CN106146352A - Idelalisib intermediate and preparation method thereof - Google Patents

Abstract

The invention discloses a new intermediate compound of Idelalisib (V)(S)-2-{[3-fluoro-2-[(phenylamino)carbonyl]phenyl]amino-1-ethyl}-carbamic acid iso butyl ester. Using this intermediate to prepare Idelalisib, compared with the existing disclosed method, not only the reaction is stable, the yield is high, but also the reaction conditions are mild, which overcomes the defects in the prior art, and is very suitable for large-scale industrial production, and the yield is higher than that of the existing one. Some methods are high.

Description

Idelalisib intermediate and preparation method thereof

technical field

The invention relates to the technical field of Idelalisib intermediates and preparation methods thereof.

Background technique

Idelalisib is the first selective oral PI3K inhibitor developed by Gilead. Compared with α, β, and γ subunits, it can highly selectively act on the δ subunit, block the PI3Kδ-Akt signaling pathway and promote cell Apoptosis, which was approved by the US FDA in July 2014, is used for the treatment of relapsed chronic lymphocytic leukemia, follicular lymphoma and small lymphocytic lymphoma. The chemical name is (S)-5-fluoro-3-phenyl-2-[1-(9H-purin-6-ylamino)propyl]-3H-quinazolin-4-one.

International patent WO2005113556A1 discloses a synthesis method of Idelalisib, the synthesis route of which is as follows:

The method uses 2-fluoro-6-nitrobenzoic acid as a raw material, first condenses with aniline, then reacts with thionyl chloride to obtain an intermediate, and then reacts with N-Boc-L-2-aminobutyric acid to obtain a bisamide product, After reduction into a ring and deprotection, (S)-2-(1-amino-propyl)-5-fluoro-3-phenyl-3H-quinazolin-4-one is obtained, and finally with 6-bromopurine After nucleophilic substitution, (S)-5-fluoro-3-phenyl-2-[1-(9H-purin-6-ylamino)propyl]-3H-quinazolin-4-one (ie Idelalisib) .

However, the defect of the above method is that compound 6 is an important raw material for preparing Idelalisib, and there is no cheap industrial product available on the market at present, and in the prior art disclosed in international patent WO2005113556A1, the yield of this step of preparing compound 4 is low , and it needs to be obtained by column chromatography. At the same time, the step of preparing compound 5 also needs to be obtained by column chromatography, and the obtained compound is a foamy solid with poor purity, which is not conducive to subsequent operations and industrial production.

Therefore need to develop a kind of raw material is easy to get, safe, the method for the preparation Idelalisib key intermediate of high yield.

Contents of the invention

The purpose of the present invention is to solve the existing technical problems, to provide a new intermediate for the preparation of Idelalisib, to use the intermediate to synthesize Idelalisib to overcome the above-mentioned defects of the prior art, and to be very suitable for large-scale industrial production, and the yield is higher than that of the existing The method is high.

Another object of the present invention is to provide a preparation method of the above-mentioned intermediate.

For reaching above-mentioned purpose, the technical scheme that the present invention takes is as follows:

Compound (V) of the formula:

The preparation method of the compound of formula (V), the method is that the carboxyl group of the compound of formula (IV) is activated into an acid anhydride and then reacted with the compound of formula (Ⅲ) to obtain:

The activator of above-mentioned activating formula (Ⅳ) BOC-L-2-aminobutyric acid carboxyl group can be chloroformate esters such as isobutyl chloroformate etc., used alkali is organic base such as N-methylmorpholine and triethylamine etc., the acid anhydride obtained after activation and the compound of formula (Ⅲ) react in the original reaction system, that is, a one-pot reaction.

Further, the above-mentioned compound of formula (III) is obtained by reducing the compound of formula (II):

The reduction reaction can be hydrogenation reduction with Pd/C as a catalyst, or reduction under the condition of Zn/ammonium chloride.

