A diphenylphosphonyloxy bisphenol A compound and its application in preparing whitening nonapeptide-1

Abstract

The present invention relates to a diphenylphosphonyloxy bisphenol A compound and its application in preparing whitening nonapeptide-1, belonging to the technical field of organic synthesis. The diphenylphosphonyloxy bisphenol A compound DPBPA has the following general structural formula. The present invention also provides a diphenylphosphonyloxy bisphenol A compound DPBPA for preparing whitening nonapeptide-1H-Met-Pro- D Phe‑Arg‑ D The invention discloses an application of Trp-Phe-Lys-Pro-Val-NH2 in the preparation of nonapeptide-1 assisted by diphenylphosphonyloxy bisphenol A compound DPBPA. The liquid phase synthesis method of nonapeptide-1 assisted by DPBPA as a carrier utilizes the auxiliary precipitation effect of the DPBPA carrier, and the strategy of coupling and deprotection of Boc with an equivalent amount of amino acids through a liquid phase reaction is used to optimize and simplify the preparation method of nonapeptide-1, and verify the recyclability and reusability of the DPBPA carrier.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis, and particularly relates to a diphenylphosphinyloxy bisphenol A compound and its application in the preparation of Melanostatine-1. Background Art

[0002] Melanostatine (also known as Nonapeptide-1 or Melanostatine) is a small molecule skin-whitening and brightening bionic peptide composed of nine amino acid molecules, and its amino acid sequence is H-Met-Pro- D Phe-Arg- D Trp-Phe-Lys-Pro-Val-NH2. Melanostatine-1 is an α-MSH antagonist, which can prevent this process by competing with α-MSH for binding to MC1-R, thereby forming a reversible inhibitory effect on the production of melanin. It acts on the skin with high specificity, can competitively bind to the receptors on melanocytes with various factor signals, and inhibit the activation of tyrosinase by melanocytes, thereby reducing the production of melanin. The research results show that Melanostatine-1 competitively blocks the entry of receptors and various factor signals on melanoblasts, weakens the activity of melanoblasts, reduces the amount of melanin produced, gradually evens out skin tone starting from 14 days, and significantly brightens skin tone after 28 days of a skin cycle. The skin becomes rosy and fair. Therefore, Melanostatine-1 is often used as a cosmetic raw material. It can inhibit the formation of melanin, has the effects of whitening and lightening spots and reducing fine lines, and has been widely favored in the field of cosmetic R & D in recent years. In addition, Melanostatine-1 can also be used in the research on the regulation of adrenal steroidogenesis, skin cancer, etc.

[0003] Currently, the main methods for polypeptide production are traditional biological synthesis and solid-phase chemical synthesis methods, which have problems such as cumbersome separation and purification steps, large waste of raw materials and solvents, and a large amount of resin solid waste that is difficult to degrade, resulting in serious environmental pollution. Summary of the Invention

[0004] In order to solve the deficiencies in the prior art, aiming at the deficiencies of the existing synthesis methods, such as environmental pollution, poor selectivity, high price, etc., the present invention provides a diphenylphosphinyloxy bisphenol A compound and its application in the preparation of Melanostatine-1, mainly solving the problems of relatively many liquid-phase reaction steps, long time-consuming cycle, high content of by-product β-type isomers, difficult separation and purification, low product purity, small purification scale, high production cost in the current chemical synthesis method of Melanostatine-1, and small production scale, expensive raw materials, large waste, a large amount of resin-based waste and serious environmental pollution in the solid-phase reaction.

[0005] A diphenylphosphinyloxy bisphenol A compound provided by the present invention has a general structural formula as follows:

[0006]

[0007] In the formula, R1=R2=H.

[0008] The present invention provides application of a diphenylphosphonyloxy bisphenol A compound in preparing whitening nonapeptide-1.

[0009] The present invention provides a method for preparing a diphenylphosphonyloxy bisphenol A compound-assisted whitening nonapeptide-1, comprising the following steps:

[0010] Using a diphenylphosphonyloxy bisphenol A compound as an auxiliary group, coupling reactions and N-terminal protective group removal reactions are performed with N-terminal protected valine, 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 after the reaction is completed, coupling reactions are performed with N-terminal protected methionine to obtain a nonapeptide precursor C;

[0011] Compound C is subjected to cleavage of the auxiliary group and removal of the protecting group on the side chain, and then subjected to purification treatment to obtain whitening nonapeptide-1.

[0012] Preferably, the precursor C of nonapeptide-1 is prepared according to the following steps:

[0013] S1, using a diphenylphosphonyloxy bisphenol A compound as a carrier, reacting with N-terminal protected valine under the action of a coupling agent, and obtaining a product A after purification;

[0014] S2, removing the N-terminal protected group in the purified product A, and purifying the product A to obtain product B;

[0015] S3. Repeat S1 and S2, and use product B as a carrier to replace the N-terminal protected valine with N-terminal protected proline, lysine protected at both the N-terminus and the side chain, phenylalanine protected at the N-terminus, D-tryptophan protected at the N-terminus, arginine protected at both the N-terminus and the side chain, D-phenylalanine protected at the N-terminus, and proline protected at the N-terminus, respectively, and carry out coupling reaction and N-terminal protecting group removal reaction. After the reaction, carry out coupling reaction with N-terminal protected methionine to obtain the precursor C of nonapeptide-1.

[0016] More preferably, the N-terminal protecting group includes Fmoc or Boc.

[0017] More preferably, the side chain protecting group includes Fmoc, Boc, Pbf or tBu.

[0018] More preferably, the structural formula of the product B is as follows:

[0019] .

[0020] More preferably, the structural formula of the nonapeptide precursor C is as follows:

[0021]

[0022] The N-terminal protecting group is Boc, and the side chain protecting group is Fmoc.

[0023] More preferably, the auxiliary group is removed from compound C to obtain a crude auxiliary group product;

[0024] The auxiliary group crude product is dissolved in an appropriate amount of ethyl acetate, and an alkane or ether solvent is added to separate the auxiliary group from other impurities; the separated auxiliary group is filtered and washed or recrystallized to obtain a purified auxiliary group.

