Process for preparing intermediate of anti-tumor drug niraparib and intermediate thereof

Abstract

Disclosed is a process for preparing an intermediate of anti-tumor drug niraparib and an intermediate thereof. The present invention discloses a process for preparing compound f, which comprises conducting a cyclization reaction of compound e in a solvent and in the presence of a base to give compound f. The process of the present invention does not involve the steps of catalytic reduction or catalytic coupling reaction of precious metals and chiral separation, which has advantages such as low equipment requirements, simple operation, favorable industrial production, avoiding waste liquid containing heavy metals and phosphorus, low cost and high product ee value. ##STR00001##

Claims

1. A process for preparing compound f, comprising precipitating a solid from a mixed solution formed by the mixture containing compound f and compound f1 with a solvent; the solvent is selected from the group consisting of a nitriles solvent, an esters solvent, an ethers solvent, a mixed solvent of an ethers solvent and an alkanes solvent, a mixed solvent of a nitriles solvent and an alkanes solvent, and a mixed solvent of an esters solvent and an alkanes solvent; ##STR00044## wherein, A is an aryl or a heteroaryl, each of which is optionally substituted by the substituent(s) selected from the group consisting of H, D, an alkyl, hydroxy, an alkoxy, a halogen, an aryl, an aryloxy, an alkynyl, an alkenyl, a cycloalkyl, a cycloalkenyl, amino, an acyl, a heteroaryl, a heterocycloalkyl, an acylamido, nitro, cyano, mercapto or a haloalkyl; R.sup.2 is H, an alkyl, hydroxy or an alkoxy; wherein the number of the substituent(s) is 1 to 6.

2. The process for preparing compound f as defined in claim 1, wherein, the nitriles solvent is acetonitrile; and/or, the esters solvent is ethyl acetate; and/or, the ethers solvent is methyl tert-butyl ether; and/or, the alkanes solvent is a C.sub.5-C.sub.8 alkanes solvent; and/or, the mixture containing compound f and compound f1 is composed of compound f and compound f1, or the amount of compound f and compound f1 determined by HPLC is 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or 99% or more of the mixture; and/or, the mixture containing compound f and compound f1 is mixed with the solvent at 0 C. to the reflux temperature of the solvent under normal pressure; and/or, the temperature for precipitating a solid is 5 to 30 C.; and/or, the mixture containing compound f and compound f1 is mixed with the solvent under the protection of a gas; and/or, A is ##STR00045## wherein, each of R.sup.1, R.sup.1a, R.sup.1b, R.sup.1c and R.sup.1d is independently H, D, an alkyl, hydroxy, an alkoxy, a halogen, an aryl, an aryloxy, an alkynyl, an alkenyl, a cycloalkyl, a cycloalkenyl, amino, an acylamido, a heteroaryl, a heterocycloalkyl, an acylamido, nitro, cyano, mercapto or a haloalkyl; and/or, R.sup.2 is H, an alkyl, hydroxy or an alkoxy.

3. The process for preparing compound f as defined in claim 1, wherein, further comprising recrystallizing the precipitated solid; and/or, A is ##STR00046## wherein, each of R.sup.1, R.sup.1a, R.sup.1b, R.sup.1c, and R.sup.1d is independently H, an alkoxy or a halogen; and/or, R.sup.2 is H, an alkyl or hydroxy.

4. The process for preparing compound f as defined in claim 1, wherein, further comprising recrystallizing the precipitated solid; the solvent for recrystallization is an ethers solvent, a nitriles solvent, an esters solvent, a mixed solvent of an ethers solvent and an alkanes solvent, a mixed solvent of a nitriles solvent and an alkanes solvent, or a mixed solvent of an esters solvent and an alkanes solvent; the recrystallization temperature is 0 C. to the reflux temperature of the solvent under normal pressure; the number of times of the recrystallization is 1 to 5 times; and/or, A is ##STR00047## wherein, R.sup.1, R.sup.1a, R.sup.1b, and R.sup.1d are H, R.sup.1c is H, an alkoxy or a halogen; R.sup.2 is H, an alkyl or hydroxy.

5. The process for preparing compound f as defined in claim 1, wherein, the process for preparing the mixture containing compound f and compound f1 comprises conducting a cyclization reaction of compound e in a solvent and in the presence of a base to give compound f as shown below; ##STR00048## A and R.sup.2 are defined as claim 1; X is a leaving group.

