CN102321069B - Preparation method of 2-trifluoromethylthioxanthone - Google Patents
Preparation method of 2-trifluoromethylthioxanthone Download PDFInfo
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- CN102321069B CN102321069B CN 201110226718 CN201110226718A CN102321069B CN 102321069 B CN102321069 B CN 102321069B CN 201110226718 CN201110226718 CN 201110226718 CN 201110226718 A CN201110226718 A CN 201110226718A CN 102321069 B CN102321069 B CN 102321069B
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- trifluoromethylbenzene
- trifluoromethyl
- benzoic acid
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- NEWRXGDGZGIHIS-UHFFFAOYSA-N 2-(trifluoromethyl)thioxanthen-9-one Chemical compound C1=CC=C2C(=O)C3=CC(C(F)(F)F)=CC=C3SC2=C1 NEWRXGDGZGIHIS-UHFFFAOYSA-N 0.000 title claims abstract description 48
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 48
- NBOMNTLFRHMDEZ-UHFFFAOYSA-N thiosalicylic acid Chemical compound OC(=O)C1=CC=CC=C1S NBOMNTLFRHMDEZ-UHFFFAOYSA-N 0.000 claims abstract description 43
- 239000011230 binding agent Substances 0.000 claims abstract description 24
- 239000002253 acid Substances 0.000 claims abstract description 22
- 239000003960 organic solvent Substances 0.000 claims abstract description 16
- 238000006482 condensation reaction Methods 0.000 claims abstract description 11
- 239000002994 raw material Substances 0.000 claims abstract description 11
- 239000003054 catalyst Substances 0.000 claims abstract description 7
- 150000007522 mineralic acids Chemical class 0.000 claims abstract description 7
- 239000012429 reaction media Substances 0.000 claims abstract description 3
- -1 trifluoromethylbenzene methylthio benzoic acid Chemical compound 0.000 claims description 55
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 36
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- DVHRWZMPFYOREG-UHFFFAOYSA-N 1-methylsulfonyl-2-(trifluoromethyl)benzene Chemical compound CS(=O)(=O)C1=CC=CC=C1C(F)(F)F DVHRWZMPFYOREG-UHFFFAOYSA-N 0.000 claims description 23
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 19
- 239000003795 chemical substances by application Substances 0.000 claims description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- 239000012065 filter cake Substances 0.000 claims description 13
- 238000003756 stirring Methods 0.000 claims description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 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
- 238000006297 dehydration reaction Methods 0.000 claims description 8
- 238000007363 ring formation reaction Methods 0.000 claims description 8
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 7
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- 238000000967 suction filtration Methods 0.000 claims description 6
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical group [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 6
- 229920000137 polyphosphoric acid Polymers 0.000 claims description 5
- 239000012074 organic phase Substances 0.000 claims description 4
- 235000017550 sodium carbonate Nutrition 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 3
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 3
- 235000015320 potassium carbonate Nutrition 0.000 claims description 3
- 230000002194 synthesizing effect Effects 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 27
- 238000009833 condensation Methods 0.000 abstract description 4
- 230000005494 condensation Effects 0.000 abstract description 4
- JKBCENKBTQPCCH-UHFFFAOYSA-N 1-methylsulfonyl-4-(trifluoromethyl)benzene Chemical compound CS(=O)(=O)C1=CC=C(C(F)(F)F)C=C1 JKBCENKBTQPCCH-UHFFFAOYSA-N 0.000 abstract 2
- 238000006210 cyclodehydration reaction Methods 0.000 abstract 2
- 239000012024 dehydrating agents Substances 0.000 abstract 1
- 239000012467 final product Substances 0.000 abstract 1
- 239000000047 product Substances 0.000 description 8
- 238000009413 insulation Methods 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 230000018044 dehydration Effects 0.000 description 4
