CN104193689B - Method for synthesizing erlotinib hydrochloride - Google Patents

Abstract

The invention relates to the technical field of drug synthesis, and relates to a new method for synthesizing erlotinib hydrochloride. The steps are as follows: 1) using acetophenone as a starting material, a nitration reaction occurs in a mixed acid to obtain m-nitroacetophenone; 2) a chlorination reaction occurs between m-nitroacetophenone and a chlorination reagent in an organic solvent to obtain 1 -Chloro-1-(3-nitrophenyl)ethylene; 3) 1-chloro-1-(3-nitrophenyl)ethylene is dehydrochlorinated in the presence of an organic solvent and a strong base to obtain m-nitrophenylacetylene; 4 ) m-nitrophenylacetylene obtains m-aminophenylacetylene through nitro selective reduction; the reduction method is reducing agent reduction or catalytic hydrogenation reduction; 5) m-aminophenylacetylene and 4-chloro-6,7-two-(2- Methoxyethoxy) quinazoline is reacted in an organic solvent to obtain erlotinib hydrochloride; the invention has the advantages of cheap and easy-to-obtain raw materials, low production cost, simple and convenient operation, and mild reaction conditions, and is suitable for industrial production.

Description

A kind of synthetic method of erlotinib hydrochloride

technical field

The invention relates to the technical field of drug synthesis, in particular to a method for synthesizing erlotinib hydrochloride.

Background technique

Erlotinib Hydrochloride (Erlotinib Hydrochloride), trade name Tarceva, is a kind of epidermal growth factor tyrosine kinase inhibitor jointly developed by Roche, Océ Biopharmaceutical Company and Genentech Pharmaceutical Company. Treatment of locally advanced and metastatic non-small cell lung cancer. Its chemical structure is shown in the following formula:

The synthesis of erlotinib hydrochloride is mainly obtained through the reaction of 4-chloro-6,7-bis-(2-methoxyethoxy)quinazoline and m-aminophenylacetylene. Patents US5747498, WO20070606091, CN101463013A, etc. all relate to the synthesis method of 4-chloro-6,7-bis-(2-methoxyethoxy)quinazoline, but as another key intermediate of erlotinib hydrochloride , there are relatively few reports on the synthesis method of m-aminophenylacetylene, which is currently mainly prepared by palladium-catalyzed coupling:

Patents EP2433931, US5902902, CN98808385, etc. have all reported the coupling reaction of m-halogenated nitrobenzene or m-halogenated aminobenzene with a protected alkyne under palladium catalysis to generate the corresponding benzynol intermediate, which is then deprotected and Reduction method for preparing m-aminophenylacetylene. But they all need to use expensive palladium catalyst and protection reagent, make the production cost of this method on the high side, not suitable for industrialized production.

Contents of the invention

For overcoming the deficiency of background technology, the object of the present invention is to provide a kind of synthetic method of Erlotinib hydrochloride. Compared with the existing synthetic methods, this route has the advantages of low production cost, simple operation, suitable for industrial production and the like.

A kind of synthetic method of erlotinib hydrochloride, this synthetic method comprises the steps:

1) Using acetophenone as a starting material, a nitration reaction occurs in a mixed acid to obtain m-nitroacetophenone; the molar ratio of acetophenone to nitrating reagent is 1:1 to 7; the reaction temperature is -40 to 50°C; The mixed acid is selected from the group consisting of concentrated nitric acid and concentrated sulfuric acid, fuming nitric acid and concentrated sulfuric acid, concentrated nitric acid and acetic acid, fuming nitric acid and acetic acid; the nitrating agent is concentrated nitric acid or fuming nitric acid in the mixed acid;

2) Chlorination reaction between m-nitroacetophenone and chlorination reagent in an organic solvent to obtain 1-chloro-1-(3-nitrophenyl)ethylene, the reaction temperature is 25～150°C; m-nitroacetophenone The molar ratio of ketone to chlorination reagent is 1:0.5～10;

