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Method for preparing anlotinib hydrochloride

A technology of anlotinib hydrochloride and a synthesis method, applied in the field of medicine and chemical industry, can solve the problems of not greatly improving the yield of the docking step of chloroquinoline and phenol intermediate, high process cost, reducing route efficiency and the like

Active Publication Date: 2019-05-14
HANGZHOU CHEMINSPIRE TECH CO LTD
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  • Abstract
  • Description
  • Claims
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AI Technical Summary

Problems solved by technology

[0012] Although the route of this method has been simplified, the carbonyl protection and deprotection steps of the phenol intermediate in the key docking reaction have reduced the route efficiency; the yield of the docking step of chloroquinoline and the phenol intermediate has not been greatly improved, and the route efficiency is lower Low; the follow-up reaction of the cyclopropylamine fragment to remove the Cbz protecting group still needs to use palladium carbon hydrogenation deprotection, the process cost is high, and an additional process is added to reduce the heavy metal residue in the final product

Method used

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  • Method for preparing anlotinib hydrochloride
  • Method for preparing anlotinib hydrochloride
  • Method for preparing anlotinib hydrochloride

Examples

Experimental program
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Effect test

Embodiment 1

[0041]

[0042] 7-benzyloxy-4-chloro-6-methoxyquinoline 1 (29.98g, 100mmol), 1-(2-fluoro-3-hydroxyl-6-nitrophenyl)propyl- 2-Kone 2 (21.32g, 100mmol) and N-methylpyrrolidone (150mL), were added with DABCO (11.22g, 100mmol), stirred evenly and then heated to 100°C to react overnight. After the reaction, water (600 mL) was added, and a large amount of solid precipitated out, which was filtered, and the crude product was recrystallized from a mixed solvent of isopropanol and water to obtain compound 3 (40.02 g, 84%).

[0043] MS(ESI)m / z=477.2[M+H] + , 1 H NMR (400MHz, DMSO-d6) δ8.57 (d, J = 5.2Hz, 1H), 8.08 (d, J = 8.4Hz, 1H), 7.51-7.59 (m, 4H), 7.49 (s, 1H) ,7.34-7.46(m,3H),6.74(d,J=5.2Hz,1H),5.32(s,2H),4.29(s,2H),3.94(s,3H),2.31(s,3H).

[0044] Here DABCO (triethylenediamine) organic base can be replaced by potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, triethylamine, diisopropylethylamine, pyridine, DMAP, DBU.

Embodiment 2

[0046]

[0047]Add compound 3 (47.65g, 100mmol) to the hydrogenation bottle, add ethyl acetate (238mL) to dissolve, add sodium acetate (16.41g, 200mmol), add acetic anhydride (20.42g, 200mmol) and palladium carbon (5%, 2.14g ), switch the hydrogen gas three times under vacuum, pressurize to 0.15-0.20Mpa and keep the internal temperature at 50-55°C for 20-24 hours. At the end of the reaction, cool the diatomaceous earth to filter off the palladium carbon, concentrate and spin off part of the ethyl acetate, slowly add petroleum ether (238mL) to make a slurry, filter, wash with a small amount of petroleum ether, collect the solid and dry it to obtain compound 4 (35.37g, yield 93%) .

[0048] MS(ESI)m / z=381.2[M+H] + , 1 H NMR (400MHz, CDCl 3 )δ8.55(br,1H),8.49(d,J=5.2Hz,1H),7.80(s,1H),7.75(s,1H),7.07(d,J=8.4Hz,1H),6.92( t,J=8.0Hz,1H),6.44(d,J=5.2Hz,1H),6.36(s,1H),4.01(s,3H),2.47(s,3H),2.41(s,3H).

[0049] Here sodium acetate can be replaced by potassium bicarbonate, sodium...

Embodiment 3

[0051]

[0052] Compound 4 (38.04g, 100mmol) and isopropanol (190mL) were added into a three-necked flask, and potassium carbonate aqueous solution (15%, 95mL) was added, stirred evenly and heated to 40-45°C for 4-6 hours. At the end of the reaction, part of the isopropanol was spun off, and 5% dilute hydrochloric acid was added to adjust the pH to 4-5, beating for 1-2 hours, filtered, and the crude product was recrystallized with a mixed solvent of isopropanol and water to obtain compound 5 (30.79g, 91%) .

[0053] MS (ESI) m / z = 361.2 [M+Na] + , 1 H NMR(400MHz,DMSO-d6)δ11.41(br,1H),10.12(br,1H),8.37(d,J=5.2Hz,1H),7.58(s,1H),7.29(s,1H) ,7.21(d,J=8.8Hz,1H),6.99(t,J=8.0Hz,1H),6.24-6.30(m,2H),3.97(s,3H),2.42(s,3H).

[0054] Here potassium carbonate can be replaced by lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium ethoxide, sodium methoxide, sodium tert-butoxide or potassium tert-butoxide, and isopropanol can be replaced by methanol, ethanol, tetrahydrofur...

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Abstract

The invention discloses a method for preparing anlotinib hydrochloride. The method has the advantages that 7-benzyloxy-4-chlorine-6-methoxyquinoline compounds 1 and 1-(2-fluorine-3-hydroxyl-6-nitrophenyl) propyl-2-ketone compounds 2 are used as starting materials and are directly butted to one another to obtain compounds 3, two technologies are developed from the compounds 3, compounds 5 are synthesized by means of single-step or two-step reaction, nitro reduction and benzyl protective group removal are accomplished in hydrogenation reaction at one step, and accordingly reaction routes can besimplified to a great extent; Boc (butyloxycarbonyl) protective groups are optimally selectively used as protective groups for cyclopropylamine fragments 6, accordingly, palladium catalytic hydrogenation can be omitted in consequent deprotection reaction, and the method is favorable for reducing heavy metal residues in final products; salt forming procedures can be accomplished in one-pot technologies, accordingly, the route efficiency can be greatly improved, and the process cost can be reduced; generation of byproducts can be reduced, accordingly, the method is favorable for improving the purity of the final products, and a synthetic route is shown.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a new method for preparing anlotinib hydrochloride. Background technique [0002] Anlotinib Hydrochloride is a new type of small molecule multi-target tyrosine kinase inhibitor, which can effectively inhibit VEGFR, PDGFR, FGFR, c-Kit, Met and other kinases, and has anti-tumor angiogenesis and Inhibition of tumor growth. The drug is a new class 1.1 anti-tumor drug independently developed by Chia Tai Tianqing Pharmaceutical Group. In 2015, it was granted orphan drug qualification by the US FDA for the treatment of ovarian cancer. Currently, a variety of cancer clinical trials are underway, including non-small cell lung cancer, soft tissue sarcoma, gastric cancer, colorectal cancer, medullary thyroid cancer, differentiated thyroid cancer, and esophageal squamous cell carcinoma, etc., with great market prospects. [0003] Anlotinib hydrochloride chemical na...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12
CPCY02P20/55
Inventor 郑旭春张一平付晨晨
Owner HANGZHOU CHEMINSPIRE TECH CO LTD
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