CN109956872A - A kind of preparation method of 4- cyclopropyl-naphthalidine - Google Patents
A kind of preparation method of 4- cyclopropyl-naphthalidine Download PDFInfo
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- CN109956872A CN109956872A CN201711405513.0A CN201711405513A CN109956872A CN 109956872 A CN109956872 A CN 109956872A CN 201711405513 A CN201711405513 A CN 201711405513A CN 109956872 A CN109956872 A CN 109956872A
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- naphthalidine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
- C07C17/10—Preparation of halogenated hydrocarbons by replacement by halogens of hydrogen atoms
- C07C17/12—Preparation of halogenated hydrocarbons by replacement by halogens of hydrogen atoms in the ring of aromatic compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/04—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups
- C07C209/06—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of halogen atoms
- C07C209/10—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of halogen atoms with formation of amino groups bound to carbon atoms of six-membered aromatic rings or from amines having nitrogen atoms bound to carbon atoms of six-membered aromatic rings
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Abstract
The present invention relates to a kind of novel processing steps of 4- cyclopropyl-naphthalidine.Low in raw material price required for the preparation method, is easy to get, and reaction step is easy to operate, and total recovery is better than state of the art.And avoid using reactions such as nitrification, hydro-reduction, Suzuki couplings, it greatly reduces and generates difficulty and production cost.One is provided more economically for the preparation of 4- cyclopropyl-naphthalidine, efficiently, safety and environmentally friendly synthesis approach.
Description
Technical field
The invention belongs to the preparation technical fields of Lesinurad intermediate, and in particular to Lesinurad key intermediate 4-
Cyclopropyl-naphthalidine preparation method.
Background technique
Gout be by monosodium urate salt (MSU) deposition caused by crystal correlation arthropathy, with purine metabolic disturbance and
(or) hyperuricemia caused by underexcretion is directly related.Global patient with gout is up to more than 2,000 ten thousand.In December, 2015,
FDA approval AstraZeneca gout drug Lesinurad is used to treat together with xanthine oxidase inhibitor the related high urine of gout
Acidaemia.New more effective, the lower process of cost of exploitation, has great social effect and economic significance.
Realize the preparation of drug Lesinurad, key intermediates 4- cyclopropyl-naphthalidine synthesis is most important, seeks
It looks for and efficiently synthesizes 4- cyclopropyl-naphthalidine method and be of great significance.4- cyclopropyl-naphthalidine synthesis at present is at home and abroad
Report less, reported route is as follows.
Route one, earliest patent CN101083987 report following synthetic route:
The route uses nitration reaction, requires height to production equipment, and the nitration reaction is selectively poor, this is caused to prepare
Route yield is low, and two step total recoverys only have 47%.In addition, there is also potential safety issues for nitration reaction.
Route two, patent CN101083987, CN105263913 report following synthetic route:
Although the route only single step reaction, and yield reaches 80% or more.However, the raw material cyclopropylboronic acid that reaction uses,
4- bromonaphthalene amine and catalyst acetic acid palladium are expensive, are not suitable for amplification production.
What the above two lines used is nitration reaction respectively, and coupling reaction prepares 4- cyclopropyl-naphthalidine.This two roads
The defect that line is individually present is difficult to apply it well in amplification production.Therefore a high yield is found, it is inexpensive
4- cyclopropyl-naphthalidine synthetic route is most important.
Summary of the invention
It is a kind of more economical the technical problem to be solved by the present invention is to overcome the deficiencies of the prior art and provide, it is more efficient, more
Environmental protection, the 4- cyclopropyl-naphthalidine preparation method for being suitble to large-scale industrial production.
In order to solve the above technical problems, the technical solution that the present invention takes is:
A kind of preparation method of 4- cyclopropyl-naphthalidine, which comprises the following steps:
1) make compound (I) and bromide reagent that bromination reaction occur under solvent action and generate compound (II):
2) it reacts compound (II) under copper class catalyst action with ammonia and generates 4- cyclopropyl-naphthalidine (III):
One according to the present invention specific and preferred aspect, bromide reagent can be Br in step 1)2, NBS, C5H6Br2N2O2 etc..
It is furthermore preferred that bromide reagent is Br2.The equivalent of bromide reagent is generally 1 to 3 equivalents, preferably 1 to 1.5 equivalents simultaneously.
According to the present invention, solvent can be in step 1), THF, methylene chloride, acetonitrile, toluene, Isosorbide-5-Nitrae-dioxane, vinegar
One of common organic solvent such as acid or a variety of mixed solvents.Preferably, use acetic acid for solvent.
