CN109912587B - Side chain protection amido n-hexanoyl carboline benzyl carboxylate, preparation, activity and application thereof - Google Patents
Side chain protection amido n-hexanoyl carboline benzyl carboxylate, preparation, activity and application thereof Download PDFInfo
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- CN109912587B CN109912587B CN201711315738.7A CN201711315738A CN109912587B CN 109912587 B CN109912587 B CN 109912587B CN 201711315738 A CN201711315738 A CN 201711315738A CN 109912587 B CN109912587 B CN 109912587B
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- carboline
- tetrahydro
- hexanoyl
- benzyl ester
- carboxylic acid
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- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses (3S) of the following structureN- (6-Aminoacylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester (wherein AA is L-Asp (OBzl), L-Glu (OBzl) and L-Arg (NO)2) Residue). Discloses a preparation method and an anti-tumor effect of the compounds, and clarifies the application of the compounds in preparing medicaments with the anti-tumor effect.
Description
Technical Field
The invention relates to (3S) -N- (6-amino acylamino N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester (AA is selected from L-Asp (OBzl), L-Glu (OBzl) and L-Arg (NO)2) Residue). Relates to a preparation method and an anti-tumor effect thereof, and relates to the application of the compounds in preparing medicaments with the anti-tumor effect. The invention belongs to the field of biological medicine.
Technical Field
Malignant tumors seriously threaten human health. Among them lung cancer is one of the most aggressive human cancers. For patients with advanced lung cancer, 10% -15% of the patients typically survive for only 5 years. The situation of this difficulty has not improved significantly over the last 30 years. In many clinical cases, lung cancer has metastasized to surrounding tissues before it is diagnosed. Tumor metastasis, especially tumor lung metastasis, is the greatest risk of death in tumor patients. To date, there is no antitumor drug that can prevent tumor metastasis for clinical use. Inflammation further worsens the prognosis of patients with tumors and tumor metastases. To date, no antitumor drug that can prevent inflammation and tumor metastasis has been used clinically. The invention relates to a medicament with triple effects of resisting tumor, tumor metastasis and inflammation, which is the leading edge of research on anti-tumor medicaments. The inventor's prior invention (patent application publication No. CN 106349148A, application No. CN201510409682.6) has disclosed that amino acid benzyl ester substituted bisindole acetic acid alcohol has triple effects of anti-tumor, anti-tumor metastasis and anti-inflammatory at 0.2 mu mol/kg (left formula). The minimum effective dose of benzyl bisindoloethanol amino acid to exert an antitumor effect by the inventors was unsatisfactory at 0.2. mu. mol/kg. The dosage is higher. Over the past two years, the inventors have been searching for compounds with an anti-tumour effect at a minimum effective dose of less than 0.2. mu. mol/kg. Finally, the inventor finds that the 6-side chain protection amino acylaminocaproic acid modified tetrahydrocarboline benzyl carboxylate has an anti-tumor effect at a dosage of 0.02 mu mol/kg. Because the toxic and side effects of the medicine can disappear along with the reduction of the dosage, the reduction of the effective dosage by 10 times shows that the structure modification has outstanding technical effect. Thus, the inventors have proposed the present invention.
Disclosure of Invention
The first aspect of the present invention provides benzyl (3S) -N- (6-aminoacylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate of the following structure (wherein AA is selected from the group consisting of L-Asp (OBzl), L-Glu (OBzl) and L-Arg (NO)2) Residue).
The second aspect of the present invention provides a process for preparing benzyl (3S) -N- (6-aminoacylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate, which comprises:
(1) carrying out a Pictet-Spengler reaction on L-tryptophan benzyl ester and formaldehyde under the catalysis of dilute sulfuric acid to generate (3S) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester;
(2) 6-aminocaproic acid and di-tert-butyl dicarbonate (Boc) in aqueous sodium hydroxide (2M), mixed solution of water and dioxane2O reaction to produce 6-tert-butyloxycarbonylaminohexanoic acid;
(3) reacting 6-tert-butoxycarbonylaminocaproic acid with (3S) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester in anhydrous tetrahydrofuran in the presence of N, N-Dicyclohexylcarbodiimide (DCC) and N-hydroxybenzotriazole (HOBt) to obtain (3S) -N- (6-tert-butoxycarbonylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester;
(4) removing Boc from (3S) -N- (6-tert-butoxycarbonylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester in hydrogen chloride ethyl acetate solution under ice bath to obtain (3S) -N- (6-amino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester;
(5) in the presence of N, N-dicyclohexylcarbodiimide and N-hydroxyBenzyl (3S) -N- (6-amino N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate and Boc-AA (AA is selected from L-Asp (OBzl), L-Glu (OBzl) and L-Arg (NO) in anhydrous tetrahydrofuran in the presence of benzotriazole2) Residue) to obtain (3S) -N- (6-tert-butoxycarbonylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-benzyl carboxylate;
(6) removing Boc from (3S) -N- (6-tert-butoxycarbonylamino-acylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester in hydrogen chloride ethyl acetate solution under ice bath to obtain (3S) -N- (6-amino-acylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester.
