CN109574821B - Intermediate for synthesis of teprenone and application thereof - Google Patents
Intermediate for synthesis of teprenone and application thereof Download PDFInfo
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- CN109574821B CN109574821B CN201811313602.7A CN201811313602A CN109574821B CN 109574821 B CN109574821 B CN 109574821B CN 201811313602 A CN201811313602 A CN 201811313602A CN 109574821 B CN109574821 B CN 109574821B
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- 229950006156 teprenone Drugs 0.000 title claims abstract description 61
- 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 60
- 230000015572 biosynthetic process Effects 0.000 title description 20
- 238000003786 synthesis reaction Methods 0.000 title description 19
- 238000006243 chemical reaction Methods 0.000 claims abstract description 31
- 238000000034 method Methods 0.000 claims abstract description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 39
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- 239000007818 Grignard reagent Substances 0.000 claims description 15
- OFERIRWCHSOJJT-UHFFFAOYSA-N 2-(3-chloropropyl)-2-methyl-1,3-dioxolane Chemical compound ClCCCC1(C)OCCO1 OFERIRWCHSOJJT-UHFFFAOYSA-N 0.000 claims description 13
- -1 Grignard reagent 2-methyl-1, 3-dioxolane-2-propyl magnesium chloride Chemical class 0.000 claims description 12
- LTUMRKDLVGQMJU-IUBLYSDUSA-N farnesyl acetone Chemical compound CC(C)=CCC\C(C)=C\CC\C(C)=C\CCC(C)=O LTUMRKDLVGQMJU-IUBLYSDUSA-N 0.000 claims description 11
- 238000007259 addition reaction Methods 0.000 claims description 9
- 238000006297 dehydration reaction Methods 0.000 claims description 9
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 8
- 150000004795 grignard reagents Chemical class 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 230000018044 dehydration Effects 0.000 claims description 7
- 238000010511 deprotection reaction Methods 0.000 claims description 7
- 239000003054 catalyst Substances 0.000 claims description 6
- 230000007062 hydrolysis Effects 0.000 claims description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 230000009471 action Effects 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 abstract description 10
- 230000008569 process Effects 0.000 abstract description 7
- 230000002194 synthesizing effect Effects 0.000 abstract description 7
- 239000002994 raw material Substances 0.000 abstract description 3
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000007086 side reaction Methods 0.000 abstract description 2
- 239000003921 oil Substances 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 10
- 239000000203 mixture Substances 0.000 description 9
- 210000001156 gastric mucosa Anatomy 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- ZVQOOHYFBIDMTQ-UHFFFAOYSA-N [methyl(oxido){1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-lambda(6)-sulfanylidene]cyanamide Chemical compound N#CN=S(C)(=O)C(C)C1=CC=C(C(F)(F)F)N=C1 ZVQOOHYFBIDMTQ-UHFFFAOYSA-N 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- XVRIEWDDMODMGA-UHFFFAOYSA-N 5-chloropentan-2-one Chemical compound CC(=O)CCCCl XVRIEWDDMODMGA-UHFFFAOYSA-N 0.000 description 5
- 230000035484 reaction time Effects 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- 239000012295 chemical reaction liquid Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 238000001514 detection method Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000010779 crude oil Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- LTUMRKDLVGQMJU-UHFFFAOYSA-N famesylacetone Natural products CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=O LTUMRKDLVGQMJU-UHFFFAOYSA-N 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000004817 gas chromatography Methods 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 230000003902 lesion Effects 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000006563 Carroll rearrangement reaction Methods 0.000 description 1
- GMEONFUTDYJSNV-UHFFFAOYSA-N Ethyl levulinate Chemical compound CCOC(=O)CCC(C)=O GMEONFUTDYJSNV-UHFFFAOYSA-N 0.000 description 1
- 208000007882 Gastritis Diseases 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 230000000767 anti-ulcer Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000003255 drug test Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 201000005917 gastric ulcer Diseases 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
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- HUCXKZBETONXFO-AJDZVAQLSA-N teprenone Chemical compound CC(C)=CCC\C(C)=C\CC\C(C)=C\CCC(C)=CCCC(C)=O HUCXKZBETONXFO-AJDZVAQLSA-N 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/20—Unsaturated compounds containing keto groups bound to acyclic carbon atoms
- C07C49/24—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing hydroxy groups
-
- 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
- C07C45/64—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 introduction of functional groups containing oxygen only in singly bound form
-
- 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
- C07C45/65—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 splitting-off hydrogen atoms or functional groups; by hydrogenolysis of functional groups
- C07C45/66—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 splitting-off hydrogen atoms or functional groups; by hydrogenolysis of functional groups by dehydration
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/20—Unsaturated compounds containing keto groups bound to acyclic carbon atoms
- C07C49/203—Unsaturated compounds containing keto groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table
- C07F3/02—Magnesium compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a new intermediate for synthesizing teprenone, namely a compound shown in a formula 5. The process for synthesizing the teprenone by using the compound shown in the formula 5 has the advantages of simple route, easily obtained raw materials, mild reaction conditions and less side reactions, thereby being beneficial to industrial production. The process route of the invention can obtain the teprenone with high purity and the ratio of the isomer single cis (5Z,9E,13E) to the all trans (5E,9E,13E) meeting the requirement under the condition of no rectification.