- 239000003814 drug Substances 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000010606 normalization Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 1
- CVBDQDVOPGEKFN-UHFFFAOYSA-N 1-chloro-2-nitro-4-(2,2,2-trifluoroethyl)benzene Chemical compound ClC1=C(C=C(CC(F)(F)F)C=C1)[N+](=O)[O-] CVBDQDVOPGEKFN-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- NJMYODHXAKYRHW-DVZOWYKESA-N cis-flupenthixol Chemical compound C1CN(CCO)CCN1CC\C=C\1C2=CC(C(F)(F)F)=CC=C2SC2=CC=CC=C2/1 NJMYODHXAKYRHW-DVZOWYKESA-N 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229960002419 flupentixol Drugs 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000001119 stannous chloride Substances 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention discloses a preparation method of 2-trifluoromethylthioxanthone. The method comprises the following steps: firstly, carrying out condensation reaction by taking o-mercaptobenzoic acid and p-mesyl benzotrifluoride as raw materials and an organic solvent as a reaction medium in the presence of an inorganic acid binding agent and a catalyst so as to generate 2-p-trifluoromethylthiophenylbenzoic acid; and then carrying out cyclodehydration on 2-p-trifluoromethylthiophenylbenzoic acid in the presence of a dehydrating agent to generate 2-trifluoromethylthioxanthone. According to the invention, 2-trifludromethylthioxanthone is obtained by condensation and cyclodehydration by taking o-mercaptobenzoic acid and p-mesyl benzotrifluoride as the raw materials, thus reaction route is simple and is easy to control, high-low temperature reaction is abolished, reaction conditions are mild and has low requirement on equipment, cost is low, post-treatment is simple, and the purity and yield of the prepared final product are high.
Description
Technical field
The present invention relates to a kind of preparation method of medicine, be specifically related to a kind of preparation method of 2-(Trifluoromethyl)thioxanthen-9-one, belong to the biological medicine technology field.
Background technology
The English name of 2-(Trifluoromethyl)thioxanthen-9-one is 2-(Trifluoromethyl) thioxanthen-9-one, has another name called 2-(Trifluoromethyl)thioxanthen-9-one, is the key intermediate of anti-psychotropic Flupenthixol Hydrochloride, and its structural formula is as follows:
Synthetic method about 2-(Trifluoromethyl)thioxanthen-9-one has relevant report, German Patent GB925539 obtains obtaining with Reduction with Stannous Chloride after then 4-chloro-3-nitro-trifluoromethyl toluene generates thioether with the o-mercaptobenzoic acid reaction through mixed acid nitrification with p-chloro benzo trifluoride-99, and then obtain through the Sodium Nitrite deaminizating, obtain behind the vitriol oil dehydration closed-loop.This route reaction route is long, yield is low, cost is high, and concrete reaction process is as follows:
Sun Hongli etc. " preparation of 2-(Trifluoromethyl)thioxanthen-9-one " (Chinese Journal of Pharmaceuticals, 2005,36(10), provide a kind of new synthetic method in 599-560).Generate 2-to the trifluoromethylbenzene methylthio benzoic acid with o-mercaptobenzoic acid and p-chloro benzo trifluoride-99 reaction, then being dehydrated into ring in the presence of the vitriol oil becomes 2-(Trifluoromethyl)thioxanthen-9-one.This route reaction is simple, but the reaction of the empirical tests the first step is relatively more difficult, can't obtain corresponding yield by its description.Concrete reaction process is as follows:
By foregoing description as can be known, there is the problem that yield is low or cost is high in the method for existing synthetic 2-(Trifluoromethyl)thioxanthen-9-one, is not suitable for industrialized production, and it is imperative to continue to explore new synthesis technique.
Summary of the invention
The present invention is directed to the deficiencies in the prior art, a kind of preparation method of 2-(Trifluoromethyl)thioxanthen-9-one is provided, the method reaction scheme is short, and is simple to operate.
