CN106565424A - Preparation method for high-purity propofol - Google Patents
Preparation method for high-purity propofol Download PDFInfo
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- CN106565424A CN106565424A CN201610966517.5A CN201610966517A CN106565424A CN 106565424 A CN106565424 A CN 106565424A CN 201610966517 A CN201610966517 A CN 201610966517A CN 106565424 A CN106565424 A CN 106565424A
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- China
- Prior art keywords
- preparation
- propofol
- acid
- purity
- hydroxide
- Prior art date
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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 57
- 229960004134 propofol Drugs 0.000 title claims abstract description 54
- 238000002360 preparation method Methods 0.000 title claims abstract description 32
- 238000006243 chemical reaction Methods 0.000 claims abstract description 26
- 239000002253 acid Substances 0.000 claims abstract description 11
- 239000003513 alkali Substances 0.000 claims abstract description 8
- 239000002904 solvent Substances 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 7
- 238000000605 extraction Methods 0.000 claims abstract description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 31
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 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 22
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 21
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 21
- -1 Aminopropyl Chemical group 0.000 claims description 20
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 claims description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 12
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 230000000694 effects Effects 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- 239000007864 aqueous solution Substances 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
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 5
- 239000003377 acid catalyst Substances 0.000 claims description 5
- 239000002585 base Substances 0.000 claims description 5
- 150000002148 esters Chemical class 0.000 claims description 5
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Chemical compound [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 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
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 238000004140 cleaning Methods 0.000 claims description 3
- 230000032050 esterification Effects 0.000 claims description 3
- 238000005886 esterification reaction Methods 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 3
- 239000001117 sulphuric acid Substances 0.000 claims description 3
- 235000011149 sulphuric acid Nutrition 0.000 claims description 3
- 238000005292 vacuum distillation Methods 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical group CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 claims description 2
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 claims description 2
- AFCIMSXHQSIHQW-UHFFFAOYSA-N [O].[P] Chemical compound [O].[P] AFCIMSXHQSIHQW-UHFFFAOYSA-N 0.000 claims description 2
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 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
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 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
- XTUSEBKMEQERQV-UHFFFAOYSA-N propan-2-ol;hydrate Chemical group O.CC(C)O XTUSEBKMEQERQV-UHFFFAOYSA-N 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- DDGDWXGKPCHUCI-UHFFFAOYSA-N strontium;hydrate Chemical compound O.[Sr] DDGDWXGKPCHUCI-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 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims 1
- 239000000920 calcium hydroxide Substances 0.000 claims 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 229910017604 nitric acid Inorganic materials 0.000 claims 1
- 239000011736 potassium bicarbonate Substances 0.000 claims 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims 1
- 235000015497 potassium bicarbonate Nutrition 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 13
- 239000002994 raw material Substances 0.000 abstract description 8
- 238000005406 washing Methods 0.000 abstract description 7
- 239000003814 drug Substances 0.000 abstract description 4
- 238000004821 distillation Methods 0.000 abstract description 3
- 238000005815 base catalysis Methods 0.000 abstract 1
- 238000000034 method Methods 0.000 description 24
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 238000004519 manufacturing process Methods 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000005516 engineering process Methods 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 238000006114 decarboxylation reaction Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 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 2
- 206010002091 Anaesthesia Diseases 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- LYDRKKWPKKEMNZ-UHFFFAOYSA-N tert-butyl benzoate Chemical group CC(C)(C)OC(=O)C1=CC=CC=C1 LYDRKKWPKKEMNZ-UHFFFAOYSA-N 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- RWGMANKDYBWNNP-UHFFFAOYSA-N 1,2,4-tri(propan-2-yl)benzene Chemical class CC(C)C1=CC=C(C(C)C)C(C(C)C)=C1 RWGMANKDYBWNNP-UHFFFAOYSA-N 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
- CRBJBYGJVIBWIY-UHFFFAOYSA-N 2-isopropylphenol Chemical class CC(C)C1=CC=CC=C1O CRBJBYGJVIBWIY-UHFFFAOYSA-N 0.000 description 1
- LCHYEKKJCUJAKN-UHFFFAOYSA-N 2-propylphenol Chemical compound CCCC1=CC=CC=C1O LCHYEKKJCUJAKN-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
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- FEXQDZTYJVXMOS-UHFFFAOYSA-N Isopropyl benzoate Chemical group CC(C)OC(=O)C1=CC=CC=C1 FEXQDZTYJVXMOS-UHFFFAOYSA-N 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 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
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229940035674 anesthetics Drugs 0.000 description 1
- 229910001863 barium hydroxide Inorganic materials 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
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000002019 doping agent Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000002692 epidural anesthesia Methods 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 239000003193 general anesthetic agent Substances 0.000 description 1
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000000977 initiatory effect Effects 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
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-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
- 230000009467 reduction Effects 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical compound [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method for high-purity propofol. The preparation method includes the following steps that S1, under the strong base catalysis condition, a compound shown in the general formula (1) is heated and conducts the decarboxylic reaction in solvent, and a solution system containing the propofol is obtained after acid regulation; and S2, after extraction and alkali washing are conducted on the solution system containing the propofol, the high-purity propofol is obtained through reduced pressure distillation. The invention belongs to the technical field of medicine. The preparation method is wide in raw material source, low in cost, gentle in reaction condition, few in product impurity type and high in product quality, purity is higher than 99.0%, and the requirements for raw material medicine can be met.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to a kind of preparation method of high-purity propofol.
