CN103288618A - Synthesis method of thymoquinone serving as blood vessel inhibition medicament - Google Patents
Synthesis method of thymoquinone serving as blood vessel inhibition medicament Download PDFInfo
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- KEQHJBNSCLWCAE-UHFFFAOYSA-N thymoquinone Chemical compound CC(C)C1=CC(=O)C(C)=CC1=O KEQHJBNSCLWCAE-UHFFFAOYSA-N 0.000 title claims abstract description 39
- 239000003814 drug Substances 0.000 title abstract description 3
- 238000001308 synthesis method Methods 0.000 title abstract 5
- 210000004204 blood vessel Anatomy 0.000 title abstract 2
- 230000005764 inhibitory process Effects 0.000 title abstract 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 78
- MGSRCZKZVOBKFT-UHFFFAOYSA-N thymol Chemical compound CC(C)C1=CC=C(C)C=C1O MGSRCZKZVOBKFT-UHFFFAOYSA-N 0.000 claims abstract description 51
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims abstract description 46
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 27
- 229960000790 thymol Drugs 0.000 claims abstract description 26
- 238000004821 distillation Methods 0.000 claims abstract description 24
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 claims abstract description 20
- 238000002425 crystallisation Methods 0.000 claims abstract description 14
- 230000008025 crystallization Effects 0.000 claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 13
- KRVSOGSZCMJSLX-UHFFFAOYSA-L chromic acid Substances O[Cr](O)(=O)=O KRVSOGSZCMJSLX-UHFFFAOYSA-L 0.000 claims abstract description 13
- AWJWCTOOIBYHON-UHFFFAOYSA-N furo[3,4-b]pyrazine-5,7-dione Chemical compound C1=CN=C2C(=O)OC(=O)C2=N1 AWJWCTOOIBYHON-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000001816 cooling Methods 0.000 claims abstract description 8
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 5
- 239000002994 raw material Substances 0.000 claims abstract description 4
- 238000005406 washing Methods 0.000 claims abstract description 4
- 238000001914 filtration Methods 0.000 claims abstract description 3
- 239000002904 solvent Substances 0.000 claims abstract description 3
- 239000000047 product Substances 0.000 claims description 36
- 239000005844 Thymol Substances 0.000 claims description 25
- 239000008367 deionised water Substances 0.000 claims description 25
- 229910021641 deionized water Inorganic materials 0.000 claims description 25
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 20
- 238000009413 insulation Methods 0.000 claims description 15
- 239000010410 layer Substances 0.000 claims description 15
- DGQOCLATAPFASR-UHFFFAOYSA-N tetrahydroxy-1,4-benzoquinone Chemical compound OC1=C(O)C(=O)C(O)=C(O)C1=O DGQOCLATAPFASR-UHFFFAOYSA-N 0.000 claims description 13
- 238000010189 synthetic method Methods 0.000 claims description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 11
- 238000013019 agitation Methods 0.000 claims description 10
- 238000012423 maintenance Methods 0.000 claims description 10
- 239000012044 organic layer Substances 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 10
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 10
- 235000017550 sodium carbonate Nutrition 0.000 claims description 10
- 239000003112 inhibitor Substances 0.000 claims description 8
- 238000006277 sulfonation reaction Methods 0.000 claims description 7
- 239000000919 ceramic Substances 0.000 claims description 6
- 239000000843 powder Substances 0.000 claims description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 6
- 235000011152 sodium sulphate Nutrition 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- 238000005292 vacuum distillation Methods 0.000 claims description 6
- 210000003298 dental enamel Anatomy 0.000 claims description 5
- 239000012065 filter cake Substances 0.000 claims description 5
- 230000003647 oxidation Effects 0.000 claims description 5
- 238000007254 oxidation reaction Methods 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- 238000000967 suction filtration Methods 0.000 claims description 5
- 238000010792 warming Methods 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 2
- 238000004140 cleaning Methods 0.000 claims description 2
- 238000001723 curing Methods 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 abstract 1