Description
Technical Field
The invention relates to the fields of medicine and fine chemistry; in particular, the invention relates to a novel intermediate for synthesis of teprenone and a novel method for synthesizing teprenone by using the intermediate.
Background
The chemical name of teprenone (teprenone) is 6,10,14, 18-tetramethyl-5, 9,13, 17-nonadecatetraen-2-one. Teprenone is a mixture of geometric isomers (0.66:1) of mono-cis (5Z,9E,13E) and all-trans (5E,9E,13E) and is a colorless to pale yellow oily liquid with a special aroma.
The teprenone has strong anti-ulcer effect and gastric mucosa lesion improvement effect on various experimental ulcers and gastric mucosa lesions, can promote synthesis and secretion of main regeneration defense factors, high-molecular glycoprotein and phospholipid in the gastric mucosa and the gastric mucosa, can promote healing of injury of the gastric mucosa, can improve biosynthesis capacity of prostaglandin in the gastric mucosa and improve blood flow of the gastric mucosa, and is suitable for treating acute gastritis, gastric ulcer and the like. Teprenone was marketed in japan in 1984, FDA approval was obtained in the united states in 1994, capsules were imported from japan in 2000, and the production of chinese approved capsules was obtained in 2009.
The purity of the teprenone is required to be more than 99.0%, and the ratio of the isomer monocis (5Z,9E,13E) to all trans (5E,9E,13E) is 0.61: 1-0.68: 1. Because the synthesis difficulty is large, no manufacturer applies for the marketing permission of the raw materials and the preparation of the product at home.
In the prior art, studies on the synthesis process of teprenone have been made, for example, US4814353 reports the Carroll reaction of (1) (6E,10E) -geranyl linalool and alkyl acetoacetate; (2) 1-halo-3, 7,11, 15-tetramethyl-hexadeca-2, 6,10, 14-tetraene and sodium salt of alkyl acetoacetate are subjected to substitution reaction, and then saponification reaction and decarboxylation are carried out to obtain the teprenone. The two methods have the advantages of longer synthesis steps, low total yield and higher synthesis cost. For another example, WO2012031028 reports a method for synthesizing cis-geranylgeranylacetone (cis-configuration of teprenone) by reacting ethyl levulinate and (2E,6E) -farnesyl alcohol in ten steps. The witting reaction is adopted, however, the witting reagent phosphine ylide needs to be prepared at deep low temperature, and the final reaction obtains geranylgeranylacetone (cis configuration of teprenone) in single cis form (5Z,9E,13E) which is not consistent with the configuration of the teprenone medicine in the market.
Therefore, there is an urgent need in the art for new methods for the synthesis of teprenone.
Disclosure of Invention
The invention aims to provide a novel method for synthesizing teprenone, which is simple, convenient, low in cost and beneficial to industrial development.