Background technology
Propofol also known as Disoprivan, disoprofol, chemical entitled 2,6-Bis(1-methylethyl)phenol.Propofol is current clinic
On be commonly used to a kind of quick, short-acting quiet of induction of anesthesia, anesthesia maintenance, ICU critical patients calmness, epidural anesthesia assisted etc.
Intravenous aneqthetic.Propofol and its injection play significant role in anesthetics field, with rapid-action, plasma clearance height,
Blood drug level reduces fast, is adapted to continuous infusion administration, regains one's consciousness after being anaesthetized rapid steady, and be a cup too low symptom, seldom causes postoperative evil
The heart is vomitted, completely, few side effects the advantages of.
The conventional preparation techniques of propofol are carried out with propylene using phenol or 2- isopropyl-phenols under high-temperature and high-pressure conditions
Alkylated reaction, one-step synthesis are obtained propofol crude product, in the patent documentations such as US4447657, US3367981, US3051762
It has been reported that synthesis technique maturation, raw material are cheap, but have the disadvantage that：Severe reaction conditions, reaction is very violent,
The reaction selectivity of propofol is relatively low, and the purity of crude product can only achieve 60-75%, and main impurity includes that 2,4- and 2,5- bis- is different
Propylphenol, 2,4,6- triisopropyl phenol and 1- isopropyl -2,4- diisopropyl benzenes, the structure of impurity is extremely similar, physics
It is less with chemical differences.
Propofol crude product refining is become into the high-purity propofol that purity is more than 99% for how, it is existing to grind in a large number
Study carefully, such as US5589598, US5175376, EP0511947, WO9610004, CN102731265 and CN100569720 patent documentation
The process for purification of middle report includes：Rectification method of purification, low temperature crystallization method of purification, column chromatography and esterification water solution.However, above-mentioned
There is the shortcomings of operating procedure is long, and separating effect is poor, process time is long, equipment requirements are high in process for purification, and be easy to lead
Cause oxidation impurities 3,3 ', 5,5 '-tetra isopropyl xenol and propofol-Isosorbide-5-Nitrae-benzoquinone it is exceeded, and oxidation impurities are big due to toxicity
It is the impurity of the core concern and control of medicinal propofol.
To reach the purpose for reducing dopant species and improving propofol purity, existing numerous studies are entered to conventional preparation techniques
Row is improved.Chinese patent application CN102603488 is disclosed with 2,6-DIPA as raw material, is reacted with sodium nitrite,
The preparation technology for obtaining propofol is hydrolyzed again.Chinese patent application CN104649867 is disclosed with paranitrophenol raw material, in acid
It is catalyzed lower and isopropanol or 2- halogenopropanes occurs Jing Friedel-Crafts reactions, then Jing acylations, reduction, diazotising, decomposition and hydrolysis
Obtain the preparation technology of propofol.There is the deficiency that raw material is difficult to obtain, production cost is expensive in this two preparation technologies.
