CN113234102A - Three-coordinate phosphorus derivative and intermediate and preparation method thereof - Google Patents

Three-coordinate phosphorus derivative and intermediate and preparation method thereof Download PDF

Info

Publication number
CN113234102A
CN113234102A CN202110542420.2A CN202110542420A CN113234102A CN 113234102 A CN113234102 A CN 113234102A CN 202110542420 A CN202110542420 A CN 202110542420A CN 113234102 A CN113234102 A CN 113234102A
Authority
CN
China
Prior art keywords
ester
reaction
phosphorus
phosphorus derivative
alkoxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202110542420.2A
Other languages
Chinese (zh)
Inventor
赵玉芬
王金辉
吴翊乐
赵华
赵钊
吴巨
郭叶挺
沈鹏
沙旭明
郑敏阳
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ningbo University
Original Assignee
Ningbo University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ningbo University filed Critical Ningbo University
Priority to CN202110542420.2A priority Critical patent/CN113234102A/en
Publication of CN113234102A publication Critical patent/CN113234102A/en
Priority to PCT/CN2022/092474 priority patent/WO2022242540A1/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/23—Heterocyclic radicals containing two or more heterocyclic rings condensed among themselves or condensed with a common carbocyclic ring system, not provided for in groups C07H19/14 - C07H19/22

Abstract

The invention discloses a three-coordinate phosphorus derivative, an intermediate and a preparation method thereof, wherein the structural formula is as follows:
Figure DDA0003072303310000011
R2is phenol group, pentafluorophenol group, C1‑4Alkoxy, said alkoxy being optionally further substituted by 0 to 4 of F, Cl, Br, I, C1‑4Alkyl or C1‑4Substituted by a substituent of alkoxy; r3Is amino acids glycine, L-alanine, L-phenylalanine, L-isoleucine, L-leucine, L-valine, L-histidine, L-tryptophan and its methyl ester, ethyl ester, isopropyl ester, tert-butyl ester, diethyl ester groupAnd 2-ethylbutyl-L-alanine ester; according to the invention, hexaethyl ammonium phosphite is used as an initial raw material, three-coordinate phosphorus derivatives are obtained through a one-pot method and three-step substitution reaction, a solvent does not need to be replaced in the reaction, the synthesis is simple, an intermediate does not need to be separated, and the problems of yield reduction, cost increase, environmental pollution caused by three wastes and the like caused by aftertreatment and purification are reduced.

