CN109970667A - A kind of refining methd of the western Nader of thunder - Google Patents
A kind of refining methd of the western Nader of thunder Download PDFInfo
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- CN109970667A CN109970667A CN201711447240.6A CN201711447240A CN109970667A CN 109970667 A CN109970667 A CN 109970667A CN 201711447240 A CN201711447240 A CN 201711447240A CN 109970667 A CN109970667 A CN 109970667A
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- 238000007670 refining Methods 0.000 title claims abstract description 19
- 238000006243 chemical reaction Methods 0.000 claims abstract description 32
- 238000000034 method Methods 0.000 claims abstract description 17
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims abstract description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 9
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims abstract description 8
- VZZBXOLWBXJHEK-UHFFFAOYSA-N 1-cyclopropylnaphthalene Chemical compound C1CC1C1=CC=CC2=CC=CC=C12 VZZBXOLWBXJHEK-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000000746 purification Methods 0.000 claims abstract description 5
- 230000007062 hydrolysis Effects 0.000 claims abstract description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 129
- 239000000243 solution Substances 0.000 claims description 41
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 37
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 32
- 239000007788 liquid Substances 0.000 claims description 30
- 238000003756 stirring Methods 0.000 claims description 28
- 230000001376 precipitating effect Effects 0.000 claims description 25
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 24
- 239000012071 phase Substances 0.000 claims description 24
- 239000000047 product Substances 0.000 claims description 21
- 239000008213 purified water Substances 0.000 claims description 20
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 claims description 18
- 238000000926 separation method Methods 0.000 claims description 17
- 238000001514 detection method Methods 0.000 claims description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 16
- 239000011259 mixed solution Substances 0.000 claims description 14
- 230000003068 static effect Effects 0.000 claims description 14
- 238000003810 ethyl acetate extraction Methods 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- 239000002244 precipitate Substances 0.000 claims description 9
- 239000012043 crude product Substances 0.000 claims description 8
- 239000012074 organic phase Substances 0.000 claims description 8
- 239000002994 raw material Substances 0.000 claims description 8
- 239000007787 solid Substances 0.000 claims description 8
- 230000006837 decompression Effects 0.000 claims description 7
- 238000010792 warming Methods 0.000 claims description 7
- 238000000967 suction filtration Methods 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 238000003786 synthesis reaction Methods 0.000 claims description 4
- SNTWKPAKVQFCCF-UHFFFAOYSA-N 2,3-dihydro-1h-triazole Chemical compound N1NC=CN1 SNTWKPAKVQFCCF-UHFFFAOYSA-N 0.000 claims description 3
- 239000012295 chemical reaction liquid Substances 0.000 claims description 3
- WBZKQQHYRPRKNJ-UHFFFAOYSA-L disulfite Chemical compound [O-]S(=O)S([O-])(=O)=O WBZKQQHYRPRKNJ-UHFFFAOYSA-L 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims description 3
- 235000010262 sodium metabisulphite Nutrition 0.000 claims description 3
- 238000005292 vacuum distillation Methods 0.000 claims description 3
- 238000005352 clarification Methods 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 claims description 2
- 239000012530 fluid Substances 0.000 claims description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims 1
- 238000004458 analytical method Methods 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 238000006386 neutralization reaction Methods 0.000 claims 1
- 238000001035 drying Methods 0.000 abstract description 6
- 239000000126 substance Substances 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 239000007858 starting material Substances 0.000 abstract description 3
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 abstract description 2
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- 239000013078 crystal Substances 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 206010013786 Dry skin Diseases 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 229940123769 Xanthine oxidase inhibitor Drugs 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000009413 insulation Methods 0.000 description 2