- 239000007800 oxidant agent Substances 0.000 abstract 1
- 230000001590 oxidative effect Effects 0.000 abstract 1
- 230000008023 solidification Effects 0.000 abstract 1
- 238000007711 solidification Methods 0.000 abstract 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 3
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 2
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 2
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 2
- 208000021045 exocrine pancreatic carcinoma Diseases 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 201000002528 pancreatic cancer Diseases 0.000 description 2
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 210000001956 EPC Anatomy 0.000 description 1
- 102100031573 Hematopoietic progenitor cell antigen CD34 Human genes 0.000 description 1
- 101000777663 Homo sapiens Hematopoietic progenitor cell antigen CD34 Proteins 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 201000001531 bladder carcinoma Diseases 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 201000010989 colorectal carcinoma Diseases 0.000 description 1
- 238000010026 decatizing Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 238000004886 process control Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 208000010570 urinary bladder carcinoma Diseases 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a synthesis method of thymoquinone serving as a blood vessel inhibition medicament. According to the method, the thymoquinone (2-isopropyl-5-methyl-1,4-benzoquinone) is obtained by performing alkaline washing, water washing, filtration, crystallization, distillation, cooling and solidification on thyme camphor serving as a start raw material, chlorosulfonic acid serving as a sulfonating agent, a chromic acid solution as an oxidant and dichloromethane and chloroform which serve as solvents by a sulfonating-oxidizing reaction synthesis line. According to the synthesis method, raw materials are readily available; the reaction conditions are mild; the synthesis method is safely and easily operated; the conversion rate is high; the quality of products is stable; and the synthesis method is clean and environmentally-friendly.
Description
Technical field
The present invention relates to the synthetic method of bulk drug, be specifically related to the synthetic method of a kind of vaso inhibitor thing thymoquinone (2-sec.-propyl-5-methyl isophthalic acid, 4-benzo quinone).
Background technology
Thymoquinone (2-sec.-propyl-5-methyl isophthalic acid, 4-benzo quinone) can significantly suppress external EPCs tubule forms, and suppress the expression of VEGF in the external carcinoma of the pancreas PANC-1 cell, significantly suppress pancreatic neoplasm growth in the tumor bearing nude mice, and downward modulation Ki-67, CD34 and the VEGF positive expression in pancreatic tumor tissue, can be used as the vaso inhibitor thing for the treatment of carcinoma of the pancreas, and can significantly suppress growth of colorectal carcinoma and transfer, suppress external transitional cell bladder carcinoma cell line production, and cell death inducing.
Summary of the invention
The objective of the invention is to: a kind of synthetic method of vaso inhibitor thing thymoquinone is provided, and raw and auxiliary material is easy to get, reaction conditions gentleness, simple and safe operation, transformation efficiency height, constant product quality, clean environment firendly, stable quality and the yield that guarantees product.
Technical solution of the present invention is: be starting raw material with the thymol, chlorsulfonic acid is sulphonating agent, and chromic acid solution is oxygenant, and methylene dichloride, chloroform are solvent, adopts sulfonation-oxidizing reaction synthetic route, the process alkali cleaning,
Washing, filtration, crystallization, distillation, cooling, curing get thymoquinone (2-sec.-propyl-5-methyl isophthalic acid, 4-benzo quinone).
Wherein, described thymol synthetic route is as follows:
Wherein, the mol ratio of sulphonating agent chlorsulfonic acid and thymol is 1～1.05:1; Oxygenant Na
2Cr
20
72H
20 with the mol ratio of sulfonated bodies be 1:2.2～2.4.