Description

Three-coordinate phosphorus derivative and intermediate and preparation method thereof
Technical Field
The invention relates to a three-coordinate phosphorus derivative, an intermediate and a preparation method thereof.
Background
Three-coordinate phosphorus compound is sp3(anisotropism) hybridization triangular cone configuration, phosphorus atom has lone pair electrons. Trivalent phosphorus compounds have the reaction characteristics of electrophilicity, amphiphilicity and dienophily, and very strong PO bonds are often formed during the reaction. For example, trialkylphosphines and trialkyl phosphites are both trivalent phosphorus compounds. The three-coordinate phosphorus compound mainly contains phosphorous acid (ester), phosphorous acid amide, trialkyl phosphite, phosphorus trihalide, and the like. Wherein the phosphite ester is phosphorous acid (HO)3Partial or total hydroxyl hydrogen atoms in the molecule P are replaced (esterified) products of alkyl R, and the products can be divided into monoalkyl phosphite ROP (OH) according to the esterification degree2Dialkyl phosphite (RO)2POH and trialkyl phosphite (RO)3And P. Phosphite ester is a phosphorus compound with high reaction activity, and has the reaction characteristics of nucleophilic, electrophilic, amphiphilic and diene affinity and the like which are peculiar to trivalent phosphorus compounds. Dialkyl phosphites (RO)2POH has tautomeric structure, mainly phosphoryl type, and its sodium salt can be reacted with alkylHalogen (R' X, X is halogen) to produce dialkyl alkylphosphonate. Trialkyl phosphite (RO)3P or a trivalent phosphorus compound having at least one alkoxy group is reacted with an alkyl halide under heating to form a dialkyl alkylphosphonate or an alkoxy-cleaved pentavalent phosphorus compound. The direct alcoholysis of phosphorus trichloride can only produce monoalkyl or dialkyl phosphite. However, phosphorus trichloride is reacted with a sufficient amount of alcohol in the presence of an organic base to form trialkyl phosphite.
Because the volume of phosphorus atom is larger, the electronegativity is smaller, the nucleophilicity and the alkalinity of trialkyl phosphine are larger than those of trialkyl amine, and the trialkyl phosphine is also easy to coordinate with transition metal, thereby forming a homogeneous catalyst with characteristics. In addition, phosphines having three different substituents have chirality and can be resolved into optical isomers. Currently, research on the chemistry of tridentate phosphorus has focused mainly on the construction of P — C bonds and their use as catalysts in chemical syntheses, while reactions with tridentate phosphorus compounds as precursors for the synthesis of materials or drug molecules have been rare. In recent years, with the development of phosphorus-containing antiviral drugs, particularly the report that sofosbuvir for treating chronic hepatitis C is successively marketed in the United states and Europe since 2013, and the candidate drug RedeCivir, a hot anti-novel coronavirus, in 2020, has received great attention as a phosphorus-containing antiviral drug.
In the synthesis of the phosphorus-containing drugs, the four-coordination phosphorus compound is used as a starting material, the synthesis route is complex, the yield is low, the atom economy is poor, the steps are complicated, a large amount of three wastes are generated, and the sustainable development of the environment is not facilitated.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a three-coordinate phosphorus derivative, an intermediate and a preparation method thereof, and the invention is realized by the following technical scheme:
the invention discloses a three-coordinate phosphorus derivative, which has a structural formula as follows:
Figure BDA0003072303300000021
wherein:
R1is a nucleoside group selected from
Figure BDA0003072303300000022
Figure BDA0003072303300000023
Figure BDA0003072303300000024
When the temperature of the water is higher than the set temperature,
R2is phenol group, pentafluorophenol group, C1-4Alkoxy, said alkoxy being optionally further substituted by 0 to 4 of F, Cl, Br, I, C1-4Alkyl or C1-4Substituted by a substituent of alkoxy;
R3is amino acids glycine, L-alanine, L-phenylalanine, L-isoleucine, L-leucine, L-valine, L-histidine, L-tryptophan and methyl ester, ethyl ester, isopropyl ester, tert-butyl ester, diethyl ester group and 2-ethylbutyl-L-alanine ester thereof;
the invention also discloses a compound of the three-coordinate phosphorus derivative and a stereoisomer thereof, wherein the compound is selected from one of the following structures:
Figure BDA0003072303300000031
as a further improvement, the structure of the invention is further oxidized into a phosphoramide compound, which is an important precursor for preparing antiviral medicaments for treating hepatitis B, hepatitis C, AIDS, new corona and the like.
As a further improvement, when R1Being nucleosides
Figure BDA0003072303300000032
When, the structure of the general formula (I) is:
Figure BDA0003072303300000033
wherein R2 is the following amino acid and derivatives thereof:
Figure BDA0003072303300000034
Figure BDA0003072303300000041
when R is1Being nucleosides
Figure BDA0003072303300000042
When, the structure of the general formula (I) is:
Figure BDA0003072303300000043
wherein R2 is the following amino acid and derivatives thereof:
Figure BDA0003072303300000044
when R is1Being nucleosides
Figure BDA0003072303300000051
When, the structure of the general formula (I) is:
Figure BDA0003072303300000052
wherein R2 is the following amino acid and derivatives thereof:
Figure BDA0003072303300000053
when R is1Being nucleosides
Figure BDA0003072303300000054
When, the structure of the general formula (I) is:
Figure BDA0003072303300000055
