CN107325060A - A kind of Lesinurad intermediates of crystal habit and preparation method thereof - Google Patents
A kind of Lesinurad intermediates of crystal habit and preparation method thereof Download PDFInfo
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- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
A kind of Lesinurad intermediates of crystal habit and preparation method thereof.The invention discloses lesinurad intermediate IIs of a kind of crystal habit and preparation method thereof.The means of differential scanning calorimetry of the Lesinurad intermediate IIs of the crystal habit of the present invention is determined has peak at 98~102 DEG C；Its powder X-ray x ray diffraction is in 2 θ：There is characteristic peak at 8.8 ± 0.2 °, 10.5 ± 0.2 °, 10.6 ± 0.2 °, 15.6 ± 0.2 °, 22.1 ± 0.2 °, 22.9 ± 0.2 °.The present invention obtains Lesinurad intermediate II crystalline solids first, and purity is high；Method for crystallising is simple to operate, column chromatography purifying is not required to, suitable for industrialization；Gained crystalline solids property is stable, is easy to storage to transport and follow-up dosing operation, and the purity by its preparation gained finished product Lesinurad is high.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to Lesinurad intermediates of a kind of crystal habit and preparation method thereof.
Background technology
Gout is the crystal correlation arthropathy caused by a kind of monosodium urate mineralization, is a kind of metabolic disease of world pop.China
The illness rate of state's gout is about 0.15%~0.67%.As economic develops rapidly, the continuous increasing that people take in high protein diet
Plus, the illness rate of gout and hyperuricemia is also constantly being raised.
Lesinurad (structural formula is shown in formula I), chemical name is 2- [[the bromo- 4- of 5- (4- cyclopropyl -1- naphthalene -1- bases) -4H-1,2,4- triazoles
- 3- bases] thio] acetic acid, it is that a kind of urate transporter 1 (URAT1) of Astrazeneca AB (AstraZeneca) exploitation suppresses
Agent, ratified to list, trade name ZURAMPIC, for combining xanthine oxidase inhibitor (XOLs) in 2015 in the U.S.
Treat the related hyperuricemia of gout.
Lesinurad is generally obtained as the intermediate hydrolysis shown in formula II, and the quality of the intermediate will directly affect finished product
Lesinurad quality.
PCT Patent WO2006026356 discloses a kind of preparation method of Lesinurad intermediate IIs, and synthetic route is as flowed
Shown in journey 1：
Flow 1
The amino of intermediate III is oxidized to diazonium through natrium nitrosum, then carries out bromo-reaction, obtained intermediate II with bromofom
Reaction solution, is directly purified through column chromatography, obtains intermediate II, is foam-like sticky solid, purity about 95%.Use post layer
Analysis purifying intermediate II, is unfavorable for industrialized production, and product purity is low, state difference.PCT Patent WO2009070740
Similar approach is disclosed with WO2011085009.
PCT Patent WO2014008295 discloses a kind of preparation method of Lesinurad intermediate IIs, and synthetic route is as flowed
Shown in journey 2：
Flow 2
The amino of intermediate III is oxidized to diazonium through potassium nitrite, then carries out bromo-reaction with copper bromide.Reaction, which is finished, uses first
Benzene is extracted, and is then repeatedly washed toluene phase with ammoniacal liquor and sodium citrate solution, to remove copper ion, is obtained intermediate II crude product,
Purity about 85%.Intermediate II without isolation and purifying, proceed sodium hydroxide hydrolysis reaction prepare Lesinurad, due to
Impurity is more, and the purifying to finished product Lesinurad brings larger difficulty.
PCT Patent WO2014008295 also discloses the preparation method of another Lesinurad intermediate II, synthesizes road
Line is as shown in flow 3：
Flow 3
Intermediate compound IV and N- bromo-succinimides (NBS) carry out bromo in tetrahydrofuran (THF) at 27-32 DEG C
Reaction.Reaction is finished, post-treated obtained intermediate II, purity about 91%.Intermediate II without isolation and purifying, after
Continuous to prepare Lesinurad through sodium hydroxide hydrolysis reaction, because impurity is more, the purifying to product Lesinurad brings larger tired
It is difficult.
