Method for preparing tyrosine kinase inhibitor and derivative thereof

Abstract

A method for preparing a tyrosine kinase inhibitor and a derivative thereof are described. In particular, the present method has a short synthesis route, low costs, easy operation, and is suitable for large-scale production.

Claims

1. A compound of formula VI, ##STR00011## wherein R.sub.2 is selected from the group consisting of an amino protecting group and alkyl; and R is hydroxy, wherein the amino protecting group is selected from the group consisting of (C.sub.1-10 alkyl or aryl)-C(O)—, (C.sub.1-6 alkyl or C.sub.6-10 aryl) sulfonyl, (C.sub.1-6 alkoxy or C.sub.6-10 aryloxy) carbonyl and Cbz.

2. A method for preparing a compound of formula VI, comprising reacting a compound of formula VIII with a phosphoryl carboxylate in the presence of a base to obtain a compound of formula X, ##STR00012## wherein R.sub.2 is selected from the group consisting of an amino protecting group and alkyl; R is hydroxy, and the phosphoryl carboxylate is triethyl phosphonoacetate; wherein the amino protecting group is selected from the group consisting of (C.sub.1-10 alkyl or aryl)-C(O) (C.sub.1-6 alkyl or C.sub.6-10 aryl) sulfonyl, (C.sub.1-6 alkoxy or C.sub.6-10 aryloxy) carbonyl and Cbz.

3. The method for preparing the compound of formula VI according to claim 2, wherein R is hydroxy or halogen, and the method further comprises hydrolyzing the compound of formula X in the presence of an alkaline medium to obtain a hydrolysis product, wherein the alkaline medium is at least one selected from the group consisting of Et.sub.3N, DBU, TMG, Py, DIPEA, K.sub.2CO.sub.3, KHCO.sub.3, Na.sub.2CO.sub.3, NaHCO.sub.3, KOH, NaOH, NaOMe, NaOEt, NaOtBu, and NaH.

4. The method for preparing the compound of formula VI according to claim 3, wherein R is chlorine, and the method further comprises reacting the hydrolysis product with an acyl halogenating reagent, wherein the acyl halogenating reagent is one or more selected from the group consisting of oxalyl chloride, phosphorus halide, thionyl halide, and triphenylphosphine halide.

5. The compound of formula VI according to claim 1, wherein the compound is ##STR00013##

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) The present invention is described in detail with reference to the following specific examples so that those skilled in the art will understand the present invention in a more comprehensive manner. The specific examples are used only to illustrate the technical solution of the present invention, but are not used to limit the scope of the present invention in any way.

EXAMPLE 1: PREPARATION OF COMPOUND 5

(2) ##STR00010##

(3) Step 1):

(4) 8.0 kg of compound 1, 264 kg of dichloromethane, and 13.0 kg of anhydrous sodium acetate were added to a 300 L reactor and stirred. The reaction system was cooled to 0° C. by freezing brine. 17.14 kg of PCC was then added in batches under nitrogen protection. After the completion of the addition, the freeze was stopped, and the reaction was carried out for 5 h with the temperature rising naturally. After the completion of the reaction was determined by TLC detection (ethyl acetate: petroleum ether=1:3), the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a black oil. The product was eluted over column chromatography (the eluent was ethyl acetate: petroleum ether=1:3). The main fraction was collected, concentrated under reduced pressure, and dissolved by addition of 64 kg of ethyl acetate. The solution was washed with 0.5 N diluted hydrochloric acid solution, water and saturated brine successively, dried over anhydrous sodium sulfate, and concentrated to obtain 6.42 kg of pale yellow oil.