wherein R2 is the following amino acid and derivatives thereof:
Figure BDA0003072303300000061
when R is1Being nucleosides
Figure BDA0003072303300000062
When, the structure of the general formula (I) is:
Figure BDA0003072303300000063
wherein R2 is the following amino acid and derivatives thereof:
Figure BDA0003072303300000071
when R is1Being nucleosides
Figure BDA0003072303300000072
When, the structure of the general formula (I) is:
Figure BDA0003072303300000073
wherein R2 is the following amino acid and derivatives thereof:
Figure BDA0003072303300000081
when R is1Being nucleosides
Figure BDA0003072303300000082
When, the structure of the general formula (I) is:
Figure BDA0003072303300000083
wherein R2 is the following amino acid and derivatives thereof:
Figure BDA0003072303300000091
when R is1Being nucleosides
Figure BDA0003072303300000092
When, the structure of the general formula (I) is:
Figure BDA0003072303300000093
wherein R2 is the following amino acid and derivatives thereof:
Figure BDA0003072303300000094
the invention also discloses a preparation method of the three-coordinate phosphorus derivative and the intermediate thereof, which comprises the following steps:
Figure BDA0003072303300000101
s1: using hexaethyl-phosphoramidite as initial phosphorus reagent, and reacting with nucleoside R1H, reacting to obtain a nucleoside substituted intermediate 1 with one P-O and two P-N bonds;
s2: taking phenol or alcohol as an exchange reagent, carrying out substitution reaction with the intermediate 1, removing one molecule of diethylamine, and preparing a three-coordinate phosphorus intermediate 2 with P-N and two P-O bonds;
s3: amino acid or ester thereof is taken as an exchange reagent to carry out substitution reaction with the intermediate 1, and one molecule of diethylamine is removed to prepare the three-coordinate phosphorus derivative (I) with one P-N and two P-O bonds.
As a further improvement, in the step S1 of the present invention, the molar ratio of the hexaethylenephosphoramidite to the nucleoside is 1/2 to 2.
In a further improvement, in step S1, the solvent a is any one of dichloromethane, chloroform and 1, 4-dioxane, and the solvent B is tetrahydrofuran or toluene.
As a further improvement, in step S1 of the present invention, the reaction is performed under anhydrous conditions.
As a further improvement, in step S2 of the present invention, the molar ratio of intermediate 1 to phenol or alcohol is 1/2 to 2.
As a further improvement, in the step S3 of the present invention, the molar ratio of the intermediate 2 to the amino acid or the ester thereof is 1/2 to 2, and 1, 4-dioxane or toluene is added to increase the reaction temperature.
The invention has the following beneficial effects:
the preparation method provided by the invention can synthesize the three-coordinate phosphorus derivative through three-step series reaction, and the three-coordinate phosphorus derivative is obtained through three-step substitution reaction by taking hexaethylenephosphoramidite as a starting material through a one-pot method. The solvent does not need to be replaced in the reaction, the synthesis is simple, the intermediate does not need to be separated, and the problems of yield reduction, cost increase, environmental pollution caused by three wastes and the like caused by aftertreatment and purification are solved.
The boiling point of the byproduct diethylamine generated by the preparation method is 55 ℃, and the diethylamine with high purity can be obtained by distillation and recovery, and can be widely applied to intermediates of medicines and pesticides and rubber accelerators in industry. Meanwhile, no halogen-containing raw material participates in the reaction, so that the pollution to the environment is further reduced, and a novel method for synthesizing the phosphorus-containing organic functional molecule in a non-halogen and green manner is realized.
The preparation method provided by the invention has mild conditions, the first two steps of reaction can be completed at room temperature, and the reaction can be spontaneously carried out without adding a catalyst. The reaction can be carried out in various solvents such as dichloromethane, chloroform, 1, 4-dioxane, etc. Meanwhile, the preparation method of the three-coordinate phosphorus has wide applicability, and can be sequentially exchanged with various nucleosides, phenolic hydroxyl groups, alkoxy groups and amino acids (esters) to obtain a series of three-coordinate phosphorus derivatives.
The three-coordinate phosphorus derivative prepared by the method contains antiviral nucleoside drugs such as stavudine, didanosine, azidothymidine and the like, and can be used as a precursor of phosphoramide drugs. The method has simple synthetic route, the intermediate can be synthesized without purification and a one-pot method, thereby not only improving the yield and being environment-friendly, but also being suitable for industrial large-scale continuous production. Thus, libraries of phosphorus-containing compounds can be rapidly constructed by the present method.
Detailed Description
The invention discloses a three-coordinate phosphorus derivative, which has a structural formula as follows:
Figure BDA0003072303300000111
wherein:
R1is a nucleoside group selected from
Figure BDA0003072303300000121
Figure BDA0003072303300000122
Figure BDA0003072303300000123
When the temperature of the water is higher than the set temperature,
R2is phenol group, pentafluorophenol group, C1-4Alkoxy, said alkoxy being optionally further substituted by 0 to 4 of F, Cl, Br, I, C1-4Alkyl or C1-4Substituted by a substituent of alkoxy;
R3is amino acids glycine, L-alanine, L-phenylalanine, L-isoleucine, L-leucine, L-valine, L-histidine, L-tryptophan and methyl ester, ethyl ester, isopropyl ester, tert-butyl ester, diethyl ester group and 2-ethylbutyl-L-alanine ester thereof;