Further, the above-mentioned compound of formula (II) is obtained by reacting the compound of formula (I) with aniline under alkaline conditions after first forming an amide:

The used acylating agent of this step reaction can be oxalyl chloride, thionyl chloride etc., the solvent used during reaction is the chlorinated alkanes known to those skilled in the art such as dichloromethane etc., and the selected solvent of reacting with aniline afterwards can be For cyclic ethers such as 1,4-dioxane and so on. The reaction temperature depends on the solvent used, and those skilled in the art can select the optimum temperature range. Bases that can be used include, for example, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate.

Beneficial effects of the present invention: The inventors of the present application unexpectedly discovered a suitable new intermediate compound (S)-2-{[3-fluoro-2-[(phenylamino) when studying the preparation method of Idelalisib Carbonyl] phenyl] amino-1-ethyl}-carbamic acid isobutyl ester, utilize this intermediate to prepare Idelalisib, compare with existing public method, not only reaction is stable, yield is high, and reaction condition is gentle, has overcome Due to the defects in the prior art, it is very suitable for large-scale industrial production, and the yield is higher than that of the existing method.

detailed description

Example 1-2: Preparation of 2-fluoro-6-nitro-N-phenyl-benzamide formula (II)

2-Fluoro-6-nitrobenzoic acid (18.5g), DMF (1ml) and dichloromethane (100ml) were mixed and stirred, and a dichloromethane solution (60ml) containing oxalyl chloride (19g) was added dropwise, and the reaction was stirred at room temperature After 2 hours, concentrate to give an orange solid syrup. The above slurry was dissolved in anhydrous dioxane (16ml), and slowly added dropwise to aniline (9ml) and sodium bicarbonate (16.8g) in dioxane (40) and water (40) at 6°C. After the addition, stir at room temperature for half an hour, add water (250ml), a solid is produced, collect the solid by filtration, wash with water, and obtain the title compound 2-fluoro-6-nitro-N-phenyl-benzene Formamide 25.6g, yield 98.4%. ¹ H NMR (400MHz, CDCl ₃ ) δ8.01(d, J=8.2Hz, 1H), 7.70-7.60(m,, 4H), 7.41(t, J=7.8Hz, 2H), 7.23(t, J =7.4Hz,1H).ESI-MS(m/z):261[M+H] ⁺

2-Fluoro-6-nitrobenzoic acid (18.5g), DMF (1ml) and dichloromethane (100ml) were mixed and stirred, and a dichloromethane solution (60ml) containing oxalyl chloride (19g) was added dropwise, and the reaction was stirred at room temperature After 2 hours, concentrate to give an orange solid syrup. The above slurry was dissolved in anhydrous THF (16ml), and slowly added dropwise to a mixed suspension of aniline (9ml) and sodium bicarbonate (16.8g) in THF (40ml) and water (40ml) at 6°C After the addition, stir at room temperature for half an hour, add water (250ml), a solid is produced, collect the solid by filtration, wash with water, and obtain the title compound 2-fluoro-6-nitro-N-phenyl-benzamide 24.6g , yield 94.6%.

Example 3-4: Preparation of 2-amino-6-fluoro-N-phenyl-benzamide formula (Ⅲ)

A mixture of 2-amino-6-fluoro-N-phenyl-benzamide (13g), Pd/C (1g) and ethyl acetate (100ml) was hydrogenated at 50°C for four hours, filtered and concentrated to dryness to obtain the title Compound 2-amino-6-fluoro-N-phenyl-benzamide 11.1 g, yield 96.5%. ¹ H NMR (400MHz, CDCl ₃ ) δ8.33(d, J=15.5Hz, 1H), 7.61(d, J=7.6Hz, 2H), 7.43–7.35(m, 2H), 7.21–7.12(m, 2H), 6.51(d, J=8.3Hz, 1H), 6.43(ddd, J=13.0, 8.1, 1.0Hz, 1H), 5.97(s, 2H).ESI-MS(m/z): 231[M +H] ⁺

2-Amino-6-fluoro-N-phenyl-benzamide (13g), Pd/C (0.8g) and ethyl acetate (100ml) were mixed and hydrogenated at 50°C for six hours, filtered and concentrated to dryness to obtain 10.5 g of the title compound 2-amino-6-fluoro-N-phenyl-benzamide, yield 91.3%.

