CN118271361A - Preparation method of phosphoric amino acid - Google Patents
Preparation method of phosphoric amino acid Download PDFInfo
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- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
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- C07F9/3882—Arylalkanephosphonic acids
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Abstract
The invention provides a preparation method of a phosphoamino acid. The method comprises the following steps: mixing PMP-S with a first solvent, adding acyl chloride under the environmental condition, heating for reaction overnight, and removing at least part of acyl chloride by rotary evaporation after the reaction is finished to obtain PMP-1; mixing PMP-1, a second solvent and alkali, dropwise adding acetyl chloride, performing rotary evaporation after the reaction to remove the second solvent, extracting by adopting a first extractant, adding water for washing, and performing rotary evaporation to obtain PMP-2; mixing PMP-2 with a third solvent, an initiator and a halogenated reagent, extracting by adopting a second extractant after the reaction is completed, adding water to obtain a second organic phase, and adding a first organic solvent to crystallize after rotary evaporation to obtain PMP-3; mixing PMP-3 with phosphate, performing reduced pressure distillation after reaction, and adding a second organic solvent for recrystallization to obtain PMP-4; and mixing PMP-4 with an acid aqueous solution, cooling after the reaction is finished, washing for three times, steaming the obtained aqueous phase in a rotary way, and adding a compound solvent for crystallization to obtain the phosphoric amino acid.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of a phosphoric acid amino acid.
Background
Tyrosine phosphorylation serves as a critical mechanism for cells to control a variety of biological processes. However, the dynamic interconversion of protein phosphorylation and dephosphorylation subtypes and the phosphorylation of multiple sites often complicate the study of the effects of individual phosphorylation events, whereas site-specific phosphorylated proteins greatly facilitate the study of the mechanisms of such post-translational modifications. There is still a lack of reliable methods for producing single phosphorylated protein subtypes, and modifications of in situ or engineered kinases to specific tyrosine residues lack selectivity, while such modifications are subject to relatively non-selective removal of phosphatases in cells. Semi-synthetic methods allow specific introduction of pTyr residues into proteins; however, the application of this approach to large proteins is limited by the complexity of synthesis and difficulty in protein renaturation. None of these methods described above achieve site-specific tyrosine phosphorylation in living cells. Therefore, they have no potential for use in the study of the important biochemical process of post-translational modification in organisms.
Previous studies have shown that modification of the phenolic hydroxyl group of phosphorylated tyrosine to a methylene structure can chemically stabilize the phosphate at the phosphorylated tyrosine site while retaining its protein bioactivity. Coli can use the cognate orthogonal amber suppressor tRNA-aminoacyl-tRNA synthetase (aaRS) pair to incorporate non-hydrolyzable phosphorylated analogs into proteins, and PMP (2-amino-3- (4- (phosphonomethyl) phenyl) propionic acid, 2-amino-3- (4- (phosphonomethyl) phenyl) propanoic acid) can meet this need very well. The use of chemically synthesized PMPs for protein expression would therefore provide a powerful tool for the study of site-specific phosphotyrosine-containing protein function.
For this reason, researchers have made various attempts: boc-DL-PMP (4-phosphomethyl-L-phenalanine, 4-phosphinomethyl-L-phenylalanine) was prepared from alpha, alpha' -dibromoxylene in 1992 by Mark Cushman and Eung-Seok Lee, and the isomers were separated by enzymatic hydrolysis. The method uses an asymmetric synthesis method to synthesize the t-boc-p-dimethyl phosphomethylene-L-phenylalanine as a key element, but the synthesis steps are complicated, diastereomer mixtures appear in the synthesis process, and the purification steps are more and more complicated. Fmoc-L-PMP (tBuO) 2 -OH was prepared by an asymmetric synthetic route using camphorine as a chiral auxiliary in E Larsson and B L u ning in 1996. Chiral reagents are not readily available in this synthetic scheme and impurities which are difficult to purify appear during the synthesis, which limits the applicability of the asymmetric synthesis method. In 1999 Liu Bo and Zhan Gurong, commercially available L-phenylalanine and D-phenylalanine were used as raw materials to synthesize N-Fmoc-4- (phosphomethylethyl) L-phenylalanine and N-Fmoc-D-phenylalanine simply and efficiently. However, the chloromethyl methyl ether chloride used in the first step of the synthesis scheme is extremely toxic, and the synthesis scheme still needs to be optimized in view of the health of the synthesis personnel and environmental friendliness. There is an urgent need in the art to develop a simple, easy, safe (avoiding the use of toxic raw materials) PMP preparation method.
