CN106565424B - Preparation method of high-purity propofol - Google Patents
Preparation method of high-purity propofol Download PDFInfo
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- CN106565424B CN106565424B CN201610966517.5A CN201610966517A CN106565424B CN 106565424 B CN106565424 B CN 106565424B CN 201610966517 A CN201610966517 A CN 201610966517A CN 106565424 B CN106565424 B CN 106565424B
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- propofol
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- hydroxide
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- OLBCVFGFOZPWHH-UHFFFAOYSA-N propofol Chemical compound CC(C)C1=CC=CC(C(C)C)=C1O OLBCVFGFOZPWHH-UHFFFAOYSA-N 0.000 title claims abstract description 54
- 229960004134 propofol Drugs 0.000 title claims abstract description 53
- 238000002360 preparation method Methods 0.000 title claims abstract description 38
- 238000006243 chemical reaction Methods 0.000 claims abstract description 23
- 239000003513 alkali Substances 0.000 claims abstract description 11
- 239000002904 solvent Substances 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 8
- 238000006114 decarboxylation reaction Methods 0.000 claims abstract description 7
- 238000010438 heat treatment Methods 0.000 claims abstract description 7
- 238000005406 washing Methods 0.000 claims abstract description 7
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 4
- 239000002253 acid Substances 0.000 claims abstract description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 36
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 32
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 30
- 238000000034 method Methods 0.000 claims description 25
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims description 21
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 14
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 claims description 11
- 230000008569 process Effects 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- 239000012024 dehydrating agents Substances 0.000 claims description 7
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical group [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- 239000003377 acid catalyst Substances 0.000 claims description 6
- 230000009471 action Effects 0.000 claims description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical group ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
- 238000004821 distillation Methods 0.000 claims description 5
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- CPRMKOQKXYSDML-UHFFFAOYSA-M rubidium hydroxide Chemical compound [OH-].[Rb+] CPRMKOQKXYSDML-UHFFFAOYSA-M 0.000 claims description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 239000002585 base Substances 0.000 claims description 3
- 238000005886 esterification reaction Methods 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- JIRHAGAOHOYLNO-UHFFFAOYSA-N (3-cyclopentyloxy-4-methoxyphenyl)methanol Chemical compound COC1=CC=C(CO)C=C1OC1CCCC1 JIRHAGAOHOYLNO-UHFFFAOYSA-N 0.000 claims description 2
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 claims description 2
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 claims description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 2
- 239000012346 acetyl chloride Substances 0.000 claims description 2
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 claims description 2
- 229910001863 barium hydroxide Inorganic materials 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 2
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 2
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 claims description 2
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims description 2
- 239000000920 calcium hydroxide Substances 0.000 claims description 2
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- UXCDUFKZSUBXGM-UHFFFAOYSA-N phosphoric tribromide Chemical compound BrP(Br)(Br)=O UXCDUFKZSUBXGM-UHFFFAOYSA-N 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 2
- UUCCCPNEFXQJEL-UHFFFAOYSA-L strontium dihydroxide Chemical compound [OH-].[OH-].[Sr+2] UUCCCPNEFXQJEL-UHFFFAOYSA-L 0.000 claims description 2
- 229910001866 strontium hydroxide Inorganic materials 0.000 claims description 2
- 241000764238 Isis Species 0.000 claims 1
- XTUSEBKMEQERQV-UHFFFAOYSA-N propan-2-ol;hydrate Chemical group O.CC(C)O XTUSEBKMEQERQV-UHFFFAOYSA-N 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 14
- 239000002994 raw material Substances 0.000 abstract description 10
- 239000003814 drug Substances 0.000 abstract description 3
- -1 4-hydroxy-3, 5-diisopropyl benzoic acid isopropyl alcohol ester Chemical class 0.000 description 19
- 239000000243 solution Substances 0.000 description 11
