WO2017121323A1 - Procédé de préparation d'un composé dérivé de pyridine, intermédiaire et forme cristalline dudit composé - Google Patents

Procédé de préparation d'un composé dérivé de pyridine, intermédiaire et forme cristalline dudit composé Download PDF

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WO2017121323A1
WO2017121323A1 PCT/CN2017/070835 CN2017070835W WO2017121323A1 WO 2017121323 A1 WO2017121323 A1 WO 2017121323A1 CN 2017070835 W CN2017070835 W CN 2017070835W WO 2017121323 A1 WO2017121323 A1 WO 2017121323A1
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compound
group
solvent
acid
sodium
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黄志刚
丁照中
汤东东
王业鹏
李自永
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CISEN PHARMACEUTICAL Co Ltd
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CISEN PHARMACEUTICAL Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
    • C07D213/127—Preparation from compounds containing pyridine rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
    • C07D213/16—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
    • C07D213/16—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
    • C07D213/18—Salts thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6

Definitions

  • the present invention relates to a high purity (1R,2S)-1-(5-(4-chlorophenyl)-2-methoxypyridin-3-yl)-4-dimethylamino-2-aryl-1
  • Mycobacterium tuberculosis is the causative agent of tuberculosis. As a globally widespread and fatal infectious disease, according to the World Health Organization, more than 8 million people are infected each year and 2 million die from tuberculosis. In the past decade, tuberculosis cases have grown at a rate of 20% worldwide, especially in poor areas. If this trend continues, tuberculosis cases are likely to continue to grow at a 41% increase over the next two decades. In the 50 years since the initial application of chemotherapy, tuberculosis has been the leading infection to adults, second only to AIDS. Complications of tuberculosis have led to the emergence of many drug-resistant strains and a symbiotic relationship with AIDS.
  • tuberculosis employs a combination of multiple agents.
  • a formula recommended by the US Department of Public Health consists of first using isoniazid, rifampicin, pyrazinamide, and ethambutol for two months, then using isoniazid and rifampin alone for four months. .
  • the use of this combination of drugs needs to be extended to seven months.
  • the drug combination also needs to add the remaining agents, such as ethambutol tablets, streptomycin, kanamycin, amikacin, capreomycin, ethionamide, Cycloserine, ciprofloxacin and ofloxacin.
  • the remaining agents such as ethambutol tablets, streptomycin, kanamycin, amikacin, capreomycin, ethionamide, Cycloserine, ciprofloxacin and ofloxacin.
  • Multi-drug resistant tuberculosis is primarily resistant to isoniazid and rifampicin in four standard treatments. Multi-drug resistant tuberculosis can be fatal if there is no treatment or if standard tuberculosis standard therapy is used. Therefore, the treatment of this disease requires the use of second-line drugs for two years. Most of these second-line drugs are toxic, expensive, and have low efficacy. Infectious drug-resistant tuberculosis patients continue to spread the disease due to the lack of effective treatment. Therefore, for multi-drug resistant tuberculosis, a new drug with a novel mechanism of action is highly demanded.
  • the present invention provides a process for the preparation of a compound of formula (I),
  • R 1 is selected from a 6- to 12-membered aryl group, a 6- to 12-membered heteroaryl group, a 6- to 12-membered aryl-alkylene group, and a 6 to 12-membered heterocyclic group, which are optionally substituted by 0, 1, 2 or 3 R 01 .
  • HX is selected from an organic or inorganic acid
  • the base A is selected from the group consisting of an alkali metal base, an alkaline earth metal base or an organometallic base;
  • the molar ratio of the compound (II) to the base A is 1:1 to 5;
  • the molar ratio of the compound (II) to the compound (III) is 1:1 to 2;
  • the reaction solvent is selected from a single ether solvent or a mixed solvent of several ether solvents;
  • the amount of the reaction solvent is 3 to 20 times the weight of the compound (IV);
  • the reaction temperature is -80 to 0 ° C;
  • the reaction time is 1 to 24 hours;
  • the number of heteroatoms is independently selected from 1, 2 or 3, respectively.
