Method for preparing urate transporter 1 inhibitor

Abstract

Provided is a method for preparing a URAT1 inhibitor, 2-((5-bromo-4-((4-bromonaphthalen-1-yl)methyl)-4H-1,2,4-triazol-3-yl)thio) acetic acid represented by the following formula ZXS-BR, the reaction equation of which being shown as follows. Compared with the prior art, the preparation method provided by the present application is of low cost, ease of handling, ease of quality control, and applicable to industrialization. ##STR00001## ##STR00002##

Claims

1. A method for preparing a urate transporter 1 inhibitor, 2-((5-bromo-4-((4-bromonaphthalen-1-yl)methyl)-4H-1,2,4-triazol-3-yl)thio) acetic acid represented by the formula ZXS-BR, comprising the following steps: 1) performing a bromination reaction of N-bromosuccinimide and starting material A′ to obtain product B′; 2) reacting product B′ obtained from step 1) with N-bromosuccinimide in the presence of a radical initiator to obtain product C′; 3) reacting product C′ obtained from step 2) with a thiocyanate at a temperature no lower than 100° C. to obtain product D; 4) reacting product D obtained from step 3) with formylhydrazine to obtain product E; 5) performing a ring closure reaction of product E obtained from step 4) in the presence of a base to obtain product F; 6) reacting product F obtained from step 5) with XCH.sub.2CO.sub.2R in the presence of a base to obtain product G′; wherein, X is selected from Cl, Br or I, and R is selected from C.sub.1-C.sub.10 alkyl or C.sub.3-C.sub.6 cycloalkyl; 7) reacting product G′ obtained from step 6) with N-bromosuccinimide to obtain product H′; and 8) hydrolyzing product H′ obtained from step 7) in the presence of a base to obtain ZXS-BR; wherein, the formulas A′, B′, C′, D, E, F, G′, H′ and ZXS-BR represent the following compounds, respectively: ##STR00025## ##STR00026##

2. The method of claim 1, wherein the reaction in step 1) is conducted in acetonitrile, and the reaction temperature is from 30 to 40° C.

3. The method of claim 1, wherein in step 2), the radical initiator is benzoyl peroxide or azodiisobutyronitrile.

4. The method of claim 1, wherein the reaction in step 2) is conducted in a solvent of the reaction selected from C.sub.5-C.sub.17 alkane or cycloalkane, or petroleum ether fraction obtained by fractionation at 30-150° C.

5. The method of claim 4, wherein C.sub.5-C.sub.17 alkane or cycloalkane is n-pentane, cyclopentane, n-hexane, cyclohexane, or n-heptane.

6. The method of claim 4, wherein in step 2), the temperature of the reaction is the reflux temperature of the solvent.

7. The method of claim 1, wherein in step 2), the temperature of the reaction is from 36° C. to 120° C.

8. The method of claim 1, wherein in step 3), the thiocyanate is a thiocyanate of alkali metal, alkaline earth metal or ammonium.

9. The method of claim 1, wherein in step 3), the thiocyanate is sodium thiocyanate, potassium thiocyanate or ammonium thiocyanate.

10. The method of claim 1, wherein in step 3), the temperature of the reaction is from 120° C. to 140° C.

11. The method of claim 1, wherein the reaction in step 3) is conducted in an aprotic dipolar solvent.

12. The method of claim 11, wherein the aprotic dipolar solvent is selected from dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, or hexamethylphosphoramide.

13. The method of claim 1, wherein in step 3), the temperature of the reaction is from 100° C. to the reflux temperature of the solvent.

14. The method of claim 1, wherein the reaction in step 4) is conducted in tetrahydrofuran.

15. The method of claim 1, wherein in step 5), the base is an alkali metal carbonate or an alkali metal hydroxide.

16. The method of claim 1, wherein in step 5), the base is Na.sub.2CO.sub.3, K.sub.2CO.sub.3, NaOH or KOH.

17. The method of claim 1, wherein in step 6), R is selected from C.sub.1-C.sub.4 alkyl.

18. The method of claim 1, wherein in step 6), R is selected from methyl or ethyl.

19. The method of claim 1, wherein in step 8), the base is selected from an alkali metal hydroxide.

20. The method of claim 1, wherein in step 8), the base is selected from LiOH, NaOH or KOH.

21. The method of claim 1, wherein the method comprises the following steps: 1) performing a bromination reaction of N-bromosuccinimide and starting material A′ in acetonitrile as a solvent at a temperature of 30-40° C. to obtain product B′; 2) heating product B′ obtained from step 1), N-bromosuccinimide and benzoyl peroxide in n-hexane to reflux to obtain product C′; 3) reacting product C′ obtained from step 2) with potassium thiocyanate in dimethylformamide as a solvent at a temperature of 140° C. to obtain product D; 4) reacting product D obtained from step 3) with formylhydrazine in tetrahydrofuran as a solvent at room temperature to obtain product E; 5) performing a ring closure reaction of product E obtained from step 4) with a base to obtain product F; 6) reacting product F obtained from step 5) with XCH.sub.2CO.sub.2R in the presence of a base to obtain product G′; wherein, X is selected from Cl, Br or I, and R is selected from C.sub.1-C.sub.10 alkyl or C.sub.3-C.sub.6 cycloalkyl; 7) reacting product G′ obtained from step 6) with N-bromosuccinimide to obtain product H′; and 8) hydrolyzing product H′ obtained from step 7) with a base to obtain ZXS-BR.

22. The method of claim 21, wherein in step 5), the base is an alkali metal carbonate or an alkali metal hydroxide.

23. The method of claim 21, wherein in step 5), the base is Na.sub.2CO.sub.3, K.sub.2CO.sub.3, NaOH or KOH.

24. The method of claim 21, wherein in step 6), R is selected from C.sub.1-C.sub.4 alkyl.

25. The method of claim 21, wherein in step 6), R is selected from methyl or ethyl.

26. The method of claim 21, wherein in step 8), the base is an alkali metal hydroxide.

27. The method of claim 21, wherein in step 8), the base is LiOH, NaOH or KOH.

28. A compound represented by the following formula H′ or G′ respectively: ##STR00027## wherein, R is selected from C.sub.1-C.sub.10 alkyl or C.sub.3-C.sub.6 cycloalkyl.

29. The compound of claim 28, wherein R is selected from C.sub.1-C.sub.4 alkyl.

30. The compound of claim 28, wherein R is selected from methyl or ethyl.

31. A compound represented by the following formula D, E or F respectively: ##STR00028##

Description

BEST MODE FOR CARRYING OUT THE INVENTION

(1) The present invention will be further described in detail in connection with the specific embodiments thereof. The examples are given only to illustrate the invention and not intended to limit the scope of the invention.

Example 1 Synthetic Route of PCT/CN2016/080468

(2) ##STR00015## ##STR00016##

Step 1. Synthesis of Compound B

(3) To a dry 1 L round bottom flask were added compound A (1,4-dibromonaphthalene, 57.19 g, 200 mmol), CuCN (10.75 g, 120 mmol) and DMF (600 mL), and the resulting mixture was stirred at 130° C. under nitrogen atmosphere for 12 hours.

