CN112778114A - Efficient and environment-friendly method for synthesizing vitamin K1 - Google Patents
Efficient and environment-friendly method for synthesizing vitamin K1 Download PDFInfo
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- CN112778114A CN112778114A CN202110082335.2A CN202110082335A CN112778114A CN 112778114 A CN112778114 A CN 112778114A CN 202110082335 A CN202110082335 A CN 202110082335A CN 112778114 A CN112778114 A CN 112778114A
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- SHUZOJHMOBOZST-UHFFFAOYSA-N phylloquinone Natural products CC(C)CCCCC(C)CCC(C)CCCC(=CCC1=C(C)C(=O)c2ccccc2C1=O)C SHUZOJHMOBOZST-UHFFFAOYSA-N 0.000 title claims abstract description 50
- ABSPRNADVQNDOU-UHFFFAOYSA-N Menaquinone 1 Natural products C1=CC=C2C(=O)C(CC=C(C)C)=C(C)C(=O)C2=C1 ABSPRNADVQNDOU-UHFFFAOYSA-N 0.000 title claims abstract description 45
- 235000019175 phylloquinone Nutrition 0.000 title claims abstract description 45
- 239000011772 phylloquinone Substances 0.000 title claims abstract description 45
- MBWXNTAXLNYFJB-NKFFZRIASA-N phylloquinone Chemical compound C1=CC=C2C(=O)C(C/C=C(C)/CCC[C@H](C)CCC[C@H](C)CCCC(C)C)=C(C)C(=O)C2=C1 MBWXNTAXLNYFJB-NKFFZRIASA-N 0.000 title claims abstract description 45
- 229960001898 phytomenadione Drugs 0.000 title claims abstract description 45
- 238000000034 method Methods 0.000 title claims abstract description 26
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 39
- 238000006243 chemical reaction Methods 0.000 claims abstract description 20
- JPUZRBGFEWQQEW-UHFFFAOYSA-N (4-hydroxy-2-methylnaphthalen-1-yl) acetate Chemical compound C1=CC=C2C(OC(=O)C)=C(C)C=C(O)C2=C1 JPUZRBGFEWQQEW-UHFFFAOYSA-N 0.000 claims abstract description 19
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 18
- 230000007062 hydrolysis Effects 0.000 claims abstract description 16
- 239000003513 alkali Substances 0.000 claims abstract description 13
- 239000011973 solid acid Substances 0.000 claims abstract description 7
- HWKHQQCBFMYAJZ-UHFFFAOYSA-N 4-amino-n-(3-aminophenyl)benzamide Chemical compound C1=CC(N)=CC=C1C(=O)NC1=CC=CC(N)=C1 HWKHQQCBFMYAJZ-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000003547 Friedel-Crafts alkylation reaction Methods 0.000 claims abstract description 6
- KEVYVLWNCKMXJX-ZCNNSNEGSA-N Isophytol Natural products CC(C)CCC[C@H](C)CCC[C@@H](C)CCC[C@@](C)(O)C=C KEVYVLWNCKMXJX-ZCNNSNEGSA-N 0.000 claims abstract description 6
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 6
- 239000003054 catalyst Substances 0.000 claims abstract description 4
- 239000007858 starting material Substances 0.000 claims abstract description 4
- 230000009471 action Effects 0.000 claims abstract description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 3
- 239000001301 oxygen Substances 0.000 claims abstract description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 36
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 27
- 239000000243 solution Substances 0.000 claims description 16
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 14
- 239000003208 petroleum Substances 0.000 claims description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 239000007810 chemical reaction solvent Substances 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 7
- 230000015572 biosynthetic process Effects 0.000 claims description 7
- 238000010438 heat treatment Methods 0.000 claims description 7
- 239000012535 impurity Substances 0.000 claims description 7
- 238000003786 synthesis reaction Methods 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- IYDGMDWEHDFVQI-UHFFFAOYSA-N phosphoric acid;trioxotungsten Chemical compound O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.OP(O)(O)=O IYDGMDWEHDFVQI-UHFFFAOYSA-N 0.000 claims description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 5
- 150000001298 alcohols Chemical class 0.000 claims description 5
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 5
- 239000011964 heteropoly acid Substances 0.000 claims description 5
- 230000003647 oxidation Effects 0.000 claims description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 4
- 230000029936 alkylation Effects 0.000 claims description 4
- 238000005804 alkylation reaction Methods 0.000 claims description 4
