CN111269125A - Imatinib intermediate and preparation method thereof - Google Patents
Imatinib intermediate and preparation method thereof Download PDFInfo
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- CN111269125A CN111269125A CN201811481700.1A CN201811481700A CN111269125A CN 111269125 A CN111269125 A CN 111269125A CN 201811481700 A CN201811481700 A CN 201811481700A CN 111269125 A CN111269125 A CN 111269125A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 146
- 239000005517 L01XE01 - Imatinib Substances 0.000 title description 2
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 title description 2
- 229960002411 imatinib Drugs 0.000 title description 2
- 238000000034 method Methods 0.000 claims abstract description 26
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 10
- 239000005551 L01XE03 - Erlotinib Substances 0.000 claims abstract description 7
- 229960001433 erlotinib Drugs 0.000 claims abstract description 7
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 claims abstract description 7
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- 238000006243 chemical reaction Methods 0.000 claims description 138
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- 239000002904 solvent Substances 0.000 claims description 71
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- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/34—Migration of groups in the molecule
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
- C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
Abstract
The invention discloses an erlotinib intermediate and a preparation method thereof. The structure of the alendronate intermediate is shown as the following formula, wherein R is C1‑C4An alkyl group. The preparation method of the Aleptinib intermediate has simple and easy reagentThe method has the advantages of simple operation, high yield and low production cost, is suitable for large-scale industrial production, and has great economic benefit and social benefit.
Description
Technical Field
The invention relates to the field of medicine research and development, and particularly relates to an erlotinib intermediate and a preparation method thereof.
Background
Eltamib (Alectinib) is an oral ALK inhibitor used to treat patients with Anaplastic Lymphoma Kinase (ALK) positive metastatic non-small cell lung cancer (NSCLC). This drug was developed by chugai pharmaceutical co, a company of roche, and was first marketed in japan in 2014. Since the therapeutic effect of the erlotinib on ALK-positive non-small cell lung cancer patients is excellent, 6 months in 2013, FDA awards breakthrough therapy approval for the use of the erlotinib for treating non-small cell lung cancer patients who are ALK fusion gene positive and still progress after crizotinib treatment. The FDA granted alendronate as an orphan drug for the treatment of ALK-positive non-small cell lung cancer 1/2015 and approved for marketing in the united states 12/2015.
The compound 1 is an important intermediate for synthesizing the alendronate, but the preparation method of the compound 1 disclosed in the current literature usually needs to use expensive reagents, has higher cost and is not suitable for industrial production.
The synthesis of the compound 1 is reported in CN102459172B for the first time, vinyl is introduced through vinyl potassium trifluoroborate, then ethyl is obtained through hydrogenation, and then iodo is carried out, and then a 4- (4-piperidyl) morpholine group is introduced through C-N coupling. Although the reaction yield is high, the expensive palladium catalyst is used for a plurality of times in the five-step reaction, the synthesis cost is high, the reaction operation is complicated, and the industrial production is not facilitated.
CN106928125A reports compound 1 obtained by six-step reaction with ethyl 2- (4-ethyl-3-methoxyphenyl) acetate as starting material. The starting materials used in the method are not commercially available, need to be synthesized independently, are expensive and are not suitable for industrial production. The synthetic route is as follows:
therefore, there is a need in the art for an efficient and economical preparation method of an erlotinib intermediate.
Disclosure of Invention
The technical problem to be solved by the invention is to provide an alendronate intermediate and a preparation method thereof, which are different from the prior art, in order to overcome the problems that the existing preparation method of the alendronate intermediate in the prior art needs to use an expensive palladium catalyst for multiple times, has higher synthesis cost and complicated reaction operation, and is not beneficial to industrial production, or the starting materials are not available in the market, need to be synthesized separately, have high price and are not suitable for industrial production. The preparation method has the advantages of simple and easily obtained reagents, simple and convenient operation, higher yield and low production cost, is suitable for large-scale industrial production, and has greater economic benefit and social benefit.
The present invention solves the above-mentioned problems by the following technical means.
The invention provides a preparation method of a compound 5, which comprises the following steps: in a solvent, carrying out rearrangement reaction on the compound 4 in the presence of a catalyst;
wherein the catalyst is boron trifluoride diethyl etherate; r is C1-C4An alkyl group.
In the preparation method of the compound 5, the compound C1-C4The alkyl group is preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group or a tert-butyl group.
In the preparation method of the compound 5, the rearrangement reaction is carried out according to the reaction mechanism of Fries rearrangement reaction in the field, and can be carried out by adopting the conditions and parameters which are conventionally used in such rearrangement reaction in the field.
In the preparation method of the compound 5, the solvent can be used conventionally in the rearrangement reaction in the field, so as not to participate or interfere the reaction; preferred for use herein are one or more of carbon disulphide, nitrobenzene, dichloromethane, chloroform, halogenated benzenes (eg chlorobenzene), and tetrahydrofuran.
In the preparation method of the compound 5, the solvent can be used in the conventional rearrangement reaction in the field, so as to completely dissolve reactants and ensure the smooth reaction.
In the preparation method of the compound 5, the rearrangement reaction can also be carried out under the condition of no solvent, or can be carried out in an excess of a reaction reagent, specifically, for example, in an excess of boron trifluoride diethyl etherate.
When the rearrangement reaction is carried out in excess boron trifluoride diethyl etherate, the amount of the boron trifluoride diethyl etherate to be used may be in the range of 1:3 to 1:6, preferably 1:3, with reference to the reaction solvent, for example, the mass ratio of the compound 4 to the boron trifluoride diethyl etherate may be 1: 3.
In the preparation method of the compound 5, the reaction temperature of the rearrangement reaction can be the one conventionally used in such reactions in the field; the present invention is preferably controlled at 140 ℃ at 120 ℃ for example 130 ℃.
In the preparation of compound 5, the progress of the rearrangement reaction can be monitored by conventional methods in the art (e.g., TLC, HPLC or NMR), and the end point of the reaction is usually the disappearance or no longer reaction of the starting material. The reaction time of the rearrangement reaction is preferably 1 to 24 hours, more preferably 2 to 4 hours.
