CN108473428B - Preparation method of pyridine derivative compound, intermediate and crystal form thereof - Google Patents
Preparation method of pyridine derivative compound, intermediate and crystal form thereof Download PDFInfo
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- CN108473428B CN108473428B CN201780005142.9A CN201780005142A CN108473428B CN 108473428 B CN108473428 B CN 108473428B CN 201780005142 A CN201780005142 A CN 201780005142A CN 108473428 B CN108473428 B CN 108473428B
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- 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
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- 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
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- 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
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- 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
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- 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
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Abstract
A preparation method, a crystal form, an intermediate compound and preparation methods of a salt of a compound (1R,2S) -1- (5- (4-chlorphenyl) -2-methoxypyridine-3-yl) -4-dimethylamino-2-aryl-1-phenylbutan-2-ol in a formula (I) for resisting mycobacterium tuberculosis.
Description
Technical Field
The invention relates to a preparation method and a crystal form of a salt of high-purity (1R,2S) -1- (5- (4-chlorphenyl) -2-methoxypyridine-3-yl) -4-dimethylamino-2-aryl-1-phenylbutan-2-ol, and also relates to an intermediate compound for preparing a compound shown in a formula (I) and a preparation method thereof.
Background
Mycobacterium tuberculosis is the causative agent of tuberculosis. As a globally widespread and life-threatening infectious disease, according to the statistics of the world health organization, about more than 800 million people are infected each year, and 200 million people die from tuberculosis. Over the past decade, tuberculosis cases have grown worldwide at a rate of 20%, with this rising amplitude being particularly pronounced in poverty-stricken areas. If this trend progresses as such, cases of tuberculosis will likely continue to grow at 41% rise in the next two decades. Tuberculosis has been second only to aids for fifty years after the initial application of chemotherapy, the leading infectious disease that causes death in adults. Tuberculosis causes the appearance of a plurality of drug-resistant strains, and simultaneously achieves a symbiotic relationship with AIDS. People who are positive in the HIV test and infected with tuberculosis have 30 times more probability of developing activated tuberculosis than people who are negative in the HIV test. On average, one of every three patients who die of aids is caused by tuberculosis.
Current treatments for tuberculosis employ a combination of multiple agents. For example, one formulation recommended by the U.S. public health agency involves first using isoniazid, rifampin, pyrazinamide and ethambutol in combination for two months, and then using isoniazid and rifampin alone in combination for four months. For patients infected with AIDS, the use of the pharmaceutical composition needs to be delayed to seven months. For patients infected with multi-drug resistant tuberculosis, the pharmaceutical composition also needs to be added with other medicaments, such as ethambutol tablet, streptomycin, kanamycin, amikacin, capreomycin, ethionamide, cycloserine, ciprofloxacin and ofloxacin.
New therapies that could improve current treatments are highly desirable, such as shorter treatment cycles, and fewer supervised treatment modalities for the benefit of the patient and the provider. In the first two months of treatment, the combined four drugs collectively inhibited the bacteria, thereby greatly reducing the number of bacteria and rendering the patient non-infectious. In the next 4-6 months, the bacteria existing in the patient are eliminated, and the possibility of relapse is reduced. A potent bactericidal agent that can shorten the treatment period to two months or less would be of great benefit. At the same time, the drug should require less supervision. Clearly, drugs that both shorten treatment time and reduce frequency of supervision may provide the greatest benefit.
The complications of infectious tuberculosis cause multidrug-resistant tuberculosis. Worldwide, 4% of cases are associated with multidrug-resistant tuberculosis. Multi-drug resistant tuberculosis is resistant to isoniazid and rifampin, among the four standard therapeutic drugs. If no treatment is available, or if the common standard therapy for tuberculosis is used, multidrug-resistant tuberculosis can be fatal. Therefore, the treatment of this disease requires the use of second-line drugs for up to two years. Most of these second-line drugs are toxic, expensive, and have little efficacy. Patients with infectious drug-resistant tuberculosis continue to spread the disease due to the lack of effective treatment. Therefore, for multi-drug resistant tuberculosis, a new drug having a novel mechanism of action is highly demanded.
Application No.: the 201410335196.X patent describes a new class of pyridine derivatives and their use as antimycobacterial agents for the treatment of tuberculosis, especially multi-drug resistant tuberculosis. The structure is shown as formula (B-1):
disclosure of Invention
The invention provides a process for the preparation of a compound of formula (I),
which comprises the following steps:
wherein the content of the first and second substances,
R1selected from the group consisting of optionally substituted by 0, 1, 2 or 3R01Substituted 6-to 12-membered aryl, 6-to 12-membered heteroaryl, 6-to 12-membered aryl-alkylene, and 6-to 12-membered heteroaryl-alkylene;
HX is selected from organic or inorganic acid;
the base A is selected from an alkali metal base, an alkaline earth metal base, or an organometallic base;
the molar use ratio of the compound (II) to the alkali A is 1: 1-5;
the molar use ratio of the compound (II) to the compound (III) is 1: 1-2;
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 3-20 times of the weight of the compound (IV);
the reaction temperature is-80-0 ℃;
the reaction time is 1-24 hours;
R01selected from F, Cl, Br, I, CN, OH, CH (CH)3)2、C(CH3)3、N(CH3)2、NH(CH3)、NH2、CHO、COOH、C(＝O)NH2、S(＝O)NH2、S(＝O)2NH2、CF3、CF3O、(NH2)CH2、(HO)CH2、CH3C(＝O)、CH3OC(＝O)、CH3S(＝O)2、CH3S(＝O)；
Said "hetero" represents a heteroatom selected from N, O or S;
the number of heteroatoms is independently selected from 1, 2 or 3.
In some embodiments of the invention, R is as defined above1Optionally substituted by 0, 1, 2 or 3R01Substituted naphthyl or phenyl.
In some embodiments of the invention, R is as defined above1Is selected from
In some embodiments of the present invention, the alkali metal base is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, and/or potassium bicarbonate.
In some embodiments of the present invention, the alkaline earth metal base is selected from sodium hydride, potassium hydride, and/or calcium hydride.
In some embodiments of the present invention, the organometallic base is selected from n-butyllithium, lithium diisopropylamide, lithium 2,2,6, 6-tetramethylpiperidine, lithium bis (trimethylsilyloxy) amide, sodium methoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, and/or aluminum isopropoxide.
In some embodiments of the present invention, the molar ratio of the compound (II) to the base a is 1: 1.2-2.
In some embodiments of the present invention, the reaction temperature is-80 to-60 ℃.
In some embodiments of the present invention, the reaction time is 2 to 12 hours.
In some embodiments of the present invention, the reaction time is 4 to 8 hours.
In some embodiments of the present invention, the reaction solvent is selected from tetrahydrofuran, diethyl ether and/or isopropyl ether.
In some embodiments of the present invention, the amount of the reaction solvent is 5 to 10 times of the weight of the compound (IV).
In some embodiments of the present invention, the above preparation method further comprises the following reaction scheme:
in some embodiments of the present invention, the above preparation method further comprises the following reaction scheme:
in some embodiments of the present invention, the above preparation method further comprises the following reaction scheme:
wherein the content of the first and second substances,
the base B is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide and aluminum isopropoxide;
the reaction solvent is selected from a mixed solvent of a ketone solvent, an alcohol solvent or an ester solvent and a polar aprotic solvent.