In a first aspect, the present invention provides a method for preparing teprenone, said method is shown in the following reaction scheme:
the method comprises the following steps:
1) reacting 2- (3-chloropropyl) -2-methyl-1, 3-dioxolane (formula 2) with magnesium metal in tetrahydrofuran to generate a Grignard reagent 2-methyl-1, 3-dioxolane-2-propyl magnesium chloride (formula 3), then carrying out addition reaction on the Grignard reagent 3 and (5E,9E) farnesyl acetone (formula 4), and carrying out hydrolysis deprotection to obtain (9E,13E) -6-hydroxy-6, 10,14,18-4 methylheptadecyl-9, 13, 17-trien-2-one (formula 5); and
2) dehydrating the (9E,13E) -6-hydroxy-6, 10,14, 18-4-methylheptadec-9, 13, 17-trien-2-one (formula 5) obtained in the step 1) in toluene under the action of a catalyst to obtain the teprenone.
In a preferred embodiment, the crude teprenone obtained in step 2) is subjected to vacuum rectification to control the boiling point of the distillate, so as to obtain high-purity teprenone with the purity of more than 99.0 percent and the ratio of the isomer single cis (5E,9E,13E) to all trans (5Z,9E,13E) of 0.61: 1-0.68: 1.
In a specific embodiment, in the step 2), the (9E,13E) -6-hydroxy-6, 10,14, 18-4-methylheptadec-9, 13, 17-trien-2-one (formula 5) reacts in toluene for 7 to 9 hours at the dehydration reflux temperature (108 to 115 ℃) under the action of a catalyst; preferably 8 hours.
In a preferred embodiment, the ratio of the isomers of teprenone, mono-cis (5E,9E,13E) and all-trans (5Z,9E,13E) obtained in step 2) is 0.61: 1 to 0.68: 1 without rectification.
In a specific embodiment, the addition reaction of the grignard reagent formula 3 with (5E,9E) farnesyl acetone (formula 4) in step 1) is performed at 0 to 35 ℃, preferably 20 to 30 ℃.
In particular embodiments, in step 2), the catalyst includes, but is not limited to, p-toluenesulfonic acid or alumina; p-toluenesulfonic acid is preferred.
In a second aspect, the present invention provides a compound represented by formula 5,
In a third aspect, the present invention provides a process for the preparation of a compound of formula 5, as shown in the following reaction scheme:
the method comprises the following steps: reacting 2- (3-chloropropyl) -2-methyl-1, 3-dioxolane (formula 2) with magnesium metal in tetrahydrofuran to generate Grignard reagent 2-methyl-1, 3-dioxolane-2-propyl magnesium chloride (formula 3), then carrying out addition reaction on the Grignard reagent 3 and (5E,9E) farnesyl acetone (formula 4), and carrying out hydrolysis deprotection to obtain (9E,13E) -6-hydroxy-6, 10,14,18-4 methylheptadecyl-9, 13, 17-trien-2-one (formula 5).
In a specific embodiment, 2- (3-chloropropyl) -2-methyl-1, 3-dioxolane (formula 2) and magnesium metal are reacted in solvent tetrahydrofuran to generate Grignard reagent 2-methyl-1, 3-dioxolane-2-propyl magnesium chloride (formula 3), then the Grignard reagent formula 3 and (5E,9E) farnesyl acetone (formula 4) are subjected to addition reaction, the reaction solution is hydrolyzed by hydrochloric acid and subjected to deprotection reaction in a one-pot method, and then the compound of formula 5 is washed by sodium bicarbonate.
In a specific embodiment, the Grignard reagent 2-methyl-1, 3-dioxolane-2-propylmagnesium chloride (formula 3) undergoes an addition reaction with (5E,9E) farnesyl acetone (formula 4) at a temperature of 0 to 35 ℃, preferably 20 to 30 ℃.
In a fourth aspect, the present invention provides the use of a compound of formula 5 in the preparation of teprenone.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Detailed Description
The inventor unexpectedly discovers a brand new intermediate for synthesizing the teprenone through extensive and intensive research, and can directly obtain the teprenone with the ratio of the isomers of the single cis (5Z,9E,13E) and the all trans (5E,9E,13E) meeting the requirement by accurately controlling the time for obtaining the teprenone through dehydrating the intermediate, so that a qualified product can be obtained without distillation. The present invention has been completed based on this finding.
