CN105985296B - It is a kind of can be with the process for refining of industrialized lesinurad intermediates 1- naphthalene triazolinthiones - Google Patents
It is a kind of can be with the process for refining of industrialized lesinurad intermediates 1- naphthalene triazolinthiones Download PDFInfo
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Abstract
The invention discloses synthesis technologies and its process for refining that one kind can be used for preparing 1,2,4 triazole 5 (4H) thioketones of gout treatment drug lesinurad intermediates 3 amino 4 (4 cyclopropyl naphthalene, 1 base) 1H.The technique by sodium carbonate liquor be added drop-wise to compound 1 and 2 B1 of compound mixed with second alcohol and water and made of in mixture；Water appropriate is added again after the completion of reaction；Crude product 3 containing 3 M of impurity is used into alkali process in a solvent, 3 M are hydrolyzed, thus obtained 3 crude solid is beaten by ethyl alcohol to get to the product 3 of high-purity.The technique has the advantages that suitable heavy industrialization operation and can generate the product of high-purity.
Description
Technical field
The invention belongs to pharmaceutical technology fields, are particularly related to one kind and can be used for preparing gout treatment drug
The method of lesinurad intermediate 3- amino -4- (4- cyclopropyl naphthalene -1- bases) -1H-1,2,4- triazoles -5 (4H)-thioketones and its
Process for refining.
Background technology
Gout is a kind of so that hyperuricemia and monosodium urate salt (MSU) are deposited on the positions such as joint and cause based on pain
It is that obstacle is discharged in purine metabolic disturbance and/or uric acid to want the chronic metabolic disease of feature, main cause.Whole world gout is suffered from present
Person has tens million of.Lesinurad (RDEA 594) is a kind of can to inhibit uric acid transporter body in kidney by what Ardea companies developed
(urate transporter 1, URAT1) and the oral drugs that uric acid in blood is discharged, earliest by the antiviral agent of Valeant
Object RDEA806 is developed.The ownership of present lesinurad belongs to Astra Zeneca.
The principal synthetic routes (WO2014/008295 and US2013345271) of Lesinurad are as follows.Wherein,
US2013345271 is disclosed synthesizes 3- amino -4- (4- by 4- cyclopropyl -1- naphthalenylisothiocyanates (1) by intermediate 2
Cyclopropyl naphthalene -1- bases) -1H-1, the detailed process (page 15, Step E) of -5 (4H)-thioketones (3) of 2,4- triazole.The technique one
It is made of altogether two steps, the first step (1 → 2) needs to react 15 hours, and second step (2 → 3) needs to react 60 hours, Er Qie
One step also relates to and high boiling DMF is evaporated off in processes after the completion of reaction, and product 3 finally also needs to column chromatography purifying,
Yield is relatively low (there was only 49% by 1 to 3 merging yield).To sum up, the shortcomings that preparing 3 technique by 1 disclosed in document is very
Obviously：Reaction time is very long, is used in technique the operation that high boiling DMF is evaporated off is relatively difficult, has used column chromatography
Purifying, yield are relatively low.
In order to solve the problems in 3 preparation process of above compound, patent CN201410340622.9 discloses one newly
Synthetic route it is (as follows.Wherein R is selected from C1-C10Alkyl, benzyl, by F, Cl, Br, I, NO on phenyl ring2、R1O、C1-C10
Alkyl and CF3Substituted benzyl, allyl, wherein R1=C1-C10Alkyl；X is selected from F, Cl, Br, I, OMs, OTs and OTf),
The route substantially overcomes disadvantages mentioned above, has the characteristics that the time is short, yield is high and does not need column chromatography purifying.
The disclosed general routes outlineds by 1 preparation 3 of CN201410340622.9：
The disclosed route by 1 preparation 3 of CN201410340622.9 embodiments 1：
But to 1 → 3 most potential synthetic route disclosed in patent CN201410340622.9 (i.e.
