CN112898380B

CN112898380B - Dioxohexa-ring modified tetrahydrocarboline-3-formyl-The-HGK, preparation thereof, antithrombotic activity thereof and application thereof

Info

Publication number: CN112898380B
Application number: CN201911216159.6A
Authority: CN
Inventors: 赵明; 彭师奇; 郤思远
Original assignee: Capital Medical University
Current assignee: Capital Medical University
Priority date: 2019-12-02
Filing date: 2019-12-02
Publication date: 2022-04-22
Anticipated expiration: 2039-12-02
Also published as: CN112898380A

Abstract

The invention discloses 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiro) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-The-His-Gly-Lys with The following formula, discloses a preparation method thereof and discloses The anti-arterial thrombosis activity thereof. Therefore, the invention discloses the application of the compound in preparing the anti-arterial thrombosis medicine.

Description

Dioxohexa-ring modified tetrahydrocarboline-3-formyl-The-HGK, preparation thereof, antithrombotic activity thereof and application thereof

Technical Field

The invention relates to a 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiro) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-The-His-Gly-Lys compound, a preparation method thereof and arterial thrombosis activity thereof. The invention thus relates to its use in the preparation of an anti-arterial thrombosis medicament. The invention belongs to the field of biological medicine.

Background

Arterial embolization has become one of the diseases with high morbidity and mortality at present. Arterial thrombosis is responsible for transient ischemic attacks, acute coronary syndromes, myocardial infarction and atrial fibrillation. Between 18% and 47% of patients with atrial fibrillation have coronary artery disease, and about 20% of patients with atrial fibrillation with coronary artery disease receive percutaneous coronary intervention. Arterial thrombosis is also responsible for artificial heart valves, arteriovenous fistulas and other post-operative arterial thrombi and unstable angina. For example, following liver transplantation surgery, patients are at risk for liver arterial thrombosis. In addition, patients with antiphospholipid syndrome are also at risk for arterial thrombosis. Although tumors are more widely associated with venous thrombi than with arterial thrombi, there is an increasing awareness of the incidence of arterial thrombi, including peripheral arterial thrombi, in the treatment of specific malignancies and tumors. Arterial cannulation and ischemic stroke have led to an increasing number of arterial thrombosis cases in children. More than a decade ago, there was an initial alert to the risk of arterial thrombosis due to ***e abuse. Venous and arterial thrombi are considered as two distinct diseases in the traditional sense because of the different etiologies. Recent epidemiological studies have shown that the association between venous and arterial thrombi is difficult to sever. This condition can be attributed to their risk factors overlapping each other. As a result, prevention and treatment of arterial thrombosis have been increasingly emphasized.

Direct oral anticoagulation is the only strategy for clinical treatment of arterial thrombosis. Although the curative effect of the oral anticoagulant on the arterial thrombosis is exact, the oral anticoagulant has bleeding side effects. For example, aspirin can induce gastrointestinal or intracranial bleeding at effective oral doses. This risk greatly limits the benefit of the patient. Clinically, there is a need for a medicament with a therapeutic effect comparable to that of aspirin, without the risk of aspirin-like gastrointestinal or intracranial hemorrhage. In response to this clinical need, researchers at home and abroad have paid a large amount of heart blood. However, no substantial progress has been made.

The search for safe and effective anti-thrombotic agents is an important interest for the research of new drugs by the inventor. Over The last 3 years The inventors have found that 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiroyl) -1,2,3, 4-tetrahydro- β -carboline-3-formyl-The-His-Gly-Lys of The formula is a safe and effective antithrombotic agent. Based on this finding, the inventors have proposed the present invention.

Disclosure of Invention

The first aspect of The present invention provides 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiro) -1,2,3, 4-tetrahydro- β -carboline-3-formyl-The-His-Gly-Lys of The formula.

The second content of The invention is to provide a preparation method of 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiro) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-The-His-Gly-Lys, which comprises The following steps:

1) synthesizing (3S) -1, 1-dihydroxymethyl-tetrahydro-beta-carboline-3-benzyl carboxylate;

2) synthesizing 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiro) -1,2,3, 4-tetrahydro-beta-carboline-3-benzyl carboxylate;

3) synthesizing 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiro) -1,2,3, 4-tetrahydro-beta-carboline-3-carboxylic acid;

4) synthesizing 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiroyl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-The-OBzl by adopting a liquid phase condensation method with Dicyclohexylcarbodiimide (DCC) as a condensing agent and 1-hydroxybenzotriazole (HOBt) as a catalyst;

5) synthesizing 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiro) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-The;

6) synthesizing HCl, His-Gly-Lys (Z) -OBzl by adopting a liquid phase condensation method with DCC as a condensing agent and HOBt as a catalyst;

7) synthesizing 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiro) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-The-His-Gly-Lys (Z) -OBzl by a liquid phase condensation method with DCC as a condensing agent and HOBt as a catalyst;

8) synthesizing 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiro) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-The-His-Gly-Lys;

the third aspect of The present invention is to evaluate The anti-arterial thrombotic activity of 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiroyl) -1,2,3, 4-tetrahydro- β -carboline-3-formyl-The-His-Gly-Lys.

