CN115385897A - Preparation method of CSF-1R inhibitor or acid salt thereof - Google Patents

Preparation method of CSF-1R inhibitor or acid salt thereof Download PDF

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CN115385897A
CN115385897A CN202210564647.1A CN202210564647A CN115385897A CN 115385897 A CN115385897 A CN 115385897A CN 202210564647 A CN202210564647 A CN 202210564647A CN 115385897 A CN115385897 A CN 115385897A
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deuterium
hydroxy
compound
cyclobutyl
cyclopropyl
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林长学
赵保卫
喻红平
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Abbisko Therapeutics Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/267—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to the ring nitrogen atom

Abstract

The invention relates to a preparation method of a CSF-1R inhibitor or an acid salt thereof, wherein the CSF-1R inhibitor has a compound structure shown in the following formula (A), and is prepared by taking 6-substituted-5- ((2- (1-substituted-1H-pyrazol-4-yl) pyridine-4-yl) oxy) pyridine-2-amine and 3,3-disubstituted pyrrolidine-2-ketone-formyl chloride or derivatives thereof as raw materials and carrying out condensation reaction in the presence of an amine reagent, morpholine or piperazine. The preparation method has the advantages of simple operation, high yield of each step, stable process, adaptability to the requirement of industrial production, solving the problem of medicament accessibility, and being beneficial to accelerating the clinical development of CSF-1R inhibitors and the marketing of medicaments.

Description

Preparation method of CSF-1R inhibitor or acid salt thereof
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a preparation method of a CSF-1R inhibitor or an acid salt thereof.
Background
CSF-1R (cFMS) is called cell colony stimulating factor-1 receptor, said receptor is membrane protein, and is expressed on the surface of macrophage and monocyte, its extracellular segment can be combined with macrophage colony stimulating factor, and its intracellular segment tyrosine kinase can activate cell growth and reproduction signal channel downstream of macrophage and monocyte. Thus, the CSF-1R signaling pathway has a major impact on macrophagy, monocyte development and differentiation, and the physiological function of Tumor-Associated macrophages (TAMs). With the recent advances in tumor immunotherapy, tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) are thought to be directly involved in the formation of an immunosuppressive microenvironment within the tumor and angiogenesis that supports tumor growth. Meanwhile, clinical studies show that the content of TAM is negatively correlated with the prognosis of tumor patients. Pharmacodynamic experiments in mice prove that the inhibition of CSF-1R signal channels can obviously reduce the number of macrophages which have inhibition on immune systems in tumors, and improve the content of CD8 positive T cells. These experimental results indicate that small molecule inhibitors of CSF-1R may reverse the immunosuppressive environment inside the tumor, promote activation of the immune system, and prolong the life of tumor patients.
In 2018, shanghai and reputation biomedicine Co., ltd discloses a series of compounds with selective CSF-1R inhibition effect in WO2018214867A1, and the structural general formula of the compounds is as follows:
Figure BDA0003657394630000011
the series of compounds are prepared by condensation reaction of 3,3-disubstituted pyrrolidine-2-ketone-formyl chloride raw materials, and the synthetic route is as follows:
Figure BDA0003657394630000021
the reaction in this step uses expensive pyridine as an acid-binding agent, has low yield of only 30.4%, needs column chromatography, and is not beneficial to industrial production. Therefore, there is an urgent need to develop a method for preparing the compound of formula (a) for industrial production and to prepare an API that is acceptable to meet the needs of clinical research and production of pharmaceutical preparations on the market.
Disclosure of Invention
The invention aims to provide a preparation method of a CSF-1R inhibitor or an acid salt thereof, wherein the CSF-1R inhibitor is 3,3-disubstituted-N- (6-substituted-5- ((2- (1-substituted-1H-pyrazol-4-yl) pyridine-4-yl) oxy) pyridine-2-yl) -2-oxopyrrolidine-1-formamide, so that the requirements of clinical research and production of medicinal preparations on the market are met.
