Synthesis of Three Stereoisomers of 4-(3-Hydroxylbutoxy)-2-butanol†

doi:10.7503/cjcu20150702

Abstract

Abstract:

Dihydroxydibutylether(DHBE) is a choleretic drug used for the treatment of gallstone and hepatic disorders due to its choleretic activity and hepatoprotective action. 4-(3-Hydroxylbutoxy)-2-butanol(1) is one of the three stereoisomers of DHBE. The compound has rapid efficacy in the body. It contains three stereoisomers, (R)-4-[(R)-3-hydroxybutoxy]-2-butanol(1a), (S)-4-[(S)-3-hydroxybutoxy]-2-butanol(1b) and (R)-4-[(S)-3-hydroxybutoxy]-2-butanol(1c). In this paper, the synthesis of the three stereoisomers of compound 1 from readily available starting materials, methyl (R/S)-3-hydroxybutanoate, in 5 steps with overall yields of 44%—50% was reported. The ether was synthesized by Williamson reaction first, followed by the removal of the benzyl. Then the target compounds 1a—1c were obtained. The synthetic approach has the advantages of easy manipulation, high yield and purity.

Key words: Dyskinebyl, Dihydroxydibutylether, Stereoisomer

CLC Number:

O623

TrendMD:

SUN Baohou, ZHAO Yi, HAI Li, GUO Li, WU Yong. Synthesis of Three Stereoisomers of 4-(3-Hydroxylbutoxy)-2-butanol^†[J]. Chem. J. Chinese Universities, 2016, 37(3): 493.

Figures/Tables 8

Fig.1 Regioisomers of dihydroxyldibutylether

Fig.2 Stereoisomers of compound 1

Scheme 1 Synthetic route of compounds 1a—1cReagents and conditions: a. benzyl trichloroacetimidate, TFA, CH2Cl2, r. t., 24 h; b. LiAlH4, THF, 0 ℃, 2 h; c. MsCl, Py, CH2Cl2, 0 ℃, 2 h; d. NaH, THF, 70 ℃, 5 h; e. H2, Pd/C, MeOH, 50 ℃, 2 h.

Table 1 Appearance, yields, optical rotation, elemental analysis and MS data of compounds 8a—8c and 1a—1c

Compd.	Appearance	Yield(%)	[α $] D 20$ /(°) (c 1.0, CHCl₃)	Elemental analysis(%, calcd.)		ESI-HRMS, m/z [M+Na]⁺
Compd.	Appearance	Yield(%)	[α $] D 20$ /(°) (c 1.0, CHCl₃)	C		H
8a	Colorless oil	85	+62.3	77.20(77.16)	8.85(8.83)	365.2092
8b	Colorless oil	86	-61.1	77.18(77.16)	8.86(8.83)	365.2093
8c	Colorless oil	83	0	77.18(77.16)	8.80(8.83)	365.2091
1a	Colorless oil	95	+10.9	59.21(59.23)	11.15(11.18)	185.1153
1b	Colorless oil	96	-10.0	59.26(59.23)	11.19(11.18)	185.1156
1c	Colorless oil	95	0	59.25(59.23)	11.20(11.18)	185.1153

Table 1 Appearance, yields, optical rotation, elemental analysis and MS data of compounds 8a—8c and 1a—1c

Compd.	Appearance	Yield(%)	[α $] D 20$ /(°) (c 1.0, CHCl₃)	Elemental analysis(%, calcd.)		ESI-HRMS, m/z [M+Na]⁺
Compd.	Appearance	Yield(%)	[α $] D 20$ /(°) (c 1.0, CHCl₃)	C		H
8a	Colorless oil	85	+62.3	77.20(77.16)	8.85(8.83)	365.2092
8b	Colorless oil	86	-61.1	77.18(77.16)	8.86(8.83)	365.2093
8c	Colorless oil	83	0	77.18(77.16)	8.80(8.83)	365.2091
1a	Colorless oil	95	+10.9	59.21(59.23)	11.15(11.18)	185.1153
1b	Colorless oil	96	-10.0	59.26(59.23)	11.19(11.18)	185.1156
1c	Colorless oil	95	0	59.25(59.23)	11.20(11.18)	185.1153

