CN112661668A - N-substituted amide compound and preparation method thereof - Google Patents
N-substituted amide compound and preparation method thereof Download PDFInfo
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Abstract
The invention relates to the field of intermediate synthesis, and discloses an N-substituted amide compound and a preparation method thereof1Is selected from C1‑6At least one of alkyl, phenyl and phenyl substituted by substituent X, wherein X is selected from C1‑6Alkyl radical, C1‑6At least one of alkoxy and halogen, R2、R3、R4、R5、R6Each independently selected from C1‑6Alkyl radical, C1‑6When the N-substituted amide compound provided by the invention is used for preparing the compound shown in the formula (III), the N-substituted amide compound has the advantages of low raw material cost, mild reaction, high yield and high hydrolysis safety.
Description
Technical Field
The invention relates to an N-substituted amide compound and a method for preparing the N-substituted amide compound shown in a formula (I).
Background
At present, the general method for synthesizing 2- (4-chlorophenoxy) -propoxyamine is to firstly use ketoxime, ketoxime derivatives, N-hydroxyphthalimide and derivatives thereof and other groups for protection, and then carry out deprotection to obtain the compound. The method is described in detail in Tetrahedron Letters,1988, Vol.29,701-704 and J.org.chem.2005,70, 6303-; the above-described method for synthesizing 2- (4-chlorophenoxy) -propoxyamine is also used for synthesizing such intermediates in patents such as Pasteur CN1055459C, TW232646B, etc. This method also has its drawbacks: the reaction raw materials involved in the whole synthesis process are expensive, the reaction yield is low, and hydrazine compounds and other compounds must be applied in the deprotection process, so the reaction safety is poor.
Disclosure of Invention
The invention aims to solve the problems of low yield and poor reaction safety in the preparation of 2- (4-chlorophenoxy) -propoxide in the prior art.
In order to achieve the above object, a first aspect of the present invention provides an N-substituted amide compound having a structure represented by formula (I),
in the formula (I), R1Is selected from C1-6At least one of alkyl, phenyl and phenyl substituted by substituent X, wherein X is selected from C1-6Alkyl radical, C1-6At least one of alkoxy and halogen, R2、R3、R4、R5、R6Each independently selected from C1-6Alkyl radical, C1-6At least one of alkoxy, halogen and H.
In a second aspect, the present invention provides a process for producing an N-substituted amide compound represented by the formula (I), which comprises: carrying out contact reaction on the compound shown in the formula (II-1) and the compound shown in the formula (II-2);
wherein R is1、R2、R3、R4、R5、R6Are as defined above;
R7is selected from C1-6Alkyl, phenyl, substituted by X1At least one of substituted phenyl, said X1Is selected from C1-6Alkyl radical, C1-6At least one of alkoxy and halogen.
In a third aspect, the invention provides the use of an N-substituted amide compound represented by the formula (I) in the preparation of a compound represented by the formula (III),
when the N-substituted amide compound provided by the invention is used for preparing 2- (4-chlorophenoxy) -propoxylamine shown in a formula (III), the N-substituted amide compound has the advantages of low raw material cost, mild reaction, high yield and high hydrolysis safety, and is suitable for industrial production.
Detailed Description
The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value, and such ranges or values should be understood to encompass values close to those ranges or values. For ranges of values, between the endpoints of each of the ranges and the individual points, and between the individual points may be combined with each other to give one or more new ranges of values, and these ranges of values should be considered as specifically disclosed herein.
In bookIn the invention, "C1-6The alkyl group of (1) represents an alkyl group having 1 to 6 carbon atoms in total, and includes a linear alkyl group, a branched alkyl group or a cyclic alkyl group, and may be, for example, a linear alkyl group, a branched alkyl group or a cyclic alkyl group having 1, 2, 3, 4, 5, 6 carbon atoms in total, and may be, for example, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a tert-butyl group, a n-pentyl group, an isopentyl group, a n-hexyl group, a cyclopropyl group, a methylcyclopropyl group, an ethylcyclopropyl group. For "C1-4The "alkyl group" has a similar explanation except that the number of carbon atoms is different.