The molar ratio of the chiral acid to the compound (IV) is 0.5-1.5;
the chiral acid is selected from alpha-hydroxy propionic acid, alpha-hydroxy succinic acid, alpha, beta-dihydroxy succinic acid, alpha-hydroxy phenylacetic acid, beta-hydroxy acid and a compound (VI);
n is 0, 1 or 2;
R2、R4each independently selected from H, F, Cl, Br, I, or optionally substituted by 0, 1, 2 or 3R01Substituted: c1-8Alkoxy radical, C1-8Alkyl, Si (Ph)36-12 membered aryl;
R3、R5each independently selected from H, F, Cl, Br, I, NO2OH, or selected from optionally substituted by 0, 1, 2 or 3R01Substituted: c1-8Alkoxy radical, C1-8Alkyl, 6-12 membered aryl;
optionally, R substituted at positions 13 and 143Or R substituted in positions 14 and 153Can be linked together to form a 6-to 12-membered aryl ring;
optionally substituted in positions 8 and 9R5Or R substituted in positions 9 and 105Can be linked together to form a 6-to 12-membered aryl ring.
In some embodiments of the invention, the molar ratio of the chiral acid to the compound (IV) is 0.8 to 1.2.
In some embodiments of the invention, the molar ratio of the chiral acid to compound (IV) is 1.0.
In some embodiments of the present invention, in the above method for preparing compound (V), the ketone solvent is selected from acetone and/or methyl ethyl ketone.
In some embodiments of the present invention, in the above method for preparing compound (V), the alcohol solvent is selected from ethanol, methanol, isopropanol and/or tert-butanol.
In some embodiments of the present invention, in the above method for preparing compound (V), the ester solvent is selected from ethyl acetate and/or tert-butyl acetate.
In some embodiments of the present invention, in the above method for preparing compound (V), the polar aprotic solvent is selected from DMF, DMSO, DMA, and/or NMP.
In some embodiments of the present invention, the above method for preparing compound (V), wherein the mixed solvent combination is a mixed solvent of ethanol and DMF or a mixed solvent of ethanol and DMSO.
In some embodiments of the invention, the solvent for preparing compound (V) from compound (IV) is selected from: acetone, methyl ethyl ketone, ethanol, methanol, isopropanol, tert-butanol, ethyl acetate, tert-butyl acetate, DMF, DMSO, DMA and/or NMP, or a mixture thereof.
In some embodiments of the present invention, in the method for preparing the compound (V), the volume ratio of the ketone, alcohol or ester solvent to the polar aprotic solvent is 1: 0.03-0.1.
In some embodiments of the present invention, the amount of the solvent used in the method for preparing compound (V) is 15 to 50 times the weight of compound (IV).
In some embodiments of the invention, R is as defined above3、R5Each independently selected from H.
In some embodiments of the invention, R is as defined above2Substitution is in the 2 position.
In some embodiments of the invention, R is as defined above4The substitution is in position 6.
In some embodiments of the invention, R is as defined above2、R4Each independently selected from: H. si (Ph)3、
In some embodiments of the present invention, the above compound (VI) is selected from
In some embodiments of the present invention, the above preparation method further comprises the following reaction scheme:
wherein HX is selected from organic or inorganic acids.
In some embodiments of the invention, the HX is selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, oxalic acid, citric acid, maleic acid, and fumaric acid
In some embodiments of the present invention, the above preparation method further comprises the following reaction scheme:
the present invention provides compounds of the formula:
the invention also provides a compound I-1 shown in the following formula,
the invention provides a crystal form I of a compound I-1, and an XRPD pattern of the crystal form I is shown as a figure 1.
In some embodiments of the invention, XRPD pattern analysis data for form I is shown in table-1.
Table-1 form I XRPD pattern analysis data
The invention provides a crystal form II of a compound I-1, and an XRPD pattern of the crystal form II is shown in figure 4.
In some embodiments of the invention, the XRPD pattern analysis data for the above form II is shown in table-2.
Table-2 XRPD pattern analysis data for crystalline form II
| NO. | 2-Theta | d(A) | I％ | NO. | 2-Theta | d(A) | I％ |
| 1 | 4.903 | 18.0073 | 22.0 | 5 | 12.263 | 7.2114 | 12.2 |
| 2 | 8.595 | 10.2792 | 100.0 | 6 | 12.778 | 6.9219 | 24.8 |
| 3 | 10.959 | 8.0665 | 12.5 | 7 | 15.560 | 5.6902 | 15.7 |
| 4 | 11.906 | 7.4269 | 14.1 | 8 | 21.700 | 4.0920 | 7.0 |
The invention provides a III crystal form of compound I-1, and an XRPD pattern is shown as figure 7.
In some embodiments of the invention, the XRPD pattern analysis data for the crystalline form III above is shown in table-3.
Table-3 XRPD pattern analysis data for form III
The invention provides a preparation method of the crystal form I, which comprises the steps of adding any one form of a compound I-1 into a solvent for crystallization, wherein the solvent is selected from alcohols, ketone solvents or a mixed solvent of the alcohol solvents and the ketone solvents; the dosage of the solvent is 3-50 times of the weight of the compound I-1.
In some embodiments of the present invention, in the above method for preparing form I, the alcohol solvent is selected from methanol, ethanol, isopropanol and/or n-butanol.
In some embodiments of the present invention, in the above method for preparing crystalline form I, the ketone solvent is selected from acetone and/or methyl ethyl ketone.
In some embodiments of the present invention, in the preparation method of the crystal form I, the mixed solvent is a mixed solvent of methanol and acetone.
In some schemes of the invention, in the preparation method of the crystal form I, the volume ratio of the mixed solvent of methanol and acetone is 1: 5-30.
Definitions and description:
as used herein, the following terms and phrases are intended to have the following meanings unless otherwise indicated. A particular phrase or term should not be considered as ambiguous or unclear without special definition, but rather construed in a generic sense. When a trade name appears herein, it is intended to refer to its corresponding commodity or its active ingredient.
The intermediate compounds of the present invention may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combinations thereof with other chemical synthetic methods, and equivalents thereof well known to those skilled in the art, with preferred embodiments including, but not limited to, the examples of the present invention.
The chemical reactions of the embodiments of the present invention are carried out in a suitable solvent that is compatible with the chemical changes of the present invention and the reagents and materials required therefor. In order to obtain the compounds of the present invention, it is sometimes necessary for a person skilled in the art to modify or select the synthesis steps or reaction schemes based on the existing embodiments.
The present invention will be specifically described below by way of examples, which are not intended to limit the present invention in any way.
All solvents used in the present invention are commercially available and can be used without further purification. The reaction is generally carried out under inert nitrogen in an anhydrous solvent. Proton NMR data were recorded on a Bruker Avance III 400(400MHz) spectrometer with chemical shifts expressed as (ppm) at the low field of tetramethylsilane. Mass spectra were measured on an agilent 1200 series plus 6110(& 1956A). LC/MS or Shimadzu MS contain a DAD: SPD-M20A (LC) and Shimadzu Micromass 2020 detector. The mass spectrometer was equipped with an electrospray ion source (ESI) operating in either positive or negative mode.
The invention employs the following abbreviations: DMF represents N, N-dimethylformamide; DMA represents N, N-dimethylacetamide; DMSO represents dimethyl sulfoxide; NMP stands for N-methylpyrrolidone; pd (OAc)2Represents palladium acetate; pd (dppf) Cl2Represents [1, 1' -bis (diphenylphosphino) ferrocene]Palladium dichloride; pd2(dba)3Represents tris (dibenzylideneacetone) dipalladium; pd (PPh)3)4Represents a tetra-triphenylphosphine bar; pd (PP)h3)2Cl2Represents dichlorobistriphenylphosphine palladium; et (Et)3N represents triethylamine; DIPEA stands for diisopropylethylamine; DBU represents 1, 8-diazabicycloundec-7-ene; AcOH represents glacial acetic acid; na (Na)2SO3Represents sodium sulfite; MeOH represents methanol; TMP represents 2,2,6, 6-tetramethylpiperidine; the pH represents the hydrogen ion concentration index.
The compound is made by hand or
The software names, and the commercial compounds are under the supplier catalog name.
Powder X-ray diffraction (X-ray powder diffractometer, XRPD)
The instrument model is as follows: bruker D8 advanced X-ray diffractometer
And (3) testing conditions are as follows: the detailed XRPD parameters are as follows:
an X-ray generator: the concentration of Cu, k alpha,
tube voltage: 40kV, tube current: 40mA.