(4) The reaction mixture was cooled to room temperature and transferred to a 5 L flask. Ethyl acetate (1.8 L) was added, and the resulting mixture was stirred at room temperature for 2-3 hours to give a grayish brown slurry. The slurry was filtered by suction, and the filtrate was collected. The filter cake was washed with a small amount of ethyl acetate, and the washing liquid was combined into the filtrate. The filtrate was washed with water (1 L×5), dried over anhydrous sodium sulfate, and evaporated on a rotary evaporator to remove the solvent. To the resulting yellow solid was added ethyl acetate-petroleum ether (400 mL, a volume ratio of 1:3), and the resulting mixture was warmed to 70° C. and stirred to give a clear solution. After the solution was cooled slowly with stirring to room temperature, a yellow slurry was obtained. The slurry was filtered by suction, the filtrate was collected which was evaporated to dryness on a rotary evaporator, and the resulting residue was purified by silica gel column chromatography, and eluted with ethyl acetate-petroleum ether (1:50.fwdarw.1:30) to obtain a pure product of B as a white solid, 12.53 g; yield: 27%; m.p.: 103-104° C.; .sup.1H NMR (DMSO-d.sub.6, 400 MHz), δ 8.26-8.31 (m, 1H, Ar—H), 8.13-8.18 (m, 1H, Ar—H), 8.07 (s, 2H, Ar—H), 7.85-7.92 (m, 3H, Ar—H).

Step 2. Synthesis of Compound C

(5) Compound B (11.60 g, 50 mmol) was dissolved in dry THF (200 mL) and stirred, and LiAlH.sub.4 (2.77 g, 73 mmol) was added slowly in portions with cooling in an ice-water bath. After completion of the addition, the reaction mixture was stirred in the ice-water bath for another 2 hours.

(6) The reaction mixture was carefully and slowly poured into stirring ice water (400 mL), stirred, and extracted with CH.sub.2Cl.sub.2 (200 mL×3). The extracted organic phases were combined, washed with 5% saline solution (200 mL), and dried over anhydrous Na.sub.2SO.sub.4. The dried organic phase was evaporated on a rotary evaporator to remove the solvent, and the resulting residue was purified by column chromatography to give product C as a colorless oil. .sup.1H NMR showed that about 30% debromination by-product (i.e., naphthalene-1-methylamine) was contained therein and a further purification was difficult, and therefore the mixture was used for the next reaction directly.

Step 3. Synthesis of Compound D

(7) The crude compound C (calculated as 50 mmol) prepared in the above step 2 and diisopropylethylamine (DIPEA, 19.39 g, 150 mmol) were dissolved in dry CH.sub.2Cl.sub.2 (200 mL), and the resulting solution was stirred with cooling in an ice-water bath. Then CSCl.sub.2 (6.90 g, 60 mmol) was slowly added dropwise, and after the dropwise addition was completed, the resulting solution was stirred at room temperature for another 1 hour. At this point the reaction was checked for completion by TLC.

(8) The reaction mixture was carefully and slowly poured into stirring ice water (400 mL) and stirred, the organic phase was separated, and the aqueous phase was extracted with CH.sub.2Cl.sub.2 (150 mL×2). The organic phases were combined, washed with 2% dilute hydrochloric acid (300 mL) and 5% saline solution (200 mL) sequentially, and dried over anhydrous Na.sub.2SO.sub.4. The dried organic phase was evaporated on a rotary evaporator to remove the solvent, and the resulting residue was purified by column chromatography to give product D as a white solid, 8.21 g; yield: 59%. .sup.1H NMR showed that about 8% debromination by-product was contained therein and a further purification was difficult, and therefore the residue was used for the next reaction directly. A small amount of the above-described crude D was subjected to three column chromatographies and two recrystallizations consecutively to give a sample of pure product D as a white solid for structural characterization; m.p.: 94.5-97.5° C. .sup.1H NM R (DMSO-d.sub.6, 400 MHz), δ 8.21-8.24 (m, 1H), 8.11-8.14 (m, 1H), 7.92 (d, 1H, J=7.6 Hz), 7.73-7.78 (m, 2H), 7.52 (d, 1H, J=8.0 Hz), 5.41 (s, 2H).

Step 4. Synthesis of Compound F

(9) The above-described crude compound D (6.95 g, calculated as 25 mmol) was dissolved in THF (100 mL), and stirred at room temperature. Formylhydrazine (1.80 g, 30 mmol) was added, and then the stirring was continued overnight. At this point the reaction was detected for completion by TLC.

(10) The reaction mixture was evaporated on a rotary evaporator to dryness, the resulting residue, i.e., a crude product of E, was dissolved in DMF (80 mL), and solid K.sub.2CO.sub.3 (3.46 g, 25 mol) was added. The reaction mixture was stirred at 50° C. until the reaction was completed (usually 5 hours).

(11) The reaction mixture was cooled to room temperature, poured into ice water (400 mL), stirred, adjusted with hydrochloric acid to pH=5-6, and extracted with CH.sub.2Cl.sub.2 (150 mL×5). The organic phases were combined, washed with 5% saline solution (200 mL), and dried over anhydrous Na.sub.2SO.sub.4. The dried organic phase was evaporated on a rotary evaporator to remove the solvent, and the resulting residue was purified by column chromatography to give product F as a white solid. .sup.1H NMR showed that about 5% debromination by-product was contained therein. The crude F was crystallized twice with ethyl acetate to give a pure product of F, 6.96 g; yield: 87% (D.fwdarw.F); m.p.: 243-244° C. .sup.1H NMR (DMSO-d.sub.6, 400 MHz), δ 13.88 (brs, 1H), 8.37 (s, 1H), 8.22 (d, 2H, J=7.6 Hz), 7.90 (d, 1H, J=7.2 Hz), 7.72 (m, 2H), 7.18 (d, 1H, J=7.2 Hz), 5.61 (s, 2H).

Step 5. Synthesis of Compound G

(12) Compound F (6.40 g, 20 mmol) was dissolved in DMF (100 mL) and stirred at room temperature, and solid K.sub.2CO.sub.3 (8.29 g, 60 mmol) and methyl bromoacetate (3.67 g, 24 mmol) were added. The resulting reaction mixture was stirred continuously at room temperature until the completion of the reaction was found by TLC determination (usually within 5 hours).

(13) The reaction mixture was poured into ice water (400 mL), stirred, and extracted with CH.sub.2Cl.sub.2 (100 mL×5). The organic phases were combined, washed with 5% saline solution (200 mL), and dried over anhydrous Na.sub.2SO.sub.4. The dried organic phase was evaporated on a rotary evaporator to remove the solvent, and the resulting residue was purified by column chromatography to give product G as a white solid, 7.37 g; yield: 94%; m.p.: 112.5-114° C. .sup.1H NMR (DMSO-d.sub.6, 400 MHz), δ 8.67 (s, 1H), 8.22-8.25 (m, 1H), 8.15-8.17 (m, 1H), 7.88 (d, 1H, J=7.6 Hz), 7.72-7.79 (m, 2H), 6.92 (d, 1H, J=7.6 Hz), 5.72 (s, 2H), 4.07 (s, 2H), 3.62 (s, 3H).