The third aspect of the present invention is to evaluate the inhibition of tumor growth in S180 mice by (3S) -N- (6-aminoacyl-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester.
Drawings
FIG. 1. scheme for the synthesis of (3S) -N- (6-Aminoacylamido-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester i) HCHO, H2O,H2SO4(ii) a Ii) N, N-Dicyclohexylcarbodiimide (DCC), N-hydroxybenzotriazole (HOBt), N-methylmorpholine, tetrahydrofuran; iii) dioxane, aqueous sodium hydroxide solution, di-tert-butyl dicarbonate (Boc)2O; iv) Hydrogen chloride/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) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate (1)
Slowly add 1.5m L concentrated H to 300m L water under ice bath2SO4Stirring for 3min, adding 5.00g (15.1mmol) of L-tryptophan benzyl ester hydrochloride and 6m L formaldehyde solution (40%). stirring at room temperature for 72h, T L C showed L-tryptophan benzyl ester hydrochloride disappearance. the reaction solution was adjusted to pH 7 with concentrated ammonia water while cooling on ice, filtering, dissolving the filter cake with 100m L ethyl acetate, washing the resulting solution with saturated sodium chloride aqueous solution (40m L× 3), and drying with anhydrous sodium sulfate. Filtering, and concentrating the filtrate under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol ═ 90:1) to give 1.9g (41%) of the objective compound as a yellow oily solid. ESI-MS (m/e): 307[ M + H]+。
EXAMPLE 2 preparation of 6-tert-Butoxycarbonylaminohexanoic acid (2)
5.00g (38.2mmol) 6-aminocaproic acid (EACA) was suspended in 50M L distilled water, the resulting suspension was added with 10M L aqueous sodium hydroxide solution (2M) under ice bath, stirred to dissolve, 9.2g (42.2 mmol) (Boc) was added to the resulting solution2Adjusting pH of O and 20M L dioxane solution with sodium hydroxide aqueous solution (2M) to 9, stirring for 30min, removing ice bath, stirring at room temperature until T L C shows 6-aminocaproic acid disappears, and adding saturated KHSO4The pH of the aqueous solution was adjusted to 7 and the dioxane was removed by concentration under reduced pressure. The reaction solution was saturated KHSO in ice bath4Adjusting pH of the aqueous solution to 2, extracting with ethyl acetate (50M L× 3), washing the ethyl acetate layer with saturated NaCl aqueous solution (40M L× 3), drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain 8.0g (91%) of the title compound as colorless oil, ESI-MS (M/e): 232[ M + H ]]+。
EXAMPLE 3 preparation of benzyl (3S) -N- (6-tert-butoxycarbonylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate (3)
Dissolving 4.15g (18mmol) of tert-butoxycarbonyl-6-aminocaproic acid in 80m L anhydrous tetrahydrofuran, adding 2.46g (18.2mmol) of N-hydroxybenzotriazole (HOBt) and 4.04g (19.6mmol) of N, N-Dicyclohexylcarbodiimide (DCC) under ice bath, stirring for 60 min, adding 5.06g (16.5mmol) of benzyl (3S) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate and 80m L anhydrous tetrahydrofuran solution to the obtained reaction solution, adjusting pH of the reaction mixture to 9 with N-methylmorpholine (NMM) under ice bath, stirring at room temperature for 24 hr, stirring at T L C to show disappearance of (3S) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate, filtering the reaction solution, concentrating the filtrate under reduced pressure, adding ethyl acetate to the residue to dissolve the solution, and sequentially using saturated NaHCO to dissolve the solution in turn3Washing with aqueous solution (40m L× 3), washing with saturated aqueous NaCl solution (40m L× 3), and washing with saturated aqueous KHSO solution4Aqueous solution (40m L× 3), saturated aqueous NaCl solution (40m L× 3), saturated aqueous NaHCO solution3Aqueous solution (40m L× 3), saturated aqueous NaCl solution (40m L× 3), Ethyl acetateAnhydrous Na for layer2SO4Drying, filtration, concentration of the filtrate under reduced pressure and purification of the residue by silica gel column chromatography (dichloromethane: methanol 160:1) gave 5.43g (64%) of the title compound as a yellow oily solid. ESI-MS (m/e): 520 [ M + H ]]+。