also disclosed are compounds of the tridentate phosphorus derivatives and stereoisomers thereof, wherein the compounds are selected from one of the following structures:
Figure BDA0003072303300000124
the structure is further oxidized into a phosphoramide compound, which is an important precursor for preparing antiviral medicaments for treating hepatitis B, hepatitis C, AIDS, new coronary disease and the like.
The invention also discloses a preparation method of the three-coordinate phosphorus derivative and the intermediate thereof, which comprises the following steps:
Figure BDA0003072303300000131
s1: using hexaethyl-phosphoramidite as initial phosphorus reagent, and reacting with nucleoside R1H, reacting to obtain a nucleoside substituted intermediate 1 with one P-O and two P-N bonds; the mol ratio of the raw material hexaethyl phosphoramidite to the nucleoside is 1/2-2, the solvent A is any one of dichloromethane, chloroform and 1, 4-dioxane, and the solvent B is tetrahydrofuran or toluene.
S2: taking phenol or alcohol as an exchange reagent, carrying out substitution reaction with the intermediate 1, removing one molecule of diethylamine, and preparing a three-coordinate phosphorus intermediate 2 with P-N and two P-O bonds; the molar ratio of intermediate 1 to phenol or alcohol is between 1/2 and 2.
S3: amino acid or ester thereof is taken as an exchange reagent to carry out substitution reaction with the intermediate 1, and one molecule of diethylamine is removed to prepare a three-coordinate phosphorus derivative (I) with one P-N and two P-O bonds; the molar ratio of the intermediate 2 to the amino acid or ester thereof is between 1/2 and 2, and 1, 4-dioxane or toluene is added to raise the reaction temperature.
The practice of the present invention is described in detail below with reference to specific examples, and the structure of the compound is determined by Nuclear Magnetic Resonance (NMR) and high resolution mass spectrometry (HR-MS).
Example 1
The synthesis method of P-d4T-Oph-L-Ile in the embodiment specifically comprises the following steps:
Figure BDA0003072303300000132
wherein: the letter below the above formula represents an abbreviation for intermediate, and the abbreviation is used to replace the formula for convenience of description.
1. Intermediate P-d4T
448mg (2.0mmol) of stavudine d4T were weighed into a 25mL Schlenk bottle, 5mL of chloroform was added, and 247mg (2.0mmol) of hexaethyl acetate was added under protection of argonAnd (3) reacting the phosphoramidite at room temperature for 30 minutes, and carrying out a phosphorus spectrum tracking reaction until no raw material remains to obtain an intermediate P-d4T which is directly used for the next reaction. And performing structural characterization by using a nuclear magnetic phosphorus spectrum and a high-resolution mass spectrum.31PNMR(162MHz,Chloroform)δ137.1.HR-MS(ESI):m/z C18H31N4O4P,calcd for[M+H]+399.2156,found 399.2161.
2. Intermediate P-d4T-OPh
188mg (2.0mmol) of phenol is added into the reaction system under the protection of argon, the reaction is carried out for 2 hours at room temperature, a phosphorus spectrum tracing reaction is carried out until no raw material is left, and an intermediate P-d4T-OPh is obtained and is directly used for the next reaction. And performing structural characterization by using a nuclear magnetic phosphorus spectrum and a high-resolution mass spectrum.31P NMR(162MHz,Chloroform)δ145.3,143.1.HR-MS(ESI):m/z C20H26N3O5P,calcd for[M+H]+420.1683,found 420.1688.
3. Target product P-d4T-OPh-L-Ile
374mg (2.0mmol) of L-isoleucine tert-butyl ester and 2mL of toluene are added into the reaction system, the mixture is heated to 80 ℃ for reaction for 24 hours, and the reaction is followed by a phosphorus spectrum until no raw material remains. And (4) draining the solvent to obtain the target product P-d 4T-OPh-L-Ile. Nuclear magnetic and high resolution mass spectrometry was used for structural characterization.31PNMR(162MHz,DMSO-d6)δ128.5.1H NMR(500MHz,DMSO-d6)δ11.32(NH),7.25-7.13(m,3H),6.98-6.78(m,3H),6.52(d,1H),5.78-5.73(m,2H),4.45-4.41(m,1H),3.83(dd,1H),3.56(dd,1H),3.18(d,1H),2.31(s,3H),2.15-2.06(m,1H),1.55-1.31(m,11H),1.15-0.88(m,6H).HR-MS(ESI):m/z C26H36N3O7P,calcd for[M+H]+534.2364,found 534.2369.
Example 2
The method for synthesizing P-d4T-Oph-L-Val in the embodiment specifically comprises the following steps:
Figure BDA0003072303300000151
wherein: the letter below the above formula represents an abbreviation for intermediate, and the abbreviation is used to replace the formula for convenience of description.
1. Intermediate P-d4T
448mg (2.0mmol) of stavudine d4T was weighed into a 25mL Schlenk bottle, 5mL of chloroform was added, 247mg (2.0mmol) of hexaethyl ammonium phosphite was added under the protection of argon, the reaction was carried out at room temperature for 30 minutes, and the reaction was followed by phosphorus spectrum until no raw material remained, to obtain intermediate P-d4T, which was directly used in the next reaction. And performing structural characterization by using a nuclear magnetic phosphorus spectrum and a high-resolution mass spectrum.31PNMR(162MHz,Chloroform)δ137.5.HR-MS(ESI):m/z C18H31N4O4P,calcd for[M+H]+399.2156,found 399.2161.
2. Intermediate P-d4T-OPh
188mg (2.0mmol) of phenol is added into the reaction system under the protection of argon, the reaction is carried out for 2 hours at room temperature, a phosphorus spectrum tracing reaction is carried out until no raw material is left, and an intermediate P-d4T-OPh is obtained and is directly used for the next reaction. And performing structural characterization by using a nuclear magnetic phosphorus spectrum and a high-resolution mass spectrum.31P NMR(162MHz,Chloroform)δ144.8,142.8.HR-MS(ESI):m/z C20H26N3O5P,calcd for[M+H]+420.1683,found 420.1688.