[0025] Compared with the prior art, the beneficial effects of the present invention are:

[0026] The present invention provides a diphenylphosphonyloxy bisphenol A compound and its application in the preparation of whitening nonapeptide-1. The liquid phase synthesis method of nonapeptide-1 mainly uses DPBPA as a carrier to assist. The auxiliary precipitation effect of the DPBPA carrier is utilized. Through the liquid phase reaction, the same equivalent of amino acids are coupled and the Boc protection is removed. The strategy optimizes and simplifies the preparation method of nonapeptide-1, and verifies the recyclability and reusability of the DPBPA carrier. In addition, the present invention designs and develops two new strategies for simplifying the synthesis of nonapeptide-1. The problems of low yield, many by-products, and complex production process existing in current biosynthesis and chemical synthesis are solved, and the greening and scale of the nonapeptide-1 synthesis process are enhanced, which is conducive to emission reduction and consumption reduction, cost saving, environmental protection and sustainable development. DETAILED DESCRIPTION

[0027] The present invention is further described below in conjunction with specific embodiments, but it should be understood that the embodiments listed are only for facilitating understanding of the core method and application field of the present invention, but the scope of the present invention is not limited thereto.

[0028] The experimental methods and detection methods described in the following embodiments are conventional methods unless otherwise specified; the reagents and materials are commercially available unless otherwise specified.

[0029] The present invention provides a diphenylphosphonyloxy bisphenol A compound (DPBPA), the general structural formula of which is:

[0030]

[0031] In the formula, R1=R2=H.

[0032] In one embodiment, a diphenylphosphonyloxy bisphenol A small molecule carrier DPBPA is prepared by reacting diphenylphosphonyl chloride with bisphenol A under alkaline conditions, and obtaining DPBPA through separation and purification.

[0033] The invention provides application of a diphenylphosphonyloxy bisphenol A compound in preparing a whitening nonapeptide.

[0034] The present invention provides a method for preparing a diphenylphosphonyloxy bisphenol A compound-assisted whitening nonapeptide-1, comprising the following steps:

[0035] Using a diphenylphosphonyloxy bisphenol A compound as an auxiliary group, coupling reactions and N-terminal protective group removal reactions are performed with N-terminal protected valine, 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 after the reaction is completed, coupling reactions are performed with N-terminal protected methionine to obtain a nonapeptide precursor C;

[0036] Compound C is subjected to cleavage of the auxiliary group and removal of the protecting group on the side chain, and then subjected to purification treatment to obtain whitening nonapeptide-1.

[0037] Wherein, the nonapeptide precursor C is prepared according to the following steps:

[0038] S1, using a diphenylphosphonyloxy bisphenol A compound as a carrier, reacting with N-terminal protected valine under the action of a coupling agent, and obtaining a product A after purification;

[0039] S2, removing the N-terminal protection group in the purified product A, and purifying it to obtain product B;

[0040] The structural formula of the product B is as follows:

[0041] ;

[0042] S3, repeat S1 and S2, use product B as a carrier, replace the N-terminal protected valine 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, N-terminal protected proline in sequence, carry out coupling reaction and N-terminal protecting group removal treatment reaction, after the reaction is completed, carry out coupling reaction with N-terminal protected methionine to obtain nonapeptide precursor C;

[0043] Specifically, the N-terminal protecting group includes Fmoc or Boc; the side chain protecting group includes Fmoc, Boc, Pbf or tBu.

[0044] In one embodiment, a method for preparing a diphenylphosphonyloxy bisphenol A compound-assisted whitening nonapeptide-1 specifically comprises the following steps:

[0045] Step 1, coupling of the auxiliary group with the first amino acid: the resin in the solid phase peptide synthesis is replaced by the auxiliary group (DPBPA), and the N-terminal protected valine (Boc-Val-OH) is stirred and reacted at 0-50°C for 1-3 hours under the action of a coupling agent 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 in a molar ratio of 1-1.2:1;

[0046] The auxiliary group is a diphenylphosphonyloxy bisphenol A compound (DPBPA);

[0047] After the DPBPA is coupled with Boc-Val-OH, the intermediate compound generated is Boc-Val-DPBPA;

[0048] Step 2, separation and purification: adding 10-15 times the volume of a low-polarity alkane or ether solvent to the product A, and separating the product A from other impurities by virtue of the easy crystallization and precipitation of the DPBPA auxiliary group in the solvent system;

[0049] The separated product A is filtered and washed or recrystallized to obtain a purified product A, Boc-Val-DPBPA;

[0050] Step 3, removing the N-terminal protecting group Boc: treating the purified product A with a de-Boc reagent, stirring and reacting at 10-50° C. for 0.5-2 hours, or treating with a de-Boc reagent, stirring and reacting at 10-50° C. for 0.5-2 hours, to obtain a de-Boc product B, H-Val-DPBPA;

[0051] Adding a low-polarity alkane or ether solvent to product B, and using the property of the DPBPA auxiliary group that is easy to crystallize and precipitate in the solvent system, separate product B from other impurities;

[0052] filtering and washing or recrystallizing the separated product B to obtain a purified product B;

[0053] The structural formula of the product B is as follows:

[0054] .

[0055] Step 4: Coupling the second amino acid and peptide chain extension: Using the purified product B containing the auxiliary group DPBPA as a carrier, repeat the above steps (2) and (3), and sequentially replace the N-terminally protected valine with N-terminally protected proline, lysine with both N-terminal and side-chain protection, N-terminally protected phenylalanine, N-terminally protected D-tryptophan, arginine with both N-terminal and side-chain protection, N-terminally protected D-phenylalanine, and N-terminally protected proline, and perform the coupling reaction and the N-terminal protecting group removal treatment reaction. After the reaction is completed, perform the coupling reaction with N-terminally protected methionine to obtain the precursor C of 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);

[0056] Among them, the N-terminal protecting group is Boc, the lysine side-chain protecting group is Fmoc; the arginine side-chain protecting group is Pbf. Specifically, after performing the coupling reaction and the de-Boc reaction on N-terminally 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 Phe-OH, and proline Boc-Pro-OH, and finally performing the coupling reaction with methionine Boc-Met-OH, the precursor C of the nonapeptide is prepared (Boc-Met-Pro- D Phe-Arg(Pbf)- D Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA);

[0057] The structural formula of the precursor C of the nonapeptide is as follows:

[0058] ;

[0059] Among them, the N-terminal protecting group is Boc, and the side-chain protecting group is Fmoc.