- 230000003301 hydrolyzing effect Effects 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- CGFYHILWFSGVJS-UHFFFAOYSA-N silicic acid;trioxotungsten Chemical compound O[Si](O)(O)O.O=[W]1(=O)O[W](=O)(=O)O[W](=O)(=O)O1.O=[W]1(=O)O[W](=O)(=O)O[W](=O)(=O)O1.O=[W]1(=O)O[W](=O)(=O)O[W](=O)(=O)O1.O=[W]1(=O)O[W](=O)(=O)O[W](=O)(=O)O1 CGFYHILWFSGVJS-UHFFFAOYSA-N 0.000 claims description 4
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 4
- 230000001476 alcoholic effect Effects 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 3
- 238000003818 flash chromatography Methods 0.000 claims description 3
- 235000011181 potassium carbonates Nutrition 0.000 claims description 3
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 3
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 3
- -1 tert-butyl ethyl Chemical group 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 238000009835 boiling Methods 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 230000007613 environmental effect Effects 0.000 claims description 2
- 230000001590 oxidative effect Effects 0.000 claims description 2
- DHRLEVQXOMLTIM-UHFFFAOYSA-N phosphoric acid;trioxomolybdenum Chemical compound O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.OP(O)(O)=O DHRLEVQXOMLTIM-UHFFFAOYSA-N 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 238000007670 refining Methods 0.000 claims description 2
- 230000000717 retained effect Effects 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims 1
- 239000012670 alkaline solution Substances 0.000 claims 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims 1
- 230000008569 process Effects 0.000 abstract description 7
- 239000012043 crude product Substances 0.000 abstract description 5
- 239000000126 substance Substances 0.000 abstract description 4
- 229940088594 vitamin Drugs 0.000 abstract description 4
- 229930003231 vitamin Natural products 0.000 abstract description 4
- 235000013343 vitamin Nutrition 0.000 abstract description 4
- 239000011782 vitamin Substances 0.000 abstract description 4
- 238000004440 column chromatography Methods 0.000 abstract description 3
- 150000003722 vitamin derivatives Chemical class 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract 2
- 239000003814 drug Substances 0.000 abstract 2
- 239000002841 Lewis acid Substances 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 150000007517 lewis acids Chemical class 0.000 abstract 1
- 238000004904 shortening Methods 0.000 abstract 1
- 238000006467 substitution reaction Methods 0.000 abstract 1
- 239000000047 product Substances 0.000 description 14
- 239000000706 filtrate Substances 0.000 description 6
- 229930003448 Vitamin K Natural products 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 235000019168 vitamin K Nutrition 0.000 description 5
- 239000011712 vitamin K Substances 0.000 description 5
- 150000003721 vitamin K derivatives Chemical class 0.000 description 5
- 229940046010 vitamin k Drugs 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 241001464837 Viridiplantae Species 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
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000002351 wastewater Substances 0.000 description 2
- RYWSYCQQUDFMAU-UHFFFAOYSA-N Acetomenaphthone Chemical compound C1=CC=C2C(OC(=O)C)=CC(C)=C(OC(C)=O)C2=C1 RYWSYCQQUDFMAU-UHFFFAOYSA-N 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- MJVAVZPDRWSRRC-UHFFFAOYSA-N Menadione Chemical compound C1=CC=C2C(=O)C(C)=CC(=O)C2=C1 MJVAVZPDRWSRRC-UHFFFAOYSA-N 0.000 description 1
- 102100027378 Prothrombin Human genes 0.000 description 1
- 108010094028 Prothrombin Proteins 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 208000031169 hemorrhagic disease Diseases 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- DKHGMERMDICWDU-GHDNBGIDSA-N menaquinone-4 Chemical compound C1=CC=C2C(=O)C(C/C=C(C)/CC/C=C(C)/CC/C=C(C)/CCC=C(C)C)=C(C)C(=O)C2=C1 DKHGMERMDICWDU-GHDNBGIDSA-N 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 229940039716 prothrombin Drugs 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 150000003716 vitamin K3 derivatives Chemical class 0.000 description 1
- 150000003718 vitamin K5 derivatives Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
- C07C67/29—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by introduction of oxygen-containing functional groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C46/00—Preparation of quinones