The invention provides a brand new intermediate for synthesizing teprenone, and the compound is shown as a formula 5:
the intermediate can be prepared as shown in the following reaction scheme:
firstly, in toluene or n-hexane, 5-chloro-2-pentanone (formula 1) is protected by ethylene glycol to obtain 2- (3-chloropropyl) -2-methyl-1, 3-dioxolane (formula 2); then, the obtained formula 2 reacts with magnesium metal in tetrahydrofuran to generate Grignard reagent 2-methyl-1, 3-dioxolane-2-propyl magnesium chloride (formula 3), then the Grignard reagent formula 3 and (5E,9E) farnesyl acetone (formula 4) have addition reaction, and (9E,13E) -6-hydroxy-6, 10,14,18-4 methyl heptadecyl-9, 13, 17-triene-2-ketone (formula 5) is obtained through hydrolysis deprotection.
Based on the intermediate and the preparation method thereof, the invention further provides a synthesis method of teprenone, which uses 5-chloro-2-pentanone as a starting material and only comprises three short steps, specifically:
1.5-chloro-2-pentanone (formula 1) is protected by ethylene glycol to obtain 2- (3-chloropropyl) -2-methyl-1, 3-dioxolane (formula 2);
2. reacting the obtained 2- (3-chloropropyl) -2-methyl-1, 3-dioxolane (formula 2) with magnesium metal in tetrahydrofuran to generate a Grignard reagent 2-methyl-1, 3-dioxolane-2-propyl magnesium chloride (formula 3), then carrying out addition reaction on the Grignard reagent formula 3 and (5E,9E) farnesyl acetone (formula 4), and carrying out hydrolysis deprotection to obtain (9E,13E) -6-hydroxy-6, 10,14,18-4 methylheptadecyl-9, 13,17, -trien-2-one (formula 5);
3. the obtained (9E,13E) -6-hydroxy-6, 10,14, 18-4-methylheptadec-9, 13, 17-trien-2-ketone (formula 5) is dehydrated under the condition of a catalyst to obtain a crude product of the teprenone.
The teprenone reference substance is purchased from China food and drug testing institute, and the ratio of 5E configuration to 5Z configuration is 0.61: 1-0.68: 1 according to the ratio of isomer monocis (5Z,9E,13E) to all trans (5E,9E,13E) by gas chromatography detection.
The gas chromatography detection method comprises the following steps: a chromatographic column: HP-INNOWAX (30m 0.53mm 1.0 μm); a detector: FID; detector temperature: 250 ℃; sample inlet temperature: 230 ℃; nitrogen pressure: 30 cm/sec; hydrogen flow rate: 40 ml/min; the air flow rate is 400 ml/min; the split ratio is as follows: 6; sample introduction amount: 1.0 μ l; column temperature: starting at 50 deg.C, holding for 2min, raising the temperature to 230 deg.C at 10 deg.C/min, and holding for 45 min. The retention time of the isomer monoccis (5Z,9E,13E) in the gas phase was about 31.7min, the retention time of the all-trans (5E,9E,13E) in the gas phase was about 33.1min, and the retention time of the compound of formula 5 was about 24.3 min.
The ratio of the 5E and 5Z configurations in the fraction can be controlled by controlling the boiling point at 2 ℃ above the boiling point of the isomer monoccis (5Z,9E,13E) configuration at 100 Pa vacuum. The product is calculated by the sum of the isomer monoccis (5Z,9E,13E) configuration and all trans (5E,9E,13E) configuration, and the yield is calculated.
Thus, those skilled in the art know that a high purity teprenone product can be collected by controlling the boiling point of the fractions by rectification under reduced pressure, and that the ratio of the isomer mono-cis (5Z,9E,13E) to all-trans (5E,9E,13E) is 0.61: 1 to 0.68: 1.