- FGQFOYHRJSUHMR-UHFFFAOYSA-N lesinurad Chemical compound OC(=O)CSC1=NN=C(Br)N1C(C1=CC=CC=C11)=CC=C1C1CC1 FGQFOYHRJSUHMR-UHFFFAOYSA-N 0.000 description 2
- JKQOBWVOAYFWKG-UHFFFAOYSA-N molybdenum trioxide Chemical compound O=[Mo](=O)=O JKQOBWVOAYFWKG-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000010583 slow cooling Methods 0.000 description 2
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 2
- 229910001948 sodium oxide Inorganic materials 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000003064 xanthine oxidase inhibitor Substances 0.000 description 2
- 201000005569 Gout Diseases 0.000 description 1
- 201000001431 Hyperuricemia Diseases 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229960003838 lesinurad Drugs 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 238000005498 polishing Methods 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000011112 process operation Methods 0.000 description 1
- 230000009103 reabsorption Effects 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 239000002893 slag Substances 0.000 description 1
- -1 stand Substances 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229940032415 zurampic Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- 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
- C07D249/12—Oxygen or sulfur atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses the method for synthesizing and refining of the western Nader of thunder a kind of, with 4- (4- cyclopropyl naphthalene -1- base) -1H-1,2,4- triazole -5 (4H)-mercaptan is starting material, it reacted, neutralized with N- bromo-succinimide bromo-reaction, through sodium hydroxide hydrolysis, hydrobromic acid, purification, drying with alkylated with ethyl bromoacetate, successfully synthesize the western Nader's bulk pharmaceutical chemicals finished product of high-purity thunder, pass through the purifying to each step intermediate, product, to obtain satisfactory high-purity finished product, the method of the invention is easy to carry out product collection, is suitble to industrialized production.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of refining methd of the western Nader of thunder.
Background technique
The western Nader of thunder, molecular formula: C17H14BrN3O2S, Chinese name: 2- ((the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- base) -
4H-1,2,4- triazole -3- bases) thio) acetic acid, trade name: Zurampic, structural formula are as follows:
The western Nader of thunder is AstraZeneca exploitation, lithate reabsorption transporter (URATI) inhibitor of the first listing in the whole world.
U.S. FDA and the listing approval of European Union EMA are obtained at the beginning of the end of the year 2015,2016, combine xanthine oxidase inhibitor
(XOI) for treating the relevant gout of hyperuricemia；In China, the western Nader of thunder only has 1 import so far, declares clinic, until
The present declares without domestic manufacturer, belongs to 3.1 class imitation medicines.
The drug, which is applied for a patent, is related to all various aspects such as synthesis technology, crystal form, crystal form preparation method, is currently known crystal form
For I crystal form, II crystal form, relative to I crystal form, II crystal form is clinical use crystal form.On the synthesis road for having seen patent literature report
In line, to the purification step of every step intermediate and finished product, some link process operations are got up cumbersome, and it is big to there is inadaptable industrialization
The defects of production requirement.
Summary of the invention
In view of the above-mentioned problems of the prior art, the present invention is with 4- (4- cyclopropyl naphthalene -1- base) -1H-1,2,4- triazoles -
5 (4H)-mercaptan be starting material, reacted with alkylated with ethyl bromoacetate, with N- bromo-succinimide bromo-reaction, through hydrogen
Sodium oxide molybdena hydrolysis, hydrobromic acid are neutralized, are refined, is dry, are successfully synthesized high-purity Lesinurad bulk pharmaceutical chemicals finished product, are being deposited
On the basis of its synthetic route of patent report, this patent is further perfect by the preparation progress to product and intermediate,
On the basis of improving yield, the method that the bulk pharmaceutical chemicals of high-purity are obtained on the basis of meeting economic performance of industrial enterprises has been searched out, it should
The solvent that process uses is cheap, and method is simple, is easy to carry out product collection, is suitble to industrialization expanding production.
