• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
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    • 专利摘要:
    A process for obtaining 4-amino-1-isobutyl-1H-imidazo [4,5-c] quinoline. The present invention describes a novel process for obtaining a quinoline derivative from the corresponding chlorinated precursor by reaction with ammonium derivatives, a base and a high boiling point solvent. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2538880A1
    申请号:ES201331909
    申请日:2013-12-24
    公开日:2015-06-24
    发明作者:Antonio BUXADÉ VIÑAS；Carlos Mola Soler；Antonio Conchillo Teruel
    申请人:Laboratorios Vinas SA；
    IPC主号:
    专利说明:

    DESCRIPTION

    A procedure to obtain 4-amino-1-isobutyl-1H-imidazo [4,5-c] quinolein.
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    Field of the Invention 5

    The present invention deals with a new process for obtaining 4-amino-1-isobutyl-1H-imidazo [4,5-c] quinolein.
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     10
    State of the Art

    4-Amino-1-isobutyl-1H-imidazo [4,5-c] quinolein (compound of formula 1) is a modifier of the immune response and stimulates the production of interferon alfa. It is used for the treatment of viral skin infections and for the treatment of genital warts. fifteen




     twenty




     25

                                             1 2


     30
    The usual obtaining of 4-amino-1-isobutyl-1H-imidazo [4,5-c] quinolein is made from 4-chloro-1-isobutyl-1H-imidazo [4,5-c] quinolein (composed of formula 2), by replacing chlorine with the radical -NH2, according to two main routes:

    a) Reaction with ammonia: in the form of ammonium hydroxide (EP 145,340, US 4,689,338, WO 35 2006/070408); or in the form of ammonia gas in an organic solvent, usually dimethylsulfoxide (WO 2008/099377, US 2008/0194822)). In any case, the reaction must be carried out in a reactor capable of withstanding high pressures. (Scheme 1).

    b) To obviate the use of high pressures, the introduction of the -NH2 radical has been made from ammonia derivatives, such as amines (benzylamine, WO 2005/033049), amides (phthalimide, WO 2004/009593; formamide, WO 2006/100226 and US 2007/0135640), ureas, carbamates, (US 2008/0177074 and WO 2008/090550), hydroxylamine, (US 2006/0004202), etc. In these cases, high pressure equipment is not necessary to perform the synthesis, but one or two additional steps are necessary to convert the new product, resulting from the reaction of compound 2 with the ammonia derivative, to 4-amino-1 -isobutyl-1H-imidazo [4,5-c] quinolein (1). In addition, in the case of using hydroxylamine, the yields are only moderate (about 50%). (Scheme 2).

    Therefore, there is still a need for an industrial method that allows the conversion of compound 2 into compound 1 in a single step, with good yields and without the need to use medium-high pressure equipment.

    Scheme 1



     5




                                                                    NH3 or 10

                                                                    NH4OH


    Scheme 2 15




     twenty




                                    R - NH2 Hydrolysis 25
                                                                                               H + or OH-


     30
    Object and presentation of the Invention

    Obtaining 4-amino-1-isobutyl-1H-imidazo [4,5-c] quinolein by reacting compound 2 with ammonium hydroxide is a simple and easy reaction to be carried out on a laboratory scale, requiring a small pressure reactor. When attempting to scale at the pilot plant level 35 or at the industrial level, the costs associated with the pressure reactor skyrocket exponentially, in parallel with the increase in pressure generated by the gas ammonia and water vapor as the reaction volume increases .