The preparation method of the compound 5 preferably comprises the following steps: under the protection of nitrogen, the compound 4 is mixed with the catalyst and the solvent, and stirred and reacted at 130 ℃.
Preferably, the preparation method of the compound 5 further comprises the following post-treatment steps after the rearrangement reaction is finished: after the rearrangement is finished, cooling the reaction liquid to room temperature, sequentially adding ice water and dilute hydrochloric acid aqueous solution to quench the reaction, extracting with dichloromethane, drying, filtering and concentrating.
Preferably, the preparation method of the compound 5 further comprises the following purification steps after the post-treatment step is finished: and purifying the crude product obtained by post-treatment by silica gel column chromatography.
In the preparation method of the compound 5, the compound 4 can be prepared by a method well known to those skilled in the art of organic chemistry.
For example, compound 4 can be prepared using the following synthetic method, which includes the following steps: in a solvent, in the presence of a base, reacting the compound 3 with acetic anhydride Ac2Performing esterification reaction on O;
wherein R is as defined above.
In the preparation method of the compound 4, the solvent can be used conventionally in the field of such esterification reaction, and the invention can specifically select one or more of dichloromethane, N-dimethylformamide, acetonitrile, tetrahydrofuran and halogenated hydrocarbon, such as dichloromethane.
In the preparation method of the compound 4, the solvent can be used in the conventional esterification reaction in the field, so as to completely dissolve reactants and ensure the smooth reaction.
In the preparation method of the compound 4, the base can be used conventionally in the field of esterification reaction, and the invention can specifically select one or more of triethylamine, diisopropylethylamine, pyridine and sodium carbonate.
In the preparation of said compound 4, said base may be used in an amount conventionally used in such esterification reactions in the art, for example, in a molar ratio of said base to said compound 3 of 1: 1.
In the preparation method of the compound 4, the acetic anhydride can be used in the conventional esterification reaction in the field, for example, the molar ratio of the acetic anhydride to the compound 3 is 1.1: 1.
In the preparation method of the compound 4, the preparation method preferably further comprises the following steps: mixing the solvent, the compound 3 and the alkali, dripping the acetic anhydride at 0 ℃, and stirring for reaction at room temperature after dripping.
In the preparation method of the compound 4, the compound 3 can be prepared by a method well known to those skilled in the art of organic chemistry.
For example, compound 3 can be prepared using the following synthetic method, which includes the following steps: in a solvent, under the condition of the existence of a catalyst, carrying out esterification reaction on a compound 2 and an alcohol ROH;
wherein R is as defined above.
In the preparation method of the compound 3, the solvent can be used conventionally in the field of esterification reaction, and methanol can be selected specifically in the invention.
In the preparation method of the compound 3, the solvent can be used conventionally in the esterification reaction in the field, so as to completely dissolve reactants and ensure the smooth reaction.
In the preparation method of the compound 3, the catalyst can be used conventionally in the field of such esterification reactions, and the invention can specifically select sulfuric acid, phosphoric acid and acyl chloride (such as thionyl chloride and acetyl chloride).
In the preparation method of the compound 3, the catalyst can be used in an amount which is conventionally used in the field of such esterification reactions, so that the catalyst can catalyze the reaction to effectively perform and is easy to carry out the post-treatment.
In the preparation method of the compound 3, the alcohol ROH may be used in an amount conventionally used in such esterification reactions in the art, for example, the molar ratio of the alcohol ROH to the compound 2 is 1: 1.
In the preparation method of the compound 3, the preparation method preferably comprises the following steps: and mixing the solvent, the compound 2 and the alcohol ROH, adding the catalyst, and heating and refluxing under the protection of nitrogen to react.
The preparation method of the compound 5 preferably also comprises a preparation method of a compound 4, and further preferably also comprises a preparation method of a compound 3, wherein the specific operation and parameters are as described above.
The invention provides a preparation method of a compound 7, which comprises the following steps: in a solvent, carrying out substitution reaction on the compound 6 and 4- (piperidine-4-yl) morpholine;
wherein the solvent is N-methylpyrrolidone (NMP); r is C1-C4An alkyl group.
In the process for preparing the compound 7, the compound C1-C4The alkyl group is preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isopropyl group or a tert-butyl group.
In the preparation method of the compound 7, the solvent can be used in the conventional substitution reaction in the field, so as to completely dissolve reactants and ensure the smooth reaction.
In the preparation method of the compound 7, the 4- (piperidine-4-yl) morpholine can be used in the conventional substitution reaction in the field, and specifically, the molar ratio of the 4- (piperidine-4-yl) morpholine to the compound 6 can be 1:1-3: 1.
In the preparation method of the compound 7, the reaction temperature of the substitution reaction can be that which is conventionally used in such reactions in the field; the present invention is preferably controlled at 100-135 deg.C, for example, 120 deg.C.
The progress of the substitution reaction in the preparation of compound 7 can be monitored by conventional testing methods in the art (e.g., TLC, HPLC, or NMR), typically by the end point of the reaction, which is the disappearance or no longer reaction of the starting material. The reaction time of the substitution reaction is preferably 1 to 24 hours, more preferably 2 to 4 hours.
The preparation method of the compound 7 preferably comprises the following steps: mixing the compound 6 with the 4- (piperidine-4-yl) morpholine and the solvent, and stirring for reaction at 120 ℃.
The preparation method of the compound 7 preferably further comprises the following post-treatment steps after the substitution reaction is finished: and after the substitution reaction is finished, pouring the reaction solution into ice water, extracting with dichloromethane, drying, filtering and concentrating.
Preferably, the preparation method of the compound 7 further comprises the following purification steps after the post-treatment step is finished: and purifying the crude product obtained by post-treatment by silica gel column chromatography.
In the preparation method of the compound 7, the compound 6 can be prepared by a method well known to those skilled in the art of organic chemistry.