3) 1-chloro-1-(3-nitrophenyl)ethylene is dehydrochlorinated in the presence of an organic solvent and a strong base to obtain m-nitrophenylacetylene at a reaction temperature of 20 to 180°C; 1-chloro-1-(3 -The molar ratio of nitrophenyl) ethylene and strong base is 1:1～10;

4) m-nitrophenylacetylene is obtained m-aminophenylacetylene by selective reduction of nitro groups; the reduction method is reducing agent reduction or catalytic hydrogenation reduction; when the reduction method is reducing agent reduction, the molar ratio of m-nitrophenylacetylene to reducing agent 1:1-10; when the reduction method is catalytic hydrogenation reduction, the hydrogen pressure is 0.1-5MPa, and the catalyst dosage is 0.1%-50% of m-nitrophenylacetylene;

5) m-aminophenylacetylene and 4-chloro-6,7-bis-(2-methoxyethoxy)quinazoline are reacted in an organic solvent to obtain erlotinib hydrochloride, and the reaction temperature is 20 to 100°C;

The synthetic route formula of erlotinib hydrochloride is as follows:

The chlorination reagent is selected from one or a mixture of two or more selected from phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, thionyl chloride, and oxalyl chloride.

In step 2), the organic solvent is selected from one or more of toluene, xylene, n-heptane, n-hexane, dimethyl sulfoxide, acetonitrile, 1,2-dichloroethane, chloroform, and dichloromethane Mixing; adding an acid-binding agent during the reaction, one or more selected from triethylamine, trimethylamine, pyridine, piperidine, p-dimethylaminopyridine, potassium carbonate, sodium carbonate, potassium bicarbonate, and sodium bicarbonate mix.

In step 3), the strong base is selected from one or more mixtures of potassium hydroxide, sodium hydroxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide, sodium hydride, and potassium hydride; the organic solvent is selected from Isoamyl alcohol, tert-amyl alcohol, tert-butanol, isopropanol, ethanol, methanol, dichloromethane, toluene, dioxane, dimethylsulfoxide, N,N-dimethylformamide, N,N- One or more than two kinds of dimethylacetamide mixed.

In step 4), the reducing agent is one or more mixtures of iron powder, zinc powder, hydrazine hydrate, sodium sulfide, sodium dithionite; the catalyst for catalytic hydrogenation is Rany-Ni, Pd/C, One or more of Pt/C and Ru/C are mixed.

In step 5), the organic solvent is selected from methanol, ethanol, isopropanol, N,N-dimethylformamide, N,N-dimethylacetamide, or a mixture of two or more.

The beneficial effects of the invention are: the synthesis method of the invention has the advantages of cheap and easy-to-obtain raw materials, low production cost, simple operation, mild reaction conditions, etc., and is suitable for industrial production.

Description of drawings

Accompanying drawing is the proton nuclear magnetic resonance spectrogram (1H NMR) of erlotinib hydrochloride.

detailed description

The present invention will be further elaborated below through specific examples, so that those skilled in the art can understand the content of the present invention and implement it accordingly, and the protection scope of the present invention cannot be limited thereby.

The synthesis of embodiment 1 m-nitroacetophenone

Add 400ml of concentrated sulfuric acid to a 1000ml reaction bottle, add 180.0g (1.5mol) of acetophenone dropwise, mix 200ml of concentrated sulfuric acid with 150ml of concentrated nitric acid and add it dropwise into the system. During the whole process, the temperature of the system should not exceed -5°C. Afterwards, the reaction was continued for 20 min, and the reaction was detected by TLC. Slowly pour the system into a large amount of ice water while stirring, filter with suction, and wash the filter cake with saturated sodium carbonate to remove residual acid to obtain a crude product. The crude product was recrystallized from ethanol to obtain 220.1 g of light yellow needle-like crystals, with a yield of 88.9% and a content of ≥99%.