The present invention take o-mercaptobenzoic acid with to the methylsulfonyl phenylfluoroform as raw material, can obtain 2-(Trifluoromethyl)thioxanthen-9-one through condensation and cyclization dehydration, reactions steps is simple, yield is higher, its concrete technical scheme is as follows:
A kind of preparation method of 2-(Trifluoromethyl)thioxanthen-9-one, it is characterized in that: at first, take o-mercaptobenzoic acid, to the methylsulfonyl phenylfluoroform as raw material, take organic solvent as reaction medium, in the presence of inorganic acid binding agent and catalyzer, carry out condensation reaction and generate 2-to the trifluoromethylbenzene methylthio benzoic acid; Then, 2-carries out cyclization dehydration reaction generation 2-(Trifluoromethyl)thioxanthen-9-one to the trifluoromethylbenzene methylthio benzoic acid in the presence of dewatering agent.
Further, before carrying out condensation reaction, first o-mercaptobenzoic acid is reacted in toluene with acid binding agent first, then toluene is removed, add again organic solvent and the methylsulfonyl phenylfluoroform is carried out condensation reaction.
Further, 2-to the concrete steps of the synthetic 2-(Trifluoromethyl)thioxanthen-9-one of trifluoromethylbenzene methylthio benzoic acid is: 2-is added in the dewatering agent the trifluoromethylbenzene methylthio benzoic acid carry out the cyclization dehydration reaction, after the reaction reaction solution is cooled to below 20 ℃, then join in the frozen water of mass ratio 1:1, suction filtration is got filter cake after icing completeization; Add successively entry and methylene dichloride in filter cake, then reconciling pH is 9-9.5, stirs standing demix; Separatory is got organic phase after the layering, and is organic phase is dry, boil off solvent and get 2-(Trifluoromethyl)thioxanthen-9-one; Wherein, frozen water quality (g) is 7-8:1 with the ratio of dewatering agent volume (ml), and the mass ratio of water and filter cake is 3-4:1, and methylene chloride volume (ml) is 4-6:1 with the ratio of filter cake quality (g).
In the aforesaid method, described inorganic acid binding agent is sodium hydroxide, potassium hydroxide, yellow soda ash or salt of wormwood, preferred sodium hydroxide.
In the aforesaid method, described organic solvent is acetonitrile, DMF or N,N-dimethylacetamide, preferred DMF.Organic solvent provides reaction environment, and its consumption can be regulated as required without particular requirement.
In the aforesaid method, described catalyzer is Tetrabutyl amonium bromide, tetrabutylammonium chloride, polyoxyethylene glycol, 15-hat-5-ether, 18-hat-6-ether, preferred Tetrabutyl amonium bromide.
In the aforesaid method, dewatering agent is the vitriol oil, oleum or polyphosphoric acid, the vitriol oil of preferred 80-98wt%.
In the aforesaid method; when synthesizing 2-to the trifluoromethylbenzene methylthio benzoic acid; o-mercaptobenzoic acid be 1:0.8-2.9 to the mol ratio of methylsulfonyl phenylfluoroform; o-mercaptobenzoic acid and catalyst molar ratio are 1:0.05-1.0; o-mercaptobenzoic acid and acid binding agent mol ratio are 1:0.9-5.0; setting-up point is 20-30 ℃, and the time is 3-5h.
Preferably, o-mercaptobenzoic acid with the mol ratio of methylsulfonyl phenylfluoroform is 1:0.98-1.20, preferred, o-mercaptobenzoic acid is 1:1.1-1.15 with mol ratio to the methylsulfonyl phenylfluoroform.
During synthetic 2-(Trifluoromethyl)thioxanthen-9-one, every gram 2-uses the 1-13ml dewatering agent to the trifluoromethylbenzene methylthio benzoic acid, and temperature of reaction is 30-100 ℃, and the reaction times is 3-5h.Preferably, every gram 2-uses the 3-5ml dewatering agent to the trifluoromethylbenzene methylthio benzoic acid, and temperature of reaction is 50-70 ℃.
