阅读说明：本技术 (s)-5-氟-3-甲基异苯并呋喃-3-酮的合成方法 (Synthesis method of (S) -5-fluoro-3-methylisobenzofuran-3-one ) 是由 沙宇 陈佳乐 张春秋 高博一 程卯生 于 2021-08-11 设计创作，主要内容包括：本发明属于医药技术领域,涉及抗肿瘤药物劳拉替尼(Lorlatinib)中间体(S)-5-氟-3-甲基异苯并呋喃-3-酮的合成方法,该方法以2-溴-4-氟苯甲酸为起始原料,经两步格氏反应与拆分得到(S)-5-氟-3-甲基异苯并呋喃-3-酮,总收率达到36.5％以上。该合成方法路线较短,耗时短,成本较低,利于实现工业化。该中间体与1-甲基-3-((甲氨基)甲基)-1H-吡唑-5-腈经缩合、取代、偶联等反应步骤最终合成劳拉替尼,为抗肿瘤药物劳拉替尼的合成提供了新的方法。(The invention belongs to the technical field of medicines, and relates to a synthesis method of an antitumor drug Laolatinib (Lorlatinib) intermediate (S) -5-fluoro-3-methylisobenzofuran-3-ketone, which takes 2-bromo-4-fluorobenzoic acid as a starting material and obtains (S) -5-fluoro-3-methylisobenzofuran-3-ketone through two steps of Grignard reaction and resolution, wherein the total yield is up to over 36.5%. The synthetic method has the advantages of short route, short time consumption and low cost, and is beneficial to realizing industrialization. The intermediate and 1-methyl-3- ((methylamino) methyl) -1H-pyrazole-5-nitrile are subjected to condensation, substitution, coupling and other reaction steps to finally synthesize the Laratinib, and a new method is provided for synthesizing the anti-tumor medicine Laratinib.)

A process for producing (S) -5-fluoro-3-methylisobenzofuran-3-one,

(1) reacting 2-bromo-4-fluorobenzoic acid with i-PrMgCl and DMF at low temperature to obtain 4-fluoro-2-formylbenzoic acid;

(2) 4-fluoro-2-formylbenzoic acid and MeMgCl are subjected to Grignard reaction at low temperature to prepare 5-fluoro-3-methylisobenzofuran-3-one;

(3) 5-fluoro-3-methylisobenzofuran-3-one is subjected to ring opening under an alkaline condition, is acidified to obtain 4-fluoro-2 (1-hydroxyethyl) phenylacetic acid, then forms a salt with (S) -methylbenzylamine, and the obtained product is subjected to recrystallization for 3 times, and is dissociated and acidified under an alkaline condition to obtain (S) -5-fluoro-3-methylisobenzofuran-3-one.

2. The preparation method of claim 1, wherein in the step (1), the 2-bromo-4-fluorobenzoic acid is prepared into the 4-fluoro-2-formylbenzoic acid under low temperature condition, the organic solvent is anhydrous tetrahydrofuran or anhydrous ether under the protection of nitrogen, the temperature for preparing the aryl Grignard reagent is-30 ℃ to-35 ℃, the temperature for adding DMF is-15 ℃ to-20 ℃, and DMF can be replaced by acetaldehyde, so as to directly obtain the compound III, the Grignard reagent can be replaced by n-butyllithium, and the molar ratio of the 2-bromo-4-fluorobenzoic acid to the Grignard reagent and the DMF is 1:3:3 to 1:3:5, preferably 1:3:4

3. The preparation method according to claim 1, wherein in the step (2), the 4-fluoro-2-formylbenzoic acid is used for preparing the 5-fluoro-3-methylisobenzofuran-3-one under low temperature conditions, the organic solvent is anhydrous tetrahydrofuran or anhydrous diethyl ether, the temperature is reduced to-15 ℃ under the protection of nitrogen, a methyl Grignard reagent is added dropwise, the Grignard reagent can be replaced by methyl magnesium bromide or methyl magnesium chloride, the mixture is transferred to room temperature after dropwise addition to prepare the 4-fluoro-2 (1-hydroxyethyl) phenylacetic acid, and the post-treatment is reduced pressure distillation to prepare the 5-fluoro-3-methylisobenzofuran-3-one