Step 6. Synthesis of Compound H

(14) Compound G (3.92 g, 10 mmol) was dissolved in acetonitrile (50 mL) and stirred at room temperature. NBS (2.14 g, 12 mmol) was added, and the stirring was continued at room temperature until the completion of the reaction was found by TLC determination (usually within 12 hours).

(15) The reaction mixture was poured into ice water (200 mL), stirred, and extracted with CH.sub.2Cl.sub.2 (100 mL×3). The organic phases were combined, and washed with a saturated Na.sub.2CO.sub.3 solution (100 mL×3) and 5% saline solution (200 mL) sequentially, and dried over anhydrous Na.sub.2SO.sub.4. The dried organic phase was evaporated on a rotary evaporator to remove the solvent, and the resulting residue was purified by column chromatography to give product H as a white solid, 3.49 g; m.p.: 141-143° C.; yield: 74%. .sup.1H NMR (DMSO-d.sub.6, 400 MHz), δ 8.21-8.26 (m, 2H), 7.84 (d, 1H, J=8.0 Hz), 7.76-7.82 (m, 2H), 6.49 (d, 1H, J=7.6 Hz), 5.74 (s, 2H), 4.08 (s, 2H), 3.61 (s, 3H).

Step 7. Synthesis of ZXS-BR

(16) Compound H (3.30 g, 7 mmol) was added into methanol (50 mL) and stirred at room temperature. A solution made by LiOH.H.sub.2O (0.84 g, 20 mmol) and water (3 mL) was added, and then stirred at room temperature until the completion of the reaction was found by TLC determination (usually 2 hours).

(17) The reaction mixture was poured into ice water (200 mL), stirred, adjusted with hydrochloric acid to pH=2-3, and extracted with CH.sub.2Cl.sub.2 (100 mL×4). The organic phases were combined, washed with 5% saline solution (200 mL), and dried over anhydrous Na.sub.2SO.sub.4. The dried organic phase was evaporated on a rotary evaporator to remove the solvent, and the resulting residue was purified by column chromatography to give product ZXS-BR as a white solid, 2.82 g; yield: 88%; m.p.: 169.5-171.5° C. .sup.1H NMR (DMSO-d.sub.6, 400 MHz), δ 12.97 (brs, 1H), 8.22-8.26 (m, 2H), 7.83 (d, 1H, J=8.0 Hz), 7.76-7.81 (m, 2H), 6.51 (d, 1H, J=8.0 Hz), 5.73 (s, 2H), 4.01 (s, 2H).

Example 2 Screening Study on Reaction Conditions in the Step of B′→C′

(18) ##STR00017##

(19) It is recognized by one of ordinary skill in the art that free radical halogenation at the benzylic position of an aralkyl group is generally carried out by heating in a solvent such as CCl.sub.4 with NBS (N-bromosuccinimide) or NCS (N-chlorosuccinimide) as a halogenating agent, BPO or azodiisobutyronitrile (AIBN) and the like as a radical initiator. However, the inventors of the present invention had found that the reaction proceeds unsmoothly in a solvent recognized by a person skilled in the art such as CCl.sub.4, and thus carried out a intensive and delicate optimization and screening of the main reaction conditions of the reaction, that is, the halogenating agent, the radical initiator and the reaction solvent, and finally found that n-hexane is the most appropriate solvent, BPO is the optimal radical initiator, and NBS is the best halogenating reagent for this reaction.

(20) Reaction operations: to a dry 250 mL round bottom flask was added a solvent to be screened (40 mL) at room temperature. B′ (3.54 g, 16 mmol), a radical initiator (0.32 mmol), and NBS or NCS (19.2 mmol) was added with stirring, and warmed to an indicated temperature while stirring, and the reaction was monitored by TLC. After the reaction started, 0.32 mmol radical initiator was added once every 8 hours, until TLC showed that the reaction was self-terminated (B′ disappeared) or aborted (no reaction occurred after 72 hours). If no reaction was found by TLC, or C′/C″ was not generated, the reaction did not need to be treated; if C′/C″ was generated, the reaction was processed in accordance with the following steps: after the reaction was completed, the system was cooled to room temperature, and the reaction mixture was concentrated to ⅓ volume on a rotary evaporator, poured into water (200 mL), stirred, and extracted with CH.sub.2Cl.sub.2 (50 mL×3). The extract phases were combined, washed with a saturated NaHCO.sub.3 solution (50 mL×3) and 5% saline solution (50 mL) sequentially, dried over anhydrous Na.sub.2SO.sub.4 and filtered by suction to remove the desiccant. Then the filtrate was evaporated to dryness on a rotary evaporator, and the residue was purified by column chromatography to give a pure product of C′/C″. The yields are calculated, and the reaction conditions and the results are shown in Table 1.