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 238000001035 drying Methods 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 5
- CRBJBYGJVIBWIY-UHFFFAOYSA-N 2-isopropylphenol Chemical compound CC(C)C1=CC=CC=C1O CRBJBYGJVIBWIY-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 206010002091 Anaesthesia Diseases 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 230000037005 anaesthesia Effects 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- VFNUNYPYULIJSN-UHFFFAOYSA-N 2,5-diisopropylphenol Chemical compound CC(C)C1=CC=C(C(C)C)C(O)=C1 VFNUNYPYULIJSN-UHFFFAOYSA-N 0.000 description 2
- YQUQWHNMBPIWGK-UHFFFAOYSA-N 4-isopropylphenol Chemical compound CC(C)C1=CC=C(O)C=C1 YQUQWHNMBPIWGK-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- RWGMANKDYBWNNP-UHFFFAOYSA-N 1,2,4-tri(propan-2-yl)benzene Chemical compound CC(C)C1=CC=C(C(C)C)C(C(C)C)=C1 RWGMANKDYBWNNP-UHFFFAOYSA-N 0.000 description 1
- 229940005561 1,4-benzoquinone Drugs 0.000 description 1
- HVFKKINZIWVNQG-UHFFFAOYSA-N 2,4,6-tri(propan-2-yl)phenol Chemical compound CC(C)C1=CC(C(C)C)=C(O)C(C(C)C)=C1 HVFKKINZIWVNQG-UHFFFAOYSA-N 0.000 description 1
- WKBALTUBRZPIPZ-UHFFFAOYSA-N 2,6-di(propan-2-yl)aniline Chemical compound CC(C)C1=CC=CC(C(C)C)=C1N WKBALTUBRZPIPZ-UHFFFAOYSA-N 0.000 description 1
- XKZQKPRCPNGNFR-UHFFFAOYSA-N 2-(3-hydroxyphenyl)phenol Chemical compound OC1=CC=CC(C=2C(=CC=CC=2)O)=C1 XKZQKPRCPNGNFR-UHFFFAOYSA-N 0.000 description 1
- WYAZPCLFZZTVSP-UHFFFAOYSA-N 4-hydroxy-3,5-di(propan-2-yl)benzoic acid Chemical compound CC(C)C1=CC(C(O)=O)=CC(C(C)C)=C1O WYAZPCLFZZTVSP-UHFFFAOYSA-N 0.000 description 1
- BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 208000031649 Postoperative Nausea and Vomiting Diseases 0.000 description 1
- 206010039897 Sedation Diseases 0.000 description 1
- 238000007171 acid catalysis Methods 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 229940035674 anesthetics Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000000911 decarboxylating effect Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000002692 epidural anesthesia Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000003193 general anesthetic agent Substances 0.000 description 1
- 229950000188 halopropane Drugs 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- AQFMOBJQAQLNSL-UHFFFAOYSA-N propan-2-yl 4-hydroxy-3,5-di(propan-2-yl)benzoate Chemical compound CC(C)OC(=O)C1=CC(C(C)C)=C(O)C(C(C)C)=C1 AQFMOBJQAQLNSL-UHFFFAOYSA-N 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- AQZYITHCFJYHIX-UHFFFAOYSA-N tert-butyl 4-hydroxy-3,5-di(propan-2-yl)benzoate Chemical compound C(C)(C)(C)OC(C1=CC(=C(C(=C1)C(C)C)O)C(C)C)=O AQZYITHCFJYHIX-UHFFFAOYSA-N 0.000 description 1
- WHWMOMRHHQLBQQ-UHFFFAOYSA-N tert-butyl 4-hydroxybenzoate Chemical compound CC(C)(C)OC(=O)C1=CC=C(O)C=C1 WHWMOMRHHQLBQQ-UHFFFAOYSA-N 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/50—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions decreasing the number of carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/68—Purification; separation; Use of additives, e.g. for stabilisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
Abstract
The invention provides a preparation method of high-purity propofol, which comprises the following steps: s1, heating the compound shown in the general formula (I) in a solvent under the catalysis of strong alkali to perform decarboxylation reaction, and adjusting acid to obtain a solution system containing propofol; s2, extracting and alkali washing the propofol-containing solution system, and distilling under reduced pressure to obtain the high-purity propofol. The preparation method provided by the invention has the advantages of wide raw material source, low cost, mild reaction conditions, few product impurity types, high product quality, purity higher than 99.0% and capability of meeting the requirements of raw material medicaments, and the product has the advantages of high purity and high purity.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a preparation method of high-purity propofol.
Background
Propofol is also known as bipropofol, and is chemically known as 2, 6-diisopropylphenol. Propofol is a rapid and short-acting intravenous anesthetic which is generally used for anesthesia induction, anesthesia maintenance, ICU critical patient sedation, auxiliary epidural anesthesia and the like in clinic at present. Propofol and injection thereof play an important role in the field of anesthetics, and have the advantages of quick response, high plasma clearance rate, quick blood concentration reduction, suitability for continuous infusion administration, quick and stable awakening after anesthesia, no mental symptoms, few postoperative nausea and vomiting, complete effect, few side effects and the like.
