Synthesis Process Research of γ-Secretase Inhibitors(LY411575)†

doi:10.7503/cjcu20160742

Abstract

Abstract:

The original synthetic route of gamma secretase inhibitors(LY411575) was improved, the yield of 35% was achieved which increased by 16% compared with the traditional process. Meanwhile, key interme-diates were resolved by chiral acid in advance so that the consumption of raw materials in latter three steps of synthetic process was decreased by 50%. The method contributed to decrease the reaction cost and the difficulty of product purification. In addition, the single-factor experiment was conducted for main factors affected the resolving process to study the influence of various factors on the e.e. value and the yield of products. The optimal reaction condition was obtained as follows: D-(+)-2 methyl benzoyl tartaric acid as the resolution agent, methanol as the solvent, heated to reflux for dissolution, the solvent of 12 mL per gram substrate, the time from the initial temperature of reflux to room temperature controlled in 120 min, the resolution yield of 40% and the e.e. value of 99%.

Key words: Alzheimer’s disease(AD), γ-Secretase, Key intermediate, Inhibitor

CLC Number:

O621.25

TrendMD:

GUO Hongyao, LI Dong, LEI Xiong, ZHANG Xu, XU Renjun, WANG Feng, LI Wenhong. Synthesis Process Research of γ-Secretase Inhibitors(LY411575)^†[J]. Chem. J. Chinese Universities, 2017, 38(2): 200.

Figures/Tables 8

References 22

[1]	Morelli S., Salerno S., Piscioneri A., Tasselli F., Drioli E., De Bartolo L., Chemical Engineering Journal,2016, 305(1), 69—78
[2]	Chen N., Sun Y., Yue H., Liu S. Y., Chem. J. Chinese Universities,2013, 34(5), 1111—1114
	(陈宁, 孙一, 越皓, 刘淑莹. 高等学校化学学报, 2013, 34(5), 1111—1114)
[3]	Chen S. D., Yang H. Q., Geriatric Medicine And Health,2004, 11(4), 193—198
	(陈生弟, 杨红旗. 老年医学与保健, 2004, 11(4), 193—198)
[4]	Long Y., Zheng Y. C., Chinese Pharmacists,2009, 12(12), 1828—1829
	(龙悦, 郑永昌. 中国药师, 2009, 12(12), 1828—1829)
[5]	Fu J. L., Shao F. Y., The World of Clinical Medicine,2010, 31(7), 390—394
	(付剑凉, 邵福源. 世界临床医药, 2010, 31(7), 390—394)
[6]	Zhang X., Yong X. C., Zhang T., China's Pharmaceutical Information,2010, 26(4), 4—18
	(张骁, 雍晓春, 张韬. 中国制药信息, 2010, 26(4), 4—18)
[7]	Yao Y., Li Z. S., Chem. Res. Chinese Universities,2008, 24(6), 778—781
[8]	Barnes D. E., Cenzer I. S., Yaffe K., Ritchie C. S., Lee S. J., Alzheimer’s and Dementia,2014, 10(6), 646—655
[9]	Fauq A. H., Simpson K., Maharvi G. M., Golde T., Das P., Bioorganic and Medicinal Chemistry Letters,2007, 17(22), 6392—6395
[10]	De La R. M., Woo K. H., Esmir G., Cheryl J., Yung-hyo B. U. K., Ilia K., Matthew A., Zhang W. J., Chen H. M., Xu W., Bioorganic and Medicinal Chemistry Letters,2006, 16(17), 4444—4449
[11]	Lukasz R., Nils M., Abdelouahid M., Stephan H., ChemBioChem,2011, 12(3), 371—376
[12]	Hoffmann-Emery F., Jakob-Roetne R., Process for Preparation of Enantiomerically Pure Compounds, US 2008293933,2008-11-27
[13]	Hoffmann-Emery F., Jakob-Roetne R., Alexander F., Fritz B., Reinhard R., Tetrahedron Letters,2009, 50(46), 6380—6382
[14]	James E. A., Thomas E. M., Jeffrey A. N., Stacey L. M., Warren J. P., Polycyclic α-Amino-ε-Caprolactams and Related Compounds US 6958330,2005-10-25
[15]	Wu J., Tung J. S., Thorsett E. D., Pleiss M. A., Nissen J. S., Neitz J. R., Latimer L. H., John V., Freedman S., Britton T. C., Audia J. A., Reel J. K., Mabry T. E., Dressman B. A., Cwi C. L., Droste J. J., Henry S. S., McDaniel S. L., Scott W. L., Stucky R. D., Porter W. J., Cycloalkyl, Lactam Lactone and Related Compounds, Pharmaceutical Compositions Comprising Same, and Methods for Inhibiting Beta-Amyloid Peptide Release and/or Its Synthesis by Use of Such Compounds, EP 951466,2003-10-14
[16]	Degussa A., Novel Phosphinine Compounds and Metal Complexes Thereof, US2002103375, 2002-8-1
[17]	Jens-Uwe P., Galley G., Helmut J., Christian C., Pascale D. P., Eric A. K., Laurence O., Bioorganic and Medicinal Chemistry Letters,2007, 17(21), 5918—5923
[18]	Wu J., Tung J. S., Thorsett E. D., Pleiss M. A., Nissen J. S., Neitz J. R., Latimer L. H., John V., Freedman S., Britton T. C., Audia J. A., Reel J. K., Mabry T. E., Dressman B. A., Cwi C. L., Droste J. J., Henry S. S., McDaniel S. L., Scott W. L., Stucky R. D., Porter W. J., Preparation of Cycloalkyl, Lactam, Lactone and Related Compounds for Inhibiting Beta-Amyloid Peptide Release and Its Synthesis US 200245747,2002-5-9
[19]	Fuwa H., Okamura Y., Morohashi Y., Tomita T., Iwatsubo T., Kan T., Fukuyama T., Natsugari H., Tetrahedron Letters,2004, 45(11), 2323—2326
[20]	Cole K. P., David M., Austin C. M., Stout J. R., Belvo M. D., Tetrahedron: Asymmetry,2009, 20(11), 1262—1266
[21]	Gu J. Y., He W. P., Shi X. F., Ji L. N., Chem. Res. Chinese Universities,2008, 24(1), 106—109
[22]	Chen R.Y., Organic Synthesis Process Optimization, Chemical Industry Press, Beijing, 2005, 42—51
	(陈荣业. 有机合成工艺优化, 北京: 化学工业出版社, 2005, 42—51)

