- Convergent approach for commercial synthesis of gefitinib and erlotinib
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An efficient, economical and large-scale convergent synthesis of epidermal growth factor receptor- tyrosine kinase inhibitors gefitinib (1, Iressa) and erlotinib (2, Tarceva) approved by U.S. FDA for the treatment of non-small-cell lung cancer is described. The formation of 4-anilinoquinazolines are achieved in a simple one-pot reaction of suitable forniamidine intermediates and substituted anilines involving Dimroth rearrangement, thereby avoiding the need to make quinazolin-4(3H)-one intermediates, which require a large experimental inputs. Using this process, we have produced drug candidates 1 with overall yield of 66% from 4-methoxy-5-[3-(4-morpholinyl) propoxy]-2-nitrobenzonitrile (3) and 2 with 63% from 4-bis(2-methoxyethoxy)-2-nitrobenzonitrile (6) on a multigram scale.
- Chandregowda, Venkateshappa,Rao, Gudapati Venkateswara,Reddy, Goukanapalli Chandrasekara
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Read Online
- Improved synthesis of gefitinib and erlotinib hydrochloride- anticancer agents
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A highly efficient and commercially viable process for the synthesis of 6,7-dihydroxy-4-anilinoquinazoline derivatives gefitinib (1) and erlotinib hydrochloride (2), used for the treatment of non-small cell lung cancer (NSCLC) and pancreatic cancer, is reported. This new process has improved yields and avoids the unstable 4-chloroquinazoline intermediate. The intermediates and final products were characterized by 1H and 13C nuclear magnetic resonance (NMR), mass spectra (MS), and elemental analysis, and purities of final products were determined by high performance liquid chromatogram (HPLC) and potentiometric titration methods. Copyright Taylor & Francis Group, LLC.
- Chandregowda, Venkateshappa,Rao, Gudapati Venkateswara,Reddy, Goukanapalli Chandrasekara
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Read Online
- Solubility of two polymorphs of erlotinib hydrochloride in isopropanol and acetone from (273.15 to 303.15) K
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In this work the solubility of two polymorphic forms A and B of erlotinib hydrochloride in isopropanol (IPA) and acetone were determined by means of high-performance liquid chromatography (HPLC) in the temperature range from (273.15 to 303.15) K. The experimental data were correlated with the modified Apelblat equation. In particular, the effect of the surfactant Tween 80 on the solubility of both polymorphs was studied as well. The results show that the solubility of both polymorphs generally increases with the temperature, and polymorph A has a higher solubility than polymorph B which indicates that polymorph A is the metastable form. The modified Apelblat equation shows a good agreement with the experimental data with a percent error less than 3 %. Furthermore, the solubility of both polymorphs increases in a linear fashion with increasing the content of Tween 80 in organic solvents, wherein Tween 80 presents a same solubilization capacity to both polymorphs and a higher solubilization capacity in acetone than in IPA.
- Lu, Jie,Zhan, Xiaolan,Chen, Lianwei,Zhang, Lijuan,Mao, Shimin
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Read Online
- Preparation method of erbtinib
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The invention discloses a preparation method of erbtinib. The method comprises the following steps: carrying out a cyclization reaction on a compound represented by formula 1 to obtain a compound represented by formula 2, carrying out a chlorination reaction on the compound of the formula 2 to obtain a compound represented by formula 3, and carrying out a substitution salification reaction on thecompound of the formula 3 to obtain the compound erbtinib represented by formula 4. The preparation method of erbtinib can greatly shorten the production cycle when used for preparing erbtinib hydrochloride, can effectively avoid the defects of long production cycle, serious environmental pollution, unstable intermediate, difficult product purification, complex operation and the like, and has theadvantages of short reaction steps, simple operation, easy reaction, high product purity, high yield and low cost. The addition amount of reactants is properly controlled, the environmental requirements are clear, and a clear and new production direction is provided for process production.
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Paragraph 0009; 0048-0053
(2020/06/16)
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- Preparation method of erlotinib hydrochloride
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The invention relates to a preparation method for erlotinib hydrochloride. The preparation method comprises the following steps: reacting 2-amino-4,5-dimethoxybenzoic acid with formamide to generate acompound 5, carrying out a bromination reaction on the compound 5, and subjecting a bromination product and 3-acetenyl aniline to a reaction and amination to generate a compound 3; and reacting the compound 3 with 48% hydrobromic acid under the action of a catalyst to obtain a compound 2, and reacting the compound 2 with iodoethylmethyl ether under the action of an alkali and the catalyst to generate erlotinib hydrochloride. The method has the advantages of mild conditions, low impurity content, safety, no pollution and environmental protection, and is suitable for industrial production.
