CN105622427A - Method for producing lesinurad intermediate 4-cyclopropyl-1-naphthylamine - Google Patents
Method for producing lesinurad intermediate 4-cyclopropyl-1-naphthylamine Download PDFInfo
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- CN105622427A CN105622427A CN201410605221.1A CN201410605221A CN105622427A CN 105622427 A CN105622427 A CN 105622427A CN 201410605221 A CN201410605221 A CN 201410605221A CN 105622427 A CN105622427 A CN 105622427A
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Abstract
The invention discloses a synthetic method which can be applied to produce gout treating drug lesinurad intermediate 4-cyclopropyl-1-naphthylamine 2. The method adopts metal or low-price salt as a reducing agent, to provide a production technique which can avoid the application of hydrogen and precious metal catalysts without producing a by-product 3. The present technique has the characteristics of high purity products, good security and low cost.
Description
Technical field
The invention belongs to pharmaceutical technology field, be specifically related to pharmaceutical intermediate preparation technology field, relate more specifically to a kind of synthetic method that may be used for preparing gout treatment medicine URAT1 inhibitor lesinurad intermediate 4-cyclopropyl-naphthalidine.
Background technology
Gout is that one is deposited on the positions such as joint with hyperuricemia and monosodium urate salt (MSU) and causes the chronic metabolic disease that pain is principal character, and main cause is purine metabolic disturbance and/or uric acid discharge obstacle. Whole world patient with gout has tens million of at present. Lesinurad (RDEA594) a kind of can be suppressed uric acid transporter body (uratetransporter1 in kidney by what Ardea company developed, URAT1) discharge the oral drugs of uric acid in blood, developed (being shown below) by the antiviral drugs RDEA806 of Valeant the earliest. The proprietary rights of present lesinurad belongs to AstraZeneca.
The principal synthetic routes (WO2014/008295 and US2013345271) of Lesinurad is as follows. Wherein, above-mentioned two patent all discloses by 4-cyclopropyl-1-nitronaphthalene 1 through catalytic hydrogenation to prepare intermediate 4-cyclopropyl-naphthalidine 2. Under study for action it was found that compound 1 prepares 2 through catalytic hydrogenation can be attended by substantial amounts of by-product 3 and generate. By-product 3 is similar with physico-chemical property with product 2 polarity, and the purification to 2 brings very big difficulty. It addition, this technique is owing to being catalytic hydrogenation, relating to inflammable and explosive hydrogen and the use of expensive Metal Palladium, therefore safety and economy are all undesirable.
Through big quantity research, we successfully solve compound 1 and produce the problem of by-product 3 in the process using catalytic hydrogenation process reduction, and solve the safety of above-mentioned technique and the problem of economy. The invention discloses this technique being prepared compound 2 by compound 1, this technique has the advantage not producing by-product 3, enormously simplify the purification of compound 2, and has the advantage that safety is good and cost is low concurrently.
Summary of the invention
The present invention be contemplated to solve prior art shortcoming (namely, compound 1 prepares the problem of adjoint a large amount of by-products 3 in the process of 2 at catalytic hydrogen reduction, and safety and economy are all undesirable), and provide a kind of preparation technology avoiding use hydrogen and noble metal catalyst and not producing by-product 3, the feature that this technique has product purity height, safety is good and cost is low.
It is of the present invention that to be synthesized the synthesis technique of compound 2 by compound 1 as follows:
It is metal or salt at a low price that compound 1 is reduced to 2 reducing agents used by the present invention, carries out under suitable solvent and temperature. Wherein, described metal or salt at a low price are selected from metallic zinc, metallic iron, stannous chloride, sodium sulfide etc., described solvent selected from lower alcohol, oxolane, Isosorbide-5-Nitrae-dioxane, water etc., and the mixture of these solvents and water, described temperature is the reflux temperature that room temperature arrives solvent for use. It is pointed out that the practical stability existence form of some slaine is hydrate, such as two hydrated stannous chloride (SnCl2��2H2O) and nine hydrated sodium sulfide (Na2S��9H2O). When using metallic reducing agent, generally require the auxiliary reagent adding a kind of acidity, such as ammonium chloride.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is further illustrated. It should be noted that following embodiment is only for illustrating, and it is not intended to limit the present invention. Those skilled in the art all should within the protection domain required by the application claim according to the various changes that the teachings of the present invention is made.