3. Target product P-d4T-OPh-L-Val
290mg (2.0mmol) of L-valine tert-butyl ester and 2mL of toluene are added into the reaction system, the mixture is heated to 80 ℃ for reaction for 20 hours, and the reaction is followed by a phosphorus spectrum until no raw material is left. The solvent is pumped to dryness to obtain the target product P-d 4T-OPh-L-Ala. Nuclear magnetic and high resolution mass spectrometry was used for structural characterization.31PNMR(162MHz,DMSO-d6)δ128.5.1H NMR(500MHz,DMSO-d6)δ11.32(NH),7.26-7.21(m,2H),7.13(s,1H),6.92-6.80(m,3H),6.52(d,1H),5.78(d,2H),4.41-4.32(m,1H),3.83(dd,1H),3.56(dd,1H),3.25(d,1H),2.31(s,3H),2.15-2.06(m,1H),1.42(s,9H),1.05(d,6H).HR-MS(ESI):m/z C25H34N3O7P,calcd for[M+H]+520.2207,found 520.2200.
Example 3
The synthesis method of P-d4T-OPh-L-Phe in this example specifically includes the following steps:
Figure BDA0003072303300000161
wherein: the letter below the above formula represents an abbreviation for intermediate, and the abbreviation is used to replace the formula for convenience of description.
1. Intermediate P-d4T
448mg (2.0mmol) of stavudine d4T was weighed into a 25mL Schlenk bottle, 5mL of chloroform was added, 247mg (2.0mmol) of hexaethyl ammonium phosphite was added under the protection of argon, the reaction was carried out at room temperature for 30 minutes, and the reaction was followed by phosphorus spectrum until no raw material remained, to obtain intermediate P-d4T, which was directly used in the next reaction. And performing structural characterization by using a nuclear magnetic phosphorus spectrum and a high-resolution mass spectrum.31PNMR(162MHz,Chloroform)δ136.9.HR-MS(ESI):m/z C18H31N4O4P,calcd for[M+H]+399.2156,found 399.2161.
2. Intermediate P-d4T-OPh
188mg (2.0mmol) of phenol is added into the reaction system under the protection of argon, the reaction is carried out for 2 hours at room temperature, a phosphorus spectrum tracing reaction is carried out until no raw material is left, and an intermediate P-d4T-OPh is obtained and is directly used for the next reaction. And performing structural characterization by using a nuclear magnetic phosphorus spectrum and a high-resolution mass spectrum.31P NMR(162MHz,Chloroform)δ144.9,142.9.HR-MS(ESI):m/z C20H26N3O5P,calcd for[M+H]+420.1683,found 420.1688.
3. Target product P-d4T-OPh-L-Phe
442mg (2.0mmol) of L-phenylalanine tert-butyl ester and 3mL of toluene were added to the above reaction system, and the mixture was heated to 80 ℃ for 20 hours, followed by reaction with a phosphorus spectrum until no starting material remained. The solvent is drained to obtain the target product P-d 4T-OPh-L-Phe. Nuclear magnetic and high resolution mass spectrometry was used for structural characterization.31PNMR(162MHz,DMSO-d6)δ128.6.1H NMR(500MHz,DMSO-d6)δ11.34(NH),7.28-7.09(m,8H),6.92-6.76(m,3H),6.49(d,1H),5.78(d,2H),4.45-4.31(m,1H),3.85-3.79(m,2H),3.57-3.52(m,2H),3.23(d,1H),2.34(s,3H),1.41(s,9H).HR-MS(ESI):m/z C29H34N3O7P,calcd for[M+H]+568.2207,found 568.2213.
Example 4
The synthesis method of P-d4T-OPh-2-EtBu-L-Ala in the embodiment specifically comprises the following steps:
Figure BDA0003072303300000171
wherein: the letter below the above formula represents an abbreviation for intermediate, and the abbreviation is used to replace the formula for convenience of description.
1. Intermediate P-d4T
448mg (2.0mmol) of stavudine d4T was weighed into a 25mL Schlenk bottle, 5mL of chloroform was added, 247mg (2.0mmol) of hexaethyl ammonium phosphite was added under the protection of argon, the reaction was carried out at room temperature for 30 minutes, and the reaction was followed by phosphorus spectrum until no raw material remained, to obtain intermediate P-d4T, which was directly used in the next reaction. And performing structural characterization by using a nuclear magnetic phosphorus spectrum and a high-resolution mass spectrum.31PNMR(162MHz,Chloroform)δ137.2.HR-MS(ESI):m/z C18H31N4O4P,calcd for[M+H]+399.2156,found 399.2161.
2. Intermediate P-d4T-OPh
188mg (2.0mmol) of phenol is added into the reaction system under the protection of argon, the reaction is carried out for 2 hours at room temperature, a phosphorus spectrum tracing reaction is carried out until no raw material is left, and an intermediate P-d4T-OPh is obtained and is directly used for the next reaction. And performing structural characterization by using a nuclear magnetic phosphorus spectrum and a high-resolution mass spectrum.31P NMR(162MHz,Chloroform)δ144.8,142.8.HR-MS(ESI):m/z C20H26N3O5P,calcd for[M+H]+420.1683,found 420.1688.
3. The target product P-d4T-OPh-2-EtBu-L-Ala
346mg (2.0mmol) of 2-ethylbutyl-L-alanine ester and 3mL of toluene were added to the above reaction system, and the mixture was heated to 80 ℃ for 28 hours, followed by phospho-spectrometric reaction until no starting material remained. The solvent is drained to obtain the target product P-d 4T-Oph-2-EtBu-L-Ala. Nuclear magnetic and high resolution mass spectrometry was used for structural characterization.31PNMR(162MHz,DMSO-d6)δ128.5.1H NMR(500MHz,DMSO-d6)δ11.32(NH),7.21-7.18(m,3H),6.82-6.79(m,3H),6.54(d,1H),5.87-5.69(m,2H),4.45-4.31(m,3H),3.83(dd,1H),3.59-3..48(m,2H),2.01-1.89(m,1H),1.21-1.10(m,4H),0.99(t,6H).HR-MS(ESI):m/z C25H34N3O7P,calcd for[M+H]+520.2207,found 520.2203.
While only a few specific embodiments of the present invention have been shown and described, it will be obvious that the invention is not limited thereto, but may be embodied in many different forms and that all changes and modifications that can be derived from the disclosure set forth herein by one of ordinary skill in the art are deemed to be within the scope of the present invention.

