CN103524440B - The preparation method of gout therapertics Lesinurad and Lesinurad intermediate - Google Patents
The preparation method of gout therapertics Lesinurad and Lesinurad intermediate Download PDFInfo
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- 0 *c(c1c2cccc1)ccc2-[n]1c(S*)nnc1 Chemical compound *c(c1c2cccc1)ccc2-[n]1c(S*)nnc1 0.000 description 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C335/40—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of thiourea or isothiourea groups further bound to other hetero atoms
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- 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
Abstract
The invention provides a kind of new Lesinurad intermediate, the preparation for Lesinurad provides more economical, more efficient, safer, a more environmental protection, is suitable for the synthesis technique of large-scale industrial production.The new Lesinurad intermediate that the present invention also provides utilization to provide simultaneously is to prepare the method for known Lesinurad intermediate and Lesinurad.Take novel Lesinurad intermediate provided by the invention to synthesize Lesinurad, there is required low in raw material price, be easy to get; Heavy metal and environmentally harmful solvent can not be adopted; Intermediate and product separation purifying are easily, simple to operate; Can avoid toxicity very greatly and the use of not easy-operating thiophosgene; Overall yield of reaction can reach and the advantages such as the equal or higher level of prior art.
Description
Technical field
The present invention relates to preparation method and the key intermediate thereof of a kind of gout therapertics Lesinurad.
Background technology
Gout is the crystal dependency joint disease caused by monosodium urate salt (MSU) deposits, directly related with the hyperuricemia caused by purine metabolic disturbance and (or) underexcretion.Whole world patient with gout is up to more than 2,000 ten thousand.Lesinurad (RDEA594) is that a kind of uricosuric escape orifice is taken medicine, and can suppress the sub-URAT1 of renal proximal tubules uric acid transporter.The exploratory study display previously carried out in patient with gout, Zyloric (ALLO), associating lesinurad treats comparable alone ALLO and more effectively reduces serum uric acid (SUA).By finding the research more than 500 routine Healthy Peoples and patient with gout, Lesinurad reduces blood uric acid with dose-dependently, and Febuxostat tolerance is good.Also be a kind of xanthine oxidase inhibitor, be approved for the high lithemia treatment of gout.The tolerance of Lesinurad and Febuxostat combination therapy is good, and obviously can reduce uric acid.
This compound initial is developed by the compound 5 (RDEA806) of Valeant synthesis in 2006 and carried out reporting (Patent:WO2006026356A2) with the form of patent, and its synthetic route is as follows.
In the near future Ardea Bio has found Lesinufad treatment gout being had to better effect.The patent right of present Lesinurad belongs to Astrazeneca.
So far, the synthesis report about Lesinurad is also fewer.Such as patent WO2009070740A2, US2010056464A1, WO2011085009A2 and Patents thereof report the synthesis of Lesinurad (compound 8), its adopt route and RDEA806 similar:
Chinese patent CN102040546A, from 4-cyclopropyl-1-naphthaldehyde, through three steps, has synthesized intermediate isothiocyanate, has avoided the use of thiophosgene.
Comprehensive analysis existing Lesinurad preparation method is known, and the structural bromine of Lesinurad is all be transformed (from compound 6 to 7) by amino.This step complicated operation and expensive raw material price, be unfavorable for reducing costs.In addition, existing Lesinurad preparation method uses thiophosgene mostly, operation inconvenience, security is bad, and although Chinese patent CN102040546A takes the method avoiding using thiophosgene, but the method substantially prolongs the synthetic route of Lesinurad, make technique more complicated, cost is higher.
Summary of the invention
Technical problem to be solved by this invention overcomes the deficiencies in the prior art, there is provided a kind of new Lesinurad intermediate, the preparation for Lesinurad provides more economical, more efficient, safer, a more environmental protection, is suitable for the synthesis technique of large-scale industrial production.
The new Lesinurad intermediate that the present invention also provides utilization to provide simultaneously is to prepare the method for known Lesinurad intermediate and Lesinurad.
For solving above technical problem, a kind of technical scheme that the present invention takes is as follows:
A kind of Lesinurad intermediate, this Lesinurad intermediate is the compound that general formula I represents,
In formula I:
R represents H or COCH
3; Or R represents CH
2r
1, wherein R
1represent ester group; CN; CH
2oH; Be not substituted or be selected from C
1~ C
6one or more phenyl replaced in alkyl, halogen;
R
2represent cyclopropane base; Halogen; OTf.
According to a concrete aspect, in formula I, R represents H, R
2represent cyclopropane base, structural formula as shown in Equation 13:
The present invention takes also to provide a kind of Lesinurad intermediate, and this Lesinurad intermediate is the compound that general formula I I represents,
In formula II, R
2represent cyclopropane base; Halogen; OTf.
According to a concrete aspect: in formula II, R
2represent cyclopropane base, the structural formula of Lesinurad intermediate as shown in Equation 12:
The another technical scheme that the present invention takes is: the preparation method of the Lesinurad intermediate that a kind of formula III represents,
it comprises makes formula I
the step that bromine substitution reaction generates formula III compound occurs, and formula I is identical with the R in III, R
2identical, wherein:
R represents H or COCH
3; Or R represents CH
2r
1, wherein R
1represent ester group; CN; CH
2oH; Be not substituted or be selected from C
1~ C
6one or more phenyl replaced in alkyl, halogen;
R
2represent cyclopropane base; Halogen; OTf.