  • R 1 is a naphthyl or phenyl group optionally substituted with 0, 1, 2 or 3 R 01 .
  • R 1 is selected from the group consisting of
  • the alkali metal base is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, barium carbonate, sodium hydrogencarbonate, and/or potassium hydrogencarbonate.
  • the alkaline earth metal base is selected from the group consisting of sodium hydride, potassium hydride, and/or calcium hydride.
  • the organometallic base is selected from the group consisting of n-butyl lithium, lithium diisopropylamide, lithium 2,2,6,6-tetramethylpiperidine, lithium bis(trimethylsilyl)amide, Sodium methoxide, lithium t-butoxide, sodium t-butoxide, potassium t-butoxide, sodium ethoxide and/or aluminum isopropoxide.
  • the molar ratio of the compound (II) to the base A is 1:1.2 to 2.
  • the above reaction temperature is from -80 to -60 °C.
  • the reaction time is from 2 to 12 hours.
  • the reaction time is from 4 to 8 hours.
  • the above reaction solvent is selected from the group consisting of tetrahydrofuran, diethyl ether and/or isopropyl ether.
  • the amount of the above reaction solvent is 5 to 10 times the weight of the compound (IV).
  • the above preparation method further comprises the following reaction route:
  • the above preparation method further comprises the following reaction route:
  • the above preparation method further comprises the following reaction route:
  • the base B is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, barium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium methoxide, lithium t-butoxide, sodium t-butoxide, Potassium tert-butoxide, sodium ethoxide, aluminum isopropoxide;
  • the reaction solvent is selected from a mixed solvent of a ketone, an alcohol or an ester solvent and a polar aprotic solvent.
  • the molar ratio of the chiral acid to the compound (IV) is from 0.5 to 1.5;
  • the chiral acid is selected from the group consisting of ⁇ -hydroxypropionic acid, ⁇ -hydroxysuccinic acid, ⁇ , ⁇ -dihydroxysuccinic acid, ⁇ -hydroxyphenylacetic acid, ⁇ -hydroxy acid, and compound (VI);
  • n 0, 1 or 2;
  • R 2 and R 4 are each independently selected from H, F, Cl, Br, I, or selected from, optionally substituted by 0, 1, 2 or 3 R 01 : C 1-8 alkoxy, C 1- 8- alkyl, Si(Ph) 3 , 6- to 12-membered aryl;
  • R 3 and R 5 are each independently selected from H, F, Cl, Br, I, NO 2 , OH, or selected from C 1-8 alkoxy optionally substituted by 0, 1, 2 or 3 R 01 a group, a C 1-8 alkyl group, a 6 to 12 membered aryl group;
  • position 13 and position 14 is substituted with R 3 or at position 14 and position 15 is substituted with R 3 may be joined together to form a 6 to 12 membered aryl ring;
  • the 8 position and R 5 is substituted at position 9 or position 9 and joined together at position 10 substituted with R 5, form a 6-12 membered aryl ring.
  • the molar ratio of the chiral acid to the compound (IV) is from 0.8 to 1.2.
  • the molar ratio of the chiral acid to the compound (IV) is 1.0.
  • the ketone solvent is selected from the group consisting of acetone and/or methyl ethyl ketone.
  • the alcohol solvent is selected from the group consisting of ethanol, methanol, isopropanol and/or tert-butanol.
  • the solvent for preparing compound (V) from compound (IV) is selected from the group consisting of acetone, methyl ethyl ketone, ethanol, methanol, isopropanol, tert-butanol, ethyl acetate, t-butyl acetate A single solvent or a mixed solvent of several solvents in DMF, DMSO, DMA and/or NMP.
  • the above method for producing the compound (V), wherein the volume ratio of the ketone, alcohol or ester solvent to the polar aprotic solvent is 1:0.03 to 0.1.
  • R 3 and R 5 are each independently selected from H.
  • the above R 2 is substituted at the 2-position.
  • the above R 4 is substituted at the 6 position.