Patent documentation WO2011161687 discloses one kind with P-hydroxybenzoic acid as raw material, with alkane under inorganic acid catalysiss
Base reagent reacting obtains 4- hydroxyl -3,5- diisopropyl benzoic acid, then again in high boiling solvent and catalyst sodium hydroxide
In the presence of, high temperature decarboxylation obtains the propofol of higher degree.Simple to operate, the low cost of the technique, energy industrialization production is pure
The higher propofol of degree, but condition is harsh during decarboxylize positioning base, needs highly basic pyroreaction long-time.
In view of existing propofol preparation method Shortcomings, there is provided a kind of simple to operate, sufficient raw, be suitable to produce
The preparation method of industry metaplasia production of high purity propofol is significant.
The content of the invention
To solve problems of the prior art, the present invention provides a kind of preparation method of high-purity propofol, has
Simple to operate, sufficient raw, it is suitable to the advantages of industrialization production, Impurity removal are simple, product purity is high.
In the present invention, high-purity refers to that purity is higher than 99.0%.
The present invention provides a kind of preparation method of high-purity propofol, comprises the steps：
Under the conditions of strong base catalyst, compound shown in logical formula (I) heats in a solvent generation decarboxylic reaction to S1, after acid adjustment
To the solution system containing propofol；
S2 the solution system containing propofol is extracted and alkali cleaning after, vacuum distillation obtains high-purity propofol；
Wherein, R is selected from
The syntheti c route figure of the present invention is as shown in figure 1, this syntheti c route impurity that may be present and removing method are as follows：
Preferably, the R of compound is shown in the logical formula (I)That is 4- hydroxyls -3,5- diisopropyls benzoic acid isopropyl
Alcohol ester, react under acid catalyst and/or dehydrant effect by P-hydroxybenzoic acid and isopropanol and is obtained, reaction temperature for 40～
90℃.It is highly preferred that reaction temperature is 60～80 DEG C.The syntheti c route of 4- hydroxyl -3,5- diisopropyl benzoic acid isopropanol esters
Figure is as shown in Fig. 2 this syntheti c route impurity that may be present and removing method are as follows：
Preferably, the R of compound is shown in the logical formula (I)That is the tertiary fourth of 4- hydroxyls -3,5- diisopropyl benzoic acid
Alcohol ester, is occurred after esterification generation ester, in acid catalyst effect by P-hydroxybenzoic acid and the tert-butyl alcohol under dehydrant effect
Under, obtaining with isopropanol reaction, reaction temperature is 40～100 DEG C.It is highly preferred that reaction temperature is 60～80 DEG C.4- hydroxyl -3,
The syntheti c route figure of 5- diisopropyl benzoic acid tert-butyl alcohol esters is as shown in figure 3, this syntheti c route impurity that may be present and removing
Method is as follows：
Preferably, the heating-up temperature is 40～100 DEG C, and the time is 4～10h；It is highly preferred that heating-up temperature is 60～80
DEG C, the time is 5～7h.
Preferably, the solvent selected from methanol, ethanol, isopropanol, the tert-butyl alcohol, water, acetone, ethylene glycol and dimethyl formyl
One or more in amine；It is highly preferred that solvent is isopropanol water solution or tertiary butanol aqueous solution.
Preferably, the highly basic is selected from Lithium hydrate, sodium hydroxide, potassium hydroxide, rubidium hydroxide, Cesium hydrate., hydrogen-oxygen
Change calcium, Strontium hydrate. or barium hydroxide；It is highly preferred that highly basic is sodium hydroxide or potassium hydroxide.
Preferably, the dehydrant is selected from thionyl chloride, chloroacetic chloride, phosphorus oxychloride, oxalyl chloride, tribromo oxygen phosphorus, two hexamethylenes
Base carbodiimide or 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides.
Preferably, the acid catalyst is selected from toluenesulfonic acid, xylene monosulfonic acid, benzenesulfonic acid, sulphuric acid, hydrochloric acid, phosphoric acid or nitre
Acid.
Preferably, the extractant is selected from toluene or ethyl acetate.
Preferably, the alkali of the alkali cleaning is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or bicarbonate
Potassium.
Compared with prior art, beneficial effects of the present invention include：
(1) the inventive method is with P-hydroxybenzoic acid as initiation material, by generating 4- hydroxyl -3,5- diisopropyl benzene first
Then sour isopropyl alcohol ester or 4- hydroxyl -3,5- diisopropyls benzoic acid tert-butyl alcohol ester reacts again generation propofol as intermediate,
Easily, reaction condition is gentle, and the response time is short decarboxylic reaction, it is to avoid high-temperature high-voltage reaction, simple to operate, to producers and
The requirement of production equipment is low.
