CN114436837B - Purification method of bevacizidine acid intermediate - Google Patents
Purification method of bevacizidine acid intermediate Download PDFInfo
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- CN114436837B CN114436837B CN202111612172.0A CN202111612172A CN114436837B CN 114436837 B CN114436837 B CN 114436837B CN 202111612172 A CN202111612172 A CN 202111612172A CN 114436837 B CN114436837 B CN 114436837B
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- 238000000034 method Methods 0.000 title claims abstract description 15
- 239000002253 acid Substances 0.000 title claims abstract description 8
- 238000000746 purification Methods 0.000 title claims description 8
- 239000007788 liquid Substances 0.000 claims abstract description 9
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical group CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 30
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- 239000002904 solvent Substances 0.000 claims description 13
- -1 8-oxo-2,2,14,14-tetramethyl pentadecane diethyl phthalate Chemical compound 0.000 claims 1
- 238000000605 extraction Methods 0.000 abstract description 9
- 239000002699 waste material Substances 0.000 abstract description 4
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 239000000463 material Substances 0.000 abstract description 3
- 238000011161 development Methods 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 239000012071 phase Substances 0.000 description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- 238000003756 stirring Methods 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 238000005303 weighing Methods 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
- 238000008214 LDL Cholesterol Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- SYRIIFZUZOIRNU-UHFFFAOYSA-N ethyl 7-bromo-2,2-dimethylheptanoate Chemical compound CCOC(=O)C(C)(C)CCCCCBr SYRIIFZUZOIRNU-UHFFFAOYSA-N 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- CFOAUYCPAUGDFF-UHFFFAOYSA-N tosmic Chemical compound CC1=CC=C(S(=O)(=O)C[N+]#[C-])C=C1 CFOAUYCPAUGDFF-UHFFFAOYSA-N 0.000 description 3
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 2
- 102000007330 LDL Lipoproteins Human genes 0.000 description 2
- 108010007622 LDL Lipoproteins Proteins 0.000 description 2
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- LDURYVDWYUCWGK-UHFFFAOYSA-N diethyl 2,2,14,14-tetramethyl-8-oxopentadecanedioate Chemical compound CCOC(=O)C(C)(C)CCCCCC(=O)CCCCCC(C)(C)C(=O)OCC LDURYVDWYUCWGK-UHFFFAOYSA-N 0.000 description 2
- WDAXFOBOLVPGLV-UHFFFAOYSA-N ethyl isobutyrate Chemical compound CCOC(=O)C(C)C WDAXFOBOLVPGLV-UHFFFAOYSA-N 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 2
- IBODDUNKEPPBKW-UHFFFAOYSA-N 1,5-dibromopentane Chemical compound BrCCCCCBr IBODDUNKEPPBKW-UHFFFAOYSA-N 0.000 description 1
- ZHUVNVRTGUOCNN-UHFFFAOYSA-N 2,2,14,14-tetramethylpentadecan-8-one Chemical compound CC(C)(C)CCCCCC(=O)CCCCCC(C)(C)C ZHUVNVRTGUOCNN-UHFFFAOYSA-N 0.000 description 1
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 208000032928 Dyslipidaemia Diseases 0.000 description 1
- 208000017170 Lipid metabolism disease Diseases 0.000 description 1
- 102000004317 Lyases Human genes 0.000 description 1
- 108090000856 Lyases Proteins 0.000 description 1
- 229940126239 Nexletol Drugs 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 229960005305 adenosine Drugs 0.000 description 1
- 230000003113 alkalizing effect Effects 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- HYHMLYSLQUKXKP-UHFFFAOYSA-N bempedoic acid Chemical compound OC(=O)C(C)(C)CCCCCC(O)CCCCCC(C)(C)C(O)=O HYHMLYSLQUKXKP-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000002910 solid waste Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/48—Separation; Purification; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/48—Separation; Purification; Stabilisation; Use of additives
- C07C67/52—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/48—Separation; Purification; Stabilisation; Use of additives
- C07C67/58—Separation; Purification; Stabilisation; Use of additives by liquid-liquid treatment
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Crystallography & Structural Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for purifying a beige acid intermediate diethyl 8-oxo-2,2,14,14-tetramethyl pentadecanedioate (BPD-3), which uses an extraction method to purify the BPD-3 to obtain the high-purity BPD-3, and the invention reduces the output of waste liquid and waste residue, reduces the input of equipment and materials, reduces the production cost, is more suitable for industrial production, and accords with the development concept of green chemistry.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a purification method of a bevacizidine acid intermediate diethyl 8-oxo-2,2,14,14-tetramethyl pentadecanedioate (BPD-3).