- C07C46/02—Preparation of quinones by oxidation giving rise to quinoid structures
- C07C46/06—Preparation of quinones by oxidation giving rise to quinoid structures of at least one hydroxy group on a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C46/00—Preparation of quinones
- C07C46/10—Separation; Purification; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
- C07C67/293—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a method for synthesizing vitamin K1 as a chemical bulk drug, which uses 2-methyl-1, 4-naphthalenediol diacetate as a starting material, hydrolyzes 4-acetyl under the hydrolysis action of alkali liquor to obtain 2-methyl-4-hydroxy-1-naphthol acetate, catalyzes friedel-crafts alkylation on a benzonaphthoquinone ring by the 2-methyl-4-hydroxy-1-naphthol acetate and plant alcohol or isophytol through a solid acid catalyst instead of strong Lewis acid, then completes hydrolysis and oxidation reaction in one step in the hydrolysis process by hydrolysis and utilizing oxygen in the air to achieve the purposes of shortening reaction steps, obtaining a high-purity vitamin K1 crude product with high efficiency, greenness and high yield, and meeting the quality requirements of vitamin K1 in European pharmacopoeia through a rapid column chromatography method. The method is simple to operate, environment-friendly, suitable for industrial production and high in yield. Compared with the traditional process, the method has great process advantages, can be further used for a process substitution method of bulk drugs with similar structures of vitamin systems, and has wide potential application.
Description
Technical Field
The invention relates to a method for synthesizing vitamin K1, in particular to a method for efficiently and environmentally synthesizing vitamin K1.
Background
Vitamin K, also known as thrombovitamine, is a generic name for a large group of 2-methyl-1, 4-naphthoquinones and their derivatives, which was first discovered by danish chemist dam, who, when studying the principle of cholesterol metabolism, unexpectedly discovered substances associated with blood coagulation and confirmed to be fat-soluble vitamins, and thus this substance having an anti-bleeding effect was named vitamin K. Vitamin K is extracted from green plants, and the vitamin K has good effect when being used for treating prothrombin hypofunction and various hemorrhagic diseases thereof. Vitamin K includes vitamin K1, K2, K3, K4 and K5, etc., and vitamin K1 is also called phylloquinone, is yellow viscous oily substance, and is widely present in green plants and animal livers. The defects of the existing method are obvious, and 1, the reaction route is long and the yield is low; 2. boron trifluoride diethyl etherate is used as a catalyst, a large amount of waste water is generated, and the environment is not facilitated; 3. the reaction uses ether as a reaction solvent, and due to the flammable and explosive characteristics of the ether, industrial scale-up production cannot be realized; therefore, the method which is environment-friendly, low in toxicity and easy to industrialize is imperatively found.
Disclosure of Invention
In order to solve the defects in the prior art, the invention discloses a method for efficiently and environmentally synthesizing vitamin K1, which is realized by adopting the following technical scheme.
A method for efficiently and environmentally synthesizing vitamin K1 specifically comprises the following steps: step 1, taking 2-methyl-1, 4-naphthalenediol diacetate as a starting material, taking alcohols as a solvent, and directionally hydrolyzing 4-acetyl under the action of alkali to obtain 2-methyl-4-hydroxy-1-naphthol acetate; step 2, carrying out Friedel-crafts alkylation reaction on 2-methyl-4-hydroxy-1-naphthol acetate and plant alcohol or isophytol under the catalysis of solid acid by taking toluene as a solvent to generate 2-methyl-3-20 alkyl alkenyl-4-hydroxy-1-naphthol acetate; step 3, hydrolyzing the 2-methyl-3-20-alkyl alkenyl-4-hydroxy-1-naphthol acetate by using ethanol and water as a mixed solvent under an alkaline condition, and oxidizing the hydrolyzed product in the air by oxygen in the air to obtain a crude vitamin K1 product; and 4, refining and purifying the crude vitamin K1 product by flash column chromatography to obtain a finished vitamin K1 product.