The synthetic route that the refining methd of the western Nader of thunder of the present invention is related to is as follows:
Intermediate C is added in purified water the refining methd of the western Nader of thunder of the present invention a kind of, and hydrogen bromine is then added
Acid for adjusting pH, specific regulative mode repeat step a)~c), until detection water phase pH is between 5.0~5.3:
A) pH value is adjusted to be 13~6, ethyl acetate extraction is added, static liquid separation, detection aqueous pH values；
B) pH value is adjusted to be 6~5, ethyl acetate extraction is added, static liquid separation, detection aqueous pH values；
C) pH value is adjusted to be 5~3, ethyl acetate extraction is added, static liquid separation, detection aqueous pH values；
Collect ethyl acetate phase of the water phase pH between 6~5；It is evaporated under reduced pressure out partial solvent to a large amount of solids to be precipitated, sink
It forms sediment, the western Nader's finished product of thunder is obtained by filtration；Wherein the structure of the intermediate C is as follows:
Inventors have found that the purity of ethyl acetate phase of the water phase pH between 6~5 western Nader containing thunder is higher, up to 99%
More than.And the organic phase under the stage of pH value 13~6 and 5~3 does not contain only the western Nader's amount of thunder seldom, and impurity accounting is more.
In order to further increase yield and purity, the present invention provides the refining methd of more specifically western Nader of thunder a kind of,
With 4- (4- cyclopropyl naphthalene -1- base) -1H-1, -5 (4H)-mercaptan of 2,4- triazole is raw material, anti-using alkylated reaction, bromo
It answers, hydrolyze, neutralizing, refining the synthesis western Nader's finished product of thunder；Wherein:
1) raw material is alkylated to obtain intermediate A crude product, in ethyl acetate, is warming up to 70~80 DEG C, the temperature is maintained to make it
It is completely dissolved, is slowly dropped to 0~20 DEG C, insulated and stirred filters, obtains intermediate A fine work；The method one side through the invention
The purifying of intermediate A crude product may be implemented, on the other hand, dry method is directly precipitated from water relative to existing, makes to produce
Product are easier drying, substantially reduce drying time, and the reaction of stringent water-less environment is required convenient for second step；
2) intermediate A fine work obtains the reaction solution of intermediate B through bromo-reaction, in 0~20 DEG C by adding into reaction solution
The purified water for entering 1~4 times of reaction liquid accumulated amount, is precipitated intermediate B from system, and suction filtration obtains Crude Intermediate B；It will be intermediate
Body B crude product is added in the mixed solution of purified water, ethyl acetate and 10%NaBr, and at 20 DEG C~30 DEG C, stirring and dissolving is quiet
It sets, liquid separation, collects organic phase, be evaporated under reduced pressure, recrystallize, precipitating filters to obtain second step intermediate B fine work；
3) intermediate B fine work hydrolyzes to obtain intermediate C, and intermediate C is added in purified water, and hydrobromic acid is then added and adjusts
PH, specific regulative mode repeat step a)~c), until detection water phase pH is between 5.0~5.3: a) adjust pH value be 13~
6, ethyl acetate extraction, static liquid separation, detection aqueous pH values are added；B) pH value is adjusted to be 6~5, ethyl acetate extraction is added, is quiet
Only liquid separation, detection aqueous pH values；C) pH value is adjusted to be 5~3, ethyl acetate extraction is added, static liquid separation, detection aqueous pH values；
Ethyl acetate phase of the water phase pH between 6~5 is collected, the ethyl acetate phase of collection is evaporated under reduced pressure out partial solvent and consolidates to a large amount of
Body is precipitated, and the western Nader's finished product of thunder is obtained by filtration in precipitating.
Further, insulated and stirred 1.5-2.5h in step 1)；The mixing of normal heptane and ethyl acetate is preferably used after suction filtration
Solution washing precipitating, then filter；The volume ratio of normal heptane and ethyl acetate is preferably 1:0.5~3 in the mixed solution.
Further, purified water, the volume ratio of ethyl acetate and 10%NaBr in mixed solution in step 2) are as follows: 15~2:
15~2:1, if 10%NaBr is more than this ratio, excessive NaBr can make NaBr in final products remain and cause blazing residual
Slag is unqualified.
