CN113754549A - Process for producing aralkylamine compounds and salts thereof - Google Patents
Process for producing aralkylamine compounds and salts thereof Download PDFInfo
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- CN113754549A CN113754549A CN202111052939.9A CN202111052939A CN113754549A CN 113754549 A CN113754549 A CN 113754549A CN 202111052939 A CN202111052939 A CN 202111052939A CN 113754549 A CN113754549 A CN 113754549A
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
Abstract
The present application provides a process for preparing a compound of formula I,wherein: each R is1Independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and alkoxy; r2、R3Each independently selected from alkyl and cycloalkyl; r4Selected from the group consisting of hydrogen, alkyl, cycloalkyl, and alkoxy; and x is an integer selected from 1 to 4; the method comprises the following steps: reacting a compound of formula a with R2NH2Reacting the formate solution to obtain the compound shown in the formula I;wherein each R in formula a1、R3、R4And x is as defined above, R2NH2R in (1)2As defined above.
Description
Technical Field
The application belongs to the field of chemistry, and particularly relates to a preparation method of an aralkyl amine compound and a salt thereof.
Background
The existing synthesis methods of the aralkyl amine compounds and salts thereof mostly adopt metal catalytic hydrogenation reaction or multi-step reaction process, and the impurities are complex and are not easy to remove. The existing synthesis method of the aralkyl amine compound (such as the compound E) comprises the steps of subjecting o-methoxy phenyl acetone and methylamine alcohol solution to noble metal high-pressure catalytic hydrogenation reaction, wherein the reaction commonly uses noble metals such as palladium carbon, platinum oxide and the like, is expensive, requires special high-pressure hydrogenation equipment, remarkably increases the production cost, and has special requirements on production sites. Or the o-methoxy phenyl acetone and the methylamine methanol solution are firstly formed into Schiff base and then reduced by a metal reducing agent. The reaction requires low temperature reaction, and impurities are easily formed and are difficult to remove. And a large amount of hydrogen can be generated in the post-treatment process, so that higher requirements on equipment sites are met. Or monomethylamine gas is introduced into o-methoxyphenyl acetone to synthesize an intermediate o-methoxyphenyl oxime, and sodium borohydride or potassium borohydride is added to reduce the o-methoxyphenyl oxime, wherein the method needs difficult aeration operation, the aeration time is 11-13 hours, the reaction time is long, the reaction process is complex, and the reaction is carried out in multiple steps.
Disclosure of Invention
According to one aspect of the present application, there is provided a process for the preparation of a compound of formula I,
wherein:
each R is1Independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and alkoxy;
R2、R3each independently selected from alkyl and cycloalkyl;
R4selected from the group consisting of hydrogen, alkyl, cycloalkyl, and alkoxy; and
x is an integer selected from 1 to 4;
the method comprises the following steps:
reacting a compound of formula a with R2NH2Reacting the formate solution to obtain the compound shown in the formula I;
wherein each R in formula a1、R3、R4And x is as defined above, R2NH2R in (1)2As defined above.
In another aspect, the application provides a process for preparing the hydrochloride salt of the compound of formula I,
wherein:
each R is1Independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and alkoxy;
R2、R3each independently selected from alkyl and cycloalkyl;
R4selected from the group consisting of hydrogen, alkyl, cycloalkyl, and alkoxy; and
x is an integer selected from 1 to 4;
the process for preparing the hydrochloride salt of the compound of formula I comprises:
preparing a compound of formula I by the above method of preparing a compound of formula I; and
the hydrochloride salt is obtained by adding a hydrogen chloride solution to the compound of formula I obtained.
Drawings
FIG. 1 is a white solid obtained in example 11H-NMR spectrum.
FIG. 2 is an MS spectrum of a white solid product obtained in example 1.
FIG. 3 is an HPLC chromatogram of the white solid product obtained in example 1.