For example, compound 6 can be prepared by the following synthetic method, which specifically comprises the following steps: in a solvent, in the presence of alkali, carrying out condensation reaction on a compound 5 and trifluoromethanesulfonic anhydride to obtain the compound;
wherein R is as defined above.
In the preparation method of the compound 6, the solvent can be used conventionally in the field of such esterification reaction, and the invention can specifically select one or more of halogenated alkane (such as dichloromethane), toluene, xylene, halogenated benzene (such as chlorobenzene), tetrahydrofuran and DMF.
In the preparation method of the compound 6, the solvent can be used in the conventional condensation reaction in the field, so as to completely dissolve reactants and ensure the smooth reaction.
In the preparation method of the compound 6, the base can be used conventionally in the field of condensation reaction, and the invention can specifically select one or more of pyridine, triethylamine and diisopropylethylamine.
In the preparation of said compound 6, said base may be used in an amount conventionally used in the art for such condensation reactions, for example the molar ratio of said base to said compound 5 may be 2: 1.
The preparation method of the compound 6 preferably comprises the following steps: under the protection of nitrogen, mixing the solvent with the compound 5, adding the alkali at 0 ℃, dropwise adding the trifluoromethanesulfonic anhydride at 0 ℃, and reacting at room temperature.
The preparation method of the compound 6 preferably further comprises the following post-treatment steps after the condensation reaction is finished: after the condensation reaction is finished, adding ice water into the reaction solution, extracting with dichloromethane, washing the organic layer with dilute hydrochloric acid aqueous solution and saturated sodium carbonate aqueous solution, drying, filtering and concentrating.
Preferably, the preparation method of the compound 6 further comprises the following purification steps after the post-treatment step is finished: and purifying the crude product obtained by post-treatment by silica gel column chromatography.
In the preparation method of the compound 6, the compound 5 can be prepared by adopting a method well known by a person skilled in the organic chemistry field, or can be prepared by adopting the preparation method.
The preparation method of the compound 7 preferably also comprises the preparation method of the compound 6, and further preferably also comprises the preparation method of the compound 5, wherein the specific operation and parameters are as described above.
The invention provides a preparation method of a compound 10, which comprises the following steps: hydrogenating the compound 9;
wherein R is as defined above.
In the process for the preparation of compound 10, the hydrogenation reaction proceeds according to reaction mechanisms known in the art for the hydrogenation reduction of double bonds and may be carried out using conditions and parameters conventionally used in such hydrogenation reactions in the art.
In the preparation method of the compound 10, the hydrogenation reaction can specifically adopt a catalyst (Pd/C, Pd (OH)2And one or more of platinum catalysts) + hydrogen, such that the reaction is carried out under the reaction system:
in the preparation of the compound 10, the catalyst may be used in an amount conventionally used in such reactions in the art.
In the preparation method of the compound 10, the reaction solvent for the hydrogenation reaction may be one or more of those conventionally used in the art, and specifically may be one or more of an alcohol solvent (e.g., methanol or ethanol), water, and tetrahydrofuran.
In the preparation method of the compound 10, the amount of the reaction solvent may be used conventionally in such hydrogenation reactions in the field, so as to completely dissolve the reactants and ensure the smooth reaction.
In the preparation method of the compound 10, the reaction temperature may be a reaction temperature conventionally used in such hydrogenation reaction in the art, for example, at normal temperature.
In the preparation of the compound 10, the reaction pressure may be one conventionally used in the art for such hydrogenation reactions, for example, under normal pressure.
In the preparation of compound 10, the progress of the hydrogenation reaction can be monitored by conventional testing methods in the art (e.g., TLC, HPLC, or NMR), typically by the end point of the reaction, which is the disappearance or no longer reaction of the starting material.
The preparation method of the compound 10 preferably comprises the following steps: and (2) mixing the compound 9 with the catalyst and the solvent under a hydrogen atmosphere, and stirring at room temperature for reaction.
The preparation method of the compound 10 preferably further comprises the following post-treatment steps after the hydrogenation reaction is finished: after the hydrogenation reaction is completed, the reaction solution is filtered and concentrated.
Preferably, the preparation method of the compound 10 further comprises the following purification steps after the post-treatment step is finished: and purifying the crude product obtained by post-treatment by silica gel column chromatography.
In the preparation method of the compound 10, the compound 9 can be prepared by a method well known to those skilled in the organic chemistry field, or can be prepared by the preparation method described in the invention.
For example, compound 9 can be prepared by the following synthetic method, which specifically comprises the following steps: carrying out dehydration reaction on the compound 8 in the presence of acid;
wherein R is as defined above.
In the preparation method of the compound 9, the dehydration reaction is carried out according to the reaction mechanism of obtaining olefin by dehydration reduction of alcohol in the field, and can be carried out by adopting the conditions and parameters which are conventionally used in the dehydration reaction in the field.
In the preparation method of the compound 9, the reaction solvent for the dehydration reaction may be one conventionally used in such reactions in the art, and specifically may be one or more of benzene, toluene, xylene, and halogenated benzene, such as toluene.
In the preparation method of the compound 9, the amount of the reaction solvent can be used conventionally in the hydrogenation reaction in the field, so as to completely dissolve reactants and ensure that the reaction is smoothly carried out.
In the preparation method of the compound 9, the acid can be used conventionally in the field, and specifically can be one or more of hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, or hydrates of the above acids; for example, p-toluenesulfonic acid monohydrate.
In the preparation method of the compound 9, the acid may be used in an amount conventionally used in such reactions in the art, and specifically, the molar ratio of the acid to the compound 8 may be 0.1: 1.
In the preparation method of the compound 9, the reaction temperature may be a temperature conventionally used in such hydrogenation reactions in the art, for example, at an atmospheric reflux temperature of the reaction solvent.
In the preparation of the compound 9, the progress of the dehydration reaction can be monitored by conventional testing methods in the art (e.g., TLC, HPLC, or NMR), and the end point of the reaction is generally the disappearance or no longer reaction of the starting material.
The preparation method of the compound 9 preferably comprises the following steps: and under the protection of nitrogen, mixing the compound 8 with the acid and the solvent, and carrying out reflux reaction.