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- Preparation method for high-purity erlotinib hydrochloride
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The invention belongs to the field of pharmaceutical synthesis, and provides a method for preparing high-purity erlotinib hydrochloride. The method comprises the following steps: 6,7-di(2-methoxyethoxy)quinazoline-4-one is used as a raw material, chlorination is performed to obtain 4-chloro-6,7-di(2-methoxyethoxy)quinazoline (compound I), refining is performed on the compound I, the refined compound I is reacted with 3-aminophenylacetylene, and therefore the high-purity erlotinib hydrochloride is obtained, wherein the purity obtained by HPLC is 99.85% or more, and the content of an impurity 1and an impurity 2 is less than 0.06%. The method provided by the invention is suitable for industrial large-scale production.
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Paragraph 0040-0049
(2019/05/16)
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- The preparation method of the [...] hydrochloride
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The invention provides a preparation method for an erlotinib hydrochloride crystal form. The preparation method is as follows: mixing erlotinib free alkaline with an organic solvent, and dropwise adding concentrated hydrochloric acid under a low-temperature condition to obtain high-purity erlotinib hydrochloride crystal form. The preparation method disclosed by the invention has characteristics of being easy in obtaining of materials, controllable in quality (concentrated hydrochloric acid), good in repeatability, simple to operate, high in yield, low in cost, and high in obtained sample purity, is more suitable for industrial production, and has very high economic benefits.
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Paragraph 0023-0036
(2019/06/11)
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- A synthesis method of erlotinib hydrochloride (by machine translation)
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The invention relates to a technical field of drug synthesis, relates to a new synthetic method of erlotinib hydrochloride. The steps are as follows: 1) to acetophenone as a starting material, in the nitration reaction takes place in the mixed between nitro acetophenone; 2) between nitro acetophenone with chlorinated reagent in the organic solvent in the reaction of chloride 1 - chloro - 1 - (3 - nitrophenyl) ethylene; 3) 1 - chloro - 1 - (3 - nitrophenyl) ethylene in the presence of an organic solvent and alkali to obtain between the dehydrochlorination nitrobenzene acetylene; 4) m acetylene through the nitro-selective reduction to obtain between amino acetylene; reduction method as a reducing agent or catalytic hydrogenation reduction; 5) between amino acetylene and 4 - chloro - 6, 7 - b - (2 - methoxyethoxy) quinazoline in reaction of organic solvent to obtain the erlotinib hydrochloride; raw materials of the invention is cheap, low production cost, simple operation, mild reaction conditions and the like, and is suitable for industrial production. (by machine translation)
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Paragraph 0052; 0053; 0054; 0055
(2017/06/30)
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- A method for preparing environmental protection of erlotinib hydrochloride
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The invention discloses an environment-friendly method for preparing high-yield erlotinib hydrochloride. The method comprises the following steps: directly performing cyclic condensation by taking 2-amino-4,5-di(2-methoxy ethyoxyl) ethyl benzoate hydrochloride as a key intermediate, reacting with aminophenylacetylene to generate erlotinib hydrochloride after performing chlorination, and refining to obtain the high-purity erlotinib hydrochloride. The process route provided by the invention is mild in reaction condition and high in yield; the first-class reagent and other reagents harmful to the environment and the operators are not used, the byproduct is few, the aftertreatment is simple and the commercial process can be easily processed.
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- Synthesis method of erlotinib hydrochloride
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The invention discloses a synthesis method of erlotinib hydrochloride. The synthesis method comprises the following steps: (1) at a first working section: preparing 3-methoxyl-4-hydroxybenzonitrile from vanillin and hydroxylammonium chloride; (2) at a second working section: synthesizing 3,4-dihydroxybenzonitrile; (3) at a third working section: synthesizing 3,4-di(2-methoxyethoxy)phenylacetonitrile; (4) at a fourth section: synthesizing 4,5-di(2-methoxyethoxy)-2-nitrophenylacetonitrile; (5) at a fifth working section: synthesizing 4,5-di(2-methoxyethoxy)-2-aminophenylacetonitrile hydrochloride; and (6) at a sixth working section: synthesizing the erlotinib hydrochloride. The synthesis method of the erlotinib hydrochloride, disclosed by the invention, has the advantages of reasonable design, easiness of obtaining raw materials, relatively low production cost, simplicity and easiness of operation and is suitable for industrial production.