Detailed Description
Detailed Description
Definition of
The following definitions and methods are provided to better define the present application and to guide those of ordinary skill in the art in the practice of the present application. Unless otherwise indicated, terms are to be understood in accordance with their ordinary usage by those of ordinary skill in the relevant art. All patent documents, academic papers, and other publications cited herein are incorporated by reference in their entirety.
The term "alkyl" refers to a straight or branched chain saturated hydrocarbon radical, e.g. C1-8Alkyl radical, C1-6Alkyl radical, C1-4An alkyl group. Examples of the alkyl group include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl) and the like; for example, the term "C1-6Alkyl "refers to an alkyl group containing 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, and the like).
Unless otherwise specified, the term "cycloalkyl" includes any stable monocyclic or polycyclic hydrocarbon group, any carbon atom of which is saturated. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, [2.2.2] bicyclooctane, [4.4.0] bicyclodecane, and the like.
The term "alkoxy" represents an alkyl group as defined above having the specified number of carbon atoms attached through an oxygen bridge, unless otherwise specified, C1-6Alkoxy radicals comprising C1、C2、C3、C4、C5And C6Alkoxy group of (2). Examples of alkoxy groups include, but are not limited to: methoxy, ethoxy, n-methoxyPropoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy and S-pentoxy.
The term "aryl" refers to an all-carbon monocyclic or fused ring having a fully conjugated pi-electron system, having 6 to 18 carbon atoms, preferably 6 to 12 carbon atoms, most preferably 6 to 10 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl.
The term "heteroaryl" refers to a monocyclic or fused ring of 5 to 18 ring atoms, e.g. having 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, the remaining ring atoms being C, and having a completely conjugated pi-electron system. Non-limiting examples of unsubstituted heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazinyl.
The term "C" as used hereinn"means that a given molecule has n carbon atoms, where n is a positive integer, e.g., C1-6It is meant that the number of carbon atoms in a given molecule may be 1, 2, 3, 4, 5 or 6. C1-4It is meant that the number of carbon atoms in a given molecule may be 1, 2, 3 or 4.
Structural unitWherein the substituent R is1The substitution may be made at any one or more of 5 substitution positions on the benzene ring.
The term "strong base" refers to a substance whose anions ionized in aqueous solution are all hydroxide ions, the solution of which has a pH >12 in the standard case (concentration 0.1mol/L) as opposed to a weak base.
The term "strong acid" refers to an acid that is nearly completely ionized in aqueous solution, or understood in the concept of acidity index, and refers to pKaValue of<-1.74 acids. This value is understood to mean that, under standard conditions, the concentration of hydrogen ions is equivalent to the solution concentration after addition of the strong acid.
Where a range of numerical values is recited herein, the range includes the endpoints thereof, and all the individual integers and fractions within the range, and also includes each of the narrower ranges therein formed by all the various possible combinations of those endpoints and internal integers and fractions to form subgroups of the larger group of values within the stated range to the same extent as if each of those narrower ranges were explicitly recited. For example, the reaction temperature of 80-150 ℃ means that the reaction temperature can be 80 ℃, 81 ℃, 82 ℃, 83 ℃, 84 ℃, 85 ℃, 86 ℃, 87 ℃, 88 ℃, 89 ℃, 90 ℃, 91 ℃, 92 ℃, 93 ℃, 94 ℃, 95 ℃, 96 ℃, 97 ℃, 98 ℃, 99 ℃, 100 ℃, 101 ℃, 102 ℃, 103 ℃, 104 ℃, 105 ℃, 106 ℃, 107 ℃, 108 ℃, 109 ℃, 110 ℃, 111 ℃, 112 ℃, 113 ℃, 114 ℃, 115 ℃, 116 ℃, 117 ℃, 118 ℃, 119 ℃, 120 ℃, 121 ℃, 122 ℃, 123 ℃, 124 ℃, 125 ℃, 126 ℃, 127 ℃, 128 ℃, 129 ℃, 130 ℃, 131 ℃, 132 ℃, 133 ℃, 134 ℃, 135 ℃, 136 ℃, 137 ℃, 138 ℃, 139 ℃, 140 ℃, 141 ℃, 142 ℃, 143 ℃, 144 ℃, 145 ℃, 146 ℃, 147 ℃, 148 ℃, 149 ℃, 150 ℃ and the like, and ranges formed by the same.
