Rimegepant is the world’s only CGRP receptor antagonist that utilizes patented orally disintegrating tablet technology and is the first drug in the world that can be used for both the treatment and prevention of acute migraine attacks.
On February 27, 2020, the U.S. Food and Drug Administration (FDA) approved the marketing of remdesivir panicol sulfate tablets under the brand name Nurtec® ODT.
To date, the main synthetic routes to the active pharmaceutical ingredient remepiride are two routes disclosed by the original manufacturer, Bristol-Myers Squibb, using (6S,9R)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-9-[[triisopropylsilyl]oxy]-5H- cycloheptatrienepyridin-5-one (compound 1) as starting material.
Route 1: Remegapan is prepared via a six-step reaction involving, among other things: reduction of the ketone group with sodium borohydride, chlorination of the hydroxyl group with triphenylphosphine and N-chlorosuccinimide, substitution of the chlorine atom with sodium azide, desiliconization with tetrabutylammonium fluoride, coupling, and reduction of the azide group with trimethylphosphine. The route is shown below (Fig. 3):
Route 2: Using compound 1 as the starting material, remepam is synthesized in three steps (one-step reaction of tetraisopropoxytitanium, alumina, and palladium on carbon to produce the key intermediate 2a, deprotection to produce the key intermediate 2b, and coupling). The route is shown below (Figure 4):
As can be seen from the structural formula, the active pharmaceutical ingredient Remegapan molecule has three chiral centers. Creating a chiral amine at the 5-position of cycloheptane poses a significant challenge for scaling up the production of the active pharmaceutical ingredient. Further research will focus on improving the synthesis process for key intermediates 2a/2b.
Patent CN114957247A describes a method for preparing key intermediates 2a/2b: using compound 3a as a starting material, a stereoselective ring-opening reaction occurs with a Lewis reagent to form compound 3b, which then undergoes a Suzuki reaction, silanization protection, substitution, and deprotection to afford the key intermediate 2b in approximately 54% overall yield. The method is shown below (Figure 5):
Patent CN116768938A describes a method for preparing the key intermediate 2a: using the carbonyl compound (4a) as a starting material, intermediate 1 is prepared by reduction, TIPS protection, and reaction with 2,3-difluorobromobenzene. Intermediate 1 undergoes an asymmetric reduction-amination reaction under the action of a FeⅡ/EDTA complexing catalyst and then undergoes ammonolysis with 20% aqueous ammonia to yield the key intermediate 2a (Figure 6a).
In another literature (Zhejiang Chemical Industry, 2022, 53(8). 13-18.), a method for preparing the key intermediate 2b is described: using compound 2 as a raw material, the key intermediate 2b is obtained via AlⅢ/EDTA catalysis. The method is as follows (Fig. 6b):
Patents CN116640811A/CN116083385A describe a method for preparing key intermediates 2a/2b: using compound 1/2 as a starting material, key chiral intermediates 2a/2b are directly generated via a one-step transaminase reaction. This process not only has a short synthetic step but also significantly improves the chiral selectivity and yield of key intermediates 2a/2b. Furthermore, the preparation method is characterized by mild reaction conditions and safe post-processing operations, which meets industrial production requirements (Fig. 7).
Chiral alcohol compound 4b is a precursor to key chiral amine intermediates 2a/2b. Currently, publicly available synthetic routes fall into two categories: chemical and chemoenzymatic.
In the literature (Organic Letters, 2012, 14(18): 4938–4941), the company that conducted the original study described a route to synthesize 4b via asymmetric reduction: using dimethyl 2,3-pyridinedicarboxylate (5a) as a starting material, intermediate 4a was obtained via Dieckmann cyclization and decarboxylation reaction, and then the chiral alcohol compound was synthesized via asymmetric reduction using a metal catalyst Rh-(R-Binapine)(COD)BF₄ with a conversion of 100% and ee≥99.9% (Fig. 8).
Initially, the research company mentioned in patent CN102066358B that the diketone compound (4a) was reduced to 4b by an enzymatic method, but did not disclose specific information about the reaction; later, it was reported in the literature (Organic Letters, 2012, 14(18):4938-4941) that the diketone compound was reduced to 4b under the catalysis of ketone reductase ES-KRED-119 with a reaction yield of 81% and an ee value of 99.2% (Figure 9).
The ketone reductase ES-KRED-119 used in the above enzymatic method was purchased from Shangke Biopharmaceutical (Shanghai) Co., Ltd. Shangke Biopharmaceutical modified the enzyme in patent CN202410502187.9, and the substrate concentration can reach 100 g/L.
Enzymatic asymmetric reduction better suits the industrial requirements for the synthesis of chiral alcohol compounds (4b). Subsequent studies have focused on improving catalysts or screening and optimizing ketone reductases, which will not be discussed in detail here.
[2] LEAHY DAVID K., FANG Y., CHAN COLLIN et al. Method for producing CGRP receptor antagonist cycloheptapyridine: USA 8669368B2 [P]. 11.03.2014.
[3] Ruan Shiwen, Yang Gongchao, Zhang Wei, et al. Synthetic methods for rimegepant and its intermediates: China, 114957247A[P]. 2022-08-30.
[4] He Lingyun, Chen Binhui, Yu Yang. Method for preparing iron catalyst and intermediate product of rimexam: China, 116768938A[P]. 2023-09-19.
[5] Lin Weikang. Preliminary study on the synthesis technology of fluorinated chiral moiety of CGRP receptor antagonist Remegapan via asymmetric catalytic amination method [J]. Zhejiang Chemical Industry, 2022, 53(8):13-18.
[6] He Lingyun, Chen Binhui, Yu Yang. Method for preparing rimexam intermediate: China, 116640811A[P]. 2023-08-25.
[8] Ma Yulei, Jiao Xuecheng, Wang Zujian, et al. Highly efficient synthesis of key polymer intermediates using a modified transaminase [J]. Organic Process Research and Development, 2022, 26(7):1971–1977.
[9] David K. Leahy, Yu Fan, Lopa V. Desai, et al. Efficient and scalable enantioselective synthesis of CGRP antagonists [J]. Organic Letters, 2012, 14(18): 4938–4941.
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