6. A process for preparing compound f, comprising conducting a cyclization reaction of compound e in a solvent and in the presence of a base to give compound f as shown below; ##STR00049## wherein, A and R.sup.2 are defined as claim 1; X is a leaving group.

7. The process for preparing compound f as defined in claim 6, wherein, further comprising a recrystallization treatment after completion of the cyclization reaction; the solvent for recrystallization is an ethers solvent, a nitriles solvent, an esters solvent, a mixed solvent of an ethers solvent and an alkanes solvent, a mixed solvent of a nitriles solvent and an alkanes solvent, or a mixed solvent of an esters solvent and an alkanes solvent.

8. The process for preparing compound f as defined in claim 6, wherein, further comprising conducting an amidation reaction of compound c or an acidic salt of compound c and compound d in a solvent in the presence of a condensing agent to give compound e as shown below; ##STR00050## ##STR00051## A and R.sup.2 are defined as claim 1, X is a leaving group; Z is a leaving group.

9. The process for preparing compound f as defined in claim 8, wherein, in the process for preparing compound e, the solvent is a haloalkanes solvent and/or an esters solvent and/or, the condensing agent is N,N-carbonyldiimidazole or 2-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate.

10. The process for preparing compound f as defined in claim 8, wherein, the process for preparing compound e comprises mixing a mixed solution of the acidic salt of compound c or compound c, compound d and the solvent, and a mixed solution of the condensing agent and the solvent at 5 to 5 C. to conduct the reaction.

11. The process for preparing compound f as defined in claim 8, wherein, further comprising conducting a substitution reaction of compound a and compound b to give compound c as shown below; ##STR00052## A and R.sup.2 are defined as claim 1, each of X and Y is a leaving group wherein Y is easier to leave than X.

12. A compound selected from the group consisting of compound e, compound f, compound g, compound f1 and compound ff as shown below; ##STR00053## ##STR00054## wherein, A and R.sup.2 are defined as claim 1; X is a leaving group.

13. The compound as defined in claim 12, wherein, compound e is selected from the group consisting of ##STR00055## ##STR00056## compound f is selected from the group consisting of ##STR00057## compound g is ##STR00058##

14. The process for preparing compound f as defined in claim 2, wherein, the mixture containing compound f and compound f1 is mixed with the solvent at 30 C. to the reflux temperature of the solvent under normal pressure; and/or, the temperature for precipitating a solid is 5 to 5 C.

15. The process for preparing compound f as defined in claim 2, wherein, the mixture containing compound f and compound f1 is mixed with the solvent at 30 to 50 C.

16. The process for preparing compound f as defined in claim 4, wherein, the recrystallization temperature is 0 to 60 C.

17. The process for preparing compound f as defined in claim 4, wherein, the recrystallization temperature is 30 to 50 C.

18. The process for preparing compound f as defined in claim 8, wherein, X is a halogen, methanesulfonyloxy or p-toluenesulfonyloxy; and/or, Z is hydroxy, a halogen, an alkoxy, pyrrolidin-2,5-dione-1-oxy, isoindole-1,3-dione-2-oxy or 1H-benzotriazol-1-oxy.

19. The process for preparing compound f as defined in claim 9, the solvent is dichloromethane and/or isopropyl acetate.

20. The process for preparing compound f as defined in claim 10, wherein the mixed solution of the condensing agent and the solvent is added dropwise to the mixed solution of the acidic salt of compound c or compound c, compound d and the solvent.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIGS. 1A-1C show TLC plate scanned in fluorescence at different reaction stage of Method 1 of Embodiment 2. Wherein FIG. 1a shows TLC plate of the reaction solution scanned in fluorescence before the start of the reaction, FIG. 1b shows TLC plate of the reaction solution scanned in fluorescence after completion of the reaction, and FIG. 1c shows TLC plate of the obtained yellow solid NIR30A scanned in fluorescence.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

(2) In the following embodiments, room temperature refers to 10 to 30 C., preferably 25 C. The temperature of ice bath refers to 5 to 5 C., preferably 0 C. Overnight refers to 8 to 16 hours, preferably 12 hours.

