CN113307812B - Preparation method of broad-spectrum tumor drug larotrectinib - Google Patents

Abstract

The invention relates to a preparation method of erlotinib, which is characterized in that a compound shown in a formula II is selectively reduced to obtain a compound shown in a formula I. The invention provides a preparation method of larotinib, which has the advantages of mild reaction conditions, high chiral selectivity, high product yield and suitability for commercial production.

Description

Preparation method of broad-spectrum tumor drug larotrectinib

technical field

The invention belongs to the field of drug synthesis, in particular to a preparation method of larotrectinib.

Background technique

Larotrectinib was developed by Loxo Oncology as a broad-spectrum oncology drug for all patients with TRK-expressing tumors, rather than targeting tumors in an anatomical location. TRK fusions are widely distributed in many cancers and affect all ages, regardless of tumor genetics. Larotrectinib has been shown to have durable antitumor activity and good tolerability in Trk fusion cancers across a broad range of ages and tumor types.

The structure of larotrectinib is shown in formula I:

SUMMARY OF THE INVENTION

The present invention provides a method for synthesizing larotrectinib, which specifically includes the following steps: selectively reducing the compound of formula II to obtain the compound of formula I,

Wherein, the selective reduction method is selected from biocatalytic asymmetric reduction or chemical asymmetric reduction.

Preferably, the selective reduction method is selected from chiral reducing agent reduction or chiral catalytic hydrogenation reduction.

Preferably, the compound of formula II is selectively reduced with a borane reagent to obtain the compound of formula I, and the reaction solvent is selected from ether solvents, more preferably 2-methyltetrahydrofuran.

Preferably, the borane reagent is selected from zinc borohydride.

Preferably, S-3-hydroxytetrahydrofuran can also be added in the reaction to improve the chiral selectivity of the reaction.

Preferably, the preparation method of the compound of formula II comprises the following steps: compound 1 is reacted with 3-pyrrolidone or 3-pyrrolidone hydrochloride to obtain compound 2, and compound 2 is reacted with compound 3 to obtain the compound of formula II;

wherein X is selected from chlorine, bromine or iodine;

In the present invention, compound 3 with optical purity greater than 99.9% is used to prepare the compound of formula II. Compounds of formula II were prepared using compound 3 without racemization and inversion of chiral configuration. The detection of the optical purity in the present invention refers to the determination of the optical purity produced by the compound of formula II after asymmetric reduction of the carbonyl group.

The liquid phase detection conditions of the compound of formula I are as follows:

Chromatographic conditions for the determination of chiral enantiomers: Daicel Chiralpak IA, 5μm, 250*4.6mm; mobile phase: n-hexane:ethanol=99:5; detection wavelength: 254nm; flow rate: 0.8mL/min; column temperature: 25°C.

Compared with the prior art, the preparation method of the present invention has mild reaction conditions, high chiral selectivity, and high product purity and yield, which are suitable for commercial production.

Detailed ways

The embodiments of the present invention will be described in detail below with reference to specific examples. The following examples are only for illustrating the present invention and should not be construed as limiting the scope of the present invention.

Example 1

42.64 g of the compound of formula II was added to 400 ml of 2-methyltetrahydrofuran, and 11.1 g of zinc borohydride was added to react at 50-60 ° C for 3 hours. After the reaction was completed, the reaction solvent was recovered by concentration under reduced pressure, and 250 ml of ethanol was added to the residue to dissolve. The clear liquid was dissolved in ethanol, 350 ml of methyl tert-butyl ether was added, the solid was precipitated by stirring at 20-30 °C, filtered and dried in vacuo to obtain 40.7 g of the compound of formula I, yield 95%, purity 99.5%, enantiomeric excess percentage ee% was 95.1%.

¹ H NMR (300 MHz, d ₆ DMSO): 9.12 (d, J=7.21 Hz, 1H), 8.72 (s, 1H), 8.77 (s, 1H), 8.10 (d, J=7.2 Hz, 1H), 6.80- 7.31(m, 3H), 4.17(m, 1H), 4.03(m, 1H), 3.61(m, 2H), 3.47(m, 2H), 1.76-2.85(m, 8H); MS: (ESI, m /z,429.18,M+H).