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Paragraph 0059-0062
(2017/08/31)
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- Method for preparing compound
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The invention provides a method for preparing a compound as shown in a formula I which is described in the specification. The method comprises a step of contacting a compound as shown in a formula III which is described in the specification or a derivative thereof with a compound as shown in a formula II which is described in the specification so as to obtain the compound as shown in the formula I. In the formulas, R1 and R2 are hydrogen, alkoxy groups or heteroaromatic rings, preferably alkoxy groups; and R is hydrogen, an alkyl group, a phenyl group, a substituted phenyl group or a naphthyl group. The compound as shown in the formula I is a tinib drug intermediate 6,7-disubstituted quinazolinone. According to the method provided in embodiments in the invention, aldoketones are used as cyclization raw materials in replacement of carboxylic acids for preparation of tinib drug intermediate, and since the aldoketones are not corrosive, the method has low requirements on reaction equipment and is more favorable for industrial production.
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- Method for preparing erlotinib hydrochloride by one step
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The invention discloses a method for preparing erlotinib hydrochloride by one step. The method comprises the following steps: performing chlorination reaction on a starting raw material 6,7-di(2-methoxyethoxy)-quinazolin-4(3H)-ketone and a chlorination agent, performing condensation reaction with 3-aminophenylacetylene after simple activated carbon adsorption, and during the condensation reaction, directly reacting hydrogen chloride produced in the reaction with erlotinib to obtain a hydrochloride product, i.e. the erlotinib hydrochloride. A process is simple, the preparation method is convenient to operate, easy, low in production cost and byproduct rate, high in yield of the whole line and product purity, stable and controllable in reaction and simple in posttreatment, and industrial continuous production can be realized.
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Paragraph 0046; 0049; 0050; 0051; 0055; 0056; 0057; 0061
(2017/07/18)
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- Antirust B erlotinid hydrochloride method for the synthesis of
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The invention discloses a synthetic method applicable to industrial production of an erlotinib hydrochloride B-type crystal. According to the method, 2-amino-4,5-di-(2-methoxyethoxy)-ethyl benzoate hydrochloride is used as a raw material, ring closure is carried out so as to obtain 6,7-di-(2-methoxyethoxy)-3,4-dihydroquinazoline-4-one, then chlorination is directly carried out so as to obtain a product which reacts with 3-aminophenylacetylene in an methanol-water mixed solvent, and cooling and crystallization are carried out after completion of the reaction so as to obtain the finished erlotinib hydrochloride B-type crystal. Compared with the prior art, the invention has the following advantages: the synthetic method is easy and practicable to operate and does not need crystal phase transformation, and the prepared erlotinib hydrochloride B-type crystal has a single and stable crystal form and high purity and is suitable for large-scale industrial production.
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Paragraph 0043-0044
(2017/01/19)
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- Erlotinib hydrochloride B crystal preparation method
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The invention relates to a preparation method of erlotinib hydrochloride form B. The preparation method comprises following steps: free erlotinib base and an organic solvent are mixed so as to obtain a clear solution; hydrochloric acid is added dropwise into the solution; the mixture is heated for backflow, and then is cooled and filtered; and the residue is washed and dried so as to obtain erlotinib hydrochloride form B. Process technology of the preparation method is simple; crystallization velocity and purity are increased effectively; processes are stable, and operational feasibility is high; the preparation method is suitable for industrialized production; crystal form purity of the obtained products is high; and the products possess significant economic value.
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Paragraph 0031-0033
(2017/03/28)
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- Industrial production method for resin B erlotinib hydrochloride
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An industrialized production method for erlotinib hydrochloride B type crystal comprises: reacting a raw material erlotinib with hydrogen chloride, and after the reaction cooling and precipitating a crystal to obtain the finished product erlotinib hydrochloride B type crystal, wherein the reaction solvent is acetone or a mixture of acetone and water. The usable raw materials of the method comprise erlotinib amorphous solid or crystal, wherein the crystal form of the crystal is unlimited and can be a singular crystal form or a mixed crystal form. The method is simple, has no crystal form conversion step, is applicable to industrialized production, and has no toxic and harmful solvents needed and no pollution to environment; and product purity reaches 99% or more and product yield reaches 95% or more.