Preferably, the preparation method of the compound 9 further comprises the following post-treatment steps after the dehydration reaction is finished: and after the dehydration reaction is finished, concentrating the reaction solution in vacuum.
The preparation method of the compound 9 preferably directly carries out the next reaction on the crude product obtained by the post-treatment after the post-treatment step is finished.
In the preparation method of the compound 9, the compound 8 can be prepared by a method well known to those skilled in the organic chemistry field, or can be prepared by the preparation method described in the invention.
For example, compound 8 can be prepared using the following synthetic method, which specifically comprises the following steps: carrying out reduction reaction on the compound 7 in the presence of a reducing agent;
wherein R is as defined above.
In the preparation method of the compound 8, the reduction reaction is carried out according to the reaction mechanism of the carbonyl reduction to obtain the alcohol in the field, and can be carried out by adopting the conditions and parameters which are conventionally used in the reduction reaction in the field.
In the preparation method of the compound 8, the reaction solvent for the reduction reaction may be one or more of alcohol solvents (such as methanol or ethanol), water, and tetrahydrofuran, such as methanol, which are conventionally used in such reactions in the art.
In the preparation method of the compound 8, the amount of the reaction solvent can be used conventionally in the reduction reaction in the field, so as to completely dissolve reactants and ensure that the reaction is smoothly carried out.
In the preparation method of the compound 8, the reducing agent can be used conventionally in the field, and specifically can be one or more of sodium borohydride, potassium borohydride, lithium borohydride and DIBAL-H; for example, sodium borohydride may be used.
In the preparation method of the compound 8, the reducing agent can be used in an amount conventionally used in such reactions in the art, and specifically, the molar ratio of the reducing agent to the compound 7 can be 3: 1.
In the preparation of the compound 8, the reaction temperature may be that conventionally used in the art for such hydrogenation reactions, for example, at room temperature.
In the preparation of the compound 8, the progress of the reduction reaction can be monitored by conventional testing methods in the art (e.g., TLC, HPLC, or NMR), and the end point of the reaction is generally the disappearance or no longer reaction of the starting material.
The preparation method of the compound 8 preferably comprises the following steps: and (3) adding the reducing agent into the compound 7 and the reaction solvent at low temperature, and stirring at room temperature for reaction.
Preferably, the preparation method of the compound 8 further comprises the following post-treatment steps after the reduction reaction is finished: after the reduction reaction is finished, adding dilute hydrochloric acid into the reaction solution, extracting with dichloromethane, drying the organic phase, filtering, and concentrating in vacuum.
Preferably, the preparation method of the compound 8 further comprises the following purification steps after the post-treatment step is finished: and pulping the crude product obtained by post-treatment in dichloromethane.
In the preparation method of the compound 8, the compound 7 can be prepared by a method well known to those skilled in the organic chemistry field, or can be prepared by the preparation method described in the invention.
The invention provides a preparation method of an erlotinib intermediate 1, which comprises the following steps:
1. in a solvent, under the condition of the existence of a catalyst, carrying out an esterification reaction on a compound 2 and an alcohol ROH to obtain a compound 3;
2. in a solvent, in the presence of a base, reacting the compound 3 with acetic anhydride Ac2Performing esterification reaction on O to obtain a compound 4;
3. carrying out rearrangement reaction on the compound 4 in a solvent in the presence of a catalyst to obtain a compound 5;
4. in a solvent, carrying out condensation reaction on a compound 5 and trifluoromethanesulfonic anhydride in the presence of a base to obtain a compound 6;
5. carrying out substitution reaction on the compound 6 and 4- (piperidine-4-yl) morpholine in a solvent to obtain a compound 7;
6. carrying out reduction reaction on the compound 7 in the presence of a reducing agent to obtain a compound 8;
7. carrying out dehydration reaction on the compound 8 in the presence of acid to obtain a compound 9;
8. hydrogenating the compound 9 to obtain a compound 10;
9. carrying out methylation reaction on the compound 10 and methyl iodide in a solvent in the presence of alkali to obtain a compound 11;
10. hydrolyzing the compound 11 in a solvent in the presence of alkali;
wherein R is as defined above; the reaction parameters and conditions for each step 1-8 are as described above.
In step 9, the methylation reaction proceeds according to reaction mechanisms of such reactions in the art and may be carried out using conditions and parameters conventionally used in such reactions in the art.
In step 9, the solvent may be one conventionally used in such methylation reactions in the art, subject to no participation or interference with the reaction; preferably, it is one or more of DMF, DMAC, tetrahydrofuran, acetonitrile, dioxane, for example tetrahydrofuran.
In step 9, the amount of the solvent may be that conventionally used in such methylation reactions in the art, so as to completely dissolve the reactants and ensure the reaction to proceed smoothly.
In step 9, the base may be one or more of sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide, such as sodium methoxide, which is conventional in the art for such methylation reactions.
In step 9, the base may be used in an amount conventionally used in such methylation reactions in the art, and specifically the molar ratio of the base to the compound 10 may be 2.4: 1.
In step 9, the methyl iodide may be used in an amount conventionally used in such methylation reactions in the art, and specifically, the molar ratio of the methyl iodide to the compound 10 may be 6: 1.
In step 9, the reaction temperature of the methylation reaction can be that conventionally used in such reactions in the art; the invention is preferably carried out at the atmospheric reflux temperature of the solvent.
In step 9, the progress of the methylation reaction can be monitored by conventional testing methods in the art (e.g., TLC, HPLC or NMR), typically by the end point of the reaction being the disappearance or no longer being reacted with the starting material.
The preparation method of the compound 1 preferably comprises the following steps: under the protection of nitrogen, the compound 10, the alkali and the solvent are mixed, and then the methyl iodide is dripped into the mixture for reflux reaction.
The preparation method of the compound 1 preferably further comprises the following post-treatment steps after the methylation reaction is finished: and after the methylation reaction is finished, concentrating the reaction solution in vacuum.
The preparation method of the compound 1 preferably further comprises the following purification steps after the post-treatment step is finished: and purifying the crude product obtained by post-treatment by silica gel column chromatography.
