature of the step 2 is 10-30 ℃, preferably 15-22 ℃.
Further, the amount of the compound 2:1b used in the step 2 is 2:1-1.5, preferably 2: 1.
Further, the acid of step 3 is selected from hydrochloric acid, p-toluenesulfonic acid and sulfuric acid.
Furthermore, the reaction temperature of the step 3 is-5-15 ℃, preferably 0-10 ℃.
The invention provides a synthesis method of pipadiric acid, which comprises the step of generating 7-chloro-2, 2-dimethyl heptanoate from isobutyrate and 1-bromo-5-chloropentane under an alkaline condition.
The invention provides a synthesis method of pipadiric acid, which comprises the steps of generating 7-chloro-2, 2-dimethyl heptanoate from isobutyrate and 1-bromo-5-chloropentane under an alkaline condition, and then treating the 7-chloro-2, 2-dimethyl heptanoate with acid under the action of p-methyl benzenesulfonyl methyl isonitrile to obtain 8-isocyanic acid-2, 2,14, 14-tetramethyl-8-p-acetyl pentadiene diester.
The present invention providesIntermediate of pipadiric acid
R is selected from alkyl and aryl, said alkyl is further selected from C1-C8 alkyl or cycloalkyl and branched alkyl or cycloalkyl such as methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like; the aryl is further selected from C6-C12 aryl and substituted aryl, such as benzene and naphthalene.
Compared with the prior art, the invention has the following advantages and beneficial effects:
(1) in the prior art, isobutyrate and 1, 5-dibromopentane react to generate a dimer impurity with a large content inevitably, the invention adopts 1-bromo-5-chloropentane to generate 7-chloro-2, 2-dimethylheptanoate and effectively synthesize the besipidic acid, the intermediate has high yield and good purity, and the dimer impurity is prevented from being generated through a simple reaction route.
(2) The preparation method of the pipadiric acid adopts a new intermediate, reduces the generation of side reaction products, optimizes reaction conditions and a purification method, has higher preparation process efficiency, does not need complicated and complex post-treatment with high cost, such as column chromatography purification, and is suitable for industrial production.
Drawings
The accompanying drawings, which are included to provide a further understanding of the embodiments of the invention and are incorporated in and constitute a part of this application, illustrate embodiment(s) of the invention and together with the description serve to explain the principles of the invention.
FIG. 1 is a gas chromatogram of ethyl 7-chloro-2, 2-dimethylheptanoate in example 1 of the present invention.
FIG. 2 is a nuclear magnetic spectrum of ethyl 7-chloro-2, 2-dimethylheptanoate in example 1 of the present invention.
FIG. 3 is a liquid chromatogram of diethyl 8-isocyano-2, 2,14, 14-tetramethyl-8-tosylpentadecanedioate in example 1 of the present invention.
FIG. 4 is a gas chromatogram of a comparative example.
Detailed Description
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Example 1
In N2BuLi (2.5M in hexane, 80mL, 200mol) was added dropwise to iPr at 0 ℃ under a protective atmosphere2NH (27.5mL, 200mmol) and dry THF (200mL), stirred for 30min, cooled to-70 deg.C, then ethyl isobutyrate (23.2g, 200mmol) was added dropwise to the reaction over 30min, then 1-bromo-5-chloropentane (37.1g, 200mmol) was added dropwise over 15min, warmed to room temperature for 5 hours, and after the reaction was complete, poured into aqueous hydrochloric acid (2M, 200mL) and extracted with ethyl acetate (2X 300 mL). Brine and saturated NaHCO3A mixture of aqueous solutions (10:1,300mL) was washed with the combined organic layers and dried, and the remaining oil was distilled to give 7-chloro-2, 2-dimethylheptanoic acid ethyl ester (41.1g, 93%) as a colorless liquid. Gas phase conditions: GC conditions were as follows: agilent 7860 series gas chromatograph (agilent corporation, usa); the chromatographic column is an Agilent HP-5 gas chromatographic column (specification: column length is 30m, column diameter is 0.32mm, and filler particle size is 0.25 um); the temperature of the sample inlet is 270 ℃, the control mode is a constant flow mode, the gas flow rate is 2.0mL/min, and the split ratio is 30: 1; temperature rising procedure: maintaining the initial temperature at 40 deg.C for 3 min; raising the temperature to 280 ℃ at the temperature rise rate of 30 ℃/min, and keeping the temperature for 4 min; the detector is a FID detector, the temperature of a detection port is 280 ℃, the hydrogen flow rate is 40mL/min, the air flow rate is 400mL/min, and the nitrogen flow rate is 30 mL/min. The purity was determined to be 94.4%, as can be seen in FIG. 1, with only 0.3% of the disubstituted by-product being formed.