    The authors of the present invention, during the investigations for scaling the reaction of compound 2 with ammonium hydroxide to obtain 4-amino-1-isobutyl-1 H -imidazo [4,5-c] quinolein have surprisingly discovered that It is possible to carry out the reaction without the need for high pressure equipment, replacing the ammonia with an ammonium salt and a base, and the water with a high boiling polar solvent.
     Four. Five
    The present invention allows obtaining 4-amino-1-isobutyl-1H-imidazo [4,5-c] quinolein (1) from chloro derivative (2) by using simple and cheap reagents, in a single step and with the usual equipment of a laboratory, pilot plant or industrial plant (open glass, enameled or steel reactors), thus resulting in economic, technical and operational advantages over previous procedures. fifty

    Regarding the technical and operational advantages, it is necessary to emphasize, fundamentally, two:

    - The process uses ammonia in the form of solid ammonium salt, the first being released very slowly by means of a base, which allows the reaction to be carried out at atmospheric pressure. The methods that use ammonia gas need expensive high pressure equipment.

    - Obtaining 4-amino-1-isobutyl-1H-imidazo [4,5-c] quinolein from chloro derivative 5 (compound 2) is done in one step, compared to the 2 or 3 steps needed when Ammonia derivatives, such as ureas, formamides, benzylamines, etc. are used.

    Being able to use reactors at atmospheric pressure, the possibility of making the reaction in one step and the use of easily reactive solvents and solvents, allow the reaction to be carried out easily on an industrial scale and with a significant cost reduction.

    The crude 4-amino-1-isobutyl-1H-imidazo [4,5-c] quinolein obtained under the conditions described reaches a wealth of at least 98.0%, and greater than 99.0% once it has been crystallized . fifteen

    The yields range (depending on the combination of reagents used) between 50% and 99%.

    Detailed description of some embodiments of the Invention 20

    The process object of the present invention consists in the reaction of the chloro derivative (compound 2), currently it is a commercial product, with an ammonium salt:
    A (-) NH4 (+), a base and a high boiling polar solvent, since the reaction is carried out at temperatures above 100 ° C 25




     30


                                                       A (-) NH4 (+) / Base

                                 2 Solvent 1 35




    Ammonium salt is the source of ammonia and for this purpose any ammonium salt serves, 40 derived from strong or weak acid (A (-) means the corresponding anion) and also mixed salts of ammonium and other cation (alkaline, alkaline earth or of transition) or mixtures of them. Examples of ammonium salts include, but are not limited to FNH4, ClNH4, BrNH4, INH4, SO4 (NH4) 2, (SO4) 2FeNH4, NO3NH4, CO3 (NH4) 2, HCOONH4, CH3COONH4, (CH3) 3COONH4, (COO NH4 )2,
    C6H5-COONH4, etc. Four. Five

    Preferred ammonium salts are the following: FNH4, ClNH4, BrNH4 and NO3NH4, or mixtures thereof.

    The base serves for the "in situ" release of ammonia from the ammonium salt, and inorganic bases such as oxides, hydroxides and carbonates, and organic ones such as alkoxides are preferable, but not limited thereto. More preferable are alkali metal, alkaline earth or transition metal hydroxides, or mixtures thereof.

    Preferred bases are: LiOH, NaOH, KOH, CsOH, Ca (OH) 2 and Mg (OH) 2, or mixtures thereof.

    Preferably the base is used in the form of powder, pellets, lentils, flakes, in aqueous solution or in alcoholic solution. 5

    The reaction is carried out in a polar solvent of boiling point equal to greater than 100 ° C, preferably of boiling point greater than 130 ° C. Among the preferred solvents suitable for this reaction are:
     10
    a) Amides such as preferably dimethylformamide, dimethylacetamide, acetamide, formamide, N-methylpyrrolidone, etc.

    b) Ureas as preferably tetramethylurea, N, N’-dimethylethyleneurea, N, N’-dimethylpropylene urea, etc. fifteen

    c) Sulfoxides and related sulfur compounds such as preferably dimethylsulfoxide, tertamethylene sulfoxide, dimethylsulfone, sulfolane, sulfolene, etc.

    d) Alcohols such as ethoxyethanol, 2- (2-ethoxyethoxy) ethanol, ethylene glycol, propylene glycol, diethylene glycol, glycerin, triethylenglycol, polyethylene glycol, polypropylene glycol, etc.

    e) Ethers such as preferably diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, polyethylene glycol dimethyl ether, etc.
     25
    f) Amines such as preferably N-ethylmorpholine, lutidine, triethanolamine,
    tris (2- (2-methoxyethoxy) ethyl) amine, etc.

    g) Mixtures of the above as such, of their different isomers, or of their polymers with chains with different degrees of polymerization. 30

    Preferred solvents to perform this reaction are: dimethylsulfoxide, glycerin, ethylene glycol and propylene glycol.