Embodiment 1

(3) ##STR00031##

(4) NIR05A was prepared using the method in the reference Journal of Organic Chemistry, 77(16), 7028-7045, 2012.

(5) NIR05A (23.4 g), NIR01 (18.1 g) and dichloromethane (100 mL) were successively added into a reaction flask, the mixture was stirred under an ice bath.

(6) A solution of N,N-carbonyldiimidazole (17.0 g) in dichloromethane was added dropwise to the above mixture. After completion of the reaction, the pH of the reaction solution was adjusted to 1 with dilute hydrochloric acid, the organic layer was washed with saturated sodium bicarbonate solution and water, and evaporated to dryness under reduced pressure to give 32.5 g NIR10A as a red oil with a yield of 90.0%.

(7) NIR10A: .sup.1H NMR (400 MHz, in CDCl.sub.3, 298K, in ppm) 1.53, 1.59 (3H, d, d, H-8); 1.47-1.54, 1.84-1.91 (2H, m, m, H10); 3.14-3.50 (4H, m, H9,11); 3.87, 3.92 (2H, s, s, H13); 5.14, 6.03 (1H, t, t, H7); 7.15-7.50 (7H, m, H2,3,4,5,15,19); 8.18-8.20 (2H, m, H16,18). .sup.13C NMR (100 MHz, in CDCl.sub.3, 298K, in ppm) 16.7, 18.6 (C8); 31.6, 33.4 (C10); 40.5, 41.0 (C13); 41.7, 42.4, 43.2 (C9,11); 51.7, 56.2 (C7); 123.9 (C16,18); 126.7, 127.7, 127.9, 128.1, 128.7, 129.1 (C2-6); 130.2 (C15,19); 139.9, 140.5 (C1); 142.8, 142.9 (C14); 147.1 (C17); 169.8 (C12). MS: 361.1 (M+H).

Embodiment 2

(8) ##STR00032##

(9) Method 1: Potassium carbonate (7.7 g) and DMF (20 mL) were added into a three-necked reaction flask, and the mixture was maintained at 50 C., followed by addition of a solution of NIR10A (10 g) in DMF (20 mL) under stirring. After completion of the reaction, the reaction solution was added to water and stirred, then extracted with MTBE (30 mL) for three times. The organic phases were combined, washed with brine and dried over anhydrous sodium sulfate. The organic phase was evaporated under reduced pressure to a volume of about 1V (i.e. 10 mL), followed by addition of 40 mL MTBE. The mixture was stirred at 50 C. under nitrogen atmosphere, then gradually cooled to 0 C. and filtered. The filter cake was washed twice with 5 mL MTBE, then dried in vacuum to give 2.7 g NIR30A (de>98%) as a yellow solid with a yield of 30%. TLC determining that NIR10A was no longer reacted was seen as completion of the reaction. The developing solvent for TLC was n-heptane:ethyl acetate=3:1 (V:V). FIGS. 1A-1C show TLC plate scanned in fluorescence at different reaction stage. FIG. 1a shows TLC plate of the reaction solution scanned in fluorescence before the start of the reaction, FIG. 1b shows TLC plate of the reaction solution scanned in fluorescence after completion of the reaction, and FIG. 1c shows TLC plate of the obtained yellow solid NIR30A scanned in fluorescence.

(10) Method 2: NIR10A (2.0 g), potassium carbonate (1.53 g) and DMF (15 mL) were added to a reaction flask, and the reaction solution was stirred at 50 C. for 18 hours. After completion of the reaction, 30 mL water was added the reaction solution, then mixture was stirred, and then extracted twice with ethyl acetate (30 mL*2). The organic phase was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to give a crude product, which was purified by column chromatography (petroleum ether/ethyl acetate=2/1) to give NIR30A (370 mg, 29%) and NIR30B (343 mg, 26%). The structure of compound NIR30B is shown below:

(11) ##STR00033##

(12) Method 3: Potassium carbonate (24.9 g), acetonitrile (60 mL) was added to a reaction flask, the mixture was warmed to 50 C., followed by addition of a solution of NIR10A (32.5 g) in acetonitrile (65 mL) under stirring. After completion of the reaction, the reaction solution was cooled to room temperature, filtered, and the filter cake was washed with acetonitrile. The filtrate was collected, combined and evaporated to dryness under reduced pressure to give a residue. Ethyl acetate (230 mL) was added to the residue and the mixture was warmed to 50 C. to make the residue dissolved, then cooled to room temperature and filtered. The filter cake was recrystallized once with MTBE (65 mL) (using the same procedure in Method 1) to give 10.4 g NIR30A (de>98%) with a yield of 35%.