EXAMPLE 4 preparation of benzyl (3S) -N- (6-amino-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate (4)
3.4g (6.6mmol) of benzyl (3S) -N- (tert-butoxycarbonylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate were dissolved in 40M L M ethyl acetate solution of hydrogen chloride (4M) under ice-bath and stirred for 3 hours, T L C showed disappearance of benzyl (3S) -N- (tert-butoxycarbonylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate, the reaction mixture was concentrated under reduced pressure to dryness under stirring, the residue was dissolved in anhydrous ethyl acetate, the solution was concentrated under reduced pressure to dryness, the operation was repeated three times, the residue was washed thoroughly with anhydrous ether to give 2.8g (94%) of the title compound as a tan solid ESI-MS (M/e):420 [ M + H ]: M]+；Mp 223-226℃。1H NMR(300MHz,DMSO-d6:/ppm＝10.963(d,J＝11.4Hz,1H), 7.894(s,3H),7.458(d,J＝7.5Hz,1H),7.327(t,J＝7.5Hz,1H),7.204(dd,J1＝1.5Hz,J2＝7.2 Hz,1H),7.158-6.972(m,6H),5.607(d,J＝4.7Hz,1H),5.059(s,2H),4767(d,J＝15.6Hz,1H),4.610(d,J＝17.4Hz,1H),3.426(m,1H),3.021(m,1H),2.754(m,2H),2.613(m,1H),2.389(m,1H),1.568-1.546(m,4H),1.399-1.323(m,2H)。
EXAMPLE 5 preparation of benzyl (3S) -N- (6-tert-Butoxycarbonyloxybenzoylaspartylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate (5a)
Dissolving 1.40g (4.3mmol) of Boc-Asp (OBzl) and 0.59g (4.3mmol) of N-hydroxybenzotriazole (HOBt) in 30m L anhydrous tetrahydrofuran, adding 0.89g (4.3mmol) of N, N-Dicyclohexylcarbodiimide (DCC) under ice bath, stirring for 40 minutes, adding a solution of 0.58g (4.2mmol) of (3S) -N- (6-amino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester and 30m L anhydrous tetrahydrofuran to the obtained reaction solution, adjusting the pH to 8 with N-methylmorpholine (NMM) under ice bath, stirring at room temperature for 12 hours, and displaying that (3S) -N- (6-amino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester disappears by T L C, filtering the reaction solution, and concentrating the filtrate under reduced pressureThe residue was taken up in 100m of L m ethyl acetate and the solution was successively taken up in saturated NaHCO3Washing with aqueous solution (40m L× 3), washing with saturated aqueous NaCl solution (40m L× 3), and washing with saturated aqueous KHSO solution4Aqueous solution (40m L× 3), saturated aqueous NaCl solution (40m L× 3), saturated aqueous NaHCO solution3Washing with aqueous solution (40m L× 3), washing with saturated aqueous NaCl solution (40m L× 3), and washing with anhydrous Na2SO4Drying, filtration, concentration of the filtrate under reduced pressure and purification of the residue by silica gel column chromatography (dichloromethane: methanol ═ 60:1) gave 2.03g (71%) of the title compound as a yellow solid. ESI-MS (M/z):725[ M + H]+。
EXAMPLE 6 preparation of benzyl (3S) -N- (6-tert-Butoxycarbonyloxybenzoylglutamylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate (5b)
The procedure of example 5 from 3.00g (6.6mmol) of benzyl (3S) -N- (6-aminohexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate and 2.44g (7.2mmol) of Boc-Glu (OBzl) gives 1.52g (31%) of the title compound as a yellow solid ESI-MS (M/z):739[ M + H ] (M + H)]+。
EXAMPLE 7 preparation of benzyl (3S) -N- (6-tert-Butoxycarbonylnitroarginylaminon-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate (5c)