“C1-6The "alkoxy group" of (a) represents an alkoxy group having 1 to 6 carbon atoms in total, and includes a linear alkoxy group, a branched alkoxy group or an epoxyalkyl group, and may be, for example, a linear alkoxy group, a branched alkoxy group or a cycloalkyl group having 1, 2, 3, 4, 5, 6 carbon atoms in total, and may be, for example, a methoxy group, an ethoxy group, an n-propyl group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a tert-butoxy group, an n-pentyloxy group, an isopentyloxy group. For "C1-6The "alkoxy group" of (1) has a similar explanation except that the number of carbon atoms is different.
In the present invention, the N-substituted amide compound is a racemic body unless otherwise specified.
As described above, the first aspect of the present invention provides an N-substituted amide compound having a structure represented by the formula (I),
in the formula (I), R1Is selected from C1-6At least one of alkyl, phenyl and phenyl substituted by substituent X, wherein X is selected from C1-6Alkyl radical, C1-6At least one of alkoxy and halogen, R2、R3、R4、R5、R6Each independently selected from C1-6Alkyl radical, C1-6At least one of alkoxy, halogen and H.
Preferably, inIn the formula (I), R1Is selected from C1-4At least one of alkyl, phenyl and phenyl substituted by substituent X, wherein X is selected from C1-4Alkyl radical, C1-4At least one of alkoxy, F, Cl, Br and I, R2、R3、R4、R5、R6Each independently selected from C1-4Alkyl radical, C1-6At least one of alkoxy, F, Cl, Br, I and H.
More preferably, in formula (I), R1At least one selected from methyl, ethyl, propyl, n-butyl, tert-butyl, methoxy, ethoxy and phenyl, R2、R3、R4、R5、R6Each independently selected from at least one of F, Cl, Br, I, H, methyl and ethyl.
Particularly preferably, the N-substituted amide compound is selected from the following compounds:
compound a 1;
compound a 2:
compound a 3:
compound a 4;
compound a 5:
compound a 6:
compound a 7:
compound a 8:
compound a 9:
compound a 10:
compound a 11:
compound a 12:
the preparation method of the compound with the general structure shown in formula (I) is not particularly limited, and one skilled in the art can determine a suitable synthetic method according to the structural formula of the compound provided by the invention and the preparation method of the preparation example.
Further, some preparation methods of the compounds are exemplarily given in the preparation examples of the present invention, and those skilled in the art can obtain the compounds provided by the present invention according to the preparation methods of these exemplary preparation examples. The present invention will not be described in detail herein with respect to specific methods of preparing the various compounds of the present invention, which should not be construed as limiting the invention to those skilled in the art.
However, in order to obtain N-substituted amide compounds represented by formula (I) in higher yield and higher purity, the present invention provides a preferred embodiment to prepare N-substituted amide compounds represented by formula (I). As described above, the second aspect of the present invention provides a process for producing an N-substituted amide compound represented by the formula (I), which comprises: carrying out contact reaction on the compound shown in the formula (II-1) and the compound shown in the formula (II-2);
wherein R is1、R2、R3、R4、R5、R6Are as defined above;
R7is selected from C1-6Alkyl, phenyl, substituted by X1At least one of substituted phenyl, said X1Is selected from C1-6Alkyl radical, C1-6At least one of alkoxy and halogen.
Preferably, said R is7At least one selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, tert-butyl, methoxy, ethoxy, and phenyl.
Preferably, the contact reaction is carried out in the presence of a solvent I and an acid-binding agent I.
Preferably, the acid-binding agent I is at least one selected from potassium carbonate, sodium methoxide, sodium hydroxide, potassium hydroxide, sodium hydride, sodium tert-butoxide and sodium isopropoxide.
Preferably, the solvent I is at least one selected from benzene, toluene, xylene, dichloromethane, dichloroethane, N-dimethylformamide, N-hydroxypyrrolidone, 1, 3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, tetrahydrofuran and acetonitrile.
Preferably, the conditions of the contact reaction at least satisfy: the temperature is 20-150 ℃.
Preferably, the compound shown in the formula (II-1), the compound shown in the formula (II-2) and the acid-binding agent I are used in a molar ratio of 1: (1-10): (1-10).
It should be noted that the present invention is not limited to the amount of the solvent, and the amount of the solvent is provided as an example hereinafter, and the person skilled in the art should not be construed as limiting the present invention.
In the second aspect of the present invention and the following N-substituted amide compounds having the structure shown in formula (I), the substituents are the same as those of the N-substituted amide compounds in the first aspect of the present invention, and in order to avoid repetition, detailed descriptions of specific types of the N-substituted amide compounds are omitted herein, and those skilled in the art should not be construed as limiting the present invention.