(13) NIR30A: .sup.1H NMR (400 MHz, in CDCl.sub.3, 298K, in ppm) 1.59 (3H, d); 1.65-1.76 (1H, m); 1.84-1.98 (2H, m); 2.15-2.23 (1H, m); 2.97 (1H, m), 3.29 (1H, m), 3.84 (1H, dd), 6.18 (1H, q), 7.29-7.38 (5H, m), 7.41 (2H, d), 8.20 (2H, d). MS: 325.1 (M+H). [].sup.25.sub.D166.1 (c 1.0, CHCl.sub.3).

(14) NIR30B: .sup.1H NMR (400 MHz, in CDCl.sub.3, 298K, in ppm) 1.58 (3H, d); 1.74-1.91 (3H, m); 2.15-2.23 (1H, m); 2.92 (1H, m), 3.24 (1H, m), 3.84 (1H, dd), 6.18 (1H, q), 7.31-7.41 (7H, m), 8.19 (2H, d). MS: 325.1 (M+H).

Embodiment 3

(15) ##STR00034##

(16) 135.9 g anhydrous aluminum trichloride was added in portions to 600 g tetrahydrofuran in a reaction flask under an ice bath and nitrogen atmosphere. The mixture was maintained at 0 to 10 C., then 35 g sodium borohydride was added in portions under nitrogen atmosphere, and the mixture was stirred for 1 hour. A solution of NIR30A (100 g) in 300 g THE was added dropwise to the above mixture under an ice bath. After the dropwise addition, the reaction solution was stirred at room temperature until completion of the reaction.

(17) 400 g water and 236 g concentrated hydrochloric acid were added to another reaction flask, and the mixture was cooled to 0 to 5 C. under stirring, followed by dropwise addition of the above reaction solution. After the dropwise addition, the reaction solution was stirred for 1 hour, and then 500 mL water was added. The pH of the mixture was adjusted to 11 to 12 with 30% aqueous NaOH solution, extracted twice with ethyl acetate. The organic phases were combined, washed with brine and evaporated to dryness under reduced pressure to give NIR40A.

(18) NIR40A: .sup.1H NMR (400 MHz, in CDCl.sub.3, 298K, in ppm) 1.40 (3H, d), 1.62-1.85 (3H, m), 1.89 (1H, d), 1.96-2.10 (2H, m), 2.83-2.94 (2H, m), 3.03 (1H, d), 3.52 (1H, q), 7.20-7.40 (7H, m), 8.09 (2H, d). MS: 311.2 (M+H).

(19) NIR40A was dissolved in 1100 g methanol, and then added into an autoclave, followed by addition of 10 g 20% palladium hydroxide on carbon and 10 g acetic acid. The autoclave was purged with hydrogen for three times and then pressurized with hydrogen to 1.0 to 1.5 MPa. The reaction solution was stirred at 45 to 50 C. under a pressure of 1.0 to 1.5 MPa. After completion of the reaction, the reaction solution was filtered and the filtrate was evaporated to dryness under reduced pressure to give a residue.

(20) 200 g water was added to the residue, and then the pH was adjusted to 10 with 30% aqueous NaOH solution and extracted twice with ethyl acetate. The organic phases were combined, washed with brine and evaporated to dryness under reduced pressure to give a residue, which was recrystallized by a mixed solvent of ethyl acetate and n-heptane, then dried in vacuum to give 30 g NIR 60A with a yield of 55% for two steps, HPLC purity was 97%, ee=98.5%.

(21) NIR60A: .sup.1H NMR (400 MHz, in CDCl.sub.3, 298K, in ppm) 1.52-1.59 (2H, m), 1.74-1.78 (1H, m), 1.94-1.96 (1H, m), 2.54-2.63 (3H, m), 3.06-3.12 (2H, m), 6.62 (2H, d), 7.00 (2H, d). MS: 177.2 (M+H).