In a first aspect, the present invention provides a process for the preparation of a compound of formula (a) or an acid salt thereof, said process comprising the steps of: condensing a compound of formula (1) or an acid salt thereof with a compound of formula (2) or a derivative thereof to generate a compound of formula (A) or an acid salt thereof, wherein the condensation reaction is carried out in the presence of an amine reagent, morpholine or piperazine,
Figure BDA0003657394630000022
wherein the content of the first and second substances,
R 1 、R 2 each independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 5-8 Aryl and 5-8 membered heteroaryl, or, R 1 、R 2 Together with the carbon atom to which they are directly attached form C 3-6 Cycloalkyl or 3-6 membered heterocyclyl, said groups optionally further substituted by one or more groups selected from deuterium, halogen, cyano, hydroxy, C 1-4 Alkyl radical, C 1-4 Alkoxy, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 An alkyl group,C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 5-8 Aryl and 5-8 membered heteroaryl;
R 3 selected from hydrogen, deuterium, C 1-4 Alkyl radical, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl, said groups optionally further substituted with one or more substituents selected from deuterium, hydroxy, halogen, cyano, C 1-4 Alkyl radical, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 1-4 Alkoxy, carboxyl and amino;
R 4 selected from hydrogen, deuterium, C 1-4 Alkyl and C 3-6 Cycloalkyl, said radicals optionally being further substituted by one or more groups selected from deuterium, hydroxy, halogen, cyano, C 1-4 Alkyl radical, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 1-4 Alkoxy, carboxyl and amino;
the "heterocyclic group" contains 1 to 2 hetero atoms selected from nitrogen atom or oxygen atom.
Preferably, R is 1 、R 2 Each independently selected from hydrogen, deuterium, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl and phenyl, or R 1 、R 2 And the carbon atom to which they are directly attached, form a cyclopropyl, cyclobutyl, cyclopentyl, morpholinyl, pyrrolyl, piperazinyl, oxetanyl or tetrahydrofuryl group, optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, hydroxy, methyl, trifluoromethyl, trideuteromethyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl and phenyl;
R 3 selected from the group consisting of hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, morpholinyl, pyrrolyl, piperazinyl, oxetanyl and tetrahydrofuranyl, the above groups are optionally further substituted with one or more groups selected from deuterium, hydroxy, halogen, cyano, methyl, ethyl, n-propyl, isopropyl,Cyclopropyl, cyclobutyl, morpholinyl, pyrrolyl, oxetanyl, tetrahydrofuryl, methoxy, ethoxy, isopropoxy, carboxy and amino;
R 4 selected from the group consisting of hydrogen, deuterium, methyl, trifluoromethyl, trideuteromethyl, ethyl, isopropyl, cyclopropyl and cyclobutyl.
Preferably, R is 1 、R 2 Each independently selected from hydrogen, deuterium, hydroxy, methyl, ethyl, methoxyethyl, n-propyl, isopropyl, methoxy, ethoxy, isopropoxy, benzyloxy, cyclopropyl, cyclobutyl, cyclopentyl and phenyl, or, R 1 、R 2 Together with the carbon atom to which they are directly attached form a cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, tetrahydrofuranyl or pyrrolyl group;
R 3 selected from the group consisting of hydrogen, deuterium, methyl, trifluoromethyl, trideuterium methyl, methoxymethyl, hydroxymethyl, ethyl, methoxyethyl, hydroxyethyl, n-propyl, isopropyl, n-butyl, hydroxy-substituted isobutyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, morpholinyl, pyrrolyl, morpholinylethyl, methyl-substituted pyrrolyl, piperazinyl, oxetanyl and tetrahydrofuranyl;
R 4 selected from hydrogen, deuterium, methyl, ethyl, trifluoromethyl and trideuteromethyl.
Preferably, the derivative of the compound of formula (2) is selected from the following compounds:
Figure BDA0003657394630000041
wherein R is 1 、R 2 Each independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 5-8 Aryl and 5-8 membered heteroaryl, or, R 1 、R 2 Together with the carbon atom to which they are directly attached form C 3-6 Cycloalkyl or 3-6 membered heterocyclyl, optionally further substituted by one or more groups selected from deuterium, halogen, cyanoHydroxy, C 1-4 Alkyl radical, C 1-4 Alkoxy, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 5-8 Aryl and 5-8 membered heteroaryl.