4. The process of claim 1, wherein in step (3), 5-fluoro-3-methylisobenzofuran-3-one is ring-opened under alkaline conditions, the base is selected from sodium salt organic base of C1-C4 alcohol or sodium hydroxide, potassium hydroxide, sodium hydride or LDA inorganic base, compound III is obtained by acidification, the acid is selected from formic acid, glacial acetic acid or hydrochloric acid, and the selected solvent is methanol/water, ethanol/water, isopropanol/water mixed system; the compound III is salified with (S) -methylbenzylamine at low temperature, and the molar ratio of the compound III to the (S) -methylbenzylamine is 1: 0.5-1: 1, preferably 1: 0.5; the salt forming temperature is 0 ℃ to-15 ℃, and is preferably-15 ℃; the salifying solvent is tetrahydrofuran or anhydrous diethyl ether or ethyl acetate or acetonitrile, wherein tetrahydrofuran is preferred; recrystallizing the carboxylic amine salt by using a recrystallization solvent selected from methanol, ethanol, acetonitrile, acetone/ethanol mixed solution, preferably acetone/ethanol mixed solution, wherein the recrystallization temperature is not higher than 30 ℃, and then the carboxylic amine salt is dissociated and acidified under the alkaline condition to obtain (S) -5-fluoro-3-methyl isobenzofuran-3-one, the alkali is selected from sodium salt organic alkali of C1-C4 alcohol or sodium hydroxide, potassium hydroxide, sodium hydride or LDA inorganic alkali, and the acid is selected from formic acid, glacial acetic acid or hydrochloric acid; the reaction temperature is 50-70 DEG C

5. The method according to claim 1Characterised in that, in step (3), the resolution of the remaining intermediate is carried out by re-ring opening under basic conditions, the base being selected from the group consisting of sodium salt organic bases of C1-C4 alcohols or sodium hydroxide, potassium hydroxide, sodium hydride or LDA inorganic bases; opening the ring, oxidizing to obtain a compound II, wherein the oxidant is selected from manganese dioxide, chromium trioxide, potassium permanganate, Jones reagent, collins reagent or sodium hypochlorite, the compound II is reduced to obtain a compound III, and the reducing agent is selected from NaBH₄、LiAlH₄Diborane and aluminium isopropoxide, and the obtained compound III is subjected to the resolution to obtain (S) -5-fluoro-3-methyl isobenzofuran-3-ketone

Technical Field

The invention relates to the technical field of medicines, and relates to a synthesis method of a medicine Laratinib key intermediate (S) -5-fluoro-3-methylisobenzofuran-3-one. The intermediate and 1-methyl-3- ((methylamino) methyl) -1H-pyrazole-5-nitrile are subjected to condensation, substitution, coupling and other reaction steps to finally synthesize the Laratinib, and a new method is provided for synthesizing the anti-tumor medicine Laratinib.

Background

Loratinib (lorelatinib) is a third-generation ALK inhibitor obtained by Pfizer, inc (Crizotinib), of Crizotinib, usa. The medicine enters clinical trials in 2014, is used for treating lung cancer and mainly aims at non-small cell lung cancer patients with drug resistance of a first generation ALK inhibitor crizotinib and drug resistance of a second generation ALK inhibitor Ceritinib (Ceritinib) and drug resistance of Aletinib (Alectininib). Four synthetic routes to loratinib and its intermediates are described in WO2013132376, US8680111, JP2015510879, EP2822953, CN 1041699286, US2016115178, WO2014207606 in the following patent documents.