Preferably, in formula I and III: R is COCH
3or CH
2r
1, and R
1represent ester group; CN; CH
2oH; Be not substituted or be selected from C
1~ C
6one or more phenyl replaced in alkyl, halogen; R
2represent cyclopropane base.
According to the present invention, the bromine source that described bromination reaction adopts can be bromine, bromine water, N-bromo-succinimide, C5H6Br2N2O2.According to a concrete aspect: bromination reaction can be implemented as follows: make formula I and bromine source in a solvent, under acid binding agent exists, there is bromination reaction.
Preferably, described formula I is 4-(4-cyclopropyl naphthalene)-3-thioacetate-1,2,4-triazole, structural formula as shown in Equation 15:
Further, the preparation method of the Lesinurad intermediate that described formula III represents also preferably includes and makes compound 13
with RX in a solvent, the step of substitution reaction production I occurs under acid binding agent exists, and wherein, the definition of R is the same, and particularly, R can be COCH
3or CH
2r
1, and R
1represent ester group; CN; CH
2oH; Be not substituted or be selected from C
1~ C
6one or more phenyl replaced in alkyl, halogen; R
2represent cyclopropane base; X represents leavings group.
Preferably, X is chlorine, bromine, iodine or OTf.
Further, the preparation method of the Lesinurad intermediate that described formula III represents also preferably includes also to comprise and makes compound 12
there is cyclization in a solvent with DMF dialkyl acetal and react the step generating described compound 13.
Described DMF dialkyl acetal can be DMF dimethylacetal or DMF diethyl acetal.
Further, the preparation method of the Lesinurad intermediate that described formula III represents also preferably includes first in a solvent, generated the salt of N-(4-cyclopropyl-1-naphthalene) dithiocarbamic acid by 4-cyclopropyl-naphthalidine, dithiocarbonic anhydride and alkali reaction, then make N-(4-cyclopropyl-1-naphthalene) salt of dithiocarbamic acid and the step of hydrazine hydrate reacting generating compound 12.Wherein, described alkali can be such as sodium hydroxide or potassium hydroxide etc. or the combination for them.
The another technical scheme that the present invention takes is: the preparation method of a kind of Lesinurad, and it comprises the step of the Lesinurad intermediate synthesis Lesinurad represented by formula III,
In formula III:
R represents H or COCH
3; Or R represents CH
2r
1, wherein R
1represent ester group; CN; CH
2oH; Be not substituted or be selected from C
1~ C
6one or more phenyl replaced in alkyl, halogen;
R
2represent cyclopropane base; Halogen; OTf;
Particularly: described method also comprises the method for taking the present invention above-mentioned to the step of the Lesinurad intermediate prepared formula III and represent.
Due to the enforcement of technique scheme, the present invention compared with prior art tool has the following advantages:
The invention provides novel Lesinurad intermediate, for preparation Lesinurad provides a new synthetic route.
Take novel Lesinurad intermediate provided by the invention to synthesize Lesinurad, there is following advantage:
(1) low in raw material price required for, is easy to get;
(2) heavy metal and environmentally harmful solvent can not be adopted;
(3) intermediate and product separation purifying are easily, simple to operate;
(4) can avoid toxicity very greatly and the use of not easy-operating thiophosgene;
(5) overall yield of reaction can reach the equal or higher level with prior art.
Embodiment
The present invention relates to novel Lesinurad intermediate and take these Lesinurad intermediates to prepare the method for Lesinurad.
In a specific embodiment of the present invention: the preparation method of Lesinurad can be expressed as follows by reaction equation:
In above formula, R
3can be any alkyl, common as methyl, ethyl.
R is preferably COCH
3or CH
2r
1, wherein R
1represent ester group; CN; CH
2oH; Be not substituted or be selected from C
1~ C
6one or more phenyl (such as phenyl) replaced in alkyl, halogen.As the preferred embodiment of the present invention, R is CH
2r
1, wherein R
1for ester group.Most preferred, R is CH
2r
1, wherein R
1for ethoxycarbonyl.
Below in conjunction with specific embodiment, the present invention is described further, but the invention is not restricted to following examples.
embodiment 1 prepares compound 12 by compound 1
In single port bottle, add 4-cyclopropyl-naphthalidine (compound 1,1.0eq), add DMF (8.2Vol) and make it to dissolve, add NaOH (1.2eq) and CS
2(1.2eq), stirred at ambient temperature reaction 1h, add hydrazine hydrate (3.0eq) to proceed to stirring and refluxing 4h, LC under 70 DEG C of oil baths and confirm that reaction is complete, stop heating and stir, after cooling, every 1g raw material adds 10mL water, suction filtration, filter cake 95% ethyl alcohol recrystallization, suction filtration, compound 12 is obtained, productive rate 50%-70% after solid drying.
Product nuclear magnetic data is as follows:
1h NMR (400MHz, DMSO) δ 9.16 (s, 1H), 8.43 (d, J=7.8Hz, 1H), 7.98 – 7.89 (m, 1H), 7.66-7.48 (m, 3H), 7.26 (d, J=7.6Hz, 1H), 5.54 – 4.50 (m, 1H), 2.46 – 2.34 (m, 1H), 1.12 – 1.02 (m, 2H), 0.80 – 0.69 (m, 2H).
embodiment 2 prepares compound 13 by compound 12
Compound 12 (1.0eq) is added in single port bottle, add 1,4-dioxane (7.5Vol) makes it to dissolve, add N, dinethylformamide dimethylacetal (1.0eq), stirring and refluxing 1.5-2h at 100 DEG C, LC confirms that reaction is complete, and after reaction solution is cooled to room temperature, 1g raw material adds 10mL water, separate out solid suction filtration, the filter cake washing with alcohol twice of 95%, obtains compound 13[Lesinurad intermediate after solid drying, chemical name: 4-(4-cyclopropyl naphthalene)-3-sulfydryl-1,2,4-triazole)].Productive rate 70%-80%.
