CN109503655B - Preparation method of Fmoc-amino acid ester derivative product - Google Patents

Preparation method of Fmoc-amino acid ester derivative product Download PDF

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CN109503655B
CN109503655B CN201910017593.5A CN201910017593A CN109503655B CN 109503655 B CN109503655 B CN 109503655B CN 201910017593 A CN201910017593 A CN 201910017593A CN 109503655 B CN109503655 B CN 109503655B
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phosphoryloxy
amino acid
fmoc
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CN109503655A (en
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钦传光
李海迪
晁洁
田广
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Shaanxi Yuanguang Hi Tech Co ltd
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Northwestern Polytechnical University
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    • C07F9/32—Esters thereof
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    • C07F9/06—Phosphorus compounds without P—C bonds
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    • C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
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    • C07F9/02—Phosphorus compounds
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    • C07F9/40—Esters thereof
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    • C07F9/02—Phosphorus compounds
    • 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)]
    • C07F9/40—Esters thereof
    • C07F9/4071—Esters thereof the ester moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4084—Esters with hydroxyaryl compounds
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Abstract

The invention relates to a phosphoryloxy benzaldehyde (or ketone) and its derivative and its preparing method, which uses (RO)2POCl or POCl3Reacting with hydroxybenzaldehyde or ketone as raw materials to obtain phosphoryloxy benzaldehyde or ketone compound 1; taking the compound 1 as a raw material, and reacting the compound 1 with hydroxylamine hydrochloride to obtain a derivative product phosphoryloxy benzyl alcohol compound 2 corresponding to the compound 1; taking the compound 1 as a raw material, and carrying out hydrogenation reduction treatment to obtain a derivative product, namely phosphoryloxy benzaldehyde or ketoxime compound 3; carrying out condensation coupling on the compound 2 and Fmoc protected amino acid (Fmoc-AA-OH) to obtain a chemical product 4; compound 3 is condensed and coupled with Boc protected amino acid (Boc-AA-OH) to obtain a chemical product 5. The method has the advantages of both liquid phase and solid phase synthesis methods, can synthesize and prepare protected amino acid or polypeptide and derivatives thereof more simply, conveniently, quickly, economically and efficiently, and the phosphate carrier can be recovered and directly reused, thereby reducing the waste of raw materials, reducing the pollution of wastes, saving the cost and being beneficial to environmental protection.

Description

Preparation method of Fmoc-amino acid ester derivative product
Technical Field
The invention belongs to the field of organic synthesis and polypeptide chemistry, and relates to a preparation method of Fmoc-amino acid ester derivative products, in particular to a phosphoryloxy benzyl alcohol compound which is a reduction product of phosphoryloxy benzaldehyde (or ketone) and has a novel structure, and a synthesis preparation method, a separation and a purification method thereof.
Background
Amino and carboxyl groups are important functional groups widely present in various bioactive compounds, and their protection and deprotection are often essential key links in modern synthetic organic chemistry, see literature:
[1]I.W.Hamley.Chem.Rev.2017,117,14015-14041.
[2]Kocienski,P.J.Protecting Groups；Georg Thieme Verlag:Stuttgart New York,2004.
[3]Green,T.W.；Wuts,P.G.M.Protective Groups in Organic Synthesis；John Wiley and Sons:New York,1999.
in particular, protection and deprotection of the amino and carboxyl functions of α -amino acids is one of the most important issues in the chemical synthesis of polypeptides. In peptide synthesis, once an amino acid is activated, it must be prevented from polymerization or other side reactions. On the other hand, peptide synthesis, whether in solution or on a solid phase, is preferentially carried out from the C-terminal to the N-terminal direction, and requires repeated removal of the temporary protecting group on the α -amino group or carboxyl group several times during the synthesis, and therefore, the deprotection reaction must be carried out under mild conditions without affecting the side chain residue protecting group or even the peptide chain, see document [4 ]: Isidro-Llobet, a.; alvarez, m.; albericio, F.chem.Rev.2009,109,2455-2504.
Although hundreds of protecting groups have been generated and removed by various methods, there remains a need to explore and continue to develop new and gentle strategies to introduce and cleave many existing protecting groups.
Polypeptide and peptidomimetic drugs involve almost all disciplines of chemistry and biomedicine, see literature:
[5]J.Clardy and C.Walsh,Nature,2004,432,829-837.
[6]H.H.Szeto and P.W.Schiller,Pharm.Res.,2011,28,2669–2679.
[7]C.J.White and A.K.Yudin,Nat.Chem.,2011,3,509–524.
[8]N.Assem and A.K.Yudin,Nat.Protoc.,2012,7,1327–1334.
