(S)-(6-氧代哌啶-3-基)氨基甲酸叔丁酯的工艺开发与放大

doi:10.6023/cjoc202406006

摘要/Abstract

介绍了一种高附加值的手性医药中间体(S)-(6-氧代哌啶-3-基)氨基甲酸叔丁酯(1)的4步高效合成方法. 同样以手性L-焦谷胺醇为原料的, 相对于现在通用的路线, 创新性地选择对甲苯磺酰基作为羟基的活化与离去基团, 替代了甲烷磺酰基, 同时利用二苄胺作为胺源, 成功替换了叠氮化钠, 这有效地避免了难以获取的管制类试剂甲烷磺酰氯和剧毒易爆的叠氮化钠的使用. 此外, 对化合物1的合成工艺进行全面优化, 在百克级别上实现了高达67%的总收率, 并且确保了目标产物的纯度达到99.4%. 整个合成路线所选用的试剂均易于获得且成本低廉, 合成路线简洁高效, 纯化方法简单易操作, 为未来的工业化生产奠定基础.

关键词: 氨基哌啶酮, 医药中间体, 工艺优化, 有机合成

An efficient four-step synthesis methodology has been devised for the synthesis of the high-value chiral pharmaceutical building block (S)-tert-butyl(6-oxopiperdin-3-yl)carbamate (1). Commencing with L-pyroglutaminol, p-tosyl (p-Ts) was innovatively employed as the activating and leaving group for the hydroxyl moiety, thereby replacing the methylsulfonyl (Ms) group. Meanwhile, dibenzylamine was successfully substituted for sodium azide as the amine source. This effectively circumventing the utilization of difficult-to-obtain controlled reagents like MsCl and the highly toxic and explosive NaN₃. The synthesis process of 1 has been comprehensively optimized, resulting in an impressive total yield of 67% at the hundred-gram scale, while maintaining a purity of 99.4% for the target product. The reagents employed throughout the synthesis route are readily available and cost-effective. The synthesis route is concise and efficient, and the purification method is simple and user-friendly, laying a robust foundation for potential industrial-scale production.

Key words: amino-piperidone, pharmaceutical intermediate, process optimization, organic synthesis

引用此文

李永胜, 唐小雯, 李旭, 杨鹏. (S)-(6-氧代哌啶-3-基)氨基甲酸叔丁酯的工艺开发与放大[J]. 有机化学, 2025, 45(1): 220-226.

Yongsheng Li, Xiaowen Tang, Xu Li, Peng Yang. Process Development and Scale-Up of (S)-tert-Butyl(6-oxopiperdin-3-yl)carbamate[J]. Chinese Journal of Organic Chemistry, 2025, 45(1): 220-226.

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参考文献 30

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Entry	Base	Solvent	Temp.^b/℃	Dibenzyamine/equiv.	Base/equiv.	Yield^c/%
1	Et₃N	CH₃CN	85	1.1	1.0	24
2	i-Pr₂NEt	CH₃CN	85	1.1	1.0	20
3	DBU	CH₃CN	85	1.1	1.0	10
4	K₂CO₃	CH₃CN	85	1.1	1.0	89
5	Cs₂CO₃	CH₃CN	85	1.1	1.0	93
6	None	CH₃CN	85	1.1	1.0	Trace
7	K₂CO₃	THF	85	1.1	1.0	60
8	K₂CO₃	DMF	85	1.1	1.0	50
9	K₂CO₃	DMSO	85	1.1	1.0	49
10	K₂CO₃	1,4-Dioxane	85	1.1	1.0	86
11	K₂CO₃	CH₃CN	75	1.1	1.0	86
12	K₂CO₃	CH₃CN	65	1.1	1.0	74
13	K₂CO₃	CH₃CN	85	1.05	1.0	86
14	K₂CO₃	CH₃CN	85	1.05	0.8	85