However, the inventor finds that the dehydration time has great influence on the product yield and the ratio of the single cis (5Z,9E,13E) configuration to the all-trans (5E,9E,13E) configuration in the product through experiments. Theoretically, the longer the dehydration time, the more complete the dehydration and the higher the yield. However, the inventors have unexpectedly found that the yield increases stepwise as the reaction proceeds, but after 9 hours the yield decreases instead. The reaction time is preferably 7 to 9 hours, and the yields are lower in 5 to 7 hours and 9 to 11 hours.
The ratio of the isomer monoccis (5Z,9E,13E) to all trans (5E,9E,13E) in the teprenone product should be 0.61: 1-0.68: 1. The inventor unexpectedly finds that when the dehydration reaction is 7-9 hours, the ratio of the single cis (5Z,9E,13E) to the all-trans (5E,9E,13E) is gradually reduced from about 1.2:1 to about 0.65:1, and the requirement that the ratio of the single cis (5Z,9E,13E) to the all-trans (5E,9E,13E) in the teprenone product is 0.61: 1-0.68: 1 is met. Preparation of a compound of formula 5 a typical assay profile of a 4 hour reaction of teprenone from a compound of formula 5 is 18.100% by area, 40.907% by area of the mono-cis (5Z,9E,13E) and 34.884% by area of the all-trans (5E,9E, 13E). The ratio of mono-cis (5Z,9E,13E) to all-trans (5E,9E,13E) was 1.17:1 at this time. When the dehydration reaction is carried out for 7-9 hours, the ratio of the single cis (5Z,9E,13E) to the all trans (5E,9E,13E) can be just reduced to about 0.65:1, and the product requirement is met.
The reaction time detection results for preparing teprenone by dehydration in formula 5 are shown in the following table.
| Time of dehydration | Formula 5 | Mono-cis form | All-trans | Mono-cis + all-trans | Mono-cis-all-trans |
| 4 hours | 18.1% | 40.9% | 34.8% | 75.7% | 1.17:1 |
| 6 hours | 4.5% | 40.9% | 46.5% | 87.5% | 0.88:1 |
| 8 hours | 2.3% | 36.5% | 56.2% | 92.7% | 0.65:1 |
| 10 hours | 4.1% | 36.8% | 49.1% | 85.9% | 0.75:1 |
| 12 hours | 6.2% | 38.9% | 42.8% | 81.8% | 0.97:1 |
The reaction time is short (4 hours and 6 hours), the ratio of the single cis form to the all trans form is high, and when the product is rectified, a fraction needs to be controlled to remove part of the single cis form, so that the requirement that the ratio of the single cis form (5Z,9E and 13E) to the all trans form (5E,9E and 13E) in the teprenone product is 0.61: 1-0.68: 1 is met, and the total yield is reduced.
The reaction time is prolonged to 10-12 hours, the ratio of the single cis (5Z,9E,13E) to the all-trans (5E,9E,13E) is increased, and the ratio of the single cis (5Z,9E,13E) to the all-trans (5E,9E,13E) in the teprenone product can not meet the requirement of 0.61: 1-0.68: 1.
Experiments show that the ratio of the single cis (5Z,9E,13E) to the all-trans (5E,9E,13E) is just up to the requirement of the teprenone product of 0.61: 1-0.68: 1 after the reaction is carried out for 8 hours, and the value of the single cis plus the all-trans is the maximum. The reaction time is 7-9 hours, and 8 hours is the best.
The invention has the advantages that:
1. the synthetic route of the invention is simple, and only 3 reaction steps are involved;
2. in the synthetic route, the hydrolysis and deprotection of the post-treatment reaction liquid in the second step are carried out simultaneously, so that the operation process is simplified and the generation of three wastes is reduced;
3. the reaction raw materials of the synthesis process are easy to purchase; and
4. the synthesis process has mild reaction conditions and few side reactions, and is favorable for industrial production.
The technical solution of the present invention will be further described with reference to the following specific embodiments, but the following embodiments are not intended to limit the present invention, and all of the various application methods adopted according to the principles and technical means of the present invention belong to the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.