Product nuclear magnetic data is as follows:
1h NMR (400MHz, DMSO) δ 8.69 (s, 1H), 8.57 (d, J=8.4Hz, 1H), 7.72 (t, J=7.3Hz, 1H), 7.64 (t, J=7.4Hz, 1H), 7.54 (d, J=7.6Hz, 1H), 7.44 – 7.37 (m, 2H), 2.56 – 2.50 (m, 1H), 1.19-1.09 (m, 2H), 0.90 – 0.75 (m, 2H).
embodiment 3 prepares compound 15 by compound 13
Product nuclear magnetic data is as follows: joined in single port bottle by compound 13 (4g, 1eq), and add solvent DMF (67mL, 16.8vol) and dissolve, stirring at room temperature, adds K
2cO
3(2.272g, 1.1eq), dropwise add compound 14 (1.74mL, 1.05eq) again, control to drip speed at 0.5mL/min, after stirring at room temperature 2h, react completely, add EA (ethyl acetate) and water dilute reaction solution, EA extracts three times, saturated common salt water washing three times, anhydrous MgSO
4dry.Organic phase is spin-dried for and obtains white solid [being compound 15, Lesinurad intermediate, chemical name: 4-(4-cyclopropyl naphthalene)-3-ethyl thioacetate-1,2,4-triazole], obtains 5.13g, productive rate 97% after drying.
Product nuclear magnetic data is as follows:
1h NMR (400MHz, CDCl
3) δ 8.54 (d, J=8.4Hz, 1H), 8.30 (s, 1H), 7.70-7.62 (m, 1H), 7.61-7.53 (m, 1H), 7.36 (m, 3H), 4.22-4.15 (m, 2H), 4.14-4.05 (m, 2H), 2.47 – 2.36 (m, 1H), 1.25 (t, J=7.1Hz, 3H), 1.19-1.14 (m, 2H), 0.93-0.78 (m, 2H).
embodiment 4 prepares compound 16 by compound 15
example 4-1 take bromine as bromine source, prepares compound 16 by bromination reaction
In the single port bottle that compound 15 is housed, add solvent acetonitrile (5mL), pyridine (0.24mL), to be dissolved completely after slowly drip acetonitrile solution (the 3eq Br of bromine
2be dissolved in 1mL acetonitrile), dropwise, room temperature reaction 2h has reacted.In reaction solution, add 30mL water and 30mL ethyl acetate, with 30mL extraction into ethyl acetate 3 times, organic phase saturated common salt water washing, anhydrous magnesium sulfate drying, crude product is crossed silicagel column and is obtained product 1.27g, productive rate 76%.
Product nuclear magnetic data is as follows:
1h NMR (400MHz, DMSO) δ 8.59 (d, J=8.4Hz, 1H), 7.77-7.70 (m, 1H), 7.69 – 7.60 (m, 2H), 7.44 (d, J=7.7Hz, 1H), 7.17 (d, J=8.3Hz, 1H), 4.13 – 3.99 (m, 4H), 2.62 – 2.52 (m, 1H), 1.16 (t, J=7.1Hz, 3H, 0.87 (q, J=5.4Hz, 2H).
example 4-2 for bromine source, prepares compound 16 by bromination reaction with N-bromo-succinimide
Compound 15 1mmol, the NBS consumption that feeds intake is 6mmol, and reflux 2h under 60 DEG C of oil baths, reacts complete, extracted by reaction solution EA, and saturated common salt is washed, anhydrous MgSO
4drying, cross column separating purification after concentrating under reduced pressure, the TEA adding 1% using PE:EA=3:1 carries out wash-out as eluent, obtains product 0.3496g, and yield is 80.8%.
Product nuclear magnetic data is as follows:
1h NMR (400MHz, DMSO) δ 8.59 (d, J=8.4Hz, 1H), 7.77-7.70 (m, 1H), 7.69 – 7.60 (m, 2H), 7.44 (d, J=7.7Hz, 1H), 7.17 (d, J=8.3Hz, 1H), 4.13 – 3.99 (m, 4H), 2.62 – 2.52 (m, 1H), 1.16 (t, J=7.1Hz, 3H, 0.87 (q, J=5.4Hz, 2H).
example 4-3 take C5H6Br2N2O2 as bromine source, prepares compound 16 by bromination reaction
Compound 15 feeds intake 1mmol, and C5H6Br2N2O2 consumption is 6mmol, and reflux 2h under 60 DEG C of oil baths, and some plate measures liquid phase and finds that raw material has exhausted, and reaction solution EA extracts, and saturated common salt is washed, anhydrous MgSO
4drying, cross column separating purification after concentrating under reduced pressure, the TEA adding 1% using PE:EA=3:1 carries out wash-out as eluent, obtains product 0.2328g, and yield is 53.9%.