(21) TABLE-US-00001 TABLE 1 Reaction conditions and results Experiment Halogenating Radical Reaction No. reagent initiator Solvent temperature* Conclusion  1 NBS BPO CCl.sub.4 reflux raw material B′ temperature of disappeared, the yield CCl.sub.4 of C′ was 8%  2 NBS BPO CHCl.sub.3 reflux raw material B′ temperature of disappeared, the yield CHCl.sub.3 of C′ was 2%  3 NBS BPO CH.sub.2Cl.sub.2 reflux raw material B′ did not temperature of react within 72 hours CH.sub.2Cl.sub.2  4 NBS BPO acetone reflux raw material B′ temperature of disappeared, the yield acetone of C′ was 0%  5 NBS BPO DMF 100° C. raw material B′ disappeared, the yield of C′ was 0%  6 NBS BPO MeCN reflux raw material B′ temperature of disappeared, the yield MeCN of C′ was 0%  7 NBS AIBN MeCN reflux raw material B′ temperature of disappeared, the yield MeCN of C′ was 4%  8 NBS BPO THF reflux raw material B′ temperature of disappeared, the yield THF of C′ was 0%  9 NBS AIBN THF reflux raw material B′ temperature of disappeared, the yield THF of C′ was 6% 10 NBS BPO n-hexane reflux raw material B′ temperature of disappeared, the yield n-hexane of C′ was 72% 11 NBS AIBN n-hexane reflux raw material B′ temperature of disappeared, the yield n-hexane of C′ was 41% 12 NBS BPO cyclohexane reflux raw material B′ temperature of disappeared, the yield cyclohexane of C′ was 67% 13 NBS BPO n-pentane reflux raw material B′ temperature of disappeared, the yield n-pentane of C′ was 61% 14 NBS BPO cyclopentane reflux raw material B′ temperature of disappeared, the yield cyclopentane of C′ was 69% 15 NBS BPO n-heptane 70-80° C. raw material B′ disappeared, the yield of C′ was 62% 16 NBS BPO cycloheptane 70-80° C. raw material B′ disappeared, the yield of C′ was 54% 17 NBS BPO n-heptane reflux raw material B′ temperature of disappeared, the yield n-heptane of C′ was 61% 18 NBS BPO cycloheptane reflux raw material B′ temperature of disappeared, the yield cycloheptane of C′ was 55% 19 NBS BPO n-octane 70-80° C. raw material B′ disappeared, the yield of C′ was 64% 20 NBS BPO n-nonane 70-80° C. raw material B′ disappeared, the yield of C′ was 59% 21 NBS BPO n-decane 70-80° C. raw material B′ disappeared, the yield of C′ was 58% 22 NBS BPO n-undecane 70-80° C. raw material B′ disappeared, the yield of C′ was 67% 23 NBS BPO n-dodecane 70-80° C. raw material B′ disappeared, the yield of C′ was 51% 24 NBS BPO n-tridecane 70-80° C. raw material B′ disappeared, the yield of C′ was 59% 25 NBS BPO n-tetradecane 70-80° C. raw material B′ disappeared, the yield of C′ was 55% 26 NBS BPO n-pentadecane 70-80° C. raw material B′ disappeared, the yield of C′ was 61% 27 NBS BPO n-hexadecane 70-80° C. raw material B′ disappeared, the yield of C′ was 62% 28 NBS BPO n-heptadecane 70-80° C. raw material B′ disappeared, the yield of C′ was 63% 29 NBS BPO petroleum reflux raw material B′ ether fraction temperature disappeared, the yield at 30-60° C. of C′ was 53% 30 NBS BPO petroleum reflux raw material B′ ether fraction temperature disappeared, the yield at 60-90° C. of C′ was 56% 31 NBS BPO petroleum 70-80° C. raw material B′ ether fraction disappeared, the yield at 90-120° C. of C′ was 53% 32 NBS BPO petroleum 70-80° C. raw material B′ ether fraction disappeared, the yield at 120-150° C. of C′ was 55% 33 NCS BPO n-hexane reflux most of raw material B′ temperature of was recovered, the n-hexane yield of C″ was 9% *Note: the boiling temperature of a solvent under a pressure of 760 mmHg is the boiling point of the solvent, but it is a common knowledge of those of ordinary skill in the art that under actual experimental conditions, the actual boiling temperature of a solvent is affected by many factors (such as the altitude of experiment site and the types and concentrations of solutes dissolved in the solvent) and may fluctuate around its standard boiling point. The actual reflux temperatures of several solvents described in the above table are also around their boiling points. The boiling point of CCl.sub.4 is 76.8° C.; the boiling point of CHCl.sub.3 is 61° C.; the boiling point of CH.sub.2Cl.sub.2 is 39.8° C.; the boiling point of acetone is 56.5° C.; the boiling point of MeCN is 81° C.; the boiling point of THF is 65° C.; the boiling point of n-hexane is 69° C.; the boiling point of cyclohexaneis 80° C.; the boiling point of n-pentane is 36° C.; the boiling point of cyclopentane is 49° C.; the boiling point of n-heptane is 98.5° C.; the boiling point of cycloheptane is 118.5° C. (a reasonable moderate reflux rate was achieved at about 120° C. in this experiment); petroleum ether fraction at 30-60° C. is moderately refluxed at about 35° C.; petroleum ether fraction at 60-90° C. is moderately refluxed at about 65° C.; petroleum ether fraction at 90-120° C. is moderately refluxed at about 95° C.; and petroleum ether fraction at 120-150° C. is moderately reflaxed at about 125° C.

(22) Conclusion: as can be seen from Table 1, NBS is the optimal halogenating reagent in this step, and the reaction is too slow when using NCS; the optimal initiator is BPO, and the effect of AIBN is average; among all solvents to be tested, C.sub.5-C.sub.17 alkane and cycloalkane and petroleum ether fraction at 30-150° C. are optimal; and the reaction temperature is in a range of from about 36° C. (the reflux temperature of n-pentane) to 120° C. (the reflux temperature of cycloheptane).

Example 3 Screening Study on Reaction Temperature in the Step of C′ to D

(23) ##STR00018##

(24) It is recognized by one of ordinary skill in the art that the reaction of an aromatic benzyl halide with a thiocyanate is relatively easy. Since the reaction can generally be carried out at a lower temperature, there is generally no motivation to operate at a higher temperature (for the sake of saving energy and power consumption). Therefore, when trying to react C′ with KSCN in DMF at room temperature, we found that the reaction was very rapid (completed within 0.5 hours), and a single product was obtained. But after separation and structural identification, it was found that the product was not the desired D (an isothiocyanate), but its isomer D′ (a thiocyanate), with the latter being a product of the reaction of S-terminal of thiocyanate ion in KSCN with C′. To this end, we carried out a detailed and intensive study on the types of thiocyanate and the temperatures of the reaction, and finally found that the reaction needed to be carried out within a specific range of higher temperatures so as to ensure the selectivity of N-terminal of thiocyanate ion to C′ in the reaction.

(25) Reaction operations: to a dry 250 mL round bottom flask was added compound C′ (3.00 g, 10 mmol), which was dissolved in a dry solvent (30 mL), and then warmed to an indicated temperature with stirring. A thiocyanate MSCN (12 mmol) was added in three portions within 1 minute. After the addition was completed, the reaction mixture was further stirred at the indicated temperature for 1 hour, and at this point the reaction was completed. The reaction mixture was cooled to room temperature, and then poured into stirring ice water (200 mL), stirred and extracted with CH.sub.2Cl.sub.2 (50 mL×3). The organic phases were combined, washed with 5% saline solution (50 mL×5), and dried over anhydrous Na.sub.2SO.sub.4. The dried organic phase was evaporated on a rotary evaporator to remove the solvent, and the resulting residue was purified and isolated by column chromatography to give products D and D′. The yields are calculated respectively, and the experimental conditions and the results are shown in Table 2.

(26) TABLE-US-00002 TABLE 2 Experimental conditions and results Experiment Temperature Yield of Yield of No. Solvent (° C.) MSCN D (%) D′ (%)  1 DMF  25 KSCN 0 90  2 DMF  40 KSCN 1 89  3 DMF  50 KSCN 1 91  4 DMF  60 KSCN 2 90  5 DMF  70 KSCN 3 87  6 DMF  80 KSCN 3 88  7 DMF  90 KSCN 14 64  8 DMF 100 KSCN 45 40  9 DMF 110 KSCN 78 12 10 DMF 120 KSCN 92 2 11 DMF 130 KSCN 93 2 12 DMF 140 90 1 13 DMF reflux temperature KSCN 90 2 of DMF* 14 DMF 120 NaSCN 92 3 15 DMF 140 NaSCN 91 1 16 DMF reflux temperature NaSCN 91 1 of DMF* 17 DMF 120 NH.sub.4SCN 90 2 18 DMF 140 NH.sub.4SCN 90 2 19 DMF reflux temperature NH.sub.4SCN 91 1 of DMF* 20 N,N-dimethyl 140 KSCN 85 1 acetamide (DMA) 21 DMSO 140 KSCN 87 1 22 N-methyl 140 KSCN 80 3 pyrrolidone (NMP) 23 hexamethyl 140 KSCN 84 2 phosphoramide (HMPA) 24 MeOH reflux temperature KSCN 0 65 of MeOH* 25 EtOH reflux temperature KSCN 0 33 of EtOH* 26 acetone reflux temperature KSCN 1 61 of acetone* 27 EtOAc reflux temperature KSCN 0 49 of EtOAc* 28 MeCN reflux temperature KSCN 0 64 of MeCN* 29 THF reflux temperature KSCN 0 54 of THF* *Note: the boiling point of DMF under a pressure of 760 mmHg is 153° C., but it is a common knowledge of those of ordinary skill in the art that under actual experimental conditions, the actual boiling temperature of DMF is affected by many factors (such as the altitude of experiment site and the types and concentrations of solutes dissolved in DMF) and may fluctuate around 153° C. Similarly, the reflux temperatures of several solvents described in the above table are also around their boiling points. The boiling point of MeOH is 65° C.; the boiling point of EtOH is 78° C.; the boiling point of acetone is 56.5° C.; the boiling point of EtOAc is 77° C.; the boiling point of MeCN is 81° C.; and the boiling point of THF is 65° C.

