CN103819396B - A kind of 1-(3,5-dichloropyridine-4-base of chirality) synthetic method of-ethanol - Google Patents

Abstract

The invention discloses an asymmetric synthesis method of 1-(3,5-dichloropyridine-4-yl)-ethanol, which comprises the following steps: (A) 3,5-dichloropyridine (I) in lithium amide Under the action of reaction with acetaldehyde to generate (±)-1-(3,5-dichloropyridin-4-yl)-ethanol (II); (B) (±)-1-(3,5-dichloropyridine -4-yl)-ethanol (II) generates 1-(3,5-dichloropyridin-4-yl)-ethanone (III) under the action of oxidant; (C) 1-(3,5-dichloro Reaction of pyridin-4-yl)-ethanone with borane reagent in the presence of chiral ligands to produce 1-(3,5-dichloropyridin-4-yl)-ethanol (IV) as a single optical isomer . Compared with traditional chiral column separation (±)-1-(3,5-dichloropyridin-4-yl)-ethanol, this method has outstanding advantages: (1) simple reaction, easy operation, high overall yield, optical The purity is greater than 98%; (2) The industrial preparation cycle is obviously shortened, and the equipment requirements are low; (3) The preparation cost is low, and it is a method suitable for industrial production.

Description

A kind of synthetic method of chiral 1-(3,5-dichloropyridin-4-yl)-ethanol

technical field

The invention belongs to the field of pharmaceutical intermediates, and relates to a chiral 1-(3,5-dichloropyridin-4-yl)-ethanol synthesis method and application thereof.

Background technique

Fibroblast growth factor receptor (FGFR) belongs to the receptor-type protein tyrosine kinase family, which mainly includes four members: FGFR1, FGFR2, FGFR3 and FGFR4. FGFR is involved in the regulation of cell proliferation, apoptosis, migration, angiogenesis and many other processes. Because of their broad range of roles, FGFRs and other RTKs are normally tightly regulated. In tumors, such as breast cancer, bladder cancer, prostate cancer, etc., FGFR activating mutations or ligand/receptor overexpression lead to its continuous activation, which is not only closely related to the occurrence, development, and poor prognosis of tumors, but also in tumor neogenesis. It also plays an important role in angiogenesis, tumor invasion and metastasis. Therefore, FGFR is recognized as an important anti-tumor target, and the development of small molecule inhibitors of FGFR has gradually received more and more attention. FGFR inhibitors have been reported as anti-tumor compounds, such as WO2002022598. Among them, LY2874455 is a specific inhibitor of FGFRs, which has entered the second phase of clinical trials, and the prospect is very promising.

S-1-(3,5-dichloropyridin-4-yl)ethanol is an important intermediate for the synthesis of FGFR inhibitor LY2874455, and the previous literature reported that the racemate was separated by HPLC chiral column to obtain a single chiral Isomer S-1-(3,5-dichloropyridin-4-yl)ethanol, and the absolute configuration of optical isomers is identified only by vibrational circular dichroism and infrared spectroscopy, such as CN102421769A. The yield of the method is low, the separation cost is high, the preparation period is long, and industrial production cannot be carried out.

Contents of the invention

The purpose of the present invention is to provide a high-yield asymmetric synthesis method for the preparation of optically active 1-(3,5-dichloropyridin-4-yl)ethanol, which has short steps, simple preparation, and equipment The requirement is low, the yield and optical purity are high, and it is a method suitable for industrial production.