PCT Patent WO2014198241 discloses a kind of preparation method of Lesinurad intermediate IIs, synthetic route such as flow
Shown in 4：
Flow 4
Intermediate compound IV and bromo- 5, the 5- DMHs back flow reaction in ethyl acetate of 1,3- bis-, post-treated obtained intermediate
II, is yellow foam sticky solid, purity about 87%, and impurity is more, if do not purified, is unfavorable for product in subsequent reactions
Lesinurad purifying.
Intermediate II is prepared by bromination reaction, has diverse location bromo or the impurity of many bromines substitution residual in intermediate II
Stay, these bromo impurity have similar property to intermediate II, be difficult to remove, the purity of intermediate II is generally below 92%.
If intermediate II is not purified, alkali is further added to carry out deesterify reaction generation Lesinurad, diverse location bromo or many
The intermediate II impurity of bromine substitution also carries out deesterify reaction, generates bromo Lesinurad impurity, due to bromo impurity character with
Product Lesinurad is not easy to be separated off than relatively similar, and the purifying to finished product Lesinurad brings larger difficulty.Example
As in WO2014008295 embodiments 2A, Lesinurad preparation is to pass through the intermediate II prepared to post-process,
Lesinurad sodium salts are generated through deesterify, then with the sour acid adjustments of HBr, is then repeatedly extracted, then concentrated again with ethyl acetate
Ethyl acetate is to certain volume, plus normal heptane crystallization is obtained, and step is more, cumbersome.
To sum up, prior art does not obtain high-purity, crystal form Lesinurad intermediate IIs, does not disclose yet and is adapted to industry
The purification process of the Lesinurad intermediate IIs of metaplasia production.Because the purity of intermediate II directly affects the pure of finished product Lesinurad
Degree, it is therefore necessary to study the purification process and solid-state form of Lesinurad intermediate IIs.
The content of the invention
Unexpected, the present inventor has obtained high-purity, easily stored crystal habit in the research to Lesinurad
Lesinurad intermediate IIs, and used method simple possible, beneficial to industrialization.
Therefore, one aspect of the present invention provides the Lesinurad intermediate IIs of crystal habit,
It is preferred that, the Lesinurad intermediate IIs of described crystal habit, its means of differential scanning calorimetry is determined has peak at 98~102 DEG C；
It is further preferred that its means of differential scanning calorimetry is determined has peak at 99~101 DEG C；Still more preferably, described crystal habit
Lesinurad intermediates, it has Differential Scanning Calorimetry substantially as shown in accompanying drawing 4-6 is any.The crystallization
Means of differential scanning calorimetry has experimental error, between an instrument and another instrument and between a sample and another sample,
The position of endothermic peak and peak value may slightly have difference, and the numerical value of experimental error or difference is likely less than equal to 5 DEG C, or less than etc.
In 4 DEG C, or less than or equal to 3 DEG C, or less than or equal to 2 DEG C, or less than or equal to 1 DEG C, therefore the means of differential scanning calorimetry absorbs heat
The peak position at peak or the numerical value of peak value can not be considered as absolute.
It is preferred that, the Lesinurad intermediate IIs of described crystal habit are radiated using Cu-K α, with 2 θ angles (°) tables
The powder x-ray diffraction shown has characteristic peak in following position：8.8±0.2°、10.5±0.2°、10.6±0.2°、15.6±0.2°、
22.1±0.2°、22.9±0.2°；The relative peak intensities (peak area ratio A%) of the characteristic peak are not less than 50%.