Entry	Base	Solvent	Temp.^b/℃	Dibenzyamine/equiv.	Base/equiv.	Yield^c/%
1	Et₃N	CH₃CN	85	1.1	1.0	24
2	i-Pr₂NEt	CH₃CN	85	1.1	1.0	20
3	DBU	CH₃CN	85	1.1	1.0	10
4	K₂CO₃	CH₃CN	85	1.1	1.0	89
5	Cs₂CO₃	CH₃CN	85	1.1	1.0	93
6	None	CH₃CN	85	1.1	1.0	Trace
7	K₂CO₃	THF	85	1.1	1.0	60
8	K₂CO₃	DMF	85	1.1	1.0	50
9	K₂CO₃	DMSO	85	1.1	1.0	49
10	K₂CO₃	1,4-Dioxane	85	1.1	1.0	86
11	K₂CO₃	CH₃CN	75	1.1	1.0	86
12	K₂CO₃	CH₃CN	65	1.1	1.0	74
13	K₂CO₃	CH₃CN	85	1.05	1.0	86
14	K₂CO₃	CH₃CN	85	1.05	0.8	85

Entry	Conditions	Result^a
1^b	Pd/C^c (1.3 mol%), H₂ (101 kPa), MeOH, 22 ℃, 48 h	1/10 (1/12, 85%)
2^b	Pd/C (1.3 mol%), H₂ (101 kPa), K₂CO₃ (0.03 equiv.), MeOH, 22 ℃, 48 h	11 (80%), 12 (10%)
3^b	Pd/C (1.3 mol%), H₂ (101 kPa), NaHCO₃ (1.0 equiv.), MeOH, 22 ℃, 48 h	1/10 (3.7/1, 88%)
4^d	Pd/C (1.3 mol%), H₂ (101 kPa), MeOH, 22 ℃, 48 h; then K₂CO₃ (0.03 equiv.), 2 h	1 (89%)
5^d	Pd(OH)₂/C^e (1.3 mol%), H₂ (101 kPa), MeOH, 22 ℃, 48 h; then K₂CO₃ (0.03 equiv.), 2 h	1 (75%)
6^d	Pt/C^f (1.3 mol%), H₂ (101 kPa), MeOH, 22 ℃, 48 h; then K₂CO₃ (0.03 equiv.), 2 h	1 (24%)

Entry	Conditions	Result^a
1^b	Pd/C^c (1.3 mol%), H₂ (101 kPa), MeOH, 22 ℃, 48 h	1/10 (1/12, 85%)
2^b	Pd/C (1.3 mol%), H₂ (101 kPa), K₂CO₃ (0.03 equiv.), MeOH, 22 ℃, 48 h	11 (80%), 12 (10%)
3^b	Pd/C (1.3 mol%), H₂ (101 kPa), NaHCO₃ (1.0 equiv.), MeOH, 22 ℃, 48 h	1/10 (3.7/1, 88%)
4^d	Pd/C (1.3 mol%), H₂ (101 kPa), MeOH, 22 ℃, 48 h; then K₂CO₃ (0.03 equiv.), 2 h	1 (89%)
5^d	Pd(OH)₂/C^e (1.3 mol%), H₂ (101 kPa), MeOH, 22 ℃, 48 h; then K₂CO₃ (0.03 equiv.), 2 h	1 (75%)
6^d	Pt/C^f (1.3 mol%), H₂ (101 kPa), MeOH, 22 ℃, 48 h; then K₂CO₃ (0.03 equiv.), 2 h	1 (24%)

Entry	Conditions	Yield^a/%	Purity^b/%
1	i-PrOH/petroleum ether (V∶V=1∶3, 5 mL), 22 ℃, 12 h	88	99.4
2	MeOt-Bu/petroleum ether (V∶V=1∶3, 5 mL), 22 ℃, 12 h	97	90.1
3	EtOAc/petroleum ether (V∶V=1∶3, 5 mL), 22 ℃, 12 h	96	93.7
4	EtOAc/petroleum ether (V∶V=1∶2, 5 mL), 22 ℃, 12 h	95	96.1
5	EtOAc/petroleum ether (V∶V=1∶1, 5 mL), 22 ℃, 12 h	94	96.7
6	EtOAc/petroleum ether (V∶V=1∶1, 7 mL), 22 ℃, 12 h	94	99.2
7	EtOAc/petroleum ether (V∶V=1∶1, 10 mL), 22 ℃, 12 h	94	99.8
8	EtOAc/petroleum ether (V∶V=1∶1, 10 mL), 0 ℃, 12 h	95	99.3
9	EtOAc/petroleum ether (V∶V=1∶1, 10 mL), 40 ℃, 12 h	94	99.8