Emission slit: 1deg.
Height limiting slit: 10mm
Scattering slit: 1deg.
Receiving a slit: 0.15mm
A monochromator: fixed monochromator
Scanning range: 4-40deg.
Scanning speed: 10deg/min
Differential thermal analysis (DSC)
The instrument model is as follows: TA Q2000 differential scanning calorimeter
And (3) testing conditions are as follows: a sample (-1 mg) was placed in a DSC aluminum pan for testing by the method: the temperature is 25-300 ℃, and the heating rate is 10 ℃/min.
Thermogravimetric analysis (Thermal Gravimetric Analyzer, TGA)
The instrument model is as follows: TA Q5000IR thermogravimetric analyzer
And (3) testing conditions are as follows: a sample (2-5 mg) is placed in a TGA platinum pan for testing, and the method comprises the following steps: the room temperature is 300 ℃ below zero, and the heating rate is 10 ℃/min.
Has the advantages that:
the crystal form I, the crystal form II and the crystal form III of the compound I-1 provided by the invention have stable properties, good solubility and good hygroscopicity, and have good pharmaceutical prospects.
The process for synthesizing the compound I-1 and the intermediate thereof overcomes the defects of high price of starting raw materials, high toxicity of used reagents, harsh reaction conditions, difficult separation and purification, difficult industrialization and the like in the prior art.
Specifically, the method comprises the following steps:
1) the raw materials of the method for preparing the compound I-1 are conventional or common reagents, are easily available in the market and have low price;
2) the intermediate compound (II) can be obtained from the compound (b) through two-step conventional reaction with higher total yield, the post-treatment is simple, and any column chromatography purification is not needed;
3) the compound (IV) is subjected to kinetic resolution by adopting organic acid, and the obtained compound (I) has high optical purity;
4) reagents used in the reactions in all the steps are small molecules, so that the purification is easy;
5) the palladium metal catalytic cross coupling is put in the former step, which is beneficial to controlling the palladium metal residue in the final product.
Drawings
FIG. 1 is an XRPD spectrum of form I Cu-Ka radiation of compound I-1.
FIG. 2 is a DSC of form I of compound I-1.
FIG. 3 is a TGA profile of crystalline form I of Compound I-1.
FIG. 4 is an XRPD spectrum of form II Cu-Ka radiation of compound I-1.
FIG. 5 is a DSC of form II of Compound I-1.
FIG. 6 is a TGA profile of the crystalline form II of Compound I-1.
FIG. 7 is an XRPD spectrum of form III Cu-Ka radiation of compound I-1.
FIG. 8 is a DSC of form III of Compound I-1.
FIG. 9 is a TGA profile of the crystalline form III of Compound I-1.
Detailed Description
For better understanding of the present invention, the following description is given with reference to specific examples, but the present invention is not limited to the specific embodiments.
The compound 1- (5- (4-chlorophenyl) -2-methoxypyridin-3-yl) -4- (dimethylamino) -2- (naphthalen-1-yl) -1-phenylbutan-2-ol has the following structure:
the compound has two chiral centers, as indicated by the formula (IV-1), and thus has four stereoisomers, namely (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-methoxypyridin-3-yl) -4- (dimethylamino) -2- (naphthalen-1-yl) -1-phenylbutan-2-ol, (1R, 2R)1- (5- (4-chlorophenyl) -2-methoxypyridin-3-yl) -4- (dimethylamino) -2- (naphthalen-1-yl) -1-phenylbut-2-ol and (1S, 2S)1- (5- (4-chlorophenyl) -2-methoxypyridin-3-yl) -4- (dimethylamino) -2- (naphthalen-1-yl) -1-phenylbut-2-ol. The four stereoisomers consist of two sets of diastereomers, with the racemic mixture (1R,2S) 1- (5- (4-chlorophenyl) -2-methoxypyridin-3-yl) -4- (dimethylamino) -2- (naphthalen-1-yl) -1-phenylbutan-2-ol and (1S, 2R)1- (5- (4-chlorophenyl) -2-methoxypyridin-3-yl) -4- (dimethylamino) -2- (naphthalen-1-yl) -1-phenylbutan-2-ol being indicated as "a" in the examples section that follows; and the racemic mixture of (1R, 2R)1- (5- (4-chlorophenyl) -2-methoxypyridin-3-yl) -4- (dimethylamino) -2- (naphthalen-1-yl) -1-phenylbut-2-ol and (1S, 2S)1- (5- (4-chlorophenyl) -2-methoxypyridin-3-yl) -4- (dimethylamino) -2- (naphthalen-1-yl) -1-phenylbut-2-ol will be designated "B" in the subsequent example section.
The examples set forth below are all prepared, isolated and characterized by the methods described herein. The following examples are merely representative of the scope of the invention, and are not intended to be exhaustive. Having described the invention in detail and having disclosed specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.
Example 1: preparation of Compound I-1
Scheme 1:
step 1: synthesis of 5- (4-chlorophenyl) -2-methoxypyridine
Potassium carbonate (5.51 kg, 39.89 mol, 1.5 eq) and Pd (dppf) Cl were added successively with stirring2(48.64 g, 66.48 mmol, 0.0025 equiv.) was added to a mixed solution of dioxane (25 l) and water (5 l) of 5-bromo-2-methoxypyridine (5.0 kg, 26.59 mol, 1.0 equiv.) and 4-chlorobenzeneboronic acid (4.49 kg, 28.72 mol, 1.08 equiv.), the nitrogen gas was replaced three times, and then the reaction system was heated to 95 to 100 ℃ and refluxed at this temperature for 16 hours. Stopping the reaction after HPLC (high performance liquid chromatography) detection of 5-bromo-2-methoxypyridine consumption is finished, cooling the reaction liquid to 25-30 ℃, removing dioxane through reduced pressure concentration, extracting residues twice (10L multiplied by 2) with ethyl acetate, combining organic phases, washing with saturated saline solution (5L multiplied by 2), and concentrating under reduced pressure at 35-40 ℃ to obtain a crude product of 5- (4-chlorophenyl) -2-methoxypyridine (6.5kg, which is a dark brown needle-shaped solid after cooling), wherein the crude product is directly used for the next reaction.1H NMR(400MHz，CDCl3)δ：8.37(d，J＝2.1Hz，1H)，7.75(dd，J＝8.6，2.6Hz，1H)，7.48-7.39(m，4H)，6.83(d，J＝8.6Hz，1H)，4.00(s，3H)。
Step 2: synthesis of 3-bromo-5- (4-chlorophenyl) -2-methoxypyridine
5- (4-chlorophenyl) -2-methoxypyridine (6.5kg, 29.59 mol, 1.00 eq) was dissolved in DMF (21 l) at 25 ℃ and slowly added dropwise over a period of 4-5 hours to a solution of liquid bromine (11.82kg, 73.97mol, 2.50eq) in AcOH (7 l). After the addition was complete, the reaction mixture was stirred at 25 ℃ for 72 hours, TLC (petroleum ether) checked for about 20% of the starting material remaining, liquid bromine (2.5 kg, 0.5 eq.) was added further to the reaction system, stirring was continued for 48 hours, and HPLC checked for the presence of a small amount of starting material (about 7-9%) which was not fully reacted. The reaction was stopped and the reaction mixture was slowly added to saturated Na with stirring2SO3(6 kg) in aqueous solution, the temperature of the quenching process is controlled below 30 ℃. A large amount of pale yellow solid precipitated, filtered, and the filter cake was washed twice with water (20L. times.2), and the resulting crude product was slurried twice with MeOH (15L. times.2), filtered, and the filter cake was vacuum dried (50 ℃ C.) to give 3-bromo-5- (4-chlorophenyl) -2-methoxypyridine (6.7 kg, white solid, 84% of two-step total yield).1H NMR(400MHz，CDCl3)δ：8.28(d，J＝2.3Hz，1H)，8.00(d，J＝2.3Hz，1H)，7.43(s，4H)，4.06(s，3H)。
And step 3: synthesis of 3-benzyl-5- (4-chlorophenyl) -2-methoxypyridine
Preparation of a benzyl zinc reagent: zinc powder (2.85 kg, 43.56 mol, 2.00 eq) was suspended in anhydrous tetrahydrofuran (21.78 l) under nitrogen, 1, 2-dibromoethane (33 ml, 0.02 eq) was added in one portion at room temperature, then heated to reflux, trimethylchlorosilane (28 ml, 0.01 eq) was added slowly (note: after addition, a large amount of bubbles were observed and the reflux was vigorous, if no bubbles were observed, trimethylchlorosilane was added), and refluxed at 66 ℃ for 30 minutes. Then the reaction solution was cooled to 25 ℃ and benzyl bromide (3.73 kg, 2.59 l, 21.78 mol, 1.00 eq) was slowly added dropwise to the reaction system (the dropping rate was such that the temperature of the system did not exceed 30 ℃) and stirring was continued at this temperature for 3 hours to obtain a tetrahydrofuran solution (concentration: 1 mol/l) of the benzyl zinc reagent, which was used directly in the next reaction.