  • R 2 and R 4 are each independently selected from the group consisting of: H, Si(Ph) 3 ,
  • the above compound (VI) is selected from the group consisting of
  • the above preparation method further comprises the following reaction route:
  • HX is selected from an organic or inorganic acid.
  • the HX is selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, oxalic acid, citric acid, maleic acid or fumaric acid.
  • the above preparation method further comprises the following reaction route:
  • the present invention provides a compound of the formula: as an intermediate for the preparation of a compound of formula (I):
  • the present invention also provides a compound I-1 represented by the following formula,
  • the present invention provides a crystalline form I of Compound I-1, the XRPD pattern of which is shown in Figure 1.
  • the XRPD pattern analysis data of the I crystal form is shown in Table-1.
  • the present invention provides a crystalline form II of Compound I-1, the XRPD pattern of which is shown in Figure 4.
  • the XRPD pattern analysis data of the above II crystal form is shown in Table-2.
  • the present invention provides a crystalline form III of Compound I-1, the XRPD pattern of which is shown in FIG.
  • the XRPD pattern analysis data of the above III crystal form is shown in Table-3.
  • the invention provides a preparation method of the above crystal form I, which comprises preparing a compound I-1 of any one form by adding to a solvent, wherein the solvent is selected from the group consisting of an alcohol, a ketone solvent or an alcohol solvent and a ketone solvent. a mixed solvent; the solvent is used in an amount of from 3 to 50 times the weight of the compound I-1.
  • the alcohol solvent is selected from the group consisting of methanol, ethanol, isopropanol and/or n-butanol.
  • the ketone solvent is selected from the group consisting of acetone and/or methyl ethyl ketone.
  • the mixed solvent is a mixed solvent of methanol and acetone.
  • the volume ratio of the mixed solvent of methanol and acetone is 1:5 to 30.
  • intermediate compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, combinations thereof with other chemical synthesis methods, and those skilled in the art.
  • Well-known equivalents, preferred embodiments include, but are not limited to, embodiments of the invention.
  • DMF stands for N,N-dimethylformamide
  • DMA stands for N,N-dimethylacetamide
  • DMSO stands for dimethyl sulfoxide
  • NMP stands for N-methylpyrrolidone
  • Pd( OAc) 2 represents palladium acetate
  • Pd(dppf)Cl 2 represents [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride
  • Pd 2 (dba) 3 represents tris(dibenzylideneacetone) Palladium
  • Pd(PPh 3 ) 4 represents tetrakistriphenylphosphine
  • Pd(PPh 3 ) 2 Cl 2 represents dichloroditriphenylphosphine palladium
  • Et 3 N represents triethylamine
  • DIPEA stands for diisopropyl Ethylamine
  • DBU stands for 1,8-diazabicycloundec-7-ene
  • AcOH
  • Tube voltage 40kV
  • tube current 40mA
  • Test conditions The sample ( ⁇ 1 mg) was placed in a DSC aluminum pan for testing at 25 ° C - 300 ° C and a heating rate of 10 ° C / min.
  • Test conditions Samples (2 to 5 mg) were placed in a TGA platinum pot for testing at room temperature - 300 ° C and a heating rate of 10 ° C / min.
  • the compound I-1 provided by the present invention has stable properties, good solubility, good wettability, and good crystallinity, crystal form and crystal form III. Prospects for medicine.
  • the process for synthesizing the compound I-1 and the intermediate thereof provided by the invention overcomes the disadvantages of the prior art that the starting materials are expensive, the reagents used are poisonous, the reaction conditions are harsh, the separation and purification are difficult, and the industrialization is difficult.
  • the method for preparing the compound I-1 of the present invention is a conventional or common reagent, which is easily available on the market and is inexpensive;
  • the intermediate compound (II) can be obtained from the compound (b) by a two-step conventional reaction in a higher total yield, and the post-treatment is simple without any column chromatography purification;
  • the reagents used in the reaction of each step are small molecules and easy to be purified
  • the metal palladium catalyzed cross-coupling is placed in a relatively advanced step, which is beneficial to control the metal palladium residue in the final product.