(5) 114 kg of dichloromethane and 3.05 kg of 60% sodium hydride were added to a 300 L reactor and stirred well, and the mixture was cooled by freezing brine. 7.66 kg of triethyl phosphonoacetate was slowly added dropwise, and the addition was completed within about 30 min. The mixture was stirred at room temperature until no bubbles were produced. A solution of 6.4 kg of compound 2 obtained in the previous step in dichloromethane (85 kg) was added slowly dropwise, and the addition was completed within about 1 h. Then the reaction was carried out at room temperature for 1.5-2 h. After the completion of the reaction was determined by TLC detection, the mixture was cooled by freezing brine. An aqueous solution of ammonium chloride (1.26 kg of ammonium chloride dissolved in 4.0 kg of water) was added slowly until no bubbles were produced. The mixture was stirred for about 0.5 h. Purified water was then slowly added dropwise until the mixture was clear. Two phases were separated, and the aqueous phase was extracted once with dichloromethane. The organic phases were combined, washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude ester product. The crude ester product was subjected to column chromatography (the eluent was ethyl acetate: petroleum ether=1:8). The main fraction was collected and concentrated to obtain 4.82 kg of compound 3, yield: 45.0%. (The TLC condition was petroleum ether: ethyl acetate=3:1, the R.sub.f of the product=0.7, the R.sub.f of the starting material=0.6).

(6) Compound 3: .sup.1H NMR (400 MHz, CDC1.sub.3) δ=6.85-6.80 (dd, 1H), 5.84-5.80 (d, 1H), 4.40 (br, 1H), 4.22-4.17 (q, 2H), 3.42 (s, 2H), 2.08-2.06 (m, 1H), 1.89-1.82 (m, 2H), 1.79-1.73 (m, 1H), 1.44 (s, 9H), 1.31-1.27 (t, 3H) ppm.

(7) MS (M+Na): 292.1

(8) Step 2):

(9) 4.8 kg of compound 3 and 58.6 kg of formic acid were added to a 100 L reactor and stirred at room temperature for 15 min. 2.63 kg of paraformaldehyde was then added, and the mixture was heated to slightly reflux at 90° C. for 3-4 h until the starting material point disappeared by TLC detection. Most of the formic acid in the reaction solution was concentrated (about ⅕ remained), and 1M hydrochloric acid was added to adjust the pH to 1.0. The mixture was washed with ethyl acetate. The aqueous phase was further added with a saturated aqueous solution of potassium carbonate to adjust the pH to 8.0, and extracted with ethyl acetate. The organic phases were combined, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain 2.42 kg of compound 4, yield: 73.5%.

(10) Compound 4: .sup.1H NMR (400 MHz, CDC1.sub.3) δ=6.85-6.80 (dd, 1H), 5.96-5.92 (d, 1H), 4.22-4.17 (q, 2H), 3.15-3.10 (m, 1H), 2.76-2.70 (m, 1H), 2.28 (s, 3H), 2.28-2.21 (m, 1H), 2.04-1.98 (m, 1H), 1.91-1.84 (m, 1H), 1.82-1.74 (m, 1H), 1.72-1.65 (m, 1H) ppm.

(11) MS (M+1): 184.2

(12) Step 3):

(13) 2.4 kg of compound 4 and then 5.9 kg of methanol were added to a 20 L reaction flask. 1.49 kg of potassium hydroxide was added in batches at a controlled temperature no more than 30° C., the addition was completed within about 1.5 h, and then the reaction was carried out at 30° C. for 2 h. After the completion of the reaction was determined by TLC detection, the pH was adjusted to 4-5 with 4N hydrochloric acid in methanol in an ice bath. The mixture was filtered, the filtrate was concentrated to dryness, and 2.7 kg of acetonitrile was added under stirring to precipitate a crystal. The mixture was filtered and dried to obtain 1.06 kg of compound 5, yield: 52.1%.

(14) Compound 5: .sup.1H NMR (400 MHz, d.sup.6 DMSO) δ=12.60 (s, 1H), 11.72 (s, 1H), 6.94-6.88 (dd, 1H), 6.21-6.17 (d, 1H), 4.00 (s, 1H), 3.57 (s, 1H), 3.07 (s, 1H), 2.67 (s, 3H), 2.28-2.20 (m, 1H), 2.02-1.99 (m, 2H), 1.92-1.82 (m, 1H) ppm.