Product nuclear magnetic data is as follows:
1h NMR (400MHz, DMSO) δ 8.59 (d, J=8.4Hz, 1H), 7.77-7.70 (m, 1H), 7.69 – 7.60 (m, 2H), 7.44 (d, J=7.7Hz, 1H), 7.17 (d, J=8.3Hz, 1H), 4.13 – 3.99 (m, 4H), 2.62 – 2.52 (m, 1H), 1.16 (t, J=7.1Hz, 3H, 0.87 (q, J=5.4Hz, 2H).
example 4-4 take methylene dichloride as solvent, prepares compound 16 by bromination reaction
In the single port bottle that compound 15 is housed, add methylene chloride (5mL), pyridine (0.24mL), to be dissolved completely after slowly drip dichloromethane solution (the 3eq Br of bromine
2be dissolved in 1mL methylene dichloride), dropwise, room temperature reaction 2h has reacted.In reaction solution, add 30mL water and 30mL ethyl acetate, with 30mL extraction into ethyl acetate 3 times, organic phase saturated common salt water washing, anhydrous magnesium sulfate drying, crude product is crossed silicagel column and is obtained product 1.17g, productive rate 70%.
This reaction all can occur preferably in solvent THF, chloroform, tetracol phenixin, 1,2-ethylene dichloride equal solvent.
embodiment 5 prepares Lesinurad (compound 8) by compound 16
95% ethanol (6.5mL) is added in the single port bottle that compound 16 (1g) is housed, THF (6.5mL), be stirred to 16 entirely molten after system is cooled to about-6 DEG C, drip the aqueous solution (6.5mL) of LiOH (1.5eq).Dropwise and continue reaction to reacting completely at 0 DEG C.
Reaction terminates rear 0.5N salt acid for adjusting pH value to neutral, the organic phase in system is spun off the hydrochloric acid soln adjust ph to 3 of rear continuation 0.5N to about 4.Gained suspension liquid CH
2cl
2extraction, organic phase is spin-dried for obtain target product, is Lesinurad, productive rate 99%.
Product nuclear magnetic data is as follows:
1h NMR (400MHz, DMSO) δ 12.98 (s, 1H), 8.58 (d, J=8.5Hz, 1H), 7.74 (t, J=7.3Hz, 1H), 7.69 – 7.57 (m, 2H), 7.44 (d, J=7.6Hz, 1H), 7.17 (d, J=8.3Hz, 1H), 4.06-3.95 (m, 2H), 2.60-2.52 (m, 1H), 1.22 – 1.10 (m, 2H), 0.87 (q, J=5.3Hz, 2H).
the preparation of embodiment 6Lesinurad intermediate (compound 13)
Add compound 12 (1.0eq) in single port bottle, add Isosorbide-5-Nitrae-dioxane (7.5Vbl) and make it to dissolve, add N, dinethylformamide diethyl acetal (1.0eq), at 100 DEG C, stirring and refluxing 1.5-2h, LC confirm that reaction is complete, after reaction solution is cooled to room temperature, 1g raw material adds 10mL water, separates out solid suction filtration, filter cake with 95% washing with alcohol twice, drying, obtains compound 13.Productive rate 82%.
the preparation of embodiment 7Lesinurad intermediate (compound 15)
Joined in single port bottle by compound 13 (1g, 1eq), add solvent DMF (16.75mL) and dissolve, stirring at room temperature, adds K
2cO
3(569mg, 1.1eq), dropwise add compound 17 (0.42mL, 1.05eq) again), control to drip speed at 0.5mL/min, after stirring at room temperature 2.5h, react completely, add EA (ethyl acetate)) and water dilute reaction solution, EA100mLx3 extracts, saturated aqueous common salt 100mLx3 washs, and anhydrous MgSO4 is dry.Organic phase is spin-dried for and obtains white solid (being compound 15), dry 1.33g, productive rate >99%.
the preparation of embodiment 8Lesinurad intermediate (compound 19)
Joined in single port bottle by compound 13 (1g, 1eq), add solvent DMF (16.75mL) and dissolve, stirring at room temperature, adds K
2cO
3(569mg, 1.1eq), dropwise add compound 18 (0.42mL, 1.05eq) again, control to drip speed at 0.5mL/min, after stirring at room temperature 2.5h, react completely, add EA (ethyl acetate) and water dilute reaction solution, EA100mLx3 extracts, saturated aqueous common salt 100mLx3 washs, anhydrous MgSO
4dry.Organic phase is spin-dried for and obtains white solid (being compound 19), dry 1.37g, productive rate >99%.
Product nuclear magnetic data is as follows:
1h NMR (400MHz, CDCl
3) δ 8.54 (d, J=8.5Hz, 1H), 8.30 (s, 1H), 7.66 (t, J=7.7Hz, 1H), 7.57 (t, J=7.6Hz, 1H), 7.43 – 7.30 (m, 3H), 4.09 (d, J=6.3Hz, 2H), 3.72 (s, 3H), 2.49 – 2.35 (m, 1H), 1.17 (d, J=8.4Hz, 2H), 0.91 – 0.76 (m, 2H).
the preparation of embodiment 9Lesinurad intermediate (compound 20)
In the single port bottle that compound 19 is housed, add solvent acetonitrile (5mL), pyridine (0.24mL), to be dissolved completely after slowly drip acetonitrile solution (the 3eq Br of bromine
2be dissolved in 1mL acetonitrile), dropwise, room temperature reaction 2h has reacted.In reaction solution, add 30mL water and 30mL ethyl acetate, with 30mL extraction into ethyl acetate 3 times, organic phase saturated common salt water washing, anhydrous magnesium sulfate drying, crude product is crossed silicagel column and is obtained product 0.70g, productive rate 56%.