Further, the mixed solution that solvent used is preferably tetrahydrofuran and normal heptane is recrystallized in step 2), is mixed
Closing the volume ratio of tetrahydrofuran and normal heptane in solution is (1~3): 1.
Further, in step 2) recrystallization solvent dissolution precipitating when solution temperature be 40 DEG C~70 DEG C, preferably 50
DEG C~70 DEG C.
Further, the volume for purified water being added in step 2) into reaction solution is preferably 2~4 times of reaction liquid accumulated amount.
Further, intermediate B is obtained in step 2) method particularly includes: intermediate A fine work is added to tetrahydrofuran
In, at 10 DEG C~30 DEG C, stirring and dissolving forms solution, it is added powdered N- bromo-succinimide in batches into solution, 10
DEG C~30 DEG C at, persistently stir 7~12 hours, the metabisulfite solution and purified water that 3% is added dropwise into medical fluid are to total
1~4 times that water volume is reaction solution volume is added, stirring to a large amount of solids is precipitated, and precipitating filters to obtain second step intermediate B
Crude product.By the way that 3% sodium pyrosulfite is added, the bromine of unreacted complete NBS and NBS production can be removed, without using end can be made
With pink in product.Preferably, the additional amount of 3% sodium pyrosulfite is 1~4 times of intermediate A fine work quality.
Further, the ethyl acetate phase collected in step 3) obtains the western Nader's finished product of thunder method particularly includes: acetic acid second
At 20~25 DEG C of ester phase, vacuum distillation is become cloudy to system by clarifying, and is closed decompression, is warming up to 40 ± 2 DEG C, insulated and stirred 1.5
~2.5 hours, 20~25 DEG C are cooled to, continuing to be evaporated under reduced pressure to the mass volume ratio of solid and ethyl acetate is 3.5~4, is closed
Close decompression, be warming up to 40 ± 2 DEG C, normal heptane is added dropwise, be cooled to 0~5 DEG C, stir 1.5~2.5 hours, filter, with normal heptane and
The mixed solution of ethyl acetate washs precipitating, filters dry get Lei Xi Nader.
Further, the volume that normal heptane is added is 0.5~1.5 times of the western Nader's Theoretical Mass of step 3) thunder.
Further, in the mixed solution of normal heptane used and ethyl acetate normal heptane and ethyl acetate volume ratio
Are as follows: 10:0.1~1.
Further, obtain intermediate C's in step 3) method particularly includes: intermediate B fine work is added to tetrahydrofuran
In, at 10 DEG C~30 DEG C, stirring and dissolving forms solution, is cooled to 0 DEG C~10 DEG C, and 10%NaOH aqueous solution is added thereto, holds
Continuous stirring 0~2 hour, obtains yellow clear solution, is evaporated under reduced pressure out tetrahydrofuran and obtains intermediate C.
Beneficial effects of the present invention:
By the purifying to each step intermediate, product, to obtain satisfactory high-purity finished product, produce simultaneously
Simple process is easy to carry out product collection, and product purity is high, every higher polishing purification method of step yield, is industrial
New mode, especially intermediate B provide by pure solid, overcomes and carries out down in the form of a solution in the prior art
Single step reaction causes impurity more, subsequent to be difficult to the problem of purifying.Hydrobromic acid of the present invention adjusts solution ph, only collects pH
It is worth the organic phase in 6~5 stage extractions, to achieve the purpose that purify finished product.
Detailed description of the invention
Fig. 1 is the western Nader's bulk pharmaceutical chemicals hydrogen spectrum of thunder prepared by the present invention；
Fig. 2 is the western Nader's bulk pharmaceutical chemicals mass spectrum of thunder prepared by the present invention.
Specific embodiment
Unless stated otherwise, the reagent selected in following embodiment is commercially available general reagent, in following embodiments
Experimental method is unless otherwise specified conventional method.