Wherein, the concrete steps of this synthetic method are as follows:
(1) chlorsulfonic acid chloroformic solution preparation: chlorsulfonic acid 31.0～32.6g is dissolved in the 30ml chloroform, stirred 20 minutes, face with before being chilled to below 20 ℃;
(2) sulfonation: in the 200ml chloroform, drop into the 40g thymol, stirring is cooled to 20～25 ℃, add anhydrous sodium sulphate 0.5g again after, slowly drip the chlorsulfonic acid chloroformic solution, dropping temperature control is at 20～25 ℃, dripped off in 2～3 hours, and dripped off the back in 25～30 ℃ of insulations 30 minutes, add deionized water 40ml, in 25～30 ℃ of Dropwise 5 % soda ash solution 10ml, stirred 20 minutes, and left standstill branch vibration layer 15 minutes;
(3) crystallization: add the deionized water 20ml distillation that heats up, drip deionized water simultaneously in system, it is close with the speed that fraction distillates to add the speed of water, the constancy of volume of maintenance system, and chloroform is constantly steamed, and product constantly folds and is scattered in the water; After chloroform steams fully, be cooled to below 25 ℃, suction filtration, filter cake water with cold water below 25 ℃ and wash, and fully dry, and get the wet product thymol sulfonated products 58.3～58.6g (giving money as a gift) of faint yellow solid;
(4) chromic acid solution preparation: with 20～22.5gNa
2Cr
20
72H
20 is dissolved in the 100ml water, under agitation, slowly adds mass concentration 97% vitriol oil 25ml, and is diluted to 200ml, faces with before being chilled to 0 ℃;
(5) oxidation: above-mentioned wet product thymol sulfonated products 50g is dropped in the 200ml methylene dichloride, be cooled to below 0 ℃ after the dissolving fully, the chromic acid solution that is chilled to 0 ℃ was under agitation splashed in the reaction flask in 10 minutes, stirred fast again 30 minutes after adding, left standstill 15 minutes, branch vibration layer, organic layer drips mass concentration 5% soda ash solution 20ml washed twice, distinguish water 50ml washed twice, branch vibration layer again;
(6) distillation, crystallization, oven dry: add deionized water 20ml intensification distillation again, simultaneously in system, drip deionized water, it is close to add the speed of water and speed that fraction distillates, the constancy of volume of maintenance system, after methylene dichloride is steamed fully, change vacuum distillation into, product in the system and water are all steamed, feed 35～40 ℃ of warm water in the prolong chuck, receiving bottle is incubated with 50～55 ℃ of hot water baths, and the later stage, distillation temperature control was at 85～90 ℃, be warming up to 60～65 ℃ of insulations 30 minutes after collecting end, add preheating and keep in 60～65 ℃ the separating funnel insulation and sufficient standing after, lower floor's organic layer branch is gone in the enamel tray cooling, solidify, dry 4 hours of negative pressure under room temperature-0.09MPa gets orange thymoquinone to brown ceramic powder (2-sec.-propyl-5-methyl isophthalic acid, 4-benzo quinone) 34.4～34.6g.
The present invention has the following advantages:
1, adds a spot of sodium sulfate in the sulfonation system, to increase the concentration of HSO4-, suppress the formation of sulfone.
2, add small amount of N a2CO3 and dispel sulfonation impurity effectively.
3, adopt water replenishing and distillation desolventizing method, pressure decatizing method of purification.
4, utilize product low melting point, water-fast characteristic, adopt the fusion partition method, cool off at last, solidify.
5, vacuum distillation, the prolong chuck leads to warm water, prevents the crystallization obstruction.
6, by changing reaction scheme or optimizing synthetic method; the synthesis and production process of industrialization is convenient in formation, and is easy and simple to handle, the process control precise and reliable; the yield height; cost is low, and starting material are easy to get, the reaction conditions gentleness; constant product quality; the three wastes are few, and contaminate environment is light, and are favourable to producer's labour protection.
7, the wet product thymol sulfonated products yield of faint yellow solid: 95.0～95.5%, purity HPLC:99.0～99.2%; Thymoquinone (2-sec.-propyl-5-methyl isophthalic acid, 4-benzo quinone) is orange to brown ceramic powder, mp:45～47 ℃, purity HPLC:98.5～99.0%, yield 96.5～97.0%.
Embodiment
Further specify technical solution of the present invention below in conjunction with specific embodiment, these embodiment can not be interpreted as it is restriction to technical solution.