Product nuclear magnetic data is as follows:
1H NMR(400MHz,CDCl
3)δ8.43(d,J=8.5Hz,1H),7.53(t,J=7.3Hz,1H),7.43(t,J=7.4Hz,1H),7.27(dd,J=17.2,7.6Hz,2H),7.15(d,J=8.3Hz,1H),3.57(s,3H),2.38–2.24(m,1H),1.10-1.08(m,2H),0.79-0.69(m,2H).
the preparation of embodiment 10Lesinurad intermediate (compound 22)
Joined in single port bottle by compound 13 (1g), add solvent DMF (16.8vol) and dissolve, stirring at room temperature, adds K
2cO
3(1.1eq), more dropwise add compound 21 (1.05eq), control to drip speed at 0.5mL/min, after stirring at room temperature 2h, react completely, add EA (ethyl acetate) and water dilute reaction solution, EA extracts three times, saturated common salt water washing three times, anhydrous MgSO
4dry.Organic phase is spin-dried for and obtains white solid (being compound 22), dry 0.99g, productive rate 87%.
Product nuclear magnetic data is as follows:
1h NMR (400MHz, DMSO) δ 9.01 (s, 1H), 8.58 (d, J=8.4Hz, 1H), 7.80 – 7.71 (m, 1H), 7.69 – 7.58 (m, 2H), 7.41 (d, J=7.6Hz, 1H), 7.18 (d, J=8.2Hz, 1H), 4.27 (s, 2H), 2.53 (m, 1H), 1.14 (d, J=8.5Hz, 2H), 0.83 (m, 2H).
the preparation of embodiment 11Lesinurad intermediate (compound 23)
In the single port bottle that compound 22 is housed, add solvent acetonitrile (5mL), pyridine (0.24mL), to be dissolved completely after slowly drip acetonitrile solution (the 3eq Br of bromine
2be dissolved in 1mL acetonitrile), dropwise, room temperature reaction 20h, oil bath 60 degrees Celsius reaction 3h.In reaction solution, add 30mL water and 30mL ethyl acetate, with 30mL extraction into ethyl acetate 3 times, organic phase saturated common salt water washing, anhydrous magnesium sulfate drying, was spin-dried for silicagel column and obtained product (compound 23) 0.63g, productive rate 50%.
Product nuclear magnetic data is as follows:
1h NMR (400MHz, CDCl
3) δ 8.56 (d, J=8.4Hz, 1H), 7.73-7.64 (m, 1H), 7.63 – 7.55 (m, 1H), 7.38 (s, 2H), 7.23 – 7.16 (m, 1H), 4.01 (d, J=1.9Hz, 2H), 2.50 – 2.40 (m, 1H), 1.21 – 1.14 (m, 2H), 0.92-0.84 (m, 2H).
Compound 23 can be passed through conventional hydrolysis reaction, can obtain Lesinurad.
the preparation of embodiment 12Lesinurad intermediate (compound 25)
Joined in single port bottle by compound 13 (1eq), add solvent DMF (16.8vol) and dissolve, stirring at room temperature, adds K
2cO
3(1.1eq), more dropwise add compound 24 (1.05eq), control to drip speed at 0.5mL/min, after stirring at room temperature reaction 18h, reaction raw materials has residue, adds 1.05eq raw material and continues reaction 6h, react completely.Add EA (ethyl acetate) and water dilute reaction solution, EA extracts three times, saturated common salt water washing once, anhydrous MgSO
4dry.Cross silicagel column and be separated to obtain target product (compound 25) 0.73g, productive rate 62%.
Product nuclear magnetic data is as follows:
1h NMR (400MHz, DMSO) δ 8.87 (s, 1H), 8.56 (d, J=8.4Hz, 1H), 7.73 (t, J=7.4Hz, 1H), 7.64 (t, J=7.4Hz, 1H), 7.55 (d, J=7.6Hz, 1H), 7.40 (d, J=7.6Hz, 1H), 7.17 (d, J=8.3Hz, 1H), 4.96 (t, J=5.5Hz, 1H), (3.62 q, J=6.2Hz, 2H), (3.21 t, J=6.5Hz, 2H), 2.59-2.51 (m, 1H), 1.19-1.08 (m, 2H), 0.92 – 0.71 (m, 2H).
the preparation of embodiment 13Lesinurad intermediate (compound 26)
Solvent acetonitrile (5mL) is added in the single port bottle that compound 25 is housed, pyridine (0.24mL), the completely rear acetonitrile solution (3eq Br2 is dissolved in 1mL acetonitrile) slowly dripping bromine to be dissolved, dropwise, room temperature reaction 41h raw material has residue, reaction is stopped.In reaction solution, add 30mL water and 30mL ethyl acetate, with 30mL extraction into ethyl acetate 3 times, organic phase saturated common salt water washing, anhydrous magnesium sulfate drying, was spin-dried for silicagel column and obtained product (compound 26) 0.13g, productive rate 18%.
Product nuclear magnetic data is as follows:
1H NMR(400MHz,DMSO)δ8.58(d,J=8.5Hz,1H),7.68-7.65(m,1H),7.68–7.65(m,1H),7.63(d,J=7.6Hz,1H),7.43(d,J=7.6Hz,1H),7.13(d,J=8.2Hz,1H),4.97(s,1H),3.61(t,J=6.5Hz,2H),3.20(t,J=6.4Hz,2H),2.60-2.52(m,1H),1.16–1.12(m,3H),0.89–0.83(m,2H).