It is further preferred that the Lesinurad intermediate IIs of described crystal habit, it is characterised in that radiated using Cu-K α,
There is characteristic peak in following position with the powder x-ray diffraction that 2 θ angles (°) are represented：
(1)8.8±0.2°、10.5±0.2°、10.6±0.2°、15.6±0.2°、22.1±0.2°、22.9±0.2°、23.1±0.2°、24.8±0.2°、
26.9±0.2°；The relative peak intensities (peak area ratio A%) of the characteristic peak are not less than 40%；Or
(2)8.0±0.2°、8.8±0.2°、10.5±0.2°、10.6±0.2°、13.0±0.2°、15.6±0.2°、19.0±0.2°、22.1±0.2°、
22.9±0.2°、23.1±0.2°、23.4±0.2°、24.3±0.2°、24.8±0.2°、26.5±0.2°、26.9±0.2°；The characteristic peak
Relative peak intensities (peak area ratio A%) be not less than 30%；Or
(3)8.0±0.2°、8.8±0.2°、10.5±0.2°、10.6±0.2°、13.0±0.2°、13.2±0.2°、15.6±0.2°、19.0±0.2°、
20.0±0.2°、21.0±0.2°、22.1±0.2°、22.9±0.2°、23.1±0.2°、23.4±0.2°、24.3±0.2°、24.8±0.2°、
26.5±0.2°、26.9±0.2°、30.8±0.2°；The relative peak intensities (peak area ratio A%) of the characteristic peak are not less than 20%；
Or
(4)8.0±0.2°、8.8±0.2°、10.5±0.2°、10.6±0.2°、13.0±0.2°、13.2±0.2°、15.6±0.2°、17.6±0.2°、
19.0±0.2°、20.0±0.2°、21.0±0.2°、21.5±0.2°、22.1±0.2°、22.9±0.2°、23.1±0.2°、23.4±0.2°、
24.3±0.2°、24.8±0.2°、25.5±0.2°、26.5±0.2°、26.9±0.2°、27.2±0.2°、28.3±0.2°、29.5±0.2°、
30.8±0.2°；The relative peak intensities (peak area ratio A%) of the characteristic peak are not less than 10%；Or
(5)8.0±0.2°、8.8±0.2°、10.5±0.2°、10.6±0.2°、13.0±0.2°、13.2±0.2°、14.9±0.2°、15.6±0.2°、
16.3±0.2°、17.6±0.2°、19.0±0.2°、19.5±0.2°、20.0±0.2°、21.0±0.2°、21.5±0.2°、22.1±0.2°、
22.9±0.2°、23.1±0.2°、23.4±0.2°、24.3±0.2°、24.8±0.2°、25.5±0.2°、26.5±0.2°、26.9±0.2°、
27.2±0.2°、28.3±0.2°、29.5±0.2°、30.8±0.2°；The relative peak intensities (peak area ratio A%) of the characteristic peak are no
Less than 5%.
It is further preferred that the Lesinurad intermediate IIs of described crystal habit, are radiated using Cu-K α, it has basic
The upper powder x-ray diffraction collection of illustrative plates as shown in accompanying drawing 1 to 3 is any.Term " substantially as shown in drawings " refers to substantially pure
At least 50% in net its powder x-ray diffraction collection of illustrative plates of certain crystal formation, or at least 60%, or at least 70%, or at least 80%,
Or at least 90%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99% peak occurs
In given powder x-ray diffraction collection of illustrative plates.When the content of the crystal formation of certain in sample is gradually reduced, its powder X-ray spreads out
The diffraction maximum that some penetrated in collection of illustrative plates belong to the crystal formation may be tailed off due to the factor of the detection sensitivity of instrument.
Another aspect of the present invention also provides a kind of preparation method of the Lesinurad intermediate IIs of crystal habit, comprises the following steps：
By Lesinurad intermediate II dissolving crude products in solvent, acid is added, -10~30 DEG C of stirring and crystallizings 0.5~10 are then cooled to
Hour, separation obtains the Lesinurad intermediate IIs of described crystal habit.