(2) impurity in products species is few obtained in the inventive method, and product quality is high, and purity is higher than 99.0%, can meet original
The requirement of material medicine.
(3) extensively, with low cost, stable performance meets industrial production demand to the raw material sources of the inventive method.
(4) the inventive method is as follows compared with patent documentation WO2011161687 synthesis techniques, the reaction of the inventive method
Condition is less demanding, and decarboxylic reaction is easier, and reduces reaction temperature, and Impurity removal method is simpler, the product for obtaining
Performance is good, reduces production cost.
Description of the drawings
The syntheti c route figure of Fig. 1 the inventive method.
The syntheti c route figure of Fig. 2 4- hydroxyl -3,5- diisopropyl benzoic acid isopropanol esters.
The syntheti c route figure of Fig. 3 4- hydroxyl -3,5- diisopropyl benzoic acid tert-butyl alcohol esters.
The HPLC figures of the gained propofol of Fig. 4 embodiments 3.
The HPLC figures of the gained propofol of Fig. 5 embodiments 4.
The HPLC figures of the gained propofol of Fig. 6 embodiments 5.
Specific embodiment
For the understanding of those skilled in the art, combine accompanying drawing below by way of specific embodiment and the present invention is done further in detail
Thin description.
The preparation of the 4- hydroxyl -3,5- diisopropyl benzoic acid isopropanol esters of embodiment 1
276.2g P-hydroxybenzoic acid (2.0mol) is dissolved in 1.1L isopropanols, is stirred, add 1mL thionyl chlorides
Afterwards, then it is slowly added dropwise into 300mL sulphuric acid, heats to 72 DEG C of reaction 5h, system activated carbon process is filtered, filtrate subtracts
Pressure concentration；Then dissolved with 700mL toluene, organic layer is washed with 300mL × 4 time 5% (w/v) sodium hydrate aqueous solution, then
300mL × 3 time water washing is to neutrality；After drying, concentrating under reduced pressure uses diisopropyl ether recrystallization, after vacuum drying, obtain 397.6g
4- hydroxyl -3,5- diisopropyl benzoic acid isopropanol esters.In terms of P-hydroxybenzoic acid, molar yield：75.2%, purity：
99.66% (HPLC).The yield of 4- hydroxyl -3,5- diisopropyl benzoic acid isopropanol esters and purity are high.
The preparation of the 4- hydroxyl -3,5- diisopropyl benzoic acid tert-butyl alcohol esters of embodiment 2
A) 276.2g P-hydroxybenzoic acid (2.0mol) is dissolved in the 830mL tert-butyl alcohols, is stirred at room temperature, be added dropwise to 3mL
Oxalyl chloride heats to 65 DEG C of reaction 5h, by system concentrating under reduced pressure as dehydrant；Then dissolved with 600mL ethyl acetate,
Organic layer is washed with 300mL × 3 time 5% (w/v) sodium bicarbonate aqueous solution, and 300mL × 3 time water washing is to neutrality；After drying, subtract
Pressure concentration, obtains P-hydroxybenzoic acid tert-butyl alcohol ester；
B) the P-hydroxybenzoic acid tert-butyl alcohol ester for obtaining is dissolved in 800mL isopropanols, stir, be slowly added dropwise into
300mL phosphoric acid, heats to 72 DEG C of reaction 5h, and system activated carbon process is filtered, filtrate reduced in volume；Then use
700mL xylene solubles, organic layer is washed with the sodium hydrate aqueous solution of 300mL × 4 time 5%, and 300mL × 3 time water washing is into
Property；After drying, concentrating under reduced pressure is done, then uses diisopropyl ether recrystallization, after vacuum drying, obtains 417.0g 4- hydroxyl -3,5- diisopropyls
Yl benzoic acid tert-butyl alcohol ester.In terms of P-hydroxybenzoic acid, molar yield：74.9%, purity:99.58% (HPLC).4- hydroxyls-
The yield of 3,5- diisopropyl benzoic acid tert-butyl alcohol esters and purity are high.