Embodiment 1
21.32g (0.1mol) 4-cyclopropyl-1-nitronaphthalene 1 is dissolved in 300mL dehydrated alcohol, stirring under room temperature, add the Pd/C of 7.68g10%, then overnight at room temperature catalytic hydrogenation, TLC shows that reaction completes.
Reactant mixture sucking filtration removes catalyst, and filtrate boils off solvent on a rotary evaporator, and the residue obtained, through column chromatography purification, obtains product 2, light red oil liquid, 13.56g, yield 74%.1HNMR(DMSO-d6, 400MHz), ��: 8.24 (d, 1H, J=8.4Hz), 8.07 (d, 1H, J=8.4Hz), 7.46-7.50 (m, 1H), 7.37-7.41 (m, 1H), 6.99 (d, 1H, J=7.6Hz), 6.59 (d, 1H, J=8.0Hz), 5.52 (bs, 2H), 2.10-2.15 (m, 1H), 0.89-0.93 (m, 2H), 0.53-0.57 (m, 2H).
Pass through1HNMR analyzes, containing a certain amount of by-product 3 (see collecting of table 1) in the compound 2 of above-mentioned preparation.
Embodiment 2
21.32g (0.1mol) 4-cyclopropyl-1-nitronaphthalene 1 is dissolved in 1000mL dehydrated alcohol, stirring under room temperature, add the Pd/C of 7.68g10%, then overnight at room temperature catalytic hydrogenation, TLC shows that reaction completes.
Reactant mixture sucking filtration removes catalyst, and filtrate boils off solvent on a rotary evaporator, and the residue obtained, through column chromatography purification, obtains product 2, light red oil liquid, 13.38g, yield 73%.
Pass through1HNMR analyzes, containing a certain amount of by-product 3 in the compound 2 of above-mentioned preparation.
Embodiment 3
21.32g (0.1mol) 4-cyclopropyl-1-nitronaphthalene 1 is dissolved in 200mL dehydrated alcohol, stirring under room temperature, add the Pd/C of 1.07g10%, then overnight at room temperature catalytic hydrogenation, TLC shows that reaction completes.
Reactant mixture sucking filtration removes catalyst, and filtrate boils off solvent on a rotary evaporator, and the residue obtained, through column chromatography purification, obtains product 2, light red oil liquid, 13.01g, yield 71%.
Pass through1HNMR analyzes, containing a certain amount of by-product 3 in the compound 2 of above-mentioned preparation.
Embodiment 4
21.32g (0.1mol) 4-cyclopropyl-1-nitronaphthalene 1,32.69g (0.5mol) zinc powder and 26.75g (0.5mol) NH4Cl adds in the mixed solution being made into by 150mLTHF and 60mL water, then stirs under reflux, until TLC shows that reaction completes (typically requiring 10 hours).
After having reacted, reactant mixture is cooled to room temperature, and sucking filtration removes solid (kieselguhr drainage), and filtrate is poured in the frozen water of 500mL stirring, continues stirring 5 minutes, with 300mL �� 3CH2Cl2Extract. Merge extracted organic phase, by the salt water washing of 500mL5%, anhydrous Na2SO4Dry, boil off solvent on a rotary evaporator, the residue by silicagel column chromatography purification obtained, it is the sterling of 2, red liquid, 15.94g, yield 87%. Its1HNMR is consistent with embodiment 1.
Embodiment 5
21.32g (0.1mol) 4-cyclopropyl-1-nitronaphthalene 1,32.69g (0.5mol) zinc powder and 26.75g (0.5mol) NH4Cl adds in 200mL dehydrated alcohol, then at room temperature stirs, until TLC shows that reaction completes (typically requiring 5 hours).