[0060] Step 5. Remove the DPBPA carrier and the side-chain protecting group Fmoc: Using a solution of ammonia or its derivative PG-NH2 (PG = BH 3, Boc, Fmoc, H) as the shearing agent, the component ratio in the PG-NH2 solution is: PG-NH2 / solvent = 25% (volume ratio), and the solvent is usually one or more of acetonitrile, ethanol, methanol, tetrahydrofuran, DMF, etc. First, treat the compound C obtained in step (4), remove the DPBPA auxiliary group, and simultaneously remove the protecting group Fmoc on the lysine side chain to obtain compound D, Boc-Met-Pro-D Phe-Arg(Pbf)- D Trp-Phe-Lys-Pro-Val-NH-PG. Then, using the cocktail reagent trifluoroacetic acid / triisopropylsilane / water = 95:2.5:2.5 (volume ratio) as the side-chain deprotecting agent to treat compound D, the reaction conditions are stirring for 1 - 3 hours at 5 - 30 °C, and all the protecting groups on the peptide chain and side chain such as Boc, Pbf, tBu, etc. are removed by the "one-pot method";

[0061] It should be noted that Fmoc and DPBPA carriers are mainly removed by alkaline deprotecting agents, while the protecting groups Boc, Pbf, tBu are removed by acidic deprotecting agents.

[0062] Dissolve the crude DPBPA obtained in step 5 in an appropriate amount of ethyl acetate, add an alkane or ether solvent with low polarity, and utilize the property that DPBPA is easily crystallized and precipitated in different solvent systems to separate DPBPA from other impurities; perform filtration, washing or recrystallization operations on the separated DPBPA to obtain purified DPBPA, which can be reused directly or after regeneration as an auxiliary group after recovery.

[0063] Step 6, separation and purification of nonapeptide-1: Concentrate the mixed solution treated by the above "one-pot method" by rotary evaporation to one-third of the original volume, and precipitate with an ether solvent (ether or methyl tert-butyl ether). After filtration or centrifugal separation, the filter cake is washed with cold ether and dried to obtain purified nonapeptide-1E (H-Met-Pro- D Phe-Arg- D Trp-Phe-Lys-Pro-Val-NH2);

[0064] Step 7, method for recycling and reusing the DPBPA auxiliary group: Combine the ether solvent phases obtained in step 6, concentrate by rotary evaporation to one-third of the original volume, add a hydrocarbon solvent with low polarity, and utilize the property that DPBPA is easily crystallized and precipitated in different solvent systems to separate DPBPA from other impurities; perform filtration, washing or recrystallization operations on the separated precipitate to obtain purified DPBPA, which can be reused directly or after regeneration as an auxiliary group after recovery.

[0065] The preparation method of a diphenylphosphoryloxy bisphenol A compound-assisted whitening nonapeptide-1 provided by the present invention, compared with the existing synthesis methods, combines the advantages of liquid-phase and solid-phase synthesis methods, can synthesize and prepare nonapeptide-1 more simply, quickly, economically and efficiently, and the DPBPA carrier can be recycled and reused directly, reducing waste of raw materials, reducing waste pollution, saving costs and being environmentally friendly.

[0066] Among them, in step 3, the intermediate compounds formed by the coupling of N-terminal Boc-protected valine with the carrier DPBPA are product A (Boc-Val-DPBPA) and its product B, that is, the Boc-deprotected product. The molecular structural formulas of Boc-Val-DPBPA and its Boc-deprotected product B (H-Val-DPBPA) are as follows:

[0067] (1) Boc-Val-DPBPA:

[0068] ;

[0069] (2) H-Val-DPBPA:

[0070] .

[0071] In step 4, the intermediate compound Boc-Pro-Val-DPBPA formed by the coupling of proline Boc-Pro-OH with product B (H-Val-DPBPA) and its Boc-deprotected product H-Pro-Val-DPBPA. The molecular structural formulas of Boc-Pro-Val-DPBPA and its Boc-deprotected product H-Pro-Val-DPBPA are as follows:

[0072] (3) Boc-Pro-Val-DPBPA:

[0073] ;

[0074] (4) H-Pro-Val-DPBPA:

[0075] .

[0076] The intermediate compound Boc-Lys(Fmoc)-Pro-Val-DPBPA formed by the coupling of lysine Boc-Lys(Fmoc)-OH with the above H-Pro-Val-DPBPA and its Boc-deprotected product H-Lys(Fmoc)-Pro-Val-DPBPA. The molecular structural formulas of Boc-Lys(Fmoc)-Pro-Val-DPBPA and its Boc-deprotected product H-Lys(Fmoc)-Pro-Val-DPBPA are as follows:

[0077] (5) Boc-Lys(Fmoc)-Pro-Val-DPBPA:

[0078] ;

[0079] (6) H-Lys(Fmoc)-Pro-Val-DPBPA:

[0080] 。

[0081] The intermediate compound Boc-Phe-Lys(Fmoc)-Pro-Val-DPBPA formed by coupling phenylalanine Boc-Phe-OH with the above H-Lys(Fmoc)-Pro-Val-DPBPA and its de-Boc product H-Phe-Lys(Fmoc)-Pro-Val-DPBPA. The molecular structural formulas of the de-Boc product H-Phe-Lys(Fmoc)-Pro-Val-DPBPA of the said Boc-Phe-Lys(Fmoc)-Pro-Val-DPBPA are respectively as follows:

[0082] (7)Boc-Phe-Lys(Fmoc)-Pro-Val-DPBPA:

[0083] ;

[0084] (8)H-Phe-Lys(Fmoc)-Pro-Val-DPBPA:

[0085] 。

[0086] D-tryptophan Boc- D Trp-OH and the intermediate compound Boc- D Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA formed by coupling it with the above H-Phe-Lys(Fmoc)-Pro-Val-DPBPA and its de-Boc product H- D Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA. The molecular structural formulas of the de-Boc product H- D Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA of the said Boc- D Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA are respectively as follows:

[0087] (9)Boc- D Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA:

[0088] ;

[0089] (10)H- D Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA:

[0090] 。

[0091] Boc-Arg(Pbf)-OH and the above-mentioned H- D intermediate compound Boc-Arg(Pbf)- D Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA, and its de-Boc product H-Arg(Pbf)- D Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA, and the de-Boc product H-Arg(Pbf)- D Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA, and the de-Boc product H-Arg(Pbf)- D The molecular structural formulas of Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA are as follows:

[0092] (11) Boc-Arg(Pbf)- D Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA:

[0093] ;

[0094] (12) H-Arg(Pbf)- D Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA:

[0095] .