As a preferred embodiment, R 1 、R 2 Each independently selected from hydrogen, deuterium, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl and phenyl, or R 1 、R 2 And the carbon atoms to which they are directly attached, form a cyclopropyl, cyclobutyl, cyclopentyl, morpholinyl, pyrrolyl, piperazinyl, oxetanyl or tetrahydrofuryl group, optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, hydroxy, methyl, trifluoromethyl, trideuteromethyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl and phenyl.
As a preferred embodiment, R 1 、R 2 Each independently selected from hydrogen, deuterium, hydroxy, methyl, ethyl, methoxyethyl, n-propyl, isopropyl, methoxy, ethoxy, isopropoxy, benzyloxy, cyclopropyl, cyclobutyl, cyclopentyl and phenyl, or, R 1 、R 2 Together with the carbon atom to which they are directly attached form a cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, tetrahydrofuranyl or pyrrolyl group.
Preferably, the ratio of the compound of formula (1) or its acid salt to the compound of formula (2) or its derivative is 1: (0.1 to 10); preferably, the feeding ratio is 1: (0.2-5), and the more preferable feeding ratio is 1: (0.5-3).
Preferably, the aminic reagent is selected from methylamine, dimethylamine, ethylamine, diethylamine, propylamine, dipropylamine, tripropylamine, 1,2-dimethylpropylamine, cyclopropylamine, diisopropylamine, diisopropylethylamine, triethylamine, n-butylamine, isobutylamine, tert-butylamine, sec-butylamine, diisobutylamine, hexylamine, dicyclohexylamine, decylamine, dodecylamine, triethanolamine, 2-propenylamine, ethanolamine, 3-propanolamine, isopropanolamine, diisopropanolamine, triisopropanolamine, dimethylethanolamine, diethylethanolamine, ethylenediamine, 1,3-propylenediamine, 1,4-butanediamine, 1,5-pentanediamine, or 1,6-hexanediamine.
Preferably, the acid salt in the preparation method comprises an inorganic acid salt or an organic acid salt.
As a further preferable embodiment, the inorganic acid salt is selected from hydrochloride, sulfate, hydrobromide, hydrofluoride, hydroiodide or phosphate.
As a further preferred solution it is possible to, the organic acid salt is selected from acetate, dichloroacetate, trichloroacetate, trifluoroacetate, benzene sulfonate, p-toluene sulfonate, 4-chlorobenzene sulfonate, 1,5-naphthalene disulfonate, naphthalene-2-sulfonate, ethane-1,2-disulfonate, methane sulfonate, ethane sulfonate, benzoate, decanoate, hexanoate, octanoate, cinnamate, citrate, cyclamate, camphorsulfonate, aspartate, camphorate, gluconate, glucuronate, glutamate, erythorbate, lactate, malate, mandelate, pyroglutamate, tartrate, dodecyl sulfate, dibenzoyltartrate, and mixtures thereof formate, fumarate, hemi-lactobionate, gentisate, acetohydroxamate, malonate, succinate, glutarate, adipate, sebacate, 2-ketoglutarate, glycolate, hippurate, isethionate, lactobionate, ascorbate, aspartate, laurate, maleate, nicotinate, oleate, orotate, oxalate, palmitate, pamoate, propionate, 4-acetamidobenzoate, 4-aminobenzoate, salicylate, 4-aminosalicylate, 2,5-dihydroxybenzoate, 1-hydroxy-2-naphthoate, stearate, thiocyanate, undecinate, or succinate.
As a preferred embodiment, the compound of formula (2) is prepared by the following steps: taking a compound of a formula (3) as a raw material to react to generate a compound of a formula (2),
Figure BDA0003657394630000061
wherein R is 1 、R 2 As described for the compound of formula (A).
As a preferred embodiment, the compound of formula (2) is prepared in an acidic system, and the acidic system is an organic acid system, preferably, the organic acid system is a trimethylchlorosilane solution or an ammonium chloride solution.
As a preferred scheme, triphosgene and triphosgene are added in the preparation process of the compound shown in the formula (2)
Figure BDA0003657394630000071
Reacting, wherein the charge ratio is 1: (1-10), preferably, the feeding ratio is 1: (1-6), and more preferably, the feeding ratio is 1: (2 to 5) wherein R 1 、R 2 As described for the compound of formula (A).
In a second aspect the present invention provides a compound of formula (A'),
Figure BDA0003657394630000072
wherein R is 1 、R 2 As described for the compound of formula (A).
Preferably, the compound of formula (a ") has the following structure:
Figure BDA0003657394630000073
compared with the prior art, the invention has the following technical advantages:
1. in the aspect of operation, the invention has the advantages of simple and easily obtained raw materials or reagents, mild reaction conditions, strong operability, no column chromatography technology in the whole preparation process, reduced reagent consumption, small environmental protection pressure and suitability for industrial production.
2. In the technical aspect, the invention adopts common amine reagents, morpholine or piperazine, and the acid-binding agent is unexpectedly found to well control the generation of impurities in the reaction process, so that higher yield is obtained. In a specific embodiment, triethylamine and diisopropylethylamine are respectively selected as acid-binding agents in the first step and the second step of reaction, so that the generation of impurities is well controlled, the yield of the product is nearly 90%, the purity is high, and compared with the yield of only 30% in the prior art, the yield is improved by nearly 3 times, and the method is suitable for industrial production.
Drawings
FIG. 1 is an HPLC chromatogram of a compound of formula (A) obtained in two hours of the example preparative reaction.
FIG. 2 is an HPLC chromatogram of the final product of the compound of formula (A) prepared in the example.
Detailed Description
The inventors of the present application have extensively and intensively studied to develop a preparation method of 3,3-disubstituted-N- (6-substituted-5- ((2- (1-substituted-1H-pyrazol-4-yl) pyridin-4-yl) oxy) pyridin-2-yl) -2-oxopyrrolidine-1-carboxamide. The preparation method is characterized in that 3,3-dimethylpyrrolidine-2-ketone-formyl chloride or a derivative thereof is subjected to condensation reaction in the presence of an amine reagent, morpholine or piperazine to prepare the compound. The preparation method has simple operation, high yield of each step and stable process, can meet the requirement of industrial production, solves the problem of medicament accessibility, and is favorable for accelerating the clinical development of CSF-1R inhibitors and the marketing of medicaments. On the basis of this, the present invention has been completed.
The present invention will be described more fully with reference to the following examples, but the present invention is not limited thereto, and the present invention is not limited to the examples.
The thin-layer chromatography silica gel plate uses a tobacco-terrace yellow sea HSGF254 or Qingdao GF254 silica gel plate, and the specification adopted by TLC is 0.15 mm-0.20 mm.
The starting materials in the examples of the present invention are known and commercially available, or may be synthesized using or according to methods known in the art.
The purity of the compounds of the invention was checked by agilent High Performance Liquid Chromatography (HPLC). A chromatographic column: waters
Figure BDA0003657394630000081
C18. Mobile phase A:0.05% aqueous trifluoroacetic acid, mobile phase B:0.05% trifluoroacetic acid in acetonitrile. Flow rate: 1.0mL/min. Detection wavelength: 245nm.
In the case where no particular limitation is imposed, the solvent is a dry solvent, and the reaction temperature is in degrees Celsius (. Degree. C.).
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The first step is as follows: 8978 Synthesis of zxft 8978-dimethyl-2-carbonylpyrrolidine-1-carbonylchloride
Figure BDA0003657394630000091
Dichloromethane (9.0L), 3,3-dimethylpyrrolidin-2-one (900.7g, 7.97mol), triethylamine (971g, 9.6 mol) were added under nitrogen protection, cooled to-15 deg.C, and trimethylchlorosilane (1730g, 15.9mol) was added dropwise to the above mixture. Triphosgene (778g, 2.6 mol) is dissolved in dichloromethane (4.5L) under the protection of nitrogen, cooled to-15 ℃, added slowly with 3,3-dimethylpyrrolidine-2-ketone mixed solution, stirred and reacted for half an hour at the temperature of-15 to-25 ℃, heated to 20-30 ℃ for 1 hour, decompressed and concentrated to dryness, added with methyl tert-butyl ether in the residue, filtered and concentrated to obtain 3,3-dimethyl-2-oxopyrrolidine-1-carbonyl chloride of 1.35kg (purity: 74.3%).
The second step is that: synthesis of 3,3-dimethyl-N- (6-methyl-5- ((2- (1-methyl-1H-pyrazol-4-yl) pyridin-4-yl) oxy) pyridin-2-yl) -2-oxopyrrolidine-1-carboxamide
Figure BDA0003657394630000092
2-methyltetrahydrofuran (115 mL), 6-methyl-5- ((2- (1-methyl-1H-pyrazol-4-yl) pyridin-4-yl) oxy) pyridin-2-amine (10.0g, 0.035mol), N, N-diisopropylethylamine (10.56g, 0.08mol) were added under nitrogen protection, cooled to 0 ℃ and a 3,3-dimethyl-2-oxopyrrolidine-1-carbonylchlorinated 2-methyltetrahydrofuran solution (10.20g, 0.058mol) was added dropwise to the above-mentioned mixed solution. Heating toStirring the mixture for reaction for 2 hours at the temperature of between 20 and 30 ℃ (the HPLC chart of the reaction for two hours is shown in the attached figure 1), washing the mixture for three times by using a 5.0 percent sodium bicarbonate solution, washing the mixture for two times by using a saturated saline solution, concentrating an organic phase, adding 12mL of ethyl acetate, concentrating the mixture to be dry again, adding the ethyl acetate into a residue, filtering the mixture, and drying a filter cake to obtain 13.3g of 3,3-dimethyl-N- (6-methyl-5- ((2- (1-methyl-1H-pyrazol-4-yl) pyridine-4-yl) oxy) pyridine-2-yl) -2-oxopyrrolidine-1-formamide (the yield is 89.26 percent, the purity is 99.95 percent, and the HPLC chart is shown in the attached figure 2). MS m/z (ESI): 421[ m ] +H] + 。
1 H NMR(400MHz,DMSO-d 6 )δ11.02(s,1H),8.37(d,J＝5.6Hz,1H),8.27(s,1H),7.98(s,1H),7.93(d,J＝8.8Hz,1H),7.67(d,J＝8.8Hz,1H),7.19(d,J＝2.5Hz,1H),6.62(dd,J＝5.7,2.5Hz,1H),3.86(s,3H),3.78(t,J＝7.0Hz,2H),2.28(s,3H),1.91(t,J＝7.0Hz,2H),1.20(s,6H).
As can be seen from the attached figure 2, the target product 3,3-dimethyl-N- (6-methyl-5- ((2- (1-methyl-1H-pyrazol-4-yl) pyridin-4-yl) oxy) pyridin-2-yl) -2-oxopyrrolidine-1-formamide has a liquid phase purity as high as 99.95%, only a few byproducts are generated in the reaction, and the main impurity compound has the following structure through pattern analysis:
Figure BDA0003657394630000101
all documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Further, it will be appreciated that various changes or modifications may be made by those skilled in the art after reading the above teachings of the invention, and such equivalents may fall within the scope of the invention as defined by the appended claims.

Claims (14)

1. A process for the preparation of a compound of formula (a) or an acid salt thereof, comprising the steps of:
carrying out condensation reaction on the compound of the formula (1) or acid salt thereof and the compound of the formula (2) or derivative thereof to generate the compound of the formula (A) or acid salt thereof, wherein the condensation reaction is carried out in the presence of an amine reagent, morpholine or piperazine,
Figure FDA0003657394620000011
wherein, the first and the second end of the pipe are connected with each other,
R 1 、R 2 each independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 5-8 Aryl and 5-8 membered heteroaryl, or, R 1 、R 2 Together with the carbon atom to which they are directly attached form C 3-6 Cycloalkyl or 3-6 membered heterocyclyl, said groups optionally further substituted by one or more groups selected from deuterium, halogen, cyano, hydroxy, C 1-4 Alkyl radical, C 1-4 Alkoxy, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 5-8 Aryl and 5-8 membered heteroaryl;
R 3 selected from hydrogen, deuterium, C 1-4 Alkyl radical, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl, said groups optionally further substituted with one or more substituents selected from deuterium, hydroxy, halogen, cyano, C 1-4 Alkyl radical, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 1-4 Alkoxy, carboxyl and amino;
R 4 selected from hydrogen, deuterium, C 1-4 Alkyl and C 3-6 Cycloalkyl, said radicals optionally being further substituted by one or more groups selected from deuterium, hydroxy, halogen, cyano, C 1-4 Alkyl radical, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 1-4 Alkoxy, carboxyl and amino;
the "heterocyclic group" contains 1 to 2 hetero atoms selected from nitrogen atom or oxygen atom.
2. The method of claim 1, wherein R is 1 、R 2 Each independently selected from hydrogen, deuterium, hydroxy, methyl, ethyl,N-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl and phenyl, or R 1 、R 2 And the carbon atom to which they are directly attached, form a cyclopropyl, cyclobutyl, cyclopentyl, morpholinyl, pyrrolyl, piperazinyl, oxetanyl or tetrahydrofuryl group, optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, hydroxy, methyl, trifluoromethyl, trideuteromethyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl and phenyl;
R 3 selected from the group consisting of hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, morpholinyl, pyrrolyl, piperazinyl, oxetanyl and tetrahydrofuryl, said groups being optionally further substituted by one or more substituents selected from deuterium, hydroxy, halogen, cyano, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, morpholinyl, pyrrolyl, oxetanyl, tetrahydrofuryl, methoxy, ethoxy, isopropoxy, carboxy and amino;
R 4 selected from the group consisting of hydrogen, deuterium, methyl, trifluoromethyl, trideuteromethyl, ethyl, isopropyl, cyclopropyl and cyclobutyl.
3. The method according to claim 1, wherein R is 1 、R 2 Each independently selected from hydrogen, deuterium, hydroxy, methyl, ethyl, methoxyethyl, n-propyl, isopropyl, methoxy, ethoxy, isopropoxy, benzyloxy, cyclopropyl, cyclobutyl, cyclopentyl and phenyl, or, R 1 、R 2 Together with the carbon atom to which they are directly attached form a cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, tetrahydrofuranyl or pyrrolyl group;
R 3 selected from hydrogen, deuterium, methyl, trifluoromethyl, trideuteromethyl, methoxymethyl, hydroxymethyl, ethyl, methoxyethyl, hydroxyethyl, n-propyl, isopropyl, n-butyl, hydroxy-substituted isopropylButyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, morpholinyl, morpholinylethyl, pyrrolyl, methyl substituted pyrrolyl, piperazinyl, oxetanyl and tetrahydrofuranyl;
R 4 selected from hydrogen, deuterium, methyl, ethyl, trifluoromethyl and trideuterium methyl.
4. The process according to claim 1, wherein the derivative of the compound of formula (2) is selected from the following compounds:
Figure FDA0003657394620000031
wherein R is 1 、R 2 Each independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 5-8 Aryl and 5-8 membered heteroaryl, or, R 1 、R 2 Together with the carbon atom to which they are directly attached form C 3-6 Cycloalkyl or 3-6 membered heterocyclyl, said groups optionally further substituted by one or more groups selected from deuterium, halogen, cyano, hydroxy, C 1-4 Alkyl radical, C 1-4 Alkoxy, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 5-8 Aryl and 5-8 membered heteroaryl.
5. The method of claim 1, wherein R is 1 、R 2 Each independently selected from hydrogen, deuterium, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl and phenyl, or R 1 、R 2 Together with the carbon atom to which they are directly attached form cyclopropyl, cyclobutyl, cyclopentyl, morpholinyl, pyrrolyl, piperazinyl, oxetanyl or tetrahydrofuranyl, the above groups are optionally further substituted with one or more substituents selected from deuterium, halogen,Cyano, hydroxy, methyl, trifluoromethyl, trideuteromethyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl and phenyl.
6. The method of claim 1, wherein R is 1 、R 2 Each independently selected from hydrogen, deuterium, hydroxy, methyl, ethyl, methoxyethyl, n-propyl, isopropyl, methoxy, ethoxy, isopropoxy, benzyloxy, cyclopropyl, cyclobutyl, cyclopentyl and phenyl, or, R 1 、R 2 Together with the carbon atom to which they are directly attached form a cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, tetrahydrofuranyl or pyrrolyl group.