Claims (9)

1. A tridentate phosphorus derivative, characterized by the structural formula:
Figure FDA0003072303290000011
wherein:
R1is a nucleoside group selected from
Figure FDA0003072303290000012
Figure FDA0003072303290000013
R2Is phenol group, pentafluorophenol group, C1-4Alkoxy, said alkoxy being optionally further substituted by 0 to 4 of F, Cl, Br, I, C1-4Alkyl or C1-4Substituted by a substituent of alkoxy;
R3is amino acids glycine, L-alanine, L-phenylalanine, L-isoleucine, L-leucine, L-valine, L-histidine, L-tryptophan and methyl ester, ethyl ester, isopropyl ester, tert-butyl ester, diethyl ester group and 2-ethylbutyl-L-alanine ester thereof.
2. A compound of the tridentate phosphorus derivative and its stereoisomers according to claim 1, wherein the compound is selected from one of the following structures:
Figure FDA0003072303290000021
3. the compound of the tridentate phosphorus derivative and the stereoisomer thereof as claimed in claim 2, wherein the structure is further oxidized into the phosphoramide compound, which is an important precursor for preparing antiviral drugs for hepatitis b, hepatitis c, aids, neocoronary disease, and the like.
4. A preparation method of a three-coordinate phosphorus derivative and an intermediate thereof is characterized by comprising the following steps:
Figure FDA0003072303290000022
s1: using hexaethyl-phosphoramidite as initial phosphorus reagent, and reacting with nucleoside R1H, reacting to obtain a nucleoside substituted intermediate 1 with one P-O and two P-N bonds;
s2: taking phenol or alcohol as an exchange reagent, carrying out substitution reaction with the intermediate 1, removing one molecule of diethylamine, and preparing a three-coordinate phosphorus intermediate 2 with P-N and two P-O bonds;
s3: amino acid or ester thereof is taken as an exchange reagent to carry out substitution reaction with the intermediate 1, and one molecule of diethylamine is removed to prepare the three-coordinate phosphorus derivative (I) with one P-N and two P-O bonds.
5. The method of claim 4, wherein the molar ratio of hexaethylenephosphoramidite to nucleoside at step S1 is 1/2-2.
6. The method for preparing the tridentate phosphorus derivative and the intermediate thereof according to claim 4, wherein in the step S1, the solvent a is any one of dichloromethane, chloroform, and 1, 4-dioxane, and the solvent B is tetrahydrofuran or toluene.
7. The method for preparing the tridentate phosphorus derivative and the intermediate thereof according to claim 4, wherein the reaction is performed under anhydrous conditions in step S1.
8. The method for preparing the tridentate phosphorus derivative and the intermediate thereof according to claim 4, 5, 6, or 7, wherein the molar ratio of the intermediate 1 to the phenol or the alcohol is 1/2 to 2 in step S2.
9. The method of claim 8, wherein the molar ratio of intermediate 2 to amino acid or ester thereof is 1/2 to 2, and 1, 4-dioxane or toluene is added to increase the reaction temperature in step S3.
CN202110542420.2A 2021-05-18 2021-05-18 Three-coordinate phosphorus derivative and intermediate and preparation method thereof Pending CN113234102A (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN202110542420.2A CN113234102A (en) 2021-05-18 2021-05-18 Three-coordinate phosphorus derivative and intermediate and preparation method thereof
PCT/CN2022/092474 WO2022242540A1 (en) 2021-05-18 2022-05-12 Tri-coordinated phosphorus derivative, intermediate, and preparation method