(15) MS (M+1): 156.1

EXAMPLE 2: PREPARATION OF THE COMPOUND OF FORMULA I

(16) 1.0 kg of compound 5 and 9.4 kg of acetonitrile were added to a 20 L reaction flask, and then 30 g of N,N-dimethylformamide was added dropwise. 630 g of oxalyl chloride was slowly added dropwise in an ice bath. After the completion of the addition, the mixture was stirred at 20° C. for 5 h. A small amount of solid remained at the bottom of the reaction solution, and the reaction solution was directly used in the following condensation reaction without treatment.

(17) 1.15 kg of compound VII was dissolved in 7.2 kg of N-methylpyrrolidone and stirred for 10 min. The previous reaction solution was added dropwise in an ice bath, and the reaction was stirred at room temperature overnight. After the completion of the reaction was determined by TLC detection, the reaction solution was poured into warm water (45.0 kg) at about 40° C., and 10% sodium hydroxide solution was slowly added under stirring to adjust the pH to 10. The mixture was filtered to obtain a yellow solid. The resulting filter cake was pulped with warm water (about 5.0 kg) at 40° C., and then filtered. The filter cake was dissolved in dichloromethane to remove water, dried, concentrated, and purified by column chromatography with gradient elution, the starting eluent was dichloromethane: methanol=25:1, and finally increased to 15:1. The main fraction was collected and concentrated to obtain 1.12 kg of the compound of formula I, yield: 74.5%, with the HPLC purity of 99.71%.

(18) Compound of formula I: .sup.1H NMR (400 MHz, CDC1.sub.3) δ=9.20 (s, 1H), 8.59-8.58 (t, 1H), 8.40 (s, 1H), 8.07-8.03 (d, 2H), 7.77-7.32 (m, 1H), 7.63-7.62 (d, 1H), 7.25-7.23 (q, 1H), 7.14 (s, 1H), 7.111-7.106 (d, 1H), 6.97-6.92 (q, 1H), 6.86-6.83 (q, 1H), 6.79-6.76 (q, 1H), 6.17-6.14 (d, 1H), 5.21 (s, 2H), 4.23-4.18 (q, 2H), 3.16-3.12 (m, 1H), 2.84-2.82 (d, 1H), 2.30-2.27 (t, 4H), 2.06-1.99 (m, 1H), 1.90-1.85 (m, 1H), 1.83-1.72 (m, 1H), 1.68-1.60 (m, 1H), 1.54-1.52 (t, 3H) ppm.

(19) MS (M+1): 583.2

EXAMPLE 3: PREPARATION OF THE COMPOUND OF FORMULA I

(20) 2.0 kg of the compound of formula VII was dissolved in 20 L of N-methylpyrrolidone in a 50 L reactor. 1.2 kg of compound 5 and then 1.7 kg of EEDQ were added, and the reaction was stirred for 14-17 h at a controlled temperature of 20-25° C. 2.5 kg of water was slowly added in an ice bath, and the pH was adjusted to 9-10 with 5% aqueous NaOH solution (about 25 L). The mixture was filtered to obtain a product with a wet weight of about 4.9 kg. The resulting yellow solid was added with 30 kg of water, and 1 M HC1 solution was added dropwise under stirring to adjust the pH to 2-5. The mixture was stirred until it was clear. The mixture was extracted with dichloromethane, the pH of the aqueous phase was adjusted to 9-10 with 5% aqueous

(21) NaOH solution, and the resulting solid was filtered to obtain a product with a wet weight of about 5.2 kg. 88.4 kg of ethanol and 8.8 kg of acetone were added, and the mixture was heated to reflux until it was clear. The solution was cooled to room temperature under stirring to precipitate a crystal for 15 h. The mixture was filtered, and the filter cake was washed with ethanol to obtain 2.1 kg of the compound of formula I as a pale yellow solid, yield: 80.3%, with the HPLC purity of 99.68%.

(22) Since the present invention has been described based on the specific embodiments thereof, some modifications and equivalent variations are apparent to those skilled in the art and are within the scope of the present invention.