CN112010927A - EGH and hydroxymethyl modified benzimidazole quinazoline, and synthesis, activity and application thereof - Google Patents

Abstract

EGH and hydroxymethyl modified benzimidazole quinazoline, and synthesis, activity and application thereof. The invention discloses a 6-hydroxymethyl-6- (His-Gly-Glu-OCH) compound with the following formula₂) -5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]Quinazoline, discloses a preparation method thereof, discloses immunosuppressive activity thereof, and discloses that the quinazoline can prolong the survival time of transplanted myocardium after ears of mice, so that the invention discloses application thereof in preparing immunosuppressant.

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Description

EGH and hydroxymethyl-modified benzimidazoquinazolines, their synthesis, activities and applications

technical field

The present invention relates to 6-hydroxymethyl-6-(His-Gly-Glu-OCH ₂ )-5,6-dihydrobenzo[4,5]imidazo[1,2-c]quinazoline, and to its The preparation method relates to its immunosuppressive activity. Therefore, the present invention relates to the application of the compound in the preparation of immunosuppressive drugs. The invention belongs to the field of biomedicine.

Background technique

In the 1960s, the first successful organ transplant was performed. After decades of development, patients with loss of organ function can be treated. However, the immune rejection of the human body's own immune system to the allogeneic organs seriously affects the short-term and long-term health of patients. Ultimately, immune rejection affects the survival time of patients after transplantation. How to avoid this immune rejection is crucial. Although various clinical measures have been implemented, the results are not satisfactory. Taking kidney transplantation as an example, although acute cellular rejection and humoral rejection can be effectively controlled by plasma exchange and the use of potent immunosuppressive agents, the effect of this treatment on chronic rejection is not satisfactory. As a result, the invention of new immunosuppressants has received extensive attention. Similarly, the effect of inventing new immunosuppressants is not ideal. Interested in inventing novel immunosuppressants, the inventors have been working on modifying N-containing heterocycles with peptides. After 3 years of exploration, the inventor found that the purpose of designing the compound was to combine two structures with immunosuppressive activity to obtain a new type of immunosuppressant. The inventors found that 6-hydroxymethyl of the following formula was generated by modifying 5,6-dihydrobenzo[4,5]imidazo[1,2-c]quinazoline with hydroxymethyl and His-Gly-Glu-OCH ₂ Radix-6-(His-Gly-Glu-OCH ₂ )-5,6-dihydrobenzo[4,5]imidazo[1,2-c]quinazoline showed in a mouse retroauricular myocardial transplantation experimental model Excellent activity. Based on this finding, the inventors have come up with the present invention.

SUMMARY OF THE INVENTION

The first content of the present invention is to provide 6-hydroxymethyl-6-(His-Gly-Glu-OCH ₂ )-5,6-dihydrobenzo[4,5]imidazo[1,2- c] Quinazoline.

The second aspect of the present invention is to provide 6-hydroxymethyl-6-(His-Gly-Glu-OCH ₂ )-5,6-dihydrobenzo[4,5]imidazo[1,2-c]quinoline The preparation method of oxazoline, the method comprises:

1) Synthesis of (6,6-dimethylol-5,6-dihydrobenzo[4,5]imidazo[1,2-c]quinazoline;

2) Synthesis of 6-hydroxymethyl-6-[Boc-Glu(OBzl)-OCH ₂ ]-5,6-dihydrobenzo[4,5]imidazo[1,2-c]quinazoline;

3) Synthesis of 6-hydroxymethyl-6-[Glu(OBzl)-OCH ₂ ]-5,6-dihydrobenzo[4,5]imidazo[1,2-c]quinazoline;

4) Synthesize Boc-His(Boc)-Gly by a liquid phase method using dicyclohexylcarbodiimide as a condensing agent and 1-hydroxybenzotriazole as a catalyst;

5) 6-hydroxymethyl-6-[Glu(OBzl)-OCH ₂ ]-5,6- Condensation of dihydrobenzo[4,5]imidazo[1,2-c]quinazoline with Boc-His(Boc)-Gly to 6-hydroxymethyl-6-[Boc-His(Boc)-Gly-Glu (OBzl)-OCH ₂ ]-5,6-dihydrobenzo[4,5]imidazo[1,2-c]quinazoline;

6) Synthesis of 6-hydroxymethyl-6-[Boc-His(Boc)-Gly-Glu-OCH ₂ ]-5,6-dihydrobenzo[4,5]imidazo[1,2-c]quinazole Lin;

7) Synthesis of 6-hydroxymethyl-6-(His-Gly-Glu-OCH ₂ )-5,6-dihydrobenzo[4,5]imidazo[1,2-c]quinazoline.