7. The method according to claim 1, wherein the compound of formula (1) or the acid salt thereof and the compound of formula (2) or the derivative thereof are fed in a molar ratio of 1: (0.1 to 10); preferably, the feeding molar ratio is 1: (0.2-5), and the feeding molar ratio is more preferably 1: (0.5-3).
8. The method of claim 1, wherein the amine reagent is selected from the group consisting of methylamine, dimethylamine, ethylamine, diethylamine, propylamine, dipropylamine, tripropylamine, 1,2-dimethylpropylamine, cyclopropylamine, diisopropylamine, diisopropylethylamine, triethylamine, n-butylamine, isobutylamine, t-butylamine, sec-butylamine, diisobutylamine, hexylamine, dicyclohexylamine, decylamine, dodecylamine, triethanolamine, 2-propenamine, ethanolamine, 3-propanolamine, isopropanolamine, diisopropanolamine, triisopropanolamine, dimethylethanolamine, diethylethanolamine, ethylenediamine, 1,3-propanediamine, 1,4-butanediamine, 1,5-pentanediamine, and 1,6-hexanediamine.
9. The production method according to claim 1, wherein the acid salt comprises an inorganic acid salt or an organic acid salt; the inorganic acid salt is selected from hydrochloride, sulfate, hydrobromide, hydrofluoride, hydroiodide or phosphate; the organic acid salt is selected from acetate, dichloroacetate, trichloroacetate, trifluoroacetate, benzene sulfonate, p-toluene sulfonate, 4-chlorobenzene sulfonate, 1,5-naphthalene disulfonate, naphthalene-2-sulfonate, ethane-1,2-disulfonate, methane sulfonate, ethane sulfonate, benzoate, decanoate, hexanoate, octanoate, cinnamate, citrate, cyclamate, camphorsulfonate, aspartate, camphorate, gluconate, glucuronate, glutamate, erythorbate, lactate, malate, mandelate, pyroglutamate, tartrate, dodecyl sulfate, dibenzoyltartrate, and mixtures thereof formate, fumarate, hemi-lactobionate, gentisate, acetohydroxamate, malonate, succinate, glutarate, adipate, sebacate, 2-ketoglutarate, glycolate, hippurate, isethionate, lactobionate, ascorbate, aspartate, laurate, maleate, nicotinate, oleate, orotate, oxalate, palmitate, pamoate, propionate, 4-acetamidobenzoate, 4-aminobenzoate, salicylate, 4-aminosalicylate, 2,5-dihydroxybenzoate, 1-hydroxy-2-naphthoate, stearate, thiocyanate, undecenate, or succinate.
10. The process according to claim 1, wherein the compound of formula (2) is prepared by the following steps: taking a compound of a formula (3) as a raw material to react to generate a compound of a formula (2),
Figure FDA0003657394620000051
wherein R is 1 、R 2 As claimed in claim 1.
11. The process according to claim 10, wherein the compound of formula (2) is prepared in an acidic system, wherein the acidic system is an organic acid system, preferably wherein the organic acid system is a solution of chlorotrimethylsilane or a solution of ammonium chloride.
12. The method according to claim 10, wherein triphosgene and triphosgene are added during the preparation of the compound of formula (2)
Figure FDA0003657394620000052
Reacting, wherein the feeding molar ratio is 1: (1-10), preferably, the feeding molar ratio is 1: (1 to 6), and more preferably, the feeding molar ratio is 1: (2 to 5) wherein R 1 、R 2 As claimed in claim 10.
13. A compound of the formula (A'),
Figure FDA0003657394620000053
wherein R is 1 、R 2 As claimed in claim 1.
14. A compound of formula (A'):
Figure FDA0003657394620000061
CN202210564647.1A 2021-05-24 2022-05-23 Preparation method of CSF-1R inhibitor or acid salt thereof Pending CN115385897A (en)

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Citations (1)

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Publication number Priority date Publication date Assignee Title
WO2018214867A1 (en) * 2017-05-24 2018-11-29 上海和誉生物医药科技有限公司 N-(azaaryl)cyclolactam-1-carboxamide derivative, preparation method therefor, and use thereof

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WO2018214867A1 (en) * 2017-05-24 2018-11-29 上海和誉生物医药科技有限公司 N-(azaaryl)cyclolactam-1-carboxamide derivative, preparation method therefor, and use thereof

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