After having reacted, reactant mixture is cooled to room temperature, and sucking filtration removes solid (kieselguhr drainage), and filtrate is poured in the frozen water of 500mL stirring, continues stirring 5 minutes, with 300mL �� 3CH2Cl2Extract. Merge extracted organic phase, by the salt water washing of 500mL5%, anhydrous Na2SO4Dry, boil off solvent on a rotary evaporator, the residue by silicagel column chromatography purification obtained, it is the sterling of 2, red liquid, 15.39g, yield 84%. Its1HNMR is consistent with embodiment 1.
Embodiment 6
21.32g (0.1mol) 4-cyclopropyl-1-nitronaphthalene 1,27.92g (0.5mol) iron powder and 26.75g (0.5mol) NH4Cl adds in the mixed solution being made into by 150mL ethanol and 60mL water, then at return stirring, until TLC shows that reaction completes (typically requiring 6 hours).
After having reacted, reactant mixture is cooled to room temperature, and sucking filtration removes solid (kieselguhr drainage), and filtrate is poured in the frozen water of 500mL stirring, continues stirring 5 minutes, with 300mL �� 3CH2Cl2Extract. Merge extracted organic phase, by the salt water washing of 500mL5%, anhydrous Na2SO4Dry, boil off solvent on a rotary evaporator, the residue by silicagel column chromatography purification obtained, it is the sterling of 2, red liquid, 13.38g, yield 73%. Its1HNMR is consistent with embodiment 1.
Embodiment 7
21.32g (0.1mol) 4-cyclopropyl-1-nitronaphthalene 1 and 120.09g (0.5mol) Na2S��9H2O adds in the mixed solution being made into by 200mL1,4-dioxanes and 80mL water, then at return stirring, until TLC shows that reaction completes (typically requiring 12 hours).
After having reacted, reactant mixture is cooled to room temperature, and sucking filtration removes solid, and filtrate is poured in the frozen water of 500mL stirring, continues stirring 5 minutes, with 300mL �� 3CH2Cl2Extract. Merge extracted organic phase, by the salt water washing of 500mL5%, anhydrous Na2SO4Dry, boil off solvent on a rotary evaporator, the residue by silicagel column chromatography purification obtained, it is the sterling of 2, red liquid, 11.18g, yield 61%. Its1HNMR is consistent with embodiment 1.
Embodiment 8
21.32g (0.1mol) 4-cyclopropyl-1-nitronaphthalene 1 and 112.83g (0.5mol) SnCl2��2H2O adds in 400mL, then at return stirring, until TLC shows that reaction completes (typically requiring 10 hours).
After having reacted, reactant mixture is cooled to room temperature, and sucking filtration removes solid, and filtrate is poured in the frozen water of 500mL stirring, continues stirring 5 minutes, with 300mL �� 3CH2Cl2Extract. Merge extracted organic phase, by the salt water washing of 500mL5%, anhydrous Na2SO4Dry, boil off solvent on a rotary evaporator, the residue by silicagel column chromatography purification obtained, it is the sterling of 2, red liquid, 13.01g, yield 71%. Its1HNMR is consistent with embodiment 1.
Embodiment 9
21.32g (0.1mol) 4-cyclopropyl-1-nitronaphthalene 1,65.38g (1mol) zinc powder and 53.49g (1mol) NH4Cl adds in the mixed solution being made into by 150mLTHF and 60mL water, then stirs under reflux, until TLC shows that reaction completes (typically requiring 6 hours).
After having reacted, reactant mixture is cooled to room temperature, and sucking filtration removes solid (kieselguhr drainage), and filtrate is poured in the frozen water of 500mL stirring, continues stirring 5 minutes, with 300mL �� 3CH2Cl2Extract. Merge extracted organic phase, by the salt water washing of 500mL5%, anhydrous Na2SO4Dry, boil off solvent on a rotary evaporator, the residue by silicagel column chromatography purification obtained, it is the sterling of 2, red liquid, 15.94g, yield 87%. Its1HNMR is consistent with embodiment 1.
