WO2015023170A1

WO2015023170A1 - A method for preparation of erlotinib

Info

Publication number: WO2015023170A1
Application number: PCT/LV2014/000007
Authority: WO
Inventors: Ivars Kalvins; Jurijs PONOMARJOVS; Larisa VARACEVA; Aleksandrs Cernobrovijs; Antons Lebedevs; Dmitrijs CERNAKS
Original assignee: Latvian Institute Of Organic Synthesis
Priority date: 2013-08-14
Filing date: 2014-08-12
Publication date: 2015-02-19
Also published as: LV14953B; LV14953A; GB2532620A; GB201522673D0

Abstract

A method for the preparation N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)- quinazolin-4-amine (erlotinib) from 6,7-bis(2-methoxyethoxy)quinazolin-4(3H)-one and 3-aminophenylacetylene in the presence of titanium(IV) chloride and anisole is reported.

Description

A METHOD FOR PREPARATION OF ERLOTINIB

TECHNICAL FIELD

0001 The present invention relates to a method for the preparation of

pharmaceutically active compounds.

0002 More specifically, the present invention relates to a method for the preparation of anti-cancer drug erlotinib.

BACKGROUND ART

0003 Erlotinib is the compound of formula (I) that used to treat non-small cell lung cancer, pancreatic cancer, and several other types of cancer

In this patent two final steps of the synthesis are claimed: transformation of quinazolone (VI) to 4-chloroquinazoline derivative (VII) (for example, by treatment with CCl4-PPh₃ mixture), and reaction of the obtained compound (VII) with 3- aminophenylacetylene, leading to the desired product (I).

0005 4-Chloroquinazoline (VII) may be obtained from the lactam (VI) using activating reagents such as POCl₃ [2, 3, 26-29], SOCl₂ [4-10, 30-32] or oxalyl chloride [11, 12, 28]. The reaction of the lactam (VI) with these reagents usually is carried out at elevated temperatures (45-110°C) and in non-polar solvents (toluene, CH₂C1₂, CHC1₃) or without solvent; in the case of oxalylchloride or SOCl₂, a catalytic amount of DMF is usually added. 4-Chloroquinazoline (VII) reacts with 3- aminophenylacetylene, forming erlotinib (I). This reaction proceeds in different solvents (toluene, MeCN, /-PrOH, CHCI3) at room temperature or, more often, at elevated temperature (60-110°C), in the presence of a base (for example, pyridine), or without it [6-9, 11-22, 26, 27, 30, 33].

0006 In some cases this reaction is carried out in the presence of an acid, thus obtaining the corresponding erlotinib's salt [23].

0007 The authors of the patent [13] provided another method for the activation of the carbonyl group of the lactam (VI), involving preparation of intermediate (VIII) as methoxy analog of chloroquinazoline (VII). However, in this method the methoxy derivative (VIII) was produced via the same chloro derivative (VII), obtained in situ by treating the lactam (VI) with POCI3 following subsequent conversion to the compound (VIII) in treatment with methanol. The main disadvantage of this method is the use of pyrophoric organometallic base (e. g., sec-butyllitium) [13] at the final step, that limites the use of this method in the large-scale production

VIII IX

0008 The authors of paper [33] reported the use of methylsulfanylquinazoline (IX) as activated intermediate in the synthesis of erlotinib (I). The compound (IX) is obtained through subsequent reatment of the lactam (VI) with P₂S₅ in pyridine and with methanol in the presence of sodium hydroxyde. The compound (IX) reacts with 3- aminophenylacetylene easier than the methoxy derivative (VIII) - in this case erlotinib (I) is obtained by the reflux of the reaction mixture in i^'-PrOH for 15 hours [13, 34]. Thus, the reactivity of the compound (IX) is similar to that of chloroquinazoline (VII). However, this method has several disadvantages, such as additional number of synthetic steps as well as the necessarity to work with toxic sulfur-containing compounds.

0009 Only few patents [13, 24, 25] describe reaction of the lactam (VI) with POCl₃ and further reaction with 3-aminophenylacetylene without isolation of the intermediate chloroquinazoline (VII). In the paper [30] authors reported a one-pot transformation of the lactam (VI) to erlotinib (I) employing SOCl₂ as activating agent.