Example 2

42.64 g of the compound of formula II was added to 400 ml of 2-methyltetrahydrofuran, 4 g of S-3-hydroxytetrahydrofuran was added, 11.1 g of zinc borohydride was added to react at 50-60 ° C for 3 hours, the reaction was completed, and the reaction solvent was recovered by concentrating under reduced pressure, Add 250 ml of ethanol to the residue to dissolve, take ethanol to dissolve the clear liquid, add 350 ml of methyl tert-butyl ether, stir at 20-30 ° C to precipitate a solid, filter, and vacuum dry to obtain 40.4 g of the compound of formula I, yield 94.5%, enantiomeric The body excess percentage ee% was 99.7%, and the purity was 99.6%. MS: (ESI, m/z, 429.16, M+H); ¹ HNMR data are basically the same as in Example 1.

Example 3

42.64 g of the compound of formula II was added to 250 ml of ethanol, 11.1 g of zinc borohydride was added, and the reaction was carried out at 50-60 ° C for 3 hours. After the reaction was completed, 350 ml of methyl tert-butyl ether was added, and the solid was precipitated by stirring at 20-30 ° C. Filter, Vacuum-drying to obtain 40.1 g of the compound of formula ^I , the yield is 93.6%, and the enantiomeric excess percentage ee% is 13.2%;

Example 4

42.64 g of the compound of formula II was added to 250 ml of ethanol, 4 g of S-3-hydroxytetrahydrofuran was added, 11.1 g of zinc borohydride was added, and the reaction was carried out at 50-60 ° C for 3 hours. After the reaction was completed, 350 ml of methyl tert-butyl ether was added. The precipitated solid was stirred at -30°C, filtered and dried in vacuo to obtain 39.4 g of the compound of formula I with ^a yield of 91.9% and an enantiomeric excess percentage ee% of 15.2%;

The preparation of embodiment 5 raw material

Compound 1 (66.7g), 25.5g of 3-pyrrolidone hydrochloride and 300ml of ethanol were added to the reaction flask, 27.6g of potassium carbonate was added, and the reaction was carried out at 20-30°C for 6-7 hours. After the reaction was completed, the filtrate was filtered and the filtrate was decompressed. Concentrate to 100ml, add 300ml of methyl tert-butyl ether, stir to precipitate solid, filter, and vacuum dry the filter cake to obtain compound 2 (49.2g), yield 88%; MS: (ESI, m/z, 280.05, M+H ).

Compound 2 (29.6 g, 106 mmol), compound 3 (18 g, 98.2 mmol) and ethanol (200 mL) were added to the reaction flask, N,N-diisopropylethylamine (16.5 g, 128 mmol) was added dropwise, and the reaction temperature was maintained Within 30°C, after the dropwise addition was completed, the reaction was continued for 5-8 hours, controlled by TLC, after the reaction was completed, methyl tert-butyl ether (300 mL) was added, a solid was precipitated, and the stirring was continued for 30 minutes, filtered, and the filter cake was vacuumized After drying, 40.2 g of the compound of formula II was obtained with a yield of 89%; MS: (ESI, m/z, 427.17, M+H).

Claims (3)

1. a preparation method of a compound of formula I, wherein the compound of formula II is selectively reduced with a borane reagent to obtain a compound of formula I,

The borane reagent is selected from zinc borohydride, and the reaction solvent is selected from 2-methyltetrahydrofuran. 2. method according to claim 1 is characterized in that, reaction has also added S-3-hydroxytetrahydrofuran. 3. The method according to claim 1, wherein compound 1 reacts with 3-pyrrolidone or 3-pyrrolidone hydrochloride to obtain compound 2, and compound 2 reacts with compound 3 to obtain compound of formula II; wherein X is selected from chlorine, bromine or iodine;