Synthesis of a Sitagliptin Intermediate via Ruthenium-Catalyzed Asymmetric Hydrogenation of Enamine Ester

doi:10.6023/cjoc202408013

Chinese Journal of Organic Chemistry ›› 2024, Vol. 44 ›› Issue (12): 3720-3726.DOI: 10.6023/cjoc202408013 Previous Articles Next Articles

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钌催化烯胺酯的不对称氢化合成西格列汀手性中间体

吕逸文^a, 廖海华^a, 汤文军^a^,^b^,^c^,^*()

a 华东理工大学药学院上海 200237
b 中国科学院上海有机化学研究所生命过程小分子调控全国重点实验室上海 200032
c 中国科学院大学杭州高等研究院化学和材料科学学院杭州 310024

收稿日期:2024-08-08 修回日期:2024-08-31 发布日期:2024-09-10
基金资助:
国家重点研发计划(2022YFA1503702); 国家重点研发计划(2021YFF0701601); 国家自然科学基金(82188101)

Synthesis of a Sitagliptin Intermediate via Ruthenium-Catalyzed Asymmetric Hydrogenation of Enamine Ester

Yiwen Lü^a, Haihua Liao^a, Wenjun Tang^a^,^b^,^c^,^*()

a School of Pharmacy, East China University of Science and Technology, Shanghai 200237
b State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032
c School of Chemistry and Materials Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024

Received:2024-08-08 Revised:2024-08-31 Published:2024-09-10
Contact: *E-mail:tangwenjun@sioc.ac.cn
Supported by:
National Key R&D Program of China(2022YFA1503702); National Key R&D Program of China(2021YFF0701601); National Natural Science Foundation of China(82188101)

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Abstract

This paper aims at developing a highly enantioselective ruthenium-catalyzed asymmetric hydrogenation of ena- mine ester to synthesize the chiral intermediate of sitagliptin. Through a comprehensive investigation of ruthenium catalyst precursors, chiral ligands, acids and ammonium salts as additives, temperature, pressure, and solvent, (R)-3-amino-4-(2,4,5- trifluorophenyl) isopropyl butyrate, the key intermediate of sitagliptin, was obtained in 97% yield and 99% ee by asymmetric hydrogenation from β-2,4,5-trifluorophenyl-β-enamine ester under the action of Ru-BIBOP catalyst, with p-toluenesulfonic acid and ammonium p-toluenesulfonate as additives, and dichloromethane/methanol as solvent, under 5 MPa of hydrogen pressure and 60 ℃ for 22 h. The use of Ru-BIBOP catalyst plays a key role in achieving high enantioselectivity for this trans- formation.

Key words: ruthnium, enamide easter, asymmetric hydrogenation, sitagliptin

Cite this article

Yiwen Lü, Haihua Liao, Wenjun Tang. Synthesis of a Sitagliptin Intermediate via Ruthenium-Catalyzed Asymmetric Hydrogenation of Enamine Ester[J]. Chinese Journal of Organic Chemistry, 2024, 44(12): 3720-3726.

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Fig. & Tab. 7

References 17

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Entry	Deviation from standard^a	Conv.^b/%	Yield^b/%	ee^c/%
1	None	>99	13	99
2	No [Ru(COD)Cl₂]₂, no Ligand	>99	0	—
3	No ligand	>99	0	—
4	No TsOH•H₂O	>99	0	—
5	[M]=[Rh(COD)Cl]₂	74	13	22
6	[M]=[Ir(COD)Cl]₂	64	51	10
7	[M]=[Ru(COD)(CF₃COO)₂]	97	48	37
8	[M]=[Ru(COD)(2-methylallyl)₂]	>99	57	23

Entry	Deviation from standard^a	Conv.^b/%	Yield^b/%	ee^c/%
1	None	>99	13	99
2	No [Ru(COD)Cl₂]₂, no Ligand	>99	0	—
3	No ligand	>99	0	—
4	No TsOH•H₂O	>99	0	—
5	[M]=[Rh(COD)Cl]₂	74	13	22
6	[M]=[Ir(COD)Cl]₂	64	51	10
7	[M]=[Ru(COD)(CF₃COO)₂]	97	48	37
8	[M]=[Ru(COD)(2-methylallyl)₂]	>99	57	23

Entry	Acid	Conv.^b/%	Yield/%^b	ee^c/%
1	AcOH	98	0	—
2	Citric acid	98	57	35
3	Benzenesulfonic acid	>99	26	95
4	p-Chlorobenzenesulfonic acid	>99	5	87
5	1-Naphthol-5-sulfonic acid	>99	0	—
6	4-Methyl-N-[(4-methylphenyl)- sulfonyl] benzenesulfonamide	>99	0	—
7	TsOH•H₂O (1.3 equiv.)	>99	40	99
8	TsOH•H₂O (1.5 equiv.)	>99	42	99
9	TsOH•H₂O (1.7 equiv.)	>99	45	99
10	TsOH•H₂O (2.0 equiv.)	>99	46	99
11	TsOH•H₂O (2.2 equiv.)	>99	52	99
12	TsOH•H₂O (2.4 equiv.)	>99	71	99
13	TsOH•H₂O (2.5 equiv.)	>99	80	99
14	TsOH•H₂O (2.6 equiv.)	>99	69	99
15	TsOH•H₂O (2.7 equiv.) TsOH•H₂O (3.0 equiv.)	>99	60	99
16	TsOH•H₂O (2.7 equiv.) TsOH•H₂O (3.0 equiv.)	>99	55	99

Entry	Acid	Conv.^b/%	Yield/%^b	ee^c/%
1	AcOH	98	0	—
2	Citric acid	98	57	35
3	Benzenesulfonic acid	>99	26	95
4	p-Chlorobenzenesulfonic acid	>99	5	87
5	1-Naphthol-5-sulfonic acid	>99	0	—
6	4-Methyl-N-[(4-methylphenyl)- sulfonyl] benzenesulfonamide	>99	0	—
7	TsOH•H₂O (1.3 equiv.)	>99	40	99
8	TsOH•H₂O (1.5 equiv.)	>99	42	99
9	TsOH•H₂O (1.7 equiv.)	>99	45	99
10	TsOH•H₂O (2.0 equiv.)	>99	46	99
11	TsOH•H₂O (2.2 equiv.)	>99	52	99
12	TsOH•H₂O (2.4 equiv.)	>99	71	99
13	TsOH•H₂O (2.5 equiv.)	>99	80	99
14	TsOH•H₂O (2.6 equiv.)	>99	69	99
15	TsOH•H₂O (2.7 equiv.) TsOH•H₂O (3.0 equiv.)	>99	60	99
16	TsOH•H₂O (2.7 equiv.) TsOH•H₂O (3.0 equiv.)	>99	55	99

Entry^a	T/℃	Conv.^b/%	Yield^b/%	ee^c/%
1	40	>99	80	99
2	50	>99	89	99
3	60	>99	97	99

钌催化烯胺酯的不对称氢化合成西格列汀手性中间体

Synthesis of a Sitagliptin Intermediate via Ruthenium-Catalyzed Asymmetric Hydrogenation of Enamine Ester

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