Reaction equation of the present invention is as follows:
The present invention to the synthetic 2-take o-mercaptobenzoic acid and p-chloro benzo trifluoride-99 as raw material of the propositions such as Sun Hongli to the trifluoromethylbenzene methylthio benzoic acid; then the method for making 2-(Trifluoromethyl)thioxanthen-9-one with vitriol oil dehydration condensation is improved; adjusted the raw material of reaction; adopt o-mercaptobenzoic acid and be raw material to the methylsulfonyl phenylfluoroform; in reaction process, also added catalyzer; at acid binding agent and organic solvent; catalyzer exists and to carry out condensation reaction and obtain 2-to the trifluoromethylbenzene methylthio benzoic acid down, and then adds dewatering agent in to the trifluoromethylbenzene methylthio benzoic acid at 2-and carry out cyclization and dewater and obtain 2-(Trifluoromethyl)thioxanthen-9-one.Adopt that Innovative method products obtained therefrom yield of the present invention is higher, reaction conditions is gentle.
Further; the present invention is when carrying out condensation reaction; first o-mercaptobenzoic acid and acid binding agent are reacted in toluene; then removing toluene adds organic solvent, catalyzer again and the methylsulfonyl phenylfluoroform is carried out condensation reaction; this operation has improved the gained intermediate product greatly---and 2-is improved the output of the finished product and purity to the content of trifluoromethylbenzene methylthio benzoic acid.
Synthetic 2-to trifluoromethylbenzene methylthio benzoic acid reaction process in, used acid binding agent is alkaline matter, mainly is that the control reaction process is under the alkaline condition always, avoids in the reaction process the carrying out of the reaction that exerts an influence of acid.When selecting, can select inorganic acid binding agent commonly used, such as sodium hydroxide, potassium hydroxide, yellow soda ash or salt of wormwood etc.The effect of organic solvent provides the medium that is fit to raw material reaction, and raw material is fully mixed, and its consumption also has no special requirements, and can regulate voluntarily in actually operating, and organic solvent selects not interfere the organic solvent of whole reaction process.Used catalyzer increases speed of response, promotes reaction to carry out along forward, improves productive rate.The present invention has optimized through great many of experiments and has been fit to organic solvent of the present invention, acid binding agent and catalyzer, adopts preferred component can improve product purity and productive rate.
When synthetic 2-(Trifluoromethyl)thioxanthen-9-one, thereby needing to add dewatering agent makes 2-slough the cyclization of a water molecules self to trifluoromethylbenzene methylthio benzoic acid molecule, the dewatering agent that the present invention selects is the strong acid with water separation capability, for example the vitriol oil, oleum or polyphosphoric acid.
Reaction conditions of the present invention is gentle, and yield is high, and cost is low, and aftertreatment is simple, is easy to suitability for industrialized production, and its preferred steps comprises:
1, synthetic 2-is to the trifluoromethylbenzene methylthio benzoic acid
With o-mercaptobenzoic acid elder generation and acid binding agent reaction in toluene, then solvent evaporated adds organic solvent and catalyzer again, and 30-35 ℃ of dropping contains methylsulfonyl phenylfluoroform solution, then at room temperature reaction.Solvent evaporated after the reaction with the solids water dissolution, is reconciled pH to 3-3.5, has a large amount of solids to separate out, and solid drying is got 2-to the trifluoromethylbenzene methylthio benzoic acid;
2, synthetic 2-(Trifluoromethyl)thioxanthen-9-one
2-is added in the dewatering agent the trifluoromethylbenzene methylthio benzoic acid, 30-100 ℃ of insulation reaction, after the reaction reaction solution is cooled to below 20 ℃, then (frozen water quality (g): dewatering agent volume (ml)=7-8:1) in the frozen water of adding mass ratio 1:1 under stirring, suction filtration is got filter cake after icing completeization, it is 3-4 water doubly that wet cake is put into mass ratio, add again methylene dichloride (methylene chloride volume (ml): wet cake (g)=4-6:1), conciliation pH is 9-9.5, separatory is left standstill in stirring, get organic layer, organic layer is dry, desolventizing gets 2-(Trifluoromethyl)thioxanthen-9-one.