(S) -5-fluoro-3-methylisobenzofuran-1 (3H) -one is a main raw material for preparing Laratinib, is an important chemical and medical intermediate, and can be used in a plurality of fields such as dyes, hair dyes, medicines, pesticide materials and the like. However, there are few reports on the preparation method of (S) -5-fluoro-3-methylisobenzofuran-1 (3H) -one. WO2013132376 shows a synthesis method for the intermediate (S) -5-fluoro-3-methylisobenzofuran-1 (3H) -one, but the synthesis route is long, the cost is high, the time consumption is long, and the yield is low. CN109134410A is a previous patent application of the inventor, and discloses a preparation method of 5-fluoro-3-methylisobenzofuran-1 (3H) -ketone, but the method still has the problems of long synthetic route, high cost, low yield and complex treatment. CN112921057A discloses a novel synthesis route of 5-fluoro-3-methyl isobenzofuran-1 (3H) -ketone, which greatly shortens the synthesis method provided by the original report, simplifies the operation and improves the yield, but the method samples biological enzyme as a catalyst, thereby limiting the application range of the preparation method.

Therefore, it is necessary to develop a new synthesis method of intermediate (S) -5-fluoro-3-methylisobenzofuran-1 (3H) -one, which has the advantages of easily available raw materials, short steps, low cost, and the like, and is easy for industrialization.

Disclosure of Invention

The invention aims to solve the technical problem of providing a novel synthesis method of (S) -5-fluoro-3-methylisobenzofuran-1 (3H) -one.

The invention is realized by the following technical scheme:

2-bromo-4-fluorobenzoic acid is taken as an initial raw material, and the (S) -5-fluoro-3-yl isobenzofuran-1 (3H) -ketone is obtained through a two-step Grignard reaction and one-step chiral resolution reaction.

The invention realizes the preparation of the antitumor drug Laratinib key intermediate (S) -5-fluoro-3-methylisobenzofuran-1 (3H) -ketone, has the total yield of over 36.5 percent, has short time consumption and low cost, is beneficial to realizing industrialization, and provides a new method for the synthesis of the antitumor drug Laratinib.

The synthesis method comprises the following steps:

the preparation method of (S) -5-fluoro-3-methylisobenzofuran-1 (3H) -one is as follows:

(1) reacting 2-bromo-4-fluorobenzoic acid with i-PrMgCl and DMF at low temperature to obtain 4-fluoro-2-formylbenzoic acid;

(2) 4-fluoro-2-formylbenzoic acid and MeMgCl are subjected to Grignard reaction at low temperature to prepare 5-fluoro-3-methylisobenzofuran-3-one;

(3) 5-fluoro-3-methylisobenzofuran-3-one is subjected to ring opening under an alkaline condition, is acidified to obtain 4-fluoro-2 (1-hydroxyethyl) phenylacetic acid, is salified with (S) -methylbenzylamine at a low temperature to separate out amine carboxylate, is subjected to recrystallization for 3 times, and is dissociated and acidified under an alkaline condition to obtain (S) -5-fluoro-3-methylisobenzofuran-3-one.

The reaction scheme for preparing the compound of the invention is as follows:

in a process for the preparation of (S) -5-fluoro-3-methylisobenzofuran-1 (3H) -one:

in the step (1), 2-bromo-4-fluorobenzoic acid is used for preparing 4-fluoro-2-formylbenzoic acid at a low temperature, an organic solvent is anhydrous tetrahydrofuran or anhydrous ether under the protection of nitrogen, the temperature for preparing the aryl Grignard reagent is-30 ℃ to-35 ℃, the temperature for adding DMF is-15 ℃ to-20 ℃, and DMF can be replaced by acetaldehyde, so that the compound III is directly obtained, the Grignard reagent can be replaced by n-butyllithium, and the molar ratio of the 2-bromo-4-fluorobenzoic acid to the Grignard reagent and the DMF is 1:3:3 to 1:3:5, preferably 1:3: 4.

In the step (2), 4-fluoro-2-formylbenzoic acid is used for preparing 5-fluoro-3-methylisobenzofuran-3-one at low temperature, an organic solvent is anhydrous tetrahydrofuran or anhydrous ether, the temperature is reduced to-15 ℃ under the protection of nitrogen, a methyl Grignard reagent is dripped, the Grignard reagent can be replaced by methyl magnesium bromide or methyl magnesium chloride, the mixture is transferred to room temperature after dripping is finished, 4-fluoro-2 (1-hydroxyethyl) phenylacetic acid is prepared, and the post-treatment is reduced pressure distillation, so that the 5-fluoro-3-methylisobenzofuran-3-one is prepared.