Detailed description of the embodiments
In one aspect, the application provides a process for preparing a compound of formula I,
wherein:
each R is1Independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and alkoxy;
R2、R3each independently selected from alkyl and cycloalkyl;
R4selected from the group consisting of hydrogen, alkyl, cycloalkyl, and alkoxy; and
x is an integer selected from 1 to 4;
the method comprises the following steps:
a compound of the following formula aAnd R2NH2Reacting the formate solution to obtain the compound shown in the formula I;
wherein each R in formula a1、R3、R4And x is as defined above, R2NH2R in (1)2As defined above.
In some embodiments, each R is1Independently selected from hydrogen, C1-6Alkyl, 3-12 membered cycloalkyl, C6-18Aryl radical, C2-18Heteroaryl group, C1-6An alkoxy group.
In some embodiments, each R is1Independently selected from hydrogen, C1-4Alkyl, 3-10 membered cycloalkyl, C6-12Aryl radical, C2-12Heteroaryl group, C1-4An alkoxy group.
In some embodiments, each R is1Independently selected from hydrogen, C1-4Alkyl, 3-8 membered cycloalkyl, C6-10Aryl radical, C2-10Heteroaryl group, C1-4An alkoxy group.
In some embodiments, each R is1Independently selected from hydrogen, C1-4Alkyl, 3-8 membered cycloalkyl, C6-10Aryl radical, C2-10Heteroaryl group, C1-4An alkoxy group.
In some embodiments, at least one R is1Is an alkoxy group.
In some embodiments, at least one R is1Is methoxy.
In some embodiments, x is 1.
In some embodiments, R2、R3Each independently selected from C1-6Alkyl, 3-12 membered cycloalkyl.
In some embodiments, R2、R3Each independently selected from C1-4Alkyl, 3-10 membered cycloalkyl.
In some embodiments, R2、R3Each of which isIndependently selected from C1-4Alkyl, 3-8 membered cycloalkyl.
In some embodiments, R2And R3Is methyl.
In some embodiments, R4Selected from hydrogen, C1-6Alkyl, 3-12 membered cycloalkyl, C1-6An alkoxy group.
In some embodiments, R4Selected from hydrogen, C1-4Alkyl, 3-10 membered cycloalkyl, C1-4An alkoxy group.
In some embodiments, R4Selected from hydrogen, C1-4Alkyl, 3-8 membered cycloalkyl, C1-4An alkoxy group.
In some embodiments, R4Selected from hydrogen.
In some embodiments, the reaction is of a compound of formula a with R2NH2In a molar ratio of 1: 2.5-6.
In some embodiments, the reaction is performed at a temperature of 80 ℃ to 150 ℃ (e.g., 80 ℃, 81 ℃, 82 ℃, 83 ℃, 84 ℃, 85 ℃, 86 ℃, 87 ℃, 88 ℃, 89 ℃, 90 ℃, 91 ℃, 92 ℃, 93 ℃, 94 ℃, 95 ℃, 96 ℃, 97 ℃, 98 ℃, 99 ℃, 100 ℃, 101 ℃, 102 ℃, 103 ℃, 104 ℃, 105 ℃, 106 ℃, 107 ℃, 108 ℃, 109 ℃, 110 ℃, 111 ℃, 112 ℃, 113 ℃, 114 ℃, 115 ℃, 116 ℃, 117 ℃, 118 ℃, 119 ℃, 120 ℃, 121 ℃, 122 ℃, 123 ℃, 124 ℃, 125 ℃, 126 ℃, 127 ℃, 128 ℃, 129 ℃, 130 ℃, 131 ℃, 132 ℃, 133 ℃, 134 ℃, 135 ℃, 136 ℃, 137 ℃, 139 ℃, 140 ℃, 141 ℃, 142 ℃, 143 ℃, 144 ℃, 145 ℃, 146 ℃, 147 ℃, 148 ℃, 149 ℃, or 150 ℃).