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202110542420.2A CN113234102A (en) 2021-05-18 2021-05-18 Three-coordinate phosphorus derivative and intermediate and preparation method thereof

Publications (1)

Publication Number Publication Date
CN113234102A true CN113234102A (en) 2021-08-10

Family

ID=77135166

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202110542420.2A Pending CN113234102A (en) 2021-05-18 2021-05-18 Three-coordinate phosphorus derivative and intermediate and preparation method thereof

Country Status (2)

Country Link
CN (1) CN113234102A (en)
WO (1) WO2022242540A1 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114487169A (en) * 2022-01-05 2022-05-13 宁波大学 Chiral amino acid detection method
WO2022242540A1 (en) * 2021-05-18 2022-11-24 宁波大学 Tri-coordinated phosphorus derivative, intermediate, and preparation method

Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103403014A (en) * 2011-01-03 2013-11-20 南京迈勒克生物技术研究中心 O-(replaced benzyl)phosphoramidate and use thereof
CN103408624A (en) * 2013-07-08 2013-11-27 江西科技师范大学 Method for synthesizing nucleotide phosphoramidate and nucleotide thio-phosphoramidate
US20140206640A1 (en) * 2011-04-13 2014-07-24 Merck Sharp & Dohme Corp. 2'-azido substituted nucleoside derivatives and methods of use thereof for the treatment of viral diseases
CN104334570A (en) * 2012-03-21 2015-02-04 艾丽奥斯生物制药有限公司 Methods of preparing substituted nucleotide analogs
CN105073766A (en) * 2012-12-21 2015-11-18 艾丽奥斯生物制药有限公司 Substituted nucleosides, nucleotides and analogs thereof
CN105669804A (en) * 2016-03-28 2016-06-15 南通常佑药业科技有限公司 Preparation method of sofosbuvir
CN106478753A (en) * 2015-09-16 2017-03-08 博瑞生物医药（苏州）股份有限公司 A kind of preparation method of NUC 1031 individual isomer and purposes
CN106543220A (en) * 2015-09-16 2017-03-29 博瑞生物医药（苏州）股份有限公司 Phosphoramidate compounds and preparation method thereof and crystal
CN106543252A (en) * 2015-09-16 2017-03-29 博瑞生物医药（苏州）股份有限公司 The Preparation Method And Their Intermediate of nucleoside phosphoramidate class prodrug
CN107226831A (en) * 2016-03-25 2017-10-03 江苏天士力帝益药业有限公司 Uridine phosphamide prodrug, its preparation method and its in application pharmaceutically
CN107286190A (en) * 2016-04-13 2017-10-24 刘沛 The preparation of oxyl benzylamino phosphoric acid/phosphate derivatives of nucleosides and its medical usage
CN109651468A (en) * 2018-12-20 2019-04-19 刘洪海 With the active nucleoside phosphoramidate analog of suppressing virus replication, preparation method and its medicinal usage

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20210277047A1 (en) * 2018-06-15 2021-09-09 The Regents Of The University Of Colorado, A Body Corporate Synthesis and Biological Activity of Phosphoramidimidate and Phosphoramidate DNA
CN113234102A (en) * 2021-05-18 2021-08-10 宁波大学 Three-coordinate phosphorus derivative and intermediate and preparation method thereof

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103403014A (en) * 2011-01-03 2013-11-20 南京迈勒克生物技术研究中心 O-(replaced benzyl)phosphoramidate and use thereof
US20140206640A1 (en) * 2011-04-13 2014-07-24 Merck Sharp & Dohme Corp. 2'-azido substituted nucleoside derivatives and methods of use thereof for the treatment of viral diseases
CN104334570A (en) * 2012-03-21 2015-02-04 艾丽奥斯生物制药有限公司 Methods of preparing substituted nucleotide analogs
CN105073766A (en) * 2012-12-21 2015-11-18 艾丽奥斯生物制药有限公司 Substituted nucleosides, nucleotides and analogs thereof
CN103408624A (en) * 2013-07-08 2013-11-27 江西科技师范大学 Method for synthesizing nucleotide phosphoramidate and nucleotide thio-phosphoramidate
CN106478753A (en) * 2015-09-16 2017-03-08 博瑞生物医药（苏州）股份有限公司 A kind of preparation method of NUC 1031 individual isomer and purposes
CN106543220A (en) * 2015-09-16 2017-03-29 博瑞生物医药（苏州）股份有限公司 Phosphoramidate compounds and preparation method thereof and crystal
CN106543252A (en) * 2015-09-16 2017-03-29 博瑞生物医药（苏州）股份有限公司 The Preparation Method And Their Intermediate of nucleoside phosphoramidate class prodrug
CN107226831A (en) * 2016-03-25 2017-10-03 江苏天士力帝益药业有限公司 Uridine phosphamide prodrug, its preparation method and its in application pharmaceutically
CN105669804A (en) * 2016-03-28 2016-06-15 南通常佑药业科技有限公司 Preparation method of sofosbuvir
CN107286190A (en) * 2016-04-13 2017-10-24 刘沛 The preparation of oxyl benzylamino phosphoric acid/phosphate derivatives of nucleosides and its medical usage
CN109651468A (en) * 2018-12-20 2019-04-19 刘洪海 With the active nucleoside phosphoramidate analog of suppressing virus replication, preparation method and its medicinal usage