Embodiment 4

(22) ##STR00035##

(23) A solution of Boc.sub.2O (59.47 g) in dichloromethane (500 mL) was added to a solution of NIR60 (50 g) in dichloromethane (500 mL) under an ice bath. After completion of the reaction, water (500 mL) was added and the mixture was stirred and warmed to 15 to 25 C. The mixture was allowed to stand for partition, and then evaporated under reduced pressure (45 to 50 C.) until the distillate was significantly reduced (about one volume). Then 200 mL isopropanol was added, the mixture was purged with nitrogen and warmed to 55 to 60 C., stirred for half an hour until the mixture became clarified, and stirred for another 2 hours. Subsequently, 400 mL water was slowly added dropwise, and the mixture was stirred for another 5 hours, then gradually cooled to 0 C. and continued stirring. The mixture was filtered at 0 C. and the filter cake was washed twice with water/isopropanol (3/1=V:V), then dried in vacuum to give 66.6 g NIR70 as a pink solid with a yield of 85%, HPLC purity was 98%, ee=98.4%.

(24) NIR70: .sup.1H NMR (400 MHz, in CDCl.sub.3, 298K, in ppm) 1.46 (9H, s), 1.53-1.58 (2H, m), 1.72-1.76 (1H, d), 1.95-1.98 (1H, m), 2.55-2.69 (3H, m), 3.60 (2H, s), 4.13 (2H, m), 6.64 (2H, d), 7.01 (2H, d). MS: 221.1 (M-C.sub.4H.sub.8+H). [].sup.25D72.7 (c 1.0, CHCl.sub.3).

Embodiment 5

(25) ##STR00036##

(26) NIR05B was prepared using the method in the reference Journal of Organic Chemistry, 77(16), 7028-7045, 2012.

(27) NIR05B (19 g, 84 mmol), NIR01 (18.2 g, 100 mmol), triethylamine (17 g, 168 mmol) and 200 mL dichloromethane were added into a reaction flask, followed by addition of HATU (33.5 g, 88 mmol) in portions under stirring. The reaction solution was stirred at room temperature for 18 hours. After completion of the reaction, 200 mL water was added, and the pH of the mixture was adjusted to 1 with 4N hydrochloric acid, and then extracted with 300 mL dichloromethane, washed successively with 100 mL saturated sodium bicarbonate solution and 100 mL water. The organic phase was evaporated to give a crude product, which was purified by column chromatography (petroleum ether:dichloromethane=2:1(V:V)) to give NIR10B as a red oil (29 g, yield 89%).

(28) NIR10B: .sup.1H NMR (400 MHz, in CDCl.sub.3, in ppm) 1.49, 1.54 (3H, d, d); 1.75-1.89 (2H, m); 3.16-3.48 (4H, m); 3.81 (3H, s); 3.86, 3.93 (2H, s, s); 5.09, 5.98 (1H, t, t); 6.84-6.88 (2H, m); 7.05-7.24 (2H, d, d); 7.43-7.51 (2H, d, d); 8.19 (2H, d). MS: 391 (M+H).

Embodiment 6

(29) ##STR00037##

(30) NIR10B (13.5 g, 34.6 mmol), anhydrous potassium carbonate (9.6 g, 69.2 mmol) and 130 mL DMF were added into a reaction flask. The reaction solution was stirred at 50 C. under nitrogen atmosphere overnight. After the reaction solution was cooled to room temperature, 500 mL water was added. The mixture was extracted twice with ethyl acetate (300 mL*2). The organic phases were combined and evaporated under reduced pressure to give a crude product of NIR30B, which was dissolved in 18 mL MTBE at 60 C. The solution was slowly cooled to room temperature under stirring, then stirred overnight and filtered. The filter cake was washed twice with 8 mL MTBE, and then dried to give pure product of NIR30B as a yellow solid (2.7 g, yield 22%). de=100% (HNMR).

(31) NIR30B: .sup.1H NMR (400 MHz, in CDCl.sub.3, in ppm) 1.58 (3H, d); 1.65-1.73 (1H, m); 1.83-1.97 (2H, m); 2.12-2.21 (1H, m); 2.97 (1H, m), 3.27 (1H, m), 3.78-3.85 (1H, m), 3.80 (3H, s), 6.13 (1H, q), 6.88 (2H, d), 7.27 (2H, d), 7.38 (2H, d), 8.21 (2H, d). MS: 354.9 (M+H).