The present invention take o-mercaptobenzoic acid with to the methylsulfonyl phenylfluoroform as raw material, obtain 2-(Trifluoromethyl)thioxanthen-9-one through condensation, cyclization dehydration.High low-temp reaction has been got rid of in simple, the easily control of reaction scheme, and reaction conditions is gentle, and low for equipment requirements, cost is low, and aftertreatment is simple, and the finished product purity and the yield that make are higher.
Embodiment
Further explain the present invention below by specific embodiment, so that the professional and technical personnel more fully understands the present invention, but do not limit the present invention in any way.
The used o-mercaptobenzoic acid of the present invention, be the commercially available prod to the methylsulfonyl phenylfluoroform, content is greater than 95%(HPLC peak area normalization method).Other also all can have been bought in market such as catalyzer, acid binding agent, solvent and dewatering agent.
Embodiment 1
The present invention preferably reacts in acid binding agent o-mercaptobenzoic acid first when carrying out condensation reaction in the presence of toluene, otherwise 2-can be very low to trifluoromethylbenzene methylthio benzoic acid productive rate, about 60%, the below is prepared 2-to the method for trifluoromethylbenzene methylthio benzoic acid according to optimal way:
O-mercaptobenzoic acid (154.19g; 1.0mol) join in the 2L there-necked flask; add toluene (1200ml); then add sodium hydroxide (82.0g; 2.04mol) the lower reflux water-dividing 1h of stirring; then evaporate to dryness toluene; add DMF(820ml after being down to room temperature); add tetrabutylammonium chloride (23.07g0.083mol); stir 30min; then contain methylsulfonyl phenylfluoroform (246.62, DMF(600ml 1.10mol)) solution 30-35 ℃ of dropping, dropwise and at room temperature stir 3h.80 ℃ of solvent evaporated, add entry (2300ml) and transfer pH=3.0-3.5 to separate out a large amount of solids with concentrated hydrochloric acid, get 2-to trifluoromethylbenzene methylthio benzoic acid (262.5g, 88%) with the Büchner funnel suction filtration.
Embodiment 2
Synthetic 2-is to the trifluoromethylbenzene methylthio benzoic acid
O-mercaptobenzoic acid (154.19g; 1.0mol) join in the 2L there-necked flask; add toluene (1200ml); then add potassium hydroxide (137.9g; 2.04mol; content 83%) stir lower reflux water-dividing 0.5h; then evaporate to dryness toluene; add DMF(820ml after being down to room temperature), add tetrabutylammonium chloride (33.62g, 0.12mol); stir 30min; then contain methylsulfonyl phenylfluoroform (246.62, DMF(600ml 1.10mol)) solution 30-35 ℃ of dropping, dropwise and at room temperature stir 3h.80 ℃ of solvent evaporated, add entry (2300ml) and transfer ph=3.0-3.5 to separate out a large amount of solids with concentrated hydrochloric acid, get 2-to trifluoromethylbenzene methylthio benzoic acid (245.9g, 85%) with the Büchner funnel suction filtration.
Embodiment 3
Adopt the synthetic 2-of method of embodiment 1 to the trifluoromethylbenzene methylthio benzoic acid; different is: o-mercaptobenzoic acid be 1:1.15 to the mol ratio of methylsulfonyl phenylfluoroform; o-mercaptobenzoic acid and catalyst molar ratio are 1:0.8; o-mercaptobenzoic acid and acid binding agent mol ratio are 1:4, and gained 2-is 87.2% to the yield of trifluoromethylbenzene methylthio benzoic acid.