According to the present invention, reaction temperature can be 0 °C to 150 °C, preferably 5 °C to 100 °C in step 1), more
Preferably 10-30 °C.
According to the present invention, the copper class catalyst in step 2) can be copper powder, copper oxide, cuprous oxide, copper chloride, chlorination
Cuprous, copper bromide, cuprous bromide, cupric iodide, cuprous iodide, copper sulphate etc., cuprous preferred selective oxidation is catalyst.Copper class
Catalyst amount can be 0.1 equivalent to 1 equivalent.
According to the present invention, the ammonia in step 2), is not specifically limited, and can provide ammonia source, the specific can be that ammonia, ammonia
Water, methanolic ammonia solution, ammonia aqueous isopropanol, ammonia tetrahydrofuran solution etc..The preferred ammonium hydroxide of the present invention.
According to the present invention, solvent is not particularly limited in step 2), can be water, methanol, ethyl alcohol, isopropanol, acetonitrile,
N-Methyl pyrrolidone, n,N-Dimethylformamide, dioxane etc..
According to the present invention, reaction temperature can be 50 °C to 150 °C, preferably 80 °C to 100 °C in step 2).
Preferably, product 4- cyclopropyl-naphthalidine (III) in step 2) can form 4- ring by way of adding hydrochloric acid
Propyl-naphthalidine hydrochloride, to be purified.
Preferably, step 1) and step 2) can be made successive reaction, the product 4- cyclopropyl -1- bromonaphthalene (II) of step 1)
It can not separate.
Due to the implementation of above-mentioned technical proposal, the invention has the following advantages over the prior art:
1) nitration reaction and coupling reaction are avoided, and intermediate does not need to purify, and can be made continuous reaction, is conducive to
Industrial amplification production；
2) each raw material is easy to get, and reaction yield is high, substantially reduces production cost.
3) it can optimize and combine as continuous reaction, final product can be by purifying to obtain the target product of high-purity at salt.
Specific embodiment:
Below in conjunction with specific embodiment, the present invention is described further, but the present invention is not limited to following embodiments.
The synthetic method of compound
The synthesis of embodiment Isosorbide-5-Nitrae-cyclopropyl -1- bromonaphthalene
1- cyclopropyl naphthalene (5.0 g, 30 mmol) is dissolved in 15 mL acetic acid, is added dropwise to bromine (5.68 g, 36 mmol), mixing
Liquid reacts 1-2 hours under 10-20 °C.Reaction solution is quenched with water after the reaction was completed, methylene chloride extraction is sub- by alkali cleaning
Metabisulfite solution washing, washing, concentration remove methylene chloride and obtain 6.24 g of 4- cyclopropyl -1- bromonaphthalene through silica gel column purification,
Yield 85%.
Product nuclear magnetic data:1H NMR (400 MHz, DMSO) δ 8.51 – 8.42 (m, 1H), 8.23 –
8.13 (m, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.73 – 7.66 (m, 2H), 7.17 (d, J = 7.7
Hz, 1H), 2.38 (m, 1H), 1.11 – 1.01 (m, 2H), 0.78 – 0.68 (m, 2H)。
Embodiment 2, the synthesis of 4- cyclopropyl -1- bromonaphthalene
1- cyclopropyl naphthalene (5.0 g, 30 mmol) is dissolved in 50 mL acetonitriles, is added NBS (7.1 g, 40 mmol), mixed liquor exists
It is reacted 24 hours under 50 °C.Reaction solution is cooled to room temperature after the reaction was completed, concentration removes acetonitrile, and 50 mL normal heptanes are added and stir
Mix filtering.Silica gel column purification is crossed after filtrate concentration, obtains 6.7 g of 4- cyclopropyl -1- bromonaphthalene, yield 90%.
