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Zicronapine Fumarate synthesis
- Product Name:Zicronapine Fumarate
- CAS Number:170381-17-6
- Molecular formula:C26H31ClN2O4
- Molecular Weight:470.99
Yield:170381-17-6 52%
Reaction Conditions:
in propan-1-ol at 20;
Steps:
11
Example 11; Synthesis of ^αw5-4-((iJ?,5S)-6-chloro-3-phenylindan-l-yl)-l,2,2- trimethylpiperazinium (IX) hydrogen fumarate Trans- 1 -(( 1 i?,3S)-6-chloro-3 -phenylindan- 1 -yl)-3 ,3 -dimethylpiperazine (I, synthesised as in example 10) is stirred with formic acid (15.2 ml) and formaldehyde (37% in water, 12.5 ml), and heated on an oil batch (temperature 1100C) for 11A hour. Water is added to the reaction mixture after cooling to room temperature, and pH is adjusted to approximately 14 with sodium hydroxide (28%). The product is extracted with diethyl ether and then ethyl acetate, adding sodium hydroxide (28%) in between the extractions, if the pH becomes lower than 12. The organic phases are combined, dried with sodium sulphate, filtered, and evaporated to dryness, using a rotary evaporator. Yield 10.9 g (100%) of (IX) as an oil, containing 20% of the cis form according to NMR.The oil (10 g) is heated with 1-propanol (150 ml), giving a solution. Fumaric acid (3.3 g) is added, and heating is continued until all is dissolved. The mixture is cooled to room temperature and seeded, whereby the product precipitates. The solid is isolated by filtration, washed with a small amount of 1-propanol, and dried in a vacuum oven at 4O0C. Yield 6.85 g (52%). Melting point 193.30C, NMR conforms to structure, [α]D20 -15.2° (c=1.0, methanol). Contains 4% of the cis form according to CE, the other two diastereoisomers are not detected (i.e. the content is below 1%). CHN calculated for C26H3iN2O4Cl: C 66.30, H 6.63, N 5.95; found: C 65.96, H 6.61, N 5.57. >98% ee according to CE.
References:
WO2006/86984,2006,A1 Location in patent:Page/Page column 24