The preparation method of the present invention may further include a necessary post-treatment step to remove, for example, impurities or unreacted raw materials, the present invention has no particular requirement on the specific operation of the post-treatment step, and a person skilled in the art may perform the post-treatment by using various operations (for example, extraction, washing, drying, etc.) which are conventional in the art, and the present invention will not be described in detail herein, and the person skilled in the art should not be construed as limiting the present invention.
The method of the present invention is not particularly limited with respect to the source of the compound represented by the formula (II-1) and the compound represented by the formula (II-2), and the compounds can be obtained commercially, for example, or can be synthesized by selecting a synthetic method known in the art according to the difference in substituents.
As described above, the third aspect of the present invention provides the use of an N-substituted amide compound represented by the aforementioned formula (I) for producing a compound represented by the formula (III),
the present invention will be described in detail below by way of examples. The reagents in the following examples are all commercially available analytical pure products unless otherwise specified.
In the following examples, the room temperature or the normal temperature is 25. + -. 1 ℃ unless otherwise specified.
In the following examples, the content of the product was determined by liquid chromatography.
2- (4-chloro-phenoxy) -propanol, prepared as follows:
adding p-chlorophenol (0.515mol), potassium carbonate (0.5mol) and petroleum ether (500ml) into a reaction bottle for refluxing and water diversion, reacting for 30min, dropwise adding methyl chloropropionate (0.5mol), after dropwise adding, continuously refluxing and water diversion for 12h at 65 ℃, adding water (100ml) after HPLC (high performance liquid chromatography) detects that the methyl chloropropionate is basically unchanged, stirring, standing for layering, washing an organic phase with water twice, and removing the petroleum ether under reduced pressure to obtain the 2- (4-chloro-phenoxy) -methyl propionate.
Adding sodium borohydride (1mol), anhydrous calcium chloride (0.05mol), toluene (500ml) and ethanol (500ml) into a reaction bottle, uniformly mixing, continuously dropwise adding the prepared 2- (4-chloro-phenoxy) -methyl propionate (0.5mol), reacting for 4h at 30 ℃ after dropwise adding, performing hydrolysis reaction by adding 20 wt% ammonium chloride aqueous solution (1mol calculated by pure substances) after HPLC detects that the content of the 2-p-chlorophenoxymethyl propionate is less than 1 wt%, standing for layering after reaction, extracting twice by using toluene, combining organic phases, and removing a solvent to obtain the 2- (4-chlorophenoxy) -1-propanol with the yield of 95% and the chemical purity of 94%.
Methanesulfonyl chloride: chemical purity > 98%, purchased from chemical reagents of national drug group, ltd.
Preparation example 1: preparation of a Compound represented by the formula (II-1-1)
Formula (II-1-1):
adding 2- (4-chloro-phenoxy) -propanol (0.5mol) shown in formula (II-3), triethylamine (0.85mol) and toluene (500ml) into a reaction bottle, dropwise adding methanesulfonyl chloride (0.6mol) shown in formula (II-4), reacting for 3h at 30 ℃ after dropwise adding, adding water, stirring and layering after HPLC (high performance liquid chromatography) detects that the content of 2- (4-chloro-phenoxy) -propanol shown in formula (II-3) is less than 1 wt%, and removing toluene from an organic phase to obtain the compound shown in formula (II-1-1).
Preparation example 2: preparation of Compound a1
Compound a 1:
formula (II-2-1):
adding a compound (0.5mol) shown in a formula (II-1-1), a compound (0.85mol) shown in a formula (II-2-1) and DMSO (600ml) into a reaction bottle, stirring and dissolving, adding sodium hydroxide (2mol), reacting for 12h at 60 ℃, detecting that the compound shown in the formula (II-1-1) is basically unchanged by HPLC, distilling and removing the DMSO, dissolving the residual organic phase in the bottle by water, extracting for three times by using dichloromethane, and removing the dichloromethane to obtain a compound a 1.
The characterization data for specific yields and substituent profiles are in part as follows:
compound a1 yield-moles of compound a 1/moles of 2- (4-chloro-phenoxy) -propanol yield of other compounds was calculated similarly to compound a 1.