[0096] Boc- D Phe-OH and the above-mentioned H-Arg(Pbf)- D intermediate compound Boc- D Phe-Arg(Pbf)- D Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA, and its de-Boc product H- D Phe-Arg(Pbf)- D Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA, and the de-Boc product H- D Phe-Arg(Pbf)- D Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA, and its de-Boc product H- D Phe-Arg(Pbf)-D The molecular structural formulas of Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA are as follows respectively:

[0097] (13) Boc- D Phe-Arg(Pbf)- D Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA:

[0098] ;

[0099] (14) H- D Phe-Arg(Pbf)- D Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA:

[0100] 。

[0101] The intermediate compound Boc-Pro- D Phe-Arg(Pbf)- D Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA coupled with proline Boc-Pro-OH and its de-Boc product H-Pro- D Phe-Arg(Pbf)- D Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA, and the molecular structural formulas of Boc-Pro- D Phe-Arg(Pbf)- D Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA and its de-Boc product H-Pro- D Phe-Arg(Pbf)- D Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA are as follows respectively: D Phe-Arg(Pbf)- D Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA,

[0102] (15) Boc-Pro- D Phe-Arg(Pbf)- D Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA:

[0103] ;

[0104] (16) H-Pro- DPhe-Arg(Pbf)- D Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA:

[0105] 。

[0106] The intermediate compound Boc-Met-Pro- D Phe-Arg(Pbf)- D Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA coupled with the above H-Pro- D Phe-Arg(Pbf)- D Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA, and the molecular structural formula of Boc-Met-Pro- D Phe-Arg(Pbf)- D Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA is:

[0107] (17) Boc-Met-Pro- D Phe-Arg(Pbf)- D Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA:

[0108] 。

[0109] Treating the precursor (17) of the above nonapeptide-1 with ammonia solution gives the intermediate compound Boc-Met-Pro- D Phe-Arg(Pbf)- D Trp-Phe-Lys-Pro-Val-NH2, and the molecular structural formula of Boc-Met-Pro- D Phe-Arg(Pbf)- D Trp-Phe-Lys-Pro-Val-NH2 is:

[0110] (18) Boc-Met-Pro- D Phe-Arg(Pbf)- D Trp-Phe-Lys-Pro-Val-NH2:

[0111] 。

[0112] It should be noted that the coupling agent used in the present invention is 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride DECI.

[0113] According to the present invention, by removing the auxiliary group from compound C, a crude product of the auxiliary group is obtained.

[0114] Dissolve the crude auxiliary group in an appropriate amount of ethyl acetate, add an alkane or ether solvent, and the auxiliary group can be separated from other impurities; perform filtration, washing or recrystallization operations on the separated auxiliary group to obtain a purified auxiliary group.

[0115] In one embodiment, the precursor (18) of the above-mentioned nonapeptide-1 is treated with a deprotection reagent of TFA / TIPS / H2O. After all the protecting groups on the peptide chain, such as Boc at the N-terminus and Pbf on the side chain of arginine, are completely removed, the obtained compound H-Met-Pro- D Phe-Arg- D Trp-Phe-Lys-Pro-Val-NH2 is the crude product of the target product nonapeptide-1. After purification and refinement, a nonapeptide-1 product meeting the quality requirements can be obtained.

[0116] Some commonly used abbreviations in the present invention have the following meanings:

[0117] Boc: tert-butoxycarbonyl; Cbz: benzyloxycarbonyl; DCM: dichloromethane CH2Cl2; DEA: diethylamine; DMAP: 4-dimethylaminopyridine; DMF: N,N-dimethylformamide; DPBPA: 4-diphenylphosphinoxyl bisphenol A; EDC-HCl: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; Fmoc: fluorenylmethoxycarbonyl; HATU: 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; HBTU: O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate; HOBT: 1-hydroxybenzotriazole; HRMS: high-resolution mass spectrometry; NMM: N-methylmorpholine; NMP: N-methylpyrrolidone; NP-1: nonapeptide-1; PyBop: benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate; TEA: triethylamine; TFA: trifluoroacetic acid; THF: tetrahydrofuran; TIPS: triisopropylsilane.

[0118] The following examples provide specific synthesis methods for preparing the above compounds and the corresponding intermediate compounds.

[0119] Example 1

[0120] A preparation method of a diphenylphosphinyloxy bisphenol A compound-assisted whitening nonapeptide-1, comprising:

[0121] The synthetic route is as follows:

[0122]

[0123] DPBPA is successively coupled with N-terminal protected valine Boc-Val-OH, 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 Phe-OH, proline Boc-Pro-OH for coupling reaction and de-Boc reaction, and then coupled with methionine Boc-Met-OH to prepare the precursor C of the nonapeptide, Boc-Met-Pro- D Phe-Arg(Pbf)- D Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA is coupled to synthesize a nonapeptide derivative, and then through the cleavage of the carrier and the removal of side chain groups, a suitable route is explored, and finally the nonapeptide is obtained. Accordingly, the application and recyclability of DPBPA in peptide synthesis are verified.

[0124] The specific synthesis steps are as follows:

[0125] Coupling of DPBPA with the first amino acid: The coupling system for the esterification coupling reaction of the DPBPA carrier with the first amino acid Boc-Val-OH is an EDCI coupling agent plus a DMAP catalyst, wherein the molar ratio of the DPBPA carrier, the first amino acid Boc-Val-OH, the EDCI coupling agent to the DMAP catalyst is 1:1.2 - 1.5:1.2 - 1.5:0.12 - 0.15. Stir at room temperature for about 2 hours. After the coupling reaction is completed, the coupling product (1) Boc-Val-DPBPA is separated and purified by the DPBPA-assisted precipitation method.

