Dorzagliatin

• CAS 1191995-00-2
• HMS5552
• Sinogliatin
• HMS-5552
• MW 462.9 g/mol MF C₂₂H₂₇ClN₄O₅
• (2S)-2-[3-(2-chlorophenoxy)-5-oxo-2H-pyrrol-1-yl]-N-[1-[(2R)-2,3-dihydroxypropyl]pyrazol-3-yl]-4-methylpentanamide
• RO5305552
• RO-5305552
• X59W6980E8

• (2S)-2-[3-(2-chlorophenoxy)-5-oxo-2H-pyrrol-1-yl]-N-[1-[(2R)-2,3-dihydroxypropyl]pyrazol-3-yl]-4-methyl-pentanamide
• 1H-PYRROLE-1-ACETAMIDE, 4-(2-CHLOROPHENOXY)-N-(1-((2R)-2,3-DIHYDROXYPROPYL)-1H-PYRAZOL-3-YL)-2,5-DIHYDRO-.ALPHA.-(2-METHYLPROPYL)-2-OXO-, (.ALPHA.S)-

Dorzagliatin(18)was developed by Hua Medicine as a treatment for diabetic kidney disease(DKD), type1diabetes mellitus(T1DM), and type2 diabetes mellitus (T2DM). CHINA 2022

Dorzagliatin is a glucokinase activator that is being developed to treat diabetes.^[1] Unlike other diabetes drugs, it is intended to increase insulin sensitivity.^[2]

Dorzagliatin is under investigation in clinical trial NCT03173391 (Long-term Efficacy and Safety of HMS5552 in T2DM).

PATENT

https://patents.google.com/patent/CN112062754A/en

(R) -1- ((2, 2-dimethyl-1, 3-dioxolane-4-yl) methyl) -1H-pyrazole-3-ammonia (II) is a very important medical intermediate for synthesizing Dorzagliatin. Dorzagliatin is a novel medicine for treating type 2 diabetes mellitus, and (R) -1- ((2, 2-dimethyl-1, 3-dioxolane-4-yl) methyl) -1H-pyrazole-3-ammonia (II) is an essential intermediate in the synthetic process of the medicine, and along with the steady promotion of new Dorzagliatin medicines to the market, the demand of the chiral intermediate in the market is required to be rapidly increased.

The main production method of the key chiral intermediate is shown as follows: reducing nitro in 3-nitro-1H-pyrazole substrate into amino, protecting free amino, carrying out N-alkylation reaction with (R) – (-) -2, 3-O-isopropylidene glycerol-OH derivative active intermediate, and deprotecting to obtain the final product. The synthetic route needs to be subjected to an N-protection process, so that route steps are added, and the cost is increased. The synthesis of N-protected substrate iv is reported: in the patent US2013203802, 1H-pyrazole-3-ammonia is protected by acetic anhydride, and in WO2017040757, N-acetyl-1H-pyrazole-3-ammonia is obtained by an N- (1-benzyl-1H-pyrazole-3-yl) acetamide debenzylation method; the protection of the N-benzoyl group of 1H-pyrazol-3-amine is reported in the patent US 6118008; in addition, WO2009106209, US2012095064, mention the phthalimide protection strategy of 1H-pyrazole-3-ammonia with phthalic anhydride.

Example 1

Preparation of (R) -1- ((2, 2-dimethyl-1, 3-dioxolan-4-yl) methyl) -1H-pyrazol-3-amine

The first step is as follows: intermediate (R) -I preparation:

under the protection of nitrogen, 3-nitro-1H-pyrazole (1) (100.00g,0.884mol), ethanol (1.0L) and sodium carbonate (133.90g, 1.26mol) are sequentially added into a 3L reaction bottle, and the system is stirred for 0.5H at room temperature; (S) – (-) -4-chloromethyl-2, 2-dimethyl-1, 3-dioxolane ((S) -2) (126.84g, 0.842mol) was dissolved and diluted with 634ml of ethanol and then added dropwise to the reaction flask. After the dropwise addition, the temperature is raised to 50 ℃ and the reaction is stirred for 5 hours. Ethanol was distilled off under reduced pressure, and the residue was diluted with (1.0L) of water and then extracted twice with dichloromethane (500ml × 2); the organic phase was washed with water and then with saturated sodium chloride brine. Concentrating under reduced pressure to remove dichloromethane to obtain crude oily substance; the crude product was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate mixed system) to give 166.5g of a pale yellow oily product, with a yield of 87% and an ee value of 98% or more.