  • Figure 1 is an XRPD spectrum of Form I Cu-K ⁇ radiation of Compound I-1.
  • Figure 2 is a DSC chart of Form I of Compound I-1.
  • Figure 3 is a TGA pattern of Form I of Compound I-1.
  • Figure 5 is a DSC chart of Form II of Compound I-1.
  • Figure 6 is a TGA pattern of Form II of Compound I-1.
  • Figure 7 is an XRPD spectrum of Form III Cu-K ⁇ radiation of Compound 1-1.
  • Figure 8 is a DSC chart of Form III of Compound I-1.
  • Figure 9 is a TGA pattern of Form III of Compound I-1.
  • This compound has two chiral centers, as indicated by * in formula (IV-1), and thus has four stereoisomers, respectively (1R, 2S) 1-(5-(4-chlorophenyl)-2 -Methoxypyridin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol, (1S,2R)1-(5- (4-chlorophenyl)-2-methoxy Pyridin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol, (1R, 2R) 1-(5-(4-chloro Phenyl)-2-methoxypyridin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol and (1S,2S)1 -(5-(4-chlorophenyl)
  • the reaction was stopped after the end of consumption of 5-bromo-2-methoxypyridine by HPLC.
  • the reaction solution was cooled to 25 to 30 ° C, and concentrated under reduced pressure to remove dioxane.
  • the residue was extracted twice with ethyl acetate (10) ⁇ ⁇ 2), the organic phase was combined, washed with saturated brine (5 liters ⁇ 2), concentrated under reduced pressure at 35-40 ° C to give crude 5-(4-chlorophenyl)-2-methoxypyridine ( 6.5 kg, dark brown needle-like solid after cooling), the crude product was directly used for the next reaction.
  • benzyl zinc reagent Zinc powder (2.85 kg, 43.56 mol, 2.00 eq.) was suspended in anhydrous tetrahydrofuran (21.78 liters) under nitrogen atmosphere, and 1,2-dibromoethane was added at room temperature. (33 ml, 0.02 eq.), then heated to reflux, slowly added trimethylchlorosilane (28 mL, 0.01 eq.) (Note: A large amount of bubbles were observed after the addition and the reflux was severe, if not observed The bubbles were generated, and trimethylchlorosilane was added, and refluxed at 66 ° C for 30 minutes.
  • the reaction solution was then cooled to 25 ° C, and benzyl bromide (3.73 kg, 2.59 liters, 21.78 moles, 1.00 equivalents) was slowly added dropwise to the reaction system (note: the dropping rate was such that the temperature of the system did not exceed 30 ° C) at this temperature. Stirring was continued for 3 hours to obtain a tetrahydrofuran solution of benzyl zinc reagent (concentration: 1 mol/liter), which was used directly for the next reaction.
  • Step 4 Synthesis of 3-dimethylamino-1-(naphthalen-1-yl)propan-1-one oxalate
  • reaction solution was concentrated under reduced pressure to remove ethanol, then the residue was dissolved in water (25 liters) and extracted twice with ethyl acetate (5 liters x 2), and the aqueous phase was adjusted to pH with 1 mol/L aqueous sodium hydroxide ⁇ 9 ⁇ 10, and then extracted twice with ethyl acetate (15 liters ⁇ 2), the second extracted organic phase was combined, washed with saturated brine (10 liters ⁇ 2), and concentrated under reduced Methylamino)-1-(1-naphthyl)propan-1-one (7.41 kg, yellow oil).
  • N-Butyllithium titration Diphenylacetic acid (1.00 g, Alfa, 4.71 mmol) was added to tetrahydrofuran (10 ml) under a nitrogen atmosphere to give a colorless, transparent solution. A solution of butyllithium in n-hexane was slowly added dropwise to the above solution with a syringe. Observing the phenomenon, the solution partially yellowed during the addition process but disappeared rapidly.
  • n-butyllithium (twice: 1.927 ml and 1.985 ml, respectively, the average volume is 1.95 ml) is recorded, so the n-butyl group used is used.