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Paragraph 0064-0066
(2017/04/11)
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- Synthesis and purification method of erlotinib hydrochloride
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The invention relates to a synthesis and purification method of erlotinib hydrochloride. The method comprises the following steps: acylating an initial raw material 6,7-di(2-methoxyethoxy)-quinazolin-4(3H)-one, condensing the acylated initial raw material and aminophenylacetylene, and carrying out salt formation on the obtained product and hydrogen chloride to obtain the erlotinib hydrochloride. The method has the advantages of simple process, mild reaction conditions, convenient post-treatment and high product quality.
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Paragraph 0020; 0021; 0029; 0030; 0038; 0039
(2016/11/28)
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- distress Luo river for Nepal method for preparing and its derivatives
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The invention discloses a preparation method of erlotinib and derivatives of erlotinib. The preparation method is characterized in that a compound II (when R2=H, the compound II is 6,7-(2-methoxyl-oxethyl)-quinoline-4-amine and a compound III (when R1=SiMe and R3=I, the compound III is 3- trimethylsilylacetylene-iodobenzene have a coupling reaction in an organic solvent under the actions of alkali, elementary substance copper and/or copper salt to obtain erlotinib and derivatives of erlotinib. The elementary substance copper and/or copper salt or palladium reagent is used as the base of the catalytic reaction, the N-(3-phenylacetylene)-6,7-di(2-methoxyl oxethyl)-4-quinoline amino acid salt (erlotinib, I) and the derivatives of erlotinib are prepared from midbody compoundS II and III. The preparation method has the advantages of use of low-price and easily available raw materials, , moderate reaction conditions, few side reaction, high yield and small environmental pollution and is applicable to the industrial production.
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Paragraph 0080; 0081
(2017/03/14)
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- A method of preparing the erlotinib hydrochloride
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The invention discloses a preparation method for erlotinib hydrochloride, and particularly relates to a synthetic method of erlotinib through Dimroth rearrangement construction. The method provided by the invention takes 2-amino-4, 5-bis(2-methoxyethoxy)benzonitrile, a dimethoxy methylene amino compound and m-aminophenylacetylene as raw materials to prepare erlotinib hydrochloride by one-pot technique. The method provided by the invention has the advantages of stable process, mild reaction condition, easy amplification feeding, simple after-treatment operation, easy separation and purification of product, and reduced generation of three wastes, and can be applied to large-scale production of erlotinib hydrochloride.
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Paragraph 0029-0030
(2017/02/23)
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- Process for the preparation of erlotinib
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A process for the preparation of Erlotinib comprising: a) the reaction of the compound of formula (II) with the compound of formula (III) b) the subsequent treatment with a source of hydrochloric acid in a suitable solvent to give Erlotinib hydrochloride, is described.
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Paragraph 0036; 0037; 0038
(2016/11/17)
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- A METHOD FOR PREPARATION OF ERLOTINIB
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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.
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Paragraph 0019
(2015/02/25)
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- PROCESS FOR PREPARING STABLE POLYMORPHIC FORM OF ERLOTINIB HYDROCHLORIDE
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The present invention discloses an improved and efficient process for preparing Erlotinib hydrochloride suitable as a cancer drug.
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Paragraph 0139
(2014/05/08)
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- Isolation of highly pure erlotinib hydrochloride by recrystallization after nucleophilic substitution of an impurity with piperazine
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Optimized synthesis and purification of erlotinib hydrochloride (N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazoline-4-amine hydrochloride) were studied. Highly polar piperazine was used in a nucleophilic substitution reaction with the chlorinated intermediate byproduct N-(3-ethynylphenyl)-6(2- chloroethoxy)-7-(2-methoxyethoxy)quinazolin-4-amine hydrochloride. As a result, N-(3-ethynylphenyl)-6(2-chloroethoxy)-7-(2-methoxyethoxy)quinazolin-4-amine hydrochloride was completely transformed to N-(3-ethynylphenyl)-6(2- piperzinoethoxy)-7-(2-methoxyethoxy)quinazolin-4-amine hydrochloride. The polarity of N-(3-ethynylphenyl)-6(2-piperzinoethoxy)-7-(2-methoxyethoxy) quinazolin-4-amine hydrochloride was changed, and its molecule was enlarged. It was easy to remove this larger, more polar, compound by recrystallization. Highly pure erlotinib hydrochloride was obtained with low impurity content (99.9 %.