(27) Conclusion: as can be seen from Table 2, in contrast to what recognized by those of ordinary skill in the art, the reaction between compound C′ and a thiocyanate was very rapid and can be rapidly completed at room temperature. However, the distribution of the products is obviously temperature dependent. At a higher temperature, it tends to be produce D which is desired in the present invention, but at a lower temperature, the products are primarily isomer D′. The temperature at which D/D′ tendency can be reversed is about 100° C. At the same time, the reaction proceeds well in an aprotic dipolar solvent such as DMF, DMA, DMSO, NMP, and HMPA, but does not proceeds well in other solvents.

Example 4 Synthetic Route of the Present Invention

(28) ##STR00019## ##STR00020##

Step 1. Synthesis of Compound B′

(29) To a dry 1 L round bottom flask were added compound A′ (1-methylnaphthalene, 28.44 g, 200 mmol), NBS (42.72 g, 240 mmol) and MeCN (700 mL), and the resulting mixture was stirred at 30° C.−40° C. for 12 hours.

(30) The reaction mixture was cooled to room temperature, poured into ice water (3 L), and extracted with dichloromethane (500 mL×3). The extracted phases were combined, washed with 5% aqueous solution of Na.sub.2CO.sub.3 (500 mL×5), 10% aqueous solution of Na.sub.2S.sub.2O.sub.3 (500 mL) and 5% saline solution (500 mL) sequentially, and dried over anhydrous Na.sub.2SO.sub.4. The dried organic phase was evaporated on a rotary evaporator to remove the solvent, and the resulting residue was purified by column chromatography to give product B′ as a colorless oil, 39.80 g; yield: 90%. .sup.1H NMR (DMSO-d.sub.6, 400 MHz), δ 8.14-8.16 (m, 1H), 8.07-8.09 (m, 1H), 7.76 (d, 1H, J=7.6 Hz), 7.66-7.70 (m, 2H), 7.30 (d, 1H, J=7.6 Hz), 2.63 (s, 3H).

Step 2. Synthesis of Compound C′

(31) To a dry 1 L round bottom flask was added n-hexane (400 mL) at room temperature, and B′ (35.37 g, 160 mmol), benzoyl peroxide (BPO, 0.775 g, 3.2 mmol) and NBS (34.17 g, 192 mmol) were added with stirring. The resulting mixture was stirred and heated to reflux, until TLC indicated that the reaction was completed (0.775 g BPO was added once every 8 hours after the start of the reaction; the reaction was usually completed within 36 hours).

(32) After the reaction was completed, the system was cooled to room temperature, stirred for 2 hours, and then filtered by suction. The filter cake was added into 800 mL water, stirred at room temperature for 1 hour and filtered by suction, and the filtrate was discarded. The filter cake was added into 800 mL water again, stirred at room temperature for 1 hour and filtered by suction, and the filtrate was discarded. The resulting filter cake was pulped by stirring in 800 mL n-hexane for 2 hours and filtered by suction. The filter cake was dried to give a pure product of C′ as a white solid, 34.56 g; yield: 72%; m.p.: 104.0-105.5° C. .sup.1H NMR (DMSO-d.sub.6, 400 MHz), δ 8.20-8.26 (m, 2H), 7.86 (d, 1H, J=8.0 Hz), 7.72-7.78 (m, 2H), 7.62 (d, 1H, J=7.6 Hz), 5.21 (s, 2H).

Step 3. Synthesis of Compound D

(33) To a dry 1 L round bottom flask was added compound C′ (30.00 g, 100 mmol), dissolved in dry DMF (300 mL), and then heated to 140° C. with stirring. KSCN (11.66 g, 120 mmol) was added in three portions within 1 minute. After the addition was completed, the reaction mixture was further stirred at 140° C. for 1 hour.

(34) The reaction mixture was cooled to room temperature, then poured into stirring ice water (2000 mL), stirred and extracted with CH.sub.2Cl.sub.2 (300 mL×3). The organic phases were combined, washed with 5% saline solution (200 mL×5), and dried over anhydrous Na.sub.2SO.sub.4. The dried organic phase was evaporated on a rotary evaporator to remove the solvent, and the resulting residue was purified by column chromatography to give product D as a white solid, 25.59 g; yield: 92%; m.p.: 94.5-97.5° C. .sup.1H NMR (DMSO-d.sub.6, 400 MHz), δ 8.21-8.24 (m, 1H), 8.11-8.14 (m, 1H), 7.92 (d, 1H, J=7.6 Hz), 7.73-7.78 (m, 2H), 7.52 (d, 1H, J=8.0 Hz), 5.41 (s, 2H).

Step 4. Synthesis of Compound F

(35) The above-described crude compound D (6.95 g, calculated as 25 mmol) was dissolved in THF (100 mL), and stirred at room temperature. Formylhydrazine (1.80 g, 30 mmol) was added, and then the stirring was continued overnight. At this point the reaction was detected for completion by TLC.

(36) The reaction mixture was evaporated on a rotary evaporator to dryness, the resulting residue, i.e., a crude product of E, was dissolved in DMF (80 mL), and a solution made by solid K.sub.2CO.sub.3 (3.46 g, 25 mol) and water (10 mL) was added. The reaction mixture was stirred at 50° C. until the reaction was completed (usually 5 hours).

(37) The reaction mixture was cooled to room temperature, poured into ice water (400 mL), stirred, adjusted with hydrochloric acid to pH=5-6, and extracted with CH.sub.2Cl.sub.2 (150 mL×5). The organic phases were combined, washed with 5% saline solution (200 mL), and dried over anhydrous Na.sub.2SO.sub.4. The dried organic phase was evaporated on a rotary evaporator to remove the solvent, and the resulting residue was purified by column chromatography to give product F as a white solid. .sup.1H NMR showed that about 5% debromination by-product was contained therein. The crude F was crystallized twice with ethyl acetate to give a pure product of F, 6.96 g; yield: 87% (D.fwdarw.F); m.p.: 243-244° C. .sup.1H NMR (DMSO-d.sub.6, 400 MHz), δ 13.88 (brs, 1H), 8.37 (s, 1H), 8.22 (d, 2H, J=7.6 Hz), 7.90 (d, 1H, J=7.2 Hz), 7.72 (m, 2H), 7.18 (d, 1H, J=7.2 Hz), 5.61 (s, 2H).