The traditional preparation process of propofol adopts phenol or 2-isopropylphenol and propylene to carry out alkylation reaction under the conditions of high temperature and high pressure, and the crude propofol product is prepared by one-step synthesis, which is reported in patent documents such as US4447657, US3367981, US3051762 and the like, and the synthesis process is mature and has cheap raw materials, but has the following defects: the reaction conditions are harsh, the reaction is very violent, the reaction selectivity of propofol is low, the purity of a crude product can only reach 60-75%, main impurities comprise 2, 4-and 2, 5-diisopropylphenol, 2,4, 6-triisopropylphenol and 1-isopropyl-2, 4-diisopropylbenzene, the structures of the impurities are extremely similar, and the physical and chemical differences are small.
There have been many studies on how to purify a crude propofol product into a high-purity propofol product with a purity of 99% or more, such as the purification methods reported in US5589598, US5175376, EP0511947, WO9610004, CN102731265 and CN100569720 patent documents, including: rectification purification, low-temperature crystallization purification, column chromatography and esterification hydrolysis. However, the above refining method has the disadvantages of long operation steps, poor separation effect, long treatment time, high equipment requirement and the like, and easily causes the oxidation impurities of 3,3 ', 5, 5' -tetraisopropyl diphenol and propofol-1, 4-benzoquinone to exceed the standard, while the oxidation impurities are impurities concerned and controlled by the core of the medicinal propofol due to high toxicity.
In order to reduce the impurity species and improve the purity of propofol, a great deal of research has been carried out to improve the traditional preparation process. Chinese patent application CN102603488 discloses a preparation process of propofol obtained by using 2, 6-diisopropylaniline as raw material, reacting with sodium nitrite, and hydrolyzing. Chinese patent application CN104649867 discloses a preparation process of propofol which is prepared from p-nitrophenol and isopropanol or 2-halopropane through friedel-crafts reaction under acid catalysis, and then through acylation, reduction, diazotization, decomposition and hydrolysis reactions. Both of the two preparation processes have the defects of difficult obtainment of raw materials and high production cost.
Patent document WO2011161687 discloses a method for preparing propofol with high purity by reacting p-hydroxybenzoic acid as a raw material with an alkylating reagent under the catalysis of inorganic acid to obtain 4-hydroxy-3, 5-diisopropylbenzoic acid, and then decarboxylating at high temperature in the presence of a high boiling point solvent and a catalyst sodium hydroxide. The process is simple to operate and low in cost, can be used for industrially producing propofol with higher purity, but has harsh conditions for removing carboxyl positioning groups, and needs strong alkali for high-temperature reaction for a long time.
In view of the defects of the existing propofol preparation method, the preparation method which is simple to operate, sufficient in raw material source and suitable for industrial production of high-purity propofol is provided, and has important significance.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides a preparation method of high-purity propofol, which has the advantages of simple operation, sufficient raw material sources, suitability for industrial production, simple impurity removal, high product purity and the like.
In the present invention, high purity means a purity higher than 99.0%.
The invention provides a preparation method of high-purity propofol, which comprises the following steps:
s1, heating the compound shown in the general formula (I) in a solvent under the catalysis of strong alkali to perform decarboxylation reaction, and adjusting acid to obtain a solution system containing propofol;
s2, extracting and alkali washing the propofol-containing solution system, and then carrying out reduced pressure distillation to obtain high-purity propofol;
The preparation route of the invention is shown in figure 1, and the impurities possibly existing in the preparation route and the removal method are as follows:
preferably, R of the compound represented by the general formula (I) is
Namely 4-hydroxy-3, 5-diisopropyl benzoic acid isopropyl alcohol ester, is obtained by reacting p-hydroxybenzoic acid and isopropyl alcohol under the action of an acid catalyst and/or a dehydrating agent, and the reaction temperature is 40-90 ℃. More preferably, the reaction temperature is 60 to 80 ℃. The preparation scheme of 4-hydroxy-3, 5-diisopropylbenzoic acid isopropanol ester is shown in figure 2The possible impurities in the preparation line and the removal method are as follows:
preferably, R of the compound represented by the general formula (I) is
Namely 4-hydroxy-3, 5-diisopropyl benzoic acid tert-butyl alcohol ester, which is obtained by esterification reaction of p-hydroxybenzoic acid and tert-butyl alcohol under the action of a dehydrating agent to generate ester and then reaction with isopropanol under the action of an acid catalyst, wherein the reaction temperature is 40-100 ℃. More preferably, the reaction temperature is 60 to 80 ℃. The preparation scheme of the 4-hydroxy-3, 5-diisopropyl benzoic acid tert-butyl alcohol ester is shown in figure 3, and possible impurities in the preparation scheme and a removal method are as follows:
preferably, the heating temperature is 40-100 ℃, and the time is 4-10 h; more preferably, the heating temperature is 60-80 ℃ and the time is 5-7 h.