[9]V.J.Hruby,G.Li,C.HaskellLuevano and M.Shenderovich,Biopolymers,1997,43,219–266.
the search for environmentally friendly synthetic methods of these products for academic research and drug production has been ongoing for over 50 years, see literature:
[10]J.L.Gustafson,D.Lim and S.J.Miller,Science,2010,328,1251–1255.
[11]V.R.Pattabiraman and J.W.Bode,Nature,2011,480,471–479.
[12]E.Ko,J.Liu,L.M.Perez,G.Lu,A.Schaefer and K.Burgess.J.Am.Chem.Soc.,2011,133,462-477.
[13]W.-K.Chan,C.-M.Ho,M.-K.Wong and C.-M.Che,J.Am.Chem.Soc.,2006,128,14796-14797.
[14]R.Hirschmann,A.B.Smith III,C.M.Taylor,et al.Science,1994,265,234-237.
[15]A.B.Smith III,A.B.Benowitz,P.A.Sprengeler,et al.J.Am.Chem.Soc.,1999,121,9286-9298.
the Solid Phase Peptide Synthesis (SPPS) invented by bruise Merrifield (Bruce Merrifield) of the nobel prize winner in the 80 s has shown a remarkable achievement of peptide synthesis, see literature: [16] r.b. merrifield.j.am.chem.soc.,1963,85, 2149-.
The milestone discovery can overcome the defects of complicated purification steps, consumption of a large amount of raw materials and reagents (including coupling agents, solvents and silica gel) and the like in the traditional liquid phase peptide synthesis, and can reduce the generation of waste; the method also greatly accelerates the synthesis and research of peptides and proteins. SPPS also exerts a tremendous impact on general chemical synthesis for drug discovery and development, particularly for combinatorial chemistry and high throughput screening, see literature: [17] sharma and d.crich, j.org.chem.,2011, 76, 6518-.
Since then, several synthetic schemes have been developed to complement SPPS to minimize the difficulty of scale-up, using excess reagents and expensive resins for coupling reactions, particularly for the synthesis of longer polypeptides and cyclic peptides of more complex structure, see literature:
[18]K.D.Eom,Z.W.Miao,J.L.Yang and J.P.Tam,J.Am.Chem.Soc.,2003,125,73-82.
[19]S.Liu,B.L.Pentelute and S.B.H.Kent,Angew.Chem.,Int.Ed.,2012,51,993-999.
[20]D.G.Mullen,B.Weigel,G.Barany and M.D.Distefano,J.Pept.Sci.,2010,16,219-222.
[21]Y.Okada,H.Suzuki,T.Nakae,et al.J.Org.Chem.,2012,78,320-327.
[22]B.C.Li,D.C.Montgomery,J.W.Puckett and P.B.Dervan,J.Org.Chem.,2013,78,124-133.
[23]K.Jin,I.H.Sam,K.H.L.Po,et al.Nat.Commn.2016,7,12394
in this respect, using soluble polymers as carriers for coupling of amino acid residues, an alternative method was subsequently developed which enables the polypeptide synthesis to be reacted in the liquid phase, but isolated and purified either in the solid phase or by a convenient extraction procedure. However, the latter method requires a high molecular weight soluble polymer, which is inconvenient for producing large amounts of small peptides having much lower molecular weights than the high molecular weight, and also does not comply with the principles of atomic economy. Furthermore, by carefully controlling the solidification/crystallization conditions, it often takes a longer time to produce a solid or crystalline product.
In recent years, a research group led by professor of prunus salicina has made a great progress in the field of purification chemistry, with particular attention to avoiding column chromatography and recrystallization, see literature:
[24]J.Wu,G.An,S.Lin,J.Xie,W.Zhou,H.Sun,Y.Pan G.Li.Chem.Commun.,2014,50,1259-1261.
[25]C.W.Seifert,A.Paniagua,G.A.White,L.Cai,G.Li.Eur.J.Org.Chem.2016,1714-1719.
this study and concept is defined as Group Assisted Purification (GAP) chemistry/technology. An organic synthetic chemistry avoids traditional purification methods such as chromatography and/or recrystallization by purposefully introducing functional groups into the starting materials or newly produced products. First, this study is likely to cover the entire field of synthetic organic chemistry. In the initial phase of research they have focused on the synthesis of chiral amines, N-phosphonoimines and N-phosphonoimides, and have met with great success in this regard. By controlling the solubility, the chiral amine product can be selectively precipitated from the crude mixture, thereby avoiding chromatography and recrystallization. In the second stage of research, they are developing methods to extend this technology to other substrates and functional groups. To this end, they have used the GAP properties of chiral auxiliaries and, by modification, have proposed the concept of GAP protecting groups. Protecting groups are present in almost every complex synthesis where multiple functional groups are present. Good protecting groups need to be stable to a variety of conditions and must be added and removed in high yield. An ideal example of GAP chemistry is that semi-permanent protecting groups result in the necessary solubility characteristics of GAP. The problem is that most conventional protecting groups are non-polar and therefore do not give the GAP solubility required for most substrates. If a protecting group can be developed that gives adequate solubility control, then the GAP chemistry can potentially be extended to all syntheses that require the use of that protecting group. By using GAP technology, organic synthesis and ternary coprecipitation can be carried out efficiently without adopting traditional purification methods such as chromatography, recrystallization and the like. Petroleum solvents or co-solvents. Therefore, the use of raw materials, silica gel, energy, manpower, etc. can be greatly reduced. GAP chemistry strategies can facilitate polypeptide synthesis, which has the advantages of Solid Phase Peptide Synthesis (SPPS) and liquid phase peptide synthesis, avoiding their disadvantages in the above factors.