A chiral 1-(3,5-dichloropyridin-4-yl)-ethanol and sulfonate synthesis method provided by the present invention is characterized by the following steps:

a. 3,5-dichloropyridine (I) reacts with acetaldehyde under the action of lithium amide to generate (±)-1-(3,5-dichloropyridin-4-yl)-ethanol (II);

b. (±)-1-(3,5-dichloropyridin-4-yl)-ethanol (II) generates 1-(3,5-dichloropyridin-4-yl)-ethanone under the action of oxidant (III);

c.1-(3,5-dichloropyridin-4-yl)-ethanone (III) reacts with borane reagent in the presence of corresponding chiral ligands to obtain 1-(3, 5-dichloropyridin-4-yl)-ethanol (IV);

As a preferred mode, in the step a, the solvent used is one or more of tetrahydrofuran, ether, n-hexane, and cyclohexane;

As a preferred mode, in the step a, the lithium amide used is lithium diisopropylamide;

As a preferred mode, in the step a, the molar ratio of 3,5-dichloropyridine to acetaldehyde is: 1:1~10; the reaction temperature is: -78 ^o C ~ 0 ^o C; the reaction time: 1 ~ 12 Hour;

As a preferred mode, in the step b, the solvent used is dichloromethane or acetonitrile; the oxidizing agent is pyridinium chlorochromate, pyridinium dichromate, Jones reagent (Jones), Dess-Martin reagent (Dess -One or more of Martin); the molar ratio of (±)-1-(3,5-dichloropyridin-4-yl)-ethanol (II) to oxidant is: 1:1~5; the reaction temperature is : -20 ^o C~60 ^o C; Reaction time: 1~12 hours;

As a preferred mode, in the step c, the solvent used is one or more of dichloromethane, tetrahydrofuran, ether, and dioxane; the chiral ligand is selected from: S-2-methyl-CBS- Oxazolidine or R-2-methyl-CBS-oxazolidine; the borane reagent is selected from one or more of borane dimethyl sulfide, borane tetrahydrofuran, and borane pyridine;

As a preferred mode, in the step c, the molar ratio of 1-(3,5-dichloropyridin-4-yl)-ethanone (III), chiral ligand and borane reagent is: 1:0.1-1 :1-10,

Further preferably, the molar ratio of 1-(3,5-dichloropyridin-4-yl)-ethanone (III), chiral ligand and borane reagent is: 1:0.2:5; the reaction temperature is -40 ^o C~60 ^o C, preferably -10 ^o C; the reaction time is 1~12 hours;

At the beginning of the preparation, we planned to use the resolution method to obtain the single isomer of 1-(3,5-dichloropyridin-4-yl)-ethanol, and tried a variety of chiral resolving agents for its enantiomer The chiral resolution of the body was carried out, but no satisfactory results were obtained. Later, the method of direct asymmetric reduction of the corresponding ketone was adopted, and various chiral ligands and reduction conditions were tried, and finally the best result was obtained with chiral 2-methyl-CBS-oxazoboridine, ee>98 %, and the total yield of the two-step reaction is greater than 80%, which is obviously better than the direct resolution method, and the operation is simple and easy, and the equipment cost is low, which is very suitable for industrial production.

Example

The following comparative examples and examples further illustrate the technical solution of the present invention, but it must not be considered that these comparative examples and examples limit the present invention.

Example 1

Preparation of 1-(3,5-dichloropyridin-4-yl)ethanol (II)

Diisopropylamine (DIPA, 13.2ml, 94.60mmol) was dissolved in anhydrous tetrahydrofuran (THF, 50ml), cooled at -78°C, and n-butyllithium (1.6M hexane solution, 50ml, 81.08 mmol), the reaction solution was gradually turbid, and after 1 hour, the drop was completed. After cooling for 20 minutes, a THF (30ml) solution of 3,5-dichloropyridine (I) (10g, 67.57mmol) was added dropwise, and the reaction solution was yellow and turbid. Cool for 30 minutes after the dropwise addition, and add dropwise a THF (20ml) solution of pre-cooled acetaldehyde (8.93g, 11.4ml, 135.14mmol), and the reaction solution becomes clear. After reacting at -78°C for 3 h, saturated ammonium chloride aqueous solution (50 ml) was added dropwise to stop the reaction, and stirred overnight at room temperature. Dilute the reaction solution with methyl tert-butyl ether (MTBE, 200ml) and saturated ammonium chloride solution (500ml), separate the organic phase, wash the aqueous layer 3 times with MTBE, wash the combined organic phase with saturated brine, and dry over sodium sulfate , concentrated red oil. Purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain 8.50 g of white solid, yield 65%; mp: 61-64 ° C; ESI-MS (m/z): 214 [M+ Na] ⁺