A tetrahydrofuran solution (16L) of 3-bromo-5- (4-chlorophenyl) -2-methoxypyridine (5 kg, 16.75 moles, 1.00 eq) was added to the freshly prepared benzyl zinc reagent tetrahydrofuran solution (1 mol/L, 21.78L, 1.3 eq) at room temperature over 30-45 minutes under nitrogen, followed by Pd (PPh)3)2Cl2(59 g, 83.75 mmol, 0.005 eq.) the reaction was stirred at room temperature for 16 hours under nitrogen atmosphere (the reaction system self-exothermed, the temperature rose to 50 ℃ at the maximum, and then slowly cooled, the reaction became grayish black). TLC (petroleum ether/ethyl acetate) ═ 20/1) detection reaction was complete, the reaction solution was filtered over celite and silica gel, the filtrate was spin-dried to give a dark brown oil, then the crude product was extracted with ethyl acetate (15 l × 2), the suspended organic phase was filtered again, the filtrate was washed twice with saturated brine (10 l × 2), dried over anhydrous sodium sulfate, filtered, and concentrated at 35-40 ℃ under reduced pressure to give a brown oil, then the crude product was poured slowly into methanol (10 l) with vigorous stirring, a large amount of white precipitate was precipitated, filtered, and the filter cake was slurried with methanol (2 l × 2) to give 3-benzyl-5- (4-chlorophenyl) -2-methoxypyridine (3.0 kg, white solid, yield 58%).1H NMR(400MHz，CDCl3)δ：8.23(d，J＝2.4Hz，1H)，7.47(d，J＝2.4Hz，1H)，7.42-7.35(m，4H)，7.35-7.29(m，2H)，7.27-7.21(m，3H)，4.02(s，3H)，3.98(s，2H)。
And (2) a flow scheme:
and 4, step 4: synthesis of 3-dimethylamino-1- (naphthalen-1-yl) propan-1-one oxalate
Paraformaldehyde (2.67 kg, 29.67 mol) and dimethylamine hydrochloride (4.00 kg, 49.06 mol) were added sequentially to a solution of 1-acetonaphthone (5.00 kg, 29.38 mol) in ethanol (25 l) at 20-30 deg.c, a catalytic amount of hydrochloric acid (139.23 g, 3.82 mol, 136.5 ml) was added, the reaction mixture was heated to 78-80 deg.c for reflux reaction for 48 hours, and 1-acetonaphthone was substantially reacted to completion (content less than 5%) by HPLC. The reaction mixture was concentrated under reduced pressure to remove ethanol, the residue was dissolved in water (25 l), extracted twice with ethyl acetate (5 l × 2), the aqueous phase was adjusted to pH 9 to 10 with 1 mol/l aqueous sodium hydroxide solution, then extracted twice with ethyl acetate (15 l × 2), the organic phases of the second extraction were combined, washed with saturated brine (10 l × 2), and concentrated under reduced pressure to give crude 3- (dimethylamino) -1- (1-naphthyl) propan-1-one (7.41 kg, yellow oil). The above crude product was dissolved in ethyl acetate (25L), and then an ethanol solution (20L) of oxalic acid dihydrate (4.2 kg, 33.3 mol) was added dropwise to the above solution, stirred at room temperature for 1 hour, and a large amount of white solid was formed, followed by filtration and washing twice with ethyl acetate (5L × 2) to obtain the oxalate salt of 3- (dimethylamino) -1- (1-naphthyl) propan-1-one (6.5kg, 22.18 mol, yield 56%, white solid).1H NMR(400MHz，CDCl3)δ：8.59(d，J＝8.5Hz，1H)，8.00(d，J＝8.3Hz，1H)，7.89(d，J＝7.3Hz，2H)，7.64-7.48(m，3H)，3.25(t，J＝7.3Hz，2H)，2.83(t，J＝7.3Hz，2H)，2.31(s，6H)。
And 5: synthesis of 3-dimethylamino-1- (naphthalen-1-yl) propan-1-one
3- (dimethylamino) -1- (naphthalen-1-yl) propyl-1-one oxalate (6.5kg, 20.4 mol) was added to water (20l) with stirring. Keeping the temperature at 0-10 ℃ and the rotating speed at 160-190 r/min to obtain white suspension. Cooled sodium hydroxide (1.8 kg, 45.0 mol)) Slowly adding a water (10 liters) solution into the suspension, and keeping the temperature at 0-10 ℃. The white suspension was gradually dissolved and a yellow oil was formed. After the addition of the sodium hydroxide solution was completed, stirring was continued for 1 hour. The reaction solution was extracted with ethyl acetate (15 l), the aqueous phase was extracted with ethyl acetate (10 l), and the combined organic phases were washed with saturated brine (20 l). The organic phase was concentrated under reduced pressure to constant weight to give 3- (dimethylamino) -1- (naphthalen-1-yl) propyl-1-one (3.4 kg, yellow oil, yield 70%).1H NMR(400MHz，CDCl3)δ：8.59(d，J＝8.8Hz，1H)，8.00(d，J＝8.4Hz，1H)，7.90(d，J＝8.4Hz，2H)，7.60-7.28(m，3H)，3.26(t，J＝7.2Hz，2H)，2.83(t，J＝7.2Hz，2H)，2.31(s，6H)。
And (3) a flow path:
and 5: synthesis of 1- (5- (4-chlorophenyl) -2-methoxypyridin-3-yl) -4- (dimethylamino) -2- (naphthalen-1-yl) -1-phenylbutan-2-ol
N-butyl lithium titration: diphenylacetic acid (1.00 g, Alfa, 4.71 mmol) was added to tetrahydrofuran (10 mL) under nitrogen to form a colorless clear solution. The n-hexane solution of butyl lithium was slowly added dropwise to the above solution by a syringe. The phenomenon was observed, and the solution was partly yellow but quickly disappeared during the dropping. When a yellow solution was formed by dropping one drop and discoloration did not occur within half a minute, the volume of n-butyllithium was recorded (1.927 ml and 1.985 ml in the two cases, respectively, and the average volume was 1.95 ml), so that the n-butyllithium n-hexane solution was used at a concentration of 2.42 mol/l.
