CN117003791A - Diphenylphosphinoyloxy bisphenol A compound and application thereof in preparation of whitening nonapeptide-1 - Google Patents

Diphenylphosphinoyloxy bisphenol A compound and application thereof in preparation of whitening nonapeptide-1 Download PDF

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CN117003791A
CN117003791A CN202310842932.XA CN202310842932A CN117003791A CN 117003791 A CN117003791 A CN 117003791A CN 202310842932 A CN202310842932 A CN 202310842932A CN 117003791 A CN117003791 A CN 117003791A
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nonapeptide
terminal
dpbpa
boc
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钦传光
石梦楠
杨露
刘淑鑫
乔宇欣
付立文
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Northwestern Polytechnical University
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    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • C—CHEMISTRY; METALLURGY
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    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • 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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    • C07F9/3258—Esters thereof the ester moiety containing a substituent or a structure which is considered as characteristic
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Abstract

The invention relates to a diphenyl phosphonooxy bisphenol A compound and application thereof in preparation of whitening nonapeptide-1, and belongs to the technical field of organic synthesis. The DPBPA structural general formula of the diphenylphosphinoyloxy bisphenol A compound is shown below. The invention also provides a preparation method of the DPBPA compound for whitening nonapeptide-1H-Met-Pro- D Phe‑Arg‑ D Trp‑Phe‑Lys‑Pro‑Val‑NH 2 The application of the compound and the preparation method of DPBPA auxiliary whitening nonapeptide-1. The invention relates to a liquid phase synthesis method of a nonapeptide-1 assisted by taking DP BPA as a carrier, which utilizes the assisted precipitation effect of the DPBPA carrier and passes through liquidThe same reaction is coupled with equivalent amino acid and the strategy of removing Boc protection optimizes and simplifies the preparation method of the nonapeptide-1, and verifies the recoverability and reusability of the DPBPA carrier.

Description

Diphenylphosphinoyloxy bisphenol A compound and application thereof in preparation of whitening nonapeptide-1
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a diphenylphosphinoyloxy bisphenol A compound and application thereof in preparation of whitening nonapeptide-1.
Background
A whitening and skin-brightening bionic peptide (also called as nine peptide-1, nonapeptide-1 or Melanostatine) is composed of nine amino acid molecules with the amino acid sequence of H-Met-Pro- D Phe-Arg- D Trp-Phe-Lys-Pro-Val-NH 2 . The nonapeptide-1 is an alpha-MSH antagonist, can inhibit the process by competing with alpha-MSH for binding MC1-R, thereby forming a reversible inhibition effect on melanin generation, can act on skin with high specificity, can competitively bind with various factor signals to the receptor on melanocytes, and inhibit the activation of tyrosinase by melanocytes, thereby reducing melanin generation, and research results show that the nonapeptide-1 competitively seals the receptor on melanocytes and the entrance of various factor signals, weakens the activity of the melanocytes, reduces the melanin generation amount, starts to gradually and evenly color the skin after 14 days, obviously lightens the skin color, ruddiness and whiteness of the skin after 28 days, and therefore the nonapeptide-1 is often used as a cosmetic raw material. It has effects of inhibiting melanin formation, whitening skin, removing speckle, and reducing fine wrinkles, and can be used for research and development of adrenal steroid, skin cancer, etc.
The existing polypeptide production method mainly adopts the traditional biosynthesis and solid-phase chemical synthesis method, and has the problems of complicated separation and purification steps, large waste of raw materials and solvents, and serious environmental pollution caused by the fact that resin solid wastes are large and difficult to degrade.
Disclosure of Invention
Aiming at the defects of the prior art, such as environmental pollution, poor selectivity, high price and the like, the invention provides a diphenylphosphonooxy bisphenol A compound and application thereof in preparing whitening nonapeptide-1, and mainly solves the problems of more liquid phase reaction steps, long time consumption period, high content of byproduct beta-type isomer, difficult separation and impurity removal, low product purity, small purification scale, high production cost, small production scale of solid phase reaction, high raw material price, high waste, more resin wastes and serious environmental pollution of the prior nonapeptide-1 chemical synthesis method.
The invention provides a diphenyl phosphonooxy bisphenol A compound, which has the following structural general formula:
wherein R is 1 ＝R 2 ＝H。
The invention provides an application of diphenyl phosphonooxy bisphenol A compounds in preparing whitening nonapeptide-1.
The invention provides a preparation method of diphenyl phosphonooxy bisphenol A compound assisted whitening nonapeptide-1, which comprises the following steps:
taking diphenylphosphonooxy bisphenol A compounds as auxiliary groups, carrying out coupling reaction and N-terminal protecting group removal reaction on the auxiliary groups respectively with N-terminal protected valyl acid, N-terminal protected proline, N-terminal and side chain protected lysine, N-terminal protected phenylalanine, N-terminal protected D-tryptophan, N-terminal and side chain protected arginine, N-terminal protected D-phenylalanine and N-terminal protected proline in sequence, and carrying out coupling reaction on the auxiliary groups with N-terminal protected methionine after the reaction is finished to obtain a precursor C of the nonapeptide;
and shearing auxiliary groups from the compound C, removing protective groups on side chains, and purifying to obtain the whitening nonapeptide-1.
Preferably, the precursor C of the nonapeptide-1 is prepared according to the following steps:
s1, taking a diphenylphosphinoyloxy bisphenol A compound as a carrier, reacting with N-terminal protected valyl acid under the action of a coupling agent, and purifying to obtain a product A;
s2, removing the N-terminal protecting group in the purified product A, and purifying to obtain a product B;
s3, repeating the steps S1 and S2, taking a product B as a carrier, respectively replacing N-terminal protected valyl acid with N-terminal protected proline, N-terminal and side chain protected lysine, N-terminal protected phenylalanine, N-terminal protected D-tryptophan, N-terminal and side chain protected arginine, N-terminal protected D-phenylalanine and N-terminal protected proline in sequence, carrying out coupling reaction and N-terminal protecting group removal treatment reaction, and carrying out coupling reaction with N-terminal protected methionine after the reaction is finished to obtain a precursor C of the nonapeptide-1.
More preferably, the N-terminal protecting group comprises Fmoc or Boc.
More preferably, the protecting group of the side chain comprises Fmoc, boc, pbf or tBu.
More preferably, the structural formula of the product B is as follows:
more preferably, the structural formula of the precursor C of the nonapeptide is as follows:
wherein the N-terminal protecting group is Boc, and the protecting group of the side chain is Fmoc.
More preferably, the compound C is sheared off the auxiliary group, so as to obtain a crude auxiliary group;
dissolving the crude auxiliary group in proper amount of ethyl acetate, adding alkane or ether solvent, and separating the auxiliary group from other impurities; filtering, washing or recrystallizing the separated auxiliary group to obtain a purified auxiliary group.