Following the procedure of example 5, starting from 1.75g (3.8mmol) of benzyl (3S) -N- (6-aminon-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate and 1.31g (4.1mmol) of Boc-Arg (NO)2) 0.91g (34%) of the title compound are obtained as a pale yellow solid. ESI-MS (M/z) 721[ M + H [ ]]+。
EXAMPLE 8 preparation of benzyl (3S) -N- (benzyloxyaspartylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate (6a)
900mg of (3S) -N- (6-tert-butoxycarbonylbenzyloxyaspartylamino N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester was added in an ice bath to a 20M ethyl acetate solution of L hydrogen chloride (4M) and stirred for 2h, and T L C (ethyl acetate: water: glacial acetic acid ═ 3: 1: 1.2) showed disappearance of (3S) -N- (6-tert-butoxycarbonylbenzyloxyaspartylamino N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester, the reaction solution was concentrated under reduced pressure to dryness, the residue was dissolved in anhydrous ethyl acetate and then concentrated under reduced pressure to drynessWashed well with ether and then with C18Column chromatography purification (methanol: water ═ 30:70) and lyophilization gave 540mg (63%) of the title compound as a pale yellow solid. ESI-MS (M/e) 625 [ M + H]+.Mp112-124℃；1H NMR(300MHz,DMSO-d6:/ppm＝10.971(d,J＝11.1Hz,1H), 8.578(m,1H),8.429(s,3H),7.454(d,J＝7.5Hz,1H),7.404-7.306(m,6H),7.233-6.974(m, 7H),5.597(d,J＝4.5Hz,1H),5.143(s,2H),5.054(s,2H),4763(d,J＝15.6Hz,1H),4.615(d, J＝17.7Hz,1H),4.085(dd,J1＝6.3Hz,J2＝11.7Hz 1H),3.446(m,1H),3.100-2.913(m,5H),2.578(m,1H),2.411(m,1H),1.574-1.499(m,2H),1.421-1.372(m,2H),1.332-1.237(m,2H)。
EXAMPLE 9 preparation of benzyl (3S) -N- (benzyloxyglutamylamino-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate (6b)
Following the procedure of example 8, from 1000mg of benzyl (3S) -N- (6-tert-butoxycarbonylbenzyloxyglutamylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate, 490mg (57%) of the title compound was obtained as a pale yellow solid ESI-MS (M/e):639[ M + H ] 639]+.Mp 103-105℃；1H NMR(300MHz,DMSO-d6:/ppm＝10.963(d, J＝10.5Hz,1H),8.608(m,1H),8.328(s,3H),7.455(d,J＝7.5Hz,1H),7.395-7.305(m,6H),7.236-7.101(m,7H),5.685(d,J＝4.5Hz,1H),5.096(s,2H),5.053(s,2H),4761(d,J＝15.6Hz, 1H),4.629(d,J＝17.1Hz,1H),3.803(dd,J1＝5.7Hz,J2＝12.0Hz 1H),3.419(m,1H), 3.145-2.965(m,3H),2.574(m,1H),2.457-2.389(m,3H),2.039-1.985(m,2H),1.582-1.508 (m,2H),1.482-1.421(m,2H),1.374-1.300(m,2H)。
EXAMPLE 10 preparation of benzyl (3S) -N- (Nitro-arginyl-amino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate (6c)
Following the procedure of example 8, from 650mg of benzyl (3S) -N- (6-tert-butoxycarbonyl-nitroanilino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate, 380mg (68%) of the title compound was obtained as a pale yellow solid ESI-MS (M/e):621 [ M + H ] ESI-MS (M/e)]+.Mp 131-133℃；1H NMR(300MHz,DMSO-d6:/ppm＝10.956(d,J＝9.6Hz,1H),8.597(m,2H),8.257(s,3H),8.011(s,2H),7.455(d,J＝7.8Hz,1H),7.330(t,J＝7.8Hz,1H), 7.211-7.187(m,1H),7.152-7.103(m,6H),5.605(d,J＝4.5Hz,1H),5.059(s,2H),4774(d, J＝15.6Hz,1H),4.632(d,J＝17.1Hz,1H),3.753(m,1H),3.475(m,1H),3.206-2.938(m,5H), 2.582(m,1H),2.426(m,1H),1.734(m,2H),1.593-1.432(m,6H),1.332(m,2H)。
Experimental example 1 evaluation of antitumor Activity of Compounds 6a-c
1) The compounds 6a-e were dissolved in physiological saline, doxorubicin was dissolved in physiological saline as a positive control, and physiological saline as a negative control;
2) the oral dosage of the compound 6 is 0.02 mu mol/kg, the oral dosage of the compound 4 is 0.2 mu mol/kg, the oral dosage of the normal saline is 0.2m L/20 g, and the intraperitoneal injection dosage of the adriamycin is 2 mu mol/kg., and the administration is started after 5 days of tumor inoculation and is continuously performed for 10 days, and the administration is performed for 10 times.