  • concentration of the lithium n-hexane solution was 2.42 mol/liter.
  • TMP (2.74 kg, 19.3 mol) was dissolved in anhydrous tetrahydrofuran (12 L), and the reaction temperature was cooled to -65 ° C in a dry ice acetone bath.
  • n-butyllithium (8 L, 19.3 mol, 2.42 mol/L) was added dropwise. Alkane solution).
  • the control temperature was between -20 ° C and -78 ° C. It was observed that the color of the reaction system gradually changed from light yellow to deep red to form a yellow suspension, and stirring was continued at this temperature for 30 minutes.
  • EtOAcjjjjjjjj 4) The mixed solvent was stirred at 5 ° C to 15 ° C for 16 hours to precipitate a white solid. Filtration, the filter cake was beaten with ethanol (4 liters ⁇ 2), filtered, and the filter cake was dried by vacuum drying to constant weight (50 ° C, 24-48 hours) to obtain the target compound 1-(5-(4-chlorophenyl)- 2-methoxypyridin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol (1.83 kg, yield 23.23%), As a white solid, HPLC determined the isomer A content to be 88.3% and the isomer B content to be 4.8%.
  • R-(-)-binaphthol phosphate (519.3 g, 1.49 mol) was suspended in DMSO (1.0 L), heated to 50 ° C and stirred to dissolve until clear.
  • S-binaphthol phosphate (473 g, 1.35 mol) was suspended in DMSO (1.1 L), and heated to 50 ° C to dissolve and clarify.
  • 1-(5-(4-Chlorophenyl)-2-methoxypyridin-3-yl)-4-(dimethylamino)-2-(naphthalenemethanol-1-yl)-1-phenyl Butyl-2-ol (780 g, 1.35 moles, isomer A content 93.5%) was suspended in ethanol (22 L) solution.
  • a solution of S-binaphthol phosphate in DMSO (1.1 L) prepared above was added dropwise over 1 hour with stirring (rpm 196 rpm).
  • reaction solution was further stirred at 15-35 ° C for 16 hours.
  • the reaction was heated to reflux with an oil bath and reflux was continued for 1 hour.
  • the reaction solution was stopped and cooled to 15 to 35 ° C and stirring was continued for 16 hours.
  • the reaction solution was filtered, and the filtration was slow due to the large viscosity of the solid.
  • the filter cake was beaten twice with ethanol (20 liters ⁇ 2) and filtered to give a white solid.
  • the solid was mixed in water (3 liters) and ethyl acetate (3 liters), and a 10% aqueous sodium hydroxide solution was added to adjust the pH of the system.
  • Step 7 (1R,2S)-1-(5-(4-Chlorophenyl)-2-methoxypyridin-3-yl)-4-(dimethylamino)-2-(naphthalenemethanol-1 -yl)-1-phenylbutyl-2-ol Fumarate Compound I-1
  • Form III The preparation of Form III was the same as Form II, and only the solvent tetrahydrofuran was changed to 0.2 mL of acetone-water (2:1).
  • Step 12 1-(5-(4-Chlorophenyl)-2-pyridyl)-2-(3,5-dichlorophenyl)-4-(dimethylamino)-1-phenyl-butyl Alkanol-2-ol
  • TMP (16.41 g, 116.2 mmol) was dissolved in tetrahydrofuran (200 ml) with stirring at room temperature, replaced with nitrogen, cooled to -78 ° C with a dry ice-acetone bath, and n-butyllithium (46.48 ml, 116.2 m) was slowly added dropwise. Molar, 2.5 mol/L n-hexane solution), stirring was continued for 30 minutes while maintaining the temperature at -78 to -20 °C.
  • the temperature of the reaction system was lowered to -78 to -65 ° C, and 3-phenyl-5-(4-chlorophenyl)-2-methoxy-pyridine (24.0 g, 77.4 mmol) of tetrahydrofuran (200 ml) was added.
  • the solution was stirred for 10 minutes after completion of the dropwise addition, and then 1-(3,5-dichlorophenyl)-3-(dimethylamino)propan-1-one (23.84 g, 77.47 mmol) of tetrahydrofuran (23.