However, the groups currently used for protecting the amino or carboxyl functional groups of amino acids, including the GAP group under development of the professor of prunus salicina mentioned above, are destroyed or decomposed during the removal process and cannot be recycled at all, which greatly consumes the production cost, and the discharge of waste materials inevitably causes serious environmental pollution problems, which is not considered to be the best solution in terms of economic cost and social benefit. Therefore, with the increasing advocation of the concept of green sustainable development of economic society, the search and discovery of new amino acid carboxyl protecting groups which can be recovered and recycled is still a promising important research topic.
Disclosure of Invention
Technical problem to be solved
In order to avoid the defects of the prior art, the invention provides a preparation method of Fmoc-amino acid ester derivatization products, which solves the problems that in the existing chemical synthesis method of polypeptide, amino acid protective groups and solid-phase resin are easy to damage or decompose in the deprotection or shearing step and can not be directly recycled, so that reaction byproducts of liquid-phase synthesis are relatively complex, the separation steps are multiple, the time consumption period is long, the purification scale is small, the production cost is high, the production scale of solid-phase synthesis is small, the raw materials are expensive, the waste is large, the resin wastes are multiple, and the environmental pollution is serious.
Technical scheme
A preparation method of Fmoc-amino acid ester derivative products is characterized by comprising the following steps:
step 1: adopt (RO)2POCl or POCl3Adding alkali into a solvent A for catalysis reaction with hydroxybenzaldehyde or hydroxybenzophenone as raw materials, performing rotary evaporation to recover the solvent after the reaction is finished, extracting the residual solution with ethyl acetate and separating the residual solution from a water phase, combining the organic phases and washing the organic phases with deionized water for multiple times;
then separating and purifying to obtain phosphoryloxy benzaldehyde or phosphoryloxy benzophenone compound 1, wherein the molecular structure general formula is as follows:
Figure GDA0003017794510000061
the (RO)2POCl or POCl3The feeding ratio of the hydroxyl benzaldehyde to hydroxybenzaldehyde or hydroxybenzophenone is 1: 1-4;
step 2: taking the phosphoryloxy benzaldehyde or phosphoryloxy benzophenone compound 1 obtained in the step 1 as a raw material, carrying out hydrogenation reduction treatment reaction in a solvent B by using a reducing agent, recovering the solvent by rotary evaporation after the reaction is finished, extracting the residual solution by using ethyl acetate and separating the residual solution from a water phase, combining organic phases, and washing the organic phases for multiple times by using deionized water;
then the corresponding derivative product phosphoryloxy benzyl alcohol compound 2 of the compound 1 is obtained by separation and purification, and the molecular structural general formula is:
Figure GDA0003017794510000071
and step 3: coupling reaction is carried out on the phosphoryloxy benzyl alcohol compound 2 obtained in the step 2 and Fmoc protected amino acid (Fmoc-AA-OH), and a derivative product of Fmoc-amino acid ester corresponding to the compound 2 is obtained through separation and purification, wherein the molecular structural general formula is as follows:
Figure GDA0003017794510000081
wherein: AA represents various amino acids.
The separation and purification of the steps 1 to 3 are as follows: extracting with ethyl acetate, separating from the water phase, combining the organic phases, and washing with deionized water for 2-3 times; dropping alkane or ether solvent with small polarity into ethyl acetate solution until crystallization or precipitation is separated out, and filtering and washing or recrystallization to complete separation and purification.
The reaction conditions of the alkali-added catalytic reaction or the hydrogenation reduction treatment reaction in the steps 1 to 3 are as follows: stirring for 2-3 hours at room temperature.
The deionized water is used for washing for multiple times in the steps 1 to 2, and the times are 2-3.
The solvent A in the step 1 and the step 2 is: tetrahydrofuran, acetonitrile, benzene, toluene, chloroform CHCl3One or more of dichloromethane DCM, N-dimethylformamide DMF and N-methylpyrrolidone NMP organic solvent.
The alkali in the step 1 and the step 3 is one or more of tertiary amines TEA, DIEA, NMM, pyridine and derivatives DMAP thereof.