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
MITRASOV, YN ET AL.: "Condensation of nitro- and amino-substituted phenylmaleimides with furfuryl alcohol", 《RUSSIAN JOURNAL OF GENERAL CHEMISTRY》 *
NIKONOROVA, L. K.ET AL.: "Production of α,β-isopropylidene glycerol diethylamidophosphites and alkoxycarbonylmethylamidophosphites", 《ZHURNAL OBSHCHEI KHIMII》 *
RASADKINA, E. N ET AL.: "Dismutation of arylene phosphorodiamidites: Specific features and aspects of preparative use", 《RUSSIAN JOURNAL OF GENERAL CHEMISTRY》 *
唐除痴等: "《不对称反应中的有机磷试剂》", 31 October 2012, 天津：南开大学出版社 *
朱梅湘等: "核苷二苯基磷酸酯的合成及大鼠体内药物动力学", 《厦门大学学报(自然科学版)》 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022242540A1 (en) * 2021-05-18 2022-11-24 宁波大学 Tri-coordinated phosphorus derivative, intermediate, and preparation method
CN114487169A (en) * 2022-01-05 2022-05-13 宁波大学 Chiral amino acid detection method
CN114487169B (en) * 2022-01-05 2024-01-16 宁波大学 Chiral amino acid detection method

Also Published As

Publication number Publication date
WO2022242540A1 (en) 2022-11-24

Similar Documents

Publication Publication Date Title
EP1753762B1 (en) Lewis acid mediated synthesis of cyclic esters
US6743937B2 (en) Efficient method of synthesizing combretastatin A-4 prodrugs
CA2485597C (en) Process for preparation of cyclic prodrugs of pmea and pmpa
WO2022242540A1 (en) Tri-coordinated phosphorus derivative, intermediate, and preparation method
AU6213899A (en) Antiviral purine derivatives
JP2002308890A (en) Process for preparing ethanebis(alkyl phosphinic) acids
Stepinski et al. Facile high yielding synthesis of symmetric esters of methylenebisphosphonic acid
Lavén et al. Preparation of benzylphosphonates via a palladium (0)-catalyzed cross-coupling of H-phosphonate diesters with benzyl halides. Synthetic and mechanistic studies
Fang et al. Asymmetric Mannich‐Type Synthesis of N‐Phosphinyl α‐Aminophosphonic Acid Monoesters
KR101249361B1 (en) Manufacturing process of high-purity Tris(trialkylsilyl)Phosphite
Bochno et al. A three-component synthesis of aminomethylenebis-H-phosphinates
Gallagher et al. MONO-AND DIALKYLATION OF ISOPROPYL PHOSPHINATE-A SIMPLE PREPARATION OF ALKYLPHOSPHINATE ESTERS1
Yuan et al. A new and efficient asymmetric synthesis of 1‐amino‐1‐alkylphosphonic acids
US9035083B2 (en) Synthesis of H-phosphonate intermediates and their use in preparing the herbicide glyphosate
US6600067B2 (en) Process for preparing ethylenediphosphonic acids
Green et al. The preparation and characterization of some fluorinated α-aminoarylmethanephosphonic acids
HU218867B (en) Process for the manufacture of aminomethanephosphonic acid and process for manufacture of n-phosphonomethylglycine from aminomethanephosphonic acid
KR910002510B1 (en) Preparation method of n-phosphone methyl glycine
Metlushka et al. Phosphorylation of betti base with diethyl chlorophosphate.
EP0104775A1 (en) Production of N-phosphonomethylglycine
EP2880041B1 (en) Process for preparation of aryl phosphorous compounds
KR101195631B1 (en) New Synthetic Method of 9-[2-phosphonomethoxyethyl]adenine
Chen et al. The study of phosphoramidite as O-phosphitylation agent and its reactivity
US20040236144A1 (en) Method for producing $g(a)-aminophosphonic acids
Even et al. Synthesis of new ligands derived from polyphosphonates partial esters

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination