Synthetic method for lapatinib and lapatinib intermediates

A synthesis method and technology of lapatinib, applied in the field of small molecule chemical drug preparation, can solve the problems of difficult post-processing, long reaction route, large environmental pollution, etc., achieve simple and practical synthesis method, shorten synthesis steps, and reduce production cost Effect

Inactive Publication Date: 2015-04-15
ARROMAX PHARMATECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] The existing synthesis technology of lapatinib has fewer sources of raw materials, high cost, long reaction route, complex reaction operation, difficult control of by-products, troublesome product purification and post-treatment, and synthetic routes 2 and 3 require the use of highly toxic Phosphorus oxychloride, difficult post-processing, and large environmental pollution and other disadvantages

Method used

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  • Synthetic method for lapatinib and lapatinib intermediates
  • Synthetic method for lapatinib and lapatinib intermediates
  • Synthetic method for lapatinib and lapatinib intermediates

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Synthetic compound (3)

[0044]

[0045]Dissolve 10g (0.058mol) of compound 1 in 40mL of DMF, add potassium carbonate (8.05g, 0.059mol, 1.3eq), add 8.5g (0.045mol) of compound 2 at 80°C, and react at 95°C for 2 hours , TLC detection, adding 150mL of water, stirring and filtering to obtain 13.5g of bright yellow solid compound 3, yield 83%.

[0046] 1 H-NMR (CDCl 3 ,400MHz, δppm):5.26(s,2H),7.01(d,J=9.2Hz,1H),7.05(t,J=8.4Hz,1H),7.17~7.26(m,2H),7.36~7.40( m, 1H), 8.13 (dd, J=2.8Hz, J=9.2Hz, 1H), 8.33 (d, J=2.4Hz, 1H).

Embodiment 2

[0048] Synthetic compound (4)

[0049]

[0050] Dissolve 1g (3.5mmol) of compound 3 in 17ml of ethanol, add 17ml of acetic acid, add 1.37g (0.024mol, 7eq) of iron powder and a catalytic amount of hydrochloric acid, and react under reflux for 1 hour. After the reaction is complete. Filtered, washed with saturated sodium bicarbonate, evaporated to dryness, and passed through the column to obtain 0.7 g of product compound 4 with a yield of 77%.

[0051] 1 H-NMR (DMSO-d6, 400MHz, δppm): 5.13(s, 2H), 6.84(dd, J=2.4, J=8.8Hz, 1H,), 7.02(d, J=2.4Hz, 1H), 7.16 (t, J=4Hz, 1H), 7.25(s, 1H), 7.31~7.35(m, 1H), 7.42~7.53(m, 2H), 7.8(brs, 2H).

Embodiment 3

[0053] Synthetic compound (6)

[0054]

[0055] Dissolve 10g (0.0169mol) of compound 5 in 100mL of acetic acid, dissolve 14g (0.0172mol) of iodine chloride in 50L of acetic acid, slowly add the above-mentioned iodine chloride acetic acid solution dropwise at room temperature, continue to react for 2h after dropping, and detect by TLC. The reaction liquid was added into ice water, stirred and filtered to obtain a pink solid, which was dried to obtain 14 g of compound 6, with an HPLC purity of 99% and a yield of 70%.

[0056] 1 H-NMR (DMSO-d6, 400MHz, δppm): 6.25(s, 2H), 6.62(d, J=8.8Hz, 1H), 7.54(dd, J=2Hz, J=8.8Hz, 1H), 7.68( d, J=2Hz, 1H).

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Abstract

The invention provides a synthetic method for lapatinib. The method comprises the following steps: (a) in an organic solvent, reacting a compound (6) with a compound (7) in the presence of alkali to obtain a compound (8); (b) in the organic solvent, reacting the compound (8) with a compound (9) in the presence of alkali, and after the reaction is ended, adding a reducing agent for producing a reductive amination reaction to obtain a compound (10); (c) in the organic solvent, reacting the compound (10) with BOC anhydride in the presence of alkali to obtain a compound (11); (d) in the organic solvent, fully reacting the compound (11) with N,N-dimethylformamide dimethyl acetal under the backflow condition, and after the reaction is ended, adding a compound (4) and reacting under the backflow condition to obtain a compound (12); (e) in the organic solvent, producing a deprotection reaction of the compound (12) to obtain lapatinib. The invention further provides two new key intermediates. The method has the characteristics of few steps, high yield and suitability for industrialized production.

Description

technical field [0001] The invention relates to the field of preparation of small molecule chemical medicines, more particularly to a synthesis method of lapatinib. Background technique [0002] Lapatinib is a tyrosine kinase inhibitor developed by GlaxoSmithKline. It is an oral small molecule epidermal growth factor tyrosine kinase inhibitor. It was approved by the FDA in March 2007. For the treatment of advanced breast cancer. It is mainly used in combination with capecitabine (Capecitabine) to treat ErbB-2 overexpression, and has previously received anthracyclines, paclitaxel, and trastuzumab (Herceptin) in the treatment of advanced or metastatic breast cancer. Lapatinib, which can effectively cut off the tyrosine kinase and its downstream signal transmission, and then stop the rapid growth of cancer cells, thereby effectively slowing down the progress of cancer. The combined use of lapatinib and capecitabine in the treatment of breast cancer has a better effect, and is...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/04C07D307/54
CPCC07D405/04C07D307/54
Inventor 洪健刘国斌武进
Owner ARROMAX PHARMATECH
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