Step 5. Synthesis of Compound G

(38) Compound F (6.40 g, 20 mmol) was dissolved in DMF (100 mL) and stirred at room temperature, and solid K.sub.2CO.sub.3 (8.29 g, 60 mmol) and methyl bromoacetate (3.67 g, 24 mmol) were added. The resulting reaction mixture was stirred continuously at room temperature until the completion of the reaction was found by TLC determination (usually within 5 hours).

(39) The reaction mixture was poured into ice water (400 mL), stirred, and extracted with CH.sub.2Cl.sub.2 (100 mL×5). The organic phases were combined, washed with 5% saline solution (200 mL), and dried over anhydrous Na.sub.2SO.sub.4. The dried organic phase was evaporated on a rotary evaporator to remove the solvent, and the resulting residue was purified by column chromatography to give product G as a white solid, 7.37 g; yield: 94%; m.p.: 112.5-114° C. .sup.1H NMR (DMSO-d.sub.6, 400 MHz), δ 8.67 (s, 1H), 8.22-8.25 (m, 1H), 8.15-8.17 (m, 1H), 7.88 (d, 1H, J=7.6 Hz), 7.72-7.79 (m, 2H), 6.92 (d, 1H, J=7.6 Hz), 5.72 (s, 2H), 4.07 (s, 2H), 3.62 (s, 3H).

Step 6. Synthesis of Compound H

(40) Compound G (3.92 g, 10 mmol) was dissolved in acetonitrile (50 mL) and stirred at room temperature. NBS (2.14 g, 12 mmol) was added, and the stirring was continued at room temperature until the completion of the reaction was found by TLC determination (usually within 12 hours).

(41) The reaction mixture was poured into ice water (200 mL), stirred, and extracted with CH.sub.2Cl.sub.2 (100 mL×3). The organic phases were combined, and washed with a saturated aqueous solution of Na.sub.2CO.sub.3 (100 mL×3) and 5% saline solution (200 mL) sequentially, and dried over anhydrous Na.sub.2SO.sub.4. The dried organic phase was evaporated on a rotary evaporator to remove the solvent, and the resulting residue was purified by column chromatography to give product H as a white solid, 3.49 g; m.p.: 141-143° C.; yield: 74%. .sup.1H NMR (DMSO-d.sub.6, 400 MHz), δ 8.21-8.26 (m, 2H), 7.84 (d, 1H, J=8.0 Hz), 7.76-7.82 (m, 2H), 6.49 (d, 1H, J=7.6 Hz), 5.74 (s, 2H), 4.08 (s, 2H), 3.61 (s, 3H).

Step 7. Synthesis of ZXS-BR

(42) Compound H (3.30 g, 7 mmol) was added into methanol (50 mL) and stirred at room temperature. A solution made by LiOH.H.sub.2O (0.84 g, 20 mmol) and water (3 mL) was added, and then stirred at room temperature until the completion of the reaction was found by TLC determination (usually 2 hours).

(43) The reaction mixture was poured into ice water (200 mL), stirred, adjusted with hydrochloric acid to pH=2-3, and extracted with CH.sub.2Cl.sub.2 (100 mL×4). The organic phases were combined, washed with 5% saline solution (200 mL), and dried over anhydrous Na.sub.2SO.sub.4. The dried organic phase was evaporated on a rotary evaporator to remove the solvent, and the resulting residue was purified by column chromatography to give product ZXS-BR as a white solid, 2.82 g; yield: 88%; m.p.: 169.5-171.5° C. .sup.1H NMR (DMSO-d.sub.6, 400 MHz), δ 12.97 (brs, 1H), 8.22-8.26 (m, 2H), 7.83 (d, 1H, J=8.0 Hz), 7.76-7.81 (m, 2H), 6.51 (d, 1H, J=8.0 Hz), 5.73 (s, 2H), 4.01 (s, 2H).

Example 5 Synthetic Route of the Present Invention

(44) ##STR00021## ##STR00022##

Step 1. Synthesis of Compound B′

(45) To a dry 1 L round bottom flask were added compound A′ (1-methylnaphthalene, 28.44 g, 200 mmol), NBS (42.72 g, 240 mmol) and MeCN (700 mL), and the resulting mixture was stirred at 30° C.-40° C. for 12 hours.

(46) The reaction mixture was cooled to room temperature, poured into ice water (5 L), and extracted with dichloromethane (500 mL×3). The extracted phases were combined, washed with 5% aqueous solution of Na.sub.2CO.sub.3 (500 mL×5), 10% aqueous solution of Na.sub.2S.sub.2O.sub.3 (500 mL) and 5% saline solution (500 mL) sequentially, and dried over anhydrous Na.sub.2SO.sub.4. The dried organic phase was evaporated on a rotary evaporator to remove the solvent, and the resulting residue was purified by column chromatography to give product B′ as a colorless oil, 39.80 g; yield: 90%. .sup.1H NMR (DMSO-d.sub.6, 400 MHz), δ 8.14-8.16 (m, 1H), 8.07-8.09 (m, 1H), 7.76 (d, 1H, J=7.6 Hz), 7.66-7.70 (m, 2H), 7.30 (d, 1H, J=7.6 Hz), 2.63 (s, 3H).

Step 2. Synthesis of Compound C′

(47) To a dry 1 L round bottom flask was added n-hexane (400 mL) at room temperature, and B′ (35.37 g, 160 mmol), benzoyl peroxide (BPO, 0.775 g, 3.2 mmol) and NBS (34.17 g, 192 mmol) were added with stirring. The resulting mixture was stirred and heated to reflux, until TLC indicated that the reaction was completed (0.775 g BPO was added once every 8 hours after the start of the reaction; the reaction was usually completed within 36 hours).

(48) After the reaction was completed, the system was cooled to room temperature, stirred for 2 hours, and then filtered by suction. The filter cake was added into 800 mL water, stirred at room temperature for 1 hour and filtered by suction, and the filtrate was discarded. The filter cake was added into 800 mL water again, stirred at room temperature for 1 hour and filtered by suction, and the filtrate was discarded. The resulting filter cake was pulped by stirring in 800 mL n-hexane for 2 hours and filtered by suction. The filter cake was dried to give a pure product of C′ as a white solid, 34.56 g; yield: 72%; imp.: 104.0-105.5° C. .sup.1H NMR (DMSO-d.sub.6, 400 MHz), δ 8.20-8.26 (m, 2H), 7.86 (d, 1H, J=8.0 Hz), 7.72-7.78 (m, 2H), 7.62 (d, 1H, J=7.6 Hz), 5.21 (s, 2H).

Step 3. Synthesis of Compound D

(49) To a dry 1 L round bottom flask was added compound C′ (30.00 g, 100 mmol), dissolved in dry DMF (300 mL), and then heated to 140° C. with stirring. KSCN (11.66 g, 120 mmol) was added in three portions within 1 minute. After the addition was completed, the reaction mixture was further stirred at 140° C. for 1 hour.

