CN114031491B - Preparation method of all-trans-teprenone - Google Patents
Preparation method of all-trans-teprenone Download PDFInfo
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- CN114031491B CN114031491B CN202111425283.0A CN202111425283A CN114031491B CN 114031491 B CN114031491 B CN 114031491B CN 202111425283 A CN202111425283 A CN 202111425283A CN 114031491 B CN114031491 B CN 114031491B
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- teprenone
- geranylgeraniol
- bromide
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- DJAHKBBSJCDSOZ-AJLBTXRUSA-N (5z,9e,13e)-6,10,14,18-tetramethylnonadeca-5,9,13,17-tetraen-2-one;(5e,9e,13e)-6,10,14,18-tetramethylnonadeca-5,9,13,17-tetraen-2-one Chemical compound CC(C)=CCC\C(C)=C\CC\C(C)=C\CC\C(C)=C/CCC(C)=O.CC(C)=CCC\C(C)=C\CC\C(C)=C\CC\C(C)=C\CCC(C)=O DJAHKBBSJCDSOZ-AJLBTXRUSA-N 0.000 title claims abstract description 38
- 238000002360 preparation method Methods 0.000 title claims description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 30
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims abstract description 20
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims abstract description 11
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims abstract description 11
- OJISWRZIEWCUBN-QIRCYJPOSA-N (E,E,E)-geranylgeraniol Chemical compound CC(C)=CCC\C(C)=C\CC\C(C)=C\CC\C(C)=C\CO OJISWRZIEWCUBN-QIRCYJPOSA-N 0.000 claims description 17
- XWRJRXQNOHXIOX-UHFFFAOYSA-N geranylgeraniol Natural products CC(C)=CCCC(C)=CCOCC=C(C)CCC=C(C)C XWRJRXQNOHXIOX-UHFFFAOYSA-N 0.000 claims description 17
- OJISWRZIEWCUBN-UHFFFAOYSA-N geranylnerol Natural products CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCO OJISWRZIEWCUBN-UHFFFAOYSA-N 0.000 claims description 17
- 229950006156 teprenone Drugs 0.000 claims description 17
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 15
- 239000012043 crude product Substances 0.000 claims description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- 230000015572 biosynthetic process Effects 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 238000003786 synthesis reaction Methods 0.000 claims description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 claims description 5
- 239000000047 product Substances 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 4
- 239000012074 organic phase Substances 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- 238000000967 suction filtration Methods 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 claims description 3
- 239000012452 mother liquor Substances 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- 238000005893 bromination reaction Methods 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 239000000376 reactant Substances 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- 239000000243 solution Substances 0.000 claims 1
- 239000003054 catalyst Substances 0.000 abstract description 3
- 238000001308 synthesis method Methods 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 2
- 239000000203 mixture Substances 0.000 description 10
- 238000010587 phase diagram Methods 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 210000001156 gastric mucosa Anatomy 0.000 description 5
- 238000001514 detection method Methods 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 101150041968 CDC13 gene Proteins 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 208000007107 Stomach Ulcer Diseases 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 201000005917 gastric ulcer Diseases 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 239000010413 mother solution Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 208000007882 Gastritis Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 230000000767 anti-ulcer Effects 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- -1 bromide compound Chemical class 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 208000023652 chronic gastritis Diseases 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- CCCXGQLQJHWTLZ-UHFFFAOYSA-N geranyl linalool Natural products CC(=CCCC(=CCCCC(C)(O)CCC=C(C)C)C)C CCCXGQLQJHWTLZ-UHFFFAOYSA-N 0.000 description 1
- IQDXAJNQKSIPGB-HQSZAHFGSA-N geranyllinalool Chemical compound CC(C)=CCC\C(C)=C\CC\C(C)=C\CCC(C)(O)C=C IQDXAJNQKSIPGB-HQSZAHFGSA-N 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups 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
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
- C07C17/16—Preparation of halogenated hydrocarbons by replacement by halogens of hydroxyl groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a synthesis method of all-trans-teprenone, which comprises the steps of selecting specific raw materials and combining a proper catalyst to prepare geranylgeranio, and then reacting the geranylgeranio with acetone and lithium diisopropylamide in the presence of cuprous iodide to synthesize the all-trans-teprenone.