NMR data: ¹ H NMR (400MHz, CDCl ₃ ) δ8.78(s, 1H), 8.47–8.40(m, 1H), 8.30(d, J＝7.8Hz, 1H), 7.69(t, J＝8.0Hz ,1H),2.70(s,3H)

The synthesis of embodiment 2 m-nitroacetophenone

Add 400ml of concentrated sulfuric acid to a 1000ml reaction bottle, add 180.0g (1.5mol) of acetophenone dropwise, mix 120ml of concentrated sulfuric acid with 80ml of fuming nitric acid and add it dropwise into the system. After completion, the reaction was continued for 10 min, and the reaction was detected by TLC. Slowly pour the system into a large amount of ice water while stirring, filter with suction, and wash the filter cake with saturated sodium carbonate to remove residual acid to obtain a crude product. The crude product was recrystallized from ethanol to obtain 223.5 g of light yellow needle-like crystals, with a yield of 90.3% and a content of ≥99%.

Example 3 Synthesis of 1-chloro-1-(3-nitrophenyl)ethene

Add 132.0g (0.8mol) of m-nitroacetophenone, 450ml of toluene, and 31.6g (0.4mol) of pyridine into a 1000ml reaction flask, stir to dissolve the raw materials, and slowly add 146.9g (0.96mol) of phosphorus oxychloride dropwise at room temperature , after the dropwise addition was completed, the temperature was raised to 115°C for reaction, and the reaction progress was detected by TLC. After the reaction was finished, it was cooled, and 100ml of water was added to the system. The organic layer was washed with saturated sodium carbonate and saturated brine, dried and concentrated to obtain a crude product, which was distilled under reduced pressure to obtain 133.2 g of a light yellow product with a yield of 91.0% and a content of ≥97%.

NMR data: ¹ H NMR (400MHz, CDCl ₃ ) δ8.48(s, 1H), 8.21(d, J＝8.4Hz, 1H), 7.95(d, J＝7.8Hz, 1H), 7.56(t, J =8.0Hz,1H),5.93(d,J=2.1Hz,1H),5.70(d,J=2.0Hz,1H)

Example 4 Synthesis of 1-chloro-1-(3-nitrophenyl)ethene

Add 132.0g (0.8mol) m-nitroacetophenone, 450ml toluene, and 40.4g (0.4mol) triethylamine into a 1000ml reaction flask, stir to dissolve the raw materials, and slowly add 244.8g (1.6mol) trichloro Oxyphosphorus, after the dropwise addition, the temperature was raised to 95°C for reaction, and the reaction progress was detected by TLC. After the reaction was finished, it was cooled, and 100ml of water was added to the system. The organic layer was washed with saturated sodium carbonate and saturated brine, dried and concentrated to obtain a crude product, which was distilled under reduced pressure to obtain 126.7 g of a light yellow product with a yield of 86.5% and a content of ≥97%.

The synthesis of embodiment 5 m-nitrophenylacetylene

Add 54.9g (0.3mol) of 1-chloro-1-(3-nitrophenyl)ethylene and 300ml of ethanol into a 500ml reaction flask, add 30.2g (0.54mol) of potassium hydroxide, and heat to reflux for 4h. After the reaction, the system was poured into aqueous ammonium chloride solution, extracted with dichloromethane, the organic layer was washed with water, washed with saturated brine, dried and concentrated to obtain a crude product, and distilled under reduced pressure to obtain 30.6 g of a light yellow product with a yield of 69.4%. ≥99%.

NMR data: ¹ H NMR (400MHz, CDCl ₃ ) δ8.38–8.30(m,1H),8.24–8.19(m,1H),7.83–7.76(m,1H),7.53(t,J＝8.0Hz, 1H),3.23(s,1H)

The synthesis of embodiment 6 m-nitrophenylacetylene

Add 54.9g (0.3mol) of 1-chloro-1-(3-nitrophenyl)ethylene and 300ml of tert-butanol into a 500ml reaction flask, add 50.4g (0.45mol) of potassium tert-butoxide, and heat at 45°C for 5h . After the reaction, the system was poured into an aqueous solution of ammonium chloride, extracted with dichloromethane, the organic layer was washed with water, washed with saturated brine, dried and concentrated to obtain a crude product, and distilled under reduced pressure to obtain 32.3 g of a light yellow product with a yield of 73.2%. ≥99%.