[0126] Removal of the Boc protecting group: A 25% TFA / DCM system is used, and the reaction is completed in about 1 - 1.5 h. The de-Boc product (2) H-Val-DPBPA is separated and purified by the DPBPA-assisted precipitation method.

[0127] Elongation of the peptide chain: During the formation of the subsequent amide bond of H-Val-DPBPA, the molar ratio of amino acid to coupling agents EDCI, HOBt, and DIEA is 1:1.2:1.2:0.12. Weigh EDCI, HOBt, DIEA, and amino acid in sequence, dissolve them in an appropriate amount of dichloromethane, activate them in an ice-water bath for 0.5 h, add the compound to be coupled dropwise, and react at room temperature. The reaction is completed in 1.5 h. Wash twice with saturated NH4Cl solution and saturated NaHCO3 solution in sequence, and then use the DCM / MTBE system for precipitation (volume ratio is about 10:1), and perform solid-liquid separation and purification by filtration or centrifugation. According to the target sequence, the amino acids to be coupled in sequence are N-terminally protected proline Boc-Pro-OH, lysine Boc-Lys(Fmoc)-OH, phenylalanine Boc-Phe-OH, 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. After appropriate separation and purification, the precursor compound (17) of nonapeptide-1, Boc-Met-Pro- D Phe-Arg(Pbf)- D Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA, is obtained.

[0128] Matters needing attention: When coupling the 6th amino acid Boc-Arg(Pbf)-OH, activate the amino acid according to the above operation, and it is found that the coupling is not successful. Try to adjust the ratio of amino acid and coupling agent, extend the reaction time, increase the reaction temperature, etc., but none of these reactions are carried out. It is later inferred that self-polymerization of arginine occurred during the activation process, so it could not be successfully coupled with H-Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA. The solution is to omit the activation time, add the amino acid, coupling agent, raw material to be coupled, etc. to the reaction system at the same time, and react at room temperature, and finally the coupling is successful. The intermediates and their yields at each step during the synthesis of nonapeptide-1 are shown in Table 1.

[0129] Table 1 Intermediates and their yields at each step during the synthesis of nonapeptide-1

[0130]

[0131] The specific structural characterization data of the intermediate compounds obtained at each step during the synthesis of nonapeptide-1 are as follows:

[0132] Boc-Val-DPBPA (1): 1 HNMR(400MHz, DMSO- d 6) δ 7.95–7.82(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) δ 148.61, 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) δ 28.99; HRMS(ESI) m / z calcd for C 37 H 42 NO6PNa + (M+Na) + 650.26420, found 650.26392.

[0133] H-Val-DPBPA (2): 1 HNMR(400MHz, DMSO- d 6) δ 8.52(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- d6) δ 168.34, 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 ¹³C NMR (162 MHz, DMSO- d 6) δ 29.00; HRMS (ESI) m / z calcd for C 32 H 35 NO₄P + (M + H) + 528.22982, found 528.22980.

[0134] Boc-Pro-Val-DPBPA (3): 1 ¹H NMR (400 MHz, DMSO- d 6) δ 8.33 (s, 1H), 7.89 (dd, J J = 12.3, 7.6 Hz, 4H), 7.65–7.53 (m, 6H), 7.17 (d, J J = 8.6 Hz, 6H), 6.95 (d, J J = 8.6 Hz, 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 J = 25.5 Hz, 9H), 1.02 (d, J J = 6.7 Hz, 6H); 13 ¹³C NMR (101 MHz, DMSO- d 6) δ 173.71, 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 ³¹P NMR (162 MHz, DMSO- d 6) δ 28.99; HRMS (ESI) m / z calcd for C 42 H 49 N₂O₇PNa + (M + Na)+ 747.31696, found 747.31671.

[0135] H-Pro-Val-DPBPA (4): 1 HNMR (400 MHz, DMSO-d6) δ 9.54 (s, 1H), 8.99 (d, J = 7.3 Hz, 1H), 8.62 (s, 1H), 7.90 (dd, J = 12.3, 7.1 Hz, 4H), 7.65–7.52 (m, 6H), 7.23–7.15 (m, 6H), 6.97 (d, J = 8.6 Hz, 2H), 4.39–4.31 (m, 1H), 3.24 (ddd, J = 24.5, 14.8, 9.6 Hz, 2H), 2.31 (dh, J = 26.6, 6.5 Hz, 2H), 2.04–1.73 (m, 1H), 1.58 (s, 6H), 1.04 (dd, J = 6.7, 2.4 Hz, 6H); HRMS (ESI) m / z calcd for C 42 H 50 N2O7P + (M + H) + 625.28000, found 625.28290.

[0136] Boc-Lys(Fmoc)-Pro-Val-DPBPA (5): 1 HNMR (400 MHz, DMSO-d6) δ 8.32 (d, J = 7.0 Hz, 1H), 7.93–7.84 (m, 6H), 7.70–7.53 (m, 8H), 7.41 (t, J = 7.5 Hz, 2H), 7.32 (dd, J = 13.4, 6.2 Hz, 2H), 7.16 (d, J = 4.1 Hz, 6H), 6.93 (d, J = 8.4 Hz, 2H), 4.35–4.07 (m, 6H), 3.62 (dd, J = 13.7, 5.2 Hz, 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 = 12.9 Hz, 11H), 1.03–0.96 (m, 6H); 13 CNMR (101 MHz, DMSO- d6) δ 170.74, 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 13C NMR (162 MHz, DMSO-d6) δ 28.98; HRMS (ESI) m / z calcd for C 63 H 71 N4O 10 PNa + (M + Na) + 1097.48000, found 1097.48083.