1H NMR(400MHz,CDCl3) δ 1.14(s,6H)1.21-1.27(m,5H),1.36-1.43(m,2H),1.48-1.52(m,2H),1.71-1.78(m,2H),3.48-3.52(t,2H),4.07-4.12(q, 2H). The nuclear magnetic data are shown in FIG. 2.
Sodium ethoxide (3.8g, 50mol), DMSO (60mL) was added to a three-necked flask at 20 ℃ followed by tetrabutylammonium iodide (1.7g, 4.5mmol), p-toluenesulfonylmethylisocyanide (4.4g, 23mol), stirred for 1 hour, ethyl 7-chloro-2, 2-dimethylheptanoate (10g, 45mmol) and DMSO (20mL) were added dropwise to the above reaction solution over 10min, reacted for 12 hours, after completion of the reaction, poured into ice (50mL) and water (50mL) and extracted with ethyl acetate (2X 100mL), the combined organic layers were washed with a mixture of brine (2X 100mL) and dried, concentrated to give diethyl 8-isocyano-2, 2,14, 14-tetramethyl-8-toluenesulfonylpentadecanedioate (21.5g, yield 90%, purity: 97.3%).
HPLC conditions: agilent 1260 series high performance liquid chromatograph (Agilent, USA); the chromatographic column is Waters XSelect CSHTMC18 reversed phase chromatographic column (specification: column length 150mm, column diameter 3.0mm, filler particle diameter 3.5 um); taking 10mmol/L ammonium bicarbonate buffer solution as a mobile phase A, and taking a mobile phase B as an acetonitrile solution; the column temperature is 30 ℃; gradient elution; the flow rate is 0.6 mL/min; the detection wavelength is 210 nm; the procedure is as follows: 0min, 55 percent of mobile phase A and 45 percent of mobile phase B; 7min, 5 percent of mobile phase A and 95 percent of mobile phase B; 15min, 5 percent of mobile phase A and 95 percent of mobile phase B; 15.1min, 55 percent of mobile phase A and 45 percent of mobile phase B; 20min, 55 percent of mobile phase A and 45 percent of mobile phase B. The purity was determined to be 97.3%, see FIG. 3.
Adding a dichloromethane solution (90mL) of 8-isocyano-2, 2,14, 14-tetramethyl-8-tosylpentadecanedioic acid diethyl ester (8.9g, 16.7mmol) into a three-necked flask, cooling to 0-10 ℃, then adding concentrated hydrochloric acid (29.4mL), stirring the obtained mixed solution at 0-10 ℃ for 3 hours, standing after the reaction is finished, carrying out layering, extracting the aqueous phase with dichloromethane (90mL × 2), washing the obtained organic phase with a sodium bicarbonate solution (2 × 90mL), drying over anhydrous magnesium sulfate, and concentrating to obtain 6.3g of the target product diethyl 2,2,14, 14-tetramethyl-8-oxoglutarate (yield 95%, purity: 95%).
Example 2
In N2Adding lithium diisopropylamide (2.0M hexane solution, 100mL, 200mol) and dry THF (200mL) into a three-necked flask under protection, cooling to-70 ℃, then adding ethyl isobutyrate (23.2g, 200mmol) dropwise into the reaction solution within 30min, then adding 1-bromo-5-chloropentane (37.1g, 200mmol) dropwise within 15min, raising the temperature to room temperature for 5 hours, and after the reaction is finished, pouring into hydrochloric acid aqueous solution (2M, 200mL) and ethyl acetate (2X 300mL)mL) was extracted. Brine and saturated NaHCO3A mixture of aqueous solutions (10:1,300mL) was washed with the combined organic layers and dried. The remaining oil was purified by fractional distillation under reduced pressure to give ethyl 7-chloro-2, 2-dimethylheptanoate (40.1g, 91%) as a colorless liquid. Substantially consistent with the nmr hydrogen spectrum data of example 1.
Sodium tert-butoxide (4.8g, 50mol), DMSO (60mL) was added to a three-necked flask at 20 ℃ followed by tetrabutylammonium iodide (1.7g, 4.5mmol), p-toluenesulfonylmethylisonitrile (4.4g, 23mol), stirred for 1 hour, ethyl 7-chloro-2, 2-dimethylheptanoate (10g, 45mmol) and DMSO (20mL) were added dropwise to the reaction over 10min, reacted for 12 hours, and after completion of the reaction, ice (50mL) and water (50mL) were poured and extracted with ethyl acetate (2X 100 mL). The combined organic layers were washed with a mixture of brine (2X 100mL) and dried. Concentration gave diethyl 8-isocyano-2, 2,14, 14-tetramethyl-8-toluenesulfonylpentadecanedioate (22.0g, 92% yield).