Wherein：
The solvent is selected from acetone, ethyl acetate, butanone, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, N, N- dimethyl formyls
One or more in amine, methanol, ethanol, isopropanol, n-hexane, normal heptane, petroleum ether, preferably N, N- dimethyl
Formamide, acetone, methanol, ethanol, the one or more of isopropanol.The solvent can be added once, can also be many
It is secondary to add.The weight ratio of the solvent and Lesinurad intermediate II crude products is 1~100:1, more preferably 5~50:1, it is optimal
Elect 5~15 as:1.Solution temperature is preferably 20~80 DEG C, more preferably 20~40 DEG C.
It is described acid selected from sulfuric acid, hydrochloric acid, phosphoric acid, nitric acid, hydrobromic acid, hydroiodic acid, formic acid, acetic acid, propionic acid, methanesulfonic acid,
One or more in ethyl sulfonic acid, p-methyl benzenesulfonic acid, maleic acid, fumaric acid, citric acid, oxalic acid, butanedioic acid and matrimony vine acid,
One or more preferably in sulfuric acid, hydrochloric acid, phosphoric acid and acetic acid.Mole of the acid and Lesinurad intermediate II crude products
Than for 0.5~50:1, consider from yield, more preferably 0.5~5:1, most preferably 1~3:1.
Recrystallization temperature is preferably -5~20 DEG C, more preferably -5~10 DEG C, most preferably 0-5 DEG C.
The separating step includes crystallizing gained Lesinurad intermediate IIs from crystallization using suitable methods such as filtering, centrifugations
Separated in liquid.
Preferably, free solvent considers from product is removed, after separating step, in addition to drying steps, and drying means can
Using any suitable known method, preferably depressurize (vacuum) and dry.Specific drying condition is, for example, temperature is excellent
Select 40~60 DEG C, more preferably 40~50 DEG C；Pressure is preferably vacuum ＞ 0.090Mpa；Drying time is preferably 5~20h,
More preferably 5~8h.No matter which kind of drying means is used, quality standard is all met with solvent residual amount in products obtained therefrom and is advisable.
Heretofore described Lesinurad intermediate IIs crude product, can be using disclosed any known method system in the prior art
It is standby, the preparation method of Lesinurad intermediate IIs as disclosed in following documents：WO2006026356、WO2009070740、
WO2011085009, WO2014008295 and WO2014198241 etc..
The Lesinurad intermediate IIs crude product can be semi-solid or amorphous solid；Can be various purity, preferably purity exists
More than 85%.
Another aspect of the present invention also provides the Lesinurad intermediate IIs of described crystal habit and pressed down preparing urate transporter 1
Application in preparation Lesinurad.The method that Lesinurad is prepared by the Lesinurad intermediate IIs of the crystal habit of the present invention
It can refer to any known method in the prior art to be prepared, such as：WO200602635, WO2014008295.
The beneficial effect of the Lesinurad intermediate IIs of the crystal habit of the present invention is：
1. Lesinurad intermediate II crystalline solids are obtained first, and purity is high, more than 98%；
2. it is simple to operate, column chromatography purifying is not required to, suitable for industrialization；
3. property is stable, is easy to storage to transport and follow-up dosing operation, and the purity by its preparation gained finished product Lesinurad is high,
More than 99%.
Brief description of the drawings
Fig. 1：The powder x-ray diffraction figure of the Lesinurad intermediate IIs of the gained crystal habit of the embodiment of the present invention 1.
Fig. 2：The powder x-ray diffraction figure of the Lesinurad intermediate IIs of the gained crystal habit of the embodiment of the present invention 2.
Fig. 3：The powder x-ray diffraction figure of the Lesinurad intermediate IIs of the gained crystal habit of the embodiment of the present invention 3.
Fig. 4：The Differential Scanning Calorimetry of the Lesinurad intermediate IIs of the gained crystal habit of the embodiment of the present invention 1.
Fig. 5：The Differential Scanning Calorimetry of the Lesinurad intermediate IIs of the gained crystal habit of the embodiment of the present invention 2.