Description
Technical Field
The invention relates to preparation of teprenone, in particular to a method for synthesizing all-trans teprenone by using chemistry.
Background
All-trans-teprenone is 6,10,14, 18-tetramethyl-5E, 9E,13E, 17-nineteen-carbon tetraen-2-one and is colorless to pale yellow oily liquid.
The teprenone on the market at present is a cis-trans mixture, wherein the teprenone only plays a role in treatment, and the teprenone has unique physicochemical properties and a good anti-ulcer mechanism as a novel gastric mucosa protective agent for treating gastric ulcer, can increase gastric mucus secretion, maintain the integrity of gastric mucosa barrier structure and function, promote the synthesis of gastric mucosa endogenous prostaglandin, effectively increase gastric mucosa blood flow, obviously improve the healing rate of gastric ulcer, and has good treatment effect on gastric mucosa injury caused by chronic gastritis and non-steroidal anti-inflammatory drugs.
Patent CN102627539B reports a method for synthesizing all-trans-teprenone, mixed teprenone is obtained by rearrangement of geranyl linalool and ethyl acetoacetate through carroll, and then all-trans-teprenone is obtained by purification through ultralow Wen Xijing, the method firstly obtains mixed teprenone and then purifies, the cis-form body contains 40%, the total yield after purification is about 35%, and the yield is lower.
Disclosure of Invention
The invention aims to provide the synthesis method of all-trans-teprenone, which has the total yield of more than 75 percent, and has the advantages of high process yield, low energy consumption, suitability for industrial production and obvious cost reduction compared with the synthesis method of all-trans-teprenone in the prior art.
The invention relates to a preparation method of all-trans-teprenone, which comprises the steps of obtaining geranylgeraniol through bromination reaction, and then reacting with acetone and lithium diisopropylamide in the presence of cuprous iodide to obtain the all-trans-teprenone. The reaction equation is as follows:
the preparation method can adopt the following steps:
1) Synthesis of geranylgeraniol bromide
Mixing geranylgeraniol, pyridine and methyl tertiary butyl ether, cooling to-10-0 ℃ under nitrogen protection, dropwise adding phosphorus tribromide, heating to room temperature for reaction for 1-5 h after dropwise adding, filtering to obtain a liquid organic phase, and performing post-treatment to obtain geranylgeraniol bromide;
2) Synthesis of teprenone
Stirring and dissolving geranylgeranio bromide, acetone and cuprous iodide, cooling to-15 to-5 ℃, dropwise adding Lithium Diisopropylamide (LDA), controlling the temperature below 0 ℃, heating to room temperature after dropwise adding, reacting for 8-15h, post-treating to obtain a crude product, and rectifying the crude product to obtain a finished product.
In the invention, the mol ratio of the geranylgeraniol to the pyridine to the phosphorus tribromide in the step 1) is 1:0.5-1.0:1.0-1.5. Methyl tertiary butyl ether is the solvent. The geranylgeraniol bromide disclosed by the invention is poor in stability, needs to be stored at a low temperature, and can be preferably prepared at present, and the preparation method is also various, and the geranylgeraniol bromide-based bromide compound can be prepared by referring to a plurality of known documents.
In the invention, the mol ratio of the geranylgeranio bromide to the cuprous iodide to the lithium diisopropylamide in the step 2) is 1:0.9-1.1:1.1-1.3, and the acetone is used as a reactant and a solvent, and the mass dosage of the acetone can be 5-10 times of the amount of the geranylgeranio bromide.
The invention provides a synthetic thinking method of all-trans-teprenone, which comprises the steps of selecting specific raw materials, combining appropriate catalyst cuprous iodide, firstly preparing geranylgeranio, then reacting the geranylgeranio with acetone and lithium diisopropylamide in the presence of the appropriate catalyst cuprous iodide to obtain the all-trans-teprenone, wherein the total process yield of the method is high (more than 75 percent) and the purity is high (100 percent).