SUMMARY OF INVENTION

TECHNICAL PROBLEM

0010 Most of the erlotinib syntheses involve isolation and purification of 4- chloroquinazoline intermediate (VII), that increases number of technological steps. Chloro derivative (VII) is the potential irritant and the toxic compound, as it is stated for unsubstituted 4-chloroquinazoline (VI) [35]. In some reports volatile toxic reagents (e. g., SOCl₂, P₂Ss) are used. To create environment-friendly technology for the erlotinib production, it is necessary to find a new method to convert lactam (VI) to erlotinib (I) without the use of the toxic reagents and without isolation of the 4- chloroquinazoline intermediate (VII).

SOLUTION TO PROBLEM

0011 We unexpectedly found, that the lactam (VI) can be converted to erlotinib (I) by reaction with 3-aminophenylacetylene and titanium(IV) chloride. Reaction of amides with amines in the presence of the titanium(IV) chloride leading to amidines is known since 1969 [36], however the report [37] stated that the practical applications of this transformation are studied unsufficiently. This reaction mainly used for the coupling of non- aromatic amides with aliphatic amines. In the study [37], authors compared reactivity of aromatic and non-aromatic amides with primary and secondary amines and it was noted that 4-phenylphtalazin-l(2H)-one, that has similar structure to the lactam (VI) in the presence of TiCl₄ reacts only with secondary amine such as N- methylpiperazine. The yield of that particular reaction did not exceed 45% even using ultrasound irradiation of the reaction mixture. The reaction with primary amines did not occurred and the employment of the aromatic amines in this reaction was not studied.

0012 So, it was quite surprisingly to obtain erlotinib (I) in the reaction of the amide (VI) with the 3-aminophenylacetylene in the presence of the slight excess (1.2-1.5 eq.) of TiCl₄. The yield was unexpectedly high, achieving 85% even without optimization of the reaction conditions.

ADVANTAGEOUS EFFECTS OF INVENTION

0013 The invented method allows to obtain erlotinib (I) with the good yield directly from the lactam (VI) and without isolation of the activated 4-substituted quinazoline (VI). Titanium(IV) chloride has higher boiling point than thionyl chloride, so the use of this reagent in the large scale production is much safer. After completion of the reaction, the reaction mixture is treated with water and titanium(IV) oxide is formed upon quench, that is non-toxic compound and may be easily separated from the mixture by filtration. The obtained product can be purified to pharmaceutical purity grade (>99%) by routine procedures, such as crystallization. The chromatographical data of the reaction mixture show that the amount of unreacted 3- aminophenylacetylene remains unchanged in the reaction mixture and, if necessary, may be isolated and regenerated for further use in this reaction.

0014 The described method can be performed in different solvents, e.g. dioxane, tetrahydrofuran, 1,2-dimethoxyethane or in a mixture of solvents. Reaction time is depending on the solvent used and is from 4 to 12 h. In the following examples, the process which is the object of the present patent application is described by way of example; these examples are not intended to limit the scope of protection of the same.

EXAMPLES

N-(3-Ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib) Example 1

0015 6,7-Bis(2-methoxyethoxy)quinazolin-4(3H)-one (VI) (14.7 g, 0.05 mol) was suspended in absolute dioxane (150 ml) and 3-aminophenylacetylene (7.0 g, 0.06 mol) was added. In a dropping funnel a mixture of TiCl₄ (11.4 g, 6.6 ml, 0.06 mol) and anisole (32.4 g, 33.0 ml, 0.30 mol) was prepared under argon atmosphere, and then the obtained brown solution was added dropwise with stirring and cooling of the suspension of amide (VI). During the addition of TiCl₄-anisole complex the clear brown solution is formed. The reaction mixture was refluxed for 4 h and then cooled to room temperature. EtOAc (300 ml) and H₂0 (10 ml) were added, and the mixture was stirred for 30 min. The formed precipitate was filtered off and washed with EtOAc (3 x 30 ml). The organic filtrate was extracted with 5% HC1 (50 ml), water phase was separated, neutralized with saturated Na₂C0₃ sloution (50 ml) and extracted with EtOAc (3 x 50 ml). The organic extract was dried with Na₂S0₄ and evaporated in vacuum. Erlotinib (I) base is obtained in a form of an yellowish oil, that crystallizes on standing. Yield 16.1 g (82%).