The solvent B in the step 2 is: one or more of alcohols, acetonitrile, tetrahydrofuran, etc.
The reducing agent in the step 2 is: NaBH4、H2/Pd/C、B2H4Or LiAlH4。
The alkane or ether solvent is one or more of petroleum ether, n-hexane, cyclohexane, diethyl ether, n-butyl ether, etc.
Advantageous effects
The invention provides a preparation method of Fmoc-amino acid ester derivative products, (1) adopts (RO)2POCl or POCl3Reacting with hydroxybenzaldehyde (or ketone) as raw material in alkaline solution, separating and purifying to obtain phosphoryloxy benzaldehyde (or ketone) compound 1; (2) reacting the obtained phosphoryloxy benzaldehyde (or ketone) compound 1 serving as a raw material with hydroxylamine hydrochloride, and separating and purifying to obtain a corresponding derivative product phosphoryloxy benzyl alcohol compound 2 of the compound 1; (3) using the obtained phosphoryloxy benzaldehyde (or ketone) compound 1 as a raw material, carrying out hydrogenation reduction treatment, and separating and purifying to obtain a corresponding derivative product phosphoryloxy benzaldehyde (or ketone) oxime compound 3 of the compound 1; (4) condensing and coupling the obtained phosphoryloxy benzyl alcohol compound 2 with Fmoc protected amino acid (Fmoc-AA-OH), and separating and purifying to obtain an Fmoc-amino acid ester derivative product 4 corresponding to the compound 1; (5) condensing and coupling the obtained phosphoryloxybenzaldehyde (or ketone) oxime compound 3 with Boc protected amino acid (Boc-AA-OH), and separating and purifying to obtain a Boc-amino acid ester derivative product 5 corresponding to the compound 1.
Through systematic screening research, the phosphoryloxy benzaldehyde (or ketone) can be coupled with amino of amino acid in a Schiff base mode to protect the amino, and can be easily removed through acidolysis. On the other hand, the small molecules of the reduction product (phosphoryloxy benzyl alcohol derivative) of phosphoryloxy benzaldehyde (or ketone) and the oximation product (phosphoryloxy benzyl alcohol or ketone oxime derivative) of the phosphoryloxy benzaldehyde (or ketone) can be subjected to esterification reaction with the carboxyl of amino acid under the conditions of alkali, normal temperature and normal pressure through the mediation of a coupling agent, so that stable amino acid ester can be generated at high yield for protecting the carboxyl of the amino acid, and the phosphate carrier and the amino acid or polypeptide derivative thereof are found to be easily crystallized and precipitated in a nonpolar solvent, can be removed from the amino acid or polypeptide derivative thereof through simple separation, purification and alkaline hydrolysis, and the by-product is also the original phosphate carrier, can be directly recycled after recovery and purification, and can realize a sustainable large-scale green generation process. From the research and analysis of the existing documents, the strategy for protecting amino acid carboxyl and assisting purification by using the phosphate carrier involved in the invention is still pioneered. Compared with the existing amino acid carboxyl protecting group (including the GAP group which is developed by the professor of the plum-cinnamon root mentioned above) or a solid-phase resin carrier, the phosphoryloxy benzaldehyde (or ketone) and the derivative thereof have the advantages of abundant and easily obtained raw materials, recyclability, simple and convenient operation, mild conditions, low equipment cost, little three wastes, environmental protection and the like.
The phosphate small molecule has obvious practical application value in organic synthesis and polypeptide chemistry, can be used as a protective group of amino acid, is not damaged after deprotection, and is easy to recycle. But also can replace a resin carrier in solid phase polypeptide synthesis, is beneficial to the separation and purification of auxiliary polypeptide, is not damaged after being sheared, and is easy to recycle. The method has the advantages of both liquid phase and solid phase synthesis methods, can synthesize and prepare protected amino acid or polypeptide and derivatives thereof more simply, conveniently, quickly, economically and efficiently, and the phosphate carrier can be recovered and directly reused, thereby reducing the waste of raw materials, reducing the pollution of wastes, saving the cost and being beneficial to environmental protection.