- Zhang, Gengzhen,Zha, Linlin
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p. 2303 - 2309
(2013/07/26)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF ERLOTINIB HYDROCHLORIDE FORM A
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The present invention relates to an improved process for the preparation of Erlotinib hydrochloride pure Form A. The present invention also provides a pharmaceutical composition using the erlotinib hydrochloride pure Form A of the invention.
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- New method for the preparation of erlotinib
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The present invention refers to an alternative method for the preparation of Erlotinib through a new chemical reaction for the preparation of the 4-(3-aminophenyl)-2-methyl-3-butyn-2-ol key intermediate of formula (IV) according to the following scheme.
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Page/Page column 10-11
(2012/04/10)
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- METHOD FOR THE PREPARATION OF ERLOTINIB
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An alternative method for the preparation of Erlotinib through a new chemical reaction for the preparation of the 4-(3-aminophenyl)-2-methyl-3-butyn-2-ol key intermediate of formula (IV) according to the following scheme.
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Page/Page column 7
(2012/04/23)
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- PURE ERLOTINIB
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The present invention relates to processes for the preparation of erlotinib and salts and polymorphs thereof, preferably of high purity. The present invention also relates to erlotinib and salts and polymorphs thereof preparable by said processes, to medical uses of said erlotinib, salts and polymorphs, and to pharmaceutical compositions comprising the same.
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Page/Page column 36-37
(2012/03/26)
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- PREPARATION PROCESS OF ERLOTINIB
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Preparation process of erlotinib or its salts comprising: reacting 6,7-bis(2-methoxyethoxy)-4-methoxyquinazoline with 3-ethynylaniline or a salt thereof in the presence of a base and a reaction-inert solvent, and optionally, treating the compound obtained with a pharmaceutically acceptable acid to form the corresponding pharmaceutically acceptable salt. The compound 6,7-bis(2-methoxyethoxy)-4-methoxyquinazoline can be prepared either from 4-methoxyquinazoline-6,7-diol or 6,7-bis(2-methoxyethoxy)quinazolinone. The compounds 6,7-bis(2-methoxyethoxy)-4-methoxyquinazoline and 4-methoxyquinazoline-6,7-diol are new intermediates useful for the preparation of erlotinib or its salts.
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Page/Page column 18
(2011/07/09)
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- Preparation process of erlotinib
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Preparation process of erlotinib or its salts comprising: reacting 6,7-bis(2-methoxyethoxy)-4-methoxyquinazoline with 3-ethynylaniline or a salt thereof in the presence of a base and a reaction-inert solvent, and optionally, treating the compound obtained with a pharmaceutically acceptable acid to form the corresponding pharmaceutically acceptable salt. The compound 6,7-bis(2-methoxyethoxy)-4-methoxyquinazoline can be prepared either from 4-methoxyquinazoline-6,7-diol or 6,7-bis(2-methoxyethoxy)quinazolinone. The compounds 6,7-bis(2-methoxyethoxy)-4-methoxyquinazoline and 4-methoxyquinazoline-6,7-diol are new intermediates useful for the preparation of erlotinib or its salts.
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Page/Page column 10
(2011/08/07)
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- An improved convergent approach for synthesis of erlotinib, a tyrosine kinase inhibitor, via a ring closure reaction of phenyl benzamidine intermediate
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An improved convergent and economical method has been developed for the synthesis of erlotinib, a 4-anilinoquinazoline and an EGFR-tyrosine kinase inhibitor for treatment of non-small-cell lung cancer. The final two steps for the formation of this 4-anilinoquinazoline from suitable 2-aminobenzonitrile intermediate and 3-ethynylaniline were modified and were performed in a simple one-pot reaction. The ring-closing mechanism for the formation of erlotinib from the suitable formamidine intermediate and 3-ethynylaniline was investigated and determined to proceed via the formation of phenyl benzamidine intermediate rather than involving Dimroth rearrangement reported earlier. The new benzamidine intermediate was isolated for the first time and characterized. Copyright
- Asgari, Davoud,Aghanejad, Ayuob,Mojarrad, Javid Shahbazi
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experimental part
p. 909 - 914
(2012/01/05)
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- CRYSTALLINE FORMS OF ERLOTINIB BASE AND ERLOTINIB HCL
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The preparation of crystalline Erlotinib base form G2 is described. This crystalline form can be converted to an Erlotinib salt, such as Erlotinib HCl, which can be used in the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC).