The following compounds were obtained in a similar manner to preparation 1 and preparation 2 (starting material replacement) and were characterized as follows:
compound a 1;
the yield thereof is 80.07 percent,1H NMR(400MHz,CDCl3)δ7.42–7.23(m,2H),6.99–6.79(m,2H),4.66–4.45(m,1H),4.61(s,1H),3.80(d,J＝5.6Hz,2H),2.02(s,3H),1.31(d,J＝6.4Hz,3H)。
compound a 2:
the yield thereof is 78.13 percent,1H NMR(400MHz,CDCl3)δ7.34–7.29(m,2H),6.90–6.83(m,2H),4.62–4.55(m,1H),4.35(s,1H),3.80(d,J＝5.6Hz,2H),2.34(q,J＝7.6Hz,2H),1.31(d,J＝6.4Hz,3H),1.12(t,J＝8.0Hz,3H)。
compound a 7:
the yield is 75.01 percent,1H NMR(400MHz,CDCl3δ7.94–7.90(m,2H),7.61–7.54(m,1H),7.51–7.44(m,2H),7.32–7.27(m,2H),6.90–6.84(m,2H),4.74(s,1H),4.66–4.52(m,1H),3.86(d,J＝5.6Hz,2H),1.32(d,J＝6.4Hz,3H)。
compound a 10:
the yield is 73.12 percent,1H NMR(400MHz,CDCl3)δ7.80–7.76(m,2H),7.32–7.28(m,2H),7.28–7.24(m,2H),6.89–6.85(m,2H),4.97(s,1H),4.66–4.54(m,1H),3.86(d,J＝5.6Hz,2H),2.42(s,3H),1.32(d,J＝6.4Hz,3H)。
example 1: preparing the compound shown in the formula (III).
Taking a compound (0.5mol) shown in a formula (I) shown in a table 1 as a raw material, adding the compound and ethanol (1mol) into a reaction bottle, dropwise adding 30 wt% of hydrochloric acid (calculated by hydrogen ions, 1mol), reacting for 2h at 30 ℃, removing ethanol in a system after detecting that the content of the compound shown in the formula (I) is less than 1 wt% by HPLC (high performance liquid chromatography), adding 30 wt% of sodium hydroxide solution to adjust the pH value to 14, extracting twice by using dichloromethane, removing the dichloromethane to obtain a compound shown in a formula (III), and calculating the yield of the compound shown in the formula (III), wherein the specific result is shown in the table 1.
Comparative example 1
Synthesizing a compound represented by the formula (IV): (Compound B1)
The compound represented by the formula (II-1-1) (0.5mol) prepared in the preparation example 1, N-hydroxyphthalimide (0.65mol) and DMF (600ml) were added to a reaction flask, stirred to dissolve, potassium carbonate (1mol) was added, the reaction was carried out at 80 ℃ for 12 hours, after detecting by HPLC that the compound represented by the formula (II-1-1) was almost unchanged, DMF was distilled off, the organic phase remaining in the flask was dissolved in water, extracted three times with dichloromethane, and dichloromethane was removed to obtain the compound represented by the formula (IV).
Synthesis of a Compound of formula (III)
The compound represented by the formula (IV) prepared as described above was used as a raw material (0.5mol), hydrazine hydrate (1mol) and methylene chloride (600ml) were charged into a reaction flask, and reacted at 60 ℃ for 8 hours, after detecting the content of the compound represented by the formula (IV) by HPLC to be less than 1 wt%, the suspended matter was filtered, the methylene chloride was removed to obtain the compound represented by the formula (III), and the yield of the compound represented by the formula (III) was calculated, and the specific results are shown in table 1.
The yield of the compound represented by formula (III) in table 1 is ═ moles of the compound represented by formula (III)/moles of the raw material in table 1;
the chemical purity of the compound represented by the formula (III) in table 1 is the content of the compound represented by the formula (III) in the obtained product as a pure substance.
TABLE 1
As can be seen from the results in table 1, the compound represented by formula (III) prepared from the compound of the present invention was obtained in high yield.
The preferred embodiments of the present invention have been described above in detail, but the present invention is not limited thereto. Within the scope of the technical idea of the invention, many simple modifications can be made to the technical solution of the invention, including combinations of various technical features in any other suitable way, and these simple modifications and combinations should also be regarded as the disclosure of the invention, and all fall within the scope of the invention.