Disclosure of Invention
In order to achieve the above object, the present invention provides a method for producing a phosphoric acid-based amino acid, comprising the steps of:
Step a), adding a compound PMP-S into a first reaction bottle, adding a first solvent, adding acyl chloride under the environmental condition, heating for reaction overnight, and removing at least part of acyl chloride by rotary evaporation after the reaction is finished to obtain a compound PMP-1; wherein the compound PMP-S has a structure shown in a formula (I):
The compound PMP-1 has a structure shown in a formula (II):
Step b), adding the compound PMP-1, a second solvent and alkali into a second reaction bottle, dropwise adding acetyl chloride, performing rotary evaporation after the reaction is finished to remove the second solvent, extracting by adopting a first extractant, washing by adding water, and performing rotary evaporation on a first organic phase to obtain the compound PMP-2; wherein the compound PMP-2 has a structure shown in a formula (III):
Step c), adding the compound PMP-2 into a third reaction bottle, adding a third solvent, an initiator and a halogenated reagent, extracting by adopting a second extractant after the reaction is completed, adding water for washing to obtain a second organic phase, and adding a first organic solvent for crystallization after rotary evaporation of the second organic phase to obtain the compound PMP-3; wherein the compound PMP-3 has a structure shown in formula (IV):
Step d), adding the compound PMP-3 into a fourth reaction bottle, adding phosphate, performing reduced pressure distillation after the reaction, and adding a second organic solvent for recrystallization to obtain a compound PMP-4; wherein the compound PMP-4 has a structure represented by formula (V):
Step e), adding the compound PMP-4 into a fifth reaction bottle, adding an acid aqueous solution, cooling to 20-25 ℃ after the reaction is finished, adopting a third extractant to wash for three times, rotationally evaporating the obtained aqueous phase, and adding a compound solvent for crystallization to obtain the phosphate amino acid; the phosphoamino acid has a chemical structure represented by formula (VI):
Further, in step a), the first solvent is a C 1～C24 alkyl alcohol, preferably methanol and/or ethanol; the acyl chloride is thionyl chloride and/or oxalyl chloride, preferably thionyl chloride; the reaction temperature in step a) is from 0 to 200℃and preferably from 60 to 100 ℃.
Further, in step b), the second solvent is one or more of dichloromethane, dichloroethane, tetrahydrofuran, dimethyltetrahydrofuran, dioxane, preferably tetrahydrofuran; the base is one or more of triethylamine, dimethylamine, diisopropylethylamine, N-methylmorpholine and imidazole, preferably triethylamine; the reaction temperature in step b) is from-70 to 100℃and preferably from 0 to 5 ℃.
Further, in step c), the third solvent is one or more of dimethylformamide, dimethylacetamide, dichloroethane, tetrahydrofuran, dimethyltetrahydrofuran, dioxane, acetonitrile, toluene, preferably acetonitrile; the initiator is one or more of benzoyl peroxide, lauroyl peroxide, cumene hydroperoxide, tert-butyl peroxybenzoate, tert-butyl peroxyvalerate, diisopropyl peroxydicarbonate, dicyclohexyl peroxydicarbonate, azodiisobutyronitrile, azodiisoheptonitrile, potassium persulfate, sodium persulfate and ammonium persulfate, preferably azodiisobutyronitrile; the halogenating agent is one or more of N-chlorosuccinimide, N-bromosuccinimide and N-iodosuccinimide, preferably N-bromosuccinimide; the first organic solvent is selected from one or more of methyl tertiary butyl ether, diethyl ether, dipropyl ether, ethylbutyl ether, diisopropyl ether, dipentyl ether and dihexyl ether, preferably methyl tertiary butyl ether; the reaction temperature in step c) is from 0 to 200℃and preferably from 60 to 100 ℃.