Embodiment 7

(32) ##STR00038##

(33) NIR05C was prepared using the method in the reference Journal of Organic Chemistry, 77(16), 7028-7045, 2012.

(34) NIR05C (16 g, 74 mmol), NIR01 (14.8 g, 82 mmol), triethylamine (15 g, 148 mmol) and 170 mL dichloromethane were added into a reaction flask, followed by addition of HATU (29.5 g, 78 mml) in portions under stirring. The reaction solution was stirred at room temperature for 4 hours. After completion of the reaction, 200 mL water was added, and the pH of the mixture was adjusted to 1 with 4N hydrochloric acid, then extracted with 200 mL dichloromethane, washed successively with 150 mL saturated sodium bicarbonate solution and 150 mL water. The organic phase was evaporated under reduced pressure to give a crude product, which was purified by column chromatography (petroleum ether:dichloromethane=2:1(V:V)) to give NIR10C as a red oil (22.2 g, yield 79%).

(35) NIR10C: .sup.1H NMR (400 MHz, in CDCl.sub.3, in ppm) 1.51-1.64 (3H, m); 1.82-1.93 (2H, m); 3.11-3.51 (4H, m); 3.86, 3.92 (2H, s, s); 5.12, 5.99 (1H, t, t); 7.00-7.07 (2H, m); 7.08-7.30 (2H, m, m); 7.42-7.50 (2H, m); 8.19 (2H, d). MS: 378.9 (M+H).

Embodiment 8

(36) ##STR00039##

(37) NIR10C (10 g, 26.4 mmol) and DMF (100 mL) were added into a reaction flask, followed by addition of anhydrous potassium carbonate (7.3 g, 52.8 mmol) under stirring. The reaction solution was stirred at 50 C. under nitrogen atmosphere overnight. After the reaction solution was cooled to room temperature, 300 mL of water was added, and the mixture was extracted three times with ethyl acetate (300 mL*3). The organic phases were evaporated under reduced pressure to give a crude product, which was dissolved in 15 mL MTBE at 60 C. The solution was slowly cooled to room temperature under stirring, then stirred overnight and filtered. The filter cake was washed twice with 5 mL MTBE and dried to give NIR30C as a yellow solid (2.5 g, yield 28%). de=100% (HNMR).

(38) NIR30C: .sup.1H NMR (400 MHz, in CDCl.sub.3, in ppm) 1.57 (3H, d); 1.65-1.74 (1H, m); 1.85-1.97 (2H, m); 2.18 (1H, m); 2.96 (1H, m), 3.29 (1H, m), 3.81 (1H, m), 3.80 (3H, s), 6.15 (1H, q), 7.04 (2H, m), 7.31 (2H, m), 6.40 (2H, m), 8.21 (2H, d). MS: 342.9 (M+H).

Embodiment 9

(39) ##STR00040##

(40) NIR5D was prepared using the method in the reference Journal of Organic Chemistry, 77(16), 7028-7045, 2012.

(41) NIR05D (6.25 g, 29.5 mmol), NIR01 (5.3 g, 29.5 mmol), triethylamine (6.0 g, 59 mmol) and 60 mL of dichloromethane were added into a reaction flask, followed by addition of HATU (1.8 g, 31 mml) in portions under stirring. The reaction solution was stirred at room temperature for 16 hours. After completion of the reaction, 150 mL water was added, and the pH of the mixture was adjusted to 1 with 1N hydrochloric acid, then extracted twice with dichloromethane (150 mL*2), washed successively with 100 mL saturated sodium bicarbonate solution and 30 mL water. The organic phases were evaporated under reduced pressure to give a crude product, which was purified by column chromatography (petroleum ether:dichloromethane=3:1(V:V)) to give NIR10D as a red oil (9.5 g, yield 86%).

(42) NIR10D: .sup.1H NMR (400 MHz, in CDCl.sub.3, in ppm) 0.83-1.02 (3H, m); 1.35-2.20 (4H, m); 3.15-3.43 (4H, m); 3.87, 3.99 (2H, d, s); 4.85, 5.80 (1H, t, t); 7.15-7.36 (5H, m); 7.49 (2H, m); 8.20 (2H, m). MS: 374.9 (M+H).

