Synthesis of (4-Fluoro-3,5-dimethylphenyl)hydrazine hydrochloride, an intermediate of Orforglipron

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Orforglipron is a non-peptide GLP-1 receptor agonist developed by Eli Lilly for the treatment of type 2 diabetes and obesity. There are multiple synthetic routes for the synthesis of its intermediate, (4-Fluoro-3,5-dimethylphenyl)hydrazine hydrochloride hydrochloride.

1.The synthetic route described in the original research patent is shown as follows.

In the first step, compound 1 underwent a Buchwald reaction with benzophenone hydrazone and the catalysis of palladium acetate to prepare compound 2, which was then deprotected to obtain compound 3.

In this route, palladium acetate was used as a catalyst. However, the palladium acetate was expensive, resulting in high industrialization costs.

2.In the improved route, the palladium-catalyzed Buchwald reaction was replaced by the copper-catalyzed Ullmann reaction.

We used copper bromide as a catalyst, and compound L with acylhydrazine structure as ligand to obtain compound 3 in 80% overall yield. We also replaced palladium acetate with cheap copper bromide, which greatly reduced the cost.
Copper bromide instead of cuprous bromide was applied as a catalyst to avoid the common problem of catalyst oxidation poisoning in Ullmann reaction.

The mechanism of Ullmann reaction catalyzed by copper bromide is that the pyrrolyl hydrazide ligand with redox activity complexed with Cu (II), and then the catalytically active product subsequently reacted with the aryl halide. Then, an aryl copper halide intermediate containing a Cu (III) center and a free radical stabilized on the conjugated ligand was produced in the irreversible oxidative addition reaction with regard to the reaction rate. After the transmetallization and reductive elimination reactions, a Cu (II) center was generated, and a coupling product with new C - N bonds was obtained.

3.Optimization strategies of the improved route are shown as follows.

1）As the equivalent of hydrazine hydrate increased, the purity of compound 3 improved.

No.	The equivalent of hydrazine hydrate	HPLC
No.	The equivalent of hydrazine hydrate	Compound 1	Compound 3
1	2.00eq	0.41%	86.37%
2	5.00eq	0.15%	92.56%
3	7.00eq	0.14%	94.35%

2）The catalytic effects of different catalysts are shown as follows.

No.	Catalysts	HPLC
No.	Catalysts	Compound 1	Compound 3
1	CuCl	4.54%	86.31%
2	CuBr	0.15%	92.56%
3	CuI	0.18%	92.46%
4	CuBr₂	0.69%	92.37%

3）The optimal solvent was DMSO.

No.	Solvents	HPLC
No.	Solvents	Compound 1	Compound 3
1	DMSO	0.69%	92.37%
2	Isopropyl acetate	59.75%	11.02%
3	tert-Butanol	0.60%	88.55%
4	2-Methyl tetrahydrofuran	10.63%	79.54%