(50) The reaction mixture was cooled to room temperature, poured into stirring ice water (2000 mL), stirred and extracted with CH.sub.2Cl.sub.2 (300 mL×3). The organic phases were combined, washed with 5% saline solution (200 mL×5), and dried over anhydrous Na.sub.2SO.sub.4. The dried organic phase was evaporated on a rotary evaporator to remove the solvent, and the resulting residue was purified by column chromatography to give product D as a white solid, 25.59 g; yield: 92%; m.p.: 94.5-97.5° C. .sup.1H NMR (DMSO-d.sub.6, 400 MHz), δ 8.21-8.24 (m, 1H), 8.11-8.14 (m, 1H), 7.92 (d, 1H, J=7.6 Hz), 7.73-7.78 (m, 2H), 7.52 (d, 1H, J=8.0 Hz), 5.41 (s, 2H).

Step 4. Synthesis of Compound F

(51) The above-described crude compound D (6.95 g, calculated as 25 mmol) was dissolved in THF (100 mL), and stirred at room temperature. Formylhydrazine (1.80 g, 30 mmol) was added, and then the stirring was continued overnight. At this point the reaction was detected for completion by TLC.

(52) The reaction mixture was evaporated on a rotary evaporator to dryness, the resulting residue, i.e., a crude product of E, was dissolved in DMF (80 mL), and a mixture made by solid Na.sub.2CO.sub.3 (2.65 g, 25 mol) and water (10 mL) was added. The reaction mixture was stirred at 50° C. until the reaction was completed (usually 5 hours).

(53) The reaction mixture was cooled to room temperature, poured into ice water (400 mL), stirred, adjusted with hydrochloric acid to pH=5-6, and extracted with CH.sub.2Cl.sub.2 (150 mL×5). The organic phases were combined, washed with 5% saline solution (200 mL), and dried over anhydrous Na.sub.2SO.sub.4. The dried organic phase was evaporated on a rotary evaporator to remove the solvent, and the resulting residue was purified by column chromatography to give product F as a white solid. .sup.1H NMR showed that about 5% debromination by-product was contained therein. The crude F was crystallized twice with ethyl acetate to give a pure product of F, 6.80 g; yield: 85% (D.fwdarw.F); m.p.: 243-244° C. .sup.1H NMR (DMSO-d.sub.6, 400 MHz), δ 13.88 (brs, 1H), 8.37 (s, 1H), 8.22 (d, 2H, J=7.6 Hz), 7.90 (d, 1H, J=7.2 Hz), 7.72 (m, 2H), 7.18 (d, 1H, J=7.2 Hz), 5.61 (s, 2H).

Step 5. Synthesis of Compound G′-1

(54) Compound F (6.40 g, 20 mmol) was dissolved in DMF (100 mL) and stirred at room temperature, and solid K.sub.2CO.sub.3 (8.29 g, 60 mmol) and ethyl chloroacetate (2.94 g, 24 mmol) were added. The resulting reaction mixture was stirred continuously at room temperature until the completion of the reaction was found by TLC determination (usually within 10 hours).

(55) The reaction mixture was poured into ice water (400 mL), stirred, and extracted with CH.sub.2Cl.sub.2 (100 mL×5). The organic phases were combined, washed with 5% saline solution (200 mL), and dried over anhydrous Na.sub.2SO.sub.4. The dried organic phase was evaporated on a rotary evaporator to remove the solvent, and the resulting residue was purified by column chromatography to give product G′-1 as a white solid, 7.72 g; yield: 95%. ESI-MS, m/z=406, 408 ([M+H].sup.+).

Step 6. Synthesis of Compound H′-1

(56) Compound G′-1 (4.06 g, 10 mmol) was dissolved in acetonitrile (50 mL) and stirred at room temperature. NBS (2.14 g, 12 mmol) was added, and the stirring was continued at room temperature until the completion of the reaction was found by TLC determination (usually within 12 hours).

(57) The reaction mixture was poured into ice water (200 mL), stirred, and extracted with CH.sub.2Cl.sub.2 (100 mL×3). The organic phases were combined, and washed with a saturated Na.sub.2CO.sub.3 solution (100 mL×3) and 5% saline solution (200 mL) sequentially, and dried over anhydrous Na.sub.2SO.sub.4. The dried organic phase was evaporated on a rotary evaporator to remove the solvent, and the resulting residue was purified by column chromatography to give product H′-1 as a white solid, 3.69 g; yield: 76%. ESI-MS, m/z=486 ([M+H].sup.+).

Step 7. Synthesis of ZXS-BR

(58) Compound H′-1 (3.40 g, 7 mmol) was added into methanol (40 mL) and stirred at room temperature. A solution made by NaOH (0.8 g, 20 mmol) and water (1 mL) was added, and then stirred at room temperature until the completion of the reaction was found by TLC determination (usually 2 hours).

(59) The reaction mixture was poured into ice water (200 mL), stirred, adjusted with hydrochloric acid to pH=2-3, and extracted with CH.sub.2Cl.sub.2 (100 mL×4). The organic phases were combined, washed with 5% saline solution (200 mL), and dried over anhydrous Na.sub.2SO.sub.4. The dried organic phase was evaporated on a rotary evaporator to remove the solvent, and the resulting residue was purified by column chromatography to give product ZXS-BR as a white solid, 2.82 g; yield: 88%; m.p.: 169.5-171.5° C. .sup.1H NMR (DMSO-d.sub.6, 400 MHz), δ 12.97 (brs, 1H), 8.22-8.26 (m, 2H), 7.83 (d, 1H, J=8.0 Hz), 7.76-7.81 (m, 2H), 6.51 (d, 1H, J=8.0 Hz), 5.73 (s, 2H), 4.01 (s, 2H).

Example 6 Synthetic Route of the Present Invention

(60) ##STR00023## ##STR00024##

Step 1. Synthesis of Compound B′

(61) To a dry 1 L round bottom flask were added compound A′ (1-methylnaphthalene, 28.44 g, 200 mmol), NBS (42.72 g, 240 mmol) and MeCN (700 mL), and the resulting mixture was stirred at 30° C.−40° C. for 12 hours.

(62) The reaction mixture was cooled to room temperature, poured into ice water (5 L), and extracted with dichloromethane (500 mL×3). The extracted phases were combined, washed with 5% aqueous solution of Na.sub.2CO.sub.3 (500 mL×5), 10% aqueous solution of Na.sub.2S.sub.2O.sub.3 (500 mL) and 5% saline solution (500 mL) sequentially, and dried over anhydrous Na.sub.2SO.sub.4. The dried organic phase was evaporated on a rotary evaporator to remove the solvent, and the resulting residue was purified by column chromatography to give product B′ as a colorless oil, 39.80 g; yield: 90%. .sup.1H NMR (DMSO-d.sub.6, 400 MHz), δ 8.14-8.16 (m, 1H), 8.07-8.09 (m, 1H), 7.76 (d, 1H, J=7.6 Hz), 7.66-7.70 (m, 2H), 7.30 (d, 1H, J=7.6 Hz), 2.63 (s, 3H).

Step 2. Synthesis of Compound C′

(63) To a dry 1 L round bottom flask was added n-hexane (400 mL) at room temperature, and B′ (35.37 g, 160 mmol), benzoyl peroxide (BPO, 0.775 g, 3.2 mmol) and NBS (34.17 g, 192 mmol) were added with stirring. The resulting mixture was stirred and heated to reflux, until TLC indicated that the reaction was completed (0.775 g BPO was added once every 8 hours after the start of the reaction; the reaction was usually completed within 36 hours).