    The reaction is carried out at a temperature between 100 ° C and 200 ° C, preferably between 130 ° C and 160 ° C.

    The reaction lasts between 5 and 24 hours, depending largely on the solvent and the reagents used. Preferably, it will be terminated when the amount of the starting product (chloro derivative) is less than 5%. 40

    The molar ratio between compound 2 and the ammonium salt may vary between 1: 1 to 1: 100 moles, with a ratio between 1:30 and 1:60 moles being preferred.

    The molar ratio between compound 2 and the base may vary between 1: 1 to 1: 100 moles, with a ratio between 1:20 and 1:40 moles being preferred. However, the amount of base needed for a given process is subject to the end of the reaction.

    The volume (liters) of solvent used in the process can vary between 5 and 50 times the number of moles of compound 2 being used, with a ratio of 10 liters per 50 mol of compound 2 being preferred.

    The reaction can be carried out in a conventional glass, vitrified or steel reactor, with stirring and a heating system that allows heating to more than 130 ° C.

    The crude 4-amino-1-isobutyl-1H-imidazo [4,5-c] quinolein is isolated from the reaction by filtration or centrifugation and can subsequently be crystallized to achieve greater purity.

    The reaction crude is easily isolated by filtration or centrifugation, and can optionally be recrystallized from a suitable solvent, such as methanol, ethanol, n-propanol, isopropanol and dimethylformamide, or mixtures thereof. 10

    The crude 4-amino-1-isobutyl-1H-imidazo [4,5-c] quinolein obtained under the conditions described reaches a wealth of at least 98.0%, and greater than 99.0% once it has been crystallized .
     fifteen
    The yields range (depending on the combination of reagents used) between 50 and 99%.

    Examples
     twenty
    The Nuclear Magnetic Resonance (NMR, δ) spectra have been performed at 300 MHz in DMSOd6 + CF3COOD solution. Coupling constants J are given in Hertz. s = singlet; d = double; t = triplet; dd = double double; AB = AB system; m = multiplet and ba = broadband or sum of several signals.
     25
    DMF means dimethylformamide.

    DMSO means dimethylsulfoxide.

    DMPU means 1,3-dimethyltetrahydro-2-pyrimidone. 30

    TRIS means triethanolamine.

    NEM means N-ethylmorpholine.
     35
    ETG means ethylene glycol.

    SDR means diethylene glycol.

    PRG means 1,2-propylene glycol. 40

    GLY means glycerin.


    Chloro derivative (compound 2, starting product), ammonium salts, bases and solvents used in these syntheses are commercial products.

    Here are some ways to carry out this invention, which is the object of the patent, but without being in any way limiting it.
    fifty
    Obtaining compound 1 (4-amino-1-isobutyl-1H-imidazo [4,5-c] quinolein).

    Method 1

    100 g (0.385 mol) of chloro derivative (compound 2), 5 1070 g (20 mol) of ammonium chloride, 4 l of DMSO and 224 g (4 mol) of KOH are placed in a 10 liter reactor. It is heated to 140-150 ° C. One hour after reaching this temperature, 112 g (2 moles) of KOH are added by the reactor mouth every hour for 8 hours.