Fig. 6：The Differential Scanning Calorimetry of the Lesinurad intermediate IIs of the gained crystal habit of the embodiment of the present invention 3.
Embodiment
Gained sample powder X-ray diffracting spectrum and Differential Scanning Calorimetry testing conditions are as follows in following examples：
1st, powder x-ray diffraction collection of illustrative plates
Device name：D/MAX-2500X- x ray diffractometer xs
Target：Cu (40KV, 150mA)
Step angle：0.02°
Scanning range：1.5~40.0 °
2nd, Differential Scanning Calorimetry
Device name：PerkinElmer Diamond differential scanning calorimeters (DSC)
Heating rate：20.00℃/min
Preparation example：The preparation of Lesinurad intermediate II crude products (with reference to WO2014198241)
In 2.5L there-necked flasks, plus 40g Lesinurad intermediate compound IVs (0.118mol), 33.7g 1, bromo- 5, the 5- dimethyl seas of 3- bis-
Because of (0.118mol) and 1L ethyl acetate, return stirring until reaction is complete.Reaction solution is cooled to room temperature, plus 1L washings
Wash, split-phase.Organic phase is washed with 1L 2% solution of sodium bisulfite, then respectively with 1L 6.5% sodium bicarbonate solution and
1L water washings.Organic phase is concentrated under reduced pressure, and obtains 44.6g foam yellow solids, yield 90.3%, purity 87.1%, XRD
It is detected as amorphous solid.
Embodiment 1：The preparation of Lesinurad intermediate IIs crystallization
In 100mL there-necked flasks, plus 10g Lesinurad intermediate IIs crude products (23.9mmol) and 30mL N, N- dimethyl
Formamide, is stirred at room temperature dissolving, and adding has a large amount of solids to separate out in 14.5mL 3N hydrochloric acid (43.5mmol), whipping process,
Add 200mL acetone.0 DEG C is cooled to, continues to stir 1h.Suction filtration, filter cake is washed with acetone, vacuum drying, is obtained
White solid 9.35g, yield 93.5%, HPLC purity is 98.8%, and gained solid sample is carried out into powder X-ray
Diffraction, testing result is crystalline solid, and gained collection of illustrative plates is shown in accompanying drawing 1, and spectrum data is shown in Table 1.
The gained Lesinurad intermediate II crystalline powder X-ray diffraction characteristic peak datas of 1 embodiment of table 1
Gained crystallized sample is subjected to differential scanning calorimetry (DSC) test, gained collection of illustrative plates endothermic peak initial temperature is 94.45 DEG C,
102.83 DEG C of end temp, 100.28 DEG C of peak value (see accompanying drawing 4).
Embodiment 2：The preparation of Lesinurad intermediate IIs crystallization
Add 10g Lesinurad intermediate IIs crude products (23.9mmol) and 50mL ethanol in 100mL there-necked flasks, be heated to 30 DEG C,
Stirring and dissolving, adding has a large amount of solids to separate out in 3.8mL acetic acid (66.3mmol), whipping process, add 150mL
Isopropanol, cools to 0 DEG C, continues to stir 2h.Suction filtration, filter cake is washed with isopropanol, vacuum drying, obtains white solid
9.09g, yield 90.9%, HPLC purity is 98.2%, and gained solid sample is carried out into powder X-ray diffraction, inspection
Survey result is crystalline solid, and gained collection of illustrative plates is shown in accompanying drawing 2, and spectrum data is shown in Table 2.