Further, in step d), the phosphate is one or more of trimethyl phosphite, triethyl phosphite, primary phosphate, secondary phosphate and tertiary phosphate, preferably triethyl phosphite; the reaction temperature in step d) is from 0 to 200 ℃, preferably from 120 to 150 ℃; the second organic solvent is one or more of dimethylformamide, dichloroethane, tetrahydrofuran, dimethyl tetrahydrofuran, dioxane, acetonitrile, toluene, ethanol and ethyl acetate, preferably ethyl acetate.
Further, in the step e), the acid aqueous solution is one or more of sulfuric acid solution, hydrochloric acid solution and nitric acid solution, preferably hydrochloric acid solution; the reaction temperature in step e) is from 0 to 200 ℃, preferably from 150 to 200 ℃; the compound solvent is two or more of dimethylformamide, dimethylacetamide, dichloroethane, methanol, ethanol, tetrahydrofuran, dimethyltetrahydrofuran, dioxane, acetonitrile, toluene, n-heptane, n-hexane, diisopropyl ether, diethyl ether, isopropyl ether, petroleum ether and methyl tertiary butyl ether, preferably a mixture of ethanol and diisopropyl ether.
Further, the first extractant, the second extractant, and the third extractant are each independently selected from one or more of the group consisting of ethyl acetate, ethyl formate, methyl acetate, amyl acetate, butyl acetate, methylene chloride, and chloroform.
Aiming at the defects of the prior art, the invention provides a preparation method of the phosphoric acid amino acid, and by applying the technical scheme of the invention, the use of a highly toxic compound (chloromethyl methyl ether chloride) is avoided, and the total yield is 66%, which is obviously improved compared with the 53% yield reported in the prior literature (Liu Bo,Zhan Jiarong.An Efficient Synthesis of Nα-Fmoc-4-(phosphonomethyl)-L-and D-Phenylalanine.Synthetic Communications,1999,29:13,2293-2299). Compared with the prior art, the invention has the advantages that: the raw materials are cheap and dangerous chemicals are not needed; the purification process is simple, and the purity and yield of the product are higher than those of the existing preparation method; the requirements on equipment are low, the operation is simple, and the popularization are convenient; the PMP obtained by the preparation method has absolute price advantage compared with the PMP sold in the market.
Drawings
The accompanying drawings, which are included to provide a further understanding of the application and are incorporated in and constitute a part of this specification, illustrate embodiments of the application and together with the description serve to explain the application. In the drawings:
FIG. 1 is a synthetic scheme of PMP;
FIG. 2 is a 1H-NMR spectrum of PMP-1 product of the example;
FIG. 3 is a 1H-NMR spectrum of PMP-2 product of example;
FIG. 4 is a 1H-NMR spectrum of PMP-3 product of example;
FIG. 5 is a 1H-NMR spectrum of PMP-4 product of example;
FIG. 6 is a 1H-NMR spectrum of PMP product of example.
Detailed Description
It should be noted that, without conflict, the embodiments of the present application and features of the embodiments may be combined with each other. The present application will be described in detail with reference to examples.
The technical scheme of the invention is realized according to the synthetic route shown in figure 1.