In the step (3), 5-fluoro-3-methyl isobenzofuran-3-one is subjected to ring opening under alkaline conditions, the alkali is selected from sodium salt organic alkali of C1-C4 alcohol or sodium hydroxide, potassium hydroxide, sodium hydride or LDA inorganic alkali, and compound III is obtained by acidification, the acid is selected from formic acid, glacial acetic acid or hydrochloric acid, and the selected solvent is a methanol/water, ethanol/water or isopropanol/water mixed system; the compound III is salified with (S) -methylbenzylamine at low temperature, and the molar ratio of the compound III to the (S) -methylbenzylamine is 1: 0.5-1: 1, preferably 1: 0.5; the salt forming temperature is 0 ℃ to-15 ℃, and is preferably-15 ℃; the salifying solvent is tetrahydrofuran or anhydrous diethyl ether or ethyl acetate or acetonitrile, wherein tetrahydrofuran is preferred; recrystallizing the carboxylic amine salt by using a recrystallization solvent selected from methanol, ethanol, acetonitrile, acetone/ethanol mixed solution, preferably acetone/ethanol mixed solution, wherein the recrystallization temperature is not higher than 30 ℃, and then the carboxylic amine salt is dissociated and acidified under the alkaline condition to obtain (S) -5-fluoro-3-methyl isobenzofuran-3-one, the alkali is selected from sodium salt organic alkali of C1-C4 alcohol or sodium hydroxide, potassium hydroxide, sodium hydride or LDA inorganic alkali, and the acid is selected from formic acid, glacial acetic acid or hydrochloric acid; the reaction temperature is 50-70 ℃.

In step (3), the remaining intermediate is resolved by re-opening the ring under basic conditions, the base being selected from the group consisting of sodium salt organic bases of C1-C4 alcohols or sodium hydroxide, potassium hydroxide, sodium hydride or LDA inorganic bases; opening the ring, oxidizing to obtain a compound II, wherein the oxidant is selected from manganese dioxide, chromium trioxide, potassium permanganate, Jones reagent, collins reagent or sodium hypochlorite, the compound II is reduced to obtain a compound III, and the reducing agent is selected from NaBH₄、LiAlH₄Diborane and aluminium isopropoxide, and resolving the obtained compound III to obtain the (S) -5-fluoro-3-methyl isobenzofuran-3-one.

Compared with the prior art, the method has the advantages of easily available raw materials, short steps, low cost, high yield, product recycling and the like, and is favorable for realizing industrialization.

Detailed Description

The invention is further illustrated with reference to specific examples. It should be understood that the specific embodiments described herein are illustrative only and are not limiting upon the scope of the invention.

The examples do not show the specific techniques or conditions, according to the technical or conditions described in the literature in the field, or according to the product specifications. The reagents or instruments used are conventional products which are not known to manufacturers and are available from normal sources.

The experimental procedures in the following examples are conventional unless otherwise specified. The test materials used in the following examples are all commercially available products unless otherwise specified.

Example 1

(1) Synthesis of 4-fluoro-2-formylbenzoic acid

Under nitrogen, 137mL (273.97mmol) of i-PrMgCl was added to a 500mL three-necked flask. At-30 ℃, a solution of 20.0g (91.32mmol) of 2-bromo-4-fluorobenzoic acid in anhydrous tetrahydrofuran (120mL) is added dropwise to the reaction flask, and after 1h, the addition is complete. The reaction was continued at this temperature for 4 h. Heating to-15 ℃, dropwise adding 35.2mL (456.62mmol) of anhydrous DMF solution, after 0.5h of dropwise adding, moving to room temperature to continue reacting for 12h, and finishing the reaction. The reaction was quenched with crushed ice, concentrated under reduced pressure to remove tetrahydrofuran, and then diluted hydrochloric acid (2 mol/L) was added to adjust pH to 1-2 under ice bath to precipitate a white solid, whereby 13.0g of the product was obtained in 85.2% yield.