The preparation of the propofol of embodiment 3
Under nitrogen protection, by 344.0g 4- hydroxyl -3 obtained in embodiment 1,5- diisopropyl benzoic acid isopropanol esters
(1.3mol), 150mL isopropanols and 350mL water are added in there-necked flask, and stirring, room temperature adds 120g sodium hydroxide (3.0mol),
70 DEG C of reaction 7h are heated to, room temperature is cooled to, 1.0L water is added, add salt acid for adjusting pH value to 1.5, stirring will contain third
Solution system 500mL × 3 time toluene the extraction of pool phenol, toluene layer 300mL × 2 time 5% (w/v) sodium bicarbonate water of merging
Solution is washed, and 300mL × 4 time water washing is to neutrality；After drying, concentrating under reduced pressure, then subtract under the high vacuum condition of 0.2mm Hg
Pressure distillation, obtains 219.9g colourless to pale yellow oily liquid propofol.With 4- hydroxyl -3,5- diisopropyl benzoic acid isopropanols
Ester meter, molar yield：94.9%, purity：99.43% (HPLC), chromatogram is as shown in Figure 4.
The preparation of the propofol of embodiment 4
Under nitrogen protection, by 390.0g 4- hydroxyl -3 obtained in embodiment 2,5- diisopropyl benzoic acid tert-butyl alcohol esters
(1.4mol) add in there-necked flask with 600mL 20% (v/v) tertiary butanol aqueous solution, stirring, room temperature adds 128g sodium hydroxide
(3.2mol) 60 DEG C of reaction 5h, are heated to, room temperature is cooled to, add sulfur acid for adjusting pH value to 1.5, stirred；The third pool will be contained
Solution system 600mL × 3 time ethyl acetate the extraction of phenol, organic layer 300mL × 2 time 5% (w/v) sodium carbonate of merging
Solution is washed, and 350mL × 4 time water washing is to neutrality；After drying, concentrating under reduced pressure, then subtract under the high vacuum condition of 0.2mm Hg
Pressure distillation, obtains 234.6g colourless to pale yellow oily liquid propofol.With the 4- hydroxyl -3,5- diisopropyl benzoic acid tert-butyl alcohols
Ester meter, molar yield：94.0%, purity：99.55% (HPLC), chromatogram is as shown in Figure 5.
The preparation of the propofol of embodiment 5
Under nitrogen protection, by 97.5g 4- hydroxyl -3 obtained in embodiment 2,5- diisopropyl benzoic acid tert-butyl alcohol esters
(0.35mol) add in there-necked flask with 300mL water, stirring, room temperature adds 50.5g potassium hydroxide (0.9mol), is heated to
62 DEG C of reaction 4.5h, are cooled to room temperature, add salt acid for adjusting pH value to 1.5, stir；Solution system containing propofol is used
200mL × 3 time ethyl acetate extraction, the organic layer of merging is washed with 100mL × 2 time 5% (w/v) aqueous sodium carbonate, 100mL
× 4 water washings are to neutrality；After drying, concentrating under reduced pressure, then the vacuum distillation under the high vacuum condition of 0.2mm Hg, obtain
53.5g is colourless to pale yellow oily liquid propofol.With 4- hydroxyl -3,5- diisopropyl benzoic acid tert-butyl alcohol ester meters, mole receipts
Rate：91.2%, purity：99.03% (HPLC), chromatogram is as shown in Figure 6.
In sum, it is simple that the high income of intermediate obtained in the inventive method and product, purity are high, impurity removes method
It is single.It is with RWhen compare, R isWhen middle production procedure it is although more complicated, but decarboxylation (propofol preparation)
Time it is shorter, temperature is lower, and decarboxylation is easier to make for.
Above content is to combine specific preferred implementation further description made for the present invention, it is impossible to assert
The present invention be embodied as be confined to these explanations.For general technical staff of the technical field of the invention,
On the premise of without departing from present inventive concept, some simple deduction or replace can also be made, should all be considered as belonging to the present invention's
Protection domain.
Claims (10)
1. a kind of preparation method of high-purity propofol, it is characterised in that：Comprise the steps：
Under the conditions of strong base catalyst, compound shown in logical formula (I) heats in a solvent generation decarboxylic reaction to S1, is contained after acid adjustment
The solution system of propofol；
S2 the solution system containing propofol is extracted and alkali cleaning after, vacuum distillation obtains high-purity propofol；
Wherein, R is selected from
2. the preparation method of high-purity propofol according to claim 1, it is characterised in that：Logical formula (I) shownization
The R of compound isReacted under acid catalyst and/or dehydrant effect with isopropanol by P-hydroxybenzoic acid and obtained.