Embodiment 1: according to the synthetic thymoquinone (2-sec.-propyl-5-methyl isophthalic acid, 4-benzo quinone) of following steps
(1) chlorsulfonic acid chloroformic solution preparation: chlorsulfonic acid 31g is dissolved in the 30ml chloroform, stirred 20 minutes, face with before being chilled to below 20 ℃;
(2) sulfonation: in the 200ml chloroform, drop into the 40g thymol, stirring is cooled to 20～22 ℃, add anhydrous sodium sulphate 0.5g again after, slowly drip the chlorsulfonic acid chloroformic solution, dropping temperature control is at 20～22 ℃, dripped off in 2 hours, and dripped off the back in 25～26 ℃ of insulations 30 minutes, add deionized water 40ml, in 25～26 ℃ of Dropwise 5 % soda ash solution 10ml, stirred 20 minutes, and left standstill branch vibration layer 15 minutes;
(3) crystallization: add the deionized water 20ml distillation that heats up, drip deionized water simultaneously in system, it is close with the speed that fraction distillates to add the speed of water, the constancy of volume of maintenance system, and chloroform is constantly steamed, and product constantly folds and is scattered in the water; After chloroform steams fully, be cooled to below 25 ℃, suction filtration, filter cake water with cold water below 25 ℃ and wash, and fully dry, and get the wet product thymol sulfonated products 58.3g (giving money as a gift) of faint yellow solid; Mp: purity (HPLC): 99.1%, yield: 95.0%
(4) chromic acid solution preparation: with 20gNa
2Cr
20
72H
20 is dissolved in the 100ml water, under agitation, slowly adds mass concentration 97% vitriol oil 25ml, and is diluted to 200ml, faces with before being chilled to 0 ℃;
(5) oxidation: above-mentioned wet product thymol sulfonated products 50g is dropped in the 200ml methylene dichloride, be cooled to below 0 ℃ after the dissolving fully, the chromic acid solution that is chilled to 0 ℃ was under agitation splashed in the reaction flask in 10 minutes, stirred fast again 30 minutes after adding, left standstill 15 minutes, branch vibration layer, organic layer drips mass concentration 5% soda ash solution 20ml washed twice, distinguish water 50ml washed twice, branch vibration layer again;
(6) distillation, crystallization, oven dry: add deionized water 20ml intensification distillation again, simultaneously in system, drip deionized water, it is close to add the speed of water and speed that fraction distillates, the constancy of volume of maintenance system, after methylene dichloride is steamed fully, change vacuum distillation into, product in the system and water are all steamed, feed 35～40 ℃ of warm water in the prolong chuck, receiving bottle is incubated with 50～55 ℃ of hot water baths, and the later stage, distillation temperature control was at 85～86 ℃, be warming up to 60～62 ℃ of insulations 30 minutes after collecting end, add preheating and keep in 60～65 ℃ the separating funnel insulation and sufficient standing after, lower floor's organic layer branch is gone in the enamel tray cooling, solidify, dry 4 hours of negative pressure under room temperature-0.09MPa gets orange thymoquinone to brown ceramic powder (2-sec.-propyl-5-methyl isophthalic acid, 4-benzo quinone) 34.4g.Mp:45.6～46.4 ℃, purity (HPLC): 98.7%, yield: 96.5%.