Examples
EXAMPLE 1 Synthesis of 2- (3-chloropropyl) -2-methyl-1, 3-dioxolane (formula 2)
A250 ml reaction flask was charged with 16.5g of 5-chloro-2-pentanone, 150 ml of toluene, 0.5g of p-toluenesulfonic acid, and 16.9g of ethylene glycol. After the addition, the oil bath is heated and refluxed for water diversion for 4 hours. The reaction solution was cooled to room temperature, washed with sodium bicarbonate solution and washed with water. The resulting toluene organic layer was distilled under reduced pressure at 60 ℃ to obtain 19.68g (yield 94.6%) of 2- (3-chloropropyl) -2-methyl-1, 3-dioxolane as an oil.
EXAMPLE 2 Synthesis of 2- (3-chloropropyl) -2-methyl-1, 3-dioxolane (formula 2)
A250 ml reaction flask was charged with 16.5g of 5-chloro-2-pentanone, 150 ml of n-hexane, 0.5g of p-toluenesulfonic acid, and 16.9g of ethylene glycol. After the addition, the reaction solution is oil-bathed, heated, refluxed and water-separated for 4 hours, cooled to room temperature, washed by sodium bicarbonate solution and washed by water. The obtained n-hexane organic layer was distilled under reduced pressure at 60 ℃ to obtain 18.15g (yield 87.24%) of 2- (3-chloropropyl) -2-methyl-1, 3-dioxolane as an oily substance.
EXAMPLE 3 Synthesis of (9E,13E) -6-hydroxy-6, 10,14, 18-4-methylnonadeca-9, 13,17, -trien-2-one (formula 5)
1.2g of magnesium chips, 20 ml of tetrahydrofuran and one iodine particle are added into a reaction bottle. Heating the mixture to 50 ℃ in an oil bath, then slowly dropwise adding 10.4g of 2- (3-chloropropyl) -2-methyl-1, 3-dioxolane (formula 2), and heating and refluxing the mixture for 2 hours after the dropwise adding. Then the temperature of the reaction liquid is reduced to 20 ℃, 13.12g of farnesyl acetone (formula 4) is added in a reverse dropwise manner, the reaction liquid is kept warm and reacts for 3 hours after the dropwise addition is finished, then the reaction liquid is poured into ice cubes and stirred, 10 ml of hydrochloric acid is added and stirred for 1 hour, 50ml of n-hexane is added for extraction, the mixture is kept still and layered, an organic layer is washed by sodium bicarbonate, saturated saline is washed to be neutral, then an organic layer of the n-hexane is cooled to below 60 ℃, and the solvent is evaporated under reduced pressure to obtain 9.4g of oily matter (9E,13E) -6-hydroxy-6, 10,14,18-4 methyl nineteen-9, 13,17, -triene-2-ketone (formula 5) (the yield is 53.9%).
ESI-MS m/z : 371.11[M+Na]+, 719.27[2M+Na]+。
1H-NMR(400MHz,CDCl3) δ：1.18~1.19 (d,3H), 1.40~1.52 (m,5H), 1.59~1.65 (t,10H), 1.67~1.70 (t,4H), 1.95~2.01 (m,4H), 2.02~2.08 (m,6H), 2.10~2.14 (s,3H), 2.43~2.47 (t,2H), 5.07~5.15 (m,3H)。
EXAMPLE 4 Synthesis of (9E,13E) -6-hydroxy-6, 10,14, 18-4-methylnonadeca-9, 13,17, -trien-2-one (formula 5)
1.2g of magnesium chips, 20 ml of tetrahydrofuran and one iodine particle are added into a reaction bottle. Heating the mixture to 50 ℃ in an oil bath, then slowly dropwise adding 10.4g of 2- (3-chloropropyl) -2-methyl-1, 3-dioxolane (formula 2), and heating and refluxing the mixture for 2 hours after the dropwise adding. Then the reaction solution was cooled to an internal temperature of 30 ℃. 13.12g of farnesyl acetone (formula 4) is added dropwise, the reaction solution is kept warm for 3 hours after the dropwise addition, then the reaction solution is poured into ice cubes and stirred, 10 ml of hydrochloric acid is added and stirred for 1 hour, 50ml of toluene is added for extraction, the mixture is stood for layering, an organic layer is washed by sodium bicarbonate, saturated saline is washed to be neutral, then a toluene organic layer is cooled to below 60 ℃, and the solvent is evaporated under reduced pressure to obtain 12.8g of oily matter (9E,13E) -6-hydroxy-6, 10,14, 18-4-methylnonadecanoyl-9, 13,17, -trien-2-one (formula 5) (yield 73.4%).