The second step is that: reducing nitro to obtain target product

A2L autoclave was charged with (R) -I substrate (150g, 0.66mol), methanol (750mL), Pd/C (0.75g, 0.5% W/W), and the mixture was subjected to nitrogen substitution three times, then hydrogen substitution three times, under a hydrogen-charging pressure of 2.0MPa, at a temperature of 50 ℃ for reaction for 8 hours. Filtering, filtering to remove Pd/C catalyst, concentrating the filtrate to remove methanol to obtain 123.70g of light yellow oily matter, wherein the yield is 95%, and the ee value is more than or equal to 98%.

Example 2

Preparation of (R) -1- ((2, 2-dimethyl-1, 3-dioxolan-4-yl) methyl) -1H-pyrazol-3-amine by Raney-Ni reduction system

The first step is the same as in example 1.

The second step is that: reduction of nitro groups by Rany-Ni

The intermediate (R) -I (150g, 0.66mol) obtained in the first step was charged into a 2L reactor, and ethanol (1.2L) was added thereto and stirred, followed by adding Rany-Ni (75g) and stirring at room temperature for reaction for 15 hours. Filtering, filtering to remove the solid catalyst, and concentrating the filtrate to dryness to obtain 106.77g of light yellow oily substance with yield of 82% and ee value of more than or equal to 97%.

Example 3

Preparation of (R) -1- ((2, 2-dimethyl-1, 3-dioxolan-4-yl) methyl) -1H-pyrazol-3-amine by hydrazine hydrate system

The first step is the same as in example 1.

The second step is that: A2L reaction flask was charged with intermediate (R) -I (150g, 0.66mol), ferric trichloride (528mg, 3.3mmol), and ethanol (1.2L), stirred, charged with hydrazine hydrate (39.5g, 0.79mol), and heated to reflux for 6 h. Ethanol was removed by concentration under reduced pressure, the residue was diluted with 750ml of water and extracted twice with ethyl acetate (250 ml. times.2). The organic phase was washed with water and then with saturated brine. The ethyl acetate is removed by concentration to obtain 110.7g of crude light yellow oily substance, the yield is 85 percent, and the ee value is more than or equal to 97 percent.

SYN

https://doi.org/10.1021/acs.jmedchem.3c02374J.Med.Chem.2024,67,4376−4418

Dorzagliatin(HuaTangNing).

Dorzagliatin(18)was developed by Hua Medicine as a treatment for diabetic kidney disease(DKD), type1diabetes mellitus(T1DM), and type2 diabetes mellitus (T2DM).133 This first-in-class, small
molecule,oral,glucokinaseactivator(GKA)wasfirst approved in ChinainSeptember2022foradultpatientswithT2DMasa monotherapy and in combination with metformin (an antidiabetic medication).134 Expression of glucokinase is reduced for individuals with T2DM, thus GKAs such as dorzagliatin serve as a novel class of antidiabetic treatment options.135,136 Theinitialpatent thatdisclosesthesynthesisofdorzagliatin (18)began fromreadily availablematerials 3-aminopyrazole
(18.1) and 2-chlorophenol (18.5). The synthetic strategy reliedonaconvergentamidecouplingofamine18.4(Scheme32) and carboxylic acid 18.9 (Scheme 33).137 A later disclosure provided an updated route toward amine 18.4 (Scheme 32), detailing the synthetic improvements with respect to yield and purity.138 This later disclosure also detailed the synthesis of dorzagliatinonmultikilogramscale fromtheamidationofacid18.9withamine18.4,yieldingover
10kgoftheactivepharmaceutical ingredient.Acetylationof3 aminopyrazole (18.1) with acetic anhydride provided the protectedpyrazole18.2(Scheme32). Subsequent alkylation with alkyl chloride 18.3 followed by base-mediated deprotectionyieldedamine18.4. The synthesis of acid 18.9 began with base-mediated
alkenylationof2-chlorophenol (18.5)withethyl 2-butynoate toprovideester18.6(Scheme33). Subsequentbromination withNBSandAIBNyieldsallylbromide18.7.Next,subjection
ofL-leucinemethylesterhydrochloride(18.8)tobaseresulted ina freeamine thatunderwent allylationwithbromide18.7. Acid 18.9was subsequently generated froma cyclization
condensation sequence and saponification reaction with NaOH. Final amidebondformationwas facilitatedbyEDCI andHOBt toprovideamide18.10, anddorzagliatin(18)was generatedonthemultikilogramscale followingacid-mediated acetonidedeprotectiontoreveal the1,2-diol.