[0137] H-Lys(Fmoc)-Pro-Val-DPBPA(6): 1 1H NMR (400 MHz, DMSO- d d6) δ 8.50 (d, J J = 7.5 Hz, 1H), 8.18 (s, 2H), 7.90 (dd, J J = 12.8, 7.8 Hz, 6H), 7.68 (d, J J = 7.0 Hz, 2H), 7.63–7.58 (m, 2H), 7.57–7.51 (m, 4H), 7.40 (t, J J = 7.3 Hz, 2H), 7.34–7.29 (m, 2H), 7.14 (q, J J = 9.1, 8.4 Hz, 6H), 6.93 (d, J J = 8.4 Hz, 2H), 4.60 (s, 1H), 4.43–4.37 (m, 1H), 4.31 (d, J J = 6.9 Hz, 2H), 4.22 (t, J J = 6.5 Hz, 1H), 4.19–4.12 (m, 1H), 3.01 (s, 2H), 2.19 (d, J J = 32.6 Hz, 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 J = 12.2 Hz, 3H), 1.06–0.99 (m, 6H); 13 13C NMR (101 MHz, DMSO- d6) δ 172.15, 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 1H NMR (162 MHz, DMSO - d 6) δ 29.05; HRMS (ESI) m / z calcd for C 58 H 63 N4O8PNa + (M + Na) + 997.42757, found 997.42725.

[0138] Boc - Phe - Lys(Fmoc) - Pro - Val - DPBPA (7): 1 1H NMR (400 MHz, DMSO - d6) δ 8.35 (d, J J = 7.4 Hz, 1H), 8.04 (d, J J = 7.6 Hz, 1H), 7.92–7.86 (m, 6H), 7.70–7.52 (m, 9H), 7.40 (t, J J = 7.3 Hz, 2H), 7.34–7.24 (m, 7H), 7.16 (d, J J = 12.1 Hz, 7H), 6.93 (d, J J = 8.5 Hz, 2H), 4.55–4.26 (m, 5H), 4.19 (t, J J = 6.8 Hz, 2H), 3.68–3.52 (m, 2H), 3.01–2.92 (m, 3H), 2.74–2.66 (m, 1H), 2.20 (dt, J J = 13.2, 6.9 Hz, 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 J = 8.8 Hz, 5H), 1.00 (dd, J J = 6.4, 3.4 Hz, 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 N5O 11 PNa + (M+Na) + 1244.54842,found1244.54895.

[0139] H-Phe-Lys(Fmoc)-Pro-Val-DPBPA (8): 1 HNMR(400MHz,DMSO-d6)δ8.76(d, J J = 7.9Hz,1H),8.37(d, J 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 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 J = 8.2,3.8Hz,2H),4.36–4.28(m,3H),4.21(t, J J = 6.6Hz,1H),4.09(dd, J J = 7.1,4.5Hz,1H),3.58(t, J= 6.0 Hz, 2H), 3.11–3.03 (m, 2H), 2.97 (dd, J = 11.6, 5.3 Hz, 2H), 2.25–1.93 (s, 3H), 1.89–1.65 (m, 3H), 1.57 (s, 5H), 1.40 (d, J = 7.4 Hz, 3H), 1.25 (d, J = 9.5 Hz, 3H), 1.00 (dd, J = 6.7, 3.4 Hz, 6H); HRMS(ESI) m / z calcd for C 67 H 72 N5O9PNa + (M + Na) + 1122.5153, found 1122.5140.

[0140] Boc- D Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA (9): 1 1H NMR (400 MHz, DMSO- d 6) δ 10.78 (s, 1H), 8.34 (dd, J = 13.9, 7.5 Hz, 3H), 7.93–7.85 (m, 6H), 7.70–7.59 (m, 4H), 7.55 (d, J = 3.6 Hz, 5H), 7.40 (t, J = 7.3 Hz, 2H), 7.35–7.11 (m, 15H), 7.05 (t, J = 7.4 Hz, 2H), 6.96 (dd, J = 17.5, 8.0 Hz, 3H), 6.87–6.81 (m, 1H), 4.67–4.60 (m, 1H), 4.50 (dd, J = 14.8, 6.9 Hz, 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 13C NMR (101 MHz, DMSO- d 6) δ 172.58, 170.52 (d, J = 48.5 Hz), 156.51, 148.51, 148.14, 144.37, 141.17, 133.19, 131.91 (d,J = 10.3 Hz), 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(162 MHz, DMSO - d 6) δ 29.00; HRMS(ESI) m / z calcd for C 83 H 90 N7O 12 PNa + (M + Na) + 1430.62773, found 1430.62781.

[0141] H - D Trp - Phe - Lys(Fmoc) - Pro - Val - DPBPA(10): 1 HNMR(400 MHz, DMSO - d 6) δ 11.02(s, 1H), 8.84(d, J = 8.1 Hz, 1H), 8.47(d, J = 7.7 Hz, 1H), 8.36(d, J = 7.4 Hz, 1H), 7.94(s, 1H), 7.92–7.86(m, 6H), 7.73–7.52(m, 9H), 7.39(q, J = 7.5 Hz, 3H), 7.29(dt, J = 12.2, 6.7 Hz, 7H), 7.23(dd, J = 6.3, 2.0 Hz, 2H), 7.15(d, J = 3.5 Hz, 6H), 7.09(d, J = 7.7 Hz, 1H), 7.03–6.98(m, 1H), 6.93(d, J = 8.6 Hz, 2H), 4.67(d, J = 5.6 Hz, 1H), 4.55–4.49(m, 2H), 4.36–4.27(m, 3H), 4.20(t, J = 6.7 Hz, 1H), 4.02(s, 1H), 3.68–3.54(m, 2H), 3.27(s, 1H), 3.02(dt, J = 21.1, 7.7 Hz, 4H), 2.87(dd,J =14.1, 8.7 Hz, 1H), 2.20 (dq, J =13.2, 6.7 Hz, 1H), 2.09–1.66 (m, 6H), 1.57 (s, 6H), 1.45–1.31 (m, 5H), 1.00 (dd, J =6.6, 3.4 Hz, 6H); 13 C NMR (101 MHz, DMSO- d 6) δ 172.56, 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 P NMR (162 MHz, DMSO- d 6) δ 29.01; HRMS (ESI) m / z calcd for C 78 H 82 N7O 10 P (M + H) + 1830.84456, found 1830.50460.