In some embodiments, the reaction time is no more than 8h (e.g., 8h, 7h, 6h, 5h, 4h, 3h, or 2h, etc.), no more than 6h, or no more than 4 h.
In some embodiments, the R is2NH2From the formate solution to R2NH2Formic acid is added to the solution of (1).
In some embodiments, the R is2NH2From the formate solution to R2NH2Formic acid was added to the solution of (1) and then the solvent was removed.
In some embodiments, the formic acid added is anhydrous formic acid.
In some embodiments, the R is2NH2In the formate solution of (2)2NH2The molar ratio of formic acid to formic acid is 0.8-1.2: 1.
in some embodiments, the R is2NH2In the solution of (1) the R2NH2Is 25 wt% to 35 wt% (e.g., 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt%, 30 wt%, 31 wt%, 32 wt%, 33 wt%, 34 wt%, or 35 wt%, etc.).
In some embodiments, the R is2NH2The solvent in the solution of (1) is an alcohol. In some embodiments, the solvent is selected from methanol, ethanol, ethylene glycol, or a combination thereof.
In some embodiments, the method further comprises:
after the reaction, the resultant product is subjected to a heat treatment in the presence of a solvent and a base or an acid.
In some embodiments, the heat treatment is performed at a temperature of 80 ℃ to 120 ℃ (e.g., 80 ℃, 81 ℃, 82 ℃, 83 ℃, 84 ℃, 85 ℃, 86 ℃, 87 ℃, 88 ℃, 89 ℃, 90 ℃, 91 ℃, 92 ℃, 93 ℃, 94 ℃, 95 ℃, 96 ℃, 97 ℃, 98 ℃, 99 ℃, 100 ℃, 101 ℃, 102 ℃, 103 ℃, 104 ℃, 105 ℃, 106 ℃, 107 ℃, 108 ℃, 109 ℃, 110 ℃, 111 ℃, 112 ℃, 113 ℃, 114 ℃, 115 ℃, 116 ℃, 117 ℃, 118 ℃, 119 ℃, or 120 ℃, etc.).
In some embodiments, the resulting product is heat treated in the presence of a solvent and 2 and more molar equivalents of a base or acid.
In some embodiments, the base or acid is a strong base or a strong acid.
In some embodiments, the strong base is selected from sodium hydroxide, potassium carbonate, lithium hydroxide, or combinations thereof.
In some embodiments, the strong acid is selected from sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, or a combination thereof.
In some embodiments, the solvent is selected from ethanol, water, methanol, ethylene glycol, isopropanol, or a combination thereof. In some embodiments, the solvent is a mixed solvent of ethanol and water.
In some embodiments, the solvent is further removed prior to the heat treatment.
In some embodiments, prior to the heat treatment, the solvent is distilled off by reduced pressure at a temperature lower than the temperature of the reaction.
In some embodiments, after the reaction and before the heat treatment, the resulting product is subjected to extraction and solvent separation (e.g., by solvent evaporation). Preferably the pH is adjusted to alkaline before the extraction.
In some embodiments, after the heat treatment, the temperature is reduced to room temperature and purification (e.g., by filtration and/or extraction) is performed.
In some embodiments, concentration is performed after the filtration.
In some embodiments, the pH is adjusted to 9-11 after the concentrating. In some embodiments, the pH is adjusted to 10.
In some embodiments, the conditioning is followed by purification, e.g., extraction.
In some embodiments, the extraction is performed using ethyl acetate.