Drawings

FIG. 1. synthetic route of 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiro) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-The-EDG: i) trifluoroacetic acid, 1, 3-dihydroxyacetone; ii) concentrated sulfuric acid, acetone; iii) Palladium on carbon (Pd), H₂(ii) a iv) Dicyclohexylcarbodiimide (DCC), 1-hydroxybenzotriazole (HOBt), N-methylmorpholine-an-line (NMM); v) a solution of hydrogen chloride in ethyl acetate (4M).

Detailed Description

To further illustrate the invention, a series of examples are given below. These examples are purely illustrative and are intended to be a detailed description of the invention only and should not be taken as limiting the invention.

EXAMPLE 1 preparation of benzyl (3S) -1, 1-dihydroxymethyl-tetrahydro- β -carboline-3-carboxylate (1)

2g (7.2mmol) of L-tryptophan benzyl ester was added to 10mL of dichloromethane, and the mixture was sufficiently stirred to dissolve it. Under ice-bath conditions, 1mL of trifluoroacetic acid was slowly added dropwise to the solution. Then, 0.78g (8.6mmol) of 1, 3-dihydroxyacetone was added to the solution and reacted at room temperature for 7 hours. TLC showed disappearance of L-tryptophan benzyl ester (dichloromethane/methanol: 30: 1). Under ice-bath conditions, 50mL of saturated NaHCO was added to the solution₃The solution was stirred well, then a dichloromethane layer was left, followed by saturated NaHCO₃The solution (30 mL. times.3) was washed with saturated NaCl solution (30 mL. times.3), and the dichloromethane layer was dried over anhydrous sodium sulfate for 12 hours. Filtration and concentration of the filtrate under reduced pressure gave 2.03g (77%) of the title compound as a yellow powder. ESI-MS (M/e):367[ M + H]⁺。

EXAMPLE 2 preparation of benzyl 3S-1- (1, 1-dimethyl-1, 3-dioxan-6-spiroyl) -1,2,3, 4-tetrahydro- β -carboline-3-carboxylate (2)

To 5mL of anhydrous acetone was added 0.2g (0.55mmol) of benzyl (3S) -1, 1-dimethylol-tetrahydro- β -carboline-3-carboxylate (1). 100. mu.L of concentrated sulfuric acid was added thereto under ice-bath conditions, followed by stirring at room temperature for 3 hours. TLC showed the disappearance of compound 1 (petroleum ether/ethyl acetate, 4: 1). Under ice-bath conditions, saturated NaHCO was used₃Adjusting pH of the reaction solution to 7, concentrating the obtained solution under reduced pressure to remove acetone, extracting and washing the residual solution with ethyl acetate for 3 times, and washing the ethyl acetate layer with saturated NaCl solution to neutrality. The ethyl acetate layer was dried over anhydrous sodium sulfate for 12 hours. Filtration and concentration of the filtrate under reduced pressure gave a tan solid which was separated by column chromatography (petroleum ether/ethyl acetate, 4:1) to give 0.08g (35.8%) of the title compound as a white solid. ESI-MS (M/e):407[ M + H]⁺。

EXAMPLE 3 preparation of 3S-1- (1, 1-dimethyl-1, 3-dioxan-6-spiroyl) -1,2,3, 4-tetrahydro-beta-carboline-3-carboxylic acid (3)

To 10mL of methanol were added 0.20g (0.5mmol) of 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiro) -1,2,3, 4-tetrahydro- β -carboline-3-carboxylic acid benzyl ester (2) and 0.02g of Pd/C. Stirring and passage of 12h hydrogen, TLC showed disappearance of Compound 2 (petroleum ether/ethyl acetate, 4: 1). The palladium-carbon (Pd/C) was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was triturated with ether to give 0.14g (90%) of the title compound as a colourless solid. ESI-MS (M/e) 317[ M + H ]]⁺。

EXAMPLE 4 preparation of 3S-1- (1, 1-dimethyl-1, 3-dioxan-6-spiroyl) -1,2,3, 4-tetrahydro- β -carboline-3-formyl-The-OBzl (4)

