Teneligliptin key intermediate preparation method
A technology for tiagliptin and intermediates, which is applied in the field of preparation of key intermediates of tiagliptin, and can solve the problems of unsuitability for industrial scale-up production, low total yield, and many steps
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Embodiment 1
[0019] (1) Preparation of compound IIIa:
[0020]
[0021] Compound IV (160 g, 1 mol) was added to 900 ml of tetrahydrofuran, sodium tert-butoxide (115.2 g, 1.2 mol) was slowly added in batches, stirred for 20 minutes, and iodobenzene (243.6 g, 1.2 mol) was added dropwise. The mixture was heated to reflux and stirred for 4 hours, then stirred at room temperature overnight, TLC showed that the reaction was complete, the reaction solution was slowly poured into ice water, ethyl acetate was added, the organic phase was separated, the aqueous phase was extracted again with ethyl acetate, the organic phases were combined, and dried , and concentrated to obtain 205.3 g of compound IIIa with a yield of 87%.
[0022] (2) Preparation of Compound IIa:
[0023]
[0024] Compound N-Boc-piperazine (149.1g, 0.8mol) was added to xylene (1500ml), then sodium hydride (32g, 0.8mol) was added, stirred for 30 minutes, and compound IIIa (188.8g, 0.8mol) was slowly added , the mixture was h...
Embodiment 2
[0029] (1) Preparation of compound IIIb:
[0030]
[0031] Compound IV (160 g, 1 mol) was added to 850 ml of acetonitrile, potassium tert-butoxide (134.6 g, 1.2 mol) was slowly added in batches, stirred for 30 minutes, and iodobenzene (243.6 g, 1.2 mol) was added dropwise. The mixture was heated to reflux and stirred for 4 hours, then stirred at room temperature overnight, TLC showed that the reaction was complete, the reaction solution was slowly poured into ice water, ethyl acetate was added, the organic phase was separated, the aqueous phase was extracted again with ethyl acetate, the organic phases were combined, and dried , and concentrated to obtain 200.5 g of compound IIIb with a yield of 85%.
[0032] (2) Preparation of Compound IIb:
[0033]
[0034] The compound N-Boc-piperazine (149.1g, 0.8mol) was added to N,N-dimethylformamide (1550ml), then sodium tert-butoxide (76.8g, 0.8mol), stirred for 40 minutes, slowly Add compound IIIb (188.8g, 0.8mol), heat the mi...
Embodiment 3
[0039] (1) Preparation of compound IIIc:
[0040]
[0041] Compound IV (160 g, 1 mol) was added to 920 ml of 1,4-dioxane, sodium hydride (48 g, 1.2 mol) was slowly added in batches, stirred for 25 minutes, and iodobenzene (243.6 g, 1.2 mol) was added dropwise. The mixture was heated to reflux and stirred for 4.5 hours, then stirred at room temperature overnight, TLC showed that the reaction was complete, the reaction solution was slowly poured into ice water, ethyl acetate was added, the organic phase was separated, the aqueous phase was extracted with ethyl acetate again, the organic phases were combined, and dried , and concentrated to obtain 195.7 g of compound IIIc with a yield of 83%.
[0042] (2) Preparation of compound IIc:
[0043]
[0044] Compound N-Boc-piperazine (149.1g, 0.8mol) was added to toluene (1700ml), then sodium tert-butoxide (76.8g, 0.8mol) was added, stirred for 40 minutes, and compound IIIc (188.8g, 0.8 mol), the mixture was heated to reflux and...
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