The invention provides a preparation method of a phosphoamino acid, which comprises the following steps:
Step a), adding a compound PMP-S into a first reaction bottle, adding a first solvent, adding acyl chloride under the environmental condition, heating for reaction overnight, and removing at least part of acyl chloride by rotary evaporation after the reaction is finished to obtain a compound PMP-1; wherein the compound PMP-S has a structure shown in a formula (I):
The compound PMP-1 has a structure shown in a formula (II):
Step b), adding the compound PMP-1, a second solvent and alkali into a second reaction bottle, dropwise adding acetyl chloride, performing rotary evaporation after the reaction is finished to remove the second solvent, extracting by adopting a first extractant, adding water for washing, and performing rotary evaporation on a first organic phase to obtain the compound PMP-2; wherein the compound PMP-2 has a structure shown in a formula (III):
Step c), adding the compound PMP-2 into a third reaction bottle, adding a third solvent, an initiator and a halogenated reagent, extracting by adopting a second extractant after the reaction is completed, adding water for washing to obtain a second organic phase, and adding a first organic solvent for crystallization after rotary evaporation of the second organic phase to obtain the compound PMP-3; wherein the compound PMP-3 has a structure shown in formula (IV):
Step d), adding the compound PMP-3 into a fourth reaction bottle, adding phosphate, performing reduced pressure distillation after the reaction, and adding a second organic solvent for recrystallization to obtain a compound PMP-4; wherein the compound PMP-4 has a structure represented by formula (V):
Step e), adding the compound PMP-4 into a fifth reaction bottle, adding an acid aqueous solution, cooling to 20-25 ℃ after the reaction is finished, adopting a third extractant to wash for three times, rotationally evaporating the obtained aqueous phase, and adding a compound solvent for crystallization to obtain the phosphate amino acid; the phosphoamino acid has a chemical structure represented by formula (VI):
in a specific embodiment, in step a), the first solvent includes, but is not limited to, a C 1～C24 alkyl alcohol, preferably methanol and/or ethanol; in a preferred embodiment, the first solvent is methanol.
In a specific embodiment, in step a), the acid chlorides include, but are not limited to, thionyl chloride and/or oxalyl chloride; in a preferred embodiment, the acid chloride is thionyl chloride.
In a specific embodiment, the reaction temperature in step a) is from 0 to 200 ℃; in a preferred embodiment, the reaction temperature in step a) is from 60 to 100 ℃.
In a specific embodiment, in step b), the second solvent includes, but is not limited to, one or more of dichloromethane, dichloroethane, tetrahydrofuran, dimethyltetrahydrofuran, dioxane; in a preferred embodiment, the second solvent is tetrahydrofuran.
In a specific embodiment, in step b), the base includes, but is not limited to, one or more of triethylamine, dimethylamine, diisopropylethylamine, N-methylmorpholine, imidazole; in a preferred embodiment, the base is triethylamine.
In a specific embodiment, the reaction temperature in step b) is from-70 to 40 ℃; in a preferred embodiment, the reaction temperature in step b) is from 0 to 5 ℃.
In a specific embodiment, in step c), the third solvent includes, but is not limited to, one or more of dimethylformamide, dimethylacetamide, dichloroethane, tetrahydrofuran, dimethyltetrahydrofuran, dioxane, acetonitrile, toluene; in a preferred embodiment, the third solvent is acetonitrile.
In a specific embodiment, in step c), the initiator includes, but is not limited to, one or more of benzoyl peroxide, lauroyl peroxide, cumene hydroperoxide, t-butyl peroxybenzoate, t-butyl peroxyvalerate, diisopropyl peroxydicarbonate, dicyclohexyl peroxydicarbonate, azobisisobutyronitrile, azobisisoheptonitrile, potassium persulfate, sodium persulfate, ammonium persulfate; in a preferred embodiment, the initiator is azobisisobutyronitrile.
In a specific embodiment, in step c), the halogenating agent includes, but is not limited to, one or more of N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide; in a preferred embodiment, the halogenating agent is N-bromosuccinimide.
In a specific embodiment, the first organic solvent is selected from one or more of the group consisting of methyl tertiary butyl ether, diethyl ether, dipropyl ether, ethyl butyl ether, diisopropyl ether, dipentyl ether and dihexyl ether, preferably methyl tertiary butyl ether.
In a specific embodiment, in step c), the reaction temperature is from 0 to 200 ℃; in a preferred embodiment, the reaction temperature in step c) is from 60 to 100 ℃.
In a specific embodiment, in step d), the phosphate esters include, but are not limited to, one or more of trimethyl phosphite, triethyl phosphite, primary phosphate (mono-phosphate, hydrocarbyl phosphate), secondary phosphate (di-phosphate), and tertiary phosphate (tri-phosphate); in a preferred embodiment, the phosphate is triethyl phosphite.
In a specific embodiment, the reaction temperature in step d) is from 0 to 200 ℃; in a preferred embodiment, the reaction temperature in step d) is 120 to 180 ℃.