The gained Lesinurad intermediate II crystalline powder X-ray diffraction characteristic peak datas of 2 embodiment of table 2
Gained crystallized sample is subjected to differential scanning calorimetry (DSC) test, gained collection of illustrative plates endothermic peak initial temperature is 93.99 DEG C,
102.53 DEG C of end temp, 99.90 DEG C of peak value (see accompanying drawing 5).
Embodiment 3：The preparation of Lesinurad intermediate IIs crystallization
Add 10g Lesinurad intermediate IIs crude products (23.9mmol) and 200mL acetonitriles in 500mL there-necked flasks, be heated to
30 DEG C, stirring and dissolving, adding has a large amount of solids to separate out in 23.9mL 2N sulfuric acid (47.8mmol), whipping process, cooling
To 0 DEG C, continue to stir 2h.Suction filtration, filter cake is washed with acetonitrile, vacuum drying, obtains white solid 8.86g, yield 88.6%,
HPLC purity is 98.6%, gained solid sample is carried out into powder X-ray diffraction, testing result is crystalline solid,
Gained collection of illustrative plates is shown in accompanying drawing 3, and spectrum data is shown in Table 3.
The gained Lesinurad intermediate II crystalline powder X-ray diffraction characteristic peak datas of 3 embodiment of table 3
Gained crystallized sample is subjected to differential scanning calorimetry (DSC) test, gained collection of illustrative plates endothermic peak initial temperature is 95.12 DEG C,
102.56 DEG C of end temp, 99.91 DEG C of peak value (see accompanying drawing 6).
Embodiment 4：Lesinurad preparation (with reference to WO2014008295 methods)
In 100mL there-necked flasks, plus 5.1g Lesinurad intermediate IIs (sample of embodiment 1,12.2mmol), 25mL first
Benzene, 0.8g sodium hydroxides (20mmol) and 20mL purified waters, in 20 DEG C of stirring reaction 2h, reaction is complete.Split-phase, is used
20mL purified waters extract organic phase, merge aqueous phase.Aqueous phase is concentrated to 25mL or so, 2h is stirred at 0~5 DEG C, suction filtration is cold
Water washing, vacuum drying, obtains 3.82g white solids, HPLC purity 99.2%.
Following comparative example is inventor's reference art methods, and/or combines what conventional method was carried out.According to art methods
Resulting Lesinurad intermediate IIs are non-solid or amorphous solid, purity difference, and being tied again through multi-solvents system
Crystalline substance purifying, products obtained therefrom is grease, it is impossible to obtain solid, and purity is not also improved.With obtained by art methods
Lesinurad intermediate IIs are the preparation that raw material directly carries out Lesinurad, and gained Lesinurad purity is poor, adds
Finished product purifies difficulty.
Comparative example 1：The preparation of Lesinurad intermediate IIs (with reference to WO2009070740)
In 5L there-necked flasks, plus 71g Lesinurad intermediate IIIs (0.2mol), 136.7g triethyl benzyl ammonia chlorides (0.6mol)
With 1L bromofoms, stirring and dissolving, to reaction bulb in plus 138g natrium nitrosums (2mol) and 33mL dichloroacetic acid (0.4mol),
Reaction 3h is stirred at room temperature.Reaction solution is directly purified with silica gel column chromatography, first with dichloromethane eluent, until bromofom is eluted completely
Out, then with acetone/dichloromethane (5:95) elute.Concentrate eluant, obtains 70g intermediate IIs, is that foam-like is shallow
Yellow solid, yield 83.7%, purity 95.3%, XRD is detected as amorphous solid.
Gained solid sample is taken with from acetone, ethyl acetate, butanone, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, N, N- dimethyl
One or more solvents in formamide, methanol, ethanol, isopropanol, n-hexane, normal heptane, petroleum ether etc. are tied again
Crystalline substance, is grease, it is impossible to obtain solid, and purity is not also improved.
Comparative example 2：Lesinurad preparation (with reference to WO2014008295)
1. the preparation of Lesinurad intermediate IIs
In 200mL four-hole bottles, plus 10g Lesinurad intermediate compound IVs (29.5mmol) and 60mL tetrahydrofurans, 35 DEG C
Lower stirring and dissolving.30 DEG C are cooled to, 7.35g N- bromo-succinimides (41.3mmol), stirring reaction, HPLC is added
Monitoring intermediate compound IV is down to less than 0.2% (if N- bromo-succinimides not enough, can be added suitably).