Example 5 Synthesis of teprenone
6.97g of (9E,13E) -6-hydroxy-6, 10,14, 18-4-methyl nonadeca-9, 13, 17-triene-2-ketone (formula 5), 50ml of toluene and 0.1g of p-toluenesulfonic acid are added into a reaction bottle, and the mixture is heated and refluxed in an oil bath (the temperature is 108-115 ℃) for water separation for 6 hours. Then the reaction solution is cooled to room temperature, washed by sodium bicarbonate, washed by saturated saline to PH =7, dried by anhydrous magnesium sulfate, filtered, the solvent is evaporated at the temperature below 50 ℃ of the filtrate to obtain crude teprenone oil, the crude teprenone oil is rectified under reduced pressure under high vacuum (10pa) to collect stable fractions (obtained by determining the fractions at 145 ℃) to obtain 3.6g (yield is 55.0%) of the teprenone product, wherein the ratio of the single cis form (5Z,9E,13E) to the all trans form (5E,9E,13E) is 0.64: 1.
ESI-MS m/z : 331.27[M+H]+, 353.24[M+Na]+。
1H-NMR(400MHz,CDCl3) δ：1.57~1.61 (t,11H), 1.68 (s,4H), 1.96~1.99 (t,5H), 2.05~2.05 (t,8H), 2.13 (s,2H), 2.23~2.29 (m,2H), 2.42~2.47 (m,2H), 5.05~5.13 (m,4H)。
Example 6 Synthesis of teprenone
13.94g of (9E,13E) -6-hydroxy-6, 10,14, 18-4-methyl nonadeca-9, 13, 17-triene-2-ketone (formula 5), 100 ml of toluene and 0.2g of p-toluenesulfonic acid are added into a reaction bottle, and oil bath is heated and refluxed (the temperature is 108-115 ℃) for water separation for 8 hours. Then the reaction solution is cooled to room temperature, washed by sodium bicarbonate, washed by saturated saline to PH =7, dried by anhydrous magnesium sulfate, filtered, the solvent is evaporated below 50 ℃ of the filtrate to obtain crude teprenone oil, the crude teprenone oil is rectified under high vacuum (10pa) under reduced pressure to collect stable fractions (obtained by determining the fractions at 145 ℃) to obtain 8.8g of teprenone (yield is 66.5%), wherein the ratio of the single cis form (5Z,9E,13E) to the all trans form (5E,9E,13E) is 0.66: 1.
Example 7 Synthesis of teprenone
13.94g of (9E,13E) -6-hydroxy-6, 10,14, 18-4-methyl nonadeca-9, 13, 17-triene-2-ketone (formula 5), 100 ml of toluene and 0.2g of p-toluenesulfonic acid are added into a reaction bottle, and oil bath is heated and refluxed (the temperature is 108-115 ℃) for water separation for 10 hours. Then the reaction solution is cooled to room temperature, washed by sodium bicarbonate, washed by saturated saline to PH =7, dried by anhydrous magnesium sulfate, filtered, the solvent is evaporated below 50 ℃ of the filtrate to obtain crude oil teprenone, the crude oil is rectified under reduced pressure under high vacuum (10pa) to collect stable fractions (obtained by determining the fractions at 145 ℃) to obtain 7.57g (yield 57.2%) of the product teprenone, wherein the ratio of the single cis form (5Z,9E,13E) to the all trans form (5E,9E,13E) is 0.63: 1.