The embodiment 1 of CN201410340622.9, R=Bn at this time, the cost of yield and RX which reports for work is in disclosed institute
It is optimal in the possible choice of technology) when being furtherd investigate, especially when being studied in pilot scale grade and the above scale, hair
The technical issues of having showed two the route hindered industrially to use.First is, by compound 1 and 2-B1 in the presence of a base in second
When reaction generates 2-C1 in the mixed solution of alcohol/water, extremely sticky jelly can be precipitated in reaction system when proceeding to mid-term,
These substances can be attached on agitating paddle, and stirring is made to be difficult to be smoothed out, extreme influence production safety；Second is, in pilot scale and
When being prepared in above scale, in-depth study is found in the sample according to the separated obtained compound 3 of technique of embodiment 1
Containing a certain amount of impurity 3-M (structural formula is as follows), content is generally in 10%-20% or so.The solubility of 3-M is poor,
The use of technique disclosed in CN201410340622.9 (being beaten in ethanol) is difficult to remove, to the sample purity shadow of compound 3
Sound is very big.Attempt also to be difficult to remove when being recrystallized using straight alcohol or ethyl acetate and hexane mixture equal solvent,
Attempt to be not easy to success when detaching 3-M and 3 using common column chromatography, because compound 3-M solubility is smaller, often in silicon
It is precipitated in rubber column gel column and pillar in column chromatography procedure is caused to block, and column chromatography does not often also use in large-scale production.
For two problems occurred in 1 → 3 technique disclosed in above-mentioned CN201410340622.9, We conducted big
The further investigation of amount discloses a kind of technique side for the product 3 that heavy industrialization can be suitble to operate and can generate high-purity
Method.
It should be strongly noted that there are two types of existence forms for compound 3, i.e. thioketones formula 3-ONE and thiol 3-OL are (as follows
It is shown).Both forms compare in the state of difference, in solution made of different solvents and present in the solution of various concentration
Example is different, but does not influence its use in synthetic reaction.
Invention content
The present invention provides one kind and industrialized can be made by compound 1 exactly in order to solve the disadvantage that the prior art
The technique of standby compound 3, the technique have the advantages that suitable heavy industrialization operation and can generate the product 3 of high-purity.
It is of the present invention by compound 1 synthesize compound 3 process route and its refined route it is as follows.
In order to solve the problems, such as two occurred in 1 → 3 technique disclosed in patent CN201410340622.9, we do
Numerous studies.
(i.e. for first problem：Compound 1 and 2B1 react in the mixed solution of ethanol/water in the presence of a base to be generated
When 2-C1, extremely sticky jelly can be precipitated in reaction system when proceeding to mid-term, these substances can be attached on agitating paddle,
Stirring is set to be difficult to be smoothed out, extreme influence production safety), it uses in former technique and primary sodium carbonate liquor, the present invention is added
2 points of improvement are carried out after research, first is：Sodium carbonate liquor has been changed to slowly be added dropwise, and process is added dropwise and continues 2-12
Between hour, preferably 3-5 hours；Second is：The volume ratio of second alcohol and water in reaction system before dropwise addition sodium carbonate liquor there is into original
1/4~1/2 come is changed to 1/1, is mended again after the completion of reaction and adds water to 1/2 and (disregarded plus the body of water that aqueous sodium carbonate is brought
Product).After our improvement, extremely sticky jelly, reaction system can be precipitated in system when above-mentioned reaction proceeds to mid-term
Stirring is more friendly, is more suitable for industrialized production.
(i.e. for Second Problem：When being prepared in the scale of pilot scale or more, in-depth study finds isolated
Contain a certain amount of impurity 3-M in the sample of compound 3, content is generally in 10%-20% or so.The solubility of 3-M is poor, makes
The technique disclosed in CN201410340622.9 (being beaten in ethanol) is difficult to remove, and is influenced on the quality of compound 3 very big.
Attempt also to be difficult to remove when being recrystallized using ethyl alcohol or ethyl acetate and hexane mixture equal solvent, it is intended to using general
Logical column chromatography is not easy to success when detaching 3-M and 3, because compound 3-M solubility is smaller, is often precipitated on a silica gel column
And pillar in column chromatography procedure is caused to block, and column chromatography does not often also use in large-scale production), we are to product 3
Way of purification has done numerous studies, has finally done significant improvement, i.e.,：The solid of crude product 3 containing impurity 3-M is used at alkali
Reason, 3-M is hydrolyzed, and then recalls to pH value again with acid in post-processing, by conventional processing after extraction, 3 obtained solid
It is beaten by ethyl alcohol, you can obtain the product 3 of high-purity.Used alkali is NaOH or KOH.The product obtained after 3-M hydrolysis
(i.e. 4- cyclopropyl-naphthalidine, benzyl mercaptan, sodium thiocarbonate) i.e. water-soluble (thio carbon in conventional process wherein
Sour sodium) or be dissolved in ethyl alcohol when being beaten using ethyl alcohol and remove (4- cyclopropyl-naphthalidine and benzyl mercaptan).By our upper
After stating improvement, the impurity 3-M for being difficult to remove in product 3 is thoroughly removed, and the quality of product 3 is improved.