TMP (2.74 kg, 19.3 mol) was dissolved in anhydrous tetrahydrofuran (12 l), and n-butyllithium (8 l, 19.3 mol, 2.42 mol/l n-hexane solution) was added dropwise starting with cooling the reaction temperature to-65 ℃ with a dry ice acetone bath. Controlling the temperatureThe temperature is between-20 ℃ and-78 ℃, the color of the reaction system can be observed to gradually change from light yellow to dark red to finally form yellow suspension, and the stirring is continued for 30 minutes at the temperature. Then the reaction temperature was lowered to-75 ℃ to-80 ℃ and a solution of 3-benzyl-5- (4-chlorophenyl) -2-methoxypyridine (4.08 kg, 12.9 mol) in anhydrous tetrahydrofuran (6 l) was slowly added dropwise over 4 to 6 hours. The temperature is maintained between-65 ℃ and-78 ℃, and the color is dark red when the heat release is not intense. After the dropwise addition is completed, the anhydrous tetrahydrofuran (2.0 liters) solution of 3- (dimethylamino) -1- (naphthalene-1-yl) propyl-1-ketone (3.26 kg, 12.9 mol and 90% purity) is slowly dropwise added over 2-4 hours, the system heat release is obvious, and the flow rate is controlled to keep the temperature between minus 65 ℃ and minus 78 ℃. After the dripping is completed, the temperature is maintained between minus 65 ℃ and minus 78 ℃ and the stirring is continued for half an hour. HPLC detection shows that the content of 3-benzyl-5- (4-chlorophenyl) -2-methoxypyridine is less than 10%, the reaction solution is slowly added into saturated ammonium chloride solution (40L) to be quenched, separated, and the aqueous phase is extracted by ethyl acetate (30L). The combined organic phases are washed and separated by saturated saline (30L), the organic phases are concentrated under reduced pressure at 40-50 ℃ to obtain yellow oily crude products (13.5 kg), and the crude products are stirred for 16 hours at 5-15 ℃ by using an ethyl acetate/n-heptane (4L, 1/4) mixed solvent to separate out white solids. Filtering, pulping the filter cake with ethanol (4L. times.2), filtering, drying the filter cake under vacuum to constant weight (50 ℃, 24-48 hours) to obtain the target compound 1- (5- (4-chlorophenyl) -2-methoxypyridin-3-yl) -4- (dimethylamino) -2- (naphthalen-1-yl) -1-phenylbut-2-ol (1.83 kg, yield 23.23%) as a white solid, and determining by HPLC that the content of the isomer A is 88.3% and the content of the isomer B is 4.8%.1H NMR(400MHz，CDCl3)δ：8.85(d，J＝2.3Hz，1H)，8.64(d，J＝8.7Hz，1H)，8.32(d，J＝2.4Hz，1H)，7.98-7.86(m，2H)，7.72-7.61(m，2H)，7.57(d，J＝8.4Hz，2H)，7.54-7.43(m，3H)，7.33(t，J＝7.8Hz，1H)，7.20-7.17(m，2H)，6.95-6.87(m，3H)，5.85(s，1H)，4.17(s，3H)，2.60-2.51(m，1H)，2.19-2.04(m，2H)，2.01-1.97(m，7H)。
Step 6: synthesis of (1R,2S) -1- (5- (4-chlorophenyl) -2-methoxypyridin-3-yl) -4- (dimethylamino) -2- (naphthalen-1-yl) -1-phenylbut-2-ol Compound I-2
The method comprises the following steps:
two parallel batches were fed: r- (-) -binaphthol phosphate (519.3 g, 1.49 mol) was suspended in DMSO (1.0 l), heated to 50 ℃ and dissolved with stirring until clear. 1- (5- (4-chlorophenyl) -2-methoxypyridin-3-yl) -4- (dimethylamino) -2- (naphthalenemethanol-1-yl) -1-phenylbutyl-2-ol (910 g, 1.49 mol, 88.3% isomer A) is added to a solution of ethanol (24 l) and a solution of the R- (-) -binaphthol phosphate prepared above in DMSO (1.0 l) is added dropwise over a period of 1 to 2 hours with stirring (196 rpm). It was observed that the insoluble particulate compounds began to dissolve, but a more viscous emulsion was formed. After the addition, the reaction solution is continuously stirred for 16 hours at 15-35 ℃. And heating the reaction liquid by using an oil bath until the reaction liquid is refluxed for 1 hour, stopping heating, cooling the reaction liquid to 15-35 ℃, and stirring for 16 hours. The reaction solution was filtered (two batches were combined), the viscosity of the solid was high, the filtration was slow, and the filter cake was slurried three times with ethanol (20 liters). The combined organic phases were concentrated to constant weight to give a yellow oil (5 kg), to this crude product were added water (10 l) and ethyl acetate (5 l), the system was adjusted to pH 11 with 10% cold aqueous sodium hydroxide solution, stirring was continued for 1 hour, then liquid separation was carried out, a large amount of solid precipitated in the system, and the solid obtained by filtration was isomer a (350 g, 97% purity, white solid). Concentrating the filtrate at 50 deg.C under reduced pressure to constant weight, adding ethanol (1.0L), stirring at 15-35 deg.C for 16 hr, filtering, washing the filter cake with ethanol (400 mL) for three times to obtain white solid, vacuum drying, and drying to constant weight (50 deg.C, 24-48 hr) to obtain compound I-2(400 g, purity 95%, ee value greater than 99.5%, yield 24%) as white solid.1H NMR(400MHz，CDCl3)δ：8.85(d，J＝2.3Hz，1H)，8.64(d，J＝8.7Hz，1H)，8.32(d，J＝2.4Hz，1H)，7.98-7.86(m，2H)，7.72-7.61(m，2H)，7.57(d，J＝8.4Hz，2H)，7.54-7.43(m，3H)，7.33(t，J＝7.8Hz，1H)，7.20-7.17(m，2H)，6.95-6.87(m，3H)，5.85(s，1H)，4.17(s，3H)，2.60-2.51(m，1H)，2.19-2.04(m，2H)，2.01-1.97(m，7H)。
The method 2 comprises the following steps:
s-binaphthol phosphate (473 g, 1.35 mol) was suspended in DMSO (1.1L) and dissolved with stirring at 50 ℃ until clear. 1- (5- (4-chlorophenyl) -2-methoxypyridin-3-yl) -4- (dimethylamino) -2- (naphthalenemethanol-1-yl) -1-phenylbutyl-2-ol (780 g, 1.35 mol, isomer A content 93.5%) was suspended in a solution of ethanol (22 l). A DMSO (1.1 l) solution of the S-binaphthol phosphate prepared above was added dropwise with stirring (196 rpm) over a period of 1 hour. It was observed that the insoluble particulate compounds began to dissolve, but a more viscous emulsion was formed. After the addition, the reaction mixture was stirred at 15-35 ℃ for 16 hours. The reaction was heated to reflux with an oil bath and reflux was continued for 1 hour. Stopping heating the reaction solution, cooling to 15-35 ℃, and continuing stirring for 16 hours. The reaction solution is filtered, and the filtering is slow due to the high viscosity of the solid. Pulping the filter cake twice with ethanol (20L multiplied by 2), filtering to obtain a white solid, mixing the solid in water (3L) and ethyl acetate (3L), adding 10% sodium hydroxide aqueous solution to adjust the pH of the system to 10-11, continuing to stir for 1 hour, separating liquid, concentrating the organic phase to constant weight, adding ethanol (1L) and stirring for one hour, filtering, recrystallizing the obtained solid in ethanol (8L) (heating to 80 ℃, continuing to stir until clarifying and cooling to 15-35 ℃, continuing to stir for 16 hours), cooling and filtering, and drying the obtained white solid in vacuum to constant weight (50 ℃, 24-48 hours) to obtain a compound I-2(280 g, 99.2% purity, 99.1% ee value, 38% yield and white solid).1H NMR(400MHz，CDCl3)δ：8.85(d，J＝2.3Hz，1H)，8.64(d，J＝8.7Hz，1H)，8.32(d，J＝2.4Hz，1H)，7.98-7.86(m，2H)，7.72-7.61(m，2H)，7.57(d，J＝8.4Hz，2H)，7.54-7.43(m，3H)，7.33(t，J＝7.8Hz，1H)，7.20-7.17(m，2H)，6.95-6.87(m，3H)，5.85(s，1H)，4.17(s，3H)，2.60-2.51(m，1H)，2.19-2.04(m，2H)，2.01-1.97(m，7H)。
And 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