Embodiment 1
1) reaction dissolvent DMF400ml is added into three mouthfuls of reaction flasks of 1000ml, is then added from three-neck flask mouth
100g starting material 4- (4- cyclopropyl naphthalene -1- base) -1H-1, -5 (4H)-mercaptan of 2,4- triazole, stirring and dissolving at 15~20 DEG C,
Obtain solution A.Powdered anhydrous sodium carbonate 39.7g is added into solution A, at 10~15 DEG C, is added dropwise to 65.7g bromoacetic acid second
Ester controls rate of addition, and temperature in the process is added dropwise and is no more than 15 DEG C, after being added dropwise, maintains interior 10~15 DEG C of temperature, heat preservation is anti-
It answers, through thin-layer chromatography, raw material fully reacting continues to stop reaction after extending reaction 15 minutes.
Reaction solution is transferred in 5L beaker, in system at 0~5 DEG C of temperature, is added dropwise to 0~5 DEG C of purified water thereto
1.2L has a large amount of precipitatings to generate, continues at 0~5 DEG C of stirring 0.5h, filters, until basic no liquid flows out, precipitates with purified water
(500ml) is washed 2 times, is filtered, until basic no liquid flows out, obtains white precipitate.
Precipitating is transferred in 5L beaker, purified water 0.6L, ethyl acetate 1.2L is added at 30~40 DEG C thereto, is opened
Stirring, makes it completely dissolved, and continues stirring 10 minutes, stands, liquid separation, ethyl acetate phase purified water 0.5L, washs 1 time, water
Mutually primary with ethyl acetate 0.1L extraction, merging is organic to be added to anhydrous sodium sulfate 0.15kg, dry 1h at 25~30 DEG C.It crosses
Filter, organic phase are spin-dried for obtaining intermediate A crude product at 35 DEG C, by the decompression of portion of ethyl acetate solution.
To equipped in thermometer 2L three-neck flask, ethyl acetate solution 0.4L is not distilled in addition, then from three-neck flask mouth
Addition has been evaporated intermediate A crude product, opens stirring, is warming up to 70~80 DEG C, maintains the temperature to make it completely dissolved, be slowly dropped to
10~15 DEG C, there are a large amount of precipitatings to generate, continue at 10~15 DEG C of stirring 2h, suction filtration, with normal heptane: ethyl acetate=1:1 solvent
It 0.2L washing precipitating 2 times, filters, until basic no liquid flows out, obtains white precipitate.
Obtained white precipitate is put into air dry oven, 40~45 DEG C of dryings obtain intermediate fine work A, purity
99.913%, yield 90.25%.
2) in Xiang Peiyou thermometer 1L three-neck flask, be added reaction dissolvent tetrahydrofuran 700ml, open stirring, then from
100g intermediate A is added in three-neck flask mouth.At 25~30 DEG C, stirring is allowed to be completely dissolved temperature in maintaining, and obtains yellow solution.
By temperature drop in solution to 15 ± 2 DEG C, point 4 crowdes of powdered N- bromo-succinimide 70.1g of addition, dimension into solution
Holding temperature in system, at 15 ± 2 DEG C, charging is finished, and is to slowly warm up to interior temperature and is no more than 25 DEG C, insulation reaction, through thin-layer chromatography, raw material
Fully reacting after extending reaction 15 minutes, stops reaction.
Slow cooling is added dropwise to 3% metabisulfite solution 0.3L into reaction solution, continues at 0~5 DEG C to 0~5 DEG C
At a temperature of, it is 2L that purified water to total volume is added dropwise into system, has a large amount of precipitatings to generate, insulated and stirred 0.5h.It filters, until base
The outflow of this no liquid, is precipitated with tetrahydrofuran: water=1:4 (200ml) washing precipitating 2 times, then with water (L) washing precipitating 1 time, take out
Filter obtains white precipitate until basic no liquid flows out.