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Page/Page column 6
(2010/02/16)
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- PROCESSES FOR THE PREPARATION OF ERLOTINIB HYDROCHLORIDE
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There is provided processes to prepare erlotinib hydrochloride. The processes may comprise exposing solid erlotinib free base containing residual solvent to hydrogen chloride gas. The processes may comprise spraying hydrogen chloride gas in an organic solvent onto solid erlotinib free base. Erlotinib hydrochloride prepared by such methods is also provided.
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Page/Page column 8
(2010/04/28)
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- PROCESS FOR THE PREPARATION OF ERLOTINIB OR ITS PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF
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The present invention relates to a process for preparation of erlotinib of Formula I or its pharmaceutically acceptable salt thereof. The present invention also relates to process for the preparation of erlotinib trifluoroacetate. The present invention also relates to a noveICrystalline form of erlotinib trifluoroacetate designated as Form E and process for its preparation. The present invention further relates to process for the preparation of erlotinib hydrochloride from erlotinib trifluoroacetate.
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Page/Page column 19
(2010/11/03)
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- FUSED RING COMPOUNDS AND USE THEREOF
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The present invention aims to provide a glucokinase activator useful as a pharmaceutical agent such as an agent for the prophylaxis or treatment of diabetes, obesity and the like. The present invention provides a glucokinase activator containing a compound represented by the formula (I): wherein each symbol is defined in the specification, or a salt thereof or a prodrug thereof.
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Page/Page column 12-13
(2009/04/25)
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- AN IMPROVED PROCESS FOR ERLOTINIB HYDROCHLORIDE
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The present invention provides an improved and commercially viable process for preparation of erlotinib substantially free of N-methoxyethyl impurity, namely N-[(3-ethynylphenyl)-(2-methoxyethyl)]-6,7-bis(2-methoxyethoxy)-4-quinazolinamine, and its pharmaceutically acceptable acid addition salts thereof in High purity and in high yield. According to the present invention, erlotinib or a pharmaceutically acceptable acid addition salt of erlotinib substantially free of N-methoxyethyl impurity is prepared by isolating erlotinib or a pharmaceutically acceptable salt of erlotinib from a solvent medium comprising dimethyl sulfoxide and an alcoholic solvent.
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Page/Page column 10-11
(2009/03/07)
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- A NOVEL HYDRATED FORM OF ERLOTINIB FREE BASE AND A PROCESS FOR PREPARATION OF ERLOTINIB HYDROCHLORIDE POLYMORPH FORM A SUBSTANTIALLY FREE OF POLYMORPH FORM B
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The present invention provides a novel and stable hydrated form of erlotinib free base, and a process for its preparation thereof. The present invention also provides a process for preparation of erlotinib hydrochloride crystalline polymorph A substantially free of polymorph B. The present invention further relates to erlotinib hydrochloride crystalline particles having mean particle size (D50) ranging from about 4 μm to 15 μm and 90 volume-% of the particles (D90) ranging from about 14 μm to 30 μm, to the methods for the manufacture of said crystalline particles, and to pharmaceutical compositions comprising said crystalline particles.
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Page/Page column 15
(2009/04/25)
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- NOVEL PROCESS FOR THE PREPARTION OF ERLOTINIB
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The present invention discloses an improved and novel process for the preparation of erlotinib (N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine) of formula (1), which comprises: (i) demethylation of commercially available 6,7-dimethoxy-4(3H)-quinazolinone of formula (8); acetylation using acetic anhydride; (iii) introduction of a leaving group at C-4 position in quinazolinone; (iv) condensation with 3-ethynylaniline to get novel compound of formula (12); (v) deacetylation to get novel dihydroxy compound of formula (13); and (vi) O-alkylation with 2-iodoethylmethyl ether to get the erlotinib base of formula (1). Erlotinib base is purified by recrystallization from ethyl acetate to get a HPLC purity of >99.5%. Salt formation of this base with hydrogen chloride gave pharmaceutically acceptable erlotinib hydrochloride of formula (1a) with a HPLC purity of >99.8%. Erlotinib hydrochloride is useful for the treatment of proliferative disorders, such as cancers, in humans.