Adding an ethyl acetate solution (90mL) of 8-isocyano-2, 2,14, 14-tetramethyl-8-tosylpentadecanedioic acid diethyl ester (8.9g, 16.7mmol) into a three-necked flask, cooling to 0-10 ℃, then adding concentrated hydrochloric acid (29.4mL), stirring the obtained mixed solution at 0-10 ℃ for 3 hours, standing after the reaction is finished, carrying out layering, extracting an aqueous phase with ethyl acetate (90mL × 2), washing an obtained organic phase with a sodium bicarbonate solution (2 × 90mL), drying with anhydrous magnesium sulfate, and concentrating to obtain 6.3g of a target product diethyl 2,2,14, 14-tetramethyl-8-oxoglutarate (yield 95%).
Example 3
In N2Lithium diisopropylamide (2.0M in hexane, 100mL, 200mol) and dry THF (200mL) were added to a three-necked flask under protective atmosphere, cooled to-30 deg.C, ethyl isobutyrate (23.2g, 200mmol) was added dropwise to the reaction over 30min, 1-bromo-5-chloropentane (37.1g, 200mmol) was added dropwise over 15min, warmed to room temperature for 5 hours, and after completion of the reaction, poured into aqueous hydrochloric acid (2M, 200mL) and extracted with methyl tert-butyl ether (2X 300 mL). Brine and saturated NaHCO3A mixture of aqueous solutions (10:1,300mL) was washed with the combined organic layers and dried. The remaining oil was purified by fractional distillation under reduced pressure to give 7-chloro-2Ethyl 2-dimethylheptanoate (39.7g, 90%) was a colorless liquid.
Potassium tert-butoxide (5.6g, 50mol), DMSO (60mL) was added to a three-necked flask at 20 ℃ followed by tetrabutylammonium iodide (1.7g, 4.5mmol), p-toluenesulfonylmethylisocyanamide (4.4g, 23mol), stirred for 1 hour, ethyl 7-chloro-2, 2-dimethylheptanoate (10g, 45mmol) and DMSO (20mL) were added dropwise to the reaction over 10min, reacted for 12 hours, and after completion of the reaction, poured into ice water (100mL) and extracted with ethyl acetate (2X 100 mL). The combined organic layers were washed with a mixture of brine (2X 100mL) and dried. Concentration gave diethyl 8-isocyano-2, 2,14, 14-tetramethyl-8-toluenesulfonylpentadecanedioate (21.3g, 89% yield).
Adding a methyl tetrahydrofuran solution (90mL) of 8-isocyano-2, 2,14, 14-tetramethyl-8-tosylpentadecanedioic acid diethyl ester (8.9g, 16.7mmol) into a three-necked flask, cooling to 0-10 ℃, then adding concentrated hydrochloric acid (29.4mL), stirring the obtained mixed solution at 0-10 ℃ for 3 hours, standing after the reaction is finished, carrying out layering, extracting an aqueous phase with methyl tetrahydrofuran (90mL multiplied by 2), washing an obtained organic phase with a sodium bicarbonate solution (2 multiplied by 90mL), drying with anhydrous magnesium sulfate, and concentrating to obtain 6.3g of a target product diethyl 2,2,14, 14-tetramethyl-8-oxoglutarate (yield 95%)
Comparative examples
In N2BuLi (2.5M in hexane, 80mL, 200mol) was added dropwise to iPr at 0 ℃ under a protective atmosphere2NH (27.5mL, 200mmol) and dry THF (200mL), stirred for 30min, cooled to-70 deg.C, then ethyl isobutyrate (23.2g, 200mmol) was added dropwise to the reaction over 30min, then 1, 5-dibromopentane (46.0g, 200mmol) was added dropwise over 15min, warmed to room temperature for 5 hours, and after the reaction was complete, poured into ice (100mL), water (100mL), brine (200mL) and aqueous hydrochloric acid (2M, 200mL) and extracted with ethyl acetate (2X 300 mL). Brine and saturated NaHCO3A mixture of aqueous solutions (10:1,300mL) was washed with the combined organic layers and dried, and the remaining oil was purified by fractional distillation under reduced pressure to give ethyl 7-bromo-2, 2-dimethylheptanoate (37.1g, 70%) as a colorless liquid, 59.8% pure, containing 22.4% disubstituted side products, as shown in FIG. 4.
Claims (11)
1. A synthesis method of a pimelic acid intermediate 7-chloro-2, 2-dimethyl heptanoate is characterized by comprising the steps of reacting isobutyrate (1) and 1-bromo-5-chloropentane (1a) in a solvent under alkaline conditions to generate 7-chloro-2, 2-dimethyl heptanoate (2), wherein the reaction formula is as follows:
r is selected from alkyl and aryl.