Compared with the prior art, the invention has the beneficial effects that:
the invention provides a diphenylphosphonooxy bisphenol A compound and application thereof in preparing whitening nonapeptide-1, wherein DPBPA is mainly used as a carrier for assisting a liquid phase synthesis method of the nonapeptide-1, and the recovery and reusability of the DPBPA carrier are verified by utilizing the assisting precipitation effect of the DPBPA carrier, coupling with equivalent amino acid and removing Boc protection strategies through liquid phase reaction, optimizing and simplifying the preparation method of the nonapeptide-1. In addition, the present design developed two new strategies to simplify the synthesis of nonapeptide-1. Solves the problems of low yield, more byproducts, complex production process and the like existing in the prior biosynthesis and chemical synthesis, enhances the greenization and the scale of the synthesis process of the nonapeptide-1, and is beneficial to emission reduction, consumption reduction, cost saving, environmental protection and sustainable development.
Detailed Description
The invention is further illustrated below in connection with specific embodiments, but it should be understood that the examples are presented merely to facilitate an understanding of the core method and field of application of the invention, and the scope of the invention is not limited thereto.
The experimental methods and the detection methods described in the following examples are all conventional methods unless otherwise specified; the reagents and materials are commercially available unless otherwise specified.
The invention provides a diphenylphosphinoyloxy bisphenol A compound (DPBPA), which has the structural general formula:
wherein R is 1 ＝R 2 ＝H。
In one embodiment, the diphenylphosphinoyloxy bisphenol A small molecule carrier DPBPA is prepared: and (3) reacting diphenylphosphonic chloride with bisphenol A under alkaline conditions, and separating and purifying to obtain DPBPA.
The invention provides an application of diphenyl phosphonooxy bisphenol A compounds in preparing whitening nonapeptide.
The invention provides a preparation method of diphenyl phosphonooxy bisphenol A compound assisted whitening nonapeptide-1, which comprises the following steps:
taking diphenylphosphonooxy bisphenol A compounds as auxiliary groups, carrying out coupling reaction and N-terminal protecting group removal reaction on the auxiliary groups respectively with N-terminal protected valyl acid, N-terminal protected proline, N-terminal and side chain protected lysine, N-terminal protected phenylalanine, N-terminal protected D-tryptophan, N-terminal and side chain protected arginine, N-terminal protected D-phenylalanine and N-terminal protected proline in sequence, and carrying out coupling reaction on the auxiliary groups with N-terminal protected methionine after the reaction is finished to obtain a precursor C of the nonapeptide;
and shearing auxiliary groups from the compound C, removing protective groups on side chains, and purifying to obtain the whitening nonapeptide-1.
Wherein, the precursor C of the nonapeptide is prepared according to the following steps:
s1, taking a diphenylphosphinoyloxy bisphenol A compound as a carrier, reacting with N-terminal protected valyl acid under the action of a coupling agent, and purifying to obtain a product A;
s2, removing the N-terminal protecting group in the purified product A, and purifying to obtain a product B;
the structural formula of the product B is as follows:
s3, repeating the steps S1 and S2, taking a product B as a carrier, sequentially replacing N-terminal protected valyl acid with N-terminal protected proline, N-terminal and side chain protected lysine, N-terminal protected phenylalanine, N-terminal protected D-tryptophan, N-terminal and side chain protected arginine, N-terminal protected D-phenylalanine and N-terminal protected proline respectively, performing a coupling reaction and an N-terminal protecting group removal treatment reaction, and performing a coupling reaction with N-terminal protected methionine after the reaction is finished to obtain a nine-peptide precursor C;
specifically, the N-terminal protecting group includes Fmoc or Boc; protecting groups for the side chains include Fmoc, boc, pbf or tBu.
In one embodiment, the preparation method of the diphenylphosphinoyloxy bisphenol A compound assisted whitening nonapeptide-1 specifically comprises the following steps:
step 1, coupling of an auxiliary group with a first amino acid: an auxiliary group (DPBPA) is used for replacing resin in solid-phase polypeptide synthesis, and is reacted with N-terminal protected valyl acid (Boc-Val-OH) for 103 hours under the action of a coupling agent under stirring at 0050 ℃ to obtain a product A; the molar ratio of the amino acid to DPBPA is 1-1.2:1; the coupling agent is a dehydration coupling activator and an alkaline substance at a molar ratio of 1-1.2:1;
the auxiliary group is diphenylphosphinoyloxy bisphenol A compound (DPBPA);
after the DPBPA is coupled with Boc-Val-OH, the generated intermediate compound is Boc-Val-DPBP A;
step 2, separation and purification: adding 10-15 times of alkane or ether solvent with small polarity into the product A, and separating the product A from other impurities by virtue of the characteristic that DPBPA auxiliary groups are easy to crystallize and precipitate in a solvent system;
filtering, washing or recrystallizing the separated product A to obtain a purified product A, boc-Val-DPBPA;
step 3, removing N-terminal protecting group Boc: the purified product A is treated by a Boc removing reagent and is stirred to react for 0.502 hour at 10050 ℃, or is treated by a Boc removing reagent and is stirred to react for 0.502 hour at 10050 ℃ to obtain a Boc removing product B, H-Val-DPBPA;
adding an alkane or ether solvent with small polarity into the product B, and separating the product B from other impurities by virtue of the characteristic that DPBPA auxiliary groups are easy to crystallize and precipitate in a solvent system;
filtering, washing or recrystallizing the separated product B to obtain a purified product B;
the structural formula of the product B is as follows:
step 4: coupling the second amino acid to peptide chain extension: repeating the steps (2) and (3) by taking a purified product B containing an auxiliary group DPBPA as a carrier, sequentially replacing N-terminal protected valyl acid with N-terminal protected proline, N-terminal and side chain protected lysine, N-terminal protected phenylalanine, N-terminal protected D-tryptophan, N-terminal and side chain protected arginine, N-terminal protected D-phenylalanine and N-terminal protected proline respectively, carrying out coupling reaction and N-terminal protecting group removal reaction, and carrying out coupling reaction with N-terminal protected methionine after the reaction is finished to obtain a precursor C of the nonapeptide-1; it should be noted that repeating the above steps (2) and (3) means repeating the coupling reaction and the N-terminal protecting group removal treatment reaction of steps (2) and (3);
wherein the N-terminal protecting group is Boc, and the lysine side chain protecting group is Fmoc; the arginine side chain protecting group is Pbf, specifically N-terminal protected proline Boc-Pro-OH, lysine Boc-Lys (Fmoc) -OH, phenylalanine Boc-Phe-OH, D-tryptophan Boc- D Trp-OH, arginine Boc-Arg (Pbf) -OH, D-phenylalanine Boc- D Coupling reaction and Boc removing reaction of Phe-OH and proline Boc-Pro-OH, and finally coupling reaction with methionine Boc-Met-OH to prepare precursor C of nonapeptide (Boc-Met-Pro- D Phe-Arg(Pbf)- D Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA)；
The structural formula of the precursor C of the nonapeptide is as follows:
wherein the N-terminal protecting group is Boc, and the protecting group of the side chain is Fmoc.