Precipitating is transferred in 5L plastic beaker, at 20~25 DEG C, purified water 1.1L, ethyl acetate are added thereto
1.1L opens stirring, makes it completely dissolved, 10% aqueous sodium bromide 450ml is added thereto, continues stirring 10 minutes, quiet
It sets, liquid separation, ethyl acetate 450ml, 10% aqueous sodium bromide 200ml is added into water phase, extract, stand, liquid separation is associated with
Anhydrous sodium sulfate 150g is added in machine phase, and dry 1 hour, filtering, organic phase was at 35 DEG C, evaporated under reduced pressure, obtain yellow liquid (Gu)
Body.
At 15~20 DEG C, in Xiang Peiyou thermometer three-neck flask, refining solvent tetrahydrofuran 250ml is added, unlatching is stirred
It mixes, then adds crude intermediate from three-neck flask mouth, make it completely dissolved, normal heptane 380ml is added into solution, have big
Amount precipitating generates, and is to slowly warm up to 55 ± 5 DEG C, makes it completely dissolved, at this temperature, continues to be added dropwise to normal heptane into solution
100ml, charging are finished, and are slowly to warm to 10~15 DEG C, have a large amount of precipitatings to generate, and are continued at 10~15 DEG C and are stirred 2 hours, filter, use
Normal heptane: tetrahydrofuran=7:1 solvent (200ml) washing precipitating 2 times filters, until basic no liquid flows out, obtains white precipitate.
Obtained precipitating is put into vacuum oven, 20~30 DEG C of dryings, obtains intermediate fine work B, purity 99.573%,
Yield 91.26%.
3) in 20~30 DEG C of water-baths, in Xiang Peiyou thermometer 1L three-neck flask, reaction dissolvent tetrahydrofuran is added
200ml opens stirring, and 100g intermediate B then is added from three-neck flask mouth.System is cooled to 0~5 DEG C, 10% hydrogen is added
Sodium oxide molybdena 100ml is added dropwise and finishes, and insulation reaction, system gradually dissolves clarification by white suspension, and through thin-layer chromatography, raw material is anti-
It should stop reaction completely, after extending reaction 15 minutes, obtain yellow solution C.
In 30~35 DEG C of water-baths, intermediate C solution is transferred in Rotary Evaporators, reaction dissolvent tetrahydrofuran is steamed
Out.
4) it is added into intermediate C aqueous solution into purified water 0.3L, then adds ethyl acetate 0.2L, stirred 5 minutes,
Static liquid separation divides and goes organic phase, obtains yellow aqueous solution.
At 25~30 DEG C, it is added 25% hydrobromic acid solution thereto, adjusts ph value of aqueous phase 6.5~7, it is water-soluble to yellow
Ethyl acetate 0.2L is added in liquid, stirs 5 minutes, static liquid separation, divides and goes organic phase, obtain yellow aqueous solution.
At 25~30 DEG C, 25% hydrobromic acid solution is added thereto, adjusts ph value of aqueous phase 5.1~5.5, yellow is water-soluble
Ethyl acetate 0.4L is added in liquid, stirs 5 minutes, static layering, detects ph value of aqueous phase 5.6~6.
It at 25~30 DEG C, repeats the above steps, until detecting ph value of aqueous phase between 5.0~5.3, merges aqueous phase extracted
The ethyl acetate phase between 5~6.
The western Nader's purification of thunder: above-mentioned ethyl acetate phase is transferred in distilling apparatus, opens and stirs, at 20~25 DEG C, is subtracted
Pressure distillation, system becomes cloudy by clarifying, and closes decompression, is to slowly warm up to 40 ± 2 DEG C, and insulated and stirred 2 hours, it is cooled to 20~
25 DEG C, continues to be decompressed to about 3.5~4 times of volumes (for the mass volume ratio of raw material Y and ethyl acetate) and close decompression, slowly heat up
To 40 ± 2 DEG C, it is slowly added dropwise thereto into normal heptane 75ml, charging is finished, and slow cooling continues at 0~5 DEG C of stirring to 0~5 DEG C
It 2 hours, filters, with normal heptane: ethyl acetate=1:1 solvent (90ml) washs precipitating 2 times, it filters, until basic no liquid flows out,
Obtain white precipitate.