Preferably, the solvent is selected from one or more of methanol, ethanol, isopropanol, tert-butanol, water, acetone, ethylene glycol and dimethylformamide; more preferably, the solvent is an aqueous isopropanol solution or an aqueous tert-butanol solution.
Preferably, the strong base is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide, calcium hydroxide, strontium hydroxide, or barium hydroxide; more preferably, the strong base is sodium hydroxide or potassium hydroxide.
Preferably, the dehydrating agent is selected from thionyl chloride, acetyl chloride, phosphorus oxychloride, oxalyl chloride, phosphorus oxybromide, dicyclohexylcarbodiimide or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride.
Preferably, the acid catalyst is selected from the group consisting of toluene sulfonic acid, xylene sulfonic acid, benzene sulfonic acid, sulfuric acid, hydrochloric acid, phosphoric acid or nitric acid.
Preferably, the extraction solvent is selected from toluene or ethyl acetate.
Preferably, the alkali for alkali washing is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate.
Compared with the prior art, the invention has the beneficial effects that:
(1) the method takes p-hydroxybenzoic acid as a starting material, generates 4-hydroxy-3, 5-diisopropyl benzoic acid isopropyl alcohol ester or 4-hydroxy-3, 5-diisopropyl benzoic acid tert-butyl alcohol ester as an intermediate, and then generates propofol by reaction, and has the advantages of easy decarboxylation reaction, mild reaction conditions, short reaction time, avoidance of high-temperature and high-pressure reaction, simple operation and low requirements on production personnel and production equipment.
(2) The product prepared by the method has less impurity types, high product quality and purity higher than 99.0 percent, and can meet the requirements of raw material medicaments.
(3) The method has the advantages of wide raw material source, low cost and stable performance, and meets the requirement of industrial production.
(4) Compared with the synthesis process of the patent document WO2011161687, the method has the advantages that the reaction condition requirement is not high, the decarboxylation reaction is easier to occur, the reaction temperature is reduced, the impurity removal method is simpler, the performance of the obtained product is good, and the production cost is reduced.
Drawings
FIG. 1 is a preparation scheme of the process of the present invention.
FIG. 24 scheme for the preparation of isopropyl-3, 5-hydroxy-diisopropylbenzoate.
FIG. 34 is a preparation scheme of tert-butyl-hydroxy-3, 5-diisopropylbenzoate.
FIG. 4 HPLC chart of propofol obtained in example 3.
FIG. 5 HPLC chart of propofol obtained in example 4.
FIG. 6 HPLC chart of propofol obtained in example 5.
Detailed Description
For those skilled in the art to understand, the present invention is further described in detail by the following specific embodiments in conjunction with the attached drawings.
EXAMPLE 14 preparation of isopropyl-3, 5-hydroxy-diisopropylbenzoate
276.2g of p-hydroxybenzoic acid (2.0mol) is dissolved in 1.1L of isopropanol, stirred, added with 1mL of thionyl chloride, slowly added with 300mL of sulfuric acid dropwise, heated to 72 ℃ for reaction for 5h, the system is treated by activated carbon, filtered, and the filtrate is concentrated under reduced pressure; then dissolved in 700mL of toluene, and the organic layer was washed with 300mL of 5% (w/v) aqueous sodium hydroxide solution × 4 times, and then washed with 300mL of water × 3 times to neutrality; after drying, concentration under reduced pressure, recrystallization from isopropyl ether and drying under vacuum, 397.6g of 4-hydroxy-3, 5-diisopropylbenzoic acid isopropyl alcohol ester were obtained. Molar yield based on p-hydroxybenzoic acid: 75.2%, purity: 99.66% (HPLC). The yield and the purity of the 4-hydroxy-3, 5-diisopropyl benzoic acid isopropyl alcohol ester are high.