Embodiment 3, the synthesis of 4- cyclopropyl-naphthalidine
4- cyclopropyl -1- bromonaphthalene (6.0 g, 24 mmol) is dissolved in 12 mL n,N-Dimethylformamide (DMF), and oxidation is added
Cuprous (0.52 g, 3.6 mmol), 12 mL of ammonium hydroxide (ammonia mass concentration 25%), enclosed high pressure kettle are simultaneously pressed into ammonia 20-30
min.100 °C of mixed system are reacted 28 hours.Reaction solution is cooled to room temperature after the reaction was completed, 36 ml water are added, use methyl
70 mL of tertbutyl ether is extracted in two times, after concentration, is crossed silica gel column purification, is obtained 4- cyclopropyl -3.56 g of naphthalidine, yield
80%。
Product nuclear magnetic data:1H NMR (400 MHz, DMSO) δ 8.25 (d, J = 7.9 Hz, 1H), 8.07
(d, J = 8.0 Hz, 1H), 7.48 (m, 1H), 7.39 (m, 1H), 6.99 (m, 1H), 6.59 (d, J =
7.7 Hz, 1H), 5.50 (s, 2H), 2.14 (m, 1H), 1.00 – 0.83 (m, 2H), 0.61 – 0.47 (m,
2H)。
Embodiment 4, the synthesis of 4- cyclopropyl-naphthalidine
4- cyclopropyl -1- bromonaphthalene (6.0 g, 24 mmol) is dissolved in 40 mL N-Methyl pyrrolidones (NMP), and it is sub- that oxidation is added
Copper (1.7 g, 12 mmol), 40 mL of ammonium hydroxide (ammonia mass concentration 25%).85 °C are reacted 24 hours.It after the reaction was completed will reaction
Liquid is cooled to room temperature, and 100 mL water are added, and is extracted 2 times with 70 mL of methyl tertiary butyl ether(MTBE), after concentration, is crossed silica gel column purification, is obtained
4- cyclopropyl -3.1 g of naphthalidine, yield 71%.
Embodiment 5, continuity method prepare 4- cyclopropyl-naphthalidine hydrochloride
1- cyclopropyl naphthalene (25.0 g, 149 mmol) is dissolved in 75 mL acetic acid, is added dropwise to Br2(28.39 g, 178 mmol) are mixed
Liquid is closed to react under 10-20 °C 1-2 hours.Reaction solution is quenched with water after the reaction was completed, methylene chloride extraction, by alkali cleaning,
Sodium sulfite solution washing, washing, concentration remove methylene chloride and obtain 4- cyclopropyl -1- bromonaphthalene crude oil, and 62 mL are added
In n,N-Dimethylformamide (DMF), it is added cuprous oxide (3.1 g, 22 mmol), ammonium hydroxide 62 mL (ammonia mass concentration
25%), enclosed high pressure kettle, indentation ammonia maintain 20-30 min.Mixed system reacts 28 hours at 100 °C.After reaction will
Reaction solution is cooled to room temperature, and 62 mL water are added, and is extracted 3 times with 62 mL of DCM.Merge DCM phase, with water backwash, decolourizes, concentration
It is replaced as isopropanol, is added with stirring hydrochloric acid aqueous isopropanol (17.36g, 119 mmol).It is small that mixed liquor is stirred at room temperature 3
When, filtering, filter cake is eluted with 100 mL isopropanols.55 °C of drying obtain 4- cyclopropyl -8.49 g of naphthalidine hydrochloride, yield
65%。
Embodiment 6, continuity method prepare 4- cyclopropyl-naphthalidine hydrochloride
1- cyclopropyl naphthalene (10.0 g, 60 mmol) is dissolved in 50 mL acetonitriles, is added NBS (14.2 g, 80 mmol), mixed liquor
It is reacted 15 hours under 50 °C.Reaction solution is cooled to room temperature after reaction, concentration removes acetonitrile, and 100 mL positive heptan is added
Alkane agitation and filtration.Grease is obtained after filtrate concentration, is added in 80 mL N-Methyl pyrrolidones (NMP), cuprous oxide is added
(4.3 g, 30 mmol), 80 mL of ammonium hydroxide (ammonia mass concentration 25%).85 °C are reacted 24 hours.After reaction by reaction solution
It is cooled to room temperature, 200 mL water is added, extracted 2 times with 100 mL of methyl tertiary butyl ether(MTBE).Merge methyl tertiary butyl ether(MTBE) phase, under stirring
It is added ethanol solution hydrochloride (2 eq).Mixed liquor is stirred at room temperature 3 hours, and filtering, filter cake is drenched with 30 mL methyl tertiary butyl ether(MTBE)s
It washes.55 °C of drying obtain 4- cyclopropyl -9.9 g of naphthalidine hydrochloride, yield 75%.
The present invention is described in detail above, its object is to allow the personage for being familiar with this field technology that can understand this
The content of invention is simultaneously implemented, and it is not intended to limit the scope of the present invention, all Spirit Essence institutes according to the present invention
The equivalent change or modification of work, should be covered by the scope of protection of the present invention.
Claims (10)
1. the preparation method of a kind of 4- cyclopropyl-naphthalidine or its hydrochloride, which comprises the following steps:
1) make compound (I) and bromide reagent that bromination reaction occur in a solvent and generate compound (II):
;
2) it reacts compound (II) with ammonia under the action of catalyst and generates 4- cyclopropyl-naphthalidine (III):
。
2. preparation method according to claim 1, it is characterised in that: bromide reagent used in step 1) is bromine,
N- bromo-succinimide, C5H6Br2N2O2 etc..