As a further improvement of the technology, in the step 1, alcohols are used as a reaction solvent, and the alcohols include methanol, ethanol, isopropanol and methanol, ethanol and isopropanol with different water contents; the alkali used for hydrolysis is sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium carbonate and ammonia water solution, and also comprises alcoholic solution of sodium methoxide and sodium ethoxide, and the product of 4-position hydrolysis, namely the 2-methyl-4-hydroxy-1-naphthol acetate, can be directionally obtained by controlling the dosage of alkali liquor and the reaction time.
As a further improvement of the technology, the 2-methyl-4-hydroxy-1-naphthol acetate in the step 2 can be subjected to a friedel-crafts alkylation reaction with plant alcohol or isophytol; toluene is used as the reaction solvent, and other solvents having the same or similar boiling point as toluene may also be used, such as including but not limited to: benzene, xylene, 1, 4-dioxane, N-dimethylformamide, acetic acid, tert-butyl ethyl ester and pyridine; and (3) taking solid acid as an alkylation catalyst for heating reaction to obtain an alkylation product, wherein the solid acid mainly refers to heteropolyacid and comprises phosphotungstic acid and phosphotungstic acid, silicotungstic acid and silicotungstic acid salts, phosphomolybdic acid and phosphomolybdate, and silicomolybdic acid and silicomolybdate.
As a further improvement of the technology, in the step 3, an alcohol-water mixed solvent is used as a reaction solvent, wherein the alcohol is methanol, ethanol, isopropanol, petroleum ether and other ethers, the hydrolysis and oxidation are performed under an alkali condition to obtain a vitamin K1 crude product, the alkali comprises sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium carbonate, an ammonia water solution, and an alcohol solution of sodium methoxide and sodium ethoxide, the reaction condition is mild, the hydrolysis and oxidation are almost simultaneously performed, and the high-purity vitamin K1 crude product is obtained by extraction after the reaction is finished.
The method as claimed in claim 1, wherein the vitamin K1 is synthesized in step 4, wherein the obtained high-purity vitamin K1 contains only two major impurities of very low polarity and very high polarity, the minor impurities can flow out along with the front edge of the developing solvent by adjusting the ratio of the developing solvent, and the major impurities are retained on the chromatographic column, so that the vitamin K1 can be purified by using a flash chromatographic column, and the developing solvent is petroleum ether and ethyl acetate or single solvent petroleum ether.
The invention is realized by the following technical scheme:
2-methyl-4-hydroxy-1-naphthol acetate synthesis: taking 2-methyl-1, 4-naphthalenediol diacetate as a starting material, adding 38.5-66.4 g of 2-methyl-1, 4-naphthalenediol diacetate into a reaction bottle, adding 180-500 mL of methanol or ethanol, stirring for dissolving, adding 28.9-57.2 g of alkali liquor at normal temperature, heating to 50-80 ℃, and carrying out heat preservation hydrolysis reaction for 1.0-8.0 hours.
After the reaction is finished, concentrating and recovering the reaction solvent, after the concentration is finished, cooling and crystallizing to obtain the high-purity 2-methyl-4-hydroxy-1-naphthol acetate, wherein the molar yield is 90-100%, and the synthesis of the 2-methyl-3-20 alkenyl-4-hydroxy-1-naphthol acetate comprises the following steps: adding 18.5-42.3 g of 2-methyl-4-hydroxy-1-naphthol acetate into 190-400 ml of toluene solution, adding 9.0-20.0 g of solid heteropoly acid, heating to 50-110 ℃, reacting for 1.0-4.0 hours, dropwise adding 9.5-26.2 g of plant alcohol or isophytol into the solution, and reacting for 1.0-4.0 hours at 50-110 ℃.
After the reaction is finished, filtering solid heteropoly acid, concentrating the filtrate to recover toluene, concentrating to be dry, recovering 2-methyl-4-hydroxy-1-naphthol acetate by using 50-500 ml of petroleum ether, directly applying the ether solution containing 2-methyl-3-20 alkenyl-4-hydroxy-1-naphthol acetate to the next step of hydrolysis without treatment, and synthesizing a crude vitamin K1 product: and adding the reaction solution into 50-500 ml of an alcohol solution, and dripping liquid alkali at room temperature for hydrolysis.