5 DEG C are cooled to, reaction solution is extracted with 50mL toluene and 50mL water, split-phase.Then toluene mutually uses 50mL 2% Asia
Sodium bisulfate is washed.At 20 DEG C, toluene is mutually respectively with 50mL 6.5% sodium bicarbonate solution and 50mL water washings.Have
Machine is mutually divided into two, and a copy of it organic phase (numbering intermediate II -1) carries out the next step, another (numbering intermediate II -2)
It is concentrated under reduced pressure, obtains 5.5g clear yellow viscous things, purity 91.2%.
2. Lesinurad preparation
Add 0.8g sodium hydroxides (20mmol) and 20mL purified waters into the toluene solution of intermediate II -1, in 20 DEG C of stirrings
2h is reacted, reaction is complete.Split-phase, organic phase is extracted with 20mL purified waters, merges aqueous phase.Concentrate aqueous phase left to 25mL
The right side, 2h is stirred at 0~5 DEG C, and suction filtration, cold water washing, vacuum drying obtains 3.75g white solids, HPLC purity 95.7%.
Comparative example 3：Lesinurad preparation (with reference to WO2014008295)
1. the preparation of Lesinurad intermediate IIs
In 100mL there-necked flasks, plus 0.71g Lesinurad intermediate IIIs (2mmol), 1.787g copper bromides (8mmol)
With 20mL acetonitriles, 15~20 DEG C of temperature control, stirring is lower to add 3.41g potassium nitrites (40mol), stirring until reaction is complete.
Add 24mL 3N NaOH solutions and 4.61g citric acids in reaction bulb, stir 5 minutes, then add the extraction of 20mL toluene, point
Phase.Organic phase is washed with 10mL 1N ammoniacal liquor and 10mL 1N sodium citrate solutions respectively.Organic phase is divided into two, wherein one
Part organic phase (numbering intermediate II -3) carries out the next step, and another (numbering intermediate II -4) organic phase is concentrated under reduced pressure,
Obtain 0.39g clear yellow viscous things, purity 85.8%.
2. Lesinurad preparation
Add 60mg sodium hydroxides (1.5mmol) and 5mL purified waters into the toluene solution of intermediate II -3, in 20 DEG C of stirrings
2h is reacted, reaction is complete.Split-phase, organic phase is extracted with 5mL purified waters, merges aqueous phase.Aqueous phase is concentrated to 2mL or so,
2h is stirred at 0~5 DEG C, suction filtration, cold water washing, vacuum drying obtains 0.233g white solids, HPLC purity 95.5%.
Claims (10)
1. the Lesinurad intermediate IIs of crystal habit,
2. the Lesinurad intermediate IIs of crystal habit as claimed in claim 1, it is characterised in that its means of differential scanning calorimetry
Measure has peak at 98~102 DEG C；It is preferred that, its means of differential scanning calorimetry is determined has peak at 99~101 DEG C.