Step 5, cutting off a DPBPA carrier and removing a side chain protecting group Fmoc: with ammonia or its derivatives PG-NH 2 (PG＝BH 3, Boc, fmoc, H) as a shearing agent, said PG-NH 2 The proportion of the components in the solution is as follows: PG-NH 2 Solvent = 25% (volume ratio), the solvent is typically one or more of acetonitrile, ethanol, methanol, tetrahydrofuran, DMF, etc. Firstly treating the compound C obtained in the step (4), cutting off DPBPA auxiliary groups, and simultaneously removing the protecting group Fmoc on the lysine side chain to obtain a compound D, boc-Met-Pro- D Phe-Arg(Pbf)- D Trp-Phe-Lys-Pro-Val-NH-PG. Then treating compound D with cocktail reagent trifluoroacetic acid/triisopropylsilane/water=95:2.5:2.5 (volume ratio) as side chain deprotection agent, stirring for 103 hours at 5030 ℃, and performing one-pot processPartial removal of protecting groups on peptide chains and side chains such as Boc, pbf, tBu, etc.;
it should be noted that Fmoc and DPBPA carriers are mainly sheared and removed by an alkaline removing agent, and protecting groups Boc, pbf and tBu are removed by an acidic removing agent.
Dissolving the DPBPA crude product obtained in the step 5 in proper amount of ethyl acetate, adding alkane or ether solvents with small polarity, and separating the DPBPA from other impurities by virtue of the characteristic that the DPBPA is easy to crystallize and precipitate in different solvent systems; the separated DPBPA is filtered, washed or recrystallized to obtain purified DPBPA, and the purified DPBPA can be directly recycled or recycled to be used as an auxiliary group.
Step 6, separation and purification of the nonapeptide-1: concentrating the mixture after the one-pot treatment to one third of the original volume by rotary evaporation, precipitating with ether solvent (diethyl ether or methyl tert-butyl ether), filtering or centrifuging, washing the filter cake with cold ether, and drying to obtain purified nonapeptide-1E (H-Met-Pro) D Phe-Arg- D Tr p-Phe-Lys-Pro-Val-NH 2 )；
Step 7, a method for recycling DPBPA auxiliary groups: combining the ether solvent phases obtained in the step 6, concentrating by rotary evaporation to one third of the original volume, adding a hydrocarbon solvent with small polarity, and separating DPBPA from other impurities by virtue of the characteristic that DPBPA is easy to crystallize and precipitate in different solvent systems; filtering, washing or recrystallizing the separated precipitate to obtain purified DPBPA, and recycling the purified DPBPA as an auxiliary group directly or after regeneration.
Compared with the existing synthesis method, the preparation method of the diphenyl phosphonooxy bisphenol A compound assisted whitening nonapeptide-1 has the advantages of both liquid phase and solid phase synthesis methods, can synthesize and prepare the nonapeptide-1 more simply, conveniently, quickly, economically and efficiently, and the DPBPA carrier can be recovered and directly recycled, so that the raw material waste is reduced, the waste pollution is reduced, the cost is saved, and the environment protection is facilitated.
In the step 3, the intermediate compound of coupling N-terminal Boc-protected valine with carrier DPBPA is a product A (Boc-Val-DPBPA) and a product B thereof, namely a Boc-removal product, and the molecular structural formulas of the Boc-Val-DPBPA and the Boc-removal product B (H-Val-DPBPA) are respectively as follows in sequence: (1) Boc-Val-DPBPA:
(2)H-Val-DPBPA：
in the step 4, the intermediate compound Boc-Pro-OH coupling with the product B (H-Val-DPBPA) is Boc-Pro-Val-DPBPA, the Boc-Pro-Val-DPBPA has the molecular structural formula of the Boc-Pro-Val-DPBPA, and the Boc-Pro-Val-DPBPA has the molecular structural formula of the Boc-Pro-Val-DPBPA, respectively:
(3)Boc-Pro-Val-DPBPA：
(4)H-Pro-Val-DPBPA：
the molecular structural formulas of the intermediate compound Bo c-Lys (Fmoc) -Pro-Val-DPBPA with the coupling of lysine Boc-Lys (Fmoc) -OH and the H-Pro-Val-DPBPA are as follows:
(5)Boc-Lys(Fmoc)-Pro-Val-DPBPA：
(6)H-Lys(Fmoc)-Pro-Val-DPBPA：
the molecular structural formula of the intermediate compound Boc-Phe-Lys (Fmoc) -Pro-Val-DPBPA with Boc-removed product H-Phe-Lys (Fmoc) -Pro-Val-DPBPA is respectively as follows:
(7)Boc-Phe-Lys(Fmoc)-Pro-Val-DPBPA：
(8)H-Phe-Lys(Fmoc)-Pro-Val-DPBPA：
d-tryptophan Boc- D Intermediate compound Boc-derived from Trp-OH coupled with H-Phe-Lys (Fmoc) -Pro-Val-DPBPA D Trp-Phe-Lys (Fmoc) -Pro-Val-DPBPA with Boc-free product H- D Trp-Phe-Lys (Fmoc) -Pro-Val-DPBPA, the Boc- D Trp-Phe-Lys (Fmoc) -Pro-Val-DPBPA with Boc-free product H- D The molecular structural formula of Trp-Phe-Lys (Fmoc) -Pro-Val-DPBPA is respectively as follows:
(9)Boc- D Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA：
(10)H- D Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA：
arginine Boc-Arg (Pbf) -OH as described above D Intermediate compound Boc-Arg (Pbf) coupled by Trp-Phe-Lys (Fmoc) -Pro-Val-DPBPA D Trp-Phe-Lys (Fmoc) -Pro-Val-DPBPA with Boc-free product H-Arg (Pbf) D Trp-Phe-Lys (Fmoc) -Pro-Val-DPBPA, the Boc-Arg(Pbf)- D Trp-Phe-Lys (Fmoc) -Pro-Val-DPBPA with Boc-free product H-Arg (Pbf) D The molecular structural formula of Trp-Phe-Lys (Fmoc) -Pro-Val-DP BPA is respectively as follows:
(11)Boc-Arg(Pbf)- D Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA：
(12)H-Arg(Pbf)- D Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA：
d-phenylalanine Boc- D Phe-OH and the above H-Arg (Pbf) D Intermediate compound Boc-Phe-Lys (Fmoc) -Pro-Val-DP BPA coupling D Phe-Arg(Pbf)- D Trp-Phe-Lys (Fmoc) -Pro-Val-DPBPA with Boc-free product H- D Phe-Arg(Pbf)- D Trp-Phe-Lys (Fmoc) -Pro-Val-DPBPA, the Boc- D Phe-Arg(Pbf)- D Trp-Phe-Lys (Fmoc) -Pro-Val-DPBPA with Boc-free product H- D Phe-Arg(Pbf)- D The molecular structural formula of Trp-Phe-Lys (Fmoc) -Pro-Val-DPBPA is respectively as follows:
(13)Boc- D Phe-Arg(Pbf)- D Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA：
(14)H- D Phe-Arg(Pbf)- D Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA：
proline Boc-Pro-OH and the above-mentioned H- D Phe-Arg(Pbf)- D Intermediate compound Boc-Pro-Phe-Lys (Fmoc) -Pro-Val-DP BPA coupling D Phe-Arg(Pbf)- D Trp-Phe-Lys (Fmoc) -Pro-Val-DP BPA and its removalBoc product H-Pro- D Phe-Arg(Pbf)- D Trp-Phe-Lys (Fmoc) -Pro-Val-DPBPA, the Boc-Pro- D Phe-Arg(Pbf)- D Trp-Phe-Lys (Fmoc) -Pro-Val-DPBPA and its Boc-free product H-Pro- D Phe-Arg(Pbf)- D The molecular structural formulas of Trp-Phe-Lys (Fmoc) -Pro-Val-DPBPA are respectively as follows:
(15)Boc-Pro- D Phe-Arg(Pbf)- D Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA：
(16)H-Pro- D Phe-Arg(Pbf)- D Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA：
methionine Boc-Met-OH and H-Pro- D Phe-Arg(Pbf)- D Intermediate compound Boc-Met-Pro for Trp-Phe-Lys (Fmoc) -Pro-Val-DPBPA coupling D Phe-Arg(Pbf)- D Trp-Phe-Lys (Fmoc) -Pro-Val-DPBPA, the Boc-Met-Pro- D Phe-Arg(Pbf)- D The molecular structural formula of Trp-Phe-Lys (Fmoc) -Pro-Val-DPBP A is as follows:
(17)Boc-Met-Pro- D Phe-Arg(Pbf)- D Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA：
treating the precursor (17) of the above-mentioned nonapeptide-1 with an ammonia solution to obtain an Fmoc-removed intermediate compound Boc-Met-Pro-after cleavage of DPBPA and removal of lysine side chains D Phe-Arg(Pbf)- D Trp-Phe-Lys-Pro-Val-NH 2 The Boc-Met-Pro- D Phe-Arg(Pbf)- D Trp-Phe-Lys-Pro-Val-NH 2 The molecular structural formula is:
(18)Boc-Met-Pro- D Phe-Arg(Pbf)- D Trp-Phe-Lys-Pro-Val-NH 2 ：
the coupling agent used in the invention is 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride DECI.
According to the invention, the compound C is sheared off the auxiliary group, and a crude auxiliary group product is obtained;
dissolving the crude auxiliary group in proper amount of ethyl acetate, adding alkane or ether solvent, and separating the auxiliary group from other impurities; filtering, washing or recrystallizing the separated auxiliary group to obtain a purified auxiliary group.
In one embodiment, TFA/TIPS/H is used 2 O deprotection reagent treatment of the precursor (18) of the above-mentioned nonapeptide-1, and removal of all protecting groups such as Boc at N-terminus and Pbf at arginine side chain on the peptide chain, the resulting compound H-Met-Pro- D Phe-Arg- D Trp-Phe-Lys-Pro-Val-NH 2 The target product, namely the crude product of the target product, namely the nonapeptide-1. The product of the nonapeptide-1 meeting the quality requirement can be obtained after purification and refining.
Some of the abbreviations commonly used in the present invention have the following meanings:
boc: t-butoxycarbonyl; cbz: benzyloxycarbonyl (Benzyloxycarbonyl); DCM: dichloromethane CH 2 Cl 2 The method comprises the steps of carrying out a first treatment on the surface of the DEA: diethylamine; DMAP 4-dimethylaminopyridine; DMF is N, N-dimethylformamide; DP BPA: diphenylphosphinoyloxy bisphenol A (4-Diphenylphosphinoxyl Bisphenol A); EDC-HCl 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride; fmoc: fluorenylmethoxycarbonyl; HATU 2- (7-oxybenzotriazole) -N, N' -tetramethyluronium hexafluorophosphate; HBTU O-benzotriazol-tetramethyluronium hexafluorophosphate; HOBT: 1-hydroxybenzotriazole; HRMS: high resolution mass spectrometry; NMM N-methylmorpholine; NMP N-methylpyrrolidone; NP-1: nonapeptide-1; pyBop: benzotriazol-1-yl-oxy-tripyrrolidinylphosphine hexafluorophosphate; TEA: triethylamine; TFA: trifluoroacetic acid; THF: tetrahydrofuran; TIPS: triisopropylsilane.
The following examples provide specific synthetic methods for preparing the above compounds and the corresponding intermediate compounds.
Example 1
A preparation method of diphenyl phosphonooxy bisphenol A compound assisted whitening nonapeptide-1 comprises the following steps:
the synthetic route is as follows:
DPBPA is sequentially and respectively combined with N-terminal protected valine Boc-Val-OH, proline Boc-Pro-OH, lysine Boc-Lys (Fmoc) -OH, phenylalanine Boc-Phe-OH and D-tryptophan Boc-OH D Trp-OH, arginine Boc-Arg (Pbf) -OH, D-phenylalanine Boc- D Coupling reaction and Boc removing reaction of Phe-OH and proline Boc-Pro-OH, and coupling reaction with methionine Boc-Met-OH to prepare precursor C of nonapeptide, boc-Met-Pro- D Phe-Arg(Pbf)- D The Trp-Phe-Lys (Fmoc) -Pro-Val-DPBPA is coupled to synthesize a nonapeptide derivative, and a proper route is explored through shearing and removing side chain groups of a carrier to finally obtain the nonapeptide, so that the application and the recoverability of the DPBPA in peptide synthesis are verified.
The specific synthesis steps are as follows:
coupling of DPBPA to the first amino acid: the coupling system of the esterification coupling reaction of the DPBPA carrier and the first amino acid Boc-Val-OH is EDCI coupling agent and DMAP catalyst, wherein the mol ratio of the DPBPA carrier, the first amino acid Boc-Val-OH, the EDCI coupling agent and the DMAP catalyst is 1:1.2-1.5:1.2-1.5:0.12-0.15. Stirring for about 2 hours at room temperature, separating and purifying by DPBPA auxiliary precipitation method after the coupling reaction is completed to obtain a coupling product (1) Boc-Val-DPBPA
Removing the Boc protecting group: the reaction was completed using 25% TFA/DCM system for about 1-1.5 h. Separating and purifying by DPBPA auxiliary precipitation method to obtain the product (2) H-Val-DPBPA without Boc
Extension of peptide chain: in the subsequent amide bond forming process of H-Val-DPBPA, the molar ratio of amino acid to coupling agent EDCI, HOBt, DIEA is 1:1.2:1.2:0.12, EDCI, HOBt, DIEA and amino acid are weighed in sequence, and a proper amount of dichloromethane is usedDissolving alkane, placing in ice-water bath for activating for 0.5h, dripping the compound to be coupled, reacting at room temperature, and finishing the reaction for 1.5 h. Sequentially with saturated NH 4 Cl solution, saturated NaHCO 3 The solution was washed 2 times and then precipitated (volume ratio about 10:1) using DCM/MTBE system and purified by solid-liquid separation by filtration or centrifugation. According to the target sequence, the amino acids are N-terminal protected proline Boc-Pro-OH, lysine Boc-Lys (Fmoc) -OH, phenylalanine Boc-Phe-OH and D-tryptophan Boc- D Trp (Fmoc) -OH, arginine Boc-Arg (Fmoc) -OH, D-phenylalanine Boc- D Phe-OH, proline Boc-Pro-OH, methionine Boc-Met-OH. The precursor compound (17) Boc-Met-Pro-peptide of the nonapeptide-1 is obtained after proper separation and purification D Phe-Arg(Pbf)- D Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA。
Noteworthy matters are: when the 6 th amino acid Boc-Arg (Pbf) -OH is coupled, the amino acid is activated according to the operation, the coupling is not successful, the reaction of attempting to adjust the proportion of the amino acid and the coupling agent, prolonging the reaction time, increasing the reaction temperature and the like is not performed, and the arginine is deduced to undergo self-polymerization reaction in the activation process, so that the coupling with H-Trp-Phe-Lys (Fmoc) -Pro-Val-DPBPA is not successful. The method is to omit the activation time, add amino acid, coupling agent, raw material to be coupled and the like into the reaction system at the same time, react at room temperature, and finally successfully couple. The intermediates of each step in the synthesis of nonapeptide-1 and the yields are shown in Table 1.
TABLE 1 intermediate of each step in the synthesis of nonapeptide-1 and yield thereof
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Specific structural characterization data for intermediate compounds obtained at each step in the synthesis of nonapeptide-1 are as follows:
Boc-Val-DPBPA(1)： 1 HNMR(400MHz,DMSO-d 6 )δ7.95–7.82(m,4H),7.68–7.37(m,7H),7.16(s,6H),6.95(d,J＝8.6Hz,2H),4.02(d,J＝7.0Hz,1H),2.15(h,J＝6.8Hz,1H),1.58(s,6H),1.40(d,J＝5.3Hz,9H),0.98(d,J＝6.6Hz,6H)； 13 CNMR(101MHz,DMSO-d 6 )δ148.61,146.72,133.16,131.97,131.86,129.44,129.31,128.32,128.03,121.41,120.46,60.18,39.96,30.83,30.00,28.63,19.49； 31 PNMR(162MHz,DMSO-d 6 )δ28.99；HRMS(ESI)m/zcalc dforC 37 H 42 NO 6 PNa + (M+Na) + 650.26420,found650.26392.
H-Val-DPBPA(2)： 1 HNMR(400MHz,DMSO-d 6 )δ8.52(s,2H),7.89(dd,J＝12.3,7.
1Hz,4H),7.66–7.53(m,6H),7.25(d,J＝8.7Hz,2H),7.17(s,4H),7.07(d,J＝8.7Hz,2H),4.22(s,1H),2.36–2.27(m,1H),1.60(s,6H),1.08(dd,J＝12.1,6.9Hz,6H)； 13 CNMR(101MHz,DMSO-d 6 )δ168.34,148.89,147.81,133.20,131.85,130.76,129.48,128.35,121.24,120.50,57.78,42.38,30.81,30.04,18.74,18.14； 31 PNMR(162MHz,DMSO-d 6 )δ29.00；HRMS(ESI)m/zcalcdforC 32 H 35 NO 4 P + (M+H) + 528.22982,found528.22980.
Boc-Pro-Val-DPBPA(3)： 1 HNMR(400MHz,DMSO-d 6 )δ8.33(s,1H),7.89(dd,J＝12.3,7.6Hz,4H),7.65–7.53(m,6H),7.17(d,J＝8.6Hz,6H),6.95(d,J＝8.6Hz,2H),4.27(s,2H),3.27(s,2H),2.21(s,2H),1.77(s,4H),1.58(s,5H),1.36(d,J＝25.5Hz,9H),1.02(d,J＝6.7Hz,6H)； 13 CNMR(101MHz,DMSO-d 6 )δ173.71,173.19,170.89,154.06,153.73,148.99,148.90,148.58,148.15,146.71,133.14,132.12,131.96,131.86,130.76,129.45,129.32,128.32,128.04,121.38,120.51,120.46,78.81,59.34,58.44,46.97,42.29,31.45,30.82,28.48,24.29,23.43； 31 PNMR(162MHz,DMSO-d 6 )δ28.99；HRMS(ESI)m/zcalcdforC 42 H 49 N 2 O 7 PNa + (M+Na) + 747.31696,found747.31671.
H-Pro-Val-DPBPA(4)： 1 HNMR(400MHz,DMSO-d6)δ9.54(s,1H),8.99(d,J＝7.
3Hz,1H),8.62(s,1H),7.90(dd,J＝12.3,7.1Hz,4H),7.65–7.52(m,6H),7.23–7.15(m,6H),6.97(d,J＝8.6Hz,2H),4.39–4.31(m,1H),3.24(ddd,J＝24.5,14.8,9.6Hz,2H),2.31(dh,J＝26.6,6.5Hz,2H),2.04–1.73(m,1H),1.58(s,6H),1.04(dd,J＝6.7,2.4Hz,6H)；HRMS(ESI)m/zcalcdforC 42 H 50 N 2 O 7 P + (M+H) + 625.28000,found625.28290.
Boc-Lys(Fmoc)-Pro-Val-DPBPA(5)： 1 HNMR(400MHz,DMSO-d6)δ8.32(d,J＝7.0Hz,1H),7.93–7.84(m,6H),7.70–7.53(m,8H),7.41(t,J＝7.5Hz,2H),7.32(dd,J＝13.4,6.2Hz,2H),7.16(d,J＝4.1Hz,6H),6.93(d,J＝8.4Hz,2H),4.35–4.07(m,6H),3.62(dd,J＝13.7,5.2Hz,1H),3.55–3.50(m,1H),2.97(s,2H),2.25–1.75(m,9H),1.57(s,8H),1.35(d,J＝12.9Hz,11H),1.03–0.96(m,6H)； 13 CNMR(101MHz,DMSO-d 6 )δ170.74,156.54,155.93,144.39,133.14,131.96,131.85,129.32,128.31,128.01,127.49,121.38,120.56,120.45,78.33,65.67,59.26,55.38,52.49,47.24,42.29,30.83,28.69,23.00,18.75； 31 PNMR(162MHz,DMSO-d6)δ28.98；HRMS(ESI)m/zcalcdforC 63 H 71 N 4 O 10 PNa + (M+Na) + 1097.48000,found1097.48083.
H-Lys(Fmoc)-Pro-Val-DPBPA(6)： 1 HNMR(400MHz,DMSO-d 6 )δ8.50(d,J＝7.
5Hz,1H),8.18(s,2H),7.90(dd,J＝12.8,7.8Hz,6H),7.68(d,J＝7.0Hz,2H),7.63–7.58(m,2H),7.57–7.51(m,4H),7.40(t,J＝7.3Hz,2H),7.34–7.29(m,2H),7.14(q,J＝9.1,8.4Hz,6H),6.93(d,J＝8.4Hz,2H),4.60(s,1H),4.43–4.37(m,1H),4.31(d,J＝6.9Hz,2H),4.22(t,J＝6.5Hz,1H),4.19–4.12(m,1H),3.01(s,2H),2.19(d,J＝32.6Hz,2H),1.97(s,1H),1.84(s,1H),1.74(s,2H),1.55(s,7H),1.44(s,4H),1.23(d,J＝12.2Hz,3H),1.06–0.99(m,6H)； 13 CNMR(101MHz,DMSO-d 6 )δ172.15,170.71,167.51,159.12,158.76,156.57,148.98,148.49,148.16,146.70,144.36,141.20,133.14,132.13,131.94,131.84,130.77,128.28,127.99,127.48,125.56,121.34,120.55,117.55,114.66,65.72,58.06,55.32,51.31,47.24,42.26,30.77,30.39,30.10,29.58,25.09,21.40,19.44,18.64； 31 PNMR(162MHz,DMSO-d 6 )δ29.05；HRMS(ESI)m/zcalcdforC 58 H 63 N 4 O 8 PNa + (M+Na) + 997.42757,found997.42725.
Boc-Phe-Lys(Fmoc)-Pro-Val-DPBPA(7)： 1 HNMR(400MHz,DMSO-d6)δ8.35(d,J＝7.4Hz,1H),8.04(d,J＝7.6Hz,1H),7.92–7.86(m,6H),7.70–7.52(m,9H),7.40(t,J＝7.3Hz,2H),7.34–7.24(m,7H),7.16(d,J＝12.1Hz,7H),6.93(d,J＝8.5Hz,2H),4.55–4.26(m,5H),4.19(t,J＝6.8Hz,2H),3.68–3.52(m,2H),3.01–2.92(m,3H),2.74–2.66(m,1H),2.20(dt,J＝13.2,6.9Hz,1H),2.09–2.00(m,1H),1.88–1.80(m,2H),1.57(s,6H),1.41–1.36(m,2H),1.29(s,9H),1.23(d,J＝8.8Hz,5H),1.00(dd,J＝6.4,3.4Hz,6H)； 13 CNMR(101MHz,DMSO-d 6 )δ174.10,172.57,171.86,171.27,170.75,170.34,156.52,155.65,148.97,148.52,148.14,146.71,144.37,141.18,138.61,135.22,133.16,132.12,131.96,131.86,129.66,128.86,128.01,127.50,126.61,125.61,121.39,120.56,120.45,78.52,65.68,59.29,58.68,58.12,56.08,55.64,50.61,49.07,47.21,42.29,37.90,36.71,31.52,30.82,29.46,28.61,28.29,24.93,22.51,22.49,19.46,18.76； 31 PNMR(162MHz,DMSO-d 6 )δ29.00；HRMS(ESI)m/zcalcdforC 72 H 80 N 5 O 11 PNa + (M+Na) + 1244.54842,found1244.54895.
H-Phe-Lys(Fmoc)-Pro-Val-DPBPA(8)： 1 HNMR(400MHz,DMSO-d6)δ8.76(d,J＝7.9Hz,1H),8.37(d,J＝7.7Hz,1H),8.14–8.10(m,2H),7.92–7.86(m,6H),7.69–7.61(m,4H),7.58–7.52(m,4H),7.41(t,J＝7.4Hz,2H),7.35–7.22(m,9H),7.19–7.14(m,5H),6.95–6.91(m,2H),4.51(dd,J＝8.2,3.8Hz,2H),4.36–4.28(m,3H),4.21(t,J＝6.6Hz,1H),4.09(dd,J＝7.1,4.5Hz,1H),3.58(t,J＝6.0Hz,2H),3.11–3.03(m,2H),2.97(dd,J＝11.6,5.3Hz,2H),2.25–1.93(s,3H),1.89–1.65(m,3H),1.57(s,5H),1.40(d,J＝7.4Hz,3H),1.25(d,J＝9.5Hz,3H),1.00(dd,J＝6.7,3.4Hz,6H)；HRMS(ESI)m/zcalcdforC 67 H 72 N 5 O 9 PNa + (M+Na) + 1122.5153,found1122.5140.
Boc- D Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA(9)： 1 HNMR(400MHz,DMSO-d6)δ10.78(s,1H),8.34(dd,J＝13.9,7.5Hz,3H),7.93–7.85(m,6H),7.70–7.59(m,4H),7.55(d,J＝3.6Hz,5H),7.40(t,J＝7.3Hz,2H),7.35–7.11(m,15H),7.05(t,J＝7.4Hz,2H),6.96(dd,J＝17.5,8.0Hz,3H),6.87–6.81(m,1H),4.67–4.60(m,1H),4.50(dd,J＝14.8,6.9Hz,1H),4.35–4.25(m,3H),4.22–4.10(m,2H),3.69–3.48(m,2H),3.06–2.75(m,6H),2.25–1.62(m,7H),1.57(s,6H),1.46–1.16(m,13H),1.05–0.98(m,6H)； 13 CNMR(101MHz,DMSO-d 6 )δ172.58,170.52(d,J＝48.5Hz),156.51,148.51,148.14,144.37,141.17,133.19,131.91(d,J＝10.3Hz),130.76,129.33,128.32,128.03,128.01,125.61,121.39,120.56,111.70,110.77,78.53,58.14,55.85,50.77,47.20,42.29,30.83,28.55,24.92,22.69,19.45,18.80； 31 PNMR(162MHz,DMSO-d 6 )δ29.00；HRMS(ESI)m/zcalcdforC 83 H 90 N 7 O 12 PNa + (M+Na) + 1430.62773,found1430.62781.
H- D Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA(10)： 1 HNMR(400MHz,DMSO-d 6 )δ11.02(s,1H),8.84(d,J＝8.1Hz,1H),8.47(d,J＝7.7Hz,1H),8.36(d,J＝7.4Hz,1H),7.94(s,1H),7.92–7.86(m,6H),7.73–7.52(m,9H),7.39(q,J＝7.5Hz,3H),7.29(dt,J＝12.2,6.7Hz,7H),7.23(dd,J＝6.3,2.0Hz,2H),7.15(d,J＝3.5Hz,6H),7.09(d,J＝7.7Hz,1H),7.03–6.98(m,1H),6.93(d,J＝8.6Hz,2H),4.67(d,J＝5.6Hz,1H),4.55–4.49(m,2H),4.36–4.27(m,3H),4.20(t,J＝6.7Hz,1H),4.02(s,1H),3.68–3.54(m,2H),3.27(s,1H),3.02(dt,J＝21.1,7.7Hz,4H),2.87(dd,J＝14.1,8.7Hz,1H),2.20(dq,J＝13.2,6.7Hz,1H),2.09–1.66(m,6H),1.57(s,6H),1.45–1.31(m,5H),1.00(dd,J＝6.6,3.4Hz,6H)； 13 CNMR(101MHz,DMSO-d 6 )δ172.56,170.76,158.56,156.54,148.89,148.52,148.16,146.71,141.18,133.19,131.96,129.79,129.46,129.33,128.32,127.49,125.57,121.38,55.38,47.22,42.29,30.82,19.45； 31 PNMR(162MHz,DMSO-d 6 )δ29.01；HRMS(ESI)m/zcalcdforC 78 H 82 N 7 O 10 P(M+H) + 1830.84456,found1830.50460.
Boc-Arg(Pbf)- D Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA(11)： 1 HNMR(500MHz,DMSO-d6)δ10.77–10.73(m,1H),8.36(d,J＝7.5Hz,1H),8.24(d,J＝7.5Hz,1H),8.06(d,J＝7.8Hz,1H),7.94–7.89(m,6H),7.72–7.55(m,10H),7.42(t,J＝7.5Hz,2H),7.36–7.15(m,16H),7.12–7.03(m,2H),6.96(d,J＝8.2Hz,3H),6.85(d,J＝8.4Hz,1H),4.69–4.49(m,5H),4.39–4.29(m,3H),4.22(t,J＝7.1Hz,1H),3.89(s,1H),3.70–3.54(m,2H),3.13–2.80(m,12H),2.46(s,4H),2.23(dt,J＝13.3,6.6Hz,1H),2.15(s,2H),2.03(d,J＝5.7Hz,4H),1.97–1.79(m,3H),1.59(s,8H),1.40(d,J＝16.0Hz,19H),1.18(s,4H),1.03(dd,J＝6.8,4.6Hz,6H)； 13 CNMR(126MHz,DMSO-d 6 )δ172.57,170.73,170.29,157.91,156.54,148.97,148.53,148.14,146.71,144.37,141.18,137.75,136.43,133.17,131.95,130.92,129.44,128.31,125.60,124.77,121.38,118.61,116.73,110.25,86.73,78.63,68.98,65.70,59.31,56.30,50.81,47.23,42.94,42.29,32.58,30.83,30.07,28.75,24.90,22.67,19.44,18.79,18.08,12.75； 31 PNMR(162MHz,DMSO-d 6 )δ29.01；HRMS(ESI)m/zcalcdforC 102 H 119 N 11 O 16 PS + (M+H) + 1817.83227,found1817.83496.
H-Arg(Pbf)- D Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA(12)： 1 HNMR(400MHz,DMSO-d 6 )δ8.52(d,J＝7.6Hz,1H),8.33–8.15(m,3H),8.00(d,J＝18.6Hz,3H),7.82(dd,J＝12.7,7.5Hz,6H),7.62–7.44(m,10H),7.35–7.04(m,21H),6.85(d,J＝8.2Hz,2H),4.61–4.39(m,4H),4.19(tt,J＝27.8,7.3Hz,4H),3.76–3.40(m,3H),3.09–2.73(m,11H),2.39–2.29(m,3H),2.13(dt,J＝13.3,6.1Hz,1H),2.06–1.87(m,9H),1.77(s,2H),1.59(d,J＝25.3Hz,4H),1.48(s,7H),1.32(d,J＝12.3Hz,10H),1.08(s,2H),0.92(dd,J＝6.8,3.6Hz,6H)； 31 PNMR(162MHz,DMSO-d 6 )δ29.02；HRMS(ESI)m/zcalcdforC 97 H 111 N 11 O 14 PS + (M+H) + 1717.77984,found1717.78149.
Boc- D Phe-Arg(Pbf)- D Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA(13)： 1 HNMR(400MHz,DMSO-d 6 )δ10.74(d,J＝21.1Hz,1H),8.34(d,J＝7.5Hz,1H),8.18(d,J＝7.8Hz,1H),7.92–7.85(m,7H),7.69–7.59(m,5H),7.54(td,J＝6.5,5.4,2.7Hz,5H),7.38(q,J＝7.5Hz,3H),7.33–7.26(m,5H),7.23–7.14(m,16H),7.03(t,J＝7.9Hz,2H),6.93(d,J＝8.2Hz,3H),4.64–4.47(m,5H),4.30(dd,J＝23.5,7.0Hz,3H),4.19(t,J＝7.1Hz,2H),3.57(d,J＝30.0Hz,2H),3.13–2.74(m,14H),2.43(s,3H),2.12(s,4H),1.98(s,3H),1.82(d,J＝16.4Hz,3H),1.56(s,7H),1.37(s,7H),1.32(s,2H),1.28(d,J＝3.0Hz,9H),1.24(d,J＝5.0Hz,2H),1.15(s,6H),0.99(dd,J＝6.8,3.9Hz,6H)； 31 PNMR(162MHz,DMSO-d6)δ29.00；HRMS(ESI)m/zcalcdforC 111 H 127 N 12 O 17 PSNa + (M+Na) + 1986.88262,found1986.88708.
H- D Phe-Arg(Pbf)- D Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA(14)： 1 HNMR(400MHz,DMSO-d 6 )δ10.82(s,1H),8.40–8.11(m,7H),7.91(dd,J＝11.7,7.5Hz,7H),7.70–7.59(m,6H),7.58–7.52(m,6H),7.25(ddd,J＝41.1,20.0,8.2Hz,24H),6.94(d,J＝8.2Hz,3H),4.60(d,J＝43.8Hz,4H),4.39–4.12(m,6H),3.58(dd,J＝31.5,15.4Hz,2H),3.15–2.82(m,13H),2.47(d,J＝7.8Hz,3H),2.25–2.16(m,1H),2.16–1.96(m,9H),1.81(s,3H),1.57(s,6H),1.41–1.33(m,12H),1.01(s,6H)； 31 PNMR(162MHz,DMSO-d6)δ29.04；HRMS(ESI)m/zcalcdforC 106 H 119 N 12 O 15 PSNa + (M+Na) + 1886.83019,found1886.83215.
Boc-Pro- D Phe-Arg(Pbf)- D Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA(15)： 1 HNMR(400MHz,DMSO-d 6 )δ8.39–7.97(m,3H),7.90(dd,J＝12.6,7.4Hz,7H),7.71–7.50(m,10H),7.40(t,J＝7.1Hz,2H),7.34–7.28(m,4H),7.25–7.10(m,17H),7.04(t,J＝7.7Hz,2H),6.94(d,J＝7.9Hz,3H),4.67–4.47(m,4H),4.38–3.94(m,7H),3.71–3.49(m,2H),3.20(d,J＝9.8Hz,2H),2.95(d,J＝28.9Hz,12H),2.44(s,3H),2.25–2.16(m,1H),2.13(s,1H),2.00(s,4H),1.94–1.73(m,5H),1.56(s,10H),1.38(t,J＝9.3Hz,18H),1.23(s,3H),1.16(s,2H),1.05(s,3H),1.00(s,6H)； 31 PNMR(162MHz,DMSO-d6)δ29.01；HRMS(ESI)m/zcalcdforC 116 H 134 N 13 O 18 PSNa + (M+Na) + 2083.93539,found2083.93872.
H-Pro- D Phe-Arg(Pbf)- D Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA(16)： 1 HNMR(400MHz,DMSO-d6)δ10.85(S,1H),7.89(dd,J＝12.4,7.7Hz,7H),7.70–7.52(m,11H),7.43–7.37(m,3H),7.34–7.14(m,24H),6.93(d,J＝8.0Hz,3H),4.57(d,J＝32.3Hz,4H),4.40–4.20(m,6H),3.59(d,J＝33.1Hz,3H),3.16–2.82(m,15H),2.45(d,J＝8.4Hz,2H),2.10(d,J＝9.2Hz,9H),1.98(d,J＝12.7Hz,4H),1.91–1.80(m,4H),1.57(s,10H),1.38(d,J＝5.3Hz,14H),1.00(s,6H).
Boc-Met-Pro- D Phe-Arg(Pbf)- D Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA(17)： 1 HNMR(400MHz,DMSO-d 6 )δ10.75(S,1H),8.26(d,J＝58.6Hz,4H),7.96(d,J＝8.4Hz,1H),7.92–7.85(m,7H),7.65(dt,J＝24.9,7.6Hz,6H),7.54(dq,J＝11.7,7.5,5.5Hz,6H),7.39(t,J＝7.5Hz,3H),7.33–7.27(m,4H),7.25–7.13(m,16H),6.93(d,J＝8.1Hz,2H),4.63–4.43(m,5H),4.36–4.16(m,7H),3.68–3.46(m,4H),3.10–2.78(m,11H),2.43(s,3H),2.19(dd,J＝11.2,4.7Hz,1H),2.12(s,2H),2.06–1.94(m,7H),1.74(s,10H),1.56(s,9H),1.35(d,J＝11.8Hz,20H),1.15(s,8H),0.99(s,6H)； 31 PNMR(162MHz,DMSO-d 6 )δ28.99；HRMS(ESI)m/zcalcdforC 121 H 143 N 14 O 19 PS 2 Na + (M+Na) + 2214.97587,found2214.97778.
preparation of nonapeptide-1: 100mg of the above-obtained nonapeptide-1 precursor compound (17) Boc-Met-Pro- D Phe-Arg(Pbf)- D Trp-Phe-Lys (Fmoc) -Pro-Val-DPBPA was dissolved by adding 10mL of tetrahydrofuran, 1mL of ammonia was added dropwise, stirred at room temperature, and TCL monitoring (developing reagent: DCM: meOH=20:1) was observed during the reaction to give fluorenene and carrier DPBPA, indicating removal of the carrier and Fmoc groups, after about 8H, the solvent was removed by concentration under reduced pressure, and the one pot method was performed using TFA/TIS/H 2 The o=95:5:5 (volume ratio) system removes Pbf and Boc groups. Reverse-rotationAfter the reaction, the target product, namely the nonapeptide, is precipitated by diethyl ether, is washed by diethyl ether for 3 times, and is dried in vacuum to obtain 46.8mg of white powder with the yield of 85 percent. The diethyl ether phase was separated to give 17.2mg of recovered carrier, and the shear recovery was 88%.
Structural characterization data for nonapeptide-1: HRMS (ESI) m/z calculated C 61 H 87 N 15 O 9 SNa + (M+Na) + 1228.64241, found 1228.64185, demonstrates that the synthesized sample matches the molecular mass of the target compound.
The above examples are only some of the examples listed to facilitate the understanding of the methods of synthesis and application of the materials of the present invention and are not intended to limit the invention. It should be understood that the construction of the invention is susceptible to suitable modifications, equivalents, and improvements therein by those skilled in the relevant art, and therefore all such modifications, equivalents, and improvements are intended to be within the spirit and scope of the present invention.

Claims (9)

1. A diphenylphosphonooxy bisphenol A compound is characterized by having the following structural general formula:
wherein R is 1 ＝R 2 ＝H。
2. Use of a diphenylphosphinoyloxy bisphenol a compound of claim 1 in the preparation of whitening nonapeptide-1.
3. The preparation method of the auxiliary whitening nonapeptide-1 by using the diphenylphosphinoyloxy bisphenol A compound is characterized by comprising the following steps of:
taking diphenylphosphonooxy bisphenol A compounds as auxiliary groups, carrying out coupling reaction and N-terminal protecting group removal reaction on the auxiliary groups respectively with N-terminal protected valyl acid, N-terminal protected proline, N-terminal and side chain protected lysine, N-terminal protected phenylalanine, N-terminal protected D-tryptophan, N-terminal and side chain protected arginine, N-terminal protected D-phenylalanine and N-terminal protected proline in sequence, and carrying out coupling reaction on the auxiliary groups with N-terminal protected methionine after the reaction is finished to obtain a precursor C of the nonapeptide;
and shearing auxiliary groups from the compound C, removing protective groups on side chains, and purifying to obtain the whitening nonapeptide-1.
4. The method for preparing the auxiliary whitening nonapeptide-1 of the diphenylphosphinoyloxy bisphenol A compounds according to claim 3, wherein the precursor C of the nonapeptide is prepared according to the following steps:
s1, taking a diphenylphosphinoyloxy bisphenol A compound as a carrier, reacting with N-terminal protected valyl acid under the action of a coupling agent, and purifying to obtain a product A;
s2, removing the N-terminal protecting group in the purified product A, and purifying to obtain a product B;
s3, repeating the steps S1 and S2, taking a product B as a carrier, respectively replacing N-terminal protected valyl acid with N-terminal protected proline, N-terminal and side chain protected lysine, N-terminal protected phenylalanine, N-terminal protected D-tryptophan, N-terminal and side chain protected arginine, N-terminal protected D-phenylalanine and N-terminal protected proline in sequence, carrying out coupling reaction and N-terminal protecting group removal treatment reaction, and carrying out coupling reaction with N-terminal protected methionine after the reaction is finished to obtain a precursor C of the nonapeptide.
5. The method for preparing the auxiliary whitening nonapeptide-1 using the diphenylphosphinoyloxy bisphenol A compound according to claim 4, wherein the N-terminal protecting group comprises Fmoc or Boc.
6. The method for preparing the auxiliary whitening nonapeptide-1 by using the diphenylphosphinoyloxy bisphenol A compound according to claim 4, wherein the protecting group of the side chain comprises Fmoc, boc, pbf or tBu.
7. The method for preparing the auxiliary whitening nonapeptide-1 of the diphenylphosphinoyloxy bisphenol A compound according to claim 4, wherein the structural formula of the product B is as follows:
8. the method for preparing the auxiliary whitening nonapeptide-1 from the diphenylphosphinoyloxy bisphenol A compounds according to claim 4, wherein the structural formula of the precursor C of the nonapeptide is as follows:
wherein the N-terminal protecting group is Boc, and the protecting group of the side chain is Fmoc.
9. The method for preparing the auxiliary whitening nonapeptide-1 by using the diphenylphosphinoyloxy bisphenol A compound according to claim 4, wherein the auxiliary group is sheared off from the compound C to obtain a crude auxiliary group;
dissolving the crude auxiliary group in proper amount of ethyl acetate, adding alkane or ether solvent, and separating the auxiliary group from other impurities; filtering, washing or recrystallizing the separated auxiliary group to obtain a purified auxiliary group.
CN202310842932.XA 2023-07-11 2023-07-11 Diphenylphosphinoyloxy bisphenol A compound and application thereof in preparation of whitening nonapeptide-1 Pending CN117003791A (en)

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