CN105085425B - A kind of method for preparing SC 69124 - Google Patents
A kind of method for preparing SC 69124 Download PDFInfo
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- CN105085425B CN105085425B CN201410221008.0A CN201410221008A CN105085425B CN 105085425 B CN105085425 B CN 105085425B CN 201410221008 A CN201410221008 A CN 201410221008A CN 105085425 B CN105085425 B CN 105085425B
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- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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Abstract
The invention discloses a kind of method for preparing SC 69124, is using the phenylbutyryl chloride of 3 oxo 2 as initiation material, generates the diketone of 1,2 diphenyl butane 1,3 by Friedel-Crafts reaction with benzene first, then obtain 4 with chlorosulfonic acid or the concentrated sulfuric acid/acetyl chlorosulfonation（The base of 1,3 dioxo, 1 phenyl fourth 2）The sulfonic acid chloride of benzene 1, then generate 4 under ammoniacal liquor effect（The base of 1,3 dioxo, 1 phenyl fourth 2）The sulfonamide of benzene 1, then react to obtain N with propionic andydride or propionyl chloride（4‑（The base of 1,3 dioxo, 1 phenyl fourth 2）Phenyl sulfonyl）Propionamide, finally obtain SC 69124 using hydroxylamine hydrochloride cyclic condensation, in acid condition dehydration.The present invention is using the phenylbutyryl chloride of 3 oxo 2 as initiation material, is prepared through series of processes such as Friedel-Crafts reaction, sulfonating reaction, amidation process, condensation reactions.Initiation material cost of the present invention is low, technical process is simple, require relatively low to reaction condition, post-processing operation is easy, product yield and purity are high and can accomplish scale production.
Description
Technical field
The invention belongs to field of medicine preparing technology, and in particular to a kind of method for preparing SC 69124.
Background technology
In recent years, NSAIDs shows a variety of medical actives, especially as cyclooxygenase-2（COX-2）Selection
Property inhibitor in terms of, and SC 69124 is then representative therein.
SC 69124, clinically use its sodium-salt form Parecoxib Sodium, English name：Parecoxib
Sodium, chemical name：N- [[4- (5- methyl -3- phenyl -4- isoxazolyls) phenyl] sulfonyl] propionamide sodium salt.Molecule
Formula：C19H17N2O4SNa.Indication：Short for postoperative pain.Parecoxib Sodium is highly selective inhibitor, is faced
Bed studies have shown that can reduce requirement and adverse reaction of the patient to arcotic in the short of pain after surgery.Grind
Study carefully and show that Parecoxib Sodium plays the role of preemptive analgesia.Current data prompting SC 69124 receive have become Multimodal analgesia and
The important component of preemptive analgesia.
SC 69124 is water-soluble prodrug, can quickly and completely be converted into valdecoxib in vivo
(valdecoxib).Important composition of the SC 69124 as Multimodal analgesia, and other analgesic use in conjunction, for postoperative
The treatment of moderate and severe pain, postoperative pain scoring can be reduced, reduce the dosage of the narcotic analgesic medicines such as morphine, reduce opiates
The related side effect of medicine, improves patient's satisfactory rate.Due to the controllability of former times dry goods safety issue, the plug of Pfizer in 2009 comes
23.8 hundred million dollars of former times cloth global marketing volume, keep the brand position of global antirheumatic drug recipe quantity first.
At present, the synthetic route reported mainly has：
Method one：
The major defect of the route is：The enamine intermediates conversion ratio of first step generation is not high, and routine preservation is unstable, needs
To be purified by way of vacuum distillation, it is higher to the equipment requirement of industrialized production；Second step acetylization reaction, it is necessary to
Acid binding agent is done using 2,6- lutidines costly, improves the production cost of whole piece process route.
Method two：
The major defect of the route is：Centre has used the very high butyl lithium reagent of activity, and the reagent amplifies in industrialization
Security requirement is very high during use, easily causes safety hazards.In the patents of CN 103172583, in same step
In, butyl lithium is replaced using lithium diisopropylamine, although security has obtained a certain degree of raising, diisopropyl ammonia
The use of base lithium needs the condition at -78 DEG C, and this brings the high difficulty of equipment requirement to industrial amplification production again, while most
When latter step generates SC 69124 with propionic acid anhydride acylation, the side of tetrahydrofuran solvent and the catalysis of 4- picolilamines is used
Method, impurity is easily produced in the method course of reaction, refining purification to SC 69124 below brings difficulty.
Method three：
The major defect of the route is：Second step acetylization reaction, the conversion ratio of base catalysis raw material reaction is done using pyridine
Relatively low, the material obtained after reaction treatment is mixed with a large amount of responseless raw materials, it is necessary to separate production by the method for column chromatography
Thing, in industry's enlarging production, add purification difficulty and production cost in this step reaction intermediate.3rd step and hydrochloric acid
During azanol reaction, be easily mixed with removing acetyl group accessory substance generation, also to this step intermediate purification add difficulty and
Cost.
Therefore, a kind of SC 69124 preparation method that can solve above-mentioned technical problem is developed to be very important.
The content of the invention
It is an object of the invention to provide a kind of method for preparing SC 69124.