Example 2

Preparation of 3,5-dichloro-4-acetylpyridine (III)

1-(3,5-Dichloropyridin-4-yl)ethanol (II) (6g, 31.24mmol) was dissolved in dichloromethane (DCM, 50ml), and pyridinium chlorochromate was added in portions within 10min ( PCC, 10.1g, 46.86mmol), react at room temperature for 10h. The insoluble matter was removed by filtration, the filter residue was washed 3 times with DCM, the organic layers were combined and concentrated to obtain a crude product. Purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain 5.10 g of a colorless turbid oil; 85% yield; ¹ H-NMR (CDCl ₃ , 400MHz) δ (ppm): 2.58 ( s,3H), 8.53(s,2H); ESI-MS(m/z):212[M+Na] ⁺

Example 3

(R)-1-(3,5-dichloropyridin-4-yl)ethanol (IV)

(S)-2-Methyl-CBS-oxazolidine (1M solution in toluene, 5.3ml, 5.26mmol) was mixed with borane dimethyl sulfide complex (BH3 _- DMS, 10M solution in dimethyl sulfide, 13.2ml, 131.5mmol) was dissolved in anhydrous dichloromethane (DCM, 100ml), stirred at -10 ^o C for 10min, and slowly added dropwise 3,5-dichloro-4-acetylpyridine (III) (5g, 26.3 mmol) in DCM (30ml), dropwise, react at -10 ^o C for 12h, then slowly rise to room temperature, and slowly drop methanol to quench the reaction. After dropping, reflux at 70 ^o C for 3 hours. The reaction solution was concentrated to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain 4.87 g of a colorless oil; yield 96%, ee value 98.14% (Dacel ChiralpakAD-H, n-hexane:isopropanol=95:5); [α] _D =11.55(c=0.3292,MeOH); ¹ H-NMR(CDCl ₃ ,400MHz)δ(ppm):1.56(d,J=6.8Hz, 3H),3.56(brs,1H),5.47(q,J=6.8Hz,1H),8.34(s,2H);ESI-MS(m/z):214[M+Na] ⁺

Example 4

(R)-1-(3,5-Dichloropyridin-4-yl)ethyl methanesulfonate (V)

(R)-1-(3,5-Dichloropyridin-4-yl)ethanol (IV) (4.5 g, 23.43 mmol) and triethylamine (8.54 g, 84.35 mmol) were dissolved in anhydrous dichloromethane ( 100ml), methanesulfonyl chloride (3.22g, 28.12mmol) was added dropwise with stirring under ice bath. After dripping, react at room temperature, TLC detects the reaction until the raw materials disappear, pour the reaction solution into saturated sodium bicarbonate solution, separate the organic layer, extract the water layer back with dichloromethane, combine the organic layer, and wash the organic layer 3 times with saturated saline Finally, after drying over anhydrous sodium sulfate, dichloromethane was distilled off under reduced pressure and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain 5.78 g of pure white crystals, with a yield of 91%. And its absolute configuration was confirmed by single crystal diffraction. ¹ H-NMR(CDCl ₃ ,400MHz)δ(ppm):8.53(s,2H),6.37(q,J=6.8Hz,1H),2.98(s,3H),1.82(d,J=6.8Hz, 3H); ESI-MS(m/z): 292[M+Na] ⁺

Example 5

(S)-1-(3,5-Dichloropyridin-4-yl)ethanol (VI)