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of all-trans-teprenone of example 2;
fig. 2 is a mass spectrum of all-trans-teprenone of example 2.
FIG. 3 is a gas phase diagram of crude all-trans-teprenone of example 2.
Fig. 4 is a gas-phase diagram of the commercially available formulation teprenone (cis: trans=2:3 ratio).
FIG. 5 is a gas phase diagram of a mixture of crude all-trans-teprenone and a commercially available formulation of teprenone from example 2.
Detailed Description
The following examples are further illustrative of the technical content of the present invention, but the essential content of the present invention is not limited to the examples described below, and those skilled in the art can and should know that any simple changes or substitutions based on the essential spirit of the present invention should fall within the scope of the present invention as claimed.
Example 1
Synthesis of geranylgeraniol bromide
Geranylgeraniol (200 g,0.688mol, beijing carboline technologies Co., ltd.), pyridine (48 g,0.607 mol) and methyl tertiary butyl ether (1000 ml) are added into a flask, the temperature is reduced to minus 5 ℃ under the protection of nitrogen, phosphorus tribromide (260 g,0.961 mol) is added dropwise, the mixture is heated to room temperature for reaction, the reaction is kept for 2 hours, suction filtration is carried out, an organic phase is washed once by 5% sodium carbonate, water is washed once, anhydrous sodium sulfate is dried, suction filtration is carried out, a mother solution is evaporated to dryness at 20 ℃ to obtain 230g geranylgeraniol liquid, and the yield is 94.6%. 1 HNMR(CDC13),δ:1.56(S,9H)；1.66(S,6H)；1.9-2.08(m,12H)；4.09(d,2H)；5.07(t,3H)；5.40(t,1H))。
Example 2
Synthesis of teprenone
100g (283 mmol) of geranylgeranio bromide was added to the flask, followed by 500ml of acetone, 53.9g (283 mmol) of cuprous iodide,stirring for dissolving, cooling to-10 ℃, dropwise adding LDA36.4g (339.6 mmol) at the temperature below 0 ℃, cooling to room temperature after dripping, preserving heat for reacting for 12 hours, post-treating, steaming out excessive acetone, adding 500ml of normal hexane for dissolving, washing twice with saturated ammonium chloride aqueous solution, washing once with saturated sodium chloride, drying with anhydrous sodium sulfate, carrying out suction filtration, evaporating the mother liquor at the temperature of 40 ℃ to obtain 90.1g of liquid, obtaining 96.3% of the yield, taking a gas-phase diagram as shown in figure 3, taking a commercial preparation of teprenone (a pharmaceutical industry Co., ltd.) as a reference, taking a gas-phase diagram as shown in figure 4 (cis: trans=2:3) as a cis-trans ratio), and taking a gas-phase diagram of a mixture of the all-trans-teprenone crude product and the commercial preparation of teprenone as shown in figure 5, wherein the purity of the obtained crude product of the invention is 99.09%. The crude product is rectified by a thorn-shaped rectifier to obtain 78g of teprenone finished product, the yield is 83.4%, and the purity is 100% by HPLC detection. The nuclear magnetic resonance detection result is shown in fig. 1, and the mass spectrum detection result is shown in fig. 2. 1 HNMR(CDC13),δ:1.58-1.60(12H.d,20,21,22,23-CH3)；1.66(3H,s,19-CH3)；1.94-1.98(6H,m,8,12,16(-CH2)；2.02-2.08(6H,m,7,11,15-CH2)；2.11(3H,s,1-CH3)；2.22-2.27(2H,m,4-CH2)；2.42-2.46(2H,m,3-CH2)；5.04-5.11(4H,m,5,9,13,17-CH＝)。MS(m/s):330.29154。
Example 3
Synthesis of teprenone
100g (283 mmol) of geranylgeranio bromide is added into a flask, 500ml of acetone and 53.9g (283 mmol) of cuprous iodide are added, stirring is carried out for dissolution, the temperature is reduced to minus 10 ℃, 42.5g (396.2 mmol) of LDA is added dropwise, the temperature is controlled below 0 ℃, the temperature is cooled to room temperature after the dripping is finished, the reaction is carried out for 12 hours under the heat preservation, the aftertreatment is carried out, excessive acetone is evaporated, 500ml of normal hexane is added for dissolution, the mixture is washed twice with saturated ammonium chloride aqueous solution, the mixture is washed once with saturated sodium chloride, the mixture is dried with anhydrous sodium sulfate, the mixture is filtered by suction, the mother solution is evaporated to dryness at 40 ℃ to obtain 88g of crude product liquid, and the yield is 94.1%. The crude product is rectified by a thorn-shaped rectifier to obtain 75.6g of teprenone finished product, the yield is 80.8%, and the purity is 100% by HPLC detection.