The object of the present invention is achieved like this, comprises the following steps：
A, the preparation of 1,2- diphenyl butanes -1,3- diketone：
Solid-liquid volume ratio 1 will be added in raw material 3- oxo -2- phenylbutyryl chlorides: 10 ~ 1 :In 5 organic solvent,
Addition lewis acid catalyst reacts 6 ~ 12 h at 40 ~ 120 DEG C and obtains the diketone of 1,2- diphenyl butanes -1,3；
B、4-（1,3- dioxo -1- phenyl butyl- 2- bases）The preparation of benzene -1- sulfonic acid chlorides：
Method one, 1,2- diphenyl butanes -1,3 diketone that step A is prepared is added portionwise at a temperature of -5 ~ 5 DEG C
To w/v 1: 2 ~ 1 :In 5 sulfonated reagent, 4 ~ 8h of stirring reaction, reaction mixture at a temperature of -5 ~ 5 DEG C
It is poured into trash ice and separates out white solid, white solid is collected by filtration, washed with the frozen water of -5 ~ 5 DEG C of temperature, is obtained after drying
4-（1,3- dioxo -1- phenyl butyl- 2- bases）Benzene -1- sulfonic acid chlorides；
Method two, 1,2- diphenyl butanes -1,3 diketone that step A is prepared is added portionwise at a temperature of -5 ~ 5 DEG C
To w/v 1: 2 ~ 1 :In 5 concentrated sulfuric acid or cigarette sulfuric acid, 4 ~ 10 h are reacted at 20 ~ 50 DEG C, are cooled to
- 5 ~ 5 DEG C, reaction mixture is poured into trash ice and separates out white solid, white solid is dissolved in solid-liquid volume ratio 1:
2 ~ 1 :In 5 thionyl chloride solvent, 6 ~ 12 h are reacted at 20 ~ 50 DEG C, is poured into trash ice separates out solid again
Obtain 4-（1,3- dioxo -1- phenyl butyl- 2- bases）Benzene -1- sulfonic acid chlorides；
C、4-（1,3- dioxo -1- phenyl butyl- 2- bases）The preparation of benzene -1- sulfonamide：
The 4- that step B is prepared（1,3- dioxo -1- phenyl butyl- 2- bases）Benzene -1- sulfonic acid chlorides are added to solid-liquid
Product ratio 1: 2 ~ 1 :In 5 10 ~ 40 % concentrated ammonia liquor, 10 ~ 15h of stirring reaction at 40 ~ 90 DEG C, cool down, filtering
White solid is collected to precipitate to obtain 4-（1,3- dioxo -1- phenyl butyl- 2- bases）Benzene -1- sulfonamide；
D、N-（4-（1,3- dioxo -1- phenyl butyl- 2- bases）Phenyl sulfonyl）The preparation of propionamide：
Method one, the 4- that step C is prepared（1,3- dioxo -1- phenyl butyl- 2- bases）Benzene -1- sulfonamide is dissolved in
Solid-liquid volume ratio 1: 2 ~ 1 :In 5 amidation reagent, catalyst is added, 2 ~ 12 h are reacted at 20 ~ 110 DEG C and are obtained
To N-（4-（1,3- dioxo -1- phenyl butyl- 2- bases）Phenyl sulfonyl）Propionamide；
Method two, the 4- that step C is prepared（1,3- dioxo -1- phenyl butyl- 2- bases）Benzene -1- sulfonamide is dissolved in
Solid-liquid volume ratio 1: 2 ~ 1 :5 tetrahydrofuran, ethyl acetate, chloroform, 1,2- dichloromethane, acetonitrile, benzene, toluene or
In a kind of solvent in dichloromethane, 4- is added（1,3- dioxo -1- phenyl butyl- 2- bases）Benzene -1- sulfonamide mol ratio 1:0.8
~ 1.2 propionyl chloride, base catalyst is added, 6 ~ 12 h are reacted at 20 ~ 110 DEG C and obtain N-（4-（1,3- dioxos-
1- phenyl butyl- 2- bases）Phenyl sulfonyl）Propionamide；
E, N- (4- (5- hydroxy-5-methyl base -3- phenyl -4,5- dihydro-isoxazole -4- bases) phenyl sulfonyl) propionamide
Prepare：
The N- that step D is prepared（4-（1,3- dioxo -1- phenyl butyl- 2- bases）Phenyl sulfonyl）Propionyl amine solvent
In solid-liquid volume ratio 1: 2 ~ 1 :In 5 70 ~ 100 % ethanol, N- is added（4-（1,3- dioxo -1- phenyl butyl-
2- bases）Phenyl sulfonyl）Propionamide mol ratio 1:0.8 ~ 1.2 hydroxylamine hydrochloride, 0.5 ~ 6 h of reaction is obtained at 50 ~ 90 DEG C
N- (4- (5- hydroxy-5-methyl base -3- phenyl -4,5- dihydro-isoxazole -4- bases) phenyl sulfonyl) propionamide；
F, the preparation of SC 69124：
N- (4- (5- hydroxy-5-methyl base -3- phenyl -4,5- dihydro-isoxazole -4- bases) phenyl that step E is prepared
Sulfonyl) propionamide is added to solid-liquid volume ratio 1 under -5 ~ 5 DEG C of condition of ice bath: 2 ~ 1 :In 3 acid flux material,
4 ~ 12h of stirring reaction obtains object SC 69124 at a temperature of being kept for 0 ~ 30 DEG C.
The present invention be using 3- oxo -2- phenylbutyryl chlorides as initiation material, it is anti-through Friedel-Crafts reaction, sulfonating reaction, amidatioon
Should, the series of processes such as condensation reaction object SC 69124 is prepared.Initiation material cost of the present invention is low, technical process is simple
It is single, relatively low is required to reaction condition, post-processing operation is easy, product yield and purity are high and can realize scale metaplasia
Production.
Brief description of the drawings
Fig. 1 is present invention process schematic flow sheet.
Embodiment
The present invention is further illustrated below in conjunction with the accompanying drawings, but the present invention is not any limitation as in any way, base
In present invention teach that any conversion or replacement made, belong to protection scope of the present invention.