3. preparation method according to claim 1, it is characterised in that: solvent used in step 1) be tetrahydrofuran, two
Chloromethanes, acetonitrile, toluene, Isosorbide-5-Nitrae-dioxane, one of common organic solvent such as acetic acid or a variety of mixed solvents.
4. preparation method according to claim 1, it is characterised in that: copper class catalyst used in step 2) is copper powder,
Copper oxide, cuprous oxide, copper chloride, stannous chloride, copper bromide, cuprous bromide, cupric iodide, cuprous iodide, copper sulphate etc..
5. preparation method according to claim 1, it is characterised in that: ammonia source used in step 2) is ammonia, ammonium hydroxide, ammonia
Methanol solution, ammonia aqueous isopropanol, ammonia tetrahydrofuran solution etc..
6. preparation method according to claim 1, it is characterised in that: solvent used in step 2) be water, tetrahydrofuran,
Methanol, ethyl alcohol, isopropanol, acetonitrile, N-Methyl pyrrolidone, n,N-Dimethylformamide, the common organic solvent such as dioxane
One of or a variety of mixed solvents.
7. a kind of be continuously synthesizing to method synthesis 4- cyclopropyl-naphthalidine preparation method, which is characterized in that including following step
It is rapid:
。
8. the preparation flow according to described by claim 7, the bromide reagent preferably is selected from bromine, N- bromo-succinimide, two
Bromine glycolylurea, reaction dissolvent preferably are selected from tetrahydrofuran, methylene chloride, acetonitrile, toluene, Isosorbide-5-Nitrae-dioxane, acetic acid, methanol, second
Alcohol, isopropanol, acetonitrile, N-Methyl pyrrolidone, n,N-Dimethylformamide, it is ammonia, ammonium hydroxide, ammonia first that ammonia source, which preferably is selected from ammonia source,
Alcoholic solution, ammonia aqueous isopropanol, ammonia tetrahydrofuran solution etc..
9. the preparation flow according to described by claim 7, it is preferred that use bromine water as bromide reagent, use ammonium hydroxide as ammonia
Source, the amination under the catalytic condition of cuprous oxide, by the way that high-purity can be obtained with the yield greater than 60% at salt crystallization purifying
Formula IV compound.
10. the preparation flow according to described by claim 7, it is preferred that use N- bromo-succinimide as bromide reagent, make
Use ammonium hydroxide as ammonia source, the amination under the catalytic condition of cuprous oxide can be obtained by purifying at salt with the yield greater than 70%
Obtain the formula IV compound of high-purity.
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| CN111908998A (en) * | 2020-08-12 | 2020-11-10 | 中国科学院化学研究所 | Preparation method of monobromoaromatic compound |
| JP6830569B1 (en) * | 2019-08-23 | 2021-02-17 | 持田製薬株式会社 | Method for Producing Heterocyclidene Acetamide Derivative |
| WO2021039023A1 (en) * | 2019-08-23 | 2021-03-04 | 持田製薬株式会社 | Method for producing heterocyclidene acetamide derivatives |
| JP2022153519A (en) * | 2019-08-23 | 2022-10-12 | 持田製薬株式会社 | Method for producing heterocyclidene acetamide derivative |
| RU2813203C2 (en) * | 2019-08-23 | 2024-02-07 | Мотида Фармасьютикал Ко., Лтд. | Method of producing heterocyclidene acetamide derivative |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP6830569B1 (en) * | 2019-08-23 | 2021-02-17 | 持田製薬株式会社 | Method for Producing Heterocyclidene Acetamide Derivative |
| WO2021039023A1 (en) * | 2019-08-23 | 2021-03-04 | 持田製薬株式会社 | Method for producing heterocyclidene acetamide derivatives |
| CN114206847A (en) * | 2019-08-23 | 2022-03-18 | 持田制药株式会社 | Process for producing heterocyclylideneacetamide derivative |
| JP2022153519A (en) * | 2019-08-23 | 2022-10-12 | 持田製薬株式会社 | Method for producing heterocyclidene acetamide derivative |
| JP7320113B2 (en) | 2019-08-23 | 2023-08-02 | 持田製薬株式会社 | Method for producing heterocyclideneacetamide derivative |
| RU2813203C2 (en) * | 2019-08-23 | 2024-02-07 | Мотида Фармасьютикал Ко., Лтд. | Method of producing heterocyclidene acetamide derivative |
| CN111908998A (en) * | 2020-08-12 | 2020-11-10 | 中国科学院化学研究所 | Preparation method of monobromoaromatic compound |
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Application publication date: 20190702 |