The synthesis of embodiment 7 m-nitrophenylacetylene

Add 54.9g (0.3mol) of 1-chloro-1-(3-nitrophenyl)ethylene and 300ml of tert-butanol into a 500ml reaction flask, add 60.0g (1.5mol) of sodium hydroxide, and heat to reflux for 10h. After the reaction, the system was poured into an aqueous solution of ammonium chloride, extracted with dichloromethane, the organic layer was washed with water, washed with saturated brine, dried and concentrated to obtain a crude product, and distilled under reduced pressure to obtain 31.1 g of a light yellow product with a yield of 70.5%. ≥99%.

The synthesis of embodiment 8 m-nitrophenylacetylene

Add 54.9g (0.3mol) of 1-chloro-1-(3-nitrophenyl)ethylene and 270ml of DMF into a 500ml reaction flask, add 8.6g (0.36mol) of sodium hydride, and heat at 55°C for 5h. After the reaction, the system was poured into aqueous ammonium chloride solution, extracted with dichloromethane, the organic layer was washed with water and saturated brine, dried and concentrated to obtain a crude product, and distilled under reduced pressure to obtain 34.5 g of a light yellow product with a yield of 78.3%. ≥99%.

The synthesis of embodiment 9 m-aminophenylacetylene

Add 21.8g (0.39mol) of reduced iron powder, 2.8g (0.052mol) of NH ₄ Cl, and 75ml of water into a 250ml reaction flask, raise the temperature to 85°C, and dissolve 19.1g (0.13mol) of m-nitrophenylacetylene in 50ml of ethanol Slowly added dropwise to the system, and reacted at 85°C for 3h. After the reaction, suction filter while hot, wash the filter cake with ethanol until no product is attached, concentrate the filtrate under reduced pressure, extract the residue with dichloromethane, wash the organic layer with water, wash with saturated brine, dry and concentrate to obtain a yellow crude product, and distill under reduced pressure 16.1 g of a colorless and transparent product was obtained with a yield of 92.8% and a content of ≥99%.

NMR data: ¹ H NMR (400MHz, CDCl ₃ ) δ7.10(t, J＝7.8Hz, 1H), 6.90(d, J＝7.6Hz, 1H), 6.84–6.77(m, 1H), 6.70–6.63 (m,1H),3.67(brs,2H),3.01(s,1H)

The synthesis of embodiment 10 m-aminophenylacetylene

Add 93.6g (0.39mol) of sodium sulfide nonahydrate and 150ml of water into a 500ml reaction flask, raise the temperature to 85°C, dissolve 19.1g (0.13mol) of m-nitrophenylacetylene in 50ml of methanol, and slowly drop it into the system, Reaction at 85°C for 5h. After the reaction, cooled, extracted with dichloromethane, washed the organic layer with water, washed with saturated brine, dried and concentrated to obtain a yellow crude product, which was distilled under reduced pressure to obtain 11.1 g of a colorless and transparent product with a yield of 73.0% and a content of ≥99%.

Embodiment 11 Synthesis of Erlotinib Hydrochloride

12.5g (0.040mol) of 4-chloro-6,7-bis-(2-methoxyethoxy)quinazoline was dissolved in 80ml of ethanol, and then 5.7g (0.049mol) of iso-aminophenylacetylene was added dropwise. 20ml of propanol solution, heated to reflux for 5h, TLC detected the end of the reaction, cooled, suction filtered, washed the filter cake 3 times with ethyl acetate, and dried to obtain 12.8g of erlotinib, with a yield of 81.3% and a content of ≥99%.