Compound I-2(395 g, 0.735 mol) was added to a solution of fumaric acid (89.6 g, 0.772 mol) in isopropanol (7 l) over 1-2 hours, followed by activated carbon (10 g) and isopropanol (1.0 l). Heating to reflux and continuing to reflux for 0.5-1 hour, and dissolving the solid until the solid is clear. Heating the colorless clear solution obtained by hot filtration to reflux, keeping the reflux for 1 hour, stopping heating, slowly cooling to 60 ℃, beginning to precipitate solids, keeping the temperature unchanged, continuously stirring for 2 hours, then cooling to 15-35 ℃ for 4-6 hours, and continuously stirring for 16 hours, wherein a large amount of solids are precipitated. The reaction solution is filtered, and a filter cake is dried to constant weight (50 ℃ for 24-48 hours) in vacuum to obtain a target compound (1R,2S) -1- (5- (4-chlorphenyl) -2-methoxypyridine-3-yl) -4- (dimethylamino) -2- (naphthalenemethanol-1-yl) -1-phenylbutyl-2-ol fumarate, namely a compound I-1(398 g, the purity is 98.8%, the ee value is more than 99.5%, the yield is 82.9%, and white solid).1H NMR(400MHz，DMSO-d6)δ：8.61(d，J＝8.2Hz，1H)，8.50(br.s.，1H)，8.40(br.s，1H)，7.91(br.s.，2H)，7.71(d，J＝8.0Hz，2H)，7.66(d，J＝8.5Hz，2H)，7.56-7.54(m，3H)，7.35(t，J＝7.7Hz，1H)，7.17(d，J＝6.3Hz，2H)，6.92-6.80(m，3H)，6.53(s，2H)，5.73(s，1H)，4.13(s，3H)，2.37(m，1H)，2.13(m，7H)，2.07-1.97(m，1H)，1.90(d，J＝8.9Hz，1H)。
Example 2: preparation of Crystal form I of Compound I-1
365 g of the compound I-1 obtained in the step 7 is suspended in a mixed solvent of acetone/methanol (20/1, 730 ml), the mixture is pulped and stirred for 16-20 hours at the temperature of 15-35 ℃, the filtering is carried out, and the filter cake is dried in vacuum to constant weight (50 ℃, 24-48 hours) to obtain the I crystal form (265 g, the purity is 99.7%, the ee value is more than 99.5%, the yield is 72.6%, and white solid) of the compound I-1.
Example 3: preparation of Crystal form II of Compound I-1
Approximately 50mg of Compound I-1 form I was taken and 0.1mL tetrahydrofuran was added to make a suspension. The suspension sample was shaken on a homomixer (40 ℃) for 2 days (protected from light). The residual solid was centrifuged and dried in a vacuum oven at 40 ℃ overnight to give compound I-1 as crystalline form II.
Example 4: preparation of crystalline form III of Compound I-1
The preparation process of the crystal form III is the same as that of the crystal form II, and only the solvent tetrahydrofuran is changed into 0.2mL of acetone-water (2: 1).
Example 5: preparation of Compound 2
Step 11: 1- (3, 5-dichlorophenyl) -3- (dimethylamino) propan-1-one
3, 5-dichloroacetophenone (25.0 g, 132.25 mmol), dimethylamine hydrochloride (43.13 g, 529 mmol) and paraformaldehyde (15.49 g, 171.93 mmol) were mixed in ethanol (300 ml) at room temperature, concentrated hydrochloric acid (4.73 ml) was added, and the reaction mixture was heated to 80 ℃ and stirred for 48 to 52 hours. The reaction solution was concentrated under reduced pressure to give a yellow solid, which was dissolved with water (500 ml) and then extracted with dichloromethane (300 ml × 3). The aqueous phase was adjusted to pH-12 with 10% aqueous sodium hydroxide solution, then extracted with dichloromethane (200 ml × 3), the organic phases of the second extraction were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound 1- (3, 5-dichlorophenyl) -3- (dimethylamino) propan-1-one (24 g, purity 83%) as a yellow oily liquid.
Step 12: 1- (5- (4-chlorophenyl) -2-pyridyl) -2- (3, 5-dichlorophenyl) -4- (dimethylamino) -1-phenyl-butan-2-ol
TMP (16.41 g, 116.2 mmol) is dissolved in tetrahydrofuran (200 ml) under stirring at normal temperature, nitrogen is replaced, the temperature is reduced to-78 ℃ by a dry ice-acetone bath, n-butyllithium (46.48 ml, 116.2 mmol, 2.5 mol/l n-hexane solution) is slowly added dropwise, and the temperature is maintained between-78 ℃ and-20 ℃ for further stirring for 30 minutes. The temperature of the reaction system is reduced to-78 to-65 ℃, a tetrahydrofuran (200 ml) solution of 3-phenyl-5- (4-chlorophenyl) -2-methoxy-pyridine (24.0 g, 77.4 mmol) is added, stirring is continued for 10 minutes after the dropwise addition is finished, a tetrahydrofuran (100 mmol) solution of 1- (3, 5-dichlorophenyl) -3- (dimethylamino) propan-1-one (23.84 g, 77.47 mmol) is slowly added into the reaction system, and after the addition is finished, the reaction solution is continuously stirred for 20 minutes at-78 to-65 ℃. Quenched with saturated aqueous ammonium chloride (100 ml), then extracted with ethyl acetate (150 ml × 2), the organic phases were combined and washed with saturated brine (150 ml × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was subjected to column chromatography (petroleum ether/ethyl acetate. cndot. 10/1 to 1/1) to give a mixture of the title compound (1R,2S) -1- (5- (4-chlorophenyl) -2-pyridyl) -2- (3, 5-dichlorophenyl) -4- (dimethylamino) -1-phenyl-butan-2-ol and (1S, 2R) -1- (5- (4-chlorophenyl) -2-pyridyl) -2- (3, 5-dichlorophenyl) -4- (dimethylamino) -1-phenyl-butan-2-ol) (5.0 g, 99% purity, yield 11.5%, white solid).1H NMR(400MHz，CDCl3)δ：8.66(d，J＝2.51Hz，1H)，8.39(br.s.，1H)，8.25(d，J＝2.51Hz，1H)，7.50-7.48(m，2H)，7.42-7.40(m，2H)，7.40-7.30(m，4H)，7.11-7.02(m，4H)，4.76(s，1H)，4.06(s，3H)，2.26-2.23(m，1H)，2.12-2.04(m，8H)，1.73-1.70(m，1H)。
Step 13: (1R,2S) -1- (5- (4-chlorophenyl) -2-pyridyl) -2- (3, 5-dichlorophenyl) -4- (dimethylamino) -1-phenyl-butan-2-ol
The corresponding isomer (1R,2S) -1- (5- (4-chlorophenyl) -2-pyridyl group) obtained in step 10 was reacted at 0 deg.C) -2- (3, 5-difluorophenyl) -4- (dimethylamino) -1-phenyl-butan-2-ol and (1S, 2R) -1- (5- (4-chlorophenyl) -2-pyridyl) -2- (3, 5-difluorophenyl) -4- (dimethylamino) -1-phenyl-butan-2-ol (8.0 g, 14.39 mmol) were suspended in ethanol (240 ml) and then a solution of R- (-) -binaphthol phosphate (5.01 g, 14.39 mmol) in dimethylsulfoxide (24 ml) was slowly added dropwise to the substrate solution and the reaction was stirred at 20 ℃ for 8 h. And then heating the reaction solution to 80 ℃ and stirring for 1 hour, slowly cooling (2-4 hours) to 20 ℃ and continuously stirring for 16 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, then dissolved in ethyl acetate (40 ml), adjusted to alkaline with 10% sodium hydroxide (pH greater than 12), separated, the organic phase was dried over anhydrous sodium sulfate, and concentrated to give the crude product. Adding the crude product into ethanol (100 ml), stirring for 1-2 hours at 20-30 ℃, filtering, and drying a filter cake in vacuum to constant weight (50 ℃, 24-48 hours) to obtain a target product (1R,2S) -1- (5- (4-chlorophenyl) -2-pyridyl) -2- (3, 5-dichlorophenyl) -4- (dimethylamino) -1-phenyl-butane-2-ol (3.1 g, purity 98.9%, ee value 98.1%, yield 38.8%, white solid).1H NMR(400MHz，CDCl3)δ：8.66(d，J＝2.51Hz，1H)，8.39(br.s.，1H)，8.25(d，J＝2.51Hz，1H)，7.50-7.48(m，2H)，7.42-7.40(m，2H)，7.40-7.30(m，4H)，7.11-7.02(m，4H)，4.76(s，1H)，4.06(s，3H)，2.26-2.23(m，1H)，2.12-2.04(m，8H)，1.73-1.70(m，1H)。
Example (b): 6: stability test of form I in non-solvent
Taking a proper amount of multiple crystal forms I, respectively adding 0.1-0.3mL of single or mixed solvent in the following table, stirring for 2 days at 40 ℃, and centrifuging. The solid was collected from all samples, dried overnight in a vacuum oven (40 ℃) and its crystalline state was detected by XRPD. The results are shown in Table-4.