It should be noted that the foregoing technical disclosure is only for explanation and illustration to enable one skilled in the art to know the technical spirit of the present invention, and the technical disclosure is not intended to limit the scope of the present invention. The essential scope of the invention is as defined in the appended claims. Those skilled in the art should understand that any modification, equivalent substitution, improvement, etc. made based on the spirit of the present invention should fall within the spirit and scope of the present invention.
Claims (3)
1. The preparation method of all-trans-teprenone adopts geranylgeraniol to obtain geranylgeraniol through bromination reaction, and then the geranylgeraniol is reacted with acetone and lithium diisopropylamide in the presence of cuprous iodide to obtain the all-trans-teprenone, and the preparation method specifically comprises the following steps:
1) Synthesis of geranylgeraniol bromide
Mixing geranylgeraniol, pyridine and methyl tertiary butyl ether, cooling to-10-0 ℃ under nitrogen protection, dropwise adding phosphorus tribromide, controlling the temperature to-10-0 ℃, raising the temperature to room temperature after dropwise adding, reacting for 1-5 h, filtering to obtain a liquid organic phase, and performing post-treatment to obtain geranylgeraniol bromide; step 1) the mole ratio of geranylgeraniol to pyridine to phosphorus tribromide is 1:0.5-1.0:1.0-1.5;
2) Synthesis of teprenone
Stirring and dissolving geranylgeranio bromide, acetone and cuprous iodide, cooling to-15 to-5 ℃, dropwise adding lithium diisopropylamide, controlling the temperature below 0 ℃, reacting for 8-15 hours at room temperature after the dropwise adding, post-treating to obtain a crude product, and rectifying the crude product to obtain a finished product; the mol ratio of the geranylgeranio bromide to the cuprous iodide to the lithium diisopropylamide in the step 2) is 1:0.9-1.1:1.1-1.3, and the acetone is used as a reactant and is also a solvent, and the mass dosage of the acetone is 5-10 times of the mass dosage of the geranylgeranio bromide.
2. The process according to claim 1, wherein the working-up in step 1) is washing the organic phase with sodium carbonate solution, washing with water, drying, suction filtration and solvent removal of the mother liquor.
3. The preparation method of claim 2, wherein the post-treatment in step 2) is to evaporate excessive acetone, then add n-hexane for dissolution, wash with saturated ammonium chloride aqueous solution, then wash with saturated sodium chloride, dry, suction-filter, remove solvent from mother liquor to obtain crude product, and rectify the crude product with a thorn-shaped rectifier to obtain the finished teprenone product.
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| CN103052619A (en) * | 2010-09-01 | 2013-04-17 | 科约特制药公司 | Methods for treating neurodegenerative diseases |
| CN109232212A (en) * | 2018-09-28 | 2019-01-18 | 万华化学集团股份有限公司 | A method of by prenol synthesizing methyl heptenone |
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| US20130085283A1 (en) * | 2011-10-04 | 2013-04-04 | Coyote Pharmaceuticals, Inc. | Geranylgeranylacetone derivatives |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103052619A (en) * | 2010-09-01 | 2013-04-17 | 科约特制药公司 | Methods for treating neurodegenerative diseases |
| CN109232212A (en) * | 2018-09-28 | 2019-01-18 | 万华化学集团股份有限公司 | A method of by prenol synthesizing methyl heptenone |
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