EXAMPLE 24 preparation of tert-butyl-hydroxy-3, 5-diisopropylbenzoate
A) 276.2g of p-hydroxybenzoic acid (2.0mol) is dissolved in 830mL of tert-butyl alcohol, stirred at room temperature, 3mL of oxalyl chloride is added dropwise as a dehydrating agent, the temperature is raised to 65 ℃ for reaction for 5h, and the system is concentrated under reduced pressure; then dissolved with 600mL of ethyl acetate, and the organic layer was washed with 300mL of 5% (w/v) aqueous sodium bicarbonate solution × 3 times, and washed with 300mL of water × 3 times to neutrality; drying, and concentrating under reduced pressure to obtain p-hydroxybenzoic acid tert-butyl alcohol ester;
B) dissolving the obtained p-hydroxybenzoic acid tert-butyl ester in 800mL of isopropanol, stirring, slowly dropwise adding 300mL of phosphoric acid, heating to 72 ℃ for reaction for 5h, treating the system with activated carbon, filtering, and concentrating the filtrate under reduced pressure; then using 700mL xylene dissolution, organic layer using 300mL x 4 times 5% sodium hydroxide aqueous solution washing, 300mL x 3 times water washing to neutral; after drying, the mixture was concentrated under reduced pressure, and then recrystallized from isopropyl ether, followed by vacuum drying, 417.0g of tert-butyl 4-hydroxy-3, 5-diisopropylbenzoate was obtained. Molar yield based on p-hydroxybenzoic acid: 74.9% and 99.58% purity (HPLC). The yield and the purity of the 4-hydroxy-3, 5-diisopropyl benzoic acid tert-butyl alcohol ester are high.
EXAMPLE 3 preparation of Propofol
344.0g of isopropyl 4-hydroxy-3, 5-diisopropylbenzoate (1.3mol), 150mL of isopropyl alcohol and 350mL of water prepared in example 1 are added into a three-necked bottle under the protection of nitrogen, stirred, 120g of sodium hydroxide (3.0mol) is added at room temperature, the temperature is raised to 70 ℃ for reaction for 7h, the temperature is lowered to the room temperature, 1.0L of water is added, hydrochloric acid is added to adjust the pH value to 1.5, the mixture is stirred, the solution system containing propofol is extracted by 500mL multiplied by 3 times of toluene, the combined toluene layers are washed by 300mL multiplied by 2 times of 5% (w/v) sodium bicarbonate aqueous solution, and 300mL multiplied by 4 times of water is washed to be neutral; after drying, concentration under reduced pressure and distillation under reduced pressure under high vacuum of 0.2mm Hg gave 219.9g of propofol as a colorless to pale yellow oil. Based on 4-hydroxy-3, 5-diisopropyl benzoic acid isopropyl alcohol ester, the molar yield is as follows: 94.9%, purity: 99.43% (HPLC), chromatogram is shown in FIG. 4.
EXAMPLE 4 preparation of Propofol
Under the protection of nitrogen, 390.0g of 4-hydroxy-3, 5-diisopropyl benzoic acid tert-butyl alcohol ester (1.4mol) prepared in example 2 and 600mL of 20% (v/v) tert-butyl alcohol aqueous solution are added into a three-neck flask, stirred, 128g of sodium hydroxide (3.2mol) is added at room temperature, heated to 60 ℃ for reaction for 5 hours, cooled to room temperature, added with sulfuric acid to adjust the pH value to 1.5, and stirred; the propofol-containing solution system was extracted with 600mL x 3 ethyl acetate, the combined organic layers were washed with 300mL x 2 times 5% (w/v) aqueous sodium carbonate solution, 350mL x 4 times water to neutrality; after drying, concentration under reduced pressure and distillation under reduced pressure under high vacuum of 0.2mm Hg gave 234.6g of propofol as a colorless to pale yellow oily liquid. Molar yield based on 4-hydroxy-3, 5-diisopropylbenzoic acid tert-butyl alcohol ester: 94.0%, purity: 99.55% (HPLC), chromatogram is shown in FIG. 5.