Example 5-6: Preparation of (S)-2-{[3-fluoro-2-[(phenylamino)carbonyl]phenyl]amino-1-ethyl}-carbamate isobutyl ester formula (V)

Dissolve BOC-L-2-aminobutyric acid (20.3g) and N-methylmorpholine (11.2g) in anhydrous THF (120ml), and add isobutyl chloroformate (13.7g ) solution in anhydrous THF (40ml), dropwise, stirred at -15°C for 1 hour, then added dropwise an anhydrous solution containing 2-amino-6-fluoro-N-phenyl-benzamide (11.5g) THF (40ml) solution, dropwise, react at this temperature for half an hour, slowly rise to room temperature, react for 1 hour, filter out the solid, and the filtrate is heated to reflux for 3.5 hours, concentrate the reaction solution, add ethyl acetate (150ml) and Water (200ml), separated, the aqueous layer was extracted with ethyl acetate (100ml×2), the organic layers were combined, washed with water, washed with saturated brine, dried, filtered, and concentrated to obtain 19.2g of crude product, which was recrystallized with isopropanol (70ml) 17.1 g of the title compound (S)-2-{[3-fluoro-2-[(phenylamino)carbonyl]phenyl]amino-1-ethyl}-carbamate isobutyl ester was obtained in a yield of 82.4%. ¹ H NMR (400MHz, CDCl ₃ ) δ11.72(s, 1H), 8.55(d, J=8.5Hz, 1H), 8.37(d, J=14.5Hz, 1H), 7.64(d, J=7.8Hz ,2H),7.51–7.45(m,1H),7.41(t,J=7.9Hz,2H),7.23(t,J=7.4Hz,1H),6.93(dd,J=12.3,8.4Hz,1H) ,5.11(s,1H),4.28(s,1H),2.07–1.97(m,1H),1.83–1.73(m,1H),1.45(s,9H),1.03(t,J＝7.4Hz,3H ).ESI-MS(m/z):416[M+H] ⁺

Dissolve BOC-L-2-aminobutyric acid (20.3g) and N-methylmorpholine (11.2g) in anhydrous THF (120ml), and add isobutyl chloroformate (13.7g ) solution in anhydrous THF (40ml), dropwise, stirred at -15°C for 1 hour, then added dropwise an anhydrous solution containing 2-amino-6-fluoro-N-phenyl-benzamide (11.5g) THF (40ml) solution, dropwise, react at this temperature for half an hour, slowly rise to room temperature, react for 1 hour, heat the filtrate to reflux for 3.5 hours, concentrate the reaction solution, add ethyl acetate (150ml) and water (200ml) , separated, the aqueous layer was extracted with ethyl acetate (100ml×2), the organic layers were combined, washed with water, washed with saturated brine, dried, filtered, and concentrated to obtain 19.2g of crude product, which was recrystallized with isopropanol (70ml) to obtain the title compound ( S)-2-{[3-fluoro-2-[(phenylamino)carbonyl]phenyl]amino-1-ethyl}-carbamic acid isobutyl ester 14.9 g, yield 71.8%.

Example 7-8: (S) - [1-(5-fluoro-4-oxo-3-phenyl-3,4-dihydro-quinazolin-2-yl)-propyl]-carbamic acid Preparation of isobutyl ester