[0142] Boc-Arg(Pbf)- D Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA (11): 1 H NMR (500 MHz, DMSO-d6) δ 10.77–10.73 (m, 1H), 8.36 (d, J =7.5 Hz, 1H), 8.24 (d, J =7.5 Hz, 1H), 8.06 (d, J =7.8 Hz, 1H), 7.94–7.89 (m, 6H), 7.72–7.55 (m, 10H), 7.42 (t, J =7.5 Hz, 2H), 7.36–7.15 (m, 16H), 7.12–7.03 (m, 2H), 6.96 (d, J =8.2 Hz, 3H), 6.85 (d, J =8.4 Hz, 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 C NMR(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 P NMR(162MHz, DMSO - d 6)δ29.01; HRMS(ESI) m / z calcd for C 102 H 119 N 11 O 16 P S + (M + H) + 1817.83227, found 1817.83496.

[0143] H - Arg(Pbf)- D Trp - Phe - Lys(Fmoc)-Pro - Val - DPBPA(12): 1 H NMR(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, 7.5 Hz, 6H), 7.62–7.44 (m, 10H), 7.35–7.04 (m, 21H), 6.85 (d, J = 8.2 Hz, 2H), 4.61–4.39 (m, 4H), 4.19 (tt, J = 27.8, 7.3 Hz, 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, 6.1 Hz, 1H), 2.06–1.87 (m, 9H), 1.77 (s, 2H), 1.59 (d, J = 25.3 Hz, 4H), 1.48 (s, 7H), 1.32 (d, J = 12.3 Hz, 10H), 1.08 (s, 2H), 0.92 (dd, J = 6.8, 3.6 Hz, 6H); 31 ¹³C NMR (162 MHz, DMSO- d d6) δ 29.02; HRMS (ESI) m / z calcd for C 97 ₁₉H 111 ₁₁N 11 ₃O 14 ₃PS + (M + H) + ⁺ 1717.77984, found 1717.78149.

[0144] Boc- D Phe-Arg(Pbf)- D Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA (13): 1 ¹H NMR (400 MHz, DMSO- d d6) δ 10.74 (d, J J = 21.1 Hz, 1H), 8.34 (d, J J = 7.5 Hz, 1H), 8.18 (d, J J = 7.8 Hz, 1H), 7.92–7.85 (m, 7H), 7.69–7.59 (m, 5H), 7.54 (td, J J = 6.5, 5.4, 2.7 Hz, 5H), 7.38 (q, J J = 7.5 Hz, 3H), 7.33–7.26 (m, 5H), 7.23–7.14 (m, 16H), 7.03 (t, J J = 7.9 Hz, 2H), 6.93 (d, J= 8.2 Hz, 3H), 4.64–4.47 (m, 5H), 4.30 (dd, J = 23.5, 7.0 Hz, 3H), 4.19 (t, J = 7.1 Hz, 2H), 3.57 (d, J = 30.0 Hz, 2H), 3.13–2.74 (m, 14H), 2.43 (s, 3H), 2.12 (s, 4H), 1.98 (s, 3H), 1.82 (d, J = 16.4 Hz, 3H), 1.56 (s, 7H), 1.37 (s, 7H), 1.32 (s, 2H), 1.28 (d, J = 3.0 Hz, 9H), 1.24 (d, J = 5.0 Hz, 2H), 1.15 (s, 6H), 0.99 (dd, J = 6.8, 3.9 Hz, 6H); 31 P NMR (162 MHz, DMSO-d6) δ 29.00; HRMS (ESI) m / z calcd for C 111 H 127 N 12 O 17 PSNa + (M + Na) + 1986.88262, found 1986.88708.

[0145] H- D Phe-Arg(Pbf)- D Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA (14): 1 H NMR (400 MHz, DMSO- d 6) δ 10.82 (s, 1H), 8.40–8.11 (m, 7H), 7.91 (dd, J = 11.7, 7.5 Hz, 7H), 7.70–7.59 (m, 6H), 7.58–7.52 (m, 6H), 7.25 (ddd, J = 41.1, 20.0, 8.2 Hz, 24H), 6.94 (d, J = 8.2 Hz, 3H), 4.60 (d, J = 43.8 Hz, 4H), 4.39–4.12 (m, 6H), 3.58 (dd, J = 31.5, 15.4 Hz, 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 ¹³C NMR(162MHz, DMSO-d6) δ 29.04; HRMS(ESI) m / z calcd for C 106 ₓH 119 ₓN 12 ₓO 15 ₓPSNa + (M + Na) + 1886.83019, found 1886.83215.

[0146] Boc-Pro- D Phe-Arg(Pbf)- D Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA (15): 1 ¹H NMR(400MHz, DMSO- d d6) δ 8.39–7.97(m, 3H), 7.90(dd, J J = 12.6, 7.4Hz, 7H), 7.71–7.50(m, 10H), 7.40(t, J J = 7.1Hz, 2H), 7.34–7.28(m, 4H), 7.25–7.10(m, 17H), 7.04(t, J J = 7.7Hz, 2H), 6.94(d, J 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 J = 9.8Hz, 2H), 2.95(d, J 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 J = 9.3Hz, 18H), 1.23(s, 3H), 1.16(s, 2H), 1.05(s, 3H), 1.00(s, 6H); 31 ¹³C NMR(162MHz, DMSO-d6) δ 29.01; HRMS(ESI) m / z calcd for C 116 ₓH 134 ₓN 13 ₓO18 PSNa + (M + Na) + 2083.93539, found 2083.93872.

[0147] 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 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 J = 8.0Hz, 3H), 4.57(d, J J = 32.3Hz, 4H), 4.40–4.20(m, 6H), 3.59(d, J J = 33.1Hz, 3H), 3.16–2.82(m, 15H), 2.45(d, J J = 8.4Hz, 2H), 2.10(d, J J = 9.2Hz, 9H), 1.98(d, J J = 12.7Hz, 4H), 1.91–1.80(m, 4H), 1.57(s, 10H), 1.38(d, J J = 5.3Hz, 14H), 1.00(s, 6H).