Table 2 1H NMR and 13C NMR data of compounds 8a—8c and 1a—1c

Compd.	¹H NMR(400 MHz, CDCl₃), δ	¹³C NMR(100 MHz, CDCl₃), δ
8a	1.20(d, 6H, J=6.4 Hz), 1.66—1.74(m, 2H), 1.79—1.87(m, 2H), 3.42—3.55(m, 4H), 3.64—3.70(m, 2H), 4.50(ABq, 4H, J=11.6 Hz), 7.27—7.33(m, 10H)	19.8(2C), 36.9(2C), 67.5(2C), 70.4(2C), 72.1(2C), 127.4(2C), 127.6(4C), 128.3(4C), 138.9(2C)
8b	1.20(d, 3H, J=6.0 Hz), 1.23(d, 3H, J=6.0 Hz), 1.66—1.90(m, 4H), 3.42—3.55(m, 4H), 3.61—3.68(m, 2H), 4.50(ABq, 4H, J=11.6 Hz), 7.25—7.33(m, 10H)
8c	1.20(d, 3H, J=6.4 Hz), 1.21(d, 3H, J=6.4 Hz), 1.66—1.74(m, 2H), 1.80—1.88(m, 2H), 3.44—3.54(m, 4H), 3.63—3.71(m, 2H), 4.50(ABq, 4H, J=11.6 Hz), 7.25—7.25(m, 10H)	19.8(2C), 36.9(2C), 67.5(2C), 70.4(2C), 72.2(2C), 127.3(2C), 127.6(4C), 128.2(4C), 138.9(2C)
1a	1.21(d, 6H, J=6.6 Hz), 1.70—1.73(m, 4H), 3.16(br, 2H), 3.57—3.60(m, 2H), 3.66—3.69(m, 2H), 3.96—4.01(m, 2H)	23.3(2C), 37.9(2C), 67.1(2C), 69.5(2C)
1b	1.18(d, 6H, J=6.0 Hz), 1.67—1.71(m, 4H), 3.48(br, 2H), 3.53—3.67(m, 4H), 3.98—3.94(m, 2H)
1c	1.17(d, 6H, J=6.4 Hz), 1.65—1.70(m, 4H), 3.52—3.66(m, 4H), 3.87(br, 2H), 3.92—4.00(m, 2H)	23.3(2C), 37.9(2C), 66.8(2C), 69.2(2C)

Scheme 2 Synthetic route of compound 8aReagents and conditions: a. imidazole, TBSCl, DMAP, DMF, r. t., 24 h; b. NaH, BnBr, THF, r. t., 10 h; c. TBAF, THF, 60 ℃, 4 h; d. MsCl, Py, CH2Cl2, 0 ℃, 2 h; e. NaH, THF, 70 ℃, 5 h.

Scheme 2 Scheme 3 Synthetic route of compound 1aReagents and conditions: a. benzyl trichloroacetimidate, TFA, CH2Cl2, r. t., 24 h; b. LiAlH4, THF, 0 ℃, 2 h; c. MsCl, Py, CH2Cl2, 0 ℃, 2 h; d. NaH, THF, 70 ℃, 5 h; e. H2, Pd/C, MeOH, 50 ℃, 2 h.

Table 3 Synthetic reaction conditions of compound 5a

Entry^*	Catalyst	n(Cat.)∶n(4a)	Solvent	Temperature/℃	Time/h	Yield(%)
1	Et₃N	8∶1	THF	r. t.	72	0
2	Imidazole	8∶1	THF	r. t.	72	0
3	NaH	1.5∶1	THF	r. t.	72	0
4	Ag₂O	8∶1	THF	r. t.	72	55
5	Ag₂O	8∶1	DMF	r. t.	72	48
6	Ag₂O	8∶1	CH₂Cl₂	r. t.	72	61
7	Ag₂O	8∶1	EA	r. t.	72	70
8	Ag₂O	8∶1	EA	r. t.	36	57
9	Ag₂O	8∶1	EA	r. t.	24	50
10	CF₃SO₃H	0.1∶1	EA	r. t.	24	59
11	CF₃SO₃H	0.1∶1	DMF	r. t.	24	45
12	CF₃SO₃H	0.1∶1	THF	r. t.	24	66
13	CF₃SO₃H	0.1∶1	CH₂Cl₂	r. t.	24	85
14	CF₃SO₃H	0.1∶1	CH₂Cl₂	0	24	58
15	CF₃SO₃H	0.1∶1	CH₂Cl₂	40	24	73

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