To 20mL of tetrahydrofuran were added 0.19g (0.6mmol) of 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiro) -1,2,3, 4-tetrahydro- β -carboline-3-carboxylic acid (3), 0.15g (0.72mmol) of N, N' -Dicyclohexylcarbodiimide (DCC) and 0.09g (0.72mmol) of 1-hydroxybenzotriazole (HOBt). Stir for 30 minutes in an ice bath. Then, 0.20g (0.66mmol) of HCl. The-OBzl was added to The reaction mixture. Subsequently, N-methylmorpholine (NMM) was added dropwise to the reaction mixture to adjust the pH of the reaction mixture to 9. After stirring at room temperature for 6 hours, TLC showed the disappearance of compound 3 (dichloromethane/methanol, 30/1). Dicyclohexylurea (DCU) was filtered off, the filtrate was concentrated under reduced pressure, the residue obtained was dissolved in 30mL of ethyl acetate, and the solution was filtered again to remove DCU. The filtrate was sequentially treated with 5% NaHCO₃Aqueous extraction (15 mL. times.3), saturated aqueous NaCl solution (15 mL. times.3), 5% KHSO₄Aqueous wash (15 mL. times.3), saturated aqueous NaCl wash (15 mL. times.3), 5% NaHCO₃The mixture was washed with an aqueous solution (15 mL. times.3) and with a saturated aqueous NaCl solution (15 mL. times.3), and dried over anhydrous sodium sulfate for 12 hours. Filtration and concentration of the filtrate under reduced pressure gave a yellow powder which was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1) to give 0.27g (80%) of the title compound as a colourless powder. ESI-MS (M/e):563[ M + H]⁺；¹H-NMR(300MHz,DMSO-d₆):δ/ppm＝10.94(s,1H),8.28(t,J＝7.2Hz,1H),7.79(s,1H),7.37(m,6H),7.07(m,1H),7.02(m,1H),5.16(s,1H),5.12(s,1H),4.40(m,1H),4.21(m,1H),3.99(m,1H),3.75(m,1H),3.61(m,2H),3.02(m,2H),2.12(m,2H),1.82(m,2H),1.65(s,3H),1.42(s,3H),1.22(m,2H),1.01(m,3H)。

EXAMPLE 5 preparation of 3S-1- (1, 1-dimethyl-1, 3-dioxan-6-spiroyl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-The (5)

To 10mL of methanol were added 0.28g (0.5mmol) of 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiro) -1,2,3, 4-tetrahydro- β -carboline-3-formyl-The-OBzl (4) and 0.02g of palladium on carbon (Pd/C). Stirring and passage of 12h hydrogen, TLC showed disappearance of compound 4 (dichloromethane/methanol, 30/1). Pd/C was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was triturated with ether to give 0.21g (90%) of the title compound as a yellow solid. ESI-MS (M/e):473[ M + H]⁺，¹H-NMR(300MHz,DMSO-d₆):δ/ppm＝10.98(s,1H),8.18(d,J＝7.5Hz,1H),7.79(s,1H),7.40(dt,J₁＝4.8Hz,J₂＝8.1Hz,2H),7.02(td,J₁＝8.1Hz,J₂＝4.8Hz,2H),4.40(m,1H),4.28(m,1H),4.12(m,1H),4.02(m,1H),3.81(m,1H),3.61(m,1H),3.02(m,2H),2.14(m,2H),1.82(m,2H),1.65(s,3H),1.41(s,3H),1.22(m,2H),1.03(m,3H)。

EXAMPLE 6 preparation of Boc-Gly-Lys (Z) -OBzl

Using the method of example 4, 2.12g (80%) of the title compound was obtained as a colorless solid from 0.96g (5.5mmol) of Boc-Gly and 1.85g (5mmol) of Hcl.Lys (z) -OBzl.

EXAMPLE 7 preparation of HCl.Gly-Lys (Z) -OBzl

1.58g (3mmol) of Boc-Gly-Lys (z) -OBzl was dissolved in 20mL of hydrogen chloride in ethyl acetate (4M) and reacted for 4 hours in ice bath. TLC monitoring indicated complete reaction (dichloromethane/methanol system, 30/1). The reaction mixture was concentrated under reduced pressure, the residue was dissolved in anhydrous ethyl acetate, and the resulting solution was concentrated under reduced pressure. This operation was repeated 3 times. The obtained white powdery substance was sufficiently washed with dehydrated ether to obtain 1.32g (95%) of the title compound as a colorless solid

Example 8 preparation of Boc-His (Boc) -Gly-Lys (Z) -OBzl

From 1.77g (5mmol) Boc-His (Boc) and 2.78g (6mmol) HCl Gly-Lys (z) -OBzl 2.56g (67%) of the title compound were obtained as colorless solid using the method of example 4. ESI-MS (M/e) 765[ M + H ] +.