EXAMPLE 5 preparation of Propofol
Under the protection of nitrogen, 97.5g of 4-hydroxy-3, 5-diisopropyl benzoic acid tert-butyl alcohol ester (0.35mol) prepared in example 2 and 300mL of water are added into a three-necked bottle, stirred, added with 50.5g of potassium hydroxide (0.9mol) at room temperature, heated to 62 ℃ for reaction for 4.5h, cooled to room temperature, added with hydrochloric acid to adjust the pH value to 1.5, and stirred; the propofol-containing solution system was extracted with 200mL × 3 ethyl acetate, the combined organic layers were washed with 100mL × 2 × 5% (w/v) aqueous sodium carbonate solution, and 100mL × 4 water to neutrality; after drying, concentration under reduced pressure and distillation under reduced pressure under high vacuum of 0.2mm Hg gave 53.5g of propofol as a colorless to pale yellow oil. Molar yield based on 4-hydroxy-3, 5-diisopropylbenzoic acid tert-butyl alcohol ester: 91.2%, purity: 99.03% (HPLC), chromatogram is shown in FIG. 6.
In conclusion, the intermediates and products prepared by the method have high yield and purity and the impurity removal method is simple. And R is
R is
Although the preparation process of the intermediate is more complicated, the decarboxylation (propofol preparation) is shorter in time and lower in temperature, and the decarboxylation is easier to perform.
The foregoing is a more detailed description of the invention in connection with specific preferred embodiments and it is not intended that the invention be limited to these specific details. For those skilled in the art to which the invention pertains, several simple deductions or substitutions can be made without departing from the spirit of the invention, and all shall be considered as belonging to the protection scope of the invention.
Claims (8)
1. A preparation method of propofol is characterized in that: the method comprises the following steps:
s1, heating the compound shown in the general formula (I) in a solvent under the catalysis of strong alkali to perform decarboxylation reaction, and adjusting acid to obtain a solution system containing propofol; heating at 60-80 ℃ for 5-7 h; the solvent is isopropanol water solution or tert-butanol water solution;
s2, extracting and alkali washing the propofol-containing solution system, and then carrying out reduced pressure distillation to obtain high-purity propofol;
2. The process for the preparation of propofol according to claim 1, wherein: r of the compound shown in the general formula (I) is
Is prepared by the reaction of p-hydroxybenzoic acid and isopropanol under the action of an acid catalyst and/or a dehydrating agent.
3. The process for the preparation of propofol according to claim 1, wherein: r of the compound shown in the general formula (I) is
The compound is prepared by the esterification reaction of p-hydroxybenzoic acid and tert-butyl alcohol under the action of a dehydrating agent to generate ester, and then the reaction of the ester and isopropanol under the action of an acid catalyst.
4. A process for the preparation of propofol according to any of claims 1-3, wherein: the strong base is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide, calcium hydroxide, strontium hydroxide or barium hydroxide.
5. A process for the preparation of propofol according to any of claims 2 to 3, wherein: the dehydrating agent is selected from thionyl chloride, acetyl chloride, phosphorus oxychloride, oxalyl chloride, phosphorus oxybromide, dicyclohexylcarbodiimide or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride.
6. A process for the preparation of propofol according to any of claims 2 to 3, wherein: the acid catalyst is selected from the group consisting of toluenesulfonic acid, xylenesulfonic acid, benzenesulfonic acid, sulfuric acid, hydrochloric acid, phosphoric acid, and nitric acid.
7. A process for the preparation of propofol according to any of claims 1-3, wherein: the solvent for extraction is selected from toluene or ethyl acetate.
8. A process for the preparation of propofol according to any of claims 1-3, wherein: the alkali for alkali washing is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US4351780A (en) * | 1980-12-09 | 1982-09-28 | Stauffer Chemical Company | Process for preparing isopropylphenyl/phenyl phosphate |
| WO2011161687A1 (en) * | 2010-06-23 | 2011-12-29 | Harman Finochem Limited | Process for preparing extra pure 2, 6-diisopropyl phenol |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4351780A (en) * | 1980-12-09 | 1982-09-28 | Stauffer Chemical Company | Process for preparing isopropylphenyl/phenyl phosphate |
| WO2011161687A1 (en) * | 2010-06-23 | 2011-12-29 | Harman Finochem Limited | Process for preparing extra pure 2, 6-diisopropyl phenol |
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