3. the Lesinurad intermediate IIs of crystal habit as claimed in claim 1, it is characterised in that use Cu-K α spokes
Penetrate, have characteristic peak in following position with the powder x-ray diffraction that 2 θ angles (°) are represented：8.8±0.2°、10.5±0.2°、
10.6±0.2°、15.6±0.2°、22.1±0.2°、22.9±0.2°。
4. the Lesinurad intermediate IIs of crystal habit as claimed in claim 3, it is characterised in that use Cu-K α spokes
Penetrate, have characteristic peak in following position with the powder x-ray diffraction that 2 θ angles (°) are represented：
(1)8.8±0.2°、10.5±0.2°、10.6±0.2°、15.6±0.2°、22.1±0.2°、22.9±0.2°、23.1±0.2°、24.8±0.2°、
26.9±0.2°；Or
(2)8.0±0.2°、8.8±0.2°、10.5±0.2°、10.6±0.2°、13.0±0.2°、15.6±0.2°、19.0±0.2°、22.1±0.2°、
22.9±0.2°、23.1±0.2°、23.4±0.2°、24.3±0.2°、24.8±0.2°、26.5±0.2°、26.9±0.2°；Or
(3)8.0±0.2°、8.8±0.2°、10.5±0.2°、10.6±0.2°、13.0±0.2°、13.2±0.2°、15.6±0.2°、19.0±0.2°、
20.0±0.2°、21.0±0.2°、22.1±0.2°、22.9±0.2°、23.1±0.2°、23.4±0.2°、24.3±0.2°、24.8±0.2°、
26.5±0.2°、26.9±0.2°、30.8±0.2°；Or
(4)8.0±0.2°、8.8±0.2°、10.5±0.2°、10.6±0.2°、13.0±0.2°、13.2±0.2°、15.6±0.2°、17.6±0.2°、
19.0±0.2°、20.0±0.2°、21.0±0.2°、21.5±0.2°、22.1±0.2°、22.9±0.2°、23.1±0.2°、23.4±0.2°、
24.3±0.2°、24.8±0.2°、25.5±0.2°、26.5±0.2°、26.9±0.2°、27.2±0.2°、28.3±0.2°、29.5±0.2°、
30.8±0.2°；Or
(5)8.0±0.2°、8.8±0.2°、10.5±0.2°、10.6±0.2°、13.0±0.2°、13.2±0.2°、14.9±0.2°、15.6±0.2°、
16.3±0.2°、17.6±0.2°、19.0±0.2°、19.5±0.2°、20.0±0.2°、21.0±0.2°、21.5±0.2°、22.1±0.2°、
22.9±0.2°、23.1±0.2°、23.4±0.2°、24.3±0.2°、24.8±0.2°、25.5±0.2°、26.5±0.2°、26.9±0.2°、
27.2±0.2°、28.3±0.2°、29.5±0.2°、30.8±0.2°。
5. the Lesinurad intermediate IIs of crystal habit as claimed in claim 3, it is characterised in that use Cu-K α spokes
Penetrate, it has the powder x-ray diffraction collection of illustrative plates substantially as shown in accompanying drawing 1 to 3 is any.
6. a kind of preparation method of the Lesinurad intermediate IIs of the crystal habit described in any one of claim 1-5, including such as
Lower step：By Lesinurad intermediate II dissolving crude products in solvent, acid is added, -10~30 DEG C of stirring analysis are then cooled to
Brilliant 0.5~10 hour, separation obtains the Lesinurad intermediate IIs of described crystal habit.
7. preparation method as claimed in claim 6, it is characterised in that：The solvent be selected from acetone, ethyl acetate, butanone,
Tetrahydrofuran, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, methanol, ethanol, isopropanol, n-hexane, normal heptane,
One or more in petroleum ether, preferably DMF, acetone, methanol, ethanol, one kind of isopropanol or
Person is a variety of.
8. preparation method as claimed in claim 7, it is characterised in that：The solvent and Lesinurad intermediate II crude products
Weight ratio is 1~100:1, preferably 5~50:1, more preferably 5~15:1.
9. preparation method as claimed in claim 6, it is characterised in that：It is described acid selected from sulfuric acid, hydrochloric acid, phosphoric acid, nitric acid,
Hydrobromic acid, hydroiodic acid, formic acid, acetic acid, propionic acid, methanesulfonic acid, ethyl sulfonic acid, p-methyl benzenesulfonic acid, maleic acid, fumaric acid,
One or more in citric acid, oxalic acid, butanedioic acid and matrimony vine acid, preferably one in sulfuric acid, hydrochloric acid, phosphoric acid and acetic acid
Plant or a variety of；It is preferred that, the mol ratio of the acid and Lesinurad intermediate II crude products is 0.5~50:1, preferably 0.5~5:1,
More preferably 1~3:1.
10. the Lesinurad intermediate IIs of the crystal habit described in claim any one of 1-5 are preparing urate transporter 1
Application in inhibitor Lesinurad.
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