Embodiment 4
Adopt the synthetic 2-of method of embodiment 1 to the trifluoromethylbenzene methylthio benzoic acid; different is: o-mercaptobenzoic acid be 1:0.98 to the mol ratio of methylsulfonyl phenylfluoroform; o-mercaptobenzoic acid and catalyst molar ratio are 1:1; o-mercaptobenzoic acid and acid binding agent mol ratio are 1:0.9, and gained 2-is 85.1% to the yield of trifluoromethylbenzene methylthio benzoic acid.
Embodiment 5
Adopt the synthetic 2-of method of embodiment 1 to the trifluoromethylbenzene methylthio benzoic acid; different is: o-mercaptobenzoic acid be 1:1.2 to the mol ratio of methylsulfonyl phenylfluoroform; o-mercaptobenzoic acid and catalyst molar ratio are 1:0.05; o-mercaptobenzoic acid and acid binding agent mol ratio are 1:5, and gained 2-is 84.9% to the yield of trifluoromethylbenzene methylthio benzoic acid.
Embodiment 6
Adopt the synthetic 2-of method of embodiment 1 to the trifluoromethylbenzene methylthio benzoic acid, different is: o-mercaptobenzoic acid is 1:0.8 with mol ratio to the methylsulfonyl phenylfluoroform, and gained 2-is 83.5% to the yield of trifluoromethylbenzene methylthio benzoic acid.
Embodiment 7
Adopt the synthetic 2-of method of embodiment 1 to the trifluoromethylbenzene methylthio benzoic acid; different is: o-mercaptobenzoic acid be 1:2.9 to the mol ratio of methylsulfonyl phenylfluoroform; o-mercaptobenzoic acid and catalyst molar ratio are 1:0.6; o-mercaptobenzoic acid and acid binding agent mol ratio are 1:3, and gained 2-is 83.1% to the yield of trifluoromethylbenzene methylthio benzoic acid.
Embodiment 8
Adopt the synthetic 2-of method of embodiment 1 to the trifluoromethylbenzene methylthio benzoic acid, different is: respectively take Tetrabutyl amonium bromide, polyoxyethylene glycol, 15-hat-5-ether, 18-hat-6-ether as catalyzer, be 1:1 with the mol ratio of o-mercaptobenzoic acid, gained 2-is followed successively by 88.1%, 85.3%, 84.9%, 84.6% to the yield of trifluoromethylbenzene methylthio benzoic acid.This shows that the yield of Tetrabutyl amonium bromide product during as catalyzer can be slightly high.
Embodiment 9
Adopt the synthetic 2-of method of embodiment 1 to the trifluoromethylbenzene methylthio benzoic acid, different is: respectively take sodium hydroxide, yellow soda ash as acid binding agent, consumption is 2 moles times of o-mercaptobenzoic acid, and gained 2-is followed successively by 88.3%, 86.1% to the yield of trifluoromethylbenzene methylthio benzoic acid.This shows that the yield of sodium hydroxide product during as acid binding agent can be slightly high.
Embodiment 10
Adopt the synthetic 2-of method of embodiment 1 to the trifluoromethylbenzene methylthio benzoic acid, different is: replace DMF with acetonitrile, gained 2-is 76.5% to the yield of trifluoromethylbenzene methylthio benzoic acid.
Embodiment 11
Synthetic 2-(Trifluoromethyl)thioxanthen-9-one
Any 2-that above-described embodiment 1-10 is made is to trifluoromethylbenzene methylthio benzoic acid (298.3g, 1.0mol) slowly add 40 ℃ the vitriol oil (900ml, content 93wt%) in, then be warming up to 60 ℃, under this temperature, be incubated 3h, reaction solution is cooled to below 20 ℃, slowly be added drop-wise to and contain ice 3.5kg, among the water 3.5kg, stir 30min after icing whole dissolvings, suction filtration, filter cake with the 200ml washing once, obtain the wet product of general 392g, filter cake is suspended in the 1.2L water, adds methylene dichloride 2.2L, stir lower to 30% sodium hydroxide solution accent pH=9.0-9.5, then stir 30min, separatory, organic layer 60g anhydrous sodium sulfate drying, filter, the 2-(Trifluoromethyl)thioxanthen-9-one (260.7g, 93%) that obtains white behind the evaporate to dryness records through HPLC peak area normalization method, and product purity is 98.37%.
Embodiment 12
Adopt the synthetic 2-(Trifluoromethyl)thioxanthen-9-one of method of embodiment 11, different is: 1.0mol2-adds 98wt% vitriol oil 500ml to the trifluoromethylbenzene methylthio benzoic acid, and at 70 ℃ of lower insulation reaction 3h, the yield of gained 2-(Trifluoromethyl)thioxanthen-9-one is 72.6%.
Embodiment 13
Adopt the synthetic 2-(Trifluoromethyl)thioxanthen-9-one of method of embodiment 11, different is: 1.0 mol 2-add 80wt% vitriol oil 1400ml to the trifluoromethylbenzene methylthio benzoic acid, and at 50 ℃ of lower insulation reaction 5h, the yield of gained 2-(Trifluoromethyl)thioxanthen-9-one is 84.5%.
Embodiment 14
Adopt the synthetic 2-(Trifluoromethyl)thioxanthen-9-one of method of embodiment 11, different is: 1.0 mol 2-add 70wt% vitriol oil 3000ml to the trifluoromethylbenzene methylthio benzoic acid, and at 30 ℃ of lower insulation reaction 5h, the yield of gained 2-(Trifluoromethyl)thioxanthen-9-one is 77.6%.
Embodiment 15
Adopt the synthetic 2-(Trifluoromethyl)thioxanthen-9-one of method of embodiment 11, different is: 1.0 mol 2-add oleum 300ml to the trifluoromethylbenzene methylthio benzoic acid, and at 100 ℃ of lower insulation reaction 3h, the yield of gained 2-(Trifluoromethyl)thioxanthen-9-one is 73.7%.
Embodiment 16
Adopt the synthetic 2-(Trifluoromethyl)thioxanthen-9-one of method of embodiment 11, different is: 1.0 mol 2-add polyphosphoric acid (PPA) 1200ml to the trifluoromethylbenzene methylthio benzoic acid, at 60 ℃ of lower insulation reaction 5h, the yield of gained 2-(Trifluoromethyl)thioxanthen-9-one is 83.7%.
Embodiment 17
Adopt the synthetic 2-(Trifluoromethyl)thioxanthen-9-one of method of embodiment 11, different is: frozen water quality (g) is 7 times of vitriol oil volume (ml), and the yield of gained 2-(Trifluoromethyl)thioxanthen-9-one is 92.6%.
Embodiment 18
Adopt the synthetic 2-(Trifluoromethyl)thioxanthen-9-one of method of embodiment 11, different is: the gained filter cake adds its 4 quality water doubly, then adds the methylene dichloride (g/ml) of 6 times of filter cakes, and the yield of gained 2-(Trifluoromethyl)thioxanthen-9-one is 92.4%.
Can find out that from above-described embodiment the yield of the present invention when synthesizing 2-to trifluoromethylbenzene methylthio benzoic acid and 2-(Trifluoromethyl)thioxanthen-9-one is all higher, total recovery is more than 70%, and this is that prior art institute is inaccessiable.
Claims (9)
1. the preparation method of a 2-(Trifluoromethyl)thioxanthen-9-one, it is characterized in that: at first, take o-mercaptobenzoic acid, to the methylsulfonyl phenylfluoroform as raw material, take organic solvent as reaction medium, in the presence of inorganic acid binding agent and catalyzer, carry out condensation reaction and generate 2-to the trifluoromethylbenzene methylthio benzoic acid; Then, 2-carries out cyclization dehydration reaction generation 2-(Trifluoromethyl)thioxanthen-9-one to the trifluoromethylbenzene methylthio benzoic acid in the presence of dewatering agent; Described catalyzer is Tetrabutyl amonium bromide, tetrabutylammonium chloride, polyoxyethylene glycol, 15-hat-5-ether or 18-hat-6-ether.