Drawings
FIG. 1: process flow chart of preparation method of phosphoryloxy benzaldehyde (or ketone) and derivative thereof
Detailed Description
The invention will now be further described with reference to the following examples and drawings:
the examples mainly include the following compounds and their preparation steps: (1) adopt (RO)2POCl or POCl3Reacting with hydroxybenzaldehyde (or ketone) as raw material in alkaline solution, separating and purifying to obtain phosphoryloxy benzaldehyde (or ketone) compound 1; (2) reacting the obtained phosphoryloxy benzaldehyde (or ketone) compound 1 serving as a raw material with hydroxylamine hydrochloride, and separating and purifying to obtain a corresponding derivative product phosphoryloxy benzyl alcohol compound 2 of the compound 1; (43) condensing and coupling the obtained phosphoryloxy benzyl alcohol compound 2 with Fmoc protected amino acid (Fmoc-AA-OH), and separating and purifying to obtain the corresponding Fmoc of the compound 1-amino acid ester derivatisation products; . The detailed synthetic route of the invention is shown in figure 1. Some of the abbreviations commonly used in the present invention have the following meanings:
boc: tert-butyloxycarbonyl radical
DCM: methylene chloride CH2Cl2
DMAP 4-dimethylaminopyridine
DMF N, N-dimethylformamide
EDC-HCl 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride
Fmoc: fmoc group
GPS green polypeptide synthetic carrier
GSH glutathione
HATU 2- (7-benzotriazol oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate
HOBT 1-hydroxybenzotriazole
HBTU O-benzotriazole-tetramethyluronium hexafluorophosphate
NMM N-methylmorpholine
NMP N-methylpyrrolidone
PyBop benzotriazol-1-yl-oxytripyrrolidinylphosphine hexafluorophosphate
t-butyl tBu
TFA: trifluoroacetic acid
THF: tetrahydrofuran (THF)
Trt trityl
The invention is suitable for preparing phosphoryloxy benzaldehyde (or ketone) and its derivative, the reaction principle and technical route are shown in figure 1.
Actual procedure
Synthesis of 4-diphenylphosphoryloxybenzophenone (DBK,1a) by accurately weighing 4-hydroxybenzophenone (5g, 25mmol, 1equiv) in a 250mL reaction flask, adding 100mL tetrahydrofuran THF, stirring in ice bath for 30min, and adding dropwise acid-binding agent triethylamine Et into the reaction system3N (4.2mL, 30mmol, 1.2equiv), measuring diphenyl hypophosphoryl chloride (5.7mL, 30mmol, 1.2equiv), dropwise adding into the reaction system, placing in an ice bath for reaction for 30min, removing the ice bath, detecting the reaction system by TLC, reacting at room temperature for 1.5h, adding dilute sulfuric acid (0.1 mol/L)10mL), concentrated on a rotary evaporator to remove the THF solvent and 20mL of deionized water was added, extracted with ethyl acetate to give an organic phase, and dried over anhydrous magnesium sulfate. After rotary evaporation to dryness, 2mL of ethyl acetate was added to fully dissolve the sample, 14mL of n-Hexane (VEA/VN-Hexane ═ 1:7) was added dropwise, a large amount of white precipitate appeared in the system, and the white precipitate was filtered and dried to obtain the objective compound (1a) in about 93% yield. Structural characterization:1HNMR(400MHz,CDCl3),δ＝7.95-7.90(m,4H),7.76-7.73(m,4H),7.59-7.55(m,3H),7.52-7.44(m,6H),7.36-7.34(d,2H)ppm；31PNMR(162MHz,CDCl3),δ＝31.51ppm；13CNMR(100MHz,CDCl3),δ＝195.4,154.4,137.5,133.9,132.8,132.4,132.1,131.8,131.7,131.2,129.9,128.8,128.7,128.3,120.5ppm；HRMS(ESI)m/z calcd for C25H20O3P+(M+H)+＝399.11446,found 399.11469。
the solvent in the reaction system can be tetrahydrofuran THF, acetonitrile, benzene, toluene, chloroform CHCl3One or more of dichloromethane DCM, N-dimethylformamide DMF and N-methylpyrrolidone NMP organic solvent.
The alkali is one or more of organic alkali such as tertiary amine TEA, DIEA, NMM, pyridine and its derivative DMAP.
The alkane or ether solvent is one or more of petroleum ether, n-hexane, cyclohexane, diethyl ether, n-butyl ether, etc.
Synthesis of 4-diphenylphosphoryloxybenzhydrol (DBM,2a) by accurately weighing 4-diphenylphosphoryloxybenzophenone (1a) (800mg, 2mmol, 1equiv) in a 100mL reaction flask, adding 20mL of methanol solution, placing in an ice bath, stirring for 30min, and adding sodium borohydride NaBH to the reaction system in three batches4(92mg, 2.4mmol, 1.2equiv), adding a balloon, transferring to room temperature, sealing, reacting for 2h, detecting by TLC, adding saturated ammonium chloride to quench the reaction after the raw materials are completely consumed, concentrating to remove a methanol solution, adding 10mL of deionized water, extracting by ethyl acetate to obtain an organic phase, and drying by anhydrous magnesium sulfate. After the mixture was evaporated to dryness, 0.5mL of ethyl acetate was added to dissolve the sample sufficiently, and 5mL of n-Hexane (VEA/VN-Hexane ═ 1:10) was added dropwise to remove the solvent from the systemA large amount of white precipitate was present, which was filtered and dried to give the objective compound (2a) in about 97% yield. Structural characterization:1H NMR(400MHz,CDCl3),δ＝7.89-7.84(m,4H),7.56-7.52(m,2H),7.48-7.43(m,4H),7.31-7.23(m,7H),7.14-7.12(d,2H),5.74(s,1H),2.99(s,1H)ppm；31PNMR(162MHz,CDCl3),δ＝30.58ppm；13CNMR(100MHz,CDCl3),δ＝150.0,143.9,140.6,132.5,131.8,131.7,130.1,128.7,128.6,128.4,128.0,127.4,126.6,120.6,75.4ppm；HRMS(ESI)m/z calcd for C25H22O3P+(M+H)+＝401.13011,found:401.12985。
the solvent in the reaction system can be one or more of alcohols, acetonitrile, tetrahydrofuran and the like.