In some embodiments, the solvent is removed after the extraction, for example by evaporation under reduced pressure.
In another aspect, the application provides a process for preparing the hydrochloride salt of the compound of formula I,
wherein:
each R is1Independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and alkoxy;
R2、R3each independently selected from alkyl and cycloalkyl;
R4selected from the group consisting of hydrogen, alkyl, cycloalkyl, and alkoxy; and
x is an integer selected from 1 to 4;
the process for preparing the hydrochloride salt of the compound of formula I comprises:
preparing a compound of formula I by the above method of preparing a compound of formula I; and
the hydrochloride salt is obtained by adding a hydrogen chloride solution to the compound of formula I obtained.
In some embodiments, the hydrogen chloride solution is a solution of hydrogen chloride in ethyl acetate, dioxane, acetone, or ethanol;
in some embodiments, stirring and filtering are performed after the addition of the hydrogen chloride solution.
specifically, compound E:the preparation method comprises the following steps: reacting (preferably under heating) a methylamine formate solution formed from formic acid and methylamine solution with o-methoxypropiophenone to formThe reaction produces the desired productAnd a small amount of N-formylation product which can be converted into the desired product by heating in a solvent using a base or an acid
The inventions of the present application provide the following advantages:
the method for preparing the aralkyl amine compound is a novel one-pot synthesis method, has the advantages of simple synthesis method, low cost, low equipment requirement, high yield and high yield (the higher yield can be achieved in a short reaction time, such as no more than 4 hours), and is suitable for high-efficiency high-yield industrial production.
The aralkyl amine compound and the salt thereof prepared by the method have high purity (the purity of a crude product HPLC is more than 99.5 percent), contain less impurity types and are easy to separate and purify, a small amount of N-formylation by-products generated can be converted into the required aralkyl amine products by heating treatment in the presence of a solvent and alkali or acid, and simultaneously another reaction by-product CO is converted into the required aralkyl amine product2Is a gas and can be directly discharged without further separation and purification.
Examples
The following examples are for the purpose of illustration only and are not intended to limit the scope of the present application.
Example 1
33 wt% methylamine methanol solution (38.5g, 0.41mol) was weighed, anhydrous formic acid (18.4g, 0.4mol) was added dropwise at room temperature, and after the addition, the solvent was removed under reduced pressure at 60 ℃ until no liquid flowed out. Adding o-methoxypropiophenone (16.4g, 0.1mol) into the rest methylamine formic acid solution, heating to 120 ℃, reacting for 4h, evaporating the solvent at 70 ℃ under reduced pressure, adding 16ml of ethanol and 1.6g of water, adding 10g of sodium hydroxide, heating to 90 ℃, stirring, reacting for 6h, cooling to room temperature, filtering, concentrating at 60 ℃ under reduced pressure, adding 3mol/L hydrochloric acid to adjust the pH to 10, adding 33ml of ethyl acetate for extraction, extracting a water layer with 33ml of ethyl acetate, combining ethyl acetate layers, washing with saturated saline water, drying, and evaporating the solvent at 50 ℃ under reduced pressure to obtain an oily substance. Adding 100ml of self-made 1mol/L ethyl acetate hydrochloride solution, stirring and filtering to obtain 15g of white solid, wherein the HPLC purity is more than 99.5 percent, and the yield is 69.5 percent.1H—NMR(400 MHz,DMSO)δ:1.36(d,3H,CH3);2.74(d,3H,N-CH3);2.83(dd,1H,CH);3.40(m, lH,CH2);3.43(m,lH,CH2);3.83(s,3H,O-CH3);6.87(m,1H,ArH);6.90(m, 1H,ArH);7.20(m,1H,ArH);7.28(m,1H,ArH);9.54(d,2H,NHHCl)。 M+1=180.10。
Example 2:
33 wt% methylamine methanol solution (29.1g, 0.31mol) was weighed, anhydrous formic acid (13.8g, 0.3mol) was added dropwise at room temperature, and after the addition, the solvent was removed under reduced pressure at 60 ℃ until no liquid flowed out. Adding o-methoxypropiophenone (16.4g, 0.1mol) into the rest methylamine formic acid solution, heating to 120 ℃, reacting for 6h, evaporating the solvent at 70 ℃ under reduced pressure, adding 16ml of methanol and 1.6g of water, adding 10g of potassium hydroxide, heating to 90 ℃, stirring, reacting for 4h, cooling to room temperature, filtering, concentrating at 60 ℃ under reduced pressure, adding 3mol/L hydrochloric acid to adjust the pH to 10, adding 33ml of ethyl acetate for extraction, extracting a water layer with 33ml of ethyl acetate, combining ethyl acetate layers, washing with saturated saline water, drying, and evaporating the solvent at 50 ℃ under reduced pressure to obtain an oily substance. Adding 100ml of self-made 1mol/L ethyl acetate hydrochloride solution, stirring and filtering to obtain 14.2g of white solid, wherein the HPLC purity is more than 99.5 percent, and the yield is 65.8 percent.