(64) After the reaction was completed, the system was cooled to room temperature, stirred for 2 hours, and then filtered by suction. The filter cake was added into 800 mL water, stirred at room temperature for 1 hour and filtered by suction, and the filtrate was discarded. The filter cake was added into 800 mL water again, stirred at room temperature for 1 hour and filtered by suction, and the filtrate was discarded. The resulting filter cake was pulped with stirring in 800 mL n-hexane for 2 hours and filtered by suction. The filter cake was dried to give a pure product of C′ as a white solid, 34.56 g; yield: 72%; m.p.: 104.0-105.5° C. .sup.1H NMR (DMSO-d.sub.6, 400 MHz), δ 8.20-8.26 (m, 2H), 7.86 (d, 1H, J=8.0 Hz), 7.72-7.78 (m, 2H), 7.62 (d, 1H, J=7.6 Hz), 5.21 (s, 2H).

Step 3. Synthesis of Compound D

(65) Compound C′ (30.00 g, 100 mmol) was added to a dry 1 L round bottom flask, dissolved in dry DMF (300 mL), and then heated to 140° C. with stirring. KSCN (11.66 g, 120 mmol) was added in three portions within 1 minute. After the addition was completed, the reaction mixture was further stirred at 140° C. for 1 hour.

(66) The reaction mixture was cooled to room temperature, then poured into stirring ice water (2000 mL), stirred and extracted with CH.sub.2Cl.sub.2 (300 mL×3). The organic phases were combined, washed with 5% saline solution (200 mL×5), and dried over anhydrous Na.sub.2SO.sub.4. The dried organic phase was evaporated on a rotary evaporator to remove the solvent, and the resulting residue was purified by column chromatography to give product D as a white solid, 25.59 g; yield: 92%; m.p.: 94.5-97.5° C. .sup.1H NMR (DMSO-d.sub.6, 400 MHz), δ 8.21-8.24 (m, 1H), 8.11-8.14 (m, 1H), 7.92 (d, 1H, J=7.6 Hz), 7.73-7.78 (m, 2H), 7.52 (d, 1H, J=8.0 Hz), 5.41 (s, 2H).

Step 4. Synthesis of Compound F

(67) The above-described crude compound D (6.95 g, calculated as 25 mmol) was dissolved in THF (100 mL), and stirred at room temperature. Formylhydrazine (1.80 g, 30 mmol) was added, and then the stirring was continued overnight. At this point the reaction was detected for completion by TLC.

(68) The reaction mixture was evaporated on a rotary evaporator to dryness, the resulting residue, i.e., a crude product of E, was dissolved in DMF (80 mL), and a mixture made by solid NaOH (1.00 g, 25 mol) and water (5 mL) was added. The reaction mixture was stirred at 50° C. until the reaction was completed (usually 5 hours).

(69) The reaction mixture was cooled to room temperature, poured into ice water (400 mL), stirred, adjusted with hydrochloric acid to pH=5-6, and extracted with CH.sub.2Cl.sub.2 (150 mL×5). The organic phases were combined, washed with 5% saline solution (200 mL), and dried over anhydrous Na.sub.2SO.sub.4. The dried organic phase was evaporated on a rotary evaporator to remove the solvent, and the resulting residue was purified by column chromatography to give product F as a white solid. .sup.1H NMR showed that about 5% debromination by-product was contained therein. The crude F was crystallized twice with ethyl acetate to give a pure product of F, 6.64 g; yield: 83% (D.fwdarw.F); m.p.: 243-244° C. .sup.1H NMR (DMSO-d.sub.6, 400 MHz), δ 13.88 (brs, 1H), 8.37 (s, 1H), 8.22 (d, 2H, J=7.6 Hz), 7.90 (d, 1H, J=7.2 Hz), 7.72 (m, 2H), 7.18 (d, 1H, J=7.2 Hz), 5.61 (s, 2H).

Step 5. Synthesis of Compound G′-1

(70) Compound F (6.40 g, 20 mmol) was dissolved in DMF (100 mL) and stirred at room temperature, and solid K.sub.2CO.sub.3 (8.29 g, 60 mmol) and ethyl chloroacetate (2.94 g, 24 mmol) were added. The resulting reaction mixture was stirred continuously at room temperature until the completion of the reaction was found by TLC determination (usually within 10 hours).

(71) The reaction mixture was poured into ice water (400 mL), stirred, and extracted with CH.sub.2Cl.sub.2 (100 mL×5). The organic phases were combined, washed with 5% saline solution (200 mL), and dried over anhydrous Na.sub.2SO.sub.4. The dried organic phase was evaporated on a rotary evaporator to remove the solvent, and the resulting residue was purified by column chromatography to give product G′-1 as a white solid, 7.72 g; yield: 95%. ESI-MS, m/z=406, 408 ([M+H].sup.+).

Step 6. Synthesis of Compound H′-1

(72) Compound G′-1 (4.06 g, 10 mmol) was dissolved in acetonitrile (50 mL) and stirred at room temperature. NBS (2.14 g, 12 mmol) was added, and the stirring was continued at room temperature until the completion of the reaction was found by TLC determination (usually within 12 hours).

(73) The reaction mixture was poured into ice water (200 mL), stirred, and extracted with CH.sub.2Cl.sub.2 (100 mL×3). The organic phases were combined, and washed with a saturated Na.sub.2CO.sub.3 solution (100 mL×3) and 5% saline solution (200 mL) sequentially, and dried over anhydrous Na.sub.2SO.sub.4. The dried organic phase was evaporated on a rotary evaporator to remove the solvent, and the resulting residue was purified by column chromatography to give product H′-1 as a white solid, 3.69 g; yield: 76%. ESI-MS, m/z=486 ([M+H].sup.+).

Step 7. Synthesis of ZXS-BR

(74) Compound H′-1 (3.40 g, 7 mmol) was added into methanol (40 mL) and stirred at room temperature. A solution made by KOH (1.12 g, 20 mmol) and water (1 mL) was added, and then stirred at room temperature until the completion of the reaction was found by TLC determination (usually 2 hours).

(75) The reaction mixture was poured into ice water (200 mL), stirred, adjusted with hydrochloric acid to pH=2-3, and extracted with CH.sub.2Cl.sub.2 (100 mL×4). The organic phases were combined, washed with 5% saline solution (200 mL), and dried over anhydrous Na.sub.2SO.sub.4. The dried organic phase was evaporated on a rotary evaporator to remove the solvent, and the resulting residue was purified by column chromatography to give product ZXS-BR as a white solid, 2.82 g; yield: 88%; m.p.: 169.5-171.5° C. .sup.1H NMR (DMSO-d.sub.6, 400 MHz), δ 12.97 (brs, 1H), 8.22-8.26 (m, 2H), 7.83 (d, 1H, J=8.0 Hz), 7.76-7.81 (m, 2H), 6.51 (d, 1H, J=8.0 Hz), 5.73 (s, 2H), 4.01 (s, 2H).