Example 8 Synthesis of teprenone
6.97g of (9E,13E) -6-hydroxy-6, 10,14, 18-4-methyl nonadeca-9, 13, 17-triene-2-ketone (formula 5), 50ml of toluene and 0.5g of alumina are added into a reaction bottle, and the mixture is heated and refluxed in an oil bath (the temperature is 108-115 ℃) for water separation for 8 hours. Then the reaction solution is cooled to room temperature, washed by sodium bicarbonate, washed by saturated saline to PH =7, dried by anhydrous magnesium sulfate, filtered, the solvent is evaporated below 50 ℃ of the filtrate to obtain crude teprenone oil, the crude teprenone oil is rectified under high vacuum (10pa) under reduced pressure to collect stable fraction (the crude teprenone oil is rectified and collected at 145 ℃ to be stable), and 3.4g of teprenone (the yield is 51.4%) is obtained, wherein the ratio of the single cis form (5Z,9E,13E) to the all trans form (5E,9E,13E) is 0.65: 1.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (3)
1. A preparation method of teprenone is shown as the following reaction flow:
the method comprises the following steps:
1) reacting 2- (3-chloropropyl) -2-methyl-1, 3-dioxolane (formula 2) with magnesium metal in tetrahydrofuran to generate Grignard reagent 2-methyl-1, 3-dioxolane-2-propyl magnesium chloride (formula 3), then carrying out addition reaction on the Grignard reagent 3 and (5E,9E) farnesyl acetone (formula 4) at 0-35 ℃, and carrying out hydrolysis deprotection to obtain (9E,13E) -6-hydroxy-6, 10,14,18-4 methylheptadecyl-9, 13,17, -trien-2-one (formula 5); and
2) dehydrating the (9E,13E) -6-hydroxy-6, 10,14, 18-4-methylheptadec-9, 13, 17-trien-2-one (formula 5) obtained in the step 1) in toluene for 7 to 9 hours under the action of a catalyst p-toluenesulfonic acid to obtain the teprenone with the ratio of the isomer mono-cis (5Z,9E,13E) to all-trans (5E,9E,13E) of 0.61: 1 to 0.68: 1.
2. The method of claim 1, wherein in the step 2), (9E,13E) -6-hydroxy-6, 10,14, 18-4-methylheptadec-9, 13, 17-trien-2-one (formula 5) is reacted in toluene at a dehydration reflux temperature of 108 to 115 ℃ for 8 hours under the action of p-toluenesulfonic acid as a catalyst.
3. The method of claim 1, wherein the addition reaction of the grignard reagent of formula 3 with (5E,9E) farnesyl acetone (formula 4) in step 1) is performed at 20 to 30 ℃.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4169157A (en) * | 1977-05-26 | 1979-09-25 | Eisai Co., Ltd. | Therapeutic preparations for peptic ulcers comprising aliphatic ketone derivative |
| CN101343219A (en) * | 2008-08-21 | 2009-01-14 | 成都理工大学 | Synthesis of Teprenone |
| WO2014055440A1 (en) * | 2012-10-01 | 2014-04-10 | Coyote Pharmaceuticals, Inc. | Preparation of gga and derivatives thereof and their co-crystallization with urea or thiourea |
| CN108047011A (en) * | 2017-09-14 | 2018-05-18 | 浙江新和成股份有限公司 | A kind of synthetic method of Teprenone and its intermediate |
-
2018
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4169157A (en) * | 1977-05-26 | 1979-09-25 | Eisai Co., Ltd. | Therapeutic preparations for peptic ulcers comprising aliphatic ketone derivative |
| CN101343219A (en) * | 2008-08-21 | 2009-01-14 | 成都理工大学 | Synthesis of Teprenone |
| WO2014055440A1 (en) * | 2012-10-01 | 2014-04-10 | Coyote Pharmaceuticals, Inc. | Preparation of gga and derivatives thereof and their co-crystallization with urea or thiourea |
| CN108047011A (en) * | 2017-09-14 | 2018-05-18 | 浙江新和成股份有限公司 | A kind of synthetic method of Teprenone and its intermediate |
Non-Patent Citations (1)
| Title |
|---|
| Deciphering the Chemical Basis of Nestmate Recognition;Ellen van Wilgenburg等;《J Chem Ecol》;20101231;第36卷;第753页最后一段，第754页图3 * |
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