Example 3:
33 wt% methylamine methanol solution (24.4g, 0.26mol) was weighed, anhydrous formic acid (11.5g, 0.25mol) was added dropwise at room temperature, and after the addition was completed, the solvent was removed under reduced pressure at 60 ℃ until no liquid flowed out. Adding o-methoxypropiophenone (16.4g, 0.1mol) into the rest methylamine formic acid solution, heating to 120 ℃, reacting for 8h, evaporating the solvent at 70 ℃ under reduced pressure, adding 30% sodium hydroxide aqueous solution to adjust the pH value to 10, adding 33ml of ethyl acetate to extract a water layer, extracting with 33ml of ethyl acetate, washing with saturated saline, evaporating the solvent at 50 ℃, adding 15ml of ethanol and 5ml of water, slowly adding 10g of concentrated sulfuric acid, heating to 90 ℃, stirring for reacting for 10h, cooling to room temperature, adjusting the pH value to 9 with 10% sodium hydroxide, extracting twice with 33ml of ethyl acetate, drying with anhydrous sodium sulfate, adding 33ml of self-made 3mol/L ethyl acetate hydrochloride solution, stirring, filtering to obtain 13.8g of white solid, wherein the HPLC purity is more than 99.5%, and the yield is 63.9%.
The present application has been described in detail with respect to the general description and the specific embodiments, but it will be apparent to those skilled in the art that some modifications or improvements may be made on the basis of the present application, and any combination may be made as necessary. Accordingly, such modifications and improvements are intended to be within the scope of this invention as claimed.
Claims (10)
1. A process for the preparation of a compound of formula I,
wherein:
each R is1Independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and alkoxy;
R2、R3each independently selected from alkyl and cycloalkyl;
R4selected from the group consisting of hydrogen, alkyl, cycloalkyl, and alkoxy; and
x is an integer selected from 1, 2, 3 and 4;
the method comprises the following steps:
reacting a compound of formula a with R2NH2Reacting the formate solution to obtain the compound shown in the formula I;
wherein each R in formula a1、R3、R4And x is as defined above, R2NH2R in (1)2As defined above.
2. The method of claim 1, wherein:
each R is1Independently selected from hydrogen, C1-6Alkyl, 3-12 membered cycloalkyl, C6-18Aryl radical, C2-18Heteroaryl group, C1-6An alkoxy group; or
Each R is1Independently selected from hydrogen, C1-4Alkyl, 3-10 membered cycloalkyl, C6-12Aryl radical, C2-12Heteroaryl group, C1-4An alkoxy group; or
Each R is1Independently selected from hydrogen, C1-4Alkyl, 3-8 membered cycloalkyl, C6-10Aryl radical, C2-10Heteroaryl group, C1-4An alkoxy group; or
Each R is1Independently selected from hydrogen, C1-4Alkyl, 3-8 membered cycloalkyl, C6-10Aryl radical, C2-10Heteroaryl group, C1-4An alkoxy group.