Example 2

0016 6,7-Bis(2-methoxyethoxy)quinazolin-4(3H)-one (VI) (29.4 g, 0.1 mol) was suspended in absolute THF (300 ml) and 3-aminophenylacetylene (22.8 g, 0.15 mol) was added. In a dropping funnel a mixture of TiCl₄ (22.8 g, 13.2 ml, 0.12 mol) and anisole (32.4 g, 33 ml, 0.30 mol) was prepared under argon atmosphere, and then the obtained brown solution was added dropwise with stirring and cooling of the suspension of amide (VI). During the addition of TiCl₄-anisole complex the clear brown solution is formed. The reaction mixture was refluxed for 12 h and then cooled to room temperature. EtOAc (500 ml) and H₂0 (20 ml) were added, and the mixture was stirred for 30 min. The precipitate formed was filtered off and washed with EtOAc (3 x 50 ml). The organic filtrate was extracted with 5% HC1 (100 ml), water phase was separated, neutralized with saturated Na₂C0₃ sloution (100 ml) and extracted with EtOAc (3 x 100 ml). The organic extract was dried with Na₂S0₄ and evaporated in vacuum. Erlotinib (I) base is obtained in a form of an yellowish oil, that crystallizes on standing. Yield 30.2 g (77%).

Example 3

0017 6,7-Bis(2-methoxyethoxy)quinazolin-4(3H)-one (VI) (29.4 g, 0.1 mol) was suspended in absolute dimethoxyethane (300 ml) and 3-aminophenylacetylene (22.8 g, 0.15 mol) was added. In a dropping funnel a mixture of TiCl₄ (22.8 g, 13.2 ml, 0.12 mol) and anisole (32.4 g, 33 ml, 0.30 mol) was prepared under argon atmosphere, and then the obtained brown solution was added dropwise with stirring and cooling of the suspension of amide (VI). During the addition of TiCl -anisole complex the clear brown solution is formed. The reaction mixture was refluxed for 6 h and then cooled to room temperature. EtOAc (500 ml) and H₂0 (20 ml) were added, and the mixture was stirred for 30 min. The precipitate formed was filtered off and washed with EtOAc (3 x 50 ml).The organic filtrate was extracted with 5% HC1 (100 ml), water phase was separated, neutralized with saturated Na₂C0₃ sloution (100 ml) and extracted with EtOAc (3 x 100 ml). The organic extract was dried with Na₂S0₄ and evaporated in vacuum. Erlotinib (I) base is obtained in a form of an yellowish oil, that crystallizes on standing. Yield 33.4 g (85%).

0018 The obtained erlotinib base has purity approximately 95%. If necessary, it can be purified to 99% or higher purity by the routine procedures, for example by converting to hydrochloride and recrystallization from the suitable solvents (MeOH, EtOH, DMF, etc).

Example 4

0019 N-(3-Ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine

hydrochloride (erlotinib hydrochloride)

The obtained raw base of erlotinib (I) (19.7 g, 0.05 mol) dissloved in i-PrOH (200 ml) and saturated HC1 solution in -PrOH (10 ml) was added with intensive stirring. The obtained suspension is stirred at room temperature for 2 h, the light- yellow precipitate filtered off, washed with -PrOH (3 x 50 ml), dried in vacuum at room temperature and recrystallized from MeOH (100 ml), obtaining erlotinib hydrochloride with >99% purity. Yield 20.3 g (94%).

INDUSTRIAL APPLICABILITY

0020 The invented method may be realized in pharmaceutical industry using the corresponding equipment and conditions. The method allows to obtain the product, which can be purified to pharmaceutical quality (>99%) by routine procedures. The process is characterized by utilizable waste and easily separable impurities in the target product.

CITATION LIST

PATENT LITERATURE

0021

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[2] WO2009/117080.

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[4] US2011/288086.

[5] WO2006/84882.

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[13] WO2011/76813.

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[16] US2012/95228.

[17] WO2004/72049.

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NON PATENT LITERATURE 0022

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Claims

1. A process for the preparation of N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)- quinazolin-4-amine (erlotinib) from 6,7-bis(2-methoxyethoxy)quinazolin-4(3H)- one, comprising the tratment of the said starting compound with 3- aminophenylacetylene in the presence of titanium(IV) chloride and anisole in appropriate solvent.

2. A process according to claim 1, wherein said solvent is selected from the group, comprising tetrahydrofuran, dioxane, 1,2-dimethoxyethane or mixture thereof.

3. A process according to claim 1 or 2, wherein said reaction is carried out at the boiling point of the solvent.