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Preparation method of key intermediate of lorlatinib

A technology of total volume and catalytic system is applied in the field of preparation of 5-fluoro-3-methylisobenzofuran-1-one, a key intermediate of lorlatinib, and can solve the problem of long synthesis route, high cost and high yield. lower problem

Pending Publication Date: 2021-06-04
SHANGHAI TIANCI INT PHARMA
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Problems solved by technology

[0004] 5-Fluoro-3-methylisobenzofuran-1(3H)-one is an important intermediate in the synthesis of lorlatinib. In the existing reports, its synthetic route is long, the cost is high, the yield is low, and the processing complex

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  • Preparation method of key intermediate of lorlatinib
  • Preparation method of key intermediate of lorlatinib
  • Preparation method of key intermediate of lorlatinib

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preparation example Construction

[0080] The preparation method of lorlatinib key intermediate (formula IV)

[0081] The present invention provides a new synthetic route of the intermediate shown in formula IV, through which the synthetic route (or method) greatly shortens the synthetic method provided by the original report, simplifies the operation, improves the yield, and greatly reduced costs. More importantly, the chemical method racemization resolution used in the past was changed, and the biological enzyme was used as the catalyst method, which is environmentally friendly, simple, high yield, and has no side reactions, which greatly improves the product quality.

[0082] Typically, the present invention provides a preparation method of a compound of formula IV, the preparation method comprising the steps of:

[0083] (1) Formula I is subjected to chiral reduction under the catalysis of biological enzymes to obtain chiral formula II

[0084]

[0085] Preferably, the biological enzyme is perakine red...

Embodiment 7

[0135] The preparation of embodiment 7 formula IV compound

[0136] Add the compound of formula III (50g, 0.27mol, prepared according to the method of Example 4) into the mixed solution of absolute ethanol (450ml) and water (50ml), add concentrated sulfuric acid (264.6g 2.7mol) dropwise, and control the temperature for 20-30 After adding at ℃, react for 2-3h, add the reaction solution dropwise into water (600ml), stir, add dichloromethane (400ml) for extraction, then add dichloromethane (200ml) for extraction and separation, combine dichloromethane, add Pressure distillation gave product (40.14g), yield: 89.1% (relative to formula III) MS (ESI): [M+1] + = 167.17. After testing, the purity is 99.8% (see Figure 4 ).

Embodiment 8

[0137] The preparation of embodiment 8 formula IV compound

[0138] The compound of formula III (50g, 0.27mol, prepared according to the method of Example 4) was added to the mixed solution of methanol (450ml) and water (50ml), and phosphoric acid (264.6g 2.7mol) was added dropwise, and the temperature was controlled at 20-30°C to complete the addition , reacted for 2-3h, added the reaction solution dropwise into water (600ml), stirred, added dichloromethane (400ml) for extraction, then added dichloromethane (200ml) for extraction and separation, combined dichloromethane, and distilled under pressure to obtain Product (39.3 g), yield: 87.2% (relative to formula III) MS (ESI): [M+1] + = 167.17. After testing, the purity is 98.9% (see Figure 5 ).

[0139] The preparation of comparative example 1 formula III compound

[0140] The compound of formula II (10g, 45.6mmol, obtained by the method of Example 1) was added in ethanol (600ml), added in the autoclave, and palladium ace...

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Abstract

The invention provides a preparation method of a key intermediate (shown as formula IV) of lorlatinib. Specifically, the preparation method provided by the invention comprises the following steps of (1) in a bio-enzyme catalytic reduction system containing bio-enzyme, carrying out a reduction reaction on a compound shown as formula I to form a compound shown as formula II; (2) in a first inert solvent, in the presence of n-butyllithium and carbon dioxide, reacting the compound shown in the formula II prepared in the step (1) to obtain a compound shown in formula III; and (3) in a second inert solvent, carrying out an esterification reaction on the compound shown in the formula III obtained in the step (2) to obtain a compound shown in formula IV. The preparation method has the advantages of a short synthetic route, low cost and simplicity in treatment.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of lorlatinib key intermediate 5-fluoro-3-methylisobenzofuran-1(3H)-one. Background technique [0002] Lorlatinib is a potent, dual ALK / ROSI inhibitor that plays an extremely important role in the treatment of cancer [0003] Lorlatinib was developed by Pfizer of the United States. It entered the clinical stage in 2014 through the modification of crizotinib (Crizotinib) as an ALK inhibitor. It has a significant effect on the treatment of lung cancer. [0004] 5-Fluoro-3-methylisobenzofuran-1(3H)-one is an important intermediate in the synthesis of lorlatinib. In the existing reports, its synthetic route is long, the cost is high, the yield is low, and the processing complex. . [0005] In summary, there is an urgent need in this field to develop a 5-fluoro-3-methylisobenzofuran-1(3H)-one with short route, simple operation, high yield, high ch...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P17/04C07D307/88
CPCC12P17/04C07D307/88C07B2200/07
Inventor 李勇刚王卓丁正杰
Owner SHANGHAI TIANCI INT PHARMA
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