Embodiment 2: according to the synthetic thymoquinone (2-sec.-propyl-5-methyl isophthalic acid, 4-benzo quinone) of following steps
(1) chlorsulfonic acid chloroformic solution preparation: chlorsulfonic acid 31.8g is dissolved in the 30ml chloroform, stirred 20 minutes, face with before being chilled to below 20 ℃;
(2) sulfonation: in the 200ml chloroform, drop into the 40g thymol, stirring is cooled to 22～24 ℃, add anhydrous sodium sulphate 0.5g again after, slowly drip the chlorsulfonic acid chloroformic solution, dropping temperature control is at 22～24 ℃, 2.5 hour drip off, drip off the back in 27～28 ℃ of insulations 30 minutes, add deionized water 40ml, in 27～28 ℃ of Dropwise 5 % soda ash solution 10ml, stirred 20 minutes, and left standstill branch vibration layer 15 minutes;
(3) crystallization: add the deionized water 20ml distillation that heats up, drip deionized water simultaneously in system, it is close with the speed that fraction distillates to add the speed of water, the constancy of volume of maintenance system, and chloroform is constantly steamed, and product constantly folds and is scattered in the water; After chloroform steams fully, be cooled to below 25 ℃, suction filtration, filter cake water with cold water below 25 ℃ and wash, and fully dry, and get the wet product thymol sulfonated products 58.6g (giving money as a gift) of faint yellow solid, mp: purity (HPLC): 99.2%, and yield: 95.5%;
(4) chromic acid solution preparation: with 22.3gNa
2Cr
20
72H
20 is dissolved in the 100ml water, under agitation, slowly adds mass concentration 97% vitriol oil 25ml, and is diluted to 200ml, faces with before being chilled to 0 ℃;
(5) oxidation: above-mentioned wet product thymol sulfonated products 50g is dropped in the 200ml methylene dichloride, be cooled to below 0 ℃ after the dissolving fully, the chromic acid solution that is chilled to 0 ℃ was under agitation splashed in the reaction flask in 10 minutes, stirred fast again 30 minutes after adding, left standstill 15 minutes, branch vibration layer, organic layer drips mass concentration 5% soda ash solution 20ml washed twice, distinguish water 50ml washed twice, branch vibration layer again;
(6) distillation, crystallization, oven dry: add deionized water 20ml intensification distillation again, simultaneously in system, drip deionized water, it is close to add the speed of water and speed that fraction distillates, the constancy of volume of maintenance system, after methylene dichloride is steamed fully, change vacuum distillation into, product in the system and water are all steamed, feed 35～40 ℃ of warm water in the prolong chuck, receiving bottle is incubated with 50～55 ℃ of hot water baths, and the later stage, distillation temperature control was at 87～88 ℃, be warming up to 60～65 ℃ of insulations 30 minutes after collecting end, add preheating and keep in 60～65 ℃ the separating funnel insulation and sufficient standing after, lower floor's organic layer branch is gone in the enamel tray cooling, solidify, dry 4 hours of negative pressure under room temperature-0.09MPa gets orange thymoquinone to brown ceramic powder (2-sec.-propyl-5-methyl isophthalic acid, 4-benzo quinone) 34.5g.Mp:46.3～47.0 ℃, purity (HPLC): 99.0%, yield: 96.75%.
Embodiment 3: according to the synthetic thymoquinone (2-sec.-propyl-5-methyl isophthalic acid, 4-benzo quinone) of following steps
(1) chlorsulfonic acid chloroformic solution preparation: chlorsulfonic acid 32.6g is dissolved in the 30ml chloroform, stirred 20 minutes, face with before being chilled to below 20 ℃;
(2) sulfonation: in the 200ml chloroform, drop into the 40g thymol, stirring is cooled to 24～25 ℃, add anhydrous sodium sulphate 0.5g again after, slowly drip the chlorsulfonic acid chloroformic solution, dropping temperature control is at 24～25 ℃ ℃, dripped off in 3 hours, and dripped off the back in 28～30 ℃ of insulations 30 minutes, add deionized water 40ml, in 28～30 ℃ of Dropwise 5 % soda ash solution 10ml, stirred 20 minutes, and left standstill branch vibration layer 15 minutes;