The third aspect of the present invention is to evaluate 6-hydroxymethyl-6-(His-Gly-Glu-OCH ₂ )-5,6-dihydrobenzo[4,5]imidazo[1,2-c]quinoline The immunosuppressive effects of oxazolines.

Description of drawings

Figure 1. Synthetic route of 6-hydroxymethyl-6-(His-Gly-Glu-OCH ₂ )-5,6-dihydrobenzo[4,5]imidazo[1,2-c]quinazoline.(i ) 2M hydrochloric acid solution, 1,3-dihydroxyacetone; (ii) dicyclohexylcarbodiimide, 1-hydroxybenzotriazole, Boc-Glu(OBzl), N-methylmorpholine; (iii) hydrogen chloride in ethyl acetate (4M); (iv) dicyclohexylcarbodiimide, 1-hydroxybenzotriazole, N-methylmorpholine; (v) Pd/C, H ₂ .

Detailed ways

In order to further illustrate the present invention, a series of examples are given below. These examples are purely illustrative, they are only used to specifically describe the present invention, and should not be construed as limiting the present invention.

Example 1 Preparation of (6,6-dimethylol-5,6-dihydrobenzo[4,5]imidazo[1,2-c]quinazoline (1)

Mp 214-215℃。¹H-NMR(300MHz,DMSO-d₆):δ/ppm＝7.86(d,J＝7.2Hz,1H),7.69(m,1H),7.59(m,1H),7.15(m,3H),6.85(d,J＝8.1Hz,1H),6.70(m,2H),5.26(t,J＝5.4,2H),4.08(dd,J₁＝6.0Hz,J₂＝5.7Hz,2H),3.82(dd,J₁＝5.7Hz,J₂＝6.0Hz,2H)。6.40 g (30.6 mmol) of 2-(2-aminophenyl)-1H-benzimidazole was suspended in 100 mL of methanol, and 2.76 g (30.7 mmol) of 1,3-dihydroxyacetone was added to the suspension. The pH of the reaction mixture was adjusted to 2 with 2M hydrochloric acid, at which point the reaction solution turned green. The reaction mixture was stirred at room temperature for 12 hours, TLC (dichloromethane/methanol=20/1) showed that the starting point disappeared, and a large amount of yellow-green solid was precipitated. The reaction was terminated, and 4M aqueous sodium hydroxide solution was added dropwise to the reaction solution to adjust the pH of the reaction solution to neutrality, and filtered to obtain 7.03 g of the title compound as a yellow-green solid. The filtrate was concentrated under reduced pressure and filtered to give 2.52 g of the title compound as a dark green solid. The yield of this step is 100%. ESI-MS (m/e): 282 [M+H] ⁺ .

Mp 214-215°C. ¹ H-NMR (300MHz, DMSO-d ₆ ): δ/ppm=7.86(d, J=7.2Hz, 1H), 7.69(m, 1H), 7.59(m, 1H), 7.15(m, 3H), 6.85(d,J=8.1Hz,1H),6.70(m,2H),5.26(t,J= _5.4,2H ),4.08(dd,J1 ₌ 6.0Hz,J2=5.7Hz,2H),3.82 (dd, J ₁ =5.7 Hz, J ₂ =6.0 Hz, 2H).

Example 2 Preparation of 6-hydroxymethyl-6-[Boc-Glu(OBzl)-OCH ₂ ]-5,6-dihydrobenzo[4,5]imidazo[1,2-c]quinazoline (2 )