2. The method for synthesizing the intermediate 7-chloro-2, 2-dimethylheptanoate of pipa according to claim 1, wherein the base is selected from Lithium Diisopropylamide (LDA), n-butyllithium, t-butyllithium, lithium bis (trimethylsilyl) amide (LiHMDS), sodium methoxide, sodium t-butoxide, potassium t-butoxide, sodium ethoxide, potassium ethoxide, sodium hydrogen, etc., preferably Lithium Diisopropylamide (LDA).
3. The process of claim 1 wherein the reaction solvent is selected from the group consisting of aprotic solvents.
4. The synthesis method of the intermediate 7-chloro-2, 2-dimethylheptanoate of the pimelic acid as claimed in claim 1, wherein the reaction temperature is-70-30 ℃, and the molar ratio of the compound 1, 1a to the base is 1:0.5-2: 0.5-2; and the post-treatment is to pour the mixture into water after the reaction is finished, extract the mixture by using an organic solvent, take an organic phase, wash, dry and distill the organic phase to obtain a target product, wherein the organic solvent is selected from ethyl acetate or methyl tert-butyl ether.
5. The method for synthesizing the intermediate 7-chloro-2, 2-dimethylheptanoate of pipadidic acid as claimed in claim 1, wherein the reaction is carried out by the following steps: slowly dripping alkali into the solvent, cooling to-70-30 ℃, slowly adding isobutyrate and 1-bromo-5-chloropentane, heating to room temperature for reaction, pouring into water after the reaction is detected, extracting by using an organic solvent, taking an organic phase, washing, drying and distilling to obtain a target product.
6. A process for the preparation of 2,2,14, 14-tetramethyl-8-p-acetylpentadiene-8-isocyanate for the synthesis of pipadic acid, comprising the step of 7-chloro-2, 2-dimethylheptanoate (2) as an intermediate of pipadic acid as described in any one of claims 1 to 5, characterized by further comprising the steps of: the 7-chloro-2, 2-dimethyl heptanoate (2) is treated by acid under the action of p-methyl benzenesulfonyl methyl isonitrile (1b) to obtain 8-isocyanic acid-2, 2,14, 14-tetramethyl-8-p-acetyl pentadiene diester (3); the reaction formula is as follows:
r is selected from alkyl and aryl.
7. The process of claim 6, wherein the reaction of 7-chloro-2, 2-dimethylheptanoate (2) with p-toluenesulfonylmethylisocyanide (1b) is carried out in the presence of a strong base selected from sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, potassium ethoxide or sodium hydrogen, a phase transfer catalyst selected from TBAI, TBAB, TBAC or crown ether.
8. The process for preparing 2,2,14, 14-tetramethyl-8-p-acetylpentadiene-8-isocyanate used for the synthesis of pipadiric acid as claimed in claim 6, wherein the reaction temperature of 7-chloro-2, 2-dimethylheptanoate (2) with p-toluenesulfonylmethyl isonitrile (1b) is 10 to 30 ℃; the dosage of the 7-chloro-2, 2-dimethyl heptanoate (2) and the p-methyl benzenesulfonyl methyl isonitrile (1b) is 2: 1-1.5; the acid in the acid treatment is selected from hydrochloric acid, p-toluenesulfonic acid or sulfuric acid.
9. A process for the synthesis of bipedac acid comprising reacting isobutyrate according to any of claims 1 to 5 with 1-bromo-5-chloropentane under basic conditions to form 7-chloro-2, 2-dimethylheptanoate.
10. A process for the synthesis of pipadiric acid, which comprises the steps of reacting isobutyrate as claimed in any of claims 6 to 8 with 1-bromo-5-chloropentane under basic conditions to form 7-chloro-2, 2-dimethylheptanoate, and treating with acid under the action of p-toluenesulfonylmethyl isonitrile to obtain 8-isocyanic acid-2, 2,14, 14-tetramethyl-8-p-acetylpentadiene diester.
11. The intermediate of bipidedic acid is shown below:
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| CN114436821A (en) * | 2021-12-27 | 2022-05-06 | 甘李药业股份有限公司 | Crystallization method of pipadiric acid intermediate |
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| CN115504914A (en) * | 2021-06-23 | 2022-12-23 | 武汉武药科技有限公司 | Preparation method of piparidic acid intermediate |
| CN116589341A (en) * | 2023-04-14 | 2023-08-15 | 苏州汉德创宏生化科技有限公司 | Preparation method of antihyperlipidemic drug intermediate |
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| CN114436821A (en) * | 2021-12-27 | 2022-05-06 | 甘李药业股份有限公司 | Crystallization method of pipadiric acid intermediate |
| CN116589341A (en) * | 2023-04-14 | 2023-08-15 | 苏州汉德创宏生化科技有限公司 | Preparation method of antihyperlipidemic drug intermediate |
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