Description of the drawings
Fig. 1 is the monocrystalline figure of the X-ray diffraction of compound 3-M.
Specific implementation mode
With reference to embodiment, the present invention is further illustrated.It should be noted that following embodiments are only for
Illustrate, and is not intended to limit the present invention.The various change that those skilled in the art's training centre according to the present invention is made should all
Within the protection domain required by the application claim.
Enlarged experiment of the embodiment 1 based on process route in CN201410340622.9
The synthesis of step 1. compound 2-C1
182.28g (2mol) thiosemicarbazides 2-A is added in the glass reaction kettle of one 20L, it is molten with 2097mL absolute ethyl alcohols
Solution, ice-water bath cooling is lower to be added dropwise 342.06g (2mol) cylite, is dripped off in 10 minutes.After being added dropwise, reaction mixture heating
Reflux 30 minutes, TLC, which is checked, finds that reaction is completed, and then reaction mixture is cooled to room temperature, and what is obtained at this time is 2-B1's
Ethanol solution.
8388mL water and 450.62g (2mol) compound 1 are sequentially added into reaction mixture, it is then primary under stiring
The saturated solution of sodium carbonate prepared by 105.99g (1mol) sodium carbonate and 321mL water is added.After adding, reaction mixture is in room
(20 DEG C -35 DEG C) are stirred using mechanical agitation under temperature, are added about 1.5 hours or so rear systems and are generated a large amount of extremely sticky glues
Object, these jellies be largely adhered on agitating paddle and bottle wall on, stirring at this time becomes more difficult, increase stirring horsepower after
Continuous stirring, and the dope being adhered on agitating paddle and bottle wall is handled using tool frequently, prevent safety accident.Continue to stir
After mixing 24-36 hours, a light yellow syrup is obtained.
Reaction system filters, and vacuum (5mmHg) is 5 hours dry at room temperature for filter cake (carrying certain viscosity), is changed
Close object 2-C1,634.25g, yield 78%, ESI-MS, m/z=407 ([M+H]+)。
The synthesis of step 2. compound 3
609.86g (1.5mol) compound 2-C1 and 6099mL absolute ethyl alcohol is added in the glass reaction kettle of one 20L, and
Temperature rising reflux 1 hour afterwards, TLC check that reaction is completed.
Reaction mixture is cooled to room temperature, continues stirring 3 hours at room temperature, obtains a light yellow brilliant slurry.It filters and receives
Collect solid, 5 hours, as compound 3,381.19g, yield 90% are dried under vacuum (5mmHg).It is analyzed by HPLC, wherein
Contain impurity 3-M 18% (mass ratio).
The above-mentioned crude Compounds 3 of 20g are taken out, attempts to use ethyl alcohol recrystallization, HPLC is used in combination to track impurity 3- in compound 3
The content of M, acquired results are as shown in the table.
Table 1 carries out crude Compound 3 using ethyl alcohol the test result of crystallization and purification
| Crystallisation times are numbered | Ethyl alcohol volume | Yield after crystallization | 3-M contents |
| 1 | 200mL | 18.34g | 17% |
| 2 | 183mL | 16.11g | 16% |
| 3 | 161mL | 14.04g | 15% |
| 4 | 140mL | 12.36g | 15% |
As can be seen from the above table, it is failure to be recrystallized to crude product 3 using ethyl alcohol to remove impurity 3-M therein
, because continuous 4 recrystallizations are very limited to the attenuating of the 3-M contents in crude product 3.Use the mixed of ethyl acetate and n-hexane
When bonding solvent is crystallized, similar result has also been obtained.