  • the solution was slowly added dropwise to the reaction system, and the reaction solution was further stirred at -78 to -65 ° C for 20 minutes.
  • Step 13 (1R,2S)-1-(5-(4-Chlorophenyl)-2-pyridyl)-2-(3,5-dichlorophenyl)-4-(dimethylamino)- 1-phenyl-butan-2-ol
  • reaction solution was then heated to 80 ° C and stirred for 1 hour, slowly cooled (2 to 4 hours) to 20 ° C and stirring was continued for 16 hours.
  • the reaction solution was filtered, and the filtrate was concentrated under reduced pressure, and then dissolved in ethyl acetate (40 ml), and adjusted to basic (pH: 12) with 10% sodium hydroxide, partitioned, and the organic phase was dried over anhydrous sodium sulfate Dry and concentrate to give the crude product.
  • the crude product was added to ethanol (100 ml), stirred at 20 to 30 ° C for 1 to 2 hours, filtered, and the filter cake was dried by vacuum drying to constant weight (50 ° C, 24 to 48 hours) to obtain the desired product (1R, 2S)-1-(5-(4-chlorophenyl)-2-pyridyl)-2-(3,5-dichlorophenyl)-4-(dimethylamino)-1-phenyl-butyl Alkan-2-ol (3.1 g, purity 98.9%, ee value 98.1%, yield 38.8%, white solid).
  • Example 7 Solid stability test of crystal form I under high temperature, high humidity and strong light conditions
  • Part I Testing the anti-tuberculosis mycobacterial compound in vitro efficacy using M. smegmatis strain ATCC19420
  • the bacteria were inoculated on Roche modified slant medium (Difco-244420) two days in advance, and cultured in a 37 ° C incubator for 48 hours. On the day of the test, bacterial colonies were collected from the slant of the medium and suspended in sterile physiological saline containing 0.02% Tween 80. Add 7-10 sterile glass beads of 3 mm diameter to the bacterial solution and use a vortex to break up the bacteria at maximum speed. The turbidity of the bacterial solution was adjusted to 0.10 using a Siemens MicroScan turbidity meter, and the corresponding bacterial concentration was -1.5 x 10 8 cfu/ml. The bacterial solution was diluted 20 times with CA-MHB + 0.02% Tween 80 medium, and then diluted 25 times (500 times total). The diluted bacterial solution will be used to inoculate the daughterboard.
  • Roche modified slant medium Difco-244420
  • each well 100 ⁇ l of the bacterial solution was added to each well of the daughter plate.
  • Each well will contain: ⁇ 3.0 x 10 4 cfu bacteria, 1% DMSO, and a gradient dilution of the compound in 200 ⁇ l CA-MHB + 0.02% Tween 80 medium.
  • the finished daughterboard was placed in a 30 ° C incubator for cultivation. The minimum inhibitory concentration (MIC) was read after 72 hours.
  • the standard for reading MICs is defined by the CLSI method M7-A7 as the lowest concentration of a drug that completely or significantly inhibits bacterial growth.
  • Compound The test results are listed in Table-6.
  • the compound was dissolved in pure DMSO (Sigma 276855-2L) to a concentration of 10 mg/ml as a mother liquor of the compound.
  • 30 ⁇ l of DMSO was added to the wells of columns 2 to 11 of the v-bottom 96-well plate (Axygen-wipp 02280).
  • Add 30 ⁇ l of compound mother liquor to the wells of column 2 mix well, and take 30 ⁇ l from the second column of wells and add to the third column of wells and mix by pipetting. Take this to the 10th column.
  • Column 11 was not administered and contained only 30 ⁇ l of DMSO. This is the compound "motherboard".
  • the H37Rv strain in the glycerol cryotube was inoculated into 7H9 medium containing 0.05% Tween 80, and cultured at 37 ° C for 4 weeks in a shaker at 200 rpm.
  • the bacterial solution was washed twice with 7H9 medium containing 0.05% Tween 80 and resuspended in the same medium.