Terminal hydroxyl is oxidized to acid through conventional oxidizing reaction by compound 26, can obtain Lesinurad.
the preparation of embodiment 14Lesinurad intermediate (compound 28)
Joined in single port bottle by compound 13 (1eq), add solvent DMF (20vol) and dissolve, stirring at room temperature, adds Cs
2cO
3(2eq), more dropwise add compound 27 (1eq), control to drip speed at 0.5mL/min, after stirring at room temperature 2h, react completely, add EA (ethyl acetate) and water dilute reaction solution, EA extracts three times, saturated common salt water washing three times, anhydrous MgSO
4dry.Filtration drying obtains white solid (compound 28), productive rate 98%.
Product nuclear magnetic data is as follows:
1h NMR (400MHz, CDCl
3) δ 8.50 (d, J=8.5Hz, 1H), 8.27 (s, 1H), 7.62 (t, J=7.3Hz, 1H), 7.49 (t, J=7.6Hz, 1H), 7.30 – 7.12 (m, 8H), 4.45 (d, J=3.7Hz, 2H), 2.47 – 2.29 (m, 1H), 1.19-1.07 (m, 2H), 0.91-0.73 (m, 2H).
the preparation of embodiment 15Lesinurad intermediate (compound 29)
In the single port bottle that compound 28 is housed, add solvent acetonitrile (5mL), pyridine (0.24mL), to be dissolved completely after slowly drip acetonitrile solution (the 3eq Br of bromine
2be dissolved in 1mL acetonitrile), dropwise, room temperature reaction 20h raw material has residue, and oil bath 60 degrees Celsius reaction 3h, stops reaction.In reaction solution, add 30mL water and 30mL ethyl acetate, with 30mL extraction into ethyl acetate 3 times, organic phase saturated common salt water washing, anhydrous magnesium sulfate drying, was spin-dried for post and obtained product (compound 29) 0.89g, productive rate 73%.
Product nuclear magnetic data is as follows:
1h NMR (400MHz, CDCl
3) δ 8.47 (d, J=8.5Hz, 1H), 7.62 – 7.53 (m, 1H), 7.43 (t, J=7.3Hz, 1H), 7.28 – 7.22 (m, 1H), 7.22 – 7.12 (m, 5H), 7.06 (m, 2H), 4.42 – 4.32 (m, 2H), 2.42 – 2.27 (m, 1H), 1.14 – 1.05 (m, 2H), 0.82 – 0.75 (m, 2H).
Compound 29 protects to obtain mercaptan through thioether debenzylation, then prepares sulfide derivative, and hydrolysis, can obtain Lesinurad.
the preparation of embodiment 16Lesinurad intermediate (compound 31)
Joined in single port bottle by compound 13 (1eq), add solvent acetic acid acid anhydride (compound 30,4.5vol), dissolve, stirring at room temperature, adds K
2cO
3(2eq), stirring at room temperature 2h, add EA (ethyl acetate) and water dilute reaction solution, EA extracts three times, saturated common salt water washing three times, anhydrous MgSO
4dry.Organic phase is spin-dried for and obtains white solid (compound 31) 1.12g, productive rate 97%.
Product nuclear magnetic data is as follows:
1h NMR (400MHz, CDCl
3) δ 8.54 (d, J=8.4Hz, 1H), 7.87 (s, 1H), 7.68 – 7.61 (m, 1H), 7.61 – 7.54 (m, 1H), 7.48-7.34 (m, 3H), 2.84 (s, 3H), 2.47 – 2.34 (m, 1H), 1.19-1.09 (m, 2H), 0.91 – 0.79 (m, 2H).
Compound 31 is through bromination, and sulphur ethanoyl deprotection, is hydrolyzed after preparing sulfide derivative, can obtain Lesinurad.
embodiment 17
In single port bottle, add compound 32 (1.0eq), add DMF (8.2eq) and make it to dissolve, add NaOH (1.2eq) and CS
2(1.2eq), stirred at ambient temperature reaction 1h, adds hydrazine hydrate (3.0eq) and proceeds to stirring and refluxing 4h, LC under 70 DEG C of oil baths and confirm that reaction is complete, stop heating and stir, after cooling, every 1g raw material adds 10mL water, suction filtration, filter cake 4mL/(g raw material) 95% ethyl alcohol recrystallization, suction filtration, solid oil pump draws dry, obtains compound 33, productive rate 27%.
Product nuclear magnetic data is as follows:
1h NMR (400MHz, DMSO) δ 9.31 (s, 1H), 8.15 (d, J=8.3Hz, 1H), 7.96 (d, J=8.1Hz, 1H), 7.88 (d, J=8.0Hz, 1H), 7.75 – 7.61 (m, 2H), 7.57 (d, J=7.7Hz, 1H), 6.62 (br, 2H).
Compound 33 (1.0eq) is added in single port bottle, add Isosorbide-5-Nitrae-dioxane (7.5Vol) to make it to dissolve, add N, dinethylformamide diethyl acetal (1.0eq), stirring and refluxing 3h at 100 DEG C, react complete be cooled to room temperature after, 1g raw material adds 10mL water, separate out solid suction filtration, filter cake with 95% washing with alcohol twice, dry, obtain compound 34.Productive rate 69%.