(3) crystallization: add the deionized water 20ml distillation that heats up, drip deionized water simultaneously in system, it is close with the speed that fraction distillates to add the speed of water, the constancy of volume of maintenance system, and chloroform is constantly steamed, and product constantly folds and is scattered in the water; After chloroform steams fully, be cooled to below 25 ℃, suction filtration, filter cake water with cold water below 25 ℃ and wash, and fully dry, and get the wet product thymol sulfonated products 58.5g (giving money as a gift) of faint yellow solid; Mp: purity (HPLC): 99.0%, yield: 95.25%;
(4) chromic acid solution preparation: with 22.5gNa
2Cr
20
72H
20 is dissolved in the 100ml water, under agitation, slowly adds mass concentration 97% vitriol oil 25ml, and is diluted to 200ml, faces with before being chilled to 0 ℃;
(5) oxidation: above-mentioned wet product thymol sulfonated products 50g is dropped in the 200ml methylene dichloride, be cooled to below 0 ℃ after the dissolving fully, the chromic acid solution that is chilled to 0 ℃ was under agitation splashed in the reaction flask in 10 minutes, stirred fast again 30 minutes after adding, left standstill 15 minutes, branch vibration layer, organic layer drips mass concentration 5% soda ash solution 20ml washed twice, distinguish water 50ml washed twice, branch vibration layer again;
(6) distillation, crystallization, oven dry: add deionized water 20ml intensification distillation again, simultaneously in system, drip deionized water, it is close to add the speed of water and speed that fraction distillates, the constancy of volume of maintenance system, after methylene dichloride is steamed fully, change vacuum distillation into, product in the system and water are all steamed, feed 35～40 ℃ of warm water in the prolong chuck, receiving bottle is incubated with 50～55 ℃ of hot water baths, and the later stage, distillation temperature control was at 89～90 ℃, be warming up to 60～65 ℃ of insulations 30 minutes after collecting end, add preheating and keep in 60～65 ℃ the separating funnel insulation and sufficient standing after, lower floor's organic layer branch is gone in the enamel tray cooling, solidify, dry 4 hours of negative pressure under room temperature-0.09MPa gets orange thymoquinone to brown ceramic powder (2-sec.-propyl-5-methyl isophthalic acid, 4-benzo quinone) 34.6g.Mp:46.1～46.9 ℃, purity (HPLC): 98.9%, yield: 97.0%.
Claims (4)
1. the synthetic method of vaso inhibitor thing thymoquinone, it is characterized in that: this synthetic method is starting raw material with the thymol, chlorsulfonic acid is sulphonating agent, chromic acid solution is oxygenant, methylene dichloride, chloroform are solvent, adopt sulfonation-oxidizing reaction synthetic route, through alkali cleaning, washing, filtration, crystallization, distillation, cooling, curing, get thymoquinone (2-sec.-propyl-5-methyl isophthalic acid, 4-benzo quinone).
2. the synthetic method of vaso inhibitor thing thymol according to claim 1, it is characterized in that: described thymol synthetic route is as follows:
。
3. the synthetic method of vaso inhibitor thing thymol according to claim 1, it is characterized in that: the mol ratio of thymol and sulphonating agent chlorsulfonic acid is 1:1～1.05; Sulfonated bodies and oxygenant Na
2Cr
20
72H
20 mol ratio is 1:0.4～0.45.
4. the synthetic method of vaso inhibitor thing thymol according to claim 1 is characterized in that the concrete steps of this synthetic method are as follows:
(1) chlorsulfonic acid chloroformic solution preparation: chlorsulfonic acid 31.0～32.6g is dissolved in the 30ml chloroform, stirred 20 minutes, face with before being chilled to below 20 ℃;
(2) sulfonation: in the 200ml chloroform, drop into the 40g thymol, stirring is cooled to 20～25 ℃, add anhydrous sodium sulphate 0.5g again after, slowly drip the chlorsulfonic acid chloroformic solution, dropping temperature control is at 20～25 ℃, dripped off in 2～3 hours, and dripped off the back in 25～30 ℃ of insulations 30 minutes, add deionized water 40ml, in 25～30 ℃ of Dropwise 5 % soda ash solution 10ml, stirred 20 minutes, and left standstill branch vibration layer 15 minutes;