(S)–[1-(5-fluoro-4-oxo-3-phenyl-3,4-dihydro-quinazolin-2-yl)-propyl]-carbamate isobutyl ester (8.3 g), trimethylchlorosilane (40ml), and triethylamine (150ml) were mixed in acetonitrile (500ml) and reacted in a closed tank for 48 hours under a nitrogen seal, filtered, concentrated to dryness, added ethyl acetate (500ml), and used successively Saturated sodium carbonate solution (150ml), water (150ml), saturated brine (150ml) washed, dried, filtered, concentrated to obtain the title compound (S) - [1-(5-fluoro-4-oxo-3-phenyl 7.2 g of isobutyl -3,4-dihydro-quinazolin-2-yl)-propyl]-carbamate, yield 90.6%. ¹ H NMR (400MHz, CDCl ₃ ) δ7.71(td, J=8.2, 5.4Hz, 1H), 7.65–7.49(m, 4H), 7.38(d, J=6.5Hz, 1H), 7.29(d, J＝7.6Hz, 1H), 7.13(dd, J＝10.4, 8.2Hz, 1H), 5.43(s, 1H), 4.43(s, 1H), 1.67–1.49(m, 2H), 1.44(s, 9H ),0.79(t,J=7.4Hz,3H).ESI-MS(m/z):398[M+H] ⁺

(S)–[1-(5-fluoro-4-oxo-3-phenyl-3,4-dihydro-quinazolin-2-yl)-propyl]-carbamate isobutyl ester (8.3 g), trimethylchlorosilane (40ml), and triethylamine (150ml) were mixed in acetonitrile (500ml) and reacted under nitrogen for 48 hours. Thin layer chromatography showed no reaction.

Example 9: Preparation of (S)-2-(1-amino-propyl)-5-fluoro-3-phenyl-3H-quinazolin-4-one

(S)–[1-(5-fluoro-4-oxo-3-phenyl-3,4-dihydro-quinazolin-2-yl)-propyl]-carbamate isobutyl ester (7.94 g) dissolved in dichloromethane (40ml) and trifluoroacetic acid (40ml), stirred at room temperature for 2 hours, concentrated to dryness, distributed in dichloromethane (100ml) and 10% potassium carbonate (100ml) solution, and separated, The aqueous layer was extracted with dichloromethane (50ml×2), the organic layers were combined, washed with water, washed with saturated brine, dried, filtered, and concentrated to obtain the title compound (S)-2-(1-amino-propyl)-5-fluoro - 5.1 g of 3-phenyl-3H-quinazolin-4-one, yield 85.8%. ¹ H NMR (400MHz, CDCl ₃ ) δ7.70 (td, J=8.2, 5.4Hz, 1H), 7.63–7.50 (m, 4H), 7.29 (dd, J=12.9, 5.9Hz, 2H), 7.12( dd,J=10.2,8.4Hz,1H),3.55–3.41(m,1H),1.88–1.76(m,1H),1.60–1.47(m,1H),0.81(t,J=9.6Hz,3H) .ESI-MS (m/z): 298[M+H] ⁺ .

Claims (8)

1. the compound (V) of following formula:

2. the preparation method of formula (V) compound, the method be the activated carboxylic of formula IV compound is become anhydride after again with formula III compound reaction obtain:

3. the preparation method of formula (V) compound as claimed in claim 2, it is characterised in that: formula III compound is formula II compound reduction reaction to be obtained:

4. the preparation method of formula (V) compound as claimed in claim 3, it is characterised in that: formula II compound be formula I compound is first become amide after obtain with aniline reaction the most in the basic conditions:

5. the preparation method of formula (V) compound as described in claim 2-4 is arbitrary, it is characterised in that: the activator of activated b OC-L-2-aminobutyric acid carboxyl is chloro-carbonic acid esters.

6. the preparation method of formula (V) compound as described in claim 2-4 is arbitrary, it is characterised in that: the anhydride obtained after BOC-L-2-aminobutyric acid activated carboxylic and formula III compound react in former reaction system.

7. the preparation method of formula (V) compound as described in claim 2-4 is arbitrary, it is characterised in that: the reduction of formula II compound carries out hydro-reduction with Pd/C for catalyst or reduces under the conditions of Zn/ ammonium chloride.

8. the preparation method of formula (V) compound as described in claim 2-4 is arbitrary, it is characterised in that: the acylating agent used by amide reaction is oxalyl chloride, thionyl chloride.