(R)-2-Methyl-CBS-oxazolidine (1M in toluene, 3.2ml, 3.15mmol) was mixed with borane dimethyl sulfide complex (BH3 _- DMS, 10M dimethyl sulfide solution, 7.9ml, 78.9mmol) was dissolved in anhydrous dichloromethane (DCM, 75ml), stirred at -10 ^o C for 10min, and slowly added dropwise 3,5-dichloro-4-acetylpyridine (III) (3g, 15.8 mmol) in DCM (15ml), dropwise, react at -10 ^o C for 10h, then slowly rise to room temperature, and slowly drop methanol to quench the reaction. After dropping, reflux at 70 ^o C for 1.5h. The reaction solution was concentrated to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain 2.83 g of a colorless oil; yield 97%, ee value 98.71% (Dacel ChiralpakAD-H, n-hexane:isopropanol=95:5); [α] _D =-11.67(c=0.3314,MeOH);ESI-MS(m/z):214[M+Na] ⁺

Example 6 (S)-1-(3,5-dichloropyridin-4-yl)ethyl methanesulfonate (VII)

(S)-1-(3,5-Dichloropyridin-4-yl)ethanol (VI) (1.8 g, 9.37 mmol) and triethylamine (3.42 g, 50.61 mmol) were dissolved in anhydrous dichloromethane ( 50ml), methanesulfonyl chloride (1.29g, 11.25mmol) was added dropwise with stirring under ice bath. After dripping, react at room temperature, TLC detects the reaction until the raw materials disappear, pour the reaction solution into saturated sodium bicarbonate solution, separate the organic layer, extract the water layer back with dichloromethane, combine the organic layer, and wash the organic layer 3 times with saturated saline Finally, after drying over anhydrous sodium sulfate, dichloromethane was distilled off under reduced pressure and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain 2.15 g of pure white crystals, with a yield of 93%; ESI-MS ( m/z):292[M+Na] ⁺ .

Figure 1 (R)-1-(3,5-dichloropyridin-4-yl) ethyl methanesulfonate single crystal diffraction pattern (see the accompanying drawing).

Claims (3)

1. an optically pure 1-(3,5-dichloropyridine-4-base) synthetic method of-ethanol, its feature includes following step:

(a) (±)-1-(3,5-dichloropyridine-4-base)-ethanol II Pyridinium chlorochromate on silica gel, pyridinium dichromate, Jones reagent, Dai Si-Martin reagent effect under generate 1-(3,5-dichloropyridine-4-base)-ethyl ketone III; Reaction temperature-20^oC~60^oC

;

(b) 1-(3,5-dichloropyridine-4-base)-ethyl ketone III reacts at a certain temperature with borane reagent under S-2-methyl-CBS-oxazaborolidine or R-2-methyl-CBS-oxazaborolidine exist, prepare 1-(3, the 5-dichloropyridine-4-base of single optical isomer)-ethanol IV; Reaction temperature-40^oC~60^oC

。

2. a kind of optically pure 1-(3,5-dichloropyridine-4-base according to claim 1) synthetic method of-ethanol, it is characterised in that: in described step a, the solvent used is dichloromethane or acetonitrile; (±)-1-(3,5-dichloropyridine-4-base) mol ratio of-ethanol II and oxidant is: 1:1 ~ 5; Response time is: 1 ~ 12 hour; Reaction temperature is-20^oC~60^oC。

3. a kind of optically pure 1-(3,5-dichloropyridine-4-base according to claim 1) synthetic method of-ethanol, it is characterised in that: in described step b, the solvent used be in dichloromethane, oxolane, ether, dioxane one or more; Borane reagent is: in borane dimethylsulf iotade, borine oxolane, boranepyridine one or more; 1-(3,5-dichloropyridine-4-base)-ethyl ketone III, chiral ligand and borane reagent mol ratio be: 1:0.1-1:1-10; Response time is 1 ~ 12 hour; Reaction temperature preferred-10^oC。