The method of the present invention for preparing SC 69124, comprises the following steps：
A, the preparation of 1,2- diphenyl butanes -1,3- diketone：
Solid-liquid volume ratio 1 will be added in raw material 3- oxo -2- phenylbutyryl chlorides: 10 ~ 1 :5 organic solvent
In, addition lewis acid catalyst reacts 6 ~ 12 h at 40 ~ 120 DEG C and obtains 1,2- diphenyl butane -1,3 diketone；
B、4-（1,3- dioxo -1- phenyl butyl- 2- bases）The preparation of benzene -1- sulfonic acid chlorides：
Method one, 1,2- diphenyl butanes -1,3 diketone that step A is prepared is added portionwise at a temperature of -5 ~ 5 DEG C
To w/v 1: 2 ~ 1 :In 5 sulfonated reagent, 4 ~ 8h of stirring reaction, reaction mixture at a temperature of -5 ~ 5 DEG C
It is poured into trash ice and separates out white solid, white solid is collected by filtration, washed with the frozen water of -5 ~ 5 DEG C of temperature, is obtained after drying
4-（1,3- dioxo -1- phenyl butyl- 2- bases）Benzene -1- sulfonic acid chlorides；
Method two, 1,2- diphenyl butanes -1,3 diketone that step A is prepared is added portionwise at a temperature of -5 ~ 5 DEG C
To w/v 1: 2 ~ 1 :In 5 concentrated sulfuric acid or cigarette sulfuric acid, 4 ~ 10 h, cooling are reacted at 20 ~ 50 DEG C
To -5 ~ 5 DEG C, reaction mixture is poured into trash ice and separates out white solid, white solid is dissolved in solid-liquid volume ratio
1 : 2 ~ 1 :In 5 thionyl chloride solvent, 6 ~ 12 h are reacted at 20 ~ 50 DEG C, is poured into trash ice separates out again
Solid obtains 4-（1,3- dioxo -1- phenyl butyl- 2- bases）Benzene -1- sulfonic acid chlorides；
C、4-（1,3- dioxo -1- phenyl butyl- 2- bases）The preparation of benzene -1- sulfonamide：
The 4- that step B is prepared（1,3- dioxo -1- phenyl butyl- 2- bases）Benzene -1- sulfonic acid chlorides are added to solid-liquid
Product ratio 1: 2 ~ 1 :In 5 10 ~ 40 % concentrated ammonia liquor, 10 ~ 15h of stirring reaction, cold at 40 ~ 90 DEG C
But, white solid is collected by filtration to precipitate to obtain 4-（1,3- dioxo -1- phenyl butyl- 2- bases）Benzene -1- sulfonamide；
D、N-（4-（1,3- dioxo -1- phenyl butyl- 2- bases）Phenyl sulfonyl）The preparation of propionamide：
Method one, the 4- that step C is prepared（1,3- dioxo -1- phenyl butyl- 2- bases）Benzene -1- sulfonamide is dissolved in
Solid-liquid volume ratio 1: 2 ~ 1 :In 5 amidation reagent, catalyst is added, 2 ~ 12 h are reacted at 20 ~ 110 DEG C
Obtain N-（4-（1,3- dioxo -1- phenyl butyl- 2- bases）Phenyl sulfonyl）Propionamide；
Method two, the 4- that step C is prepared（1,3- dioxo -1- phenyl butyl- 2- bases）Benzene -1- sulfonamide is dissolved in
Solid-liquid volume ratio 1: 2 ~ 1 :5 tetrahydrofuran, ethyl acetate, chloroform, 1,2- dichloromethane, acetonitrile, benzene, toluene or
In a kind of solvent in dichloromethane, 4- is added（1,3- dioxo -1- phenyl butyl- 2- bases）Benzene -1- sulfonamide mol ratio 1:0.8
~ 1.2 propionyl chloride, base catalyst is added, 6 ~ 12 h are reacted at 20 ~ 110 DEG C and obtain N-（4-（1,3- dioxos-
1- phenyl butyl- 2- bases）Phenyl sulfonyl）Propionamide；
E, N- (4- (5- hydroxy-5-methyl base -3- phenyl -4,5- dihydro-isoxazole -4- bases) phenyl sulfonyl) propionamide
Prepare：
The N- that step D is prepared（4-（1,3- dioxo -1- phenyl butyl- 2- bases）Phenyl sulfonyl）Propionyl amine solvent
In solid-liquid volume ratio 1: 2 ~ 1 :In 5 70 ~ 100 % ethanol, N- is added（4-（1,3- dioxo -1- phenyl butyl-
2- bases）Phenyl sulfonyl）Propionamide mol ratio 1:0.8 ~ 1.2 hydroxylamine hydrochloride, 0.5 ~ 6 h of reaction is obtained at 50 ~ 90 DEG C
N- (4- (5- hydroxy-5-methyl base -3- phenyl -4,5- dihydro-isoxazole -4- bases) phenyl sulfonyl) propionamide；
F, the preparation of SC 69124：
N- (4- (5- hydroxy-5-methyl base -3- phenyl -4,5- dihydro-isoxazole -4- bases) phenyl that step E is prepared
Sulfonyl) propionamide is added to solid-liquid volume ratio 1 under -5 ~ 5 DEG C of condition of ice bath: 2 ~ 1 :In 3 acid flux material,
4 ~ 12h of stirring reaction obtains object SC 69124 at a temperature of being kept for 0 ~ 30 DEG C.
Organic solvent described in step A is benzene, toluene, tetrahydrofuran, ethyl acetate, dichloromethane, chloroform or acetonitrile
In one kind.
Lewis acid catalyst described in step A is alchlor, titanium tetrachloride, boron trifluoride, iron chloride, chlorination
One kind in zinc, niobium pentoxide, three width sulfonate, p-methyl benzenesulfonic acid, addition are the 5 ~ 20% of feed molar amount.