The impurity 3-M samples for isolating a small amount of sterling from crude product 3 by careful multiple column chromatography, to identify its standard
True structure, and the refined method for removing 3-M is found accordingly.3-M sterlings, white solid, fusing point：155-157℃；HR-MS,m/z
=350.1029.3-M's1H NMR and13C NMR spectras are relatively stranger, multiple bulge shape signals occur, it is impossible to be used in knot
The determination of structure.It takes 100mg 3-M to be dissolved in the mixture of 10mL absolute ethyl alcohols and 5mL dichloromethane, slowly volatilizees at room temperature,
The monocrystalline for being suitble to X-ray diffraction is obtained after 3 days.Diffraction is carried out using X-ray single crystal diffractometer, is collected according to conventional operation
Data simultaneously parse data, have obtained the accurate structural of 3-M, as shown in Figure 1.Contain a dithiocarbamates in 3-M structures
Formic acid ester structure, it is concluded that the structure is destroyed perhaps by hydrolyzed under basic conditions, and the product destroyed can be molten
It can be removed by being beaten in water or in usual vehicle.The accurate determination of 3-M structures finds us of the present invention
Play key effect to handle 3 crude product to remove 3-M using alkali.
The 2 improved technique of the present invention of embodiment
The synthesis of step 1. compound 2-C1
182.28g (2mol) thiosemicarbazides 2-A is added in the round-bottomed flask of one 10L, is dissolved with 2097mL absolute ethyl alcohols,
Ice-water bath cooling is lower to be added dropwise 342.06g (2mol) cylite, is dripped off in 10 minutes.After being added dropwise, reaction mixture heats up back
Stream 30 minutes, TLC, which is checked, finds that reaction is completed, and then reaction mixture is cooled to room temperature, and what is obtained at this time is the second of 2-B1
Alcoholic solution.
2097mL water and 450.62g (2mol) compound 1 are sequentially added into reaction mixture, then under stiring slowly
The saturated solution of sodium carbonate prepared by 105.99g (1mol) sodium carbonate and 321mL water is added dropwise, time for adding continues 4 hours.It is added dropwise
After, (20 DEG C -35 DEG C) are stirred overnight reaction mixture using mechanical agitation at room temperature, obtain a light yellow magma shape
Object does not generate sticky mucilage binding object in whole process.2097mL water is slowly added into reaction mixture, is dripped in 10 minutes
It is complete, it adds rear reaction mixture and is further continued for stirring 3 hours.
Reaction system filters, and vacuum (5mmHg) is 5 hours dry at room temperature for filter cake, obtains compound 2-C1,658.64g,
Yield 81%, ESI-MS, m/z=407 ([M+H]+)。
The synthesis of step 2. compound 3
650.51g (1.6mol) compound 2-C1 and 6505mL absolute ethyl alcohol is added in the glass reaction kettle of one 20L, and
Temperature rising reflux 1 hour afterwards, TLC check that reaction is completed.
Reaction mixture is cooled to room temperature, and 6505mL n-hexanes are added, and continues stirring 3 hours at room temperature, it is pale yellow to obtain one
Color crystalline substance slurry.Collected by suction solid, preliminarily dried 1 hour, the as crude product of compound 3 under vacuum (20mmHg), passes through
HPLC is analyzed, wherein containing impurity 3-M 15% (mass ratio).
Above-mentioned crude product is all added in 4000mL absolute ethyl alcohols, and stirring adds the NaOH solution of 300mL 30%, mixes
Close object temperature rising reflux 10 minutes, TLC, which is checked, finds that 3-M consumption is complete, and then reaction mixture is cooled to room temperature.
Reaction mixture is added in 16L ice water, stirring, is adjusted pH=7 with concentrated hydrochloric acid, is extracted using the dichloromethane of 2L × 3
It takes.Merge extraction phase, the washing of 1L 10%NaCl solution, anhydrous sodium sulfate drying.It filters and removes drier, filtrate is under vacuum
It is concentrated to dryness, 2000mL ethyl alcohol is added in obtained solid residue, is stirred overnight at room temperature, obtain the brilliant slurry of a white,
Collected by suction solid, it is 5 hours dry under vacuum (5mmHg), obtain compound 3, white solid, 365.94g, 81% (2- of yield
C1 → 3), 3-M is not detected in HPLC purity 99.41%.1H NMR(DMSO-d6,400MHz),12.85(bs,1H,D2O-
), exchangable 8.51 (d, 1H, J=8.8Hz), 7.66 (t, 1H, J=7.2Hz), 7.57 (t, 1H, J=7.4Hz), 7.37
(s, 2H), 7.31 (d, 1H, J=8.0Hz), 5.84 (bs, 2H, D2O-exchangable),1.11-1.15(m,2H),0.81-
0.83(m,2H).