In step 10, the hydrolysis reaction proceeds according to reaction mechanisms of such reactions in the art and may be carried out using conditions and parameters conventionally used in such reactions in the art.
In step 10, the solvent may be one conventionally used in the art for such hydrolysis reactions, so as not to participate in or interfere with the reaction, such as tetrahydrofuran.
In step 10, the solvent may be used in the conventional hydrolysis reaction in the field, so as to completely dissolve the reactant and ensure the reaction to proceed smoothly.
In step 10, the base may be one conventionally used in the art for such hydrolysis reactions, such as sodium hydroxide.
In step 10, the base may be used in an amount conventionally used in such methylation reactions in the art, and specifically the molar ratio of the base to the compound 11 may be 1.1: 1.
In step 10, the reaction temperature of the hydrolysis reaction may be that conventionally used in such reactions in the art; the invention is preferably carried out at room temperature.
In step 10, the progress of the hydrolysis reaction can be monitored by conventional testing methods in the art (e.g., TLC, HPLC or NMR), typically with the end point of the reaction being the disappearance or no longer being reacted with the starting material.
The preparation method of the compound 1 preferably comprises the following steps: and mixing the compound 11, the alkali and the solvent, and stirring at room temperature for reaction.
The preparation method of the compound 1 preferably further comprises the following post-treatment steps after the hydrolysis reaction is finished: after the hydrolysis reaction is finished, adding water into the reaction solution, removing the solvent under reduced pressure, extracting with ethyl acetate, adjusting the pH to about 2 with dilute hydrochloric acid, extracting with chloroform/isopropanol (3:1, v/v), drying the organic phase, and concentrating under reduced pressure.
The present invention further provides the following compounds:
wherein R is as defined above.
On the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: according to the invention, through a Fries rearrangement and reduction elimination route design scheme, the problem that an expensive metal catalyst or a vinylboron reagent needs to be used for coupling to construct an exocyclic ethyl group in the prior art is avoided, the used starting materials and reaction reagents are very simple and easy to obtain, the reaction conditions are mild, the reaction operation is simple and convenient, no adverse conditions of industrial amplification production such as high temperature and high pressure are introduced in the whole reaction process, the industrial amplification is easy, and the market competitiveness is very good.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Example 1
Compound 2(50g,32.9mmol) and methanol (500mL) were added to the reaction flask and dissolved with stirring. Concentrated sulfuric acid (10mL) was then added and heated at 70 deg.C under nitrogen at reflux overnight. After the reaction, the reaction mixture was cooled to room temperature, and the solvent methanol was removed by vacuum concentration. Ethyl acetate (500mL) was added to the concentrate, which was washed with aqueous sodium bicarbonate (2X 100mL) and water (100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and the organic phase was concentrated in vacuo to give compound 3-1 as a pale yellow oil (53.9g, 98%). LCMS [ M-H ]]-:166.8。1H-NMR(400MHz,CDCl3):δ7.20-7.17(t,J=7.8Hz,1H),6.84-6.82(d,J=7.6Hz,1H),6.77(s,1H),6.75-6.73(d,J=8.1Hz,1H),5.26(s,1H),3.70(s,3H),3.58(s,2H).
Example 2
Compound 3-1(53.9g,32.5mmol), dichloromethane (450mL) and triethylamine (65.6g,64.9mmol) were added to the reaction flask and dissolved with stirring under nitrogen. The reaction temperature was lowered to 0 ℃ in an ice-water bath, and a solution of acetic anhydride (36.4g,35.7mmol) in dichloromethane (50mL) was added dropwise to the reaction mixture. After the dropwise addition, the reaction system was naturally warmed to room temperature and stirred overnight. After completion of the reaction, ice water (300mL) was added to the reaction mixture to quench the reaction, and the lower dichloromethane layer was extracted. The dichloromethane layer was washed with 2N dilute hydrochloric acid (170mL) followed by saturated aqueous sodium carbonate (200mL), dried over anhydrous sodium sulfate, filtered and the organic phase was concentrated in vacuo to afford compound 4-1 as a pale yellow oil (66.2g, 98%). LCMS [ M-H ]]-:208.7。1H-NMR(400MHz,CDCl3):δ7.30-7.26(t,J=7.9Hz,1H),7.12-7.10(d,J=7.6Hz,1H),7.02(s,1H),6.99-6.97(d,J=8.1Hz,1H),3.63(s,3H),3.58(s,2H),2.22(s,3H).
Example 3
Compound 4-1(66.2g,31.8mmol), boron trifluoride diethyl etherate (200g) were added to a reaction flask and dissolved with stirring under nitrogen. The oil bath pan was heated to a reaction temperature of 130 ℃ and the reaction was carried out at 130 ℃ for two hours. After the reaction, the reaction system was cooled to room temperature, and then ice water (200mL) and 2N diluted hydrochloric acid (200mL) were added thereto, followed by quenching, followed by extraction with dichloromethane (3X 250 mL). The dichloromethane phases were combined, washed with water (200mL) and dried over anhydrous sodium sulfate. Filtering, and vacuum concentrating the organic phase to obtain crude product. The crude product was purified by column chromatography on silica gel to give 5-1(55.2g, 84%) as a red oily compound. LCMS [ M-H ] -: 208.8. 1H-NMR (400MHz, CDCl3): delta 12.26(s,1H),7.70-7.68(d, J ═ 8.2Hz,1H),6.89(s,1H),6.84-6.82(m,1H),3.71(s,3H),3.62(s,2H),2.61(s,3H).
Example 3-1 examination of conditions for the preparation of Compound 5-1 in example 3
In addition to the experiment described in example 3, the reaction reagents, the amounts of the reaction reagents used, the reaction solvents, the reaction temperatures, and the like were examined, and the results are shown in table 1.
TABLE 1 screening and optimization results of reaction conditions and parameters in the preparation of Compound 5-1
Note: the experimental conditions and parameters not specified in this experiment were in full agreement with example 3.