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Page/Page column 8
(2009/12/24)
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- Amorphous Erlotinib, processes for the preparation thereof, and processes to prepare additional forms of Erlotinib
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The present invention provides amorphous erlotinib, processes for the preparation thereof, and processes to prepare additional forms of erlotinib.
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Page/Page column 5
(2009/01/24)
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- PROCESS FOR PREPARATION OF ERLOTINIB AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS
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A process for the preparation of a salt of N-(3-ethynylphenyl)-6,7-bis(2- methoxyethoxy)quinazolin-4-amine comprising reacting a 4~halo-6,7-bis(2-methoxyethoxy) quinazoline with 3-aminophenyl acetylene or an acid salt thereof under acidic conditions to form the corresponding acid salt of N-(3-ethynylphenyl)-6,7-bis(2- methoxyethoxy)quinazolin-4-amine, the process optionally further comprising converting the acid salt of N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine to N-(3- ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine.
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Page/Page column 9-11
(2008/12/04)
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- NOVEL POLYMORPHS OF ERLOTINIB HYDROCHLORIDE AND METHOD OF PREPARATION
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The present invention relates to three novel crystalline forms of Erlotinib hydrochloride and method of preparation thereof. Erlotinib hydrochloride is N-(3-ethynylphenyl)-6,7-bis(2-methoxy ethoxy)-4-quinazolinamine hydrochloride of formula-(I). The present invention provides stable novel crystalline forms of Erlotinib hydrochloride designated as Form-M, Form-N and Form-P, and processes for the preparation of the same. Erlotinib hydrochloride can be used as medicament for the treatment of hyperproliferative disorders, such as cancers, in humans.
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Page/Page column 5
(2008/12/08)
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- One-pot conversion of 2-nitrobenzonitriles to quinazolin-4(3H)-ones and synthesis of gefitinib and erlotinib hydrochloride
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A simple and efficient one-pot conversion of 2-nitrobenzonitriles to quinazolin-4(3H)-ones involving reduction, formylation, hydrolysis and cyclization is reported. These quinazolinones have been used for making in economical way the anticancer drug molecules gefitinib (Iressa) and erlotinib HCl (Tarceva).
- Chandregowda, Venkateshappa,Venkateswara Rao, Gudapati,Chandrasekara Reddy, Goukanapalli
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- Combination therapy of her expressing tumors
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The invention relates to tumors expressing HER2 and EGFR, using HER2-dimerization inhibitors (HDIs) and EGFR inhibitors.
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Page/Page column 59-60
(2008/06/13)
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- A PROCESS FOR SYNTHESIS OF [6,7-BIS-(2-METHOXYETHOXY)-QUINAZOLIN-4- YL]-(3-ETHYNYLPHENYL)AMINE HYDROCHLORIDE
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A process for synthesizing [6,7-bis(2-methoxyethoxy)quinazolin-4-yl]-(3-ethynylphenyl)amine hydrochloride (Erlitinib Hydrochloride) having the formula (I) comprising reacting 3,4-dihydroxy benzaldehyde with bromo derivative of ethyl methyl ether to obtain 3,4-bis(2-methoxyethoxy)benzaldehyde having formula (III). This is converted to give 3,4- bis (2-methoxyethoxy)-benzonitrile. On further nitration we obtain 4,5- bis (2-methoxyethoxy)-2-nitrobenzonitrile which on nitro reduction we get 2-amino-4,5-bis(2-methoxyethoxy)benzonitrile and reacting this with N'-(3-ethynylphenyl)-N,N-dimethyl formamidine gives erlotinib free base. On further treatment of this free base with methanolic/ethanolic hydrochloric acid gives us erlotinib hydrochloride.