Mp 80-82℃；¹H-NMR(300 MHz,DMSO-d₆):δ/ppm＝7.86(d,J＝7.8Hz,1H),7.72(dd,J₁＝7.8Hz,J₂＝19.5Hz,1H), 7.59(m,1H),7.35(s,5H),7.14(m,4H),6.96(d,J＝19.5Hz 1H),6.82(t,J＝6.3Hz,1H), 5.54(m,1H),5.03(s,2H),4.79(m,1H),4.45(m,1H),4.16(m,1H),3.95(m,1H),3.78(m, 1H),2.13(m,1H),1.45(m,1H),1.32(s,9H)。337 mg (1.00 mmol) of Boc-Glu(OBzl), 250 mg (1.20 mmol) of dicyclohexylcarbodiimide and 135 mg (1.00 mmol) of 1-hydroxybenzotriazole were dissolved in 10 mL of DMF. The resulting solution was stirred in an ice bath for 30 minutes, after which 1.12 g (4.00 mmol) of 6,6-dimethylol-5,6-dihydrobenzo[4,5]imidazo[1,2-c]quinazole was added Phosphine (1). The reaction mixture was adjusted to pH 7-8 with N-methylmorpholine. After that, the reaction mixture was stirred at room temperature for 12 hours, and TLC (dichloromethane/methanol=20/1) showed that Boc-Glu(OBzl) disappeared. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in 50 mL of ethyl acetate, filtered, and the filtrate was washed with saturated aqueous sodium bicarbonate solution (30 mL × 3), washed with saturated aqueous sodium chloride solution (30 mL × 3), and dried over anhydrous sodium sulfate for 12 hours, filtered, the filtrate was concentrated under reduced pressure, the residue was diluted with dichloromethane, sonicated, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=80/1) to obtain 370 mg (62 %) title compound as a pale yellow-green solid. ESI-MS (m/e): 635 [M+Cl] ⁻ .

Mp 80-82°C; ¹ H-NMR (300 MHz, DMSO-d ₆ ): δ/ppm=7.86 (d, J=7.8 Hz, 1H), 7.72 (dd, J ₁ =7.8 Hz, J ₂ =19.5 Hz, 1H), 7.59(m, 1H), 7.35(s, 5H), 7.14(m, 4H), 6.96(d, J=19.5Hz 1H), 6.82(t, J=6.3Hz, 1H), 5.54 (m, 1H), 5.03(s, 2H), 4.79(m, 1H), 4.45(m, 1H), 4.16(m, 1H), 3.95(m, 1H), 3.78(m, 1H), 2.13( m, 1H), 1.45 (m, 1H), 1.32 (s, 9H).

Example 3 Preparation of 6-hydroxymethyl-6-[Glu(OBzl)-OCH ₂ ]-5,6-dihydrobenzo[4,5]imidazo[1,2-c]quinazoline (3)

300 mg (0.500 mmol) of 6-hydroxymethyl-6-[Boc-Glu(OBzl)-OCH ₂ ]-5,6-dihydrobenzo[4,5]imidazo[1,2-c]quinazoline (2) Dissolve with 1 mL of anhydrous ethyl acetate, add 5 mL of hydrogen chloride ethyl acetate solution (4M) under ice bath, after 4 hours of reaction, TLC (dichloromethane/methanol=20/1) shows that compound 2 disappears, and the reaction solution decreases Concentrated under reduced pressure, the residue was dissolved in anhydrous ethyl acetate, concentrated under reduced pressure, and the residue was dissolved in anhydrous ethyl acetate. This operation is repeated 3 times. The residue was dispersed in 10 mL of anhydrous ether, allowed to stand, and the ether was discarded to obtain 280 mg (100%) of the title compound as a green solid. ESI-MS (m/e): 535 [M+Cl] ⁻ .

Example 4 Preparation of Boc-His(Boc)-Gly-OBzl

5.23 mg (14.7 mmol) of Boc-His (Boc), 3.70 g (16.0 mmol) of dicyclohexylcarbodiimide and 2.00 g (15.0 mmol) of 1-hydroxybenzotriazole were dissolved in 150 mL of anhydrous tetrahydrofuran, 0 °C was stirred for 30 minutes. Add 3.00g (15.0mmol) Gly-OBzl to the reaction solution, adjust the pH of the reaction solution to 7-8 with N-methylmorpholine, stir at room temperature for 12 hours, TLC (dichloromethane/methanol=20/1) shows the reaction Finish. The reaction mixture was deconcentrated, the residue was diluted with 100 mL of ethyl acetate, filtered, the filtrate was washed with saturated aqueous sodium bicarbonate solution (30 mL×3), washed with saturated aqueous sodium chloride solution (30 mL×3), and dried over anhydrous sodium sulfate for 12 hours , filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=80/1) to obtain 2.23 g (30%) of the title compound as a yellow oil. ESI-MS (m/e): 503 [M+H] ⁺ .

Example 5 Preparation of Boc-His(Boc)-Gly

Dissolve 1.32 g (2.64 mmol) of Boc-His(Boc)-Gly-OBzl in 100 mL of methanol, add 140 mg of Pd/C to the resulting solution, pass hydrogen gas, stir at room temperature for 12 hours, TLC (dichloromethane/methanol=20 /1) shows that the reaction is complete. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain 1.16 g (100%) of the title compound as a colorless solid. ESI-MS (m/e): 413 [M+H] ⁺ .