ESI-MS(m/z)：167.01[M-H]^-。¹H NMR(600MHz,DMSO-d6)δ8.29(s,1H),7.91(dd,J＝8.5,4.7Hz,1H),7.57(dd,J＝8.2,2.3Hz,1H),7.51(td,J＝9.0,2.3Hz,1H),6.65(s,1H)。

(2) Synthesis of 5-fluoro-3-methylisobenzofuran-3-one

Under the protection of nitrogen, 20.0g (119.04mol) of 4-fluoro-2-formylbenzoic acid and anhydrous tetrahydrofuran (120mL) are added into a 500mL three-necked bottle, 60mL (357.12mmol) of MeMgCl is added dropwise at-15 ℃, the temperature is kept for reaction for 2h, then the mixture is moved to room temperature for further reaction for 12h, and the reaction is finished. Crushed ice is added into the reaction liquid to quench the reaction, the pH value is adjusted to 5-6 by acetic acid, and the water layer is distilled under reduced pressure to obtain white solid. 200mL of ethyl acetate was added to dissolve the product, and the filter cake was discarded by filtration. The filtrate was concentrated, and a white solid precipitated in 86.7% yield.

ESI-MS(m/z)：167.05[M+H]⁺。¹H NMR(600MHz,DMSO-d6)δ7.90(dd,J＝8.4,4.9Hz,1H),7.63(dd,J＝8.5,2.3Hz,1H),7.44(td,J＝8.9,2.2Hz,1H),5.69(q,J＝6.7Hz,1H),1.57(d,J＝6.7Hz,3H)。

(3) Synthesis of (S) -5-fluoro-3-methylisobenzofuran-3-one

Dissolving 10.0g (59.52mmol) of 5-fluoro-3-methylisobenzofuran-3-one in a mixed solution of methanol (50mL) and water (20mL), adding 2mol/L sodium hydroxide solution under the stirring condition, heating to 70 ℃, and carrying out reflux reaction for 0.5h to finish the reaction. The reaction mixture was concentrated to remove methanol, the pH was adjusted to 5 to 6 with 2mol/L dilute hydrochloric acid under ice bath conditions, tetrahydrofuran (80mL) was extracted, 6.8mL (59.52mmol) of (S) -methylbenzylamine was added dropwise to the reaction mixture at 0 ℃, and after 10min, stirring was stopped and the mixture was allowed to stand in a cold trap for 1 h. After the mixture was allowed to stand at room temperature for 12 hours, white crystals precipitated, and 7.6g of white needle-like crystals were obtained by filtration. Recrystallizing for 2 times by using a mixed solvent of ethanol and acetone to obtain 6.1g of salified product. Dissolving the obtained salt-forming product in water, adding 2mol/L sodium hydroxide solution, stirring at room temperature for 0.5h, extracting (S) -methylbenzylamine with diethyl ether, neutralizing the water layer with 2mol/L dilute hydrochloric acid solution at room temperature until the pH value is 1-2, and separating out white solid. After filtration and concentration, 2.2g of the product is obtained. The yield thereof was found to be 83.4%.>99.9％ee(HPLC/ChiralpakIC/mobile phase: n-hexane: isopropyl alcohol: diethylamine-90: 10: 0.1). ESI-MS (m/z): 167.05[ M + H]⁺。

Compared with the method provided by the prior art document, the reaction process of the invention can improve the yield and save the cost.

Example 2

(1) Synthesis of 5-fluoro-3-methylisobenzofuran-3-one

Under nitrogen, 137mL (273.97mmol) of i-PrMgCl was added to a 500mL three-necked flask. At-30 ℃, a solution of 20.0g (91.32mmol) of 2-bromo-4-fluorobenzoic acid in anhydrous tetrahydrofuran (120mL) is added dropwise to the reaction flask, and after 1h, the addition is complete. The reaction was continued at this temperature for 4 h. Heating to-15 ℃, dropwise adding 35.2mL (456.62mmol) of acetaldehyde, after 0.5h of dropwise adding, moving to room temperature to continue reacting for 12h, after the reaction is finished, adding crushed ice to quench the reaction, adjusting the pH value to 5-6 with acetic acid, and distilling the water layer under reduced pressure to obtain a white solid. 200mL of ethyl acetate was added to dissolve the product, and the filter cake was discarded by filtration. The filtrate was concentrated, and a white solid precipitated in 86.7% yield.