Embodiment 10

(43) ##STR00041##

(44) Anhydrous potassium carbonate (6.8 g, 49.6 mmol) and 30 mL DMF were added into a reaction flask, followed by dropwise addition of a solution of NIR10D (9.3 g, 24.8 mmol) in DMF (4 mL) under stirring. The reaction solution was stirred at 50 C. under nitrogen atmosphere for 6 hours. After the reaction solution was cooled to room temperature, 600 mL water was added, and then the mixture was extracted three times with ethyl acetate (100 mL*3). The organic phase was evaporated under reduced pressure to give 8.3 g crude product. 14 mL MTBE was added to the crude product, and the mixture was gradually warmed to 50 C. and the crude product was completely dissolved. The solution was naturally cooled to room temperature, then cooled under an ice bath and filtered. The filter cake was washed twice with cold MTBE and then dried to give NIR30D as a white solid (2.6 g, yield 30%). de=100% (HNMR).

(45) NIR30D: .sup.1H NMR (400 MHz, in CDCl.sub.3, in ppm) 1.05 (3H, d); 1.68 (1H, m); 1.86-2.19 (5H, m); 3.01 (1H, m), 3.24 (1H, m), 3.82 (1H, m), 5.95 (1H, q), 7.27-7.38 (5H, m), 7.40 (2H, d), 8.20 (2H, d). MS: 339.0 (M+H).

Embodiment 11

(46) ##STR00042##

(47) NIR05E was prepared using the method in the reference Journal of Organic Chemistry, 77(16), 7028-7045, 2012.

(48) NIR05E (11.45 g, 53.7 mmol), NIR01 (12.65 g, 69.9 mmol), triethylamine (10.85 g, 56.4 mmol) and 100 mL dichloromethane were added into a reaction flask, followed by addition of HATU (21.4 g, 56.4 mmol) in portions under stirring. The reaction solution was stirred at room temperature for 16 hours. After completion of the reaction, 50 mL water was added, then the pH of the mixture was adjusted to 1 with 4N hydrochloric acid, extracted with 50 mL dichloromethane, washed successively with 70 mL saturated sodium bicarbonate solution and 50 mL water. The organic phase was evaporated under reduced pressure to give a crude product, which was purified by column chromatography (petroleum ether:ethyl acetate=4:1(V:V)) to give NIR10E as a red oil (7 g, yield 35%).

(49) NIR10E: .sup.1H NMR (400 MHz, in CDCl.sub.3, in ppm) 1.66, 1.95 (2H, m, m); 3.27-3.46 (4H, m); 3.85-4.17 (4H, m); 5.14, 5.55 (1H, m, m); 7.04-7.37 (5H, m); 7.47 (2H, m); 8.19 (2H, m). MS: 377.0 (M+H).

Embodiment 12

(50) ##STR00043##

(51) Anhydrous potassium carbonate (6.6 g, 47.8 mmol) and 50 mL DMF were added into a reaction flask, followed by dropwise addition of a solution of NIR10E (9 g, 23.9 mmol) in DMF (50 mL) under stirring. The reaction solution was stirred at 50 C. under nitrogen atmosphere for 6 hours. After the reaction solution was cooled to room temperature, 200 mL water was added, and then the mixture was extracted three times with ethyl acetate (200 mL*3). The organic phases were combined and evaporated under reduced pressure to give a crude product, which was dissolved in 14 mL MTBE under heating condition (50 C.). The solution was slowly cooled to room temperature under slowly stirring, then stirred overnight and filtered. The filter cake was washed twice with 10 mL MTBE and then dried to give NIR30E as a white solid (500 mg, yield 6%). de=100% (HNMR).

(52) NIR30E: .sup.1H NMR (400 MHz, in CDCl.sub.3, in ppm) 1.76 (1H, m); 1.90 (2H, m); 2.21 (1H, m), 3.09 (1H, m), 3.37 (1H, m), 3.88 (1H, m), 4.21 (2H, m), 5.97 (1H, q), 7.28-7.40 (5H, m), 7.43 (2H, d), 8.20 (2H, d). MS: 340.9 (M+H).

(53) It is to be understood that the foregoing description of two preferred embodiments is intended to be purely illustrative of the principles of the invention, rather than exhaustive thereof, and that changes and variations will be apparent to those skilled in the art, and that the present invention is not intended to be limited other than expressly set forth in the following claims.