Example 4
Compound 5-1(7g,33.6mmol) and dichloromethane (30mL) were added to the reaction flask and dissolved with stirring under nitrogen. Pyridine (5.3g,67.3mmol) was added under an ice-water bath and a solution of trifluoromethanesulfonic anhydride (11.4g,40.3mmol) in dichloromethane (15mL) was added dropwise. After the dropwise addition, the reaction system was naturally warmed to room temperature and stirred for two hours. The reaction was quenched by adding ice water (50mL) to the reaction system, and the lower methylene chloride layer was extracted. The dichloromethane layer was washed with 2N diluted hydrochloric acid (20mL) and saturated aqueous sodium carbonate (50mL), and dried over anhydrous sodium sulfate. Filtering, and vacuum concentrating the organic phase to obtain crude product. The crude product was purified by column chromatography on silica gel to give 6-1(9.7g, 85%) as a pale yellow oil. LCMS [ M-H ] -: 340.8. 1H-NMR (400MHz, DMSO-d6): delta 8.10-8.08(d, J ═ 8.0Hz,1H),7.58-7.56(dd, J ═ 8.0,1.5Hz,1H),7.48(s,1H),3.92(s,2H),3.65(s,3H),2.63(s, 3H).
Example 5
Compound 6-1(2g,5.9mmol) and 4- (piperidin-4-yl) morpholine (3g,17.6mmol) were added to N-methylpyrrolidone (6mL), dissolved with stirring, heated to 120 ℃ and reacted for two hours. After completion of the reaction, the reaction system was poured into ice water (20mL) and extracted with dichloromethane (3X 100 mL). The dichloromethane layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude. The crude product was purified by column chromatography on silica gel to give 7-1(1.9g, 81%) as a pale yellow oil. LCMS [ M-H ]]-:360.6,1H NMR(400MHz,CDCl3)δ7.35-7.33(d,J=7.8Hz,1H),6.93-6.90(m,2H),3.73-3.71(m,2H),3.68(s,3H),3.59(s,2H),3.37-3.34(t,J=7.9Hz,4H),2.60(s,3H),2.57–2.55(m,3H),2.37-2.33(t,J=8.3Hz,4H),1.99-1.96(m,4H).
Example 5-1 examination of conditions for the preparation of Compound 7-1 in example 5
Based on the experiment described in example 5, the reaction reagents, the reaction solvent, and the reaction temperature were examined, and the results are shown in table 2.
TABLE 2 screening and optimization results of reaction conditions and parameters in the preparation method of Compound 7-1
Note: the experimental conditions and parameters not specified in this experiment were in full agreement with example 5.
Example 6
Adding the compound 7-1(1.3g,3.6mmol) and methanol (6mL) into a reaction bottle, stirring and dissolving, adding sodium borohydride (411mg,10.8mmol) under ice-water bath, stirring and dissolving, naturally heating to room temperature, reacting for one hour, and detecting that the reaction is finished. 2N diluted hydrochloric acid (5mL) was added to the reaction system, and dichloromethane (3X 30mL) was extracted. The dichloromethane layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude. CoarseThe product was slurried with dichloromethane, filtered, and the filter cake was collected to give compound 8-1(1.2g, 92%) as a white powdery solid. LCMS [ M-H ]]-:363.1。1H NMR(400MHz,DMSO)δ7.39-7.37(d,J=7.7Hz,1H),6.98-6.96(d,J=8.2Hz,2H),4.15-4.14(m,1H),4.04-4.00(m,1H),3.60(s,5H),3.59-3.58(d,J=4.8Hz,2H),3.17-3.16(d,J=4.6Hz,4H),2.93-2.89(m,1H),2.73-2.67(m,2H),2.61-2.51(m,1H),2.28-2.22(m,1H),1.87-1.84(t,J=7.6Hz,2H),1.58-1.51(m,2H),1.30-1.29(d,J=4.6Hz,3H),1.19-1.16(t,J=7.8Hz,2H).
Example 7
Compound 8-1(1g,3mmol), p-toluenesulfonic acid crystalline hydrate (55mg,0.3mmol) and toluene (20mL) were added to a reaction flask under nitrogen. Heating to reflux at 110 deg.c, and reacting for half an hour to complete the reaction. The reaction system is concentrated in vacuum to obtain a crude product of the intermediate 9-1. The crude product was dissolved in ethanol (20ml), palladium on carbon (10mg) was added, and hydrogenation was carried out under normal pressure. After the reaction was completed, filtration was carried out, and the solvent was removed by vacuum concentration to obtain a crude product, which was then chromatographed on silica gel to give Compound 10-1(0.86g, 89%). LCMS [ M-H ]]-:347.4。1H NMR(400MHz,CDCl3)δ7.14-7.12(d,J=8.3Hz,1H),6.93-6.91(d,J=6.4Hz,2H),3.74-3.72(m,4H),3.65(s,3H),3.54(s,2H),3.37-3.33(t,J=7.1Hz,3H),3.10-3.07(d,J=12.0Hz,2H),2.61-2.58(d,J=6.2Hz,2H),2.36-2.32(t,J=18.7Hz,3H),2.03-1.92(m,3H),1.91(d,J=11.9Hz,2H),1.67-1.61(m,2H),1.20-1.16(t,J=7.5Hz,3H).
Example 8
Compound 10-1(3.4g,10mmol), sodium tert-butoxide (2.3g,24mmol) and tetrahydrofuran (40mL) were added to a reaction flask and methyl iodide (8.5g,60mmol) was added dropwise slowly under nitrogen. Heating and refluxing, and detecting the completion of the reaction. And vacuum concentrating the reaction system to obtain a crude product. The crude product was purified by chromatography on silica gel to give compound 11-1(3.5g, 95%). LCMS [ M-H ] -: 375.2. 1H NMR (400MHz, DMSO) δ 7.17-7.15(d, J ═ 7.9Hz,1H),6.97-6.95(d, J ═ 9.9Hz,2H),3.59(s,7H),3.40(s,1H),3.04-3.01(d, J ═ 11.6Hz,2H),2.65-2.59(m,4H),2.51-2.49(m,4H),2.30-2.24(t, J ═ 11.2, 1H),1.88-1.85(d, J ═ 11.3Hz,2H),1.51-1.58(t, J ═ 13.2Hz,1H),1.49(s,6H),1.21-1.17(t, J ═ 7.5, 3H).