NMR data: ¹ H NMR (400MHz, MeOD) δ8.62(s,1H),7.95(s,1H),7.87(s,1H),7.73(d,J＝8.0Hz,1H),7.48–7.33( m, 2H), 7.24 (s, 1H), 4.40–4.32 (m, 4H), 3.89–3.83 (m, 4H), 3.56 (s, 1H), 3.46 (d, J=4.4Hz, 6H).

Claims (3)

1. a kind of synthetic method of erlotinib Hydrochloride is it is characterised in that following steps：

1) with acetophenone as initiation material, nitration reaction is occurred to obtain m-nitroacetophenone in nitration mixture；Acetophenone and nitrification examination The mol ratio of agent is 1:1～7；Reaction temperature is -40～50 DEG C；Described nitration mixture be selected from red fuming nitric acid (RFNA) and the concentrated sulfuric acid, fuming nitric aicd with In the concentrated sulfuric acid, red fuming nitric acid (RFNA) and acetic acid, fuming nitric aicd and acetic acid one group；Nitrating agent is red fuming nitric acid (RFNA) or fuming nitric aicd in nitration mixture；

2) m-nitroacetophenone and chlorination reagent occur chlorination reaction to obtain the chloro- 1- of 1- (3- nitrobenzophenone) second in organic solvent Alkene, reaction temperature is 25～150 DEG C；M-nitroacetophenone is 1 with the mol ratio of chlorination reagent:0.5～10；

Described chlorination reagent is selected from one of POCl3, phosphorus pentachloride, phosphorus trichloride, thionyl chloride, oxalyl chloride or two kinds Mixed above；Described machine solvent is selected from toluene, dimethylbenzene, normal heptane, n-hexane, dimethyl sulfoxide, acetonitrile, 1,2- bis- chloroethene One of alkane, chloroform, dichloromethane or two or more mixing；Course of reaction add acid binding agent, selected from triethylamine, trimethylamine, Pyridine, piperidines, to one of dimethylamino naphthyridine, potassium carbonate, sodium carbonate, saleratus, sodium acid carbonate or two or more mixed Close；

3) the chloro- 1- of 1- (3- nitrobenzophenone) ethene dehydrochlorination in the presence of organic solvent and highly basic obtains m-nitrobenzene acetylene, Reaction temperature is 20～180 DEG C；The chloro- 1- of 1- (3- nitrobenzophenone) ethene is 1 with the mol ratio of highly basic:1～10；

4) m-nitrobenzene acetylene obtains 3-aminophenylacetylene by nitro selective reduction；Method of reducing reduces for reducing agent, Nitrobenzene acetylene is 1 with the mol ratio of reducing agent:1～10；Described reducing agent is iron powder, zinc powder, hydrazine hydrate, vulcanized sodium, company One of sodium sulfite or two or more mixing；

5) 3-aminophenylacetylene and the chloro- 6,7- of 4- bis--(2- methoxy ethoxy) quinazoline react in organic solvent and obtain salt Sour Tarceva, reaction temperature is 20～100 DEG C；

The synthetic route of erlotinib Hydrochloride is as follows：

2. synthetic method according to claim 1 is it is characterised in that step 3) in, described highly basic be selected from potassium hydroxide, One of NaOH, potassium tert-butoxide, sodium methoxide, caustic alcohol, sodium hydride, hydrofining or two or more mixing；Organic solvent Selected from isoamyl alcohol, tert-pentyl alcohol, the tert-butyl alcohol, isopropanol, ethanol, methyl alcohol, dichloromethane, toluene, dioxane, dimethyl sulfoxide, N, One of dinethylformamide, DMAC N,N' dimethyl acetamide or two or more mixing.

3. synthetic method according to claim 1 and 2 is it is characterised in that step 5) in, organic solvent is selected from methyl alcohol, second One of alcohol, isopropanol, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide or two or more mixing.