In a preferred embodiment, the second organic solvent in step d) includes, but is not limited to, one or more of dimethylformamide, dichloroethane, tetrahydrofuran, dimethyltetrahydrofuran, dioxane, acetonitrile, toluene, ethanol, ethyl acetate; in a preferred embodiment, the second organic solvent is ethyl acetate.
In a specific embodiment, in step e), the aqueous acid solution includes, but is not limited to, one of sulfuric acid solution, hydrochloric acid solution, nitric acid solution; in a preferred embodiment, the aqueous acid solution is a hydrochloric acid solution.
In a specific embodiment, the reaction temperature in step e) is from 0 to 200 ℃; in a preferred embodiment, the reaction temperature in step e) is 120 to 200 ℃.
In a specific embodiment, the complex solvent includes, but is not limited to, dimethylformamide, dimethylacetamide, dichloroethane, methanol, ethanol, tetrahydrofuran, dimethyltetrahydrofuran, dioxane, acetonitrile, toluene, n-heptane, n-hexane, diisopropylether, diethyl ether, isopropyl ether, petroleum ether, methyl tert-butyl ether, and mixtures of two or more thereof; in a preferred embodiment, the complex solvent is a mixture of ethanol and diisopropyl ether.
In a specific embodiment, the first extractant, the second extractant, and the third extractant each independently include, but are not limited to, one or more of the group consisting of ethyl acetate, ethyl formate, methyl acetate, amyl acetate, butyl acetate, methylene chloride, and chloroform.
Examples
1. Synthesis of Compound PMP-1
25G of compound PMP-S is added into a 1000mL three-necked flask, 700mL of methanol is added, 80mL of thionyl chloride is added at room temperature, the reaction is carried out overnight at 80 ℃, and after TLC detection, most of thionyl chloride is removed by rotary evaporation, thus 21g of product PMP-1 is obtained.
FIG. 2 is a 1 H-NMR spectrum of PMP-1, characterized as calculated for ：1H NMR(400MHz,CD3OD)δ7.21(d,J＝7.9Hz,2H),7.15(d,J＝8.1Hz,2H),4.30(dd,J＝7.4,6.0Hz,1H),3.83(s,3H),3.24(dd,J＝14.4,6.0Hz,1H),3.14(dd,J＝14.4,7.5Hz,1H),2.35(s,3H).ESI-MS m/z：C11H15NO2.[M+H]+：, 194.11, found 194.12.
2. Synthesis of Compound PMP-2
The above-mentioned product PMP-1, 100mL of tetrahydrofuran and 21g of Et 3 N are added into a reaction bottle, placed in a low-temperature reactor to be cooled to 0 ℃, 9.8g of acetyl chloride is added dropwise, after the TLC detection reaction is completed for 2 hours, tetrahydrofuran is removed by rotary evaporation, ethyl acetate is dissolved, water is added to wash for 3 times, and the organic phase is subjected to rotary evaporation to obtain 20g of solid product PMP-2.
FIG. 3 is a 1 H-NMR spectrum of PMP-2, characterized as calculated for ：1HNMR(400MHz,CDCl3)δ7.12(d,J＝7.8Hz,2H),6.99(d,J＝8.0Hz,2H),5.91(d,J＝7.1Hz,1H),4.89(dt,J＝7.8,5.7Hz,1H),3.75(s,3H),3.13(dd,J＝13.9,5.7Hz,1H),3.08(dd,J＝13.9,5.6Hz,1H),2.34(s,3H),2.00(s,3H).ESI-MS m/z：C13H17NO3.[M+H]+：, 236.12, found 236.09.
3. Synthesis of Compound PMP-3
Adding 20g of compound PMP-2 into a reaction bottle, adding 80mL of acetonitrile, 1.4g of azodiisobutyronitrile and 16.6gNBS, stirring until the compound PMP-2 is completely dissolved, carrying out reflux reaction, detecting the reaction completely by TLC after 2 hours, adding ethyl acetate, washing by adding water, separating liquid, extracting the water phase by adding ethyl acetate, combining organic phases, drying by spin, crystallizing and pulping by methyl tertiary butyl ether, and obtaining 20g of compound PMP-3 as yellow solid.
