Preparation method for optically active diamino derivative
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A kind of amino, amino protecting group technology, applied in the field of diamino derivatives, to achieve significant technical effect, high optical purity effect
Active Publication Date: 2018-10-23
ZHEJIANG JIUZHOU PHARM CO LTD
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However, there is another problem in this route, that is, due to the presence of active hydrogen on the NH connected to the tert-butoxycarbonyl group in the azidation reaction, an impurity with the following structure will be formed:
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Embodiment 1
[0067]
[0068] Put 2.2g of compound D, 22ml of toluene, and 1.3g of benzylamine into a four-necked flask, raise the temperature to 80-90°C, and keep it warm for 4-6 hours. Concentrate to dryness to obtain 3.2 target product F1 with a yield of 90%.
Embodiment 2
[0070]
[0071] Put 5 g of compound F1, 50 ml of ethanol, 5 ml of water, and 23 ml of 30% sodium hydroxide into a four-necked bottle. Heating up to 40-45°C, add 5g BOC dropwise 2 O acid anhydride, after dropping, react for 4-6 hours. After the reaction, concentrate to dry ethanol, add 50ml of EA, 30ml of water, separate layers, wash the organic layer with 10ml of saturated brine, dry 5g of sodium bicarbonate, filter with suction, and concentrate to dryness to obtain 6.1g of the target product F with a yield of 91%. , with a purity of 98%.
Embodiment 3
[0073]
[0074] Put 2.5g of compound F, 2g of phthalimide, 4g of triphenylphosphine, and 50ml of tetrahydrofuran into a four-necked bottle, and lower the temperature to 0-5°C under the protection of nitrogen, and add 2.4g of diethyl azodicarboxylate dropwise. After dripping and keeping warm for 4-6 hours, the reaction is complete. Add 20ml of water, 30ml of EA to extract the organic layer, wash the organic layer with 10ml of saturated brine, dry 3g of sodium bicarbonate, filter with suction, and concentrate the filtrate to dryness to obtain 4g of compound H with a yield of 82% and a purity of 98%.
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Abstract
The invention provides an optically active diamino derivative, and intermediates and a preparation method thereof. The intermediates comprise intermediates F1 and F with a (1R,2R,5S) configuration; and the optically active diamino derivative is a compound with a (1R,2S,5S) configuration and as shown in a formula H. F1, F and H are described in the specification. In F1, F and H, R1 is an alkyl amino-protecting group or an aryl amino-protecting group, e.g., a benzyl group, an alkyl-substituted benzyl group, an alkoxy-substituted benzyl group, an alkoxycarbonyl group or a benzyloxycarbonyl group;R2 is an alkoxycarbonyl, alkyl or aryl amino-protecting group, e.g., a tertbutyloxycarbonyl group, a benzyloxycarbonyl group or a methoxycarbonyl group; X is a hydroxyl group, halogen, OMs, OTf or OTs; R is an alkoxy group or as described in the specification; and R3 is an amino group protected by an amide amino-protecting group, imine groups such as phthalimido, succinimido or naphthalimido groups, diphenyl azidophosphate, -N3, an amino group or a substituted amino group.
Description
technical field [0001] The invention relates to the field of pharmaceutical synthesis, in particular to optically active diamino derivatives, intermediates and preparation methods thereof. Background technique [0002] Compounds with the following structure of formula L-1 or formula L-2 are optically active diamino derivatives, and are intermediates for the synthesis of edoxaban: [0003] [0004] Chinese patent application CN103080078A (applicant: Daiichi Sankyo Co., Ltd.) discloses the salt of the optically active diamino derivative with the same structure. And in its instruction manual [0010] section, disclose the reaction equation that this compound involves in chemical formula 3: [0005] [0006] As disclosed in the patent application, this process exists that when compound 2 is azide, the trans isomer of compound 3 will be formed, and then when reduced, the trans isomer will also be reduced to form 1a-trans Mode. In order to solve this problem, referred to as...
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