Product nuclear magnetic data is as follows:
1h NMR (400MHz, DMSO) δ 14.09 (s, 1H), 8.72 (s, 1H), 8.29 (d, J=8.4Hz, 1H), 8.09 (d, J=7.9Hz, 1H), 7.81 (t, J=7.7Hz, 1H), 7.72 (t, J=7.6Hz, 1H), 7.60 (d, J=7.9Hz, 1H), 7.44 (d, J=8.4Hz, 1H).
By compound 34(0.98g, 1eq) join in single port bottle, add solvent DMF (16.5mL) and dissolve, stirring at room temperature, adds K
2cO
3(486mg, 1.1eq), more dropwise add compound 19(0.37mL, 1.05eq), control to drip speed at 0.5mL/min, after stirring at room temperature 3h, react completely, add EA(ethyl acetate) and water dilute reaction solution, EA60mLx3 extracts, and saturated aqueous common salt 60mLx3 washs, anhydrous MgSO
4dry.Organic phase is spin-dried for and obtains white solid (being compound 35), dry 1.36g, productive rate >99%.
Product nuclear magnetic data is as follows:
1h NMR (400MHz, CDCl
3) δ 8.38 (d, J=8.5Hz, 1H), 8.32 (s, 1H), 7.92 (d, J=7.8Hz, 1H), 7.78 – 7.69 (m, 1H), 7.68 – 7.59 (m, 1H), 7.37 (m, 2H), 4.19 (q, J=7.1Hz, 2H), 4.09 (d, J=5.8Hz, 2H), 1.26 (t, J=7.1Hz, 3H).
Solvent acetonitrile (4mL) is added in the single port bottle that compound 35 (0.78g) is housed, pyridine (0.48mL), the completely rear acetonitrile solution (3eq Br2in1mL acetonitrile) slowly dripping bromine to be dissolved, dropwise, reaction stops by room temperature reaction 1h.In reaction solution, add 30mL water and 30mL ethyl acetate, with 30mL extraction into ethyl acetate 3 times, organic phase Brine washs, and anhydrous magnesium sulfate drying was spin-dried for post and obtains product 360.71g, productive rate 75%.
Product nuclear magnetic data is as follows:
1h NMR (400MHz, CDCl
3) δ 8.39 (d, J=8.5Hz, 1H), 7.95 (d, J=7.9Hz, 1H), 7.78 – 7.70 (m, 1H), 7.65 (dd, J=11.3,4.0Hz, 1H), 7.35 (d, J=7.9Hz, 1H), 7.26 (t, J=4.2Hz, 1H), 4.19 (q, J=7.1Hz, 2H), 4.10 – 3.98 (m, 2H), 1.26 (t, J=7.1Hz, 3H).
Compound 32-36 can convert Br to cyclopropyl by linked reaction, then obtains target compound 8 through the reaction similar with the application's route.
Above to invention has been detailed description; its object is to allow the personage being familiar with this art can understand content of the present invention and be implemented; can not limit the scope of the invention with this; the equivalence change that all spirit according to the present invention are done or modification, all should be encompassed in protection scope of the present invention.
Claims (11)
1. a Lesinurad intermediate, is characterized in that: described Lesinurad intermediate is the compound that general formula I represents,
In formula I:
R represents H or COCH
3; Or R represents CH
2r
1, wherein R
1represent CN; CH
2oH; Be not substituted or be selected from C
1~ C
6one or more phenyl replaced in alkyl, halogen;
R
2represent cyclopropane base; Halogen; OTf.
2. Lesinurad intermediate according to claim 1, it is characterized in that: in formula I, R represents H, R
2represent cyclopropane base, structural formula as shown in Equation 13:
3. the preparation method of Lesinurad intermediate that represents of formula III,
it is characterized in that: comprise and make formula I
the step that bromine substitution reaction generates formula III compound occurs, and formula I is identical with the R in III, R
2identical, wherein:
R represents H or COCH
3; Or R represents CH
2r
1, wherein R
1represent CN; CH
2oH; Be not substituted or be selected from C
1~ C
6one or more phenyl replaced in alkyl, halogen;
R
2represent cyclopropane base;
The bromine source that described bromination reaction adopts is bromine, bromine water, N-bromo-succinimide, C5H6Br2N2O2;
Described method also comprises:
Make compound 13
with RX in a solvent, the step of substitution reaction production I occurs under acid binding agent exists, and wherein the definition of R is the same, and X represents leavings group; And
Make compound 12
with N, there is the step that cyclization reaction generates described compound 13 in dinethylformamide dialkyl acetal, wherein said DMF dialkyl acetal is N in a solvent, dinethylformamide dimethylacetal or DMF diethyl acetal.
4. the preparation method of Lesinurad intermediate that represents of formula III according to claim 3, is characterized in that: in formula I and III: R is COCH
3or CH
2r
1, and R
1represent CN; CH
2oH; Be not substituted or be selected from C
1~ C
6one or more phenyl replaced in alkyl, halogen.
5. the preparation method of Lesinurad intermediate that represents of formula III according to claim 3, it is characterized in that, described bromination reaction is implemented as follows: make formula I and described bromine source in a solvent, under acid binding agent exists, bromination reaction occurs.
6. the preparation method of Lesinurad intermediate that represents of formula III according to claim 3, it is characterized in that, X is chlorine, bromine, iodine or OTf.
7. the preparation method of Lesinurad intermediate that represents of formula III according to claim 3, it is characterized in that: described method also comprises first in a solvent, generated the salt of N-(4-cyclopropyl-1-naphthalene) dithiocarbamic acid by 4-cyclopropyl-naphthalidine, dithiocarbonic anhydride and alkali reaction, then make N-(4-cyclopropyl-1-naphthalene) salt of dithiocarbamic acid and the step of hydrazine hydrate reacting generating compound 12.
