CN102146075A - Preparation method of quinazoline compound - Google Patents

Abstract

The invention provides a method for preparing a quinazoline compound, in the method, the compound in a form of salt is directly used as a raw material, the reaction step is shortened, the number of used agents is decreased and the cost is lowered.

Description

A kind of preparation method of quinazoline compound

technical field

The invention relates to the fields of organic chemistry and medicinal chemistry, in particular to a preparation method of a quinazoline compound, namely lapatinib.

Background technique

A quinazoline compound, specifically, U.S. Patent US6713485 (name: Heterocyclic compounds (Heterocyclic compounds), patentee: Smith Kline Beecham Corporation (SmithKline Beecham Corporation), date of publication: March 2004 30th) a kind of medicinal compound that can be used for human body of report, name is lapatinib, and structure is as shown in formula (I):

Its English name is Lapatinib, and its chemical name is: N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[5[[[2-(methylsulfonyl) Ethyl]amino]methyl]-2-furyl]-4-quinazolinamine (N-[3-Chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[5[[[2 -(methylsulfonyl)ethyl]amino]methyl]-2-furanyl]-4-quinazolinamine), CAS number is 231277-92-2, molecular formula: C29H26ClFN4O4S.

It is a new anti-cancer drug, and its p-toluenesulfonate monohydrate was approved for marketing by the US Food and Drug Administration (FDA) on March 13, 2007. The drug is a kinase inhibitor, which mainly deprives tumor cells of biological signals needed for growth through multiple pathways to exert anti-tumor effects. It is used in combination with another anticancer drug, capecitabine, to treat advanced metastatic HER2-positive breast cancer. Compared with trastuzumab (trastuzumab), a macromolecular protein monoclonal antibody, lapatinib is a small molecule compound that can enter cells to prevent the function of certain proteins, and can be used to treat trastuzumab Breast cancer that doesn't work.

The method for preparing lapatinib is described in the patent US6713485, and it is to use following formula (1) compound (5-(4-(4-(3-fluorobenzyloxy)-3-chloroanilino)-6- Quinolinyl)-2-furylcarbaldehyde) and formula (2) compound (thiamphenicol ethylamine) as raw materials, first generate Schiff base, then in the presence of reducing reagent triacetoxy sodium borohydride, the reduction of C =N bond makes target product. The specific route is as follows:

Wherein compound (1) and compound (2) are both monomeric compounds. Their synthesis methods are as follows:

1. The synthetic route of compound (1) is:

Note: where R1, R2 represent alkyl

After removing the aldehyde protecting group with an acid (such as hydrochloric acid), the hydrochloride compound (II) is obtained; then adding a base (such as sodium hydroxide, sodium carbonate or potassium carbonate, etc.) for neutralization reaction to obtain the compound (1) .

2. The synthetic route of compound (2) is:

While removing the amino protecting group (tert-butoxycarbonyl) with an acid (such as p-toluenesulfonic acid), the compound (III) is obtained; then the compound (III) is neutralized by adding a base to obtain the monomeric compound (2).

Another US patent US7157466 (name: Quinazoline ditosylate salt compounds), patentee: SmithKline Beecham (Cork) Limited, publication date: 2007 On January 2, 2010) announced a preparation method of lapatinib, the difference between it and the previous method is that the compound (1), one of the raw materials, is replaced by its p-toluenesulfonate form (that is, the following formula (4) shown compound), and compound (4) is obtained by hydrochloric acid 5-(4-(4-(3-fluorobenzyloxy)-3-chloroanilino)-6-quinolyl)-2-furan Formaldehyde (that is, the compound of formula (II)) is obtained by conversion, and the process is relatively cumbersome. The specific route is as follows:

Wherein, THF represents tetrahydrofuran, and IPA represents isopropanol.

The route announced by patent WO2008024439 (publication date: February 28, 2008) is as follows:

In this route, monomeric compound (1) and thiamphenicol ethylamine monomer generate Schiffer's base, which is also reduced with sodium triacetoxyborohydride, and Boc is used to protect the amine group. The main purpose should be to ensure that the amine group is NH instead of ND; finally de-Boc with hydrochloric acid, and use p-toluenesulfonic acid to form a salt, the process is relatively cumbersome.

It can thus be concluded that the prior art all uses monomeric compound (1) (or its p-toluenesulfonate compound (4)) and monomeric compound (2) for the preparation of quinazoline compound lapatinib. As a raw material, instead of using a compound that is in the form of a salt for the raw material to react; the monomer (or its p-toluenesulfonate) needs to be converted with a compound in other salt form, which undoubtedly increases the reaction step by one step, making the cost increase and lead to a decrease in yield. Moreover, thiamphenicol ethylamine monomer itself is a liquid, even if it is free, it is inconvenient to handle, but if it forms a salt, it is much easier to handle. Moreover, in the existing methods, sodium triacetoxyborohydride is used as the reducing agent, which is not only expensive, but also has a rather low atom utilization rate and a low yield.