Claims (9)
1. An N-substituted amide compound, which is characterized in that the compound has a structure shown in a formula (I),
in the formula (I), R1Is selected from C1-6At least one of alkyl, phenyl and phenyl substituted by substituent X, wherein X is selected from C1-6Alkyl radical, C1-6At least one of alkoxy and halogen, R2、R3、R4、R5、R6Each independently selected from C1-6Alkyl radical, C1-6At least one of alkoxy, halogen and H.
2. A compound according to claim 1, wherein, in formula (I), R1Is selected from C1-4At least one of alkyl, phenyl and phenyl substituted by substituent X, wherein X is selected from C1-4Alkyl radical, C1-6At least one of alkoxy, F, Cl, Br and I, R2、R3、R4、R5、R6Each independently selected from C1-6Alkyl radical, C1-6At least one of alkoxy, F, Cl, Br, I and H.
3. A compound according to claim 1, wherein, in formula (I), R1At least one selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, phenyl and benzyl, R2、R3、R4、R5、R6Each independently selected from at least one of F, Cl, Br, I, H, methyl and ethyl.
4. The compound of claim 1, wherein the N-substituted amide compound is selected from any one of the following compounds:
compound a 1;
compound a 2:
compound a 3:
compound a 4;
compound a 5:
compound a 6:
compound a 7:
compound a 8:
compound a 9:
compound a 10:
compound a 11:
compound a 12:
5. a process for producing an N-substituted amide compound represented by the formula (I) as claimed in any one of claims 1 to 4, which comprises: carrying out contact reaction on the compound shown in the formula (II-1) and the compound shown in the formula (II-2);
wherein R is1、R2、R3、R4、R5、R6Is as defined in any one of claims 1 to 4;
R7is selected from C1-6Alkyl, phenyl, substituted by X1At least one of substituted phenyl, said X1Is selected from C1-6Alkyl radical, C1-6At least one of alkoxy and halogen.
6. The process of claim 5, wherein the contacting reaction is carried out in the presence of a solvent I and an acid scavenger I.
7. The method of claim 6, wherein the acid scavenger I is selected from at least one of potassium carbonate, sodium methoxide, sodium hydroxide, potassium hydroxide, sodium hydride, sodium tert-butoxide, sodium isopropoxide;
preferably, the solvent I is at least one selected from benzene, toluene, xylene, dichloromethane, dichloroethane, N-dimethylformamide, N-hydroxypyrrolidone, 1, 3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, tetrahydrofuran and acetonitrile.
8. The method according to any one of claims 5 to 7, wherein the conditions of the contact reaction at least satisfy: the temperature is 20-150 ℃.
9. The method of claim 6, wherein the compound of formula (II-1), the compound of formula (II-2), and the acid scavenger I are used in a molar ratio of 1: (1-10): (1-10).
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| CN114989142A (en) * | 2022-05-09 | 2022-09-02 | 沈阳万菱生物技术有限公司 | Preparation method of pyrazole compound |
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| CN1245487A (en) * | 1997-01-03 | 2000-02-23 | 巴斯福股份公司 | 3-aminocarbonyl/1-aminothiocarbonyl-substituted 2-benzoyl-cyclohexan-1,3-diones with herbicidal effect |
| CN101983191A (en) * | 2008-02-01 | 2011-03-02 | 武田药品工业株式会社 | Oxim derivatives as hsp90 inhibitors |
| CN103467470A (en) * | 2013-09-11 | 2013-12-25 | 中国科学院化学研究所 | Ocycloimino sugar compound and intermediate, medicament, preparation method and application thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1245487A (en) * | 1997-01-03 | 2000-02-23 | 巴斯福股份公司 | 3-aminocarbonyl/1-aminothiocarbonyl-substituted 2-benzoyl-cyclohexan-1,3-diones with herbicidal effect |
| CN101983191A (en) * | 2008-02-01 | 2011-03-02 | 武田药品工业株式会社 | Oxim derivatives as hsp90 inhibitors |
| CN103467470A (en) * | 2013-09-11 | 2013-12-25 | 中国科学院化学研究所 | Ocycloimino sugar compound and intermediate, medicament, preparation method and application thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114989142A (en) * | 2022-05-09 | 2022-09-02 | 沈阳万菱生物技术有限公司 | Preparation method of pyrazole compound |
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