Embodiment 10
21.32g (0.1mol) 4-cyclopropyl-1-nitronaphthalene 1,19.61g (0.3mol) zinc powder and 16.05g (0.3mol) NH4Cl adds in the mixed solution being made into by 150mLTHF and 60mL water, then stirs under reflux, until TLC shows that reaction completes (typically requiring 6 hours).
After having reacted, reactant mixture is cooled to room temperature, and sucking filtration removes solid (kieselguhr drainage), and filtrate is poured in the frozen water of 500mL stirring, continues stirring 5 minutes, with 300mL �� 3CH2Cl2Extract. Merge extracted organic phase, by the salt water washing of 500mL5%, anhydrous Na2SO4Dry, boil off solvent on a rotary evaporator, the residue by silicagel column chromatography purification obtained, it is the sterling of 2, red liquid, 15.94g, yield 87%. Its1HNMR is consistent with embodiment 1.
Content (molar ratio) list of by-product 3 in above-described embodiment the 2 of preparation is compared as follows,
Table 1 distinct methods prepare 2 in the content of by-product 3
| Embodiment | The ratio of the by-product 3 in product 2 | Embodiment | The ratio of the by-product 3 in product 2 |
| 1 | 22% | 6 | 0% |
| 2 | 19% | 7 | 0% |
| 3 | 18% | 8 | 0% |
| 4 | 0% | 9 | 0% |
| 5 | 0% | 10 | 0% |
[0049]As can be seen from the above table, the product 2 that the reaction of all use catalytic hydrogenations generates all can produce considerable amount of by-product 3, and use the method for the present invention all will not produce by-product 3.
Claims (9)
1. the method being prepared compound 2 by compound 1, it is characterised in that: compound 1 dissolves in a solvent, under the effect of reducing agent, obtains compound 2; The reducing agent used is selected from metallic zinc, metallic iron, sodium sulfide or stannous chloride;
2. the method being prepared compound 2 by compound 1 described in claim 1, wherein the molal quantity of reducing agent is 3-10:1 with the molal quantity ratio of compound 1.
3. the method being prepared compound 2 by compound 1 described in claim 1, wherein the molal quantity of reducing agent is 5-10:1 with the molal quantity ratio of compound 1.
4. the method being prepared compound 2 by compound 1 described in claim 1, wherein the molal quantity of reducing agent is 5:1 with the molal quantity ratio of compound 1.
5. the method being prepared compound 2 by compound 1 described in claim 1, wherein solvent selected from lower alcohol, oxolane, Isosorbide-5-Nitrae-dioxanes, and they arbitrary mixture with water.
6. the method being prepared compound 2 by compound 1 described in claim 1, wherein solvent selected from ethanol, methanol, oxolane, Isosorbide-5-Nitrae-dioxanes, and they arbitrary mixture with water.
7. the method being prepared compound 2 by compound 1 described in claim 1, wherein reaction temperature is the room temperature reflux temperature to reaction dissolvent used.
8. the method being prepared compound 2 by compound 1 described in claim 1, wherein reaction temperature is the reflux temperature of reaction dissolvent used.
9. the method being prepared compound 2 by compound 1 described in claim 1, wherein with metallic reducing agent joined together by use acid auxiliary reagent be ammonium chloride.
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| CN201410605221.1A CN105622427A (en) | 2014-10-31 | 2014-10-31 | Method for producing lesinurad intermediate 4-cyclopropyl-1-naphthylamine |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109206323A (en) * | 2017-07-07 | 2019-01-15 | 上海现代制药股份有限公司 | A kind of preparation method of naphthylamines pharmaceutical intermediate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102363597A (en) * | 2010-10-22 | 2012-02-29 | 连云港市金囤农化有限公司 | Preparation method of 2,4-dichloro-5-isopropoxy aniline salt |
| 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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- 2014-10-31 CN CN201410605221.1A patent/CN105622427A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN102363597A (en) * | 2010-10-22 | 2012-02-29 | 连云港市金囤农化有限公司 | Preparation method of 2,4-dichloro-5-isopropoxy aniline salt |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109206323A (en) * | 2017-07-07 | 2019-01-15 | 上海现代制药股份有限公司 | A kind of preparation method of naphthylamines pharmaceutical intermediate |
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