3) The experimental animals were ICR male mice (clean grade) weighing 20 + -2 g, 12 mice per group.
4) The tumor source is mouse S180 sarcoma purchased from animal experiment center of department of medicine of Beijing university and maintained by self passage.
5) Inoculating S180 ascites tumor liquid with vigorous growth under aseptic condition, diluting with normal saline to obtain liquid (1:2), mixing, staining tumor cell suspension with freshly prepared 0.2% trypan blue, mixing, counting by white cell counting method, wherein the blue stained cell is dead cell and the non-stained cell is live cell, and the cell concentration is 4 check live cell number/4 × 104× the cell concentration was calculated by the dilution factor of cell number/m L the cell survival rate was calculated as live cell number/(live cell number + dead cell number) × 100%.
Preparing tumor solution with survival rate of more than 90% into 2.0 × 10 by homogenizing method7The cell suspension of each m L is inoculated to the axilla of a mouse subcutaneously, 0.2m L is prepared into S180 tumor-bearing mice, the tumor is administrated after 5 days, the oral dose of a compound 4 in a treatment group of mice is 0.2 mu mol/kg every day, or the oral dose of a compound 6a in a blank group of mice is 0.02 mu mol/kg., the oral dose of normal saline every day is 0.2m L/20 g, the oral dose of adriamycin in positive control group of mice is 2 mu mol/kg. per day, the mice are killed by being subjected to intraperitoneal injection every day, the weight of the mice is weighed on the eleventh day, ether anesthesia is carried out, cervical vertebra is removed, and then the mice are fixed by tweezers to the right axilla tumor of the miceGrowing sites, skin cut, tumor exposed, blunt dissection, and weighing. Experimental data were expressed as (mean ± SDg) tumor weights using t-test and analysis of variance. The results are shown in Table 1. As can be seen from Table 1, compounds 6a-c were effective in inhibiting tumor regrowth in mice at an oral dose of 0.02 μmol/kg. The invention has obvious technical effect.
In vivo antitumor Activity of the Compounds of Table 1
a) P <0.05 to saline; b) p <0.01 to saline; n is 12.
Claims (3)
1.(3S) -N- (6-aminoacylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester compound with the structure shown in the formula, wherein AA is selected from L-Asp (OBzl) or L-Glu (OBzl) or L-Arg (NO)2) The residue(s) of the amino acid sequence,
2. a process for preparing a benzyl (3S) -N- (6-aminoacylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate compound of the structure of claim 1, which comprises the steps of:
(1) carrying out a Pictet-Spengler reaction on L-tryptophan benzyl ester and formaldehyde under the catalysis of dilute sulfuric acid to generate (3S) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester;
(2) 6-aminocaproic acid and di-tert-butyl dicarbonate (Boc) in a 2M aqueous solution of sodium hydroxide, a mixed solution of water and dioxane2O reaction to produce 6-tert-butyloxycarbonylaminohexanoic acid;
(3) reacting 6-tert-butoxycarbonylaminocaproic acid with (3S) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester in anhydrous tetrahydrofuran in the presence of N, N-Dicyclohexylcarbodiimide (DCC) and N-hydroxybenzotriazole (HOBt) to obtain (3S) -N- (6-tert-butoxycarbonylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester;
(4) removing Boc from (3S) -N- (6-tert-butoxycarbonylamino N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester in 4M hydrogen chloride ethyl acetate solution under ice bath to obtain (3S) -N- (6-amino N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester;
(5) reacting (3S) -N- (6-amino N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester with Boc-AA in the presence of N, N-dicyclohexylcarbodiimide and N-hydroxybenzotriazole in anhydrous tetrahydrofuran to obtain (3S) -N- (6-tert-butoxycarbonylamino amido N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester;
(6) removing Boc from (3S) -N- (6-tert-butoxycarbonylamino-acylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester in 4M hydrogen chloride ethyl acetate solution under ice bath to obtain (3S) -N- (6-amino-acylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester.
3. The use of a benzyl (3S) -N- (6-aminoacylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate compound of the structure of claim 1 in the preparation of an anti-tumor medicament.
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