Solvent	D-(+)-2 Methyl benzoyl tartaric acid		D-Malic acid		L-Mandelic acid		D-Tartaric acid		D-Ethyl diketone tartaric acid		L-Camphors ulfonic acid
Solvent	e.e.(%)	Yield(%)	e.e.(%)	Yield(%)	e.e.(%)	Yield(%)	e.e.(%)	Yield(%)	e.e.(%)	Yield(%)	e.e.(%)	Yield(%)
Methanol	88	49	<5	—	<5	—	7	—	15	73	<5	—
Acetonitrile	39	62	<5	—	<5	—	<5	—	12	68	<5	—

Solvent	D-(+)-2 Methyl benzoyl tartaric acid		D-Malic acid		L-Mandelic acid		D-Tartaric acid		D-Ethyl diketone tartaric acid		L-Camphors ulfonic acid
Solvent	e.e.(%)	Yield(%)	e.e.(%)	Yield(%)	e.e.(%)	Yield(%)	e.e.(%)	Yield(%)	e.e.(%)	Yield(%)	e.e.(%)	Yield(%)
Methanol	88	49	<5	—	<5	—	7	—	15	73	<5	—
Acetonitrile	39	62	<5	—	<5	—	<5	—	12	68	<5	—

Solvent	Methanol	Acetonitrile	Ethyl alcohol
e.e.(%)	88	39	59
Yield(%)	49	62	51

Solvent	Methanol	Acetonitrile	Ethyl alcohol
e.e.(%)	88	39	59
Yield(%)	49	62	51

t/℃	64.5(reflux)	70	80	90
e.e.(%)	88	87	89	88
Yield(%)	49	48	49	47