4-取代苯基-1,5-苯并硫氮杂䓬-2-甲酸的合成及抑菌活性

doi:10.7503/cjcu20140588

摘要/Abstract

摘要：

合成了七元环的杂?化合物2a~2k, 并发现化合物2a~2k会向其同分异构体六元环内酰胺3a~3k转化. 化合物2a~2k的结构通过红外光谱(IR)、核磁共振波谱(NMR)、质谱(MS)和元素分析确证. 初步的抑菌活性测试结果表明, 化合物2a~2k对白色念珠菌、标准新生隐球菌、临床新生隐球菌、大肠杆菌和枯草牙孢杆菌均有较好的抑菌活性, 而六元环内酰胺3a~3k对所测菌种没有活性. 实验还测定了部分混合物(2a~2e和3a~3e)的抑菌活性, 结果表明化合物2a~2e和3a~3e混合物的抑真菌效果比单一的化合物2a~2e要好, 化合物3a~3e的存在增强了化合物2a~2e的抑菌活性.

关键词: α,β,-不饱和羧酸, 1,5-苯并硫氮杂?, 抑菌活性

Abstract:

It was reported the products of α,β-unsaturated carboxylic acid and o-aminothiophenol with acid catalyst were seven-membered ring benzothiazepins containing a carboxyl group. Subsequent literature suggested that the structure of the reaction product was a six-membered ring lactam structure. According to the reported method we carried out the reaction and the products obtained were not the reported seven-membered ring benzothiazepin structure, but the six-membered ring lactam structures 3a—3k, which structures were confirmed by mapping and crystal structure analysis. Under the different experimental conditions, we obtained seven-membered ring benzothiazepins 2a—2k, and found that compounds 2a—2k could converted to its isomers six-membered ring lactam 3a—3k. The structures of compounds 2a—2k were confirmed by IR, ¹H NMR, ¹³C NMR, MS and elemental analysis. Antibacterial activity tests showed that compounds 2a—2k had good antibacterial activity against Candida albicans, Cryptococcus neoformans(standard and clinical), E. coli and B. subtilis. While compounds 3a—3k had no activities of the measured strains. It was noteworthy that the mixtures of compounds 2a—2e and 3a—3e had better antifungal effects than those of compounds 2a—2e single, the presence of compound 3a—3e enhanced the antibacterial activities of compounds 2a—2e.

Key words: α,β,-Unsaturated carboxylic acid, 1,5-Benzothiazepine, Antibacterical activity

中图分类号:

O626

TrendMD:

王娇, 田克情, 薛子桥, 武云云, 杨田, 赵惠敏, 张萍. 4-取代苯基-1,5-苯并硫氮杂䓬-2-甲酸的合成及抑菌活性. 高等学校化学学报, 2015, 36(3): 505.

WANG Jiao, TIAN Keqing, XUE Ziqiao, WU Yunyun, YANG Tian, ZHAO Huimin, ZHANG Ping. Syntheses and Antimicrobial Activities of 4-Substituted Phenyl 1,5-Benzothiazepines-2-carboxylic Acids. Chem. J. Chinese Universities, 2015, 36(3): 505.

图/表 8

Scheme 1 Synthetic routes of compounds 2a—2k a: X=H, R=H; b:X=H, R=F; c: X=H, R=Cl; d: X=H, R=Br; e: X=H, R=CH3; f: X=H, R=OCH3;g: X=Cl, R=H; h: X=Cl, R=F; i: X=Cl, R=Cl; j: X=Cl, R=Br; k: X=Cl, R=CH3.

Table 1 Appearance, yields, melting points, elemental analysis, MS and IR data for compounds 2a—2k

Compd.	Appearance	Yield(%)	m. p./℃	Elemental analysis(%, calcd. )			MS([M+H]⁺), m/z	IR(KBr), $ν ˙$ /cm^-1
Compd.	Appearance	Yield(%)	m. p./℃	C			H	N
2a	White solid	53	186—189	67.70(67.84)	4.68(4.59)	4.84(4.95)	284.2	2502,1705,1601
2b	White solid	54	171—173	63.59(63.79)	4.42(4.31)	4.55(4.68)	302.0	2509,1701,1601
2c	White solid	55	167—169	60.35(60.47)	3.61(3.78)	4.31(4.41)	318.7	2507,1713,1607
2d	White solid	52	167—168	53.21(53.04)	3.70(3.87)	3.40(3.32)	363.8	2504,1713,1705
2e	White solid	49	153—156	68.48(68.67)	5.16(5.05)	4.63(4.71)	298.9	2978,1693,1609
2f	White solid	48	198—200	58.56(58.71)	4.07(4.19)	4.03(4.09)	348.8	3503,1701,1601
2g	White solid	53	183—186	60.32(60.47)	3.61(3.78)	4.39(4.41)	318.8	3063,1705,1599
2h	White solid	54	196—199	57.12(57.23)	3.19(3.38)	4.12(4.17)	336.8	3074,1705,1601
2i	White solid	51	170—172	54.40(54.55)	3.02(3.13)	3.85(3.98)	352.7	3049,1709,1574
2j	White solid	52	178—180	48.57(48.42)	2.83(2.77)	3.40(3.53)	397.7	2880,1709,1574
2k	White solid	49	236—238	61.41(61.54)	4.12(4.22)	4.34(4.22)	332.5	3049,1701,1607

Table 1 Appearance, yields, melting points, elemental analysis, MS and IR data for compounds 2a—2k

Compd.	Appearance	Yield(%)	m. p./℃	Elemental analysis(%, calcd. )			MS([M+H]⁺), m/z	IR(KBr), $ν ˙$ /cm^-1
Compd.	Appearance	Yield(%)	m. p./℃	C			H	N
2a	White solid	53	186—189	67.70(67.84)	4.68(4.59)	4.84(4.95)	284.2	2502,1705,1601
2b	White solid	54	171—173	63.59(63.79)	4.42(4.31)	4.55(4.68)	302.0	2509,1701,1601
2c	White solid	55	167—169	60.35(60.47)	3.61(3.78)	4.31(4.41)	318.7	2507,1713,1607
2d	White solid	52	167—168	53.21(53.04)	3.70(3.87)	3.40(3.32)	363.8	2504,1713,1705
2e	White solid	49	153—156	68.48(68.67)	5.16(5.05)	4.63(4.71)	298.9	2978,1693,1609
2f	White solid	48	198—200	58.56(58.71)	4.07(4.19)	4.03(4.09)	348.8	3503,1701,1601
2g	White solid	53	183—186	60.32(60.47)	3.61(3.78)	4.39(4.41)	318.8	3063,1705,1599
2h	White solid	54	196—199	57.12(57.23)	3.19(3.38)	4.12(4.17)	336.8	3074,1705,1601
2i	White solid	51	170—172	54.40(54.55)	3.02(3.13)	3.85(3.98)	352.7	3049,1709,1574
2j	White solid	52	178—180	48.57(48.42)	2.83(2.77)	3.40(3.53)	397.7	2880,1709,1574
2k	White solid	49	236—238	61.41(61.54)	4.12(4.22)	4.34(4.22)	332.5	3049,1701,1607

Table 2 1H NMR and 13C NMR data for compounds 2a—2k

Compd.	¹H NMR(500 MHz, CDCl₃), δ	¹³C NMR(125 MHz, CDCl₃), δ
2a	4.52(dd, 1H, J_XA=12.5 Hz, J_XB=5.5 Hz, H_X), 3.42(dd, 1H, J_AX=12.5 Hz, J_AB=13.5 Hz, H_A), 3.04(dd, 1H, J_BX=5.5 Hz, J_BA=13.5 Hz, H_B), 11.15(s, 1H, —COOH), 7.12—8.22(m, 9H, ArH)
2b	4.52(dd, 1H, J_XA=12.5 Hz, J_XB=5.5 Hz, H_X), 3.42(dd, 1H, J_AX=12.5 Hz, J_AB=13.5 Hz, H_A), 3.04(dd, 1H, J_BX=5.5 Hz, J_BA=13.5 Hz, H_B), 11.20(s, 1H, —COOH), 7.12—8.31(m, 8H, ArH)
2c	4.53(dd, 1H, J_XA=12.8 Hz, J_XB=5.4 Hz, H_X), 3.40(dd, 1H, J_AX=12.8 Hz, J_AB=13.5 Hz, H_A), 3.04(dd, 1H, J_BX=5.4 Hz, J_BA=13.5 Hz, H_B), 11.17(s, 1H, —COOH), 7.12—8.17(m, 8H, ArH)	171.6, 169.9, 138.2, 136.6, 133.1, 131.8, 130.7, 126.6, 126.0, 122.7, 57.1, 32.4
2d	4.54(dd, 1H, J_XA=12.5 Hz, J_XB=5.5 Hz, H_X), 3.40(dd, 1H, J_AX=12.5 Hz, J_AB=13.3 Hz, H_A), 3.04(dd, 1H, J_BX=5.5 Hz, J_BA=13.3 Hz, H_B), 11.18(s, 1H, —COOH), 7.13—8.17(m, 8H, ArH),	171.8, 169.5, 153.7, 137.7, 136.2, 132.6, 131.3, 130.3, 126.1, 125.5, 122.3, 56.8, 32.0
2e	4.48(dd, 1H, J_XA=12.8 Hz, J_XB=5.8 Hz, H_X), 3.40(dd, 1H, J_AX=12.5 Hz, J_AB=13.3 Hz, H_A), 3.06(dd, 1H, J_BX=5.8 Hz, J_BA=13.3 Hz, H_B), 11.16(s, 1H, —COOH), 7.10—8.12(m, 8H, ArH), 2.42(s, 3H, —CH₃)
Compd.	¹H NMR(500 MHz, CDCl₃), δ		¹³C NMR(125 MHz, CDCl₃), δ
2f	4.47(dd, 1H, J_XA=12.8 Hz, J_XB=5.3 Hz, H_X), 3.43(dd,1H, J_AX=12.8 Hz, J_AB=13.5 Hz, H_A), 2.99(dd, 1H, J_BX=5.3 Hz, J_BA=13.5 Hz, H_B), 11.20(s, 1H, —COOH), 7.05—8.18(m,7H, ArH), 3.89(s, 3H, —OCH₃)
2g	4.55(dd, 1H, J_XA=12.5 Hz, J_XB=5.5 Hz, H_X), 3.48(dd, 1H, J_AX=12.5 Hz, J_AB=13.5 Hz, H_A), 3.04(dd, 1H, J_BX=5.5 Hz, J_BA=13.5 Hz, H_B), 11.27(s, 1H, —COOH), 7.16—8.23(m, 8H, ArH)
2h	4.56(dd, 1H, J_XA=12.5 Hz, J_XB=5.5 Hz , H_X), 3.41(dd, 1H, J_AX=12.5 Hz, J_AB=13.8 Hz, H_A), 3.05(dd, 1H, J_BX=5.5 Hz, J_BA=13.8 Hz, H_B), 11.27(s, 1H, —COOH), 7.17—8.23(m, 7H, ArH)
2i	4.56(dd, 1H, J_XA=12.5 Hz, J_XB=5.5 Hz, H_X), 3.45(dd, 1H, J_AX=12.5 Hz, J_AB=13.5 Hz, H_A), 3.05(dd, 1H, J_BX=5.5 Hz, J_BA=13.5 Hz , H_B), 11.25(s, 1H, —COOH), 7.17—8.24(m, 7H, ArH)		171.7, 169.5, 138.9, 136.1, 133.6, 131.2, 130.7, 125.9, 125.5, 122.2, 58.1, 31.0
2j	4.57(dd, 1H, J_XA=12.8 Hz, J_XB=5.3 Hz, H_X), 3.46(dd, 1H, J_AX=12.8 Hz, J_AB=13.8 Hz, H_A), 3.05(dd, 1H, J_BX=5.3 Hz, J_BA=13.8 Hz, H_B), 11.28(s, 1H, —COOH), 7.18—8.18(m, 7H, ArH)		171.8, 169.6, 152.6, 137.8, 136.4, 131.4, 131.3, 130.2, 126.8, 125.6, 122.6, 55.4, 32.5
2k	4.49(dd, 1H, J_XA=12.8 Hz, J_XB=5.8 Hz, H_X), 3.43(dd, 1H, J_AX=12.8 Hz, J_AB=13.5 Hz, H_A), 3.00(dd, 1H, J_BX=5.8 Hz, J_BA=13.5 Hz, H_B), 11.2(s, 1H, —COOH), 7.13—8.11(m, 7H, ArH), 2.41(s, 3H, CH₃)

Table 2 1H NMR and 13C NMR data for compounds 2a—2k

Compd.	¹H NMR(500 MHz, CDCl₃), δ	¹³C NMR(125 MHz, CDCl₃), δ
2a	4.52(dd, 1H, J_XA=12.5 Hz, J_XB=5.5 Hz, H_X), 3.42(dd, 1H, J_AX=12.5 Hz, J_AB=13.5 Hz, H_A), 3.04(dd, 1H, J_BX=5.5 Hz, J_BA=13.5 Hz, H_B), 11.15(s, 1H, —COOH), 7.12—8.22(m, 9H, ArH)
2b	4.52(dd, 1H, J_XA=12.5 Hz, J_XB=5.5 Hz, H_X), 3.42(dd, 1H, J_AX=12.5 Hz, J_AB=13.5 Hz, H_A), 3.04(dd, 1H, J_BX=5.5 Hz, J_BA=13.5 Hz, H_B), 11.20(s, 1H, —COOH), 7.12—8.31(m, 8H, ArH)
2c	4.53(dd, 1H, J_XA=12.8 Hz, J_XB=5.4 Hz, H_X), 3.40(dd, 1H, J_AX=12.8 Hz, J_AB=13.5 Hz, H_A), 3.04(dd, 1H, J_BX=5.4 Hz, J_BA=13.5 Hz, H_B), 11.17(s, 1H, —COOH), 7.12—8.17(m, 8H, ArH)	171.6, 169.9, 138.2, 136.6, 133.1, 131.8, 130.7, 126.6, 126.0, 122.7, 57.1, 32.4
2d	4.54(dd, 1H, J_XA=12.5 Hz, J_XB=5.5 Hz, H_X), 3.40(dd, 1H, J_AX=12.5 Hz, J_AB=13.3 Hz, H_A), 3.04(dd, 1H, J_BX=5.5 Hz, J_BA=13.3 Hz, H_B), 11.18(s, 1H, —COOH), 7.13—8.17(m, 8H, ArH),	171.8, 169.5, 153.7, 137.7, 136.2, 132.6, 131.3, 130.3, 126.1, 125.5, 122.3, 56.8, 32.0
2e	4.48(dd, 1H, J_XA=12.8 Hz, J_XB=5.8 Hz, H_X), 3.40(dd, 1H, J_AX=12.5 Hz, J_AB=13.3 Hz, H_A), 3.06(dd, 1H, J_BX=5.8 Hz, J_BA=13.3 Hz, H_B), 11.16(s, 1H, —COOH), 7.10—8.12(m, 8H, ArH), 2.42(s, 3H, —CH₃)
Compd.	¹H NMR(500 MHz, CDCl₃), δ		¹³C NMR(125 MHz, CDCl₃), δ
2f	4.47(dd, 1H, J_XA=12.8 Hz, J_XB=5.3 Hz, H_X), 3.43(dd,1H, J_AX=12.8 Hz, J_AB=13.5 Hz, H_A), 2.99(dd, 1H, J_BX=5.3 Hz, J_BA=13.5 Hz, H_B), 11.20(s, 1H, —COOH), 7.05—8.18(m,7H, ArH), 3.89(s, 3H, —OCH₃)
2g	4.55(dd, 1H, J_XA=12.5 Hz, J_XB=5.5 Hz, H_X), 3.48(dd, 1H, J_AX=12.5 Hz, J_AB=13.5 Hz, H_A), 3.04(dd, 1H, J_BX=5.5 Hz, J_BA=13.5 Hz, H_B), 11.27(s, 1H, —COOH), 7.16—8.23(m, 8H, ArH)
2h	4.56(dd, 1H, J_XA=12.5 Hz, J_XB=5.5 Hz , H_X), 3.41(dd, 1H, J_AX=12.5 Hz, J_AB=13.8 Hz, H_A), 3.05(dd, 1H, J_BX=5.5 Hz, J_BA=13.8 Hz, H_B), 11.27(s, 1H, —COOH), 7.17—8.23(m, 7H, ArH)
2i	4.56(dd, 1H, J_XA=12.5 Hz, J_XB=5.5 Hz, H_X), 3.45(dd, 1H, J_AX=12.5 Hz, J_AB=13.5 Hz, H_A), 3.05(dd, 1H, J_BX=5.5 Hz, J_BA=13.5 Hz , H_B), 11.25(s, 1H, —COOH), 7.17—8.24(m, 7H, ArH)		171.7, 169.5, 138.9, 136.1, 133.6, 131.2, 130.7, 125.9, 125.5, 122.2, 58.1, 31.0
2j	4.57(dd, 1H, J_XA=12.8 Hz, J_XB=5.3 Hz, H_X), 3.46(dd, 1H, J_AX=12.8 Hz, J_AB=13.8 Hz, H_A), 3.05(dd, 1H, J_BX=5.3 Hz, J_BA=13.8 Hz, H_B), 11.28(s, 1H, —COOH), 7.18—8.18(m, 7H, ArH)		171.8, 169.6, 152.6, 137.8, 136.4, 131.4, 131.3, 130.2, 126.8, 125.6, 122.6, 55.4, 32.5
2k	4.49(dd, 1H, J_XA=12.8 Hz, J_XB=5.8 Hz, H_X), 3.43(dd, 1H, J_AX=12.8 Hz, J_AB=13.5 Hz, H_A), 3.00(dd, 1H, J_BX=5.8 Hz, J_BA=13.5 Hz, H_B), 11.2(s, 1H, —COOH), 7.13—8.11(m, 7H, ArH), 2.41(s, 3H, CH₃)

Table 3 Experimental conditions of compound 1a with o-aminothiophenol

Entry	T/℃	Catalyst	t/min	Product	Yield(%)
1	Reflux		30	3a	47
2	Reflux	HAc	120	3a	56
3	Reflux	HOTs	60	3a	72
4	0		300	2a	45
5	0	HAc	300	2a	56
6	0	HOTs	120	3a	64
7	Room temperature		2	2a	53
8	Room temperature	HAc	2	2a	64
9	Room temperature	HOTs	2	3a	76

Table 4 Integral area ratio of 2c/3c on VT 1H NMR

Temperature/℃	20	30	40	50
Integral area ratio of 2c/3c	1.03:1	0.78:1	0.43:1	0.30:1

Scheme 2 Formation of compound A

Table 5 Antimicrobial activities of compounds 2a—2k

Dose/(μg·disc^-1)	Zone of inhibition^*/mm
	C.albicans				C.neoformans(stand)				B.subtilis
	200	100	50	25	200	100	50	25	200	100	50	25
2a	17.5	16.6	8.9	7.0	18.4	11.5	7.0	6.0	15.8	8.7	7.0	6.0
2b	11.1	10.2	6.9	6.9	12.5	6.0	6.0	6.0	7.8	6.0	6.0	6.0
2c	16.9	14.8	9.9	7.0	12.2	9.6	6.0	6.0	15.1	9.0	6.0	6.0
2d	12.8	10.9	7.0	6.0	16.4	9.3	7.0	7.0	14.4	9.9	7.0	6.0
2e	14.1	7.8	7.0	6.0	21.2	6.0	6.0	6.0	12.4	7.5	6.0	6.0
2f	25.9	22.7	17.9	10.2	27.1	23.5	12.5	8.0	14.7	7.7	6.0	6.0
2g	23.9	21.4	17.4	9.6	25.7	16.7	7.0	6.0	11.9	7.0	6.0	6.0
2h	19.0	15.6	12.8	9.4	26.9	16.8	12.9	6.0	13.2	7.5	6.0	6.0
2i	16.5	13.3	7.0	7.0	21.2	17.0	6.0	6.0	9.30	6.0	6.0	6.0
2j	29.5	17.0	18.5	9.8	28.4	24.7	15.3	6.0	11.1	6.0	6.0	6.0
2k	17.8	11.5	9.5	7.0	25.9	20.9	14.4	6.0	14.0	7.6	6.0	6.0
2a+3a	20.9				42.5
2b+3b	18.5				21.3
2c+3c	22.7				32.9
2d+3d	19.8				32.8
2e+3e	21.1				34.8

Table 6 Antimicrobial activities of the mixtures of 2a—2e and 3a—3e

Dose/(μg·disc^-1)	Zone of inhibition^*/mm
	C.neoformans(clinical)				E. coli
	200	100	50	25	200	100	50	25
2a	15.4	14.4	7.0	6.0	16.2	8.9	7.0	6.0
2b	10.9	6.0	6.0	6.0	8.2	6.0	6.0	6.0
2c	8.1	6.0	6.0	6.0	15.9	7.0	6.0	6.0
2d	11.1	7.0	6.0	6.0	14.9	7.8	6.0	6.0
2e	23.6	6.0	6.0	6.0	12.2	7.8	6.0	6.0
2f	24.7	22.1	17.1	12.5	11.4	7.0	7.0	6.0
2g	25.0	21.0	17.5	10.1	14.1	9.2	7.0	6.0
2h	19.2	16.8	14.4	9.8	11.2	7.0	6.0	6.0
2i	16.8	13.4	6.0	6.0	7.0	6.0	6.0	6.0
2j	23.4	16.2	18.9	6.0	16.8	10.2	7.0	6.0
2k	20.1	14.1	9.0	6.0	8.9	7.0	6.0	6.0
2a+3a	30.4
2b+3b	16.2
2c+3c	25.1
2d+3d	30.4
2e+3e	22.2

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