(3) crystallization: add the deionized water 20ml distillation that heats up, drip deionized water simultaneously in system, it is close with the speed that fraction distillates to add the speed of water, the constancy of volume of maintenance system, and chloroform is constantly steamed, and product constantly folds and is scattered in the water; After chloroform steams fully, be cooled to below 25 ℃, suction filtration, filter cake water with cold water below 25 ℃ and wash, and fully dry, and get the wet product thymol sulfonated products 58.3～58.6g (giving money as a gift) of faint yellow solid;
(4) chromic acid solution preparation: with 20～22.5gNa
2Cr
20
72H
20 is dissolved in the 100ml water, under agitation, slowly adds mass concentration 97% vitriol oil 25ml, and is diluted to 200ml, faces with before being chilled to 0 ℃;
(5) oxidation: above-mentioned wet product thymol sulfonated products 50g is dropped in the 200ml methylene dichloride, be cooled to below 0 ℃ after the dissolving fully, the chromic acid solution that is chilled to 0 ℃ was under agitation splashed in the reaction flask in 10 minutes, stirred fast again 30 minutes after adding, left standstill 15 minutes, branch vibration layer, organic layer drips mass concentration 5% soda ash solution 20ml washed twice, distinguish water 50ml washed twice, branch vibration layer again;
(6) distillation, crystallization, oven dry: add deionized water 20ml intensification distillation again, simultaneously in system, drip deionized water, it is close to add the speed of water and speed that fraction distillates, the constancy of volume of maintenance system, after methylene dichloride is steamed fully, change vacuum distillation into, product in the system and water are all steamed, feed 35～40 ℃ of warm water in the prolong chuck, receiving bottle is incubated with 50～55 ℃ of hot water baths, and the later stage, distillation temperature control was at 85～90 ℃, be warming up to 60～65 ℃ of insulations 30 minutes after collecting end, add preheating and keep in 60～65 ℃ the separating funnel insulation and sufficient standing after, lower floor's organic layer branch is gone in the enamel tray cooling, solidify, dry 4 hours of negative pressure under room temperature-0.09MPa gets orange thymoquinone to brown ceramic powder (2-sec.-propyl-5-methyl isophthalic acid, 4-benzo quinone) 34.4～34.6g.
Priority Applications (1)
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108084006A (en) * | 2017-10-30 | 2018-05-29 | 浙江新和成药业有限公司 | A kind of preparation method of trimethylbenzoquinone and trimethylhydroquinone |
| CN108938610A (en) * | 2018-09-21 | 2018-12-07 | 江苏大学附属医院 | For treating the pharmaceutical composition and its related preparations of oophoroma |
| CN110041222A (en) * | 2019-05-10 | 2019-07-23 | 江苏耐雀生物工程技术有限公司 | Thymoquinone derivative, intermediate, preparation method and applications |
| CN110759822A (en) * | 2018-07-27 | 2020-02-07 | 江苏恒正合生命科学有限公司 | Preparation method of thymoquinone |
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| CN102643185A (en) * | 2012-05-15 | 2012-08-22 | 山东大学 | Green and simple preparation method for 2,3,5-trimethylbenzoquinone (TMBQ) |
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| CN102643185A (en) * | 2012-05-15 | 2012-08-22 | 山东大学 | Green and simple preparation method for 2,3,5-trimethylbenzoquinone (TMBQ) |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108084006A (en) * | 2017-10-30 | 2018-05-29 | 浙江新和成药业有限公司 | A kind of preparation method of trimethylbenzoquinone and trimethylhydroquinone |
| CN108084006B (en) * | 2017-10-30 | 2020-12-29 | 浙江新和成药业有限公司 | Preparation method of trimethylbenzoquinone and trimethylhydroquinone |
| CN110759822A (en) * | 2018-07-27 | 2020-02-07 | 江苏恒正合生命科学有限公司 | Preparation method of thymoquinone |
| CN108938610A (en) * | 2018-09-21 | 2018-12-07 | 江苏大学附属医院 | For treating the pharmaceutical composition and its related preparations of oophoroma |
| CN108938610B (en) * | 2018-09-21 | 2019-05-31 | 江苏大学附属医院 | For treating the pharmaceutical composition and its related preparations of oophoroma |
| CN110041222A (en) * | 2019-05-10 | 2019-07-23 | 江苏耐雀生物工程技术有限公司 | Thymoquinone derivative, intermediate, preparation method and applications |
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