Background
Bemphadic Acid (bemperoic Acid) is an adenosine triphosphate-citrate lyase (ACL) inhibitor developed by us Esperion Therapeutics and approved for sale by the us FDA on 21 months 2020 under the trade name Nexletol. Bevacizidine, which reduces cholesterol biosynthesis by upregulating Low Density Lipoprotein (LDL) receptors and reduces the level of LDL cholesterol (LDL-C), is useful in the treatment of dyslipidemia and in reducing the risk of other cardiovascular diseases. Compared with the statin drugs widely applied clinically at present, the bevacizidine has the advantages of good tolerance and can be used for treating the LDL-C which is not controlled by the prior method when being used together with the statin drugs.
The synthetic route disclosed in the original patent US9000041B is as follows:
the method takes ethyl isobutyrate (SM 1) and 1, 5-dibromopentane (SM 2) as starting materials, and 7-bromo-2, 2-dimethylheptanoic acid ethyl ester (BPD-1) is obtained through the condensation of Lithium Diisopropylamide (LDA) at low temperature; BPD-1 is used as an alkylating reagent and p-toluenesulfonyl methyl isonitrile (TosMIC) to prepare an adduct BPD-2 of the p-toluenesulfonyl methyl isonitrile through tetrabutylammonium iodide (TBAI) catalysis under a strong alkaline condition; hydrolyzing the compound BPD-2 under an acidic condition to obtain 8-oxo-2,2,14,14-tetramethyl pentadecane diethyl diacid (BPD-3); alkalizing and hydrolyzing the compound BPD-3 in an ethanol system, and then acidifying to obtain 8-oxo-2,2,14,14-tetramethyl pentadecane diacid (BPD-4); the compound BPD-4 is reduced by NaBH4 in methanol, and finally is acidified by HCl to obtain the target product bevacizidine.
The above synthetic route has the following problems: 1. the compound 8-oxo-2,2,14,14-tetramethyl pentadecanedioic acid diethyl ester (BPD-3) must be purified by water phase and then matched with another organic solvent for extraction operation, and the separation and purification requirements cannot be met in practical operation; 2. the purification of the compound diethyl 8-oxo-2,2,14,14-tetramethyl pentadecanedioate (BPD-3) requires column chromatography operation, which not only prolongs the production period and increases the output of solid waste, but also increases the input of equipment (chromatographic column), is not beneficial to commercialization and does not accord with the aim of green chemistry.
Disclosure of Invention
In order to solve the problems, the invention provides a purification method of a bevacizidine acid intermediate diethyl 8-oxo-2,2,14,14-tetramethyl pentadecanedioate (BPD-3), which comprises the steps of dissolving a BPD-3 crude product in a first solvent with larger polarity, adding a second solvent with smaller polarity, extracting and separating liquid, and concentrating a second solvent phase under reduced pressure to obtain purified BPD-3; wherein the solvent 1 is selected from one or more of methanol, ethanol, isopropanol, acetonitrile and acetone, and the solvent 2 is selected from one or more of n-heptane, n-hexane, petroleum ether, toluene and methyl tertiary butyl ether.
In certain embodiments, the first solvent is acetonitrile and the second solvent is n-heptane.
In certain embodiments, the volume ratio of acetonitrile to n-heptane is from 10:1 to 1:10, preferably the volume ratio of acetonitrile to n-heptane is 2:3.
In certain embodiments, the reduced pressure concentration is at a temperature of 35-55deg.C, preferably the temperature is 50deg.C.
In certain embodiments, the reduced pressure concentration is at a pressure of 0.07 to 0.1Mpa, preferably the pressure is 0.08Mpa.
In certain embodiments, the method comprises repeating the method 1-5 times to obtain the purified BPD-3.
Compared with the prior art, the invention has the beneficial effects that:
the non-conventional extraction process is adopted innovatively, two organic phases (respectively smaller polar solvent and larger polar solvent) are used as extraction solvents, and the BPD-3 product with high purity is obtained through extraction, the purity is more than or equal to 90%, and the yield reaches 81% -97%.
2) The method reduces the output of waste liquid and waste residue, reduces the investment of equipment and materials, reduces the production cost, is more suitable for industrial production, and accords with the development concept of green chemistry.