Obtained precipitating is put into vacuum oven, 40~50 DEG C of dryings, obtains finished product, hydrogen is composed as shown in Figure 1, matter
Spectrum is as shown in Fig. 2, purity 99.898%, yield 82.54%.
Claims (10)
1. a kind of refining methd of the western Nader of thunder, it is characterised in that intermediate C is added in purified water, hydrobromic acid tune is then added
PH is saved, specific regulative mode repeats step a)~c), until detection water phase pH is between 5.0~5.3:
A) pH value is adjusted to be 13~6, ethyl acetate extraction is added, static liquid separation, detection aqueous pH values；
B) pH value is adjusted to be 6~5, ethyl acetate extraction is added, static liquid separation, detection aqueous pH values；
C) pH value is adjusted to be 5~3, ethyl acetate extraction is added, static liquid separation, detection aqueous pH values；
Collect ethyl acetate phase of the water phase pH between 6~5；It is evaporated under reduced pressure out partial solvent to a large amount of solids to be precipitated, precipitate, mistake
Filter obtains the western Nader's finished product of thunder；Wherein the structure of the intermediate C is as follows:
2. the refining methd of the western Nader of thunder according to claim 1, it is characterised in that with 4- (4- cyclopropyl naphthalene -1- base) -
1H-1, -5 (4H)-mercaptan of 2,4- triazole are raw material, using alkylated reaction, bromo-reaction, hydrolysis, neutralization, purification synthesis thunder west
Nader's finished product；Synthetic route is as follows:
Wherein:
1) raw material is alkylated to obtain intermediate A crude product, in ethyl acetate, is warming up to 70~80 DEG C, and the temperature is maintained to make it completely
Dissolution, is slowly dropped to 0~20 DEG C, and insulated and stirred filters, obtains intermediate A fine work；
2) intermediate A fine work obtains the reaction solution of intermediate B through bromo-reaction, anti-by being added into reaction solution in 0~20 DEG C
The purified water for answering 1~4 times of liquid accumulated amount, is precipitated intermediate B from system, and suction filtration obtains Crude Intermediate B；By intermediate B
Crude product is added in the mixed solution of purified water, ethyl acetate and 10%NaBr, and at 20 DEG C~30 DEG C, stirring and dissolving is stood, point
Liquid is collected organic phase, is evaporated under reduced pressure, and recrystallizes, and precipitating filters to obtain second step intermediate B fine work；
3) intermediate B fine work hydrolyzes to obtain intermediate C, and intermediate C is added in purified water, and hydrobromic acid is then added and adjusts pH, tool
Body regulative mode repeats step a)~c), until detection water phase pH is between 5.0~5.3: a) adjusting pH value and be 13~6, be added
Ethyl acetate extraction, static liquid separation, detection aqueous pH values；B) pH value is adjusted to be 6~5, ethyl acetate extraction, static point is added
Liquid, detection aqueous pH values；C) pH value is adjusted to be 5~3, ethyl acetate extraction is added, static liquid separation, detection aqueous pH values；It collects
Ethyl acetate phase of the water phase pH between 6~5, the ethyl acetate phase of collection are evaporated under reduced pressure out partial solvent to a large amount of solids and analyse
Out, it precipitates, the western Nader's finished product of thunder is obtained by filtration.
3. the refining methd of the western Nader of thunder according to claim 2, it is characterised in that insulated and stirred 1.5- in step 1)
2.5h；Precipitating preferably is washed with the mixed solution of normal heptane and ethyl acetate after suction filtration, then is filtered；Positive heptan in the mixed solution
The volume ratio of alkane and ethyl acetate is preferably 1:0.5~3.