Contents of the invention

The object of the present invention is exactly for above-mentioned problem and deficiency, provides a kind of preparation method of quinazoline compound, more precisely, provides a kind of method for preparing lapatinib, and this method directly uses the compound of salt form as raw material, reaction steps Shorter, less reagents used, lower costs.

In order to achieve the above object, the technical scheme adopted in the present invention is as follows:

A kind of preparation method of quinazoline compound is characterized in that, reaction scheme is as follows:

Wherein, HX is inorganic acid or organic acid; inorganic acid can be hydrohalic acid or sulfuric acid etc.; organic acid can be p-toluenesulfonic acid, fumaric acid, tartaric acid or acetic acid etc.; preferably hydrochloric acid, acetic acid.

HY is hydrochloric acid or p-toluenesulfonic acid (TsOH), etc.; p-toluenesulfonic acid is preferred.

The present invention uses 5-(4-(4-(3-fluorobenzyloxy)-3-chloroanilino)-6-quinolyl)-2-furan carboxylate (compound (II)) and methylsulfonyl Ethanolate (compound (III)) is used as a raw material, and the quinazoline compound lapatinib (compound (I)) is obtained by reaction.

Further, in the reaction process, compound (II) directly reacts with compound (III) to generate Schiff's base, that is, compound (3) shown in the following structure:

The Schiffer base is reduced with metal hydroxide to obtain the lapatinib (compound I).

Further, the metal hydroxide may be selected from: sodium borohydride (NaBH ₄ ) or potassium borohydride (KBH ₄ ).

Furthermore, Lewis acid can be added in the reaction process to improve the reduction ability, so that the reduction effect is better, that is, the combination of metal hydroxide and Lewis acid can be selected from: NaBH ₄ /LiBr, NaBH ₄ /LiCl, KBH ₄ /LiBr, NaBH ₄ /CH ₃ COOH or NaBH ₄ /I ₂ etc.; most preferably NaBH ₄ /LiBr.

Further, during the reaction, the solvent used is an ether solvent, preferably tetrahydrofuran (THF).

Further, the reaction temperature is controlled at 10-70°C, preferably 20-30°C.

The beneficial effects of the present invention are as follows:

(1) process condition is reasonable, directly reacts with salt form compound and generates Schiff's base, does not need to adjust compound (II) as p-toluenesulfonate as the method described in patent US7157466, also does not use compound (II) as the route announced by patent US6713485 ) and compound (III) are free into monomers, which reduces one-step reaction process than the patented two methods.

(2) Using Lewis acid to improve the reducing activity of sodium borohydride instead of sodium triacetoxyborohydride for reduction has low cost and high atom economy. Moreover, the stability of sodium borohydride itself is far better than that of sodium triacetoxy borohydride, unlike sodium triacetoxy borohydride, which is easy to decompose and deteriorate due to contact with moisture in the air during storage. Moreover, thiamphenicol directly participates in the reaction with a salt instead of a free base, which is also simpler than the patented method.

In summary, the present invention directly uses salt-form compounds as raw materials, shortens the reaction steps, and reduces the reagents used; moreover, sodium borohydride is used instead of expensive sodium triacetoxyborohydride, so that the materials used are cheap and easy to obtain, and the cost is reduced , high atom economy, avoids the inconvenience of storage and transportation of sodium triacetoxyborohydride, and has great advantages in industrial production.

Detailed ways

Embodiment 1 The preparation of lapatinib

Put 5-(4-(4-(3-fluorobenzyloxy)-3-chloroanilino)-6-quinolyl)-2-furancarbaldehyde hydrochloride (10g) into the four-necked bottle, and methylsulfonyl Ethylamine p-toluenesulfonate (9g), THF (200ml), acetic acid (5g), diisopropylethylamine (10g), heat at 20-25°C for 30min. Then NaBH ₄ (1.8g) and LiBr (0.1g) were added slowly, and the temperature was controlled at 20-30°C for 10h. After the reaction is over, add 10ml of water, drop the temperature to 20-30°C, drop in sodium hydroxide solution to stop the reaction, and stir at room temperature. Stand to separate the layers, extract, combine the organic phases, and wash, and evaporate to dry THF under reduced pressure to obtain lapatinib (10 g, yield 87.8%, content 99.1%).

Embodiment 2 The preparation of lapatinib

Put 5-(4-(4-(3-fluorobenzyloxy)-3-chloroanilino)-6-quinolyl)-2-furancarbaldehyde hydrochloride (10g) into the four-necked bottle, and methylsulfonyl Ethylamine hydrochloride (4.2g), THF (200ml), acetic acid (5g), diisopropylethylamine (10g), keep warm at 30-35°C for 30min. Then NaBH ₄ (1.8g) was added slowly, and LiBr (0.1g) was heated to 50°C for 10h. After the reaction is over, add 10ml of water, drop the temperature to 20-30°C, drop in sodium hydroxide solution to stop the reaction, and stir at room temperature. The layers were separated, extracted, the organic phases were combined, washed, and evaporated to THF under reduced pressure to obtain lapatinib (9.5 g, yield 83.5%, content 99.2%).