Example 6 Preparation of 6-hydroxymethyl-6-[Boc-His(Boc)-Gly-Glu(OBzl)-OCH ₂ ]-5,6-dihydrobenzo[4,5]imidazo[1,2- c]quinazoline (4)

Mp 110-111℃。¹H-NMR(300MHz,DMSO-d₆):δ/ppm＝8.18(d,J＝7.2Hz,1H),8.06(m,2H),7.87(d,J＝6.9Hz,1H),7.73(m,1H),7.59(m,1H),7.34(m,5H),7.16 (m,4H),6.89(m,2H),6.82(d,J＝6.9Hz,1H),6.72(t,J＝6.9Hz,1H),5.55(q,J＝6.6Hz,1 H),5.02(s,2H),4.56(m,2H),4.20(m,2H),4.04(m,2H),3.62(m,2H),2.87(m,1H),2.70 (m,1H),2.15(t,J＝8.1Hz,2H),1.53(s,11H),1.32(s,9H)。¹³C-NMR(300MHz, DMSO-d₆):δ/ppm＝172.1,171.4,169.4,155.7,148.0,147.9,147.1,144.4,143.5,139.9,137.0, 136.6,133.4,133.3,131.9,128.8,128.4,124.9,122.5,122.3,119.2,118.1,144.8,133.0,122.7, 111.4,78.7,76.4,65.9,63.9,63.6,54,2,51.4,42.3,30.8,30.0,28.5,27.8,26.0。Under ice bath, 240 mg (0.60 mmol) of Boc-His(Boc)-Gly, 130 mg (0.630 mmol) of dicyclohexylcarbodiimide and 75.0 mg (0.550 mmol) of 1-hydroxybenzotriazole were mixed with 10 mL of anhydrous tetrahydrofuran. Dissolve, stir for 30 minutes, add 270 mg (0.60 mmol) of 6-hydroxymethyl-6-[Glu(OBzl)-OCH ₂ ]-5,6-dihydrobenzo[4,5]imidazole[1 to the reaction solution ,2-c]quinazoline (3). The reaction mixture was adjusted to pH 8 with N-methylmorpholine, stirred at room temperature for 6 hours, TLC (dichloromethane:methanol=15:1) showed that compound 3 disappeared. The reaction solution was concentrated under reduced pressure, the residue was diluted with 50 mL of ethyl acetate, filtered, the filtrate was washed with saturated aqueous sodium bicarbonate solution (30 mL×3), washed with saturated aqueous sodium chloride solution (30 mL×3), and dried over anhydrous sodium sulfate for 12 hours, filtered, and the filtrate was concentrated under reduced pressure, and the obtained pale yellow solid was purified by silica gel column chromatography (dichloromethane/methanol=30/1) to obtain 81.0 mg (41%) of the title compound as a pale yellow solid. ESI-MS (m/e): 896 [M+H] ⁺ .

Mp 110-111°C. ¹ H-NMR (300 MHz, DMSO-d ₆ ): δ/ppm=8.18 (d, J=7.2 Hz, 1H), 8.06 (m, 2H), 7.87 (d, J=6.9 Hz, 1H), 7.73 ( m,1H),7.59(m,1H),7.34(m,5H),7.16(m,4H),6.89(m,2H),6.82(d,J＝6.9Hz,1H),6.72(t,J =6.9Hz,1H),5.55(q,J=6.6Hz,1H),5.02(s,2H),4.56(m,2H),4.20(m,2H),4.04(m,2H),3.62( m, 2H), 2.87 (m, 1H), 2.70 (m, 1H), 2.15 (t, J=8.1Hz, 2H), 1.53 (s, 11H), 1.32 (s, 9H). ¹³ C-NMR (300MHz, DMSO-d ₆ ): δ/ppm=172.1, 171.4, 169.4, 155.7, 148.0, 147.9, 147.1, 144.4, 143.5, 139.9, 137.0, 136.6, 133.4, 133.3, 131.9, 128.8, 128 , 124.9, 122.5, 122.3, 119.2, 118.1, 144.8, 133.0, 122.7, 111.4, 78.7, 76.4, 65.9, 63.9, 63.6, 54, 2, 51.4, 42.3, 30.8, 30.0, 28.5, 27.8, 26.0.

Example 7 Preparation of 6-hydroxymethyl-6-[Boc-His(Boc)-Gly-Glu-OCH ₂ ]-5,6-dihydrobenzo[4,5]imidazo[1,2-c]quinoline oxazoline (5)

60.0 mg (0.067 mmol) of 6-hydroxymethyl-6-[Boc-His(Boc)-Gly-Glu(OBzl) _-OCH2 ]-5,6-dihydrobenzo[ 4,5]imidazo[1,2-c]quinazoline (4) gave 55 mg (100%) of the title compound as a green solid. ESI-MS (m/e): 806 [M+H] ⁺ .

Example 8 Preparation of 6-hydroxymethyl-6-[His-Gly-Glu-OCH ₂ ]-5,6-dihydrobenzo[4,5]imidazo[1,2-c]quinazoline (6)

Mp 181-183℃。IR(cm^-1):3029.60, 2321.11,2166.95,2109.11,1741.91,1682.54,1628.73,1568.08,1531.98,1492.60,1386.95, 1337.38,1261.81,1186.85,1073,10,1019.19,823.60,750.73,622.09。¹H-NMR(300MHz, DMSO-d₆):δ/ppm＝8.89(s,2H),8.53(dd,J₁＝6.3Hz,J₂＝15.0Hz,1H),7.89(d,J＝7.5Hz, 1H),7.74(dd,J₁＝6.3Hz,J₂＝15.0Hz,1H),7.62(d,J＝6.0Hz,1H),7.44(s,1H),7.20(m,4 H),6.88(m,1H),6.76(q,J＝6.6Hz,1H),5.62(m,1H),4.75(m,qH),,4.47(m,1H),4.18 (m,3H),3.97(m,2H),3.81(m,1H),3.62(m,2H),2.04(m,2H),1.53(m,2H)。¹³C-NMR (300MHz,DMSO-d₆):δ/ppm＝174.1,173.8,171.4,169.2,168.1,147.4,144.1,134.6,133.3, 132.4,126.9,125.4,123.6,118.5,118.3,114.9,113.6,77.2,65.8,63.8,63.5,51.6,42.0,30.1, 26.6,26.1。55.0 mg (0.067 mmol) of 6-hydroxymethyl-6-[Boc-His(Boc)-Gly-Glu-OCH ₂ ]-5,6-dihydrobenzo[4,5]imidazo[1 ,2-c]quinazoline (5) was dissolved with 2 mL of hydrogen chloride in ethyl acetate (4M) and stirred for 4 hours. TLC (ethyl acetate/water/glacial acetic acid = 2/1/1) showed that compound 5 disappeared. The reaction solution was concentrated under reduced pressure, the residue was dissolved in anhydrous ethyl acetate, and the obtained solution was concentrated under reduced pressure. This operation is repeated 3 times. The residue was washed three times with anhydrous ether. The obtained green solid was purified by C18 column (water/methanol=80/20), and the fractions were lyophilized to obtain 9.60 mg (26%) of the title compound as a green solid. ESI-MS (m/e): 606 [M+H] ⁺ .

Mp 181-183°C. IR(cm ^-1 ):3029.60, 2321.11,2166.95,2109.11,1741.91,1682.54,1628.73,1568.08,1531.98,1492.60,1386.95, 1337.38,1261.81,1186.85,1073,10,1019.19,823.60,750.73,622.09。 ¹ H-NMR (300 MHz, DMSO-d ₆ ): δ/ppm=8.89 (s, 2H), 8.53 (dd, J ₁ =6.3 Hz, J ₂ =15.0 Hz, 1H), 7.89 (d, J=7.5 Hz, 1H), 7.74(dd, J1 ₌ 6.3Hz, J2= _15.0Hz , 1H), 7.62(d, J=6.0Hz, 1H), 7.44(s, 1H), 7.20(m, 4H) ,6.88(m,1H),6.76(q,J=6.6Hz,1H),5.62(m,1H),4.75(m,qH),,4.47(m,1H),4.18(m,3H),3.97 (m, 2H), 3.81 (m, 1H), 3.62 (m, 2H), 2.04 (m, 2H), 1.53 (m, 2H). ¹³ C-NMR (300MHz, DMSO-d ₆ ): δ/ppm=174.1, 173.8, 171.4, 169.2, 168.1, 147.4, 144.1, 134.6, 133.3, 132.4, 126.9, 125.4, 123.6, 118.5, 116.3, 114.9, 113. , 77.2, 65.8, 63.8, 63.5, 51.6, 42.0, 30.1, 26.6, 26.1.

Example 9 Evaluation of the immunosuppressive effect of compound 6

Male Balb/c mice (20±2 g) were anesthetized with 10% urethane (10 mg/10 g body weight) by intraperitoneal injection. Topically sterilize mouse auricles with 75% alcohol. Cut a 3-4 mm long incision perpendicular to the midline of the auricle at about 1/3 of the dorsal midline of the auricle, taking care not to damage the auricular vein. The subcutaneous tissue is bluntly dissected towards the ear tip through this opening to create an artificial lumen. The C57bl/6j donor rat was frozen in crushed ice for one minute, the skin was disinfected with 75% alcohol, and the heart was harvested after thoracotomy. The heart was placed in a watch dish covered with saline-wet gauze and beat to drain the remaining blood in the heart chamber. The donor rat heart was longitudinally sectioned into two myocardium with substantially equal muscle fibers and inclined planes. The myocardium was filled into the artificial lumen of Balb/c recipient mice. During the operation, the myocardial tissue was isolated for no more than 2 minutes. Gently press the artificial lumen filled with myocardium to drain excess saline and air bubbles, so that the transplanted myocardium is close to the tissue around the ear of the recipient mouse. Compound 6 (dose of 0.1 μmol/kg/day) or cyclosporine A (dose of 2.5 μmol/kg/day) or normal saline was administered orally on the day of myocardial transplantation. Continuous administration until the electrocardiogram of the transplanted myocardium disappeared.

From the seventh day of myocardial transplantation, the ECG signal of the transplanted myocardial tissue was measured with a biosignal device every day (if there was no ECG signal from the seventh day to the later, it was judged that the myocardial transplantation operation failed). When measuring ectopic ECG, the positive and negative electrodes were placed on both sides of the transplanted myocardial tissue, and the ground electrodes were connected to the hind limbs of mice. After all the ECG signals of the transplanted myocardial tissue disappeared, the ectopic ECG measurement was terminated, and the survival time of the transplanted myocardium was counted (mean ± SD). The results are shown in Table 1. It can be seen that the activity of compound 6 in prolonging the survival of transplanted myocardium at the dose of 0.1 μmol/kg/day was not significantly different from that of cyclosporin A at the dose of 2.5 μmol/kg/day. The present invention has outstanding technical effects.

Table 1 The effect of compound 6 on the survival time of mouse retroauricular myocardial transplantation

a) Compared with normal saline, P<0.01; b) Compared with normal saline, P<0.05, and compared with cyclosporin A, P>0.05; n=12.

Claims (3)

1. 6-hydroxymethyl-6- (His-Gly-Glu-OCH) of formula₂) -5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]A quinazoline in the form of a salt,

2. the 6-hydroxymethyl-6- (His-Gly-Glu-OCH of claim 1₂) -5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]A process for the preparation of a quinazoline, the process comprising:

2.1. synthesizing (6, 6-dihydroxymethyl-5, 6-dihydrobenzo [4,5] imidazole [1,2-c ] quinazoline;

2.2. synthesis of 6-hydroxymethyl-6- [ Boc-Glu (OBzl) -OCH₂]-5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]A quinazoline;

2.3. synthesis of 6-hydroxymethyl-6- [ Glu (OBzl) -OCH₂]-5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]A quinazoline;

2.4. synthesizing Boc-His (Boc) -Gly by using dicyclohexylcarbodiimide as a condensing agent and 1-hydroxybenzotriazole as a catalyst through a liquid phase method;

2.5. the liquid phase method which adopts dicyclohexylcarbodiimide as a condensing agent and 1-hydroxybenzotriazole as a catalyst is adopted to prepare the 6-hydroxymethyl-6- [ Glu (OBzl) -OCH₂]-5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]Condensation of quinazoline with Boc-His (Boc) -Gly to 6-hydroxymethyl-6- [ Boc-His (Boc) -Gly-Glu (OBzl) -OCH₂]-5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]A quinazoline;

2.6. synthesis of 6-hydroxymethyl-6- [ Boc-His (Boc) -Gly-Glu-OCH₂]-5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]A quinazoline;

2.7. synthesis of 6-hydroxymethyl-6- (His-Gly-Glu-OCH₂) -5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]A quinazoline.

3. The 6-hydroxymethyl-6- (His-Gly-Glu-OCH of claim 1₂) -5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]The application of quinazoline in preparing immunosuppressant.

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