(133) Syed, Y. Y. Dorzagliatin: First approval. Drugs 2022, 82,
1745−1750.
(134) Xu, H.; Sheng, L.; Chen, W.; Yuan, F.; Yang, M.; Li, H.; Li, X.;
Choi, J.; Zhao, G.; Hu, T.; et al. Safety, tolerability, pharmacokinetics,
and pharmacodynamics of novel glucokinase activator HMS5552:
results from a first-in-human single ascending dose study. Drug Des.
Devel. Ther. 2016, 10, 1619−26.
(135) Ren, Y.; Li, L.; Wan, L.; Huang, Y.; Cao, S. Glucokinase as an
emerging anti-diabetes target and recent progress in the development
of its agonists. J. Enzyme Inhib. Med. Chem. 2022, 37, 606−615.
(136) Toulis, K. A.; Nirantharakumar, K.; Pourzitaki, C.; Barnett, A.
H.; Tahrani, A. A. Glucokinase activators for type 2 diabetes:
Challenges and future developments. Drugs 2020, 80, 467−475.
(137) Berthel, S. J.; Brinkman, J. A.; Hayden, S.; Haynes, N.-E.;
Kester, R. F.; McDermott, L. A.; Qian, Y.; Sarabu, R.; Scott, N. R.;
Tilley, J. W. Pyrrolidinone as glucokinase activators and their
preparation, pharmaceutical compositions and use in the treatment
of metabolic disorders. WO 2009127546, 2009.
(138) Chen, J.; Ren, Y.; She, J.; Wang, L. Process for the preparation
of 1-([1,3]dioxolan-4-ylmethyl)-1h-pyrazol-3-ylamine. U.S. Patent US
20150315176, 2015.

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References

1.  Chow, Elaine; Wang, Ke; Lim, Cadmon K.P.; Tsoi, Sandra T.F.; Fan, Baoqi; Poon, Emily; Luk, Andrea O.Y.; Ma, Ronald C.W.; Ferrannini, Ele; Mari, Andrea; Chen, Li; Chan, Juliana C.N. (1 February 2023). “Dorzagliatin, a Dual-Acting Glucokinase Activator, Increases Insulin Secretion and Glucose Sensitivity in Glucokinase Maturity-Onset Diabetes of the Young and Recent-Onset Type 2 Diabetes”. Diabetes. 72 (2): 299–308. doi:10.2337/db22-0708. PMC 9871194.
2.  Zhu, Dalong; Li, Xiaoying; Ma, Jianhua; Zeng, Jiao’e; Gan, Shenglian; Dong, Xiaolin; Yang, Jing; Lin, Xiaohong; Cai, Hanqing; Song, Weihong; Li, Xuefeng; Zhang, Keqin; Zhang, Qiu; Lu, Yibing; Bu, Ruifang; Shao, Huige; Wang, Guixia; Yuan, Guoyue; Ran, Xingwu; Liao, Lin; Zhao, Wenjuan; Li, Ping; Sun, Li; Shi, Lixin; Jiang, Zhaoshun; Xue, Yaoming; Jiang, Hongwei; Li, Quanmin; Li, Zongbao; Fu, Maoxiong; Liang, Zerong; Guo, Lian; Liu, Ming; Xu, Chun; Li, Wenhui; Yu, Xuefeng; Qin, Guijun; Yang, Zhou; Su, Benli; Zeng, Longyi; Geng, Houfa; Shi, Yongquan; Zhao, Yu; Zhang, Yi; Yang, Wenying; Chen, Li (May 2022). “Dorzagliatin in drug-naïve patients with type 2 diabetes: a randomized, double-blind, placebo-controlled phase 3 trial”. Nature Medicine. 28 (5): 965–973.

• [1]. Zhu XX, et al. Dorzagliatin (HMS5552), a novel dual-acting glucokinase activator, improves glycaemic control and pancreatic β-cell function in patients with type 2 diabetes: A 28-day treatment study using biomarker-guided patient selection. Diabetes Obes Metab. 2018 Sep;20(9):2113-2120.  [Content Brief][2]. Wang P, et al. Effects of a Novel Glucokinase Activator, HMS5552, on Glucose Metabolism in a Rat Model of Type 2 Diabetes Mellitus. J Diabetes Res. 2017;2017:5812607.  [Content Brief]

//////////Dorzagliatin, APPROVALS 22, CHINA 22, DIABETES, Hua Medicine, 1191995-00-2, HMS 5552, Sinogliatin, HMS-5552, RO 5305552, RO-5305552, X59W6980E8