    After the reaction is finished, after 24 hours, it is cooled and then 4 l of distilled water 10 are added when the indoor temperature is between 90 ° C and 100 ° C. Without stopping the stirring, the inside of the reactor is allowed to reach room temperature. The precipitated solid is filtered and washed with 1N soda, with distilled water and with methanol. The crude obtained is recrystallized from DMF and dried for a minimum of 5 hours under vacuum and at room temperature, obtaining 46.8 g of 4-amino-1-isobutyl-1 H -imidazo [4,5-c] quinolein (52% yield ). fifteen

    The 4-amino-1-isobutyl-1H-imidazo [4,5-c] quinolein obtained has an NMR spectrum consistent with a pattern.

    1 H NMR (DMSOd6 + CF3COOD): 20

    0.921 (d, J: 6.8 Hz, 6H, ((CH3) 2C)), 2.135 (m, 1H (CH)), 4.457 (d, J: 7.2 Hz, 2H (CH2)), 7.548 ( dd, J: 7.6 Hz, 1H (= CH)), 7.681 (dd, J: 7.6 Hz, 1H (= CH)), 7.767 (dd, J: 8.0 Hz, 1H (= CH) ), 8,134 (dd, J: 8.0 Hz, 1H (= CH)), 8,472 (s, 1H (N = CHN)), 9,104 (m, 1H (+ NH3)) ppm.
     25
    Table 1 shows several examples of obtaining 4-amino-1-isobutyl-1H-imidazo [4,5-c] quinolein, according to method 1, but without these examples being limiting of this method.

    Table 1
     Reaction No.  1 2 3 4 5 6
     Solvent  DMSO DMSO DEG ETG ETG TRIS
     Ammonium Salt  ClNH4 ClNH4 ClNH4 ClNH4 ClNH4 ClNH4
     Base  KOH NaOH KOH KOH CsOH KOH
     Wealth (%)  > 99 (b)> 98 (b)> 99 (b)> 99 (a)> 99 (a)> 98 (b)
     Performance (%)  52 51 84 93 85 52
     30
    (a): Uncrystallized raw
    (b): DMF crystallized
    Method 2

    In a 10 liter reactor 130 g (0.5 mol) of chloro derivative (compound 2), 1,600 g (30 mol) of ammonium chloride, 5 l of ethylene glycol and 925 g (12.5 mol) of calcium hydroxide are placed. It is heated to 140-150 ° C for 24 hours. After the reaction is cooled, 2.6 l 5 of a mixture of distilled water / conc. HCl are added. 1: 1, when the indoor temperature is between 90 ºC and 100 ºC. It is cooled to 5 ° C and the precipitated solid is isolated by filtration.

    The solid is dissolved in 7 liters of hot water (70 ° C) and basified with 1N NaOH until pH = 12. The precipitated solid is filtered and washed with 1N soda, distilled water and methanol. 10

    The resulting solid is crystallized from DMF and allowed to cool to 10 ° C.

    The 4-amino-1-isobutyl-1H-imidazo [4,5-c] quinolein obtained after filtering, is dried under vacuum and at room temperature, resulting in a weight of 115.8 g (yield 96.5%). fifteen

    The 1 H NMR spectrum (DMSOd 6 + CF 3 COOD) of the 4-amino-1-isobutyl-1 H -imidazo [4,5-c] quinolein obtained according to method 2 matches that of the 4-amino-1-isobutyl-1 H -imidazo [4,5-c] quinolein obtained according to method 1.
     twenty
    Table 2 shows several examples of obtaining 4-amino-1-isobutyl-1H-imidazo [4,5-c] quinolein, according to method 2, but without these examples being limiting of this method.

    Table 2
     Reaction No.  7 8 9 10 11 12 13
     Solvent  ETG ETG DMSO DEG PRG ETG GLY
     Ammonium Salt  ClNH4 ClNH4 ClNH4 ClNH4 ClNH4 ClNH4 ClNH4
     Base  Ca (OH) 2 Mg (OH) 2 KOH KOH KOH KOH KOH
     Wealth (%)  > 99 (b)> 99 (b)> 99 (b)> 98 (b)> 98 (a)> 99 (a)> 99 (b)
     Performance (%)  96 95 52 80 84 94 87

    25
    Table 2 (continued)
     Reaction No.  14 15 16 17 18 19
     Solvent  ETG ETG ETG ETG ETG ETG
     Ammonium Salt  ClNH4 ClNH4 ClNH4 FNH4 BrNH4 NO3NH4
     Base  LiOH NaOH NaOH 33% (c) KOH KOH KOH
     Wealth (%)  > 99 (a)> 99 (a)> 99 (a)> 99 (a)> 99 (a)> 98 (a)
     Performance (%)  89 93 91 87 82 86

    (a): Raw uncrystallized.
    (b): DMF crystallized.
    (c): 33% NaOH in water. It is previously mixed with ethylene glycol and distilled at 180-185 ° C. 5

    Method 3

    In a 50 liter reactor, 260 g (1 mol) of chloro derivative (compound 2), 2,675 g (50 moles) of ammonium chloride, 12 l of glycerin and 280 g (5 moles) of KOH are placed. It is heated to 140-10150 ° C. After 30 minutes of reaching this temperature, 1 l of an 1120 g solution (20 moles) of KOH dissolved in 8 l of ethylene glycol is added dropwise over 5 hours. After the reaction cools. 20 liters of distilled water are added when the indoor temperature is between 90 ºC and 100 ºC. Without stopping the stirring, the inside of the reactor is allowed to reach room temperature. The precipitated solid is filtered and washed therein centrifuged with distilled water, with 1N soda, with distilled water and with methanol. The solid obtained is dried under vacuum and at room temperature, resulting in 221.5 g (92.3% yield).

    The 1H NMR spectrum (DMSOd6 + CF3COOD) of the 4-amino-1-isobutyl-1H-imidazo [4,5-20 c] quinolein obtained according to method 3 matches that of 4-amino-1-isobutyl- 1H-imidazo [4,5-c] quinolein obtained according to methods 1 and 2.

    Table 3 shows several examples of obtaining 4-amino-1-isobutyl-1H-imidazo [4,5-c] quinolein, according to method 3, but without these examples being limiting of this method.
    Table 3

     Reaction no.  20 21 22 23 24
     Solvent  GLY ETG ETG ETG ETG
     Ammonium Salt  ClNH4 ClNH4 ClNH4 FNH4 NO3NH4
     Base / Solvent  KOH / ETG KOH / ETG NaOH / ETG NaOH / ETG CsOH / ETG
     Wealth (%)  > 99 (a)> 99 (a)> 98 (a)> 99 (a)> 99 (a)
     Performance (%)  92 99 89 98 90
    (a): Raw uncrystallized.

    Recrystallization of crude 4-amino-1-isobutyl-1H-imidazo [4,5-c] quinolein. 5

    When the crude resulting from the above reactions contains less than 98% in 4-amino-1-isobutyl-1H-imidazo [4,5-c] quinolein, then it is recrystallized from dimethylformamide, as follows: 100 g of 4- Raw amino-1-isobutyl-1H-imidazo [4,5-c] quinolein is dissolved in 5 L of DMF and the mixture is heated to 120-130 ° C, with stirring. It is allowed to cool with stirring 10 to a temperature of 10 ° C and is maintained at this temperature for 3 hours. It is then filtered and washed with 500 ml of DMF at 0 ° C and with 1 liter of methanol. The solid obtained is dried at 45 ° C and under vacuum.


    fifteen
    权利要求:
    Claims (1)
    [1]
    image 1
    image2

    1 - A process for obtaining 4-amino-1-isobutyl-1H-imidazo [4,5-c] quinolein (compound 1) from 4-chloro-1-isobutyl-1H-imidazo [4,5-c] quinolein (compound 2),
     5