  • This bacterial solution was dispensed into a microcentrifuge tube and stored at -80 °C. Storage time is less than 1 month. On the day of the test, the dispensed bacteria were lyophilized.
  • the lyophilized broth was diluted 20-fold with 7H9 medium and then diluted 50-fold, and diluted 1000 times. This broth was used to inoculate the daughter plate. 100 ⁇ l of the bacterial solution was inoculated into each well of the daughter plate, and the column 12 was added with 100 ⁇ l of 7H9 medium without adding a bacterial solution.
  • test panels were placed in a 37 ° C incubator and the humidity was maintained at >80%. Starting one week later, add 12.5 ⁇ l of 7H9 medium containing 20% Tween 80 and 20 ⁇ l of Alamar Blue (Invitrogen DAL1100) to a column of bacteria-containing wells and a column 12 containing no bacteria. Observed after 24 hours of culture. When the bacterial solution in the first column of pores can reduce the added Alamar blue to pink within 24 hours, add 7H9 medium containing 20% Tween 80 and Alamar blue to all wells on the test plate, 37 ° C Fluorescence values were measured after 24 hours of continued incubation.
  • 7H9 medium containing 20% Tween 80 and Alamar blue
  • the minimum inhibitory concentration (MIC) is defined as the minimum drug concentration that can completely inhibit the discoloration of Alamar blue by visual observation, or the minimum drug concentration that can inhibit the formation of more than 90% reduced Alamar blue by fluorometer.
  • the compound test results are shown in Table-6.
  • ATCC--American type culture strains MABA--microplate Alamar blue color test; LORA--recovery test under anaerobic conditions; Vero Cell--African green monkey kidney cells; IC50--half suppression Concentration; Hela--human cervical cancer cells; CC50--half cytotoxic concentration.
  • Compound I-2 has a good inhibitory activity against Mycobacterium smegmatis, and compound I-2 is still in aerobic (MABA)
  • MABA aerobic
  • LORA anaerobic
  • Compound 1-2 showed no significant cytotoxicity against both Vero and Hela cells.
  • Part III Evaluation of in vitro efficacy of compounds against drug-resistant Mycobacterium tuberculosis
  • Table-7 MIC (uM) of some test compounds against drug-sensitive and drug-resistant Mycobacterium tuberculosis
  • Compound I-2 not only inhibited the wild-type Mycobacterium tuberculosis H37Rv, but also showed good inhibition to rifampicin and isoniazid-resistant strains.
  • the inhibitory activities of the three strains tested were comparable to those of the marketed antitubercular drug betaxazoline.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé de préparation d'un sel d'un composé (1R,2S)-1-(5-(4-chlorophényl)-2-méthoxypyridin-3-yl)-4-diméthylamino-2-aryl-1-phénylbutan-2-ol de formule (I) utile pour résister à la Mycobacterium tuberculosis, une forme cristalline, un composé intermédiaire et un procédé de préparation associé.
PCT/CN2017/070835 2016-01-13 2017-01-11 Procédé de préparation d'un composé dérivé de pyridine, intermédiaire et forme cristalline dudit composé Ceased WO2017121323A1 (fr)

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WO2020047596A1 (fr) * 2018-09-04 2020-03-12 Monash University Composés antibactériens et procédés d'utilisation
CN117050006A (zh) * 2022-05-13 2023-11-14 广州嘉越医药科技有限公司 一种吡啶衍生物、中间体、制备方法和应用
CN117122595A (zh) * 2022-05-27 2023-11-28 广州嘉越医药科技有限公司 吡啶衍生物的用途

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WO2020047596A1 (fr) * 2018-09-04 2020-03-12 Monash University Composés antibactériens et procédés d'utilisation
CN117050006A (zh) * 2022-05-13 2023-11-14 广州嘉越医药科技有限公司 一种吡啶衍生物、中间体、制备方法和应用
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CN117122595B (zh) * 2022-05-27 2026-04-17 广州嘉越医药科技有限公司 吡啶衍生物的用途

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