2. preparation method according to claim 1 is characterized in that: before carrying out condensation reaction, first o-mercaptobenzoic acid is reacted in toluene with acid binding agent first, then toluene is removed, add organic solvent again and the methylsulfonyl phenylfluoroform is carried out condensation reaction.
3. preparation method according to claim 1, it is characterized in that, 2-to the concrete steps of the synthetic 2-(Trifluoromethyl)thioxanthen-9-one of trifluoromethylbenzene methylthio benzoic acid is: 2-is added in the dewatering agent the trifluoromethylbenzene methylthio benzoic acid carry out the cyclization dehydration reaction, after the reaction reaction solution is cooled to below 20 ℃, then join in the frozen water of mass ratio 1:1, suction filtration is got filter cake after icing completeization; Add successively entry and methylene dichloride in filter cake, then reconciling pH is 9-9.5, stirs standing demix; Separatory is got organic phase after the layering, and is organic phase is dry, boil off solvent and get 2-(Trifluoromethyl)thioxanthen-9-one;
Wherein, frozen water quality (g) is 7-8:1 with the ratio of dewatering agent volume (ml), and the mass ratio of water and filter cake is 3-4:1, and methylene chloride volume (ml) is 4-6:1 with the ratio of filter cake quality (g).
4. according to claim 1,2 or 3 described preparation methods, it is characterized in that: described inorganic acid binding agent is sodium hydroxide, potassium hydroxide, yellow soda ash or salt of wormwood; Described organic solvent is acetonitrile, DMF or N,N-dimethylacetamide; Dewatering agent is the vitriol oil, oleum or polyphosphoric acid.
5. preparation method according to claim 4, it is characterized in that: described inorganic acid binding agent is sodium hydroxide; Organic solvent is DMF; Catalyzer is Tetrabutyl amonium bromide; Dewatering agent is the vitriol oil of 80-98wt%.
6. preparation method according to claim 1, it is characterized in that: when synthesizing 2-to the trifluoromethylbenzene methylthio benzoic acid, o-mercaptobenzoic acid be 1:0.8-2.9 to the mol ratio of methylsulfonyl phenylfluoroform, o-mercaptobenzoic acid and catalyst molar ratio are 1:0.05-1.0, o-mercaptobenzoic acid and acid binding agent mol ratio are 1:0.9-5.0, setting-up point is 20-30 ℃, and the time is 3-5h; During synthetic 2-(Trifluoromethyl)thioxanthen-9-one, every gram 2-uses the 1-13ml dewatering agent to the trifluoromethylbenzene methylthio benzoic acid, and temperature of reaction is 30-100 ℃, and the reaction times is 3-5h.
7. preparation method according to claim 6 is characterized in that: o-mercaptobenzoic acid is 1:0.98-1.20 with mol ratio to the methylsulfonyl phenylfluoroform.
8. preparation method according to claim 7 is characterized in that: o-mercaptobenzoic acid is 1:1.1-1.15 with mol ratio to the methylsulfonyl phenylfluoroform.
9. preparation method according to claim 6 is characterized in that: every gram 2-uses the 3-5ml dewatering agent to the trifluoromethylbenzene methylthio benzoic acid, and temperature of reaction is 50-70 ℃.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US3192204A (en) * | 1960-03-07 | 1965-06-29 | Smith Kline French Lab | Trifluoromethylthiaxanthene and -xanthene derivatives |
| CN1446811A (en) * | 2003-03-03 | 2003-10-08 | 华东理工大学 | Method for preparing 2-trifluoromethyl-10-oxaneones |
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| US3192204A (en) * | 1960-03-07 | 1965-06-29 | Smith Kline French Lab | Trifluoromethylthiaxanthene and -xanthene derivatives |
| CN1446811A (en) * | 2003-03-03 | 2003-10-08 | 华东理工大学 | Method for preparing 2-trifluoromethyl-10-oxaneones |
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