EXAMPLE 9 preparation of HCl His-Gly-Lys (Z) -OBzl

From 2.29g (3mmol) Boc-His (Boc) -Gly-Lys (z) -OBzl 1.66g (92%) of the title compound was obtained as colorless solid using the method of example 7.

EXAMPLE 10 preparation of 3S-1- (1, 1-dimethyl-1, 3-dioxan-6-spiroyl) -1,2,3, 4-tetrahydro- β -carboline-3-formyl-The-His-Gly-Lys (Z) -OBzl (6)

To 30mL of anhydrous tetrahydrofuran were added 0.47g (1mmol) of (3S) -1-bis (methyl) -mono, tris-dioxane-tetrahydro- β -carboline-3-formyl-The (5), 0.25g (1.2mmol) of DCC and 0.16g (1.2mmol) of HOBt, and The mixture was stirred for 30 minutes in an ice bath. Then, 0.66g (2.2mmol) of HCl. His-Gly-Lys (z) -OBzl was added to the reaction mixture. N-methylmorpholine (NMM) was added dropwise to adjust the pH of the reaction mixture to 9. The reaction was carried out at room temperature for 8 hours. TLC showed compound 5 to disappear (dichloromethane/methanol, 15/1), Dicyclohexylurea (DCU) was filtered off and the filtrate was concentrated under reduced pressure. The residue was dissolved in 100mL of ethyl acetate and the solution was filtered to remove DCU. The filtrate was washed with a 5% aqueous NaHCO3 solution (30 mL. times.3), a saturated aqueous NaCl solution (30 mL. times.3), a 5% aqueous KHSO4 solution (30 mL. times.3), a saturated aqueous NaCl solution (30 mL. times.3), a 5% aqueous NaHCO3 solution (30 mL. times.3), a saturated aqueous NaCl solution (30 mL. times.3), and dried over anhydrous sodium sulfate for 12 hours. Filtration and concentration of the filtrate under reduced pressure gave a yellow powder which was purified by silica gel column chromatography (dichloromethane/methanol, 15/1) to give 0.71g (70%) of the title compound as a yellow powder. ESI-MS (M/e) 1020[ M + H ] +; 1H-NMR (300MHz, DMSO-d6): δ/ppm ═ 10.93(s,1H),8.53(m,1H),8.24(m,1H),8,11(m,1H),8.03(m,1H),7.76(m,1H),7.55(s,1H),7.34(m,11H),7.19(m,1H),7.06(m,1H),6.98(m,1H),6.89(s,1H),5.12(s,2H),4.99(s,2H),4.47(m,1H),4.43-4.28(m,2H),4.00(m,1H),3.89-3.78(m,2H),3.68-3.51(m,4H),3.08-2.93(m,6H),2.12(m,2H), 1H), 1.67(m, 1H), 1.18H, 18H, 1H, 18H, 2H, 1H, 18H, 1H, 18H, 1H, 18H, 1H, 18H, 1H, 18H, 1H, 18H, 1H, 2H, 18H, 1H, 18H, 1H, 18H, 1H, 18H, 1H, 2H, 18H, 1H, 18H, 1H, and the like, 3H) in that respect

EXAMPLE 11 preparation of 3S-1- (1, 1-dimethyl-1, 3-dioxan-6-spiroyl) -1,2,3, 4-tetrahydro- β -carboline-3-formyl-The-His-Gly-Lys (7)

Adding 0.05g (0.05mmol) of 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiro) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-The-His-Gly-Lys (Z) -OBzl (6) and 0.005g of Pd/C into 10mL of methanol, stirring and introducing hydrogen for 12h, and displaying TLCIndicating that compound 6 disappeared (ethyl acetate: water: glacial acetic acid 4:1: 1). The palladium-carbon (Pd/C) was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was triturated with ether to give 0.035g (90%) of the title compound as a colorless solid. ESI-MS (M/e):795[ M-H]^-，¹H-NMR(300MHz,DMSO-d₆):δ/ppm＝10.98(s,1H),8.41(m,1H),8.26(m,1H),8.07(m,1H),7.92(m,2H),7.52(m,1H),7.40(m,2H),7.00(m,2H),6.86(m,1H),4.47(m,1H),4.41(m,1H),4.38(m,1H),3.99(m,2H),3.77(m,2H),3.64(m,3H),3.04(m,4H),2.73(m,2H),2.12(m,2H),1.74(m,2H),1.61(s,3H),1.50(m,2H),1.38(s,3H),1.23(m,4H),1.00(t,J＝7.2Hz,3H).¹³C-NMR(125MHz,DMSO-d₆):δ/ppm＝173.25,171.82,171.58,136.54,126.70,119.10,111.75,109.04,98.13,52.94,51.58,33.79,32.24,28.37,28.19,27.09,25.79,24.93,22.44,20.21,15.20。