FIG. 4 is a 1 H-NMR spectrum of PMP-3, characterized as calculated for ：1HNMR(400MHz,CDCl3)δ7.34(d,J＝7.7Hz,2H),7.09(d,J＝7.7Hz,2H),5.97(d,J＝6.8Hz,1H),4.90(dd,J＝13.0,6.0Hz,1H),4.49(s,2H),3.75(s,3H),3.17(dd,J＝13.9,5.8Hz,1H),3.10(dd,J＝13.8,5.6Hz,1H),2.01(s,3H).ESI-MS m/z：C13H16BrNO3.[M+H]+：, 314.03, found 314.02.
4. Synthesis of Compound PMP-4
20G of compound PMP-3 is added into a reaction bottle, 40mL of triethyl phosphite is added, reflux reaction is carried out at 170 ℃ for overnight, TLC detection is carried out, the solution is distilled under reduced pressure, and ethyl acetate is recrystallized to obtain 22g of product PMP-4.
FIG. 5 shows a 1 H-NMR spectrum of PMP-4, characterized as follows ：1HNMR(400MHz,CD3OD)δ7.27(dd,J＝8.1,2.4Hz,2H),7.20(d,J＝8.0Hz,2H),4.66(dd,J＝9.0,5.7Hz,1H),4.07-4.01(m,4H),3.70(s,3H),3.20(d,J＝2.7Hz,2H),3.15(d,J＝8.1Hz,1H),2.96(d,J＝4.8Hz,1H),1.93(s,3H),1.27(t,J＝7.1Hz,6H).
5. Synthesis of Compound PMP
22G of compound PMP-4 is added into a reaction bottle, 70mL of 9.0mol/L hydrochloric acid aqueous solution is added for reaction overnight at 140 ℃, the reaction is cooled to room temperature after the reaction is finished, the reaction is washed three times with ethyl acetate, the aqueous phase is subjected to rotary evaporation, ethanol is added for complete dissolution, and diisopropylether is added dropwise to obtain 15g of target product PMP.
FIG. 6 is a 1 H-NMR spectrum of PMP, characterized as calculated as ：1HNMR(400MHz,D2O)δ7.23(dd,J＝8.2,2.3Hz,2H),7.18(d,J＝8.1Hz,2H),4.22(dd,J＝7.8,5.4Hz,1H),3.26(dd,J＝14.6,5.2Hz,1H),3.14-3.08(m,2H),3.04(s,1H),2.58(s,2H).ESI-MSm/z：C10H14NO5P.[M+H]+：, 260.06, found 260.08.
It should be noted that the terms "first," "second," and the like in the description and in the claims are used for distinguishing between similar objects and not necessarily for describing a particular sequential or chronological order. It is to be understood that the terms so used are interchangeable under appropriate circumstances such that the embodiments of the application described herein are, for example, capable of operation in sequences other than those described herein.
Claims (7)
1. A method for preparing a phosphoamino acid, the method comprising the steps of:
Step a), adding a compound PMP-S into a first reaction bottle, adding a first solvent, adding acyl chloride under the environmental condition, heating for reaction overnight, and removing at least part of the acyl chloride by rotary evaporation after the reaction is finished to obtain a compound PMP-1; wherein the compound PMP-S has a structure shown in a formula (I):
The compound PMP-1 has a structure shown in a formula (II):
Step b), adding the compound PMP-1, a second solvent and alkali into a second reaction bottle, dropwise adding acetyl chloride, performing rotary evaporation after the reaction is finished to remove the second solvent, extracting by adopting a first extractant, adding water for washing, and performing rotary evaporation on a first organic phase to obtain the compound PMP-2; wherein the compound PMP-2 has a structure shown in a formula (III):
step c), adding the compound PMP-2 into a third reaction bottle, adding a third solvent, an initiator and a halogenated reagent, extracting by adopting a second extractant after the reaction is completed, adding water for washing to obtain a second organic phase, and adding a first organic solvent for crystallization after rotary evaporation of the second organic phase to obtain the compound PMP-3; wherein the compound PMP-3 has a structure shown in a formula (IV):
step d), adding the compound PMP-3 into a fourth reaction bottle, adding phosphate, performing reduced pressure distillation after the reaction, and adding a second organic solvent for recrystallization to obtain a compound PMP-4; wherein the compound PMP-4 has a structure shown in formula (V):
Step e), adding the compound PMP-4 into a fifth reaction bottle, adding an acid aqueous solution, cooling to 20-25 ℃ after the reaction is finished, adopting a third extractant to wash for three times, rotationally evaporating an obtained aqueous phase, adding a compound solvent for crystallization, and obtaining the phosphate amino acid; the phosphoamino acid has a chemical structure represented by formula (VI):
2. The method according to claim 1, wherein in step a) the first solvent is a C 1～C24 alkyl alcohol, preferably methanol and/or ethanol; the acyl chloride is thionyl chloride and/or oxalyl chloride, preferably thionyl chloride; the reaction temperature in step a) is from 0 to 200 ℃, preferably from 60 to 100 ℃.