The reducing agent is: NaBH4、H2/Pd/C、B2H4Or LiAlH4。
The alkane or ether solvent is one or more of petroleum ether, n-hexane, cyclohexane, diethyl ether, n-butyl ether, etc.
Synthesis of 4-Diphenylphosphoryloxy benzophenone oxime (DBO,3a) 4-Diphenylphosphoryloxy benzophenone (DBK,1a) (800mg, 2mmol, 1equiv) was accurately weighed into a 100mL reaction flask, 50mL of anhydrous ethanol solution was added, 5mL of Pyridine (EtOH: 10:1) was added with stirring, and NH was subsequently added2OH & HCl (280mg, 4mmol, 2equiv), stirring at room temperature for 10h, concentrating to remove ethanol solvent and part of pyridine after reaction, adding 50mL ethyl acetate to dissolve, adding diluted HCl to wash twice continuously, removing residual pyridine and excess hydroxylamine, drying with anhydrous magnesium sulfate for 2h, adding 0.5mL ethyl acetate to fully dissolve sample after spin-drying, and adding 4mL n-hexane dropwise (V)EA/VN-Hexane1:8), a large amount of white precipitate appeared in the system, and the white precipitate was filtered and dried to obtain the target compound (3a) in about 92% yield. Structural characterization:1HNMR(400MHz,CDCl3),δ＝9.50(s,1H),7.99-7.90(m,4H),7.59-7.28(m,14H),7.22-7.20(m,1H)ppm；31PNMR(162MHz,CDCl3),δ＝31.09ppm；13CNMR(100MHz,CDCl3),δ＝156.5,151.3,136.4,132.7,131.9,131.3,130.0,129.8,129.3,129.0,128.8,128.6,128.3,128.0,120.4ppm；HRMS(ESI)m/z calcd for C25H22O3P+(M+H)+401.13011,found:401.29789。
the solvent in the reaction system can be tetrahydrofuran THF, acetonitrile, benzene, toluene, chloroform CHCl3One or more of dichloromethane DCM, N-dimethylformamide DMF and N-methylpyrrolidone NMP organic solvent.
The alkali is one or more of organic alkali such as tertiary amine TEA, DIEA, NMM, pyridine and its derivative DMAP.
The alkane or ether solvent is one or more of petroleum ether, n-hexane, cyclohexane, diethyl ether, n-butyl ether, etc.
4-Diphenylphosphoryloxy-benzhydryltyrosine ester [ DBM-O-Tyr (OtBu) -Fmoc, 4a]The synthesis of (2): accurately weighing 4-diphenylphosphoryloxybenzhydrol (DBM,2a) (200mg, 0.5mmol, 1equiv) into a 100mL reaction bottle, adding 30mL DCM for dissolution, sequentially adding Fmoc-Tyr (OtBu) -OH (276mg, 0.6mmol, 1.2equiv), 4-dimethylaminopyridine DMAP (7.32mg, 0.06mmol, 0.12equiv), dicyclohexylcarbodiimide DCC (123mg, 0.6mol, 1.2equiv) into the reaction system, reacting for 2h at room temperature, cooling to 0 ℃ after TLC detection reaction is finished, filtering to obtain filtrate, concentrating, adding ethyl acetate 30mL for dissolution, sequentially using saturated NH4Aqueous Cl solution and saturated Na2CO3The solution was washed and dried over anhydrous magnesium sulfate. After rotary evaporation and concentration, a sample is dissolved by using 1mL of ethyl acetate, 6mL of n-Hexane (VEA/VN-Hexane ═ 1:6) is added dropwise, a large amount of white precipitates appear in a system, the white precipitates are filtered and dried to obtain a target compound DBM-O-Tyr (tBu) -Fmoc (4a), the yield is about 95%, the target compound DBM-O-Tyr (tBu) -Fmoc can be used as a raw material to be fed in the next step after one-time precipitation, and the sample can be subjected to NMR characterization after 2-3-. Structural characterization:1HNMR(400MHz,CDCl3),δ＝7.93-7.88(m,4H),7.80-7.78(d,2H),7.59-7.54(m,4H),7.50-7.40(m,6H),7.33-7.20(m,11H),6.87(s,1H),6.82-6.79(d,4H),5.32-5.29(d,1H),4.79-4.74(m,1H),4.44-4.32(m,2H),4.23-4.19(m,1H),3.16-3.10(m,2H),1.34(s,9H)ppm；31PNMR(162MHz,CDCl3),δ＝30.86ppm；13CNMR(100MHz,CDCl3),δ＝170.6,155.6,154.5,150.5,143.8,141.3,139.1,135.7,132.6,131.8,130.2,129.8,129.1,128.7,128.6,128.1,127.7,127.1,125.1,124.1,120.8,120.0,78.4,67.0,54.8,47.2,37.4,33.9,28.9ppm；HRMS(ESI)m/z calcd for C53H49NO7P+(M+H)+＝842.32412,found:842.32422.