Sulfonated reagent described in step B is chlorosulfonic acid, one kind in the concentrated sulfuric acid, oleum, sulfur trioxide.
Described sulfonated reagent is chlorosulfonic acid.
Amidation reagent described in step D methods one is propionic andydride, one kind in propionyl chloride, propionic acid.
Described amidation reagent is propionic andydride.
Catalyst described in step D methods one is p-methyl benzenesulfonic acid, benzene sulfonic acid, 4- dimethylaminopyridines, silicon
One kind in glue, sulfuric acid, ferric trichloride, titanium tetrachloride or BFEE.
Described catalyst is p-methyl benzenesulfonic acid.
Base catalyst described in step D methods two is lewis acid, carbonate, triethylamine, diisopropyl ethyl amine,
One kind in DMAP.
Acid flux material described in F-step is one in trifluoracetic acid, hydrochloric acid, sulfuric acid, acetic acid, formic acid, phosphoric acid or oxalic acid
Kind.
The method of the present invention for preparing SC 69124, comprises the following steps：
Comprise the following steps that：
A) using 3- oxo -2- phenylbutyryl chlorides as initiation material, in the solvent of benzene, lewis acid catalyst is added,
1,2- diphenyl butane -1,3- diketone is prepared by Friedel-Crafts reaction under heating condition.Wherein described Louis acid catalysis
Agent is selected from：Alchlor, titanium tetrachloride, boron trifluoride, iron chloride, zinc chloride, columbium pentachloride, trifluoro sulfonate, to toluene sulphur
Acid, the addition of catalyst are the 5% ~ 20% of the 3- oxos -2- phenylbutyryl chloride moles；The heating-up temperature is 40 DEG C
~ 120℃。
B) prepare step a 1,2- diphenyl butane -1,3- diketone are added portionwise in chlorosulfonic acid at low temperature, instead
After certain time, it should be poured into trash ice and separate out white solid, be collected by filtration to obtain 4-（1,3- dioxo -1- phenyl butyl- 2-
Base）Benzene -1- sulfonic acid chlorides；Or the concentrated sulfuric acid or oleum is added portionwise in 1,2- diphenyl butane -1,3- diketone at low temperature
In acid, after heating stirring reaction certain time, be poured into trash ice after band cooling and separate out white solid, collect this solid dissolving in
It is poured into again in trash ice after heating response certain time in thionyl chloride solvent, the solid for collecting precipitation obtains 4-（1,3- dioxies
Generation -1- phenyl butyl- 2- bases）Benzene -1- sulfonic acid chlorides, described cryogenic temperature are -15 DEG C ~ 5 DEG C；Described heating-up temperature be 40 DEG C ~
90℃。
C) 4- for preparing step b（1,3- dioxo -1- phenyl butyl- 2- bases）Benzene -1- sulfonic acid chlorides are added to ammonia spirit
In, after heating stirring certain time, stopping reaction being collected by filtration white solid and precipitates to obtain 4- after cooling（1,3- dioxos-
1- phenyl butyl- 2- bases）Benzene -1- sulfonamide, described heating-up temperature are 40 DEG C ~ 90 DEG C.
D) 4- for preparing step c（1,3- dioxo -1- phenyl butyl- 2- bases）Benzene -1- sulfonamide is dissolved in a certain amount of
In propionic andydride, catalyst is added, N- is prepared in reaction in a heated condition（4-（1,3- dioxo -1- phenyl butyl- 2- bases）Benzene
Base sulfonyl）Propionamide, or by 4-（1,3- dioxo -1- phenyl butyl- 2- bases）Benzene -1- sulfonamide is dissolved in a kind of solvent
In, a certain amount of propionyl chloride and base catalyst are added, is reacted under the conditions of addition and N- is prepared（4-（1,3- dioxos -1-
Phenyl butyl- 2- bases）Phenyl sulfonyl）Propionamide, described catalyst are selected from：Lewis acid, carbonate, triethylamine, diisopropyl
Base ethylamine, DMAP；Described heating-up temperature is 40 DEG C ~ 100 DEG C；The dosage of the propionyl chloride is 4-（1,3-
Dioxo -1- phenyl butyl- 2- bases）Benzene -1- sulfonamide moles for 100% ~ 110%.
E) N- for preparing step d（4-（1,3- dioxo -1- phenyl butyl- 2- bases）Phenyl sulfonyl）Propionyl amine solvent
In ethanol, hydroxylamine hydrochloride is added, reaction in a heated condition obtains N-（4-（5- hydroxy-5-methyl base -3- phenyl -4,5- dihydros
Isoxazole -4- bases）Phenyl sulfonyl）Propionamide, the dosage of the hydroxylamine hydrochloride is N-（4-（1,3- dioxo -1- phenyl butyl-
2- bases）Phenyl sulfonyl）The 100% ~ 120% of propionamide mole, the heating-up temperature are 50 DEG C ~ 90 DEG C.
F) N- for preparing step e（4-（5- hydroxy-5-methyl base -3- phenyl -4,5- dihydro-isoxazole -4- bases）Phenyl sulphur
Acyl group）Propionamide is added in acid flux material under condition of ice bath, after holding is stirred at room temperature 4 ~ 12 hours, obtains SC 69124,
Described acid flux material is selected from：Trifluoracetic acid, 1M ~ 4M aqueous hydrochloric acid solution, 1M ~ 4M aqueous sulfuric acid.
Catalyst used is preferably alchlor in synthesis step a, and addition is the 3- oxos -2- phenylbutyryl chlorides
The 10% of mole, temperature control is at 100 ~ 105 DEG C.