[0148] Boc - Met - Pro - D Phe - Arg(Pbf) - D Trp - Phe - Lys(Fmoc) - Pro - Val - DPBPA(17): 1 HNMR(400MHz, DMSO - d d6) δ10.75(S, 1H), 8.26(d, J J = 58.6Hz, 4H), 7.96(d, J J = 8.4Hz, 1H), 7.92–7.85(m, 7H), 7.65(dt, J J = 24.9, 7.6Hz, 6H), 7.54(dq, J J = 11.7, 7.5, 5.5Hz, 6H), 7.39(t, J= 7.5 Hz, 3H), 7.33–7.27 (m, 4H), 7.25–7.13 (m, 16H), 6.93 (d, J = 8.1 Hz, 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, 4.7 Hz, 1H), 2.12 (s, 2H), 2.06–1.94 (m, 7H), 1.74 (s, 10H), 1.56 (s, 9H), 1.35 (d, J = 11.8 Hz, 20H), 1.15 (s, 8H), 0.99 (s, 6H); 31 ¹³C NMR (162 MHz, DMSO- d d6) δ 28.99; HRMS (ESI) m / z calcd for C 121 ₉₀H₁₁₅N₂₁O₁₆PS₂Na 143 ₂(M + Na) 14 ₂₂₁₄.₉₇₅₈₇, found 2214.97778. 19 Preparation of Nonapeptide-1: 100 mg of the above-obtained nonapeptide-1 precursor compound (17) Boc-Met-Pro- + Phe-Arg(Pbf)- + Trp-Phe-Lys(Fmoc)-Pro-Val-DPBPA was dissolved in 10 mL of tetrahydrofuran, 1 mL of ammonia water was added dropwise, and the mixture was stirred at room temperature. TCL monitoring (developing solvent: DCM:MeOH = 20:1) showed that fluorenyl and the carrier DPBPA were generated during the reaction, indicating that the carrier and the Fmoc group were removed. After about 8 h, the solvent was removed by concentration under reduced pressure. The Pbf and Boc groups were removed in one pot using the TFA / TIS / H₂O = 95:5:5 (volume ratio) system. After the reaction, the target nonapeptide was precipitated with diethyl ether, washed 3 times with diethyl ether, and dried in vacuo to obtain 46.8 mg of a white powder with a yield of 85%. The recovered carrier of 17.2 mg was obtained by separating the diethyl ether phase, and the cleavage recovery rate was 88%.

[0149] Structural characterization data of Nonapeptide-1: HRMS (ESI) m / z calcd for C D ₉₀H₁₁₅N₂₁O₁₆PS₂Na D (M + Na)

[0150] ₉₀H₁₁₅N₂₁O₁₆PS₂Na 61 ₉₀H₁₁₅N₂₁O₁₆PS₂Na 87 ₂₂₁₄.₉₇₅₈₇, found 2214.97778. 15 O₉SNa + (M + Na) +1228.64241, the measured value is 1228.64185, which proves that the synthesized sample is in line with the molecular mass of the target compound.

[0151] The above embodiments are only partial embodiments listed for the convenience of understanding the synthesis and application methods of the materials of the present invention, and are not used to limit the present invention. It can be understood that relevant practitioners can easily make appropriate modifications to this structure. Therefore, any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included within the protection scope of the present invention.

Claims

1. A diphenylphosphinyloxy bisphenol A compound, characterized in that, The general structural formula is as follows: In the formula, R1 = R2 = H.

2. Use of the diphenylphosphinyloxy bisphenol A compound according to claim 1 in the preparation of Melanostatine-1.

3. A preparation method of diphenylphosphinyloxy bisphenol A compound-assisted whitening nonapeptide-1, characterized in that, It includes the following steps: Using the diphenylphosphinyloxy bisphenol A compound as an auxiliary group, successively coupling with N-terminal protected valine, N-terminal protected proline, lysine with both N-terminal and side-chain protected, N-terminal protected phenylalanine, N-terminal protected D-tryptophan, arginine with both N-terminal and side-chain protected, N-terminal protected D-phenylalanine, and N-terminal protected proline, and performing N-terminal protecting group removal treatment reaction. After the reaction is completed, then coupling with N-terminal protected methionine to obtain the precursor C of the nonapeptide; Removing the auxiliary group from compound C, simultaneously removing the protecting groups on the side chains, and then performing purification treatment to obtain Melanostatine-1.

4. The preparation method of the diphenylphosphinyloxy bisphenol A compound-assisted whitening nonapeptide-1 according to claim 3, characterized in that, The precursor C of the nonapeptide is prepared according to the following steps: S1. Using the diphenylphosphinyloxy bisphenol A compound as a carrier, reacting with N-terminal protected valine under the action of a coupling agent, and after purification, obtaining product A; S2. After removing the N-terminal protecting group in the purified product A through treatment, and after purification, obtaining product B; S3. Repeating S1 and S2, using product B as a carrier, successively replacing N-terminal protected valine with N-terminal protected proline, lysine with both N-terminal and side-chain protected, N-terminal protected phenylalanine, N-terminal protected D-tryptophan, arginine with both N-terminal and side-chain protected, N-terminal protected D-phenylalanine, and N-terminal protected proline, performing coupling reaction and N-terminal protecting group removal treatment reaction. After the reaction is completed, then coupling with N-terminal protected methionine to obtain the precursor C of the nonapeptide.

5. The preparation method of diphenylphosphinyloxy bisphenol A compound-assisted whitening nonapeptide-1 according to claim 4, characterized in that, The N-terminal protecting group includes Fmoc or Boc.

6. The preparation method of diphenylphosphinyloxy bisphenol A compound-assisted whitening nonapeptide-1 according to claim 4, characterized in that, The protecting groups on the side chains include Fmoc, Boc, Pbf or tBu.

7. The preparation method of diphenylphosphinyloxy bisphenol A compound-assisted whitening nonapeptide-1 according to claim 4, characterized in that, The structural formula of the product B is as follows: 。 8. The preparation method of diphenylphosphoryloxy bisphenol A compound-assisted whitening nonapeptide-1 according to claim 4, characterized in that, The structural formula of the precursor C of the nonapeptide is as follows: Among them, the N-terminal protecting group is Boc, and the protecting group on the side chain is Fmoc.

9. The preparation method of diphenylphosphinyloxy bisphenol A compound-assisted whitening nonapeptide-1 according to claim 4, characterized in that, Removing the auxiliary group from compound C to obtain the crude product of the auxiliary group; Dissolving the crude product of the auxiliary group in an appropriate amount of ethyl acetate, adding an alkane or ether solvent, the auxiliary group can be separated from other impurities; performing filtration, washing or recrystallization operations on the separated auxiliary group to obtain the purified auxiliary group.

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