3. The process according to claim 1, wherein in step b) the second solvent is one or more of dichloromethane, dichloroethane, tetrahydrofuran, dimethyltetrahydrofuran, dioxane, preferably tetrahydrofuran; the base is one or more of triethylamine, dimethylamine, diisopropylethylamine, N-methylmorpholine and imidazole, preferably triethylamine; the reaction temperature in step b) is-70 to 40 ℃, preferably 0 to 5 ℃.
4. The process according to claim 1, wherein in step c) the third solvent is one or more of dimethylformamide, dimethylacetamide, dichloroethane, tetrahydrofuran, dimethyltetrahydrofuran, dioxane, acetonitrile, toluene, preferably acetonitrile; the initiator is one or more of benzoyl peroxide, lauroyl peroxide, cumene hydroperoxide, tert-butyl peroxybenzoate, tert-butyl peroxyvalerate, diisopropyl peroxydicarbonate, dicyclohexyl peroxydicarbonate, azodiisobutyronitrile, azodiisoheptonitrile, potassium persulfate, sodium persulfate and ammonium persulfate, preferably azodiisobutyronitrile; the halogenating reagent is one or more of N-chlorosuccinimide, N-bromosuccinimide and N-iodinated succinimide, and is preferably N-bromosuccinimide; the first organic solvent is selected from one or more of methyl tertiary butyl ether, diethyl ether, dipropyl ether, ethyl butyl ether, diisopropyl ether, dipentyl ether and dihexyl ether, preferably methyl tertiary butyl ether; the reaction temperature in step c) is from 0 to 200 ℃, preferably from 60 to 100 ℃.
5. The method according to claim 1, wherein in step d), the phosphate is one or more of trimethyl phosphite, triethyl phosphite, primary phosphate, secondary phosphate and tertiary phosphate, preferably triethyl phosphite; the reaction temperature in step d) is 0 to 200 ℃, preferably 120 to 180 ℃; the second organic solvent is one or more of dimethylformamide, dichloroethane, tetrahydrofuran, dimethyl tetrahydrofuran, dioxane, acetonitrile, toluene, ethanol and ethyl acetate, preferably ethyl acetate.
6. The method according to any one of claims 1 to 5, wherein in step e) the aqueous acid solution is one or more of sulfuric acid solution, hydrochloric acid solution, nitric acid solution, preferably hydrochloric acid solution; the reaction temperature in step e) is 0 to 200 ℃, preferably 120 to 200 ℃; the compound solvent is a mixture of two or more of dimethylformamide, dimethylacetamide, dichloroethane, methanol, ethanol, tetrahydrofuran, dimethyltetrahydrofuran, dioxane, acetonitrile, toluene, n-heptane, n-hexane, diisopropyl ether, diethyl ether, isopropyl ether, petroleum ether and methyl tertiary butyl ether, preferably a mixture of ethanol and diisopropyl ether.
7. The method according to claim 1, wherein the first extractant, the second extractant, and the third extractant are each independently selected from one or more of the group consisting of ethyl acetate, ethyl formate, methyl acetate, amyl acetate, butyl acetate, methylene chloride, and chloroform.
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| CN (1) | CN118271361A (en) |
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2024
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