3. the preparation method of high-purity propofol according to claim 1, it is characterised in that：Logical formula (I) shownization
The R of compound isOccurred under dehydrant effect after esterification generation ester, in acid by P-hydroxybenzoic acid and the tert-butyl alcohol
Under catalyst action, obtain with isopropanol reaction.
4. the preparation method of high-purity propofol according to any one of claim 1 to 3, it is characterised in that：It is described to add
Hot temperature is 40～100 DEG C, and the time is 4～10h；It is preferred that heating-up temperature is 60～80 DEG C, the time is 5～7h.
5. the preparation method of high-purity propofol according to any one of claim 1 to 3, it is characterised in that：It is described molten
Agent is selected from one or more in methanol, ethanol, isopropanol, the tert-butyl alcohol, water, acetone, ethylene glycol and dimethylformamide；It is preferred that
Solvent is isopropanol water solution or tertiary butanol aqueous solution.
6. the preparation method of high-purity propofol according to any one of claim 1 to 3, it is characterised in that：It is described strong
Alkali is selected from Lithium hydrate, sodium hydroxide, potassium hydroxide, rubidium hydroxide, Cesium hydrate., calcium hydroxide, Strontium hydrate. or hydroxide
Barium；It is preferred that highly basic is sodium hydroxide or potassium hydroxide.
7. the preparation method of high-purity propofol according to any one of claim 1 to 3, it is characterised in that：It is described de-
Water preparation is selected from thionyl chloride, chloroacetic chloride, phosphorus oxychloride, oxalyl chloride, tribromo oxygen phosphorus, dicyclohexylcarbodiimide or 1- (3- diformazans
Aminopropyl) -3- ethyl-carbodiimide hydrochlorides.
8. the preparation method of high-purity propofol according to any one of claim 1 to 3, it is characterised in that：The acid
Catalyst is selected from toluenesulfonic acid, xylene monosulfonic acid, benzenesulfonic acid, sulphuric acid, hydrochloric acid, phosphoric acid or nitric acid.
9. the preparation method of high-purity propofol according to any one of claim 1 to 3, it is characterised in that：The extraction
Solvent is taken selected from toluene or ethyl acetate.
10. the preparation method of high-purity propofol according to any one of claim 1 to 3, it is characterised in that：The alkali
The alkali washed is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108530269A (en) * | 2018-04-11 | 2018-09-14 | 南安市创培电子科技有限公司 | A kind of production method of high-purity propofol |
| US11767281B2 (en) | 2020-02-06 | 2023-09-26 | Nandkumar Kashinath Chodankar | Manufacturing and purification technology for high purity Propofol |
Citations (2)
| 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 |
-
2016
- 2016-11-05 CN CN201610966517.5A patent/CN106565424B/en active Active
Patent Citations (3)
| 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 |
| US20130072573A1 (en) * | 2010-06-23 | 2013-03-21 | Harman Finochem Limited | Process for preparing extra pure 2, 6-diisopropyl phenol |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108530269A (en) * | 2018-04-11 | 2018-09-14 | 南安市创培电子科技有限公司 | A kind of production method of high-purity propofol |
| US11767281B2 (en) | 2020-02-06 | 2023-09-26 | Nandkumar Kashinath Chodankar | Manufacturing and purification technology for high purity Propofol |
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Inventor after: Yue Feng Inventor after: Zeng Shaoqun Inventor after: Chen Sanmei Inventor after: Li Qing Inventor after: Xu Lifeng Inventor before: Xu Lifeng Inventor before: Zeng Shaoqun Inventor before: Chen Sanmei Inventor before: Li Qing Inventor before: Yue Feng |
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Denomination of invention: A method for preparing high-purity propofol Effective date of registration: 20231130 Granted publication date: 20200519 Pledgee: Industrial and Commercial Bank of China Co.,Ltd. Qingyuan Economic Development Zone Sub branch Pledgor: GUANGDONG JIABO PHARMACEUTICAL Co.,Ltd. Registration number: Y2023980068637 |