After hydrolysis, standing and layering, reserving an organic layer, extracting the organic layer with 50-500 ml of water to remove impurities, concentrating the organic layer to obtain a crude vitamin K1 product, and purifying vitamin K1: and (2) performing flash column chromatography purification on 20g of the crude vitamin K1 by using 200-1400 silica gel or neutral alumina, purifying by using a developing agent which is petroleum ether or a mixed solution of petroleum ether and ethyl acetate (the petroleum ether and the ethyl acetate are 10: 1-100: 1), and concentrating the developing agent containing the product to obtain the purified vitamin K1.
The invention has the beneficial effects that:
when the company solves the problem, the low-cost and environment-friendly heteropoly acid is used for carrying out the friedel-crafts alkylation reaction, the product vitamin K1 is directly obtained through one-step hydrolysis oxidation, and the improved synthesis process has the advantages that: 1. the process has obvious advantages in the aspect of environmental protection, can replace ether, omit heavy metal oxidants, recover all reaction solvents, partially recycle, generate no wastewater and pollute the environment. 2. The reaction steps are reduced, the yield is greatly improved, the actual yield is 80-90%, and the 2-methyl-4-hydroxy-1-naphthol acetate can be basically recovered by 100%. 3. The proportion of the isomers is between 3.9 and 19.6 percent and is less than 21 percent. 4. Through the improved synthesized vitamin content meeting the standard, the content of the crude product in the process can be more than 97 percent after column chromatography purification.
Detailed Description
The first embodiment is as follows: 2-methyl-4-hydroxy-1-naphthol acetate synthesis:
adding 58g of 2-methyl-1, 4-naphthalenediol diacetate into a reaction bottle, adding 300mL of methanol, stirring for dissolving, adding 29g of ammonia water solution at normal temperature, heating to 65-70 ℃, carrying out thermal insulation hydrolysis reaction for 1.0 hour, concentrating the reaction solution under reduced pressure until no methanol drips out after the reaction is finished, cooling to 0-10 ℃, carrying out stirring crystallization for 2-3 hours, and filtering and drying to obtain 48.5g of light yellow 2-methyl-4-hydroxy-1-naphthol acetate.
Example two: 2-methyl-3-20 alkyl alkenyl-4-hydroxy-1-naphthol acetate synthesis:
dissolving 18g of 2-methyl-4-hydroxy-1-naphthol acetate in 150ml of toluene at the temperature of 60-70 ℃, adding 5g of phosphotungstic acid, activating for 1 hour at the temperature of 60-70 ℃, adding 9g of plant alcohol, heating to 60-70 ℃, reacting for 2 hours, filtering phosphotungstic acid solid, concentrating the filtrate at the temperature of 50 ℃ under reduced pressure until the filtrate is dry, adding 60ml of petroleum ether, stirring for dissolving, and standing at the temperature of 0-10 ℃ for crystallization. Filtering, recovering incompletely reacted 2-methyl-4-hydroxy-1-naphthol acetate from a filter cake, and keeping the filtrate for the next step.
Example three: synthesis of crude vitamin K1:
dissolving 9g of potassium hydroxide in 30ml of water to prepare an alkali liquor, adding the reserved filtrate obtained in the second embodiment into 120ml of methanol, cooling the reaction solution to 0-10 ℃, adding the alkali liquor into the reaction solution, heating to 10-20 ℃, reacting for 4-5 hours, extracting with 200ml of water each time after the reaction is finished, collecting an organic layer after three times of extraction, drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate at 50 ℃ under reduced pressure to dryness to obtain 12.5g of a yellow oily vitamin K1 crude product.
Example four: purification of crude vitamin K1:
12.5g of the crude vitamin K1 product obtained in the third embodiment is subjected to rapid column chromatography purification, 125g of silica gel and petroleum ether as a developing agent, 12.5g of the crude vitamin K1 product is dissolved in 25ml of petroleum ether, then the crude vitamin K1 product is slowly added into a chromatographic column for chromatographic separation, a yellow colored ribbon is separated and collected in a dark place, after vitamin K1 liquid is collected, the mixture is concentrated to be dry at a reduced pressure of 60 ℃, the temperature is kept at 60-70 ℃, the reduced pressure drying is continued for 3-4 hours, 11g of a light yellow oily vitamin finished product is obtained, the molar yield is 80.4% (calculated by plant alcohol), the cis-isomer is 12.8%, and the content is 99.9%.