The 3 improved technique of the present invention of embodiment
The synthesis of step 1. compound 2-C1
182.28g (2mol) thiosemicarbazides 2-A is added in the round-bottomed flask of one 10L, is dissolved with 2097mL absolute ethyl alcohols,
Ice-water bath cooling is lower to be added dropwise 342.06g (2mol) cylite, is dripped off in 10 minutes.After being added dropwise, reaction mixture heats up back
Stream 30 minutes, TLC, which is checked, finds that reaction is completed, and then reaction mixture is cooled to room temperature, and what is obtained at this time is the second of 2-B1
Alcoholic solution.
2097mL water and 450.62g (2mol) compound 1 are sequentially added into reaction mixture, then under stiring slowly
The saturated solution of sodium carbonate prepared by 105.99g (1mol) sodium carbonate and 321mL water is added dropwise, time for adding continues 2 hours.It is added dropwise
After, (20 DEG C -35 DEG C) are stirred overnight reaction mixture using mechanical agitation at room temperature, obtain a light yellow magma shape
Object.2097mL water is slowly added into reaction mixture, is dripped off in 10 minutes, and adding rear reaction mixture, to be further continued for stirring 3 small
When.
Reaction system filters, and vacuum (5mmHg) is 5 hours dry at room temperature for filter cake, obtains compound 2-C1,666.77g,
Yield 82%, ESI-MS, m/z=407 ([M+H]+)。
The synthesis of step 2. compound 3
650.51g (1.6mol) compound 2-C1 and 6505mL absolute ethyl alcohol is added in the glass reaction kettle of one 20L, and
Temperature rising reflux 1 hour afterwards, TLC check that reaction is completed.
Reaction mixture is cooled to room temperature, and 6505mL n-hexanes are added, and continues stirring 3 hours at room temperature, it is pale yellow to obtain one
Color crystalline substance slurry.Collected by suction solid, preliminarily dried 1 hour, the as crude product of compound 3 under vacuum (20mmHg), passes through
HPLC is analyzed, wherein containing impurity 3-M 14% (mass ratio).
Above-mentioned crude product is all added in 4000mL absolute ethyl alcohols, and stirring adds the NaOH solution of 300mL 30%, mixes
Close object temperature rising reflux 10 minutes, TLC, which is checked, finds that 3-M consumption is complete, and then reaction mixture is cooled to room temperature.
Reaction mixture is added in 16L ice water, stirring, is adjusted pH=7 with concentrated hydrochloric acid, is extracted using the dichloromethane of 2L × 3
It takes.Merge extraction phase, the washing of 1L 10%NaCl solution, anhydrous sodium sulfate drying.It filters and removes drier, filtrate is under vacuum
It is concentrated to dryness, 2000mL ethyl alcohol is added in obtained solid residue, is stirred overnight at room temperature, obtain the brilliant slurry of a white,
Collected by suction solid, it is 5 hours dry under vacuum (5mmHg), obtain compound 3, white solid, 361.42g, 80% (2- of yield
C1 → 3), 3-M is not detected in HPLC purity 99.43%.1H NMR spectras are consistent with embodiment 2.
The 4 improved technique of the present invention of embodiment
The synthesis of step 1. compound 2-C1
182.28g (2mol) thiosemicarbazides 2-A is added in the round-bottomed flask of one 10L, is dissolved with 2097mL absolute ethyl alcohols,
Ice-water bath cooling is lower to be added dropwise 342.06g (2mol) cylite, is dripped off in 10 minutes.After being added dropwise, reaction mixture heats up back
Stream 30 minutes, TLC, which is checked, finds that reaction is completed, and then reaction mixture is cooled to room temperature, and what is obtained at this time is the second of 2-B1
Alcoholic solution.