Chlorosulfonic acid is preferably used in synthesis step b, and as sulfonated reagent, temperature control is at -5 DEG C ~ 5 DEG C.
Preferably using propionic andydride it is amidation reagent in synthesis step d, catalyst preferably uses p-methyl benzenesulfonic acid, temperature
Control is at 60 DEG C ~ 80 DEG C.
Acid solution used is preferably trifluoracetic acid in synthesis step f.
Embodiment 1
1,2- diphenyl butane -1,3- diketone（III）Preparation
3- oxo -2- phenylbutyryl chlorides 4.0 grams (20.4 mmol, 1e.q) are weighed to be dissolved in into 40 mL benzole solns,
150 milligrams of alchlor solids are added, are heated to reflux 12 hours, after TLC shows raw material reaction completely, stop reaction, saturation
Sodium bicarbonate aqueous solution extraction is washed once, and saturated common salt is washed once, organic phase anhydrous sodium sulfate drying, must be consolidated after being spin-dried for solvent
About 4.0 grams of body product, yield 84%.1H NMR (500 MHz, CDCl3): δ = 7.6-7.1 (m, 10H), 5.40 (s,
1H), 2.26 (s, 3H)。
Embodiment 2
4-（1,3- dioxo -1- phenyl butyl- 2- bases）Benzene -1- sulfonic acid chlorides（IV）Preparation
2.4 grams of 1,2- diphenyl butane -1,3- diketone are weighed, under condition of ice bath, above-mentioned raw materials is added portionwise and stirred
In 5 milliliters of chlorosulfonic acids under the conditions of mixing, keep 0 DEG C of condition to stir 6 hours, after stopping reaction, reaction mixture is poured into 10
In gram trash ice, there is white solid precipitation, this white solid is collected by filtration, washed with a small amount of frozen water, dried white solid production
3.1 grams of thing, yield 91%.1H NMR (500 MHz, CDCl3): δ = 7.70 (dd, J = 8.1 Hz, 2H), 7.60
(dd, J = 8.1 Hz, 2H), 7.53-7.41 (m, 5H), 5.48 (s, 1H), 2.26 (s, 3H)。
Embodiment 3
（1,3- dioxo -1- phenyl butyl- 2- bases）Benzene -1- sulfonamide（V）Preparation
Weigh 3.4 grams of 4-（1,3- dioxo -1- phenyl butyl- 2- bases）Benzene -1- sulfonic acid chlorides are added in 20 milliliters of concentrated ammonia liquors,
It is heated to 60 DEG C of stirring reactions 12 hours, TLC detection raw material reactions finish.Stop reaction, frozen water is placed in after the cooling of question response liquid
Middle placement is overnight, and solid product is collected by filtration, is washed with a small amount of frozen water.3.0 grams of white products, yield about 95% are obtained after drying.1H
NMR (500 MHz, CDCl3): δ = 8.00 (dd, J = 8.1 Hz, 2H), 7.60-7.41 (m, 7H), 6.0
(br, 2H), 5.29 (s, 1H), 2.26 (s, 3H)。
Embodiment 4
N-（4-（1,3- dioxo -1- phenyl butyl- 2- bases）Phenyl sulfonyl）Propionamide（VI）Preparation
Weigh 3.1 grams（1,3- dioxo -1- phenyl butyl- 2- bases）Benzene -1- sulfonamide is dissolved in 6 milliliters of propionic andydrides, is added
Entering 20 milligrams of p-methyl benzenesulfonic acid, be heated to 70 DEG C of stirring reactions 12 hours, TLC detection raw material reactions finish, natural cooling reaction,
There is crystalline solid precipitation, solid is collected by filtration, washed with a small amount of t-butyl methyl ether, about 3.2 grams of white solid, yield are obtained after drying
About 85%.1H NMR (500 MHz, CDCl3): δ = 9.86 (br 1H), 7.85 (dd, J = 8.1 Hz, 2H),
7.61(dd, J = 7.8 Hz, 2H), 7.59 (dd, J = 8.1 Hz, 2H), 7.53 (m, 1H), 7.41 (dd,J = 7.6 Hz, 2H), 5.29 (s, 1H), 2.47 (q, J = 6.6 Hz , 6.3, 2H), 2.26 (s, 3H),
1.15 (t, J = 6.3 Hz, 3H) .
Embodiment 5
N- (4- (5- hydroxy-5-methyl base -3- phenyl -4,5- dihydro-isoxazole -4- bases) phenyl sulfonyl) propionamide（VII）
Preparation
Weigh 3.8 grams of N-（4-（1,3- dioxo -1- phenyl butyl- 2- bases）Phenyl sulfonyl）Propionamide is dissolved in 30 milliliters
In ethanol, 0.7 gram of hydroxylamine hydrochloride is added, is heated to the reflux state reaction moon 6 hours, after stopping reaction, is spin-dried for most of second
Alcohol, 30 milliliters of ethyl acetate are added, respectively with saturated sodium bicarbonate aqueous solution and saturated common salt washing once, organic phase is with anhydrous
Sodium sulphate is dried, and is spin-dried for 3.6 grams of the white solid product of organic phase, yield about 92%.1H NMR (500 MHz, CDCl3): δ
= 7.98 (dd, J = 8.1 Hz , 2H), 7.74 (dd, J = 7.7 Hz , 2H), 7.46 (dd, J = 7.7
Hz , 2H), 7.38 (m, 1H), 7.30 (dd, J = 8.1 Hz , 2H), 7.23 (br, 2H), 4.3 (s,
1H), 2.47 (q, J = 6.3 Hz , 2H), 1.48 (s, 3H), 1.15 (t, J = 6.3 Hz , 3H)。
Embodiment 6
SC 69124（I）Preparation
Weigh above-mentioned N- (4- (5- hydroxy-5-methyl base -3- phenyl -4,5- dihydro-isoxazole -4- bases) phenyl sulfonyl) third
4 grams of acid amides, it is added in 15 milliliters of trifluoroacetic acid solutions, holding is stirred at room temperature 2 hours, there are a large amount of solid products to generate.Stop
After reaction, solid product is collected by filtration, is washed with t-butyl methyl ether, dried 3.5 grams of white solid product, yield 92%.1H
NMR (500 MHz, D2O): δ= 8.60 （brs, 1H）, 8.04 (d,J = 8.7 Hz, 2H), 7.38-7.31
(m, 7H), 2.50 (s, 3H), 2.32 (q, J = 7.2 Hz, 2H), 1.10 (t, J = 7.2 Hz, 3H)。
Embodiment 7
1,2- diphenyl butane -1,3- diketone（III）Preparation
3- oxo -2- phenylbutyryl chlorides 1.9 grams (10.0 mmol, 1e.q) are weighed to be dissolved in 30 mL toluene solutions
In, 5 milliliters of BFEEs are added, are heated to reflux 10 hours, after TLC shows raw material reaction completely, stop reaction, saturation
Sodium bicarbonate aqueous solution extraction is washed once, and saturated common salt is washed once, organic phase anhydrous sodium sulfate drying, must be consolidated after being spin-dried for solvent
About 1.7 grams of body product, yield 73%.
Embodiment 8
4-（1,3- dioxo -1- phenyl butyl- 2- bases）Benzene -1- sulfonic acid chlorides（IV）Preparation
2.6 grams of 1,2- diphenyl butane -1,3- diketone are weighed, under condition of ice bath, above-mentioned raw materials is added portionwise and stirred
In 6 milliliters of oleums under the conditions of mixing, keep 0 DEG C of condition to stir 6 hours, after stopping reaction, reaction mixture is poured into
In 10 grams of trash ices, there is white solid precipitation, this white solid is collected by filtration, be dissolved in 5 milliliters of thionyl chlorides, be heated to 50 DEG C
Reaction 10 hours, after cooling, is poured into 10 grams of trash ices, there is white solid precipitation, this white solid is collected by filtration again, uses
A small amount of frozen water washing, dried 2.9 grams of white solid product, yield 86.3%.
Embodiment 9
（1,3- dioxo -1- phenyl butyl- 2- bases）Benzene -1- sulfonamide（V）Preparation
Weigh 3.5 grams of 4-（1,3- dioxo -1- phenyl butyl- 2- bases）Benzene -1- sulfonic acid chlorides are added to 50 milliliter 20% of ammoniacal liquor
In, it is heated to 60 DEG C of stirring reactions 12 hours, TLC detection raw material reactions finish.Stop reaction, ice is placed in after the cooling of question response liquid
Place overnight in water, solid product is collected by filtration, is washed with a small amount of frozen water.2.5 grams of white products, yield about 78% are obtained after drying.
Embodiment 10
N-（4-（1,3- dioxo -1- phenyl butyl- 2- bases）Phenyl sulfonyl）Propionamide（VI）Preparation
Weigh 3.1 grams（1,3- dioxo -1- phenyl butyl- 2- bases）Benzene -1- sulfonamide is dissolved in 6 milliliters of propionyl chlorides, is added
Enter 10 milligrams of 4- dimethylaminopyridines, be heated to 60 DEG C of stirring reactions 10 hours, TLC detection raw material reactions finish, naturally cold
But react, be extracted with ethyl acetate, washed successively with sodium acid carbonate, sodium-chloride water solution, organic phase anhydrous sodium sulfate drying,
Solid product after being spin-dried for is dissolved by heating in absolute ethyl alcohol, has crystalline solid precipitation after cooling, solid is collected by filtration, with less
T-butyl methyl ether washing is measured, about 2.5 grams of white solid, yield about 67% are obtained after drying.
Embodiment 11
N- (4- (5- hydroxy-5-methyl base -3- phenyl -4,5- dihydro-isoxazole -4- bases) phenyl sulfonyl) propionamide（VII）
Preparation
Weigh 4.2 grams of N-（4-（1,3- dioxo -1- phenyl butyl- 2- bases）Phenyl sulfonyl）Propionamide is dissolved in 30 milliliters
In 70% ethanol, 1.2 grams of hydroxylamine hydrochlorides are added, are heated to the reflux state reaction moon 10 hours, after stopping reaction, are spin-dried for big
Part ethanol, 30 milliliters of ethyl acetate are added, respectively with saturated sodium bicarbonate aqueous solution and saturated common salt washing once, organic phase
With anhydrous sodium sulfate drying, 3.4 grams of the white solid product of organic phase, yield about 77% are spin-dried for.
Embodiment 12
SC 69124（I）Preparation
Weigh above-mentioned N- (4- (5- hydroxy-5-methyl base -3- phenyl -4,5- dihydro-isoxazole -4- bases) phenyl sulfonyl) third
3.8 grams of acid amides, is added in 15 milliliters of 3M hydrochloric acid solution, and holding is stirred at room temperature 5 hours, has a large amount of solid products to generate.Stop
After only reacting, solid product is collected by filtration, is washed with t-butyl methyl ether, dried 3.1 grams of white solid product, yield 83%.
Embodiment 13
1,2- diphenyl butane -1,3- diketone（III）Preparation
Weigh 3- oxo -2- phenylbutyryl chlorides 1.9 grams (10.0 mmol, 1e.q) be dissolved in it is molten to 30 mL ethyl acetate
In liquid, 0.5 milliliter of titanium tetrachloride is added, is heated to reflux 10 hours, after TLC shows raw material reaction completely, stop reaction, saturation
Sodium bicarbonate aqueous solution extraction is washed once, and saturated common salt is washed once, organic phase anhydrous sodium sulfate drying, must be consolidated after being spin-dried for solvent
About 1.3 grams of body product, yield 54%.
Embodiment 14
4-（1,3- dioxo -1- phenyl butyl- 2- bases）Benzene -1- sulfonic acid chlorides（IV）Preparation
3.5 grams of 1,2- diphenyl butane -1,3- diketone are weighed, under condition of ice bath, above-mentioned raw materials is added portionwise and stirred
Sulfur trioxide gas are passed through under the conditions of mixing, keep 0 DEG C of condition to stir 3 hours, after stopping reaction, reaction mixture is poured into
In 10 grams of trash ices, there is white solid precipitation, this white solid is collected by filtration, be dissolved in 5 milliliters of thionyl chlorides, be heated to 50 DEG C
Reaction 10 hours, after cooling, is poured into 10 grams of trash ices, there is white solid precipitation, this white solid is collected by filtration again, uses
A small amount of frozen water washing, dried 3.1 grams of white solid product, yield 63%.
Embodiment 15
（1,3- dioxo -1- phenyl butyl- 2- bases）Benzene -1- sulfonamide（V）Preparation
Weigh 3.3 grams of 4-（1,3- dioxo -1- phenyl butyl- 2- bases）Benzene -1- sulfonic acid chlorides are added to 100 milliliter 15% of ammonia
In water, 60 DEG C of stirring reactions are heated to 12 hours, TLC detection raw material reactions finish.Stop reaction, be placed in after the cooling of question response liquid
Place overnight in frozen water, solid product is collected by filtration, is washed with a small amount of frozen water.1.5 grams of white products are obtained after drying, yield is about
47%。
Embodiment 16
N-（4-（1,3- dioxo -1- phenyl butyl- 2- bases）Phenyl sulfonyl）Propionamide（VI）Preparation
Weigh 3.2 grams（1,3- dioxo -1- phenyl butyl- 2- bases）Benzene -1- sulfonamide is dissolved in 6 milliliters of propionic acid, is added
10 milligrams of 4- dimethylaminopyridines, are heated to 60 DEG C of stirring reactions 12 hours, and TLC detection raw material reactions finish, natural cooling
Reaction, is extracted with ethyl acetate, successively with sodium acid carbonate, sodium-chloride water solution washing, organic phase anhydrous sodium sulfate drying, rotation
Solid product after dry is dissolved by heating in absolute ethyl alcohol, has crystalline solid precipitation after cooling, solid is collected by filtration, with a small amount of
T-butyl methyl ether is washed, and about 1.9 grams of white solid, yield about 51% are obtained after drying.
Embodiment 17
N- (4- (5- hydroxy-5-methyl base -3- phenyl -4,5- dihydro-isoxazole -4- bases) phenyl sulfonyl) propionamide（VII）
Preparation
Weigh 3.7 grams of N-（4-（1,3- dioxo -1- phenyl butyl- 2- bases）Phenyl sulfonyl）Propionamide is dissolved in 40 milliliters
In 80% ethanol, 1.1 grams of hydroxylamine hydrochlorides are added, are heated to the reflux state reaction moon 10 hours, after stopping reaction, are spin-dried for big
Part ethanol, 30 milliliters of ethyl acetate are added, respectively with saturated sodium bicarbonate aqueous solution and saturated common salt washing once, organic phase
With anhydrous sodium sulfate drying, 3.1 grams of the white solid product of organic phase, yield about 83% are spin-dried for.
Embodiment 18
SC 69124（I）Preparation
Weigh above-mentioned N- (4- (5- hydroxy-5-methyl base -3- phenyl -4,5- dihydro-isoxazole -4- bases) phenyl sulfonyl) third
3.9 grams of acid amides, is added in 15 milliliters of 3M sulfuric acid solution, and holding is stirred at room temperature 5 hours, has a large amount of solid products to generate.Stop
After only reacting, solid product is collected by filtration, is washed with t-butyl methyl ether, dried 2.9 grams of white solid product, yield 78%.
Claims (9)
- A kind of 1. method for preparing SC 69124, it is characterised in that comprise the following steps：A, the preparation of 1,2- diphenyl butanes -1,3- diketone：Solid-liquid volume ratio 1 will be added in raw material 3- oxo -2- phenylbutyryl chlorides:10~1:In 5 benzole soln, Louis is added Acid catalyst reacts 6 ~ 12 h at 40 ~ 120 DEG C and obtains the diketone of 1,2- diphenyl butanes -1,3；B、4-（1,3- dioxo -1- phenyl butyl- 2- bases）The preparation of benzene -1- sulfonic acid chlorides：Method one, weight is added portionwise in 1,2- diphenyl butanes -1,3 diketone that step A is prepared at a temperature of -5 ~ 5 DEG C Measure volume ratio 1:2~1:In 5 sulfonated reagent, 4 ~ 8h of stirring reaction, reaction mixture are poured into trash ice at a temperature of -5 ~ 5 DEG C Middle precipitation white solid, is collected by filtration white solid, is washed with the frozen water of -5 ~ 5 DEG C of temperature, and 4- is obtained after drying（1,3- dioxies Generation -1- phenyl butyl- 2- bases）Benzene -1- sulfonic acid chlorides；Method two, weight is added portionwise in 1,2- diphenyl butanes -1,3 diketone that step A is prepared at a temperature of -5 ~ 5 DEG C Measure volume ratio 1:2~1:In 5 concentrated sulfuric acid or oleum, 4 ~ 10h is reacted at 20 ~ 50 DEG C, is cooled to -5 ~ 5 DEG C, will be anti- Answer mixed liquor to be poured into trash ice and separate out white solid, white solid is dissolved in solid-liquid volume ratio 1:2~1:5 thionyl chloride In solvent, 6 ~ 12h is reacted at 20 ~ 50 DEG C, precipitation solid in trash ice is poured into again and obtains 4-（1,3- dioxo -1- phenyl Butyl- 2- bases）Benzene -1- sulfonic acid chlorides；C、4-（1,3- dioxo -1- phenyl butyl- 2- bases）The preparation of benzene -1- sulfonamide：The 4- that step B is prepared（1,3- dioxo -1- phenyl butyl- 2- bases）Benzene -1- sulfonic acid chlorides are added to solid-liquid volume ratio 1:2~1:In 5 10 ~ 40% ammoniacal liquor, 10 ~ 15h of stirring reaction at 40 ~ 90 DEG C, cooling, white solid is collected by filtration and precipitates To 4-（1,3- dioxo -1- phenyl butyl- 2- bases）Benzene -1- sulfonamide；D、N-（4-（1,3- dioxo -1- phenyl butyl- 2- bases）Phenyl sulfonyl）The preparation of propionamide：Method one, the 4- that step C is prepared（1,3- dioxo -1- phenyl butyl- 2- bases）Benzene -1- sulfonamide is dissolved in solid-liquid Volume ratio 1:2~1:In 5 acylating reagent, catalyst is added, 2 ~ 12h is reacted at 20 ~ 110 DEG C and obtains N-（4-（1,3- dioxies Generation -1- phenyl butyl- 2- bases）Phenyl sulfonyl）Propionamide；Method two, the 4- that step C is prepared（1,3- dioxo -1- phenyl butyl- 2- bases）Benzene -1- sulfonamide is dissolved in solid-liquid Volume ratio 1:2~1:In 5 tetrahydrofuran, ethyl acetate, chloroform, 1,2- dichloromethane, acetonitrile, benzene, toluene or dichloromethane A kind of solvent in, add and 4-（1,3- dioxo -1- phenyl butyl- 2- bases）Benzene -1- sulfonamide mol ratio is 1:0.8 ~ 1.2 Propionyl chloride, base catalyst is added, 6 ~ 12h is reacted at 20 ~ 110 DEG C and obtains N-（4-（1,3- dioxo -1- phenyl butyl- 2- Base）Phenyl sulfonyl）Propionamide；E, the preparation of N- (4- (5- hydroxy-5-methyl base -3- phenyl -4,5- dihydro-isoxazole -4- bases) phenyl sulfonyl) propionamide：The N- that step D is prepared（4-（1,3- dioxo -1- phenyl butyl- 2- bases）Phenyl sulfonyl）Propionamide is dissolved in solid Liquid volume ratio 1:2~1:In 5 70 ~ 100% ethanol, addition and N-（4-（1,3- dioxo -1- phenyl butyl- 2- bases）PhenylSulphon Base）Propionamide mol ratio is 1:0.8 ~ 1.2 hydroxylamine hydrochloride, 0.5 ~ 6h of reaction obtains N- (4- (5- hydroxyls -5- at 50 ~ 90 DEG C Methyl -3- phenyl -4,5- dihydro-isoxazole -4- bases) phenyl sulfonyl) propionamide；F, the preparation of SC 69124：N- (4- (5- hydroxy-5-methyl base -3- phenyl -4,5- dihydro-isoxazole -4- bases) phenylSulphons that step E is prepared Base) propionamide is added to solid-liquid volume ratio 1 under -5 ~ 5 DEG C of condition of ice bath:2~1:In 3 acid flux material, kept for 0 ~ 30 DEG C At a temperature of 4 ~ 12h of stirring reaction obtain object SC 69124.
- 2. the method for SC 69124 is prepared according to claim 1, it is characterised in that the Louis acid catalysis described in step A Agent is in alchlor, titanium tetrachloride, boron trifluoride, iron chloride, zinc chloride, niobium pentoxide, trifluoro sulfonate, p-methyl benzenesulfonic acid One kind, addition be feed molar amount 5 ~ 20%.
- 3. the method for SC 69124 is prepared according to claim 1, it is characterised in that the sulfonated reagent described in step B is chlorine One kind in sulfonic acid, the concentrated sulfuric acid, oleum, sulfur trioxide.
- 4. according to the method for preparing SC 69124 of claim 1 or 3, it is characterised in that described sulfonated reagent is chlorine sulphur Acid.
- 5. the method for SC 69124 is prepared according to claim 1, it is characterised in that the acylated examination described in step D methods one Agent is one kind in propionic andydride, propionyl chloride, propionic acid.
- 6. according to the method for preparing SC 69124 of claim 1 or 5, it is characterised in that described acylating reagent is propionic acid Acid anhydride.
- 7. the method for SC 69124 is prepared according to claim 1, it is characterised in that the catalyst described in step D methods one For p-methyl benzenesulfonic acid, benzene sulfonic acid, 4- dimethylaminopyridines, silica gel, sulfuric acid, ferric trichloride, titanium tetrachloride or boron trifluoride One kind in ether.
- 8. the method for SC 69124 is prepared according to claim 1, it is characterised in that the alkalescence described in step D methods two is urged Agent is one kind in carbonate, triethylamine, diisopropyl ethyl amine, DMAP.
- 9. the method for SC 69124 is prepared according to claim 1, it is characterised in that the acid flux material described in F-step is three One kind in fluorine acetic acid, hydrochloric acid, sulfuric acid, acetic acid, formic acid, phosphoric acid or oxalic acid.
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