While the present invention has been described in conjunction with the above embodiments, the present invention is not limited to the above embodiments but is limited only by the appended claims, and those skilled in the art can easily make modifications and variations thereto without departing from the true spirit and scope of the present invention.
Claims (5)
1. The method for efficiently and environmentally synthesizing vitamin K1 is characterized by comprising the following steps: step 1, taking 2-methyl-1, 4-naphthalenediol diacetate as a starting material, taking alcohols as a solvent, and directionally hydrolyzing 4-acetyl under the action of alkali to obtain 2-methyl-4-hydroxy-1-naphthol acetate; step 2, carrying out Friedel-crafts alkylation reaction on 2-methyl-4-hydroxy-1-naphthol acetate and plant alcohol or isophytol under the catalysis of solid acid by taking toluene as a solvent to generate 2-methyl-3-20 alkyl alkenyl-4-hydroxy-1-naphthol acetate; step 3, hydrolyzing the 2-methyl-3-20-alkyl alkenyl-4-hydroxy-1-naphthol acetate by using ethanol and water as a mixed solvent under an alkaline condition, and oxidizing the hydrolyzed product in the air by oxygen in the air to obtain a crude vitamin K1 product; and 4, refining and purifying the crude vitamin K1 product by flash column chromatography to obtain a finished vitamin K1 product.
2. The method for synthesizing vitamin K1 in an efficient and environment-friendly manner according to claim 1, wherein alcohols including methanol, ethanol, isopropanol and methanol, ethanol, isopropanol with different water contents are used as reaction solvents in step 1; the alkali used for hydrolysis is sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium carbonate and ammonia water solution, and also comprises alcoholic solution of sodium methoxide and sodium ethoxide, and the product of 4-position hydrolysis, namely the 2-methyl-4-hydroxy-1-naphthol acetate, can be directionally obtained by controlling the dosage of alkali liquor and the reaction time.
3. The method for synthesizing vitamin K1 in high efficiency and environmental protection mode according to claim 1, wherein 2-methyl-4-hydroxy-1-naphthol acetate in step 2 can be subjected to friedel-crafts alkylation reaction with plant alcohol or isophytol; toluene is used as the reaction solvent, and other solvents having the same or similar boiling point as toluene may also be used, such as including but not limited to: benzene, xylene, 1, 4-dioxane, N-dimethylformamide, acetic acid, tert-butyl ethyl ester and pyridine; and (3) taking solid acid as an alkylation catalyst for heating reaction to obtain an alkylation product, wherein the solid acid mainly refers to heteropolyacid and comprises phosphotungstic acid and phosphotungstic acid, silicotungstic acid and silicotungstic acid salts, phosphomolybdic acid and phosphomolybdate, and silicomolybdic acid and silicomolybdate.
4. The method for efficient and environment-friendly synthesis of vitamin K1 according to claim 1, wherein in step 3, alcohol-water mixed solvent is used as reaction solvent, wherein the alcohol is ether such as methanol, ethanol, isopropanol and petroleum ether, and the hydrolysis and oxidation are carried out under alkaline conditions to obtain crude vitamin K1, wherein the alkaline solution comprises sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium carbonate, aqueous ammonia solution, and alcoholic solution of sodium methoxide and sodium ethoxide, and the reaction conditions are mild, hydrolysis and oxidation are almost simultaneously carried out, and the crude vitamin K1 with high purity is obtained by extraction after the reaction is finished.
5. The method as claimed in claim 1, wherein the vitamin K1 is synthesized in step 4, wherein the obtained high-purity vitamin K1 contains only two major impurities of very low polarity and very high polarity, the minor impurities can flow out along with the front edge of the developing solvent by adjusting the ratio of the developing solvent, and the major impurities are retained on the chromatographic column, so that the vitamin K1 can be purified by using a flash chromatographic column, and the developing solvent is petroleum ether and ethyl acetate or single solvent petroleum ether.
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