synthesis of 4-diphenylphosphoryloxydiphenylmethanone oxime Boc-valine ester (DBO-O-Val-Boc,5a) by accurately weighing 4-diphenylphosphoryloxydiphenylmethanone oxime (DBO,3a) (206mg, 0.5mmol, 1equiv) in a 100mL reaction flask, adding 30mL DCM for dissolution, sequentially adding Boc-Val-OH (130mg, 0.6mmol, 1.2equiv), 4-dimethylaminopyridine DMAP (7.32mg, 0.06mmol, 0.12equiv), dicyclohexylcarbodiimide (123mg, 0.6mol, 1.2equiv) to the reaction system, reacting at room temperature for 2h, detecting by TLC, cooling to 0 deg.C, filtering to obtain a filtrate, concentrating, adding ethyl acetate 30mL for dissolution, sequentially adding saturated NH4Aqueous Cl solution, saturated NaHCO3The solution was washed, dried over anhydrous magnesium sulfate, concentrated, and the sample was dissolved in 0.5mL of ethyl acetate, and 6mL (V) of n-hexane was added dropwiseEA/VN-Hexane1: 12) and (3) a large amount of white precipitates appear in the system, the white precipitates are filtered and dried to obtain a compound GAP-C ═ N-O-Val-Boc (5a), the yield is about 98%, the compound GAP-C ═ N-O-Val-Boc can be used as a raw material for feeding in the next step after one-time precipitation, and the sample can be subjected to NMR characterization after 2-3 times of continuous washing. Structural characterization:1HNMR(400MHz,CDCl3),δ＝7.97-7.87(m,4H),7.61-7.21(m,15H),5.04-5.02(m,1H),4.20-4.17(m,1H),1.95-1.90(m,1H),1.45(s,9H),0.88-0.77(m,6H)ppm；31PNMR(162MHz,CDCl3),δ＝30.66ppm；13CNMR(100MHz,CDCl3),δ＝169.9,164.9,155.5,151.9,134.2,132.7,132.1,131.8,131.7,131.2,130.6,129.8,129.1,128.8,128.7,128.4,128.3,120.5,79.9,57.7,31.3,28.3,18.8,17.6ppm；HRMS(ESI)m/z calcd for C35H37N2O6P+(M+H)+613.23892,found:613.23795。
synthesis of 4-diphenylphosphoryloxydiphenyl ketoxime valine ester (DBO-O-Val-Fmoc,5 a'), namely accurately weighing 4-diphenylphosphorusAcyloxybenzophenone oxime (DBO,3a) (206mg, 0.5mmol, 1equiv) was dissolved in 30mL of DCM in a 100mL reaction flask, Fmoc-Val-OH (203mg, 0.6mmol, 1.2equiv), 4-dimethylaminopyridine DMAP (7.32mg, 0.06mmol, 0.12equiv), dicyclohexylcarbodiimide DCC (123mg, 0.6mol, 1.2equiv) were sequentially added to the reaction system to react at room temperature for 2h, after the TLC detection reaction was completed, the reaction system was cooled to 0 deg.C and then filtered to obtain a filtrate, after concentration, ethyl acetate was added to dissolve the filtrate in 30mL, saturated NH was sequentially used to dissolve the filtrate4Aqueous Cl solution, saturated NaHCO3The solution was washed, dried over anhydrous magnesium sulfate, concentrated, and the sample was dissolved in 0.5mL of ethyl acetate, and 6mL (V) of n-hexane was added dropwiseEA/VN-Hexane1: 12) and a large amount of white precipitate appears in the system, the white precipitate is filtered and dried to obtain a compound GAP-C ═ N-O-Val-Fmoc (5a '), the yield is about 95%, the compound GAP-C ═ N-O-Val-Fmoc (5 a'), the yield can be used as a raw material for feeding in the next step after one-time precipitation, and the sample can be subjected to NMR characterization after 2-3-time continuous washing. Structural characterization:1HNMR(400MHz,CDCl3),δ＝7.95-7.89(m,4H),7.79-7.78(d,2H),7.62-7.25(m,21H),5.36-5.31(m,1H),4.43-4.39(m,2H),4.29-4.23(m,2H),2.01-1.99(m,1H),0.98-0.80(m,6H)ppm；31PNMR(162MHz,CDCl3),δ＝30.56ppm；13CNMR(100MHz,CDCl3),δ＝169.6,165.2,156.1,152.1,143.7,141.3,134.1,132.7,131.8,131.7,131.3,130.7,130.6,129.8,129.2,128.8,128.7,128.5,128.3,127.7,127.1,125.1,120.7,120.0,67.1,58.2,47.2,31.6,22.7,17.6ppm；HRMS(ESI)m/z calcd for C45H39N2O6P+(M+H)+735.25457,found:735.25534。

Claims (9)

1. a preparation method of Fmoc-amino acid ester derivative products is characterized by comprising the following steps:
step 1: adopt (RO)2POCl or POCl3Adding alkali into a solvent A for catalysis reaction with hydroxybenzaldehyde or hydroxybenzophenone as raw materials, performing rotary evaporation to recover the solvent after the reaction is finished, extracting the residual solution with ethyl acetate and separating the residual solution from a water phase, combining the organic phases and washing the organic phases with deionized water for multiple times;
then separating and purifying to obtain phosphoryloxy benzaldehyde or phosphoryloxy benzophenone compound 1, wherein the molecular structure general formula is as follows:
Figure FDA0003062346160000011
R1＝CH3，CH3O，C2H5，C2H5O，Ph，PhO，
Figure FDA0003062346160000012
R2＝CH3，CH3O，C2H5，C2H5O，Ph，PhO，
Figure FDA0003062346160000013
Figure FDA0003062346160000014
X＝NO2，F，Cl，Br，I，H，CH3，OCH3
the (RO)2POCl or POCl3The feeding ratio of the hydroxyl benzaldehyde to hydroxybenzaldehyde or hydroxybenzophenone is 1: 1-4;
step 2: taking the phosphoryloxy benzaldehyde or phosphoryloxy benzophenone compound 1 obtained in the step 1 as a raw material, carrying out hydrogenation reduction treatment reaction in a solvent B by using a reducing agent, recovering the solvent by rotary evaporation after the reaction is finished, extracting the residual solution by using ethyl acetate and separating the residual solution from a water phase, combining organic phases, and washing the organic phases for multiple times by using deionized water;
then the corresponding derivative product phosphoryloxy benzyl alcohol compound 2 of the compound 1 is obtained by separation and purification, and the molecular structural general formula is:
Figure FDA0003062346160000021
X＝NO2，F，Cl，Br，I，H，CH3，OCH3
and step 3: coupling reaction is carried out on the phosphoryloxy benzyl alcohol compound 2 obtained in the step 2 and Fmoc-protected amino acid Fmoc-AA-OH, and a derivative product of Fmoc-amino acid ester corresponding to the compound 2 is obtained through separation and purification, wherein the molecular structural general formula is as follows:
Figure FDA0003062346160000022
X＝NO2，F，Cl，Br，I，H，CH3，OCH3
AA＝amino acid。
2. the method of claim 1, further comprising: the separation and purification of the steps 1 to 3 are as follows: extracting with ethyl acetate, separating from the water phase, combining the organic phases, and washing with deionized water for 2-3 times; dropping alkane or ether solvent with small polarity into ethyl acetate solution until crystallization or precipitation is separated out, and filtering and washing or recrystallization to complete separation and purification.
3. The method of claim 1, further comprising: the reaction conditions of the alkali-added catalytic reaction or the hydrogenation reduction treatment reaction in the steps 1 to 2 are as follows: stirring for 2-3 hours at room temperature.
4. The method of claim 1, further comprising: the deionized water is used for washing for multiple times in the steps 1 to 2, and the times are 2-3.
5. The method of claim 1, further comprising: the solvent A in the step 1 and the step 2 is: tetrahydrofuran, acetonitrile, benzene, toluene, chloroform, dichloromethane, N-dimethylformamide and N-methylpyrrolidone.
6. The method of claim 1, further comprising: the alkali in the step 1 and the step 2 is one or more of tertiary amines TEA, DIEA, NMM, pyridine and DMAP.
7. The method of claim 1, further comprising: the solvent B in the step 2 is: one or more of alcohols, acetonitrile and tetrahydrofuran.
8. The method of claim 1, further comprising: the reducing agent in the step 2 is: NaBH4、H2/Pd/C、B2H4Or LiAlH4。
9. The method of claim 2, further comprising: the alkane or ether solvent is one or more of petroleum ether, n-hexane, cyclohexane, diethyl ether and n-butyl ether.
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