Piperidine Minoxidil

Piperidines. A significant use of piperidine (18) has been ia the manufacture of vulcanization accelerators, eg, thiuram disulfide [120-54-7] (115) (see Rubber chemicals). Mepiquat dichloride [24307-26-4] the dimethyl quaternary salt of (18), is used as a plant growth regulator for cotton (qv). Piperidine is used to make vasodilators such as dipyridamole [58-32-2] (116) and minoxidil [38304-91-5] (117), and diuretics such as etozoline [73-09-6] (118). 

In the pharmaceutical synthesis industry, piperidine is used in some drugs such as budipine (antiparkinsonian drug), raloxifene (used in the prevention of osteoporosis), minoxidil (an oral drug to treat high blood pressure). Minoxidil has the interesting side effect of hair growth and reverses hair loss. A two percent minoxidil solution can be used to treat this condition. 

The initial patent describing the Upjohn synthesis of minoxidil (2) was issued in 1972 (Scheme 5). The synthesis began with the assembly of phenoxypyrimidine 25 from the SwAr displacement of 4-chloropynmidine-2,6-diamine (24) with 2,4-dichlorophenol. The aryl ether installed here serves as a leaving group in the last step, and is more tolerant of the ensuing oxidation step. Therefore, oxidation of phenoxypyrimidine 25 gave 6-amino-4-(2,4-dichlorophenoxy)-2-imino-2H-pyrimidin-l-ol (26), which was then condensed with piperidine in sealed tube at 250 °C to deliver minoxidil (3). 

The second patent by Upjohn describes an improved route, obviating the use of the sealed tube reactor (Scheme 6). Therefore, 6-amino-4-chloro-2-imino-2H-pyrimidin-l-ol (28) was prepared from the oxidation of 4-chloro-pynmidine-2,6-diamine (27). The crude product was extracted with boiling acetonitrile to give pure 28 in 44.7% yield. Refluxing 28 with excess of piperidine for 1.5 h then afforded minoxidil (3) after extraction with boiling acetonitrile. 

Likewise, heating of 2,5-diamino-l-oxy-4-tosyloxypyrimidine (203) in excess piperidine gives 60% of minoxidil 204 (87EUP27020I). 

Allergic contact dermatitis occurred in a 54-year-old man who had used 1% minoxidil on the scalp for 8 months (14). He had positive patch tests to minoxidil in alcohol, but not to minoxidil in petrolatum, piperidine, pyrimidine, or diaminopyrimidine. 

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