ESI-MS(m/z)：167.05[M+H]⁺。1H NMR(600MHz,DMSO-d6)δ7.90(dd,J＝8.4,4.9Hz,1H),7.63(dd,J＝8.5,2.3Hz,1H),7.44(td,J＝8.9,2.2Hz,1H),5.69(q,J＝6.7Hz,1H),1.57(d,J＝6.7Hz,3H)。

(2) Synthesis of (S) -5-fluoro-3-methylisobenzofuran-3-one

PF1-410.0g (60.24mmol) is dissolved in a mixed solution of methanol (50mL) and water (20mL), 2.4g (60.24mmol) of NaOH is added under the condition of stirring, the temperature is raised to 70 ℃, reflux reaction is carried out for 0.5h, and the reaction is finished. The mixture was concentrated to remove methanol, the pH was adjusted to 3 to 4 with 2mol/L dilute hydrochloric acid under ice-bath conditions, a white solid was precipitated, and the ring-opened product was filtered off to obtain 11.0g, with a yield of 99.9%. 10.0g (54.34mmol) of the ring-opened product was dissolved in THF (80mL), 3.4mL (27.72mmol) of (S) -methylbenzylamine was added dropwise to the reaction mixture at-15 ℃ and after 10min, stirring was continued for 0.5 h. 3.7mL (26.63mmol) of triethylamine was added to the reaction mixture, and after 10min, the dropwise addition was completed, the stirring was stopped, and the mixture was allowed to stand in a cold trap for 1 h. The reaction flask was allowed to stand at room temperature for 12 hours, and white crystals were precipitated and filtered to obtain 7.6g of white needle-like crystals with a yield of 45.6%. Recrystallizing for 2 times by using a mixed solvent of ethanol and acetone to obtain 6.1g of salified product with the yield of 80.4 percent. The obtained salt-forming product was dissolved in water, 2mol/L sodium hydroxide solution was added, stirring was carried out at room temperature for 0.5h, the (S) -methylbenzylamine was extracted with diethyl ether, and the aqueous layer was neutralized with 3mol/L dilute salt solution at room temperature to pH 1-2, and a white solid was precipitated. After filtration and concentration, 2.2g of the product was obtained with a yield of 81.6%. 99.9% ee (HPLC/Chiralpak IC/mobile phase: n-hexane: isopropanol: diethylamine ═ 90: 10: 0.1).

(3) Synthesis of 4-fluoro-2 (1-hydroxyethyl) phenylacetic acid

Recovering 4.7g (28.31mmol) of (R) -5-fluoro-3-methylisobenzofuran-3-one in the mother liquor, dissolving in a mixed solution of methanol (20mL) and water (10mL), adding 2.4g (60.24mmol) of NaOH under stirring, heating to 70 ℃, and carrying out reflux reaction for 0.5h to finish the reaction. The reaction mixture was concentrated to remove methanol, and the mixture was adjusted to pH 3-4 with 2mol/L dilute hydrochloric acid in ice bath to precipitate a white solid, which was then filtered to obtain 5.2g of ring-opened product VIII in 99.9% yield. Dissolving 5.2g (28.31mmol) of compound VIII in THF (20mL), cooling to 0 ℃, and then adding KBr and NaHCO in sequence₃And TEMPO, then slowly dripping NaClO solution, wherein the temperature of the solution is 0-5 ℃, and reacting for 3 hours to obtain 4.7g of a compound II, wherein the yield is 91.3%. 4.7g (25.82mmol) of the compound II is dissolved in methanol (20mL), cooled in an ice bath, added with sodium borohydride and stirred for reaction for 4 hours to obtain 3.85g of 4-fluoro-2 (1-hydroxyethyl) phenylacetic acid with the yield of 81.2 percent.

Compared with the method provided by the prior art document, the reaction process of the invention can improve the yield and save the cost.

It will be apparent to those skilled in the art that various changes and modifications may be made in the present invention without departing from the spirit and scope of the invention. Thus, if such modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include such modifications and variations.