3. The method of claim 1 or 2, wherein:
at least one R1Is an alkoxy group; or
At least one R1Is methoxy; or
x is 1.
4. The method of any one of claims 1 to 3, wherein:
R2、R3each independently selected from C1-6Alkyl, 3-12 membered cycloalkyl; or
R2、R3Each independently selected from C1-4Alkyl, 3-10 membered cycloalkyl; or
R2、R3Each independently selected from C1-4Alkyl, 3-8 membered cycloalkyl; or
R2And R3Is methyl.
5. The method of any one of claims 1 to 4, wherein:
R4selected from hydrogen, C1-6Alkyl, 3-12 membered cycloalkyl, C1-6An alkoxy group; or
R4Selected from hydrogen, C1-4Alkyl, 3-10 membered cycloalkyl, C1-4An alkoxy group; or
R4Selected from hydrogen, C1-4Alkyl, 3-8 membered cycloalkyl, C1-4An alkoxy group; or
R4Selected from hydrogen.
6. The method of any one of claims 1 to 5, wherein:
in the reaction, a compound of formula a and R2NH2In a molar ratio of 1: 2.5-6;
the reaction is carried out at a temperature of 80 ℃ to 150 ℃; or
The reaction time is not more than 8h, not more than 6h or not more than 4 h; or
The R is2NH2From the formate solution to R2NH2Adding formic acid to the solution of (1); or
The R is2NH2From the formate solution to R2NH2Adding formic acid to the solution of (1) and removing the solvent to form; or
Preferably, the formic acid added is anhydrous formic acid;
preferably, said R is2NH2In the formate solution of (2)2NH2The molar ratio of formic acid to formic acid is 0.8-1.2: 1;
preferably, said R is2NH2In the solution of (1) the R2NH2The concentration of (A) is 25 wt% -35 wt%;
preferably, said R is2NH2The solvent in the solution of (a) is alcohol or water; more preferably, the solvent is selected from methanol, ethanol, ethylene glycol, water, or a combination thereof.
7. The method of any one of claims 1 to 6, further comprising:
after the reaction, subjecting the resultant product to a heat treatment in the presence of a solvent and a base or an acid;
preferably, the heat treatment is carried out at a temperature of 80 ℃ to 120 ℃;
preferably, the resulting product is subjected to heat treatment in the presence of a solvent and 2 times or more molar equivalent of a base or an acid;
preferably, the base or acid is a strong base or acid;
preferably, the strong base is selected from sodium hydroxide, potassium carbonate, lithium hydroxide, or combinations thereof;
preferably, the strong acid is selected from sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, or a combination thereof;
preferably, the solvent is selected from ethanol, water, methanol, ethylene glycol, isopropanol, or a combination thereof.
8. The method of claim 7, wherein:
further removing the solvent before the heat treatment; preferably, the solvent is distilled off at a temperature lower than the reaction temperature by reduced pressure; and/or
After the heat treatment, the temperature was lowered to room temperature and purified.
9. A process for preparing the hydrochloride salt of the compound of formula I,
wherein:
each R is1Independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and alkoxy;
R2、R3each independently selected from alkyl and cycloalkyl;
R4selected from the group consisting of hydrogen, alkyl, cycloalkyl, and alkoxy; and
x is an integer selected from 1 to 4;
the process for preparing the hydrochloride salt of the compound of formula I comprises:
preparing a compound of formula I by a process for preparing a compound of formula I as claimed in any one of claims 1 to 8; and
adding a hydrogen chloride solution to the obtained compound of formula I to obtain the hydrochloride;
preferably, the hydrogen chloride solution is a solution of hydrogen chloride in ethyl acetate, dioxane, acetone or ethanol;
preferably, after the addition of the hydrogen chloride solution, stirring and filtration are carried out.
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