TABLE-4 stability test of the crystalline modification I without solvent
| Serial number | Solvent(s) | Appearance (2 days) | |
| 1 | Methanol | Suspension | Crystal form I |
| 2 | Ethanol | Suspension | Crystal form I |
| 3 | Acetone (II) | Suspension | Crystal form I |
| 4 | Ethyl acetate | Suspension | Crystal form I |
| 5 | Tetrahydrofuran (THF) | Suspension | Crystal form I |
| 6 | Methanol-water (3: 1) | Suspension | Crystal form I |
| 7 | Ethanol-water (3: 1) | Suspension | Crystal form I/ |
| 8 | Acetone-water (2: 1) | Suspension | III crystal form |
Example 7: solid stability test of crystal form I under conditions of high temperature, high humidity and strong illumination
About 10mg of the crystal form I sample is weighed, placed at the bottom of a glass sample bottle and spread into a thin layer. Sealing the bottle mouth of a sample placed at 60 ℃ and 92.5% RH by using aluminum foil paper, and pricking small holes on the aluminum foil paper to ensure that the sample can be fully contacted with ambient air; samples placed under intense light (5Klux) were sealed with a screw cap. Samples placed under different conditions were sampled and tested on days 5 and 10, the test results were compared with the initial test results of day 0, and the test results are shown in the following table-5:
TABLE-5 solid stability test of crystalline form I
Pharmacological moieties
A first part: in vitro efficacy of anti-M.tuberculosis compounds using M.smegmatis strain ATCC19420
On the day of testing, the dissolved compound was dissolved in pure DMSO (Sigma 276855-2L) to a concentration of 12.8mg/ml as compound stock. Mu.l DMSO was added to all wells of a v-bottom 96 well plate (Axygen-wipp 02280). And adding 30 mu l of compound mother liquor into the 1 st hole, uniformly blowing, adding 30 mu l of compound mother liquor into the 2 nd hole from the 1 st hole, and uniformly blowing. Thereby operating to column 11. Column 12 contained no drug, 30. mu.l DMSO only. This is the compound "master". From column 1 to column 12, the corresponding compound concentrations were 6.4, 3.2, 1.6, 0.8, 0.4, 0.2, 0.1, 0.05, 0.025, 0.0125, 0.00625, 0 mg/ml. For compounds with good efficacy, the test concentration was appropriately reduced. A u-bottom 96-well plate (Costar 3788) was used as a "daughter plate". 98 μ l of CA-MHB (BD-212322) medium containing 0.02% Tween 80 was added to the wells of all the daughter plates. 2 μ l of compound was pipetted from the master plate into the daughter plate at the corresponding position.
The bacteria were inoculated two days in advance on Roche modified slant medium (Difco-244420) and incubated in an incubator at 37 ℃ for 48 hours. Bacterial colonies were harvested from the media slant on the day of testing and suspended in sterile saline containing 0.02% tween 80. 7-10 sterile glass beads with a diameter of 3mm were added to the bacterial solution and the bacteria were broken up using a vortex apparatus at maximum rotation speed. The turbidity of the bacterial liquid was adjusted to 0.10 using a Siemens MicroScan turbidity meter (Siemens MicroScan turbidity meter) corresponding to a bacterial concentration of-1.5X 108cfu/ml. The bacterial solution was diluted 20 times and then 25 times (500 times) with CA-MHB + 0.02% Tween 80 medium. The diluted bacterial solution will be used to inoculate the daughter plates.
100. mu.l of the bacterial suspension was added to each well of the daughter plate. Each well will contain: 3.0X 104cfu bacteria, 1% DMSO, and a gradient of diluted compounds in 200. mu.l CA-MHB + 0.02% Tween 80 medium. The completed daughter plate was placed in a 30 ℃ incubator for cultivation. The Minimum Inhibitory Concentration (MIC) was read after 72 hours.
The standard reference for MIC reading is defined by CLSI method M7-a7 as: the lowest concentration of drug that completely or significantly inhibits bacterial growth. The results of compound detection are shown in Table-6.
A second part: in vitro efficacy of anti-mycobacterium tuberculosis compounds using strain H37Rv
On the day of testing, the compound was dissolved in pure DMSO (Sigma 276855-2L) to a concentration of 10mg/ml as compound stock. Mu.l DMSO was added to the wells from column 2 to column 11 of a v-bottom 96 well plate (Axygen-wipp 02280). Adding 30 μ l of compound mother liquor into the 2 nd row of holes, mixing uniformly, taking 30 μ l from the 2 nd row of holes, adding into the 3 rd row of holes, and blowing, beating and mixing uniformly. Thereby operating on column 10. Column 11 contains no drug, 30. mu.l DMSO only. This is the compound "master". From column 2 to column 11, the corresponding compound concentrations were 5, 2.5, 1.25, 0.625, 0.3125, 0.156, 0.078, 0.039, 0.02, 0 mg/ml. For compounds with good efficacy, the test concentration was appropriately reduced. Flat-bottomed 96-well plates (Greiner 655090) were used as "daughter plates". 98. mu.l of 7H9(SigmaM0178) medium was added to the wells of all the daughter plates. 2 μ l of compound was pipetted from the master plate into the daughter plate at the corresponding position. Daughter plate A and H rows, columns 1 and 12 contained only 7H9 medium.
The H37Rv strain in the glycerol vial was inoculated into 7H9 medium containing 0.05% Tween 80 and cultured at 37 ℃ for 4 weeks on a shaker at 200 rpm. The broth was washed twice with 7H9 medium containing 0.05% tween 80 and resuspended in the same medium. The absorbance of the bacterial solution was adjusted to OD using the same medium5500.4-0.5. The bacterial solution was dispensed into a microcentrifuge tube and stored at-80 ℃. The storage time is not more than 1 month. On the day of testing, the dispensed bacterial solution was thawed. The thawed bacteria solution was diluted 20-fold with 7H9 medium and then 50-fold and 1000-fold, and was used to inoculate daughter plates. Mu.l of the inoculum was inoculated into each well of the daughter plate, and 100. mu.l of 7H9 medium was added to column 12 without the inoculum.