EXAMPLE 12 evaluation of the anti-arterial Thrombus Activity of Compound 7

1) Drawing a polyethylene tube into a thin tube with one end being an oblique opening, wherein the fixed length is 10.0cm, and the thin tube is respectively used for inserting a right jugular vein (with a thicker tube diameter) and a left carotid artery (with a thinner tube diameter); the length of the middle section polyethylene tube is 8.0cm, the thrombus line is pressed in the carotid intubation direction, and the tube needs to be filled with heparin before intubation.

2) Male rats weighing 200 ± 20g were acclimatized and fasted for one day prior to surgery. The groups were randomly divided into a physiological saline (0.3mL/100g,10 rats), aspirin (167 μmol/kg,10 rats), and 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiroyl) -1,2,3, 4-tetrahydro- β -carboline-3-formyl-The-His-Gly-Lys (compound 7) (0.01 μmol/kg,10 rats). The drug was administered orally to rats in the prescribed dose. After 30min of administration, rats were anesthetized by intraperitoneal injection of 20% urethane solution (7mL/kg), and surgery was started 2min later. The rat lies on the back on the fixed plate in the operation, cuts open neck skin, separates right common carotid artery and left jugular vein, line ball under the blood vessel, ligature telecentric end, near telecentric end department at the vein and cut a osculum, insert the intubate vein end, inject heparin, then take off the syringe of injection heparin, the tie line is fixed, reuse artery presss from both sides and presss from both sides the artery and nears the heart end, cuts a osculum near telecentric end direction, ligates the artery end, loosens the artery after the tie line is fixed and presss from both sides, establishes the extracorporeal circulation bypass. After circulating for 15 minutes, the venous end is firstly cut off to observe whether the blood circulation is normal, if the blood circulation is normal, a thrombus line is taken out from the arterial end, dry floating blood is stained on paper, then weighing is carried out, the activity is expressed by the weight of the thrombus, and the data are listed in table 1. The thrombus weights in the table show that aspirin is effective in inhibiting arterial thrombosis in rats at an oral dose of 167 μmol/kg, and that compound 7 is also effective in inhibiting arterial thrombosis in rats at an oral dose of 0.01 μmol/kg. This is a prominent technical effect of the present invention.

TABLE 1 anti-arterial thrombotic Activity of Compound 7

a) P <0.01 to saline; n is 10.

Claims

1. The application of 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiro) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-The-His-Gly-Lys with The following formula in preparing The anti-arterial thrombosis medicine,

2. the use of 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiro) -1,2,3, 4-tetrahydro- β -carboline-3-formyl-The-His-Gly-Lys as defined in claim 1 for The manufacture of an anti-arterial thrombosis medicament, wherein The synthesis of The compound 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiro) -1,2,3, 4-tetrahydro- β -carboline-3-formyl-The-His-Gly-Lys comprises The steps of:

a) synthesizing (3S) -1, 1-dihydroxymethyl-tetrahydro-beta-carboline-3-benzyl carboxylate;

b) synthesizing 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiro) -1,2,3, 4-tetrahydro-beta-carboline-3-benzyl carboxylate;

c) synthesizing 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiro) -1,2,3, 4-tetrahydro-beta-carboline-3-carboxylic acid;

d) adopting dicyclohexylcarbodiimide as a condensing agent and 1-hydroxybenzotriazole as a catalyst to synthesize 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiroyl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-The-OBzl in a liquid phase manner;

e) synthesizing 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiro) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-The;

f) adopting dicyclohexylcarbodiimide as a condensing agent and 1-hydroxybenzotriazole as a catalyst to synthesize HCl, His-Gly-Lys (Z) -OBzl in a liquid phase;

g) synthesizing 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiro) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-The-His-Gly-Lys (Z) -OBzl by using dicyclohexylcarbodiimide as a condensing agent and 1-hydroxybenzotriazole as a catalyst;

h) synthesizing 3S-1- (1, 1-dimethyl-1, 3-dioxane-6-spiro) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-The-His-Gly-Lys.