     10


                                          1 2 15
    characterized in that the reaction is carried out in the presence of an ammonium salt and a base.
    2 - A process according to claim 1, characterized in that the reaction is carried out in the presence of a polar solvent, at atmospheric pressure. twenty
    3 - A method according to one of the preceding claims, characterized in that the ammonium salt used is chosen from the group consisting of FNH4, ClNH4, BrNH4, and NO3NH4 and mixtures of the foregoing.
     25
    4 - A method according to claim 3, characterized in that the ammonium salt is ClNH4.
    5 - A method according to any of the preceding claims, characterized in that the base used is chosen from the group consisting of the alkali, alkaline earth and transition elements hydroxides. 30
    6 - A method according to claim 5, characterized in that the base is used in the form of powder, pellets, lentils, flakes, in aqueous solution or in alcoholic solution.
    7 - A process according to one of claims 5 or 6, characterized in that the base used is sodium hydroxide.
    8 - A process according to one of claims 5 or 6, characterized in that the base used is potassium hydroxide.
     40
    9 - A process according to one of claims 5 or 6, characterized in that the base used is lithium hydroxide.
    10 - A process according to one of claims 5 or 6, characterized in that the base used is cesium hydroxide. Four. Five
    11 - A process according to one of claims 5 or 6, characterized in that the base used is calcium hydroxide.
    12 - A process according to one of claims 5 or 6, characterized in that the base 50 used is magnesium hydroxide.
    13 - A process according to any of claims 2 to 12, characterized in that the polar solvent used for the reaction has a boiling point greater than 100 ° C.
    14 - A process according to claim 13, characterized in that the polar solvent has a boiling point greater than 130 ° C. 5
    15 - A process according to one of claims 13 or 14, characterized in that the polar solvent is selected from the group consisting of dimethylsulfoxide, diethylene glycol, propylene glycol, ethylene glycol and glycerin.
     10
    16 - A process according to any of the preceding claims, characterized in that the temperature at which the reaction is carried out to obtain the compounds of structure (1), is comprised between 100 ° C and 200 ° C.
    17 - A process according to any of the preceding claims, characterized in that the temperature at which the reaction is carried out to obtain the compounds of structure (1), is comprised between 135 ° C and 160 ° C.
    18 - A process according to any of the preceding claims, characterized in that the molar ratio between compound 2 and the ammonium salt is between 1: 1 to 20 1: 100 moles, preferably between 1:30 and 1:60 moles.
    19 - A process according to any of the preceding claims, characterized in that the molar ratio between compound 2 and the base is between 1: 1 to 1: 100 moles, preferably between 1:20 and 1:40 moles. 25
    20 - A process according to any of the preceding claims, characterized in that the volume of solvent, expressed in liters, used in the process is between 5 and 50 times the number of moles of compound 2 being used, and preferably there is a ratio 10 liters of solvent per mole of compound 2. 30
    21 - A process according to any of the preceding claims, characterized in that the compound of formula (2), the ammonium salt, the solvent and the base are initially mixed in the reactor at a temperature below 100 ° C and subsequently heated to start the reaction. 35
    22 - A process according to any of claims 1 to 21, characterized in that the crystallization solvent is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol and dimethylformamide and mixtures thereof.

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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    EP0310950A1|1983-11-18|1989-04-12|Riker Laboratories, Inc.|Quinoline intermediates for the synthesis of 1H-imidazo[4,5-c]quinolines and 1H-imidazo[4,5-c]quinolin-4-amimes|
    WO1992006093A1|1990-10-05|1992-04-16|Minnesota Mining And Manufacturing Company|Process for the preparation of imidazo[4,5-c]quinolin-4-amines|
    US20110269965A1|2005-04-01|2011-11-03|Coley Pharmaceutical Group, Inc.|Ring Closing and Related Methods and Intermediates|EP3950687A1|2020-08-07|2022-02-09|PHV Pharma|Industrial method for synthesising imiquimod from quinoline-2,4-diol applicable to the pharmaceutical use thereof|
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