2097mL water and 450.62g (2mol) compound 1 are sequentially added into reaction mixture, then under stiring slowly
The saturated solution of sodium carbonate prepared by 105.99g (1mol) sodium carbonate and 321mL water is added dropwise, time for adding continues 12 hours.Drop
After adding, (20 DEG C -35 DEG C) are stirred overnight reaction mixture using mechanical agitation at room temperature, obtain a light yellow magma shape
Object.2097mL water is slowly added into reaction mixture, is dripped off in 10 minutes, and adding rear reaction mixture, to be further continued for stirring 3 small
When.
Reaction system filters, and vacuum (5mmHg) is 5 hours dry at room temperature for filter cake, obtains compound 2-C1,662.71g,
Yield 81.5%, ESI-MS, m/z=407 ([M+H]+)。
The synthesis of step 2. compound 3
650.51g (1.6mol) compound 2-C1 and 6505mL absolute ethyl alcohol is added in the glass reaction kettle of one 20L, and
Temperature rising reflux 1 hour afterwards, TLC check that reaction is completed.
Reaction mixture is cooled to room temperature, and 6505mL n-hexanes are added, and continues stirring 3 hours at room temperature, it is pale yellow to obtain one
Color crystalline substance slurry.Collected by suction solid, preliminarily dried 1 hour, the as crude product of compound 3 under vacuum (20mmHg), passes through
HPLC is analyzed, wherein containing impurity 3-M 13.7% (mass ratio).
Above-mentioned crude product is all added in 4000mL absolute ethyl alcohols, and stirring adds the NaOH solution of 300mL 30%, mixes
Close object temperature rising reflux 10 minutes, TLC, which is checked, finds that 3-M consumption is complete, and then reaction mixture is cooled to room temperature.
Reaction mixture is added in 16L ice water, stirring, is adjusted pH=7 with concentrated hydrochloric acid, is extracted using the dichloromethane of 2L × 3
It takes.Merge extraction phase, the washing of 1L 10%NaCl solution, anhydrous sodium sulfate drying.It filters and removes drier, filtrate is under vacuum
It is concentrated to dryness, 2000mL ethyl alcohol is added in obtained solid residue, is stirred overnight at room temperature, obtain the brilliant slurry of a white,
Collected by suction solid, it is 5 hours dry under vacuum (5mmHg), obtain compound 3, white solid, 365.94g, 81% (2- of yield
C1 → 3), 3-M is not detected in HPLC purity 99.45%.1H NMR spectras are consistent with embodiment 2.
The 5 improved technique of the present invention of embodiment
The synthesis of step 1. compound 2-C1
182.28g (2mol) thiosemicarbazides 2-A is added in the round-bottomed flask of one 10L, is dissolved with 2097mL absolute ethyl alcohols,
Ice-water bath cooling is lower to be added dropwise 342.06g (2mol) cylite, is dripped off in 10 minutes.After being added dropwise, reaction mixture heats up back
Stream 30 minutes, TLC, which is checked, finds that reaction is completed, and then reaction mixture is cooled to room temperature, and what is obtained at this time is the second of 2-B1
Alcoholic solution.
450.62g (2mol) compound 1 is added into reaction mixture, is then slowly added dropwise by 105.99g under stiring
The saturated solution of sodium carbonate that (1mol) sodium carbonate and 321mL water are prepared, time for adding continue 4 hours.After being added dropwise, reaction is mixed
Closing object, (20 DEG C -35 DEG C) are stirred overnight using mechanical agitation at room temperature, obtain a light yellow brilliant slurry.Toward reaction mixture
In slowly add 2097 × 2mL water, dripped off in 10 minutes, add rear reaction mixture be further continued for stirring 3 hours.
Reaction system filters, and vacuum (5mmHg) is 5 hours dry at room temperature for filter cake, obtains compound 2-C1,670.84g,
Yield 82.5%, ESI-MS, m/z=407 ([M+H]+)。
The synthesis of step 2. compound 3
650.51g (1.6mol) compound 2-C1 and 6505mL absolute ethyl alcohol is added in the glass reaction kettle of one 20L, and
Temperature rising reflux 1 hour afterwards, TLC check that reaction is completed.