4. the refining methd of the western Nader of thunder according to claim 2, it is characterised in that purified in mixed solution in step 2)
The volume ratio of water, ethyl acetate and 10%NaBr are as follows: 15~2:15~2:1.
5. the refining methd of the western Nader of thunder according to claim 2, it is characterised in that molten used in recrystallization in step 2)
Agent is the mixed solution of tetrahydrofuran and normal heptane, and the volume ratio of tetrahydrofuran and normal heptane is (1~3) in mixed solution: 1.
6. the refining methd of the western Nader of thunder according to claim 2, it is characterised in that recrystallization is molten with solvent in step 2)
Solution temperature when solution precipitating is 40 DEG C~70 DEG C, preferably 50 DEG C~70 DEG C.
7. the refining methd of the western Nader of thunder according to claim 2, it is characterised in that be added in step 2) into reaction solution
The volume of purified water is 2~4 times of reaction liquid accumulated amount.
8. the refining methd of the western Nader of thunder according to claim 2, it is characterised in that obtain the tool of intermediate B in step 2)
Body method are as follows: intermediate A fine work is added in tetrahydrofuran, at 10 DEG C~30 DEG C, stirring and dissolving forms solution, into solution
It is added powdered N- bromo-succinimide in batches, at 10 DEG C~30 DEG C, persistently stirs 7~12 hours, be added dropwise into medical fluid
The metabisulfite solution and purified water to total water volume that is added for entering 3% are 1~4 times of reaction solution volume, are stirred to big
It measures solid to be precipitated, precipitating filters to obtain second step Crude Intermediate B；The additional amount of 3% sodium pyrosulfite is preferably intermediate A essence
1~4 times of quality.
9. the refining methd of the western Nader of thunder according to claim 2, it is characterised in that the ethyl acetate collected in step 3)
Mutually obtain the western Nader's finished product of thunder method particularly includes: at 20~25 DEG C of ethyl acetate phase, vacuum distillation to system becomes muddy by clarification
It is turbid, decompression is closed, 40 ± 2 DEG C is warming up to, insulated and stirred 1.5~2.5 hours, is cooled to 20~25 DEG C, continues vacuum distillation extremely
The mass volume ratio of solid and ethyl acetate is 3.5~4, closes decompression, is warming up to 40 ± 2 DEG C, and normal heptane is added dropwise, it is cooled to 0
~5 DEG C, stir 1.5~2.5 hours, filter, wash precipitating with the mixed solution of normal heptane and ethyl acetate, suction filtration it is dry thunder
Western Nader；The volume ratio of normal heptane and ethyl acetate is preferred in the mixed solution of normal heptane and ethyl acetate used are as follows: 10:
0.1~1；Preferably, the volume that the normal heptane is added is 0.5~1.5 times of the western Nader's Theoretical Mass of step 3) thunder.
10. the refining methd of the western Nader of thunder according to claim 2, it is characterised in that obtain intermediate C's in step 3)
Method particularly includes: intermediate B fine work is added in tetrahydrofuran, and at 10 DEG C~30 DEG C, stirring and dissolving forms solution, is cooled to 0
DEG C~10 DEG C, 10%NaOH aqueous solution is added thereto, persistently stirs 0~2 hour, obtains yellow clear solution, be evaporated under reduced pressure out
Tetrahydrofuran obtains intermediate C.
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| CN111116500A (en) * | 2019-12-30 | 2020-05-08 | 北京鑫开元医药科技有限公司海南分公司 | Purification method of Resinard key intermediate |
| CN111116501A (en) * | 2019-12-30 | 2020-05-08 | 北京鑫开元医药科技有限公司海南分公司 | Synthesis method of Ravinard intermediate capable of effectively reducing impurity content |
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| CN111116500B (en) * | 2019-12-30 | 2021-06-08 | 北京鑫开元医药科技有限公司海南分公司 | Purification method of Resinard key intermediate |
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