Example 9
Compound 11-1(3.5g,9.4mmol), sodium hydroxide (0.41g,10.3mmol) and tetrahydrofuran (20mL) were added to the reaction flask, stirred at room temperature and the starting material was detected by TLC to be reacted. 50mL of water was added, THF was removed under reduced pressure, the aqueous phase was extracted with EA and diluted HCl was acidified to Ph 2, CHCl3iPrOH 3:1, the organic phase was dried, and the solvent was removed under reduced pressure to give compound 1(3.1g, 92%). LCMS [ M-H ]]-:361.1。1H NMR(400MHz,DMSO)δ7.15-7.13(d,J=7.9Hz,1H),7.00-6.97(dd,J=6.2,3.5Hz,2H),3.59–3.57(m,4H),3.02-2.99(d,J=11.6Hz,2H),2.63-2.56(m,4H),2.29-2.24(m,1H),1.87-1.84(d,J=11.3Hz,2H),1.58-1.50(dd,J=21.6,10.1Hz,2H),1.43(s,6H),1.18-1.15(t,J=7.5Hz,3H).
Claims (10)
2. A process for the preparation of compound 5 according to claim 1,
said C1-C4Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl;
and/or in the preparation method of the compound 5, the solvent is one or more of carbon disulfide, nitrobenzene, dichloromethane, chloroform, halogenated benzene and tetrahydrofuran; or, in the preparation method of the compound 5, the rearrangement reaction is carried out under the condition of no solvent, or in the excess of the reaction reagent, specifically, in the excess of boron trifluoride diethyl etherate; when the rearrangement reaction is carried out in excess boron trifluoride diethyl etherate, the mass ratio of the compound 4 to the boron trifluoride diethyl etherate is specifically 1:3-1: 6;
and/or, in the preparation method of the compound 5, the reaction temperature of the rearrangement reaction is 120-140 ℃, specifically 130 ℃;
and/or, in the preparation method of the compound 5, the reaction time of the rearrangement reaction is 1-24h, preferably 2-4 h;
and/or, the preparation method of the compound 5 preferably comprises the following steps: under the protection of nitrogen, mixing the compound 4 with the catalyst and the solvent, and stirring for reaction at 130 ℃; further preferably, after the rearrangement reaction is completed, the method further comprises the following post-treatment steps: after the rearrangement is finished, cooling the reaction liquid to room temperature, sequentially adding ice water and dilute hydrochloric acid aqueous solution to quench the reaction, extracting with dichloromethane, drying, filtering and concentrating; still more preferably, after the post-treatment step, the method further comprises the following purification steps: and purifying the crude product obtained by post-treatment by silica gel column chromatography.
3. The method of claim 1 or 2, further comprising the steps of: in a solvent, in the presence of a base, reacting the compound 3 with acetic anhydride Ac2Performing esterification reaction on O;
wherein R is as defined in claim 1 or 2;
in the preparation method of the compound 4, the solvent is preferably one or more of dichloromethane, N-dimethylformamide, acetonitrile, tetrahydrofuran and halogenated hydrocarbon;
in the preparation method of the compound 4, the base is preferably one or more of triethylamine, diisopropylethylamine, pyridine and sodium carbonate;
in the method for producing the compound 4, the molar ratio of the base to the compound 3 is preferably 1: 1;
in the preparation method of the compound 4, the molar ratio of the acetic anhydride to the compound 3 is preferably 1.1: 1;
in the preparation method of the compound 4, the preparation method preferably further comprises the following steps: mixing the solvent, the compound 3 and the alkali, dripping the acetic anhydride at 0 ℃, and stirring for reaction at room temperature after dripping.
4. The method of claim 3, further comprising the steps of: in a solvent, under the condition of the existence of a catalyst, carrying out esterification reaction on a compound 2 and an alcohol ROH;
wherein R is as defined in claim 1 or 2;
in the preparation method of the compound 3, the solvent is preferably methanol;
in the preparation method of the compound 3, the catalyst is preferably sulfuric acid, phosphoric acid and acyl chloride, wherein the acyl chloride is preferably thionyl chloride or acetyl chloride;
in the preparation method of the compound 3, the molar ratio of the alcohol ROH to the compound 2 is preferably 1: 1;
in the preparation method of the compound 3, the preparation method preferably further comprises the following steps: and mixing the solvent, the compound 2 and the alcohol ROH, adding the catalyst, and heating and refluxing under the protection of nitrogen to react.
6. The method according to claim 5,
in the process for preparing the compound 7, the compound C1-C4Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isopropyl or tert-butyl;
and/or, in the preparation method of the compound 7, the molar ratio of the 4- (piperidine-4-yl) morpholine to the compound 6 is 1:1-3: 1;
and/or, in the preparation method of the compound 7, the reaction temperature of the substitution reaction is 100-135 ℃, in particular 120 ℃;
and/or, in the preparation method of the compound 7, the reaction time of the substitution reaction is preferably 1-24h, more preferably 2-4 h;
and/or, the preparation method of the compound 7 preferably comprises the following steps: mixing the compound 6 with the 4- (piperidine-4-yl) morpholine and the solvent, and stirring for reaction at 120 ℃; further preferably, the method further comprises the following post-treatment step after the substitution reaction is completed: after the substitution reaction is finished, pouring the reaction solution into ice water, extracting with dichloromethane, drying, filtering and concentrating; still more preferably, after the post-treatment step, the method further comprises the following purification steps: and purifying the crude product obtained by post-treatment by silica gel column chromatography.