Embodiment 3 The preparation of lapatinib

Put 5-(4-(4-(3-fluorobenzyloxy)-3-chloroanilino)-6-quinolyl)-2-furancarbaldehyde hydrochloride (10g) into the four-necked bottle, and methylsulfonyl Ethylamine p-toluenesulfonate (9g), THF (200ml), acetic acid (5g), diisopropylethylamine (10g), heat at 20-25°C for 30min. Then NaBH ₄ (1.8 g) was added slowly, and the temperature was controlled at 20-30° C. for 10 h. After the reaction is over, add 10ml of water, drop the temperature to 20-30°C, drop in sodium hydroxide solution to stop the reaction, and stir at room temperature. Stand to separate the layers, extract, combine the organic phases, and wash, and evaporate to dry THF under reduced pressure to obtain lapatinib (7.5 g, yield 65.9%, content 79.5%).

Embodiment 4 The preparation of lapatinib

Replace 5-(4-( 4-(3-fluorobenzyloxy)-3-chloroanilino)-6-quinolyl)-2-furancarbaldehyde hydrochloride, the operation method is the same as in Example 1, and lapatinib (8.5g, obtained rate 81.2%, content 85.2%).

Embodiment 5 The preparation of lapatinib

An equimolar amount of thiamphenicol ethylamine hydrochloride was used to replace thiamphenicol ethylamine p-toluenesulfonate, and the operation method was the same as in Example 1 to obtain lapatinib (8 g, yield 78.5%, content 89.2%).

Preparation of thiamphenicol ethylamine p-toluenesulfonate (compound III)

Embodiment 6 The preparation of methylmercaptoethylamine (compound 7)

Put 40g of chlorethylamine hydrochloride and 160g of sodium methyl mercaptide into a 500ml four-necked bottle, stir and react at 70°C for 1 hour, and cool. The product was directly used in the next reaction without isolation.

Example 7 The preparation of methylmercaptoethylamine-Boc (compound 8)

(Boc)2O (75g) was added dropwise to the reaction solution of the previous example, and a large amount of oily matter was generated after the dropwise completion. Continue to keep warm for about 2h. After the reaction was over, the layers were left to stand, and the upper organic layer was taken. The lower aqueous layer was extracted, the organic layers were combined, beaten, and the phases were separated. The upper organic layer was taken and evaporated under reduced pressure to obtain a pale yellow oil, about 61.3 g, with a two-step yield of 93.8%.

Example 8 Preparation of thiamphenicol ethylamine-BOC (compound 9)

Put 20g of methylmercaptoethylamine-BOC into a 250ml four-necked bottle, and cool to 20°C. Add 40g of peracetic acid dropwise, and keep warm at room temperature for 12h after dropping. Add sodium bisulfite aqueous solution dropwise, and the starch potassium iodide test paper does not develop color. Control the temperature at 10-20°C and add dropwise 25% sodium hydroxide aqueous solution to adjust the pH to 8-9. Cool to 0-5°C and keep stirring, filter with suction, rinse until pH=7-8, filter with suction, and dry the filter cake in vacuum to obtain about 10.5 g of the product with a yield of 90.9%.

Embodiment 9 Preparation of thiamphenicol ethylamine-BOC (compound 9)

Put 20g of methylmercaptoethylamine-BOC into a 250ml four-necked bottle, and cool to 20°C. Add 40g of glacial acetic acid, 2g of concentrated sulfuric acid, and then dropwise add 60g of hydrogen peroxide, and keep warm at room temperature for 12h after dropping. Add sodium bisulfite aqueous solution dropwise, and the starch potassium iodide test paper does not develop color. Control the temperature at 10-20°C and add dropwise 25% sodium hydroxide aqueous solution to adjust the pH to 8-9. Cool to 0-5°C and keep stirring, filter with suction, rinse until pH=7-8, filter with suction, and dry the filter cake in vacuum to obtain about 10.2 g of the product with a yield of 87.4%.

Example 10 Preparation of thiamphenicol ethylamine p-toluenesulfonate (compound III)

Put 40ml of absolute ethanol into a 100ml four-necked bottle, and put in 10g of thiamphenicol ethylamine-Boc, and then put in 8.5g of p-toluenesulfonic acid, heat to reflux for 1h, and cool to room temperature. Suction filtration, rinse the filter cake, and dry at 40°C. About 12.0 g of the product was obtained, and the yield was 95%.

Claims (1)

1. preparation method suc as formula the quinazoline compound shown in (I) comprises that the phosphate compounds of using suc as formula shown in (II) and the formula (III) prepares:

Wherein, HX is mineral acid or organic acid; Mineral acid is selected from haloid acid or sulfuric acid; Organic acid is selected from tosic acid, fumaric acid, tartrate or acetic acid; HY is selected from hydrochloric acid or tosic acid.