The test daughter plates were incubated in an incubator at 37 ℃ with humidity maintained at > 80%. Starting after one week, 12.5. mu.l of 7H9 medium containing 20 % Tween 80 and 20. mu.l of Alamar blue (Invitrogen DAL1100) were added to one row of wells 1 containing bacteria and one row of wells 12 containing no bacteria daily and observed after further culturing for 24 hours. When the added Alamar blue was reduced to pink within 24 hours by the inoculum from the well in column 1, the fluorescence was measured after adding 7H9 medium containing 20% Tween 80 and Alamar blue to all wells on the test plate and incubating for a further 24 hours at 37 ℃.
The Minimum Inhibitory Concentration (MIC) was defined as: the minimum drug concentration that completely inhibits Alamar blue discoloration by visual observation or that inhibits more than 90% of reduced Alamar blue production as measured by fluorometry. The results of compound detection are shown in Table-6.
TABLE-6 in vitro screening results
Note: ATCC-american type culture collection; MABA- -microplate Alma blue color development test; LORA-recovery test under anaerobic conditions; vero Cell-african green monkey kidney Cell; IC 50-median inhibitory concentration; hela-human cervical cancer cells; CC 50-half cytotoxic concentration.
And (4) analyzing results: the compound I-2 has good inhibitory activity to mycobacterium smegmatis, and the inhibitory activity of the compound I-2 to mycobacterium tuberculosis under aerobic (MABA) or anaerobic (LORA) conditions is superior to or equal to that of the marketed antituberculosis drug bedaquiline. Moreover, the compound I-2 has no obvious cytotoxicity to Vero and Hela cells.
And a third part: in vitro efficacy evaluation of compound against drug-resistant mycobacterium tuberculosis
We performed activity tests on Compound I-2 using the same procedure as mentioned in the second section, using drug-sensitive and drug-resistant strains of Mycobacterium tuberculosis, and the results are shown in Table-7.
TABLE-7: some of the compounds tested for drug sensitive and resistant Mycobacterium tuberculosis Activity MIC (uM)
Note: MIC-minimum inhibitory concentration; MABA- -microplate Alma blue color development test; vs- -pair, relative; h37Rv — wild-type H37Rv strain; rRMP- -rifampicin resistant Mycobacterium tuberculosis strain; rINH- -an isoniazid resistant Mycobacterium tuberculosis strain.
And (4) analyzing results: the compound I-2 has better inhibition effect on wild mycobacterium tuberculosis H37Rv and rifampicin and isoniazid resistant strains, wherein the inhibition activity of the compound I-2 on the three tested strains is equivalent to that of the marketed antitubercular drug Bedaquin.
Claims (16)
1. A process for the preparation of a compound of formula (I),
which comprises the following steps:
wherein the content of the first and second substances,
R1selected from the group consisting of optionally substituted by 0, 1, 2 or 3R01Substituted 6-to 12-membered aryl, 6-to 12-membered heteroaryl, 6-to 12-membered aryl-alkylene, and 6-to 12-membered heteroaryl-alkylene;
HX is selected from organic or inorganic acid;
the base A is selected from an alkali metal base, an alkaline earth metal base, or an organometallic base;
the molar use ratio of the compound (II) to the alkali A is 1: 1-5;
the molar use ratio of the compound (II) to the compound (III) is 1: 1-2;
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 3-20 times of the weight of the compound (IV);
the reaction temperature is-80-0 ℃;
the reaction time is 1-24 hours;
R01selected from F, Cl, Br, I, CN, OH, CH (CH)3)2、C(CH3)3、N(CH3)2、NH(CH3)、NH2、CHO、COOH、C(＝O)NH2、S(＝O)NH2、S(＝O)2NH2、CF3、CF3O、(NH2)CH2、(HO)CH2、CH3C(＝O)、CH3OC(＝O)、CH3S(＝O)2、CH3S(＝O)；
Said "hetero" represents a heteroatom selected from N, O or S;
the number of heteroatoms is independently selected from 1, 2 or 3.
2. The method of claim 1, wherein R1Optionally substituted by 0, 1, 2 or 3R01Substituted naphthyl or phenyl.
3. The method of claim 2, wherein R1Is selected from
4. The production method according to claim 1, wherein the alkali metal base is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogencarbonate, sodium hydride, potassium hydride and/or potassium hydrogencarbonate;
the alkaline earth metal base is selected from calcium hydride;
the organometallic base is selected from n-butyllithium, lithium diisopropylamide, lithium 2,2,6, 6-tetramethylpiperidine, lithium bis (trimethylsilyloxy) amide, sodium methoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide and/or aluminum isopropoxide.
5. The preparation method according to claim 1, wherein the molar ratio of the compound (II) to the base A is 1: 1.2-2;
the reaction temperature is-80 to-60 ℃;
the reaction time is 2-12 hours;
the reaction solvent is selected from tetrahydrofuran, diethyl ether and/or isopropyl ether; and/or
The amount of the reaction solvent is 5-10 times of the weight of the compound (IV).
6. The method according to claim 5, wherein the reaction time is 4 to 8 hours.
7. The preparation method according to any one of claims 1 to 6, comprising the following reaction scheme:
wherein the content of the first and second substances,
the base B is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide or aluminum isopropoxide;
the chiral acid is selected from alpha-hydroxypropionic acid, alpha-hydroxysuccinic acid, alpha, beta-dihydroxysuccinic acid, alpha-hydroxyphenylacetic acid, beta-hydroxy acid and a compound (VI);
n is 0, 1 or 2;
R2、R4each independently selected from H, F, Cl, Br, I, or optionally substituted by 0, 1, 2 or 3R01Substituted: c1-8Alkoxy radical, C1-8Alkyl, Si (Ph)36-12 membered aryl;
R3、R5each independently selected from H, F, Cl, Br, I, NO2OH, or selected from optionally substituted by 0, 1, 2 or 3R01Substituted: c1-8Alkoxy radical, C1-8Alkyl, 6-12 membered aryl;
optionally, R substituted at positions 13 and 143Or R substituted in positions 14 and 153Can be linked together to form a 6-to 12-membered aryl ring;
optionally, R substituted in position 8 and position 95Or in position 9 andr substituted in position 105Can be linked together to form a 6-to 12-membered aryl ring;
the solvent for preparing compound (v) from compound (iv) is selected from: acetone, methyl ethyl ketone, ethanol, methanol, isopropanol, tert-butanol, ethyl acetate, tert-butyl acetate, DMF, DMSO, DMA and/or NMP, or a mixture of several solvents;
the molar ratio of the chiral acid to the compound (IV) is 0.5-1.5;
HX is selected from hydrochloric acid, sulfuric acid, phosphoric acid, oxalic acid, citric acid, maleic acid or fumaric acid.
8. The method of claim 7, wherein R3、R5Each independently selected from H;
R2substitution is at the 2-position;
R4substitution at position 6;
R2、R4each independently selected from: H. si (Ph)3、
9. The preparation method according to claim 7, wherein the molar ratio of the chiral acid to the compound (IV) is 0.8 to 1.2.
10. The production method according to claim 7, wherein the molar ratio of the chiral acid to the compound (IV) is 1.0.
11. The process according to claim 7, wherein the compound (VI) is selected from
12. A compound of the formula:
13. a compound represented by the following formula I-1,
14. the compound of claim 13, wherein the compound i-1 is in form i, form ii and form iii, wherein the XRPD patterns are shown in figure 1, figure 4 and figure 7, respectively.
15. The process for preparing the crystalline form I according to claim 14, which comprises crystallizing compound I-1 in any one of its forms by adding it to a solvent,
the solvent is selected from alcohols, ketone solvents or mixed solvents of the alcohol solvents and the ketone solvents;
the dosage of the solvent is 3-50 times of the weight of the compound I-1.
16. A process for preparing the crystalline form i according to claim 15, wherein the alcoholic solvent is selected from methanol, ethanol, isopropanol and/or n-butanol;
the ketone solvent is selected from acetone and/or methyl ethyl ketone;
the mixed solvent is a mixed solvent of methanol and acetone; or
The volume ratio of the mixed solvent of the methanol and the acetone is 1: 5-30.
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