7. The method of claim 5 or 6, further comprising the steps of: in a solvent, in the presence of alkali, carrying out condensation reaction on a compound 5 and trifluoromethanesulfonic anhydride to obtain the compound;
wherein R is as defined in claim 5 or 6;
in the preparation method of the compound 6, the solvent is preferably one or more of halogenated alkane, toluene, xylene, halogenated benzene, tetrahydrofuran and DMF;
in the preparation method of the compound 6, the base is preferably one or more of pyridine, triethylamine and diisopropylethylamine;
in the preparation method of the compound 6, the molar ratio of the base to the compound 5 is preferably 2: 1;
in the preparation method of the compound 6, the preparation method preferably further comprises the following steps: under the protection of nitrogen, mixing the solvent with the compound 5, adding the alkali at 0 ℃, dropwise adding the trifluoromethanesulfonic anhydride at 0 ℃, and reacting at room temperature; further preferably, after the condensation reaction is finished, the method further comprises the following post-treatment steps: after the condensation reaction is finished, adding ice water into the reaction solution, extracting with dichloromethane, washing an organic layer with a dilute hydrochloric acid aqueous solution and a saturated sodium carbonate aqueous solution, drying, filtering and concentrating; still more preferably, after the post-treatment step, the method further comprises the following purification steps: and purifying the crude product obtained by post-treatment by silica gel column chromatography.
8. A method of preparing compound 10, comprising the steps of: hydrogenating the compound 9;
wherein R is C1-C4An alkyl group;
in the preparation method of the compound 10, the hydrogenation reaction is preferably carried out in the presence of a catalyst Pd/C, Pd (OH)2And one or more of platinum catalysts and hydrogen;
in the preparation method of the compound 10, the reaction solvent for the hydrogenation reaction is preferably one or more of an alcohol solvent, water and tetrahydrofuran;
in the preparation method of the compound 10, the reaction temperature is preferably normal temperature;
in the preparation method of the compound 10, the reaction pressure is preferably normal pressure;
in the preparation method of the compound 10, the preparation method preferably further comprises the following steps: mixing the compound 9 with the catalyst and the solvent under hydrogen atmosphere, and stirring at room temperature for reaction; further preferably, after the hydrogenation reaction is finished, the method further comprises the following post-treatment steps: after the hydrogenation reaction is finished, filtering and concentrating the reaction solution; still more preferably, after the post-treatment step, the method further comprises the following purification steps: purifying the crude product obtained by post-treatment by silica gel column chromatography;
in the preparation method of the compound 10, the preparation method preferably further comprises the following steps: carrying out dehydration reaction on the compound 8 in the presence of acid;
wherein, the reaction solvent of the dehydration reaction is preferably one or more of benzene, toluene, xylene and halogenated benzene; the acid is preferably one or more of hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, or hydrates of the above acids; for example, p-toluenesulfonic acid monohydrate; the molar ratio of said acid to said compound 8 is preferably 0.1: 1; the dehydration reaction is preferably carried out at the atmospheric reflux temperature of the reaction solvent;
in the preparation method of the compound 10, the preparation method preferably further comprises the following steps: carrying out reduction reaction on the compound 7 in the presence of a reducing agent;
wherein, the reaction solvent of the reduction reaction is preferably one or more of alcohol solvent, water and tetrahydrofuran, such as methanol; the reducing agent is preferably one or more of sodium borohydride, potassium borohydride, lithium borohydride and DIBAL-H, and can be sodium borohydride for example; the molar ratio of the reducing agent to the compound 7 is preferably 3: 1; the reaction temperature of the reduction reaction is preferably room temperature.
9. A preparation method of an erlotinib intermediate 1 comprises the following steps:
1. in a solvent, under the condition of the existence of a catalyst, carrying out an esterification reaction on a compound 2 and an alcohol ROH to obtain a compound 3;
2. in a solvent, in the presence of a base, reacting the compound 3 with acetic anhydride Ac2Performing esterification reaction on O to obtain a compound 4;
3. carrying out rearrangement reaction on the compound 4 in a solvent in the presence of a catalyst to obtain a compound 5;
4. in a solvent, carrying out condensation reaction on a compound 5 and trifluoromethanesulfonic anhydride in the presence of a base to obtain a compound 6;
5. carrying out substitution reaction on the compound 6 and 4- (piperidine-4-yl) morpholine in a solvent to obtain a compound 7;
6. carrying out reduction reaction on the compound 7 in the presence of a reducing agent to obtain a compound 8;
7. carrying out dehydration reaction on the compound 8 in the presence of acid to obtain a compound 9;
8. hydrogenating the compound 9 to obtain a compound 10;
9. carrying out methylation reaction on the compound 10 and methyl iodide in a solvent in the presence of alkali to obtain a compound 11;
10. hydrolyzing the compound 11 in a solvent in the presence of alkali;
wherein R is as defined in claim 1 or 2;
the reaction parameters and conditions of steps 1-3 are as defined in any one of claims 1-4;
the reaction parameters and conditions of steps 4-5 are as defined in any one of claims 5-7;
the reaction parameters and conditions of steps 6-8 are as defined in claim 8;
in step 9, the solvent is preferably one or more of DMF, DMAC, tetrahydrofuran, acetonitrile, dioxane; the alkali is preferably one or more of sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide; the molar ratio of said base to said compound 10 is preferably 2.4: 1; the molar ratio of the methyl iodide to the compound 10 is preferably 6: 1; the reaction temperature of the methylation reaction is preferably the atmospheric reflux temperature of the solvent;
in step 10, the solvent is preferably tetrahydrofuran; the alkali is preferably sodium hydroxide; the molar ratio of said base to said compound 11 is preferably 1.1: 1; the reaction temperature of the hydrolysis reaction is preferably room temperature.
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CN105916506A (en) * | 2013-11-20 | 2016-08-31 | 圣诺康生命科学公司 | Quinazoline derivatives as TAM family kinase inhibitors |
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CN105916506A (en) * | 2013-11-20 | 2016-08-31 | 圣诺康生命科学公司 | Quinazoline derivatives as TAM family kinase inhibitors |
Non-Patent Citations (1)
Title |
---|
ZHILI XIN等: "《Discovery of 4-aminomethylphenylacetic acids as γ-secretase modulators via a scaffold design approach》", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
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