Description of the embodiments
The experimental methods in the following examples are conventional methods unless otherwise specified. The chemical materials, reagents, etc. used in the examples described below were commercially available products unless otherwise specified.
First, reference is made to the description of patent US9000041B, examples 6.11-6.18, to prepare a crude product of diethyl 8-oxo-2,2,14,14-tetramethylpentadecanedioate (BPD-3).
Example 1
Weighing 3.00kg of BPD-3 crude product, adding 6L of acetonitrile, stirring, mixing uniformly, adding 9L of n-heptane, stirring, extracting, separating liquid, and concentrating the n-heptane phase under reduced pressure at 50 ℃ and 0.09Mpa until the n-heptane phase is dried to obtain a BPD-3 refined product. Concentrating and recovering the obtained n-heptane phase, and repeating the extraction operation twice until the product is completely extracted. The yield of BPD-3 was 96.5% and the purity was 92.93%.
Example 2
Weighing 3.00kg of BPD-3 crude product, adding 6L of methanol, stirring, mixing uniformly, adding 12L of n-hexane, stirring, extracting, separating liquid, and concentrating n-hexane phase under reduced pressure at 48 ℃ and 0.08Mpa until the n-hexane phase is dried to obtain a BPD-3 refined product. Concentrating and recovering the obtained normal hexane phase, and repeating the extraction operation procedure twice until the product is completely extracted. The final yield of BPD-3 was 94.5% and the purity was 92.05%.
Example 3
Weighing 1.00kg of crude BPD-3, adding 1L of acetone, stirring, mixing, adding 20L of petroleum ether, stirring, extracting, separating liquid, and concentrating petroleum ether phase under reduced pressure at 35 ℃ and 0.1Mpa until dry to obtain refined BPD-3 product. The final yield of BPD-3 was 81.0% and the purity was 89.83%.
Example 4
Weighing 3.00kg of BPD-3 crude product, adding 5L of ethanol, stirring, mixing uniformly, adding 15L of methyl tertiary butyl ether, stirring, extracting and separating liquid, and concentrating the methyl tertiary butyl ether phase under reduced pressure at 35 ℃ and 0.09Mpa until the solution is dried to obtain a BPD-3 refined product. Concentrating and recovering the obtained methyl tertiary butyl ether phase, and repeating the extraction operation procedure twice until the product is completely extracted. The final yield of BPD-3 was 92.1% and the purity was 90.48%.
Example 5
Weighing 3.00kg of BPD-3 crude product, adding 6L of isopropanol, stirring, mixing uniformly, adding 24L of toluene, stirring, extracting and separating liquid, and concentrating the toluene phase to dryness under reduced pressure at 50 ℃ and 0.085Mpa to obtain a BPD-3 refined product. Concentrating and recovering the obtained toluene phase, and repeating the extraction operation twice until the product is completely extracted. The final yield of BPD-3 was 90.3% and the purity was 89.95%.
The present invention has been illustrated by the above-described embodiments, but it should be understood that the above-described embodiments are for purposes of illustration and description only and are not intended to limit the invention to the embodiments described. In addition, it will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, and that many variations and modifications are possible in light of the teachings of the invention, which variations and modifications are within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (2)
1. A method for purifying the intermediate 8-oxo-2,2,14,14-tetramethyl pentadecane diethyl phthalate BPD-3 of bevacizidine acid comprises dissolving crude BPD-3 in a first solvent with larger polarity, adding a second solvent with smaller polarity, extracting and separating liquid, and concentrating the second solvent phase under reduced pressure to obtain purified BPD-3; the first solvent is acetonitrile, the second solvent is n-heptane, and the volume ratio of the acetonitrile to the n-heptane is 2:3; wherein the temperature of the reduced pressure concentration is 50 ℃, and the pressure of the reduced pressure concentration is 0.09Mpa.
2. The purification method according to claim 1, which comprises repeating the purification method 1 to 5 times to obtain the purified BPD-3.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202111612172.0A CN114436837B (en) | 2021-12-27 | 2021-12-27 | Purification method of bevacizidine acid intermediate |
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| Application Number | Priority Date | Filing Date | Title |
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| CN202111612172.0A CN114436837B (en) | 2021-12-27 | 2021-12-27 | Purification method of bevacizidine acid intermediate |
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| Publication Number | Publication Date |
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| CN114436837A CN114436837A (en) | 2022-05-06 |
| CN114436837B true CN114436837B (en) | 2024-02-20 |
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