8. the preparation method of Lesinurad intermediate that represents of formula III according to claim 7, is characterized in that: described alkali is sodium hydroxide or potassium hydroxide or the combination of the two.
9. a preparation method of Lesinurad, it comprises the step of the Lesinurad intermediate synthesis Lesinurad represented by formula III,
In formula III:
R represents H or COCH
3; Or R represents CH
2r
1, wherein R
1represent CN; CH
2oH; Be not substituted or be selected from C
1~ C
6one or more phenyl replaced in alkyl, halogen;
R
2represent cyclopropane base;
It is characterized in that: described method also comprises takes the method any one of claim 3 ~ 8 described in claim to the step of the Lesinurad intermediate prepared formula III and represent.
10. a Lesinurad intermediate, is characterized in that: described Lesinurad intermediate is the compound that formula 15 or 19 represents:
The preparation method of the Lesinurad intermediate that 11. 1 kinds of formula IIIs represent,
it is characterized in that: comprise and make formula I
the step that bromine substitution reaction generates formula III compound occurs, and formula I is identical with the R in III, R
2identical, wherein:
R represents CH
2r
1, wherein R
1represent ethoxycarbonyl;
R
2represent cyclopropane base;
The bromine source that described bromination reaction adopts is bromine, bromine water, N-bromo-succinimide, C5H6Br2N2O2;
Described method also comprises:
Make compound 13
with RX in a solvent, the step of substitution reaction production I occurs under acid binding agent exists, and wherein the definition of R is the same, and X is leavings group; And
Make compound 12
with DMF dialkyl acetal, cyclization occurs in a solvent and react the step generating described compound 13, wherein said DMF dialkyl acetal is
DMF dimethylacetal or DMF diethyl acetal.
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| CN104292123B (en) * | 2014-09-27 | 2015-12-02 | 张远强 | The succinamide derivative of phenyl naphthalene nucleus, Preparation Method And The Use |
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| CN105622531A (en) * | 2015-04-03 | 2016-06-01 | 南京明德新药研发股份有限公司 | Axial chiral isomers and preparation method and pharmaceutical application thereof |
| CN105017169A (en) * | 2015-06-30 | 2015-11-04 | 安徽万邦医药科技有限公司 | Preparation method for 4-(4-cyclopropyl-naphthalene-1-yl)-5-thio-[1,2,4]triazolidine-3-ketone and intermediate 4-cyclopropyl-naphthalene-1-yl-ethyl carbamate |
| CN104987311A (en) * | 2015-06-30 | 2015-10-21 | 安徽万邦医药科技有限公司 | Preparing method for (4-(4-cyclopropyl-naphthalene-1-yl)-5-nitr-4H-(1, 2, 4) triazole-3-ylsulfanyl)-ethyl acetate and intermediate (5-nitr-4H-(1, 2, 4) triazole-3-sulfenyl)-ethyl acetate thereof |
| CN105017168A (en) * | 2015-07-01 | 2015-11-04 | 安徽万邦医药科技有限公司 | New preparation method of [5-bromo-4-(4-cyclopropyl-naphthalene-1-yl)-4H-[1, 2, 4]triazole-3-ylsulfanyl]-methyl acetate |
| CN105153056A (en) * | 2015-07-01 | 2015-12-16 | 安徽万邦医药科技有限公司 | New preparation method of [5-bromo-4-(4-cyclopropyl-naphthalene-1-yl)-4H-[1, 2, 4]triazole-3-ylthioalkyl]-methyl acetate |
| CN106478531B (en) * | 2015-08-25 | 2019-06-28 | 南京华威医药科技集团有限公司 | 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- base) -4H-1,2,4- triazole -3- base sulfenyls) acid intermediates |
| CN105175348A (en) * | 2015-10-16 | 2015-12-23 | 北京康立生医药技术开发有限公司 | Preparation method for lesinurad |
| WO2017147270A1 (en) * | 2016-02-24 | 2017-08-31 | Ardea Biosciences, Inc. | Atropisomers of triazole derivative |
| CN105906576B (en) * | 2016-06-12 | 2018-04-17 | 成都百裕制药股份有限公司 | It is a kind of come Si Nuolei intermediates preparation method |
| DK3473617T3 (en) * | 2016-06-17 | 2022-11-28 | Medshine Discovery Inc | HALOGENATED COMPOUND AND AXIAL, CHIRAL ISOMERS THEREOF |
| EP3281941B1 (en) | 2016-08-11 | 2019-07-24 | Zentiva K.S. | Process for preparing 2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4h-1,2,4-triazol-3-ylthio)acetic acid |
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| CN106916115B (en) * | 2017-03-22 | 2018-03-06 | 北京新领先医药科技发展有限公司 | A kind of quaternary ammonium salt catalysis and application |
| CN106866560B (en) * | 2017-03-30 | 2023-05-30 | 浙江美诺华药物化学有限公司 | Lesinurad synthesis method |
| CN108947919B (en) | 2017-05-17 | 2023-05-02 | 上海奥博生物医药股份有限公司 | Novel preparation method of anti-gout drug Lesinurad and key intermediate thereof |
| CN108047148A (en) * | 2017-12-28 | 2018-05-18 | 北京沃邦医药科技有限公司 | A kind of preparation method of the western Nader's impurity of thunder |
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