Reaction mixture is cooled to room temperature, and 6505mL n-hexanes are added, and continues stirring 3 hours at room temperature, it is pale yellow to obtain one
Color crystalline substance slurry.Collected by suction solid, preliminarily dried 1 hour, the as crude product of compound 3 under vacuum (20mmHg), passes through
HPLC is analyzed, wherein containing impurity 3-M 13.4% (mass ratio).
Above-mentioned crude product is all added in 4000mL absolute ethyl alcohols, and stirring adds the NaOH solution of 300mL 30%, mixes
Close object temperature rising reflux 10 minutes, TLC, which is checked, finds that 3-M consumption is complete, and then reaction mixture is cooled to room temperature.
Reaction mixture is added in 16L ice water, stirring, is adjusted pH=7 with concentrated hydrochloric acid, is extracted using the dichloromethane of 2L × 3
It takes.Merge extraction phase, the washing of 1L 10%NaCl solution, anhydrous sodium sulfate drying.It filters and removes drier, filtrate is under vacuum
It is concentrated to dryness, 2000mL ethyl alcohol is added in obtained solid residue, is stirred overnight at room temperature, obtain the brilliant slurry of a white,
Collected by suction solid, it is 5 hours dry under vacuum (5mmHg), obtain compound 3, white solid, 369.10g, yield 81.7%
(2-C1 → 3), HPLC purity 99.49%, are not detected 3-M.1H NMR spectras are consistent with embodiment 2.
Claims (5)
1. a kind of process for refining preparing high-purity compound 3 by compound 1, it is characterised in that：
1) by sodium carbonate liquor be added drop-wise to compound 1 and 2-B1 mixed with second alcohol and water and made of in mixture；
2) volume ratio of second alcohol and water is 1 in reaction system before dropwise addition sodium carbonate liquor：1, to straight alcohol, mends again after the completion of reaction
The volume ratio for adding water to second alcohol and water is 1：2；
3) 2-C1 reacts in refluxing ethanol sloughs benzyl mercaptan, obtains 3 and by-product 3-M；
4) crude product 3 containing impurity 3-M is used into alkali process in a solvent, 3-M is hydrolyzed, the thiocarbonic acid in follow-up water process
Sodium is dissolved in water and removes, and 3 obtained crude solid removes by-product 4- cyclopropyl-naphthalidine and benzyl mercaptan by mashing, i.e.,
Obtain the product 3 of high-purity.
2. technique as described in claim 1, wherein the time that aqueous sodium carbonate is added dropwise is 2-12 hours.
3. technique as claimed in claim 2, wherein the time that aqueous sodium carbonate is added dropwise is 3-5 hours.
4. technique as described in claim 1, wherein the volume ratio that second alcohol and water in reaction system before sodium carbonate liquor is added dropwise is
1/1。
5. technique as described in claim 1, wherein alkali used in processing crude product 3 is NaOH or KOH.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102741234A (en) * | 2010-01-08 | 2012-10-17 | 亚德生化公司 | Polymorphic, crystalline and mesophase forms of sodium 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4h-1,2,4-triazol-3-ylthio)acetate, and uses thereof |
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| AR091651A1 (en) * | 2012-07-03 | 2015-02-18 | Ardea Biosciences Inc | ACID ELABORATION 2- (5-BROMO-4- (4-CICLOPROPILNAFTALEN-1-IL) -4H-1,2,4-TRIAZOL-3-ILTIO) ACETIC |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102741234A (en) * | 2010-01-08 | 2012-10-17 | 亚德生化公司 | Polymorphic, crystalline and mesophase forms of sodium 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4h-1,2,4-triazol-3-ylthio)acetate, and uses thereof |
Non-Patent Citations (2)
| Title |
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| Microwave-Assisted Synthesis of Novel 4-N,N-Dimethylamino- and 4-Cycloamino-Substituted 1,2,4-Triazole-3-thiones;Katarzyna Gobis，et al.;《Heteroatom Chemistry》;20101231;第21卷(第3期);第188-195页 * |
| Oxidation and eliminative cyclisation of S-Alkylisodithiobiureas;P.V.Indukumari，et al.;《Indian journal of chemistry》;19811231;第20B卷;第384-387页 * |
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