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Page/Page column 11-12
(2008/06/13)
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- A PROCESS FOR SYNTHESIS OF [6,7-BIS-(2-METHOXYETHOXY)-QUINAZOLIN-4-YL]-(3-ETHYNYLPHENYL)AMINE HYDROCHLORIDE
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The present invention provides a process for synthesizing [6,7-bis(2-methoxyethoxy)quinazolin-4-yl]-(3-ethynylphenyl)amine hydrochloride (Erlitinib Hydrochloride) having the formula (I) comprising reacting 3,4-dihydroxy benzaldehyde with bromo derivative of ethyl methyl ether to obtain 3,4-bis(2-methoxyethoxy)benzaldehyde having formula (III). This is converted to give 3,4- bis (2-methoxyethoxy)-benzonitrile which on furthur nitration we obtain 4,5- bis (2-methoxyethoxy)-2-nitrobenzonitrile which on nitro reduction we get 2-amino-4,5-bis(2-methoxyethoxy)benzonitrile. Formylation of this compound yields N'-[2-cyano-4,5-bis(2methoxyethoxy)phenyl]-N,N-dimethylformamidine. Coupling of this formamidine with 3-ethynyl aniline gives erlotinib free base. On furthur treatment of this free base with methanolic/ethanolic hydrochloric acid gives us erlotinib hydrochloride.
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Page/Page column 13
(2008/06/13)
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- Improved synthesis of substituted 6,7-dihydroxy-4-quinazolineamines: Tandutinib, erlotinib and gefitinib
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The synthesis of three substituted 6,7-dihydroxy-4-quinazolineamines: tandutinib (1), erlotinib (2) and gefitinib (3) in improved yields is reported. The intermediates were characterized by NMR and the purities determined by HPLC.
- Knesl, Petr,Roeseling, Dirk,Jordis, Ulrich
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p. 286 - 297
(2007/10/03)
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- Methods of using death receptor agonists and EGFR inhibitors
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Methods for using death receptor ligands, such as Apo-2 ligand/TRAIL polypeptides or death receptor antibodies, and EGFR inhibitors to treat pathological conditions such as cancer are provided. Embodiments of the invention include methods of using Apo2L/TRAIL or death receptor antibodies such as DR5 antibodies and DR4 antibodies in combination with EGFR inhibitors, such as Tarceva?.
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Page/Page column 35-36
(2008/06/13)
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- Novel amorphous form of erlotinib hydrochloride and its solid amorphous dispersion
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The present invention relates to novel amorphous form of [6,7-Bis(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl) (erlotinib hydrochloride), to solid amorphous dispersion of erlotinib hydrochloride and a carrier such as PVP or solid PEG, to processes for their preparations, to pharmaceutical compositions containing them and to method of treatment using the same. The amorphous form or solid amorphous dispersion of erlotinib hydrochloride obtained in this invention is useful in preparing pharmaceutical dosage forms.
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Page/Page column 6
(2008/06/13)
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- Stable polymorph of N-(3-ethynylphenyl)-6, 7-bis (2-methoxyethoxy)-4-quinazolinamine hydrochloride, methods of production, and pharmaceutical uses thereof
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The present invention relates to a stable crystalline form of N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine hydrochloride designated the B polymorph, its production in essentially pure form, and its use. The invention also relates to the pharmaceutical compositions containing the stable polymorph B form of N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine as hydrochloride, as well other forms of the compound, and to methods of treating hyperproliferative disorders, such as cancer, by administering the compound.
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Page/Page column 16
(2008/06/13)
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- POLYMORPH OF {6,7-BIS(2-METHOXY-ETHOXY)-QUINAZOLIN-4-YL}-(3E)
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The invention is concerned with a novel polymorph of [6,7-Bis(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)amine hydrochloride. This polymorph exhibits superior properties compared to the previously known forms of [6,7-Bis(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)amine hydrochloride and can be used as medicament for the treatment of hyperproliferative disorders.
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- PROCESS FOR PRODUCING 4-AMINOQUINAZOLINE COMPOUND
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A 4-aminoquinazoline derivative can be obtained by the steps of reacting quinazolin-4-one or its derivative with a chlorinating agent in a first organic solvent in the presence of an organic base, and subsequently reacting the reaction product with an amine compound represented by the formula R5-NH-R6 (each of R5 and R6 represents hydrogen or an optionally substituted hydrocarbyl group) in the presence of a second organic solvent.
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- Processes and intermediates for preparing anti-cancer compounds
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The present invention relates to methods and intermediates for preparing compounds of the formula 1 and the pharmaceutically acceptable salts and solvates thereof, as well as structurally related compounds, wherein R1, R2and R15are as defined herein. The foregoing compounds are useful in the treatment of hyperproliferative disorders, such as cancers, in mammals.
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