Vortioxetine intermediate and synthesis process thereof

Abstract

The present invention provides a new intermediate II and a method for synthesizing the same. The method comprises: (a) firstly diazotizing a compound of formula I as a raw material, and then halogenating to obtain an intermediate II; and (b) reacting the intermediate II with a compound III to obtain a compound IV, hydrolyzing the obtained compound IV directly without being separated to obtain Vortioxetine represented by compound V. The intermediate II can be used for synthesizing Vortioxetine. ##STR00001##

Claims

1. A method for synthesizing an intermediate II, characterized by firstly diazotizing a compound of formula I as a raw material, and then halogenating to obtain the intermediate II: ##STR00023## in each formula, R is a protective group for amino, and X is halogen.

2. The method of claim 1, wherein R is selected from: tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, carboxybenzyl, acetyl or trifluoroacetyl.

3. The method of claim 2, wherein R is tert-butoxycarbonyl or acetyl.

4. The method of claim 1, wherein X is selected from: chlorine, bromine or iodine.

5. The method of claim 4, wherein X is bromine.

6. The method of claim 1, wherein the halogenating agent used in the halogenating reaction is selected from: NaX, KX, LiX, MgX.sub.2, CuX, CuX.sub.2, or a mixture of any two thereof, or a mixture of copper sulfate and NaX.

7. The method of claim 6, wherein the halogenating agent is a mixture of sodium bromide and cuprous bromide, or a mixture of lithium bromide and cuprous bromide.

8. The method of claim 1, further comprising reacting the intermediate II with a compound III to obtain a compound IV, hydrolyzing the obtained compound IV directly without being separated to obtain Vortioxetine represented by compound V, ##STR00024##

9. A compound of following formula ##STR00025## wherein R is 9-fluorenylmethoxycarbonyl or carboxybenzyl; and X is halogen.

10. The compound of claim 9, wherein X is selected from: chlorine, bromine or iodine.

11. The compound of claim 10, wherein X is bromine.

12. A method for synthesizing Vortioxetine represented by formula V, comprising: reacting the intermediate II with the compound III, wherein bis(2-diphenylphosphinophenyl)ether is used as a phosphine ligand, ##STR00026## wherein R is acetyl, 9-fluorenylmethoxycarbonyl, carboxybenzyl, or truflyoroacetyl; and X is a halogen.

13. The method of claim 12, wherein the obtained compound IV is hydrolyzed directly without being separated to obtain Vortioxetine represented by compound V.

14. The method of claim 12, wherein the molar ratio of bis(2-diphenylphosphinophenyl)ether to the intermediate II is 0.6 to 6.0%.

15. The method of claim 13, wherein the molar ratio of bis(2-diphenylphosphinophenyl)ether to the intermediate II is 0.6 to 6.0%.

16. The method of claim 12, wherein the molar ratio of bis(2-diphenylphosphinophenyl)ether to the intermediate II is 0.75 to 1.5%.

17. The method of claim 12, wherein the molar ratio of bis(2-diphenylphosphinophenyl)ether to the intermediate II is 0.75 to 0.9%.

18. The method of claim 13, wherein the molar ratio of bis(2-diphenylphosphinophenyl)ether to the intermediate II is 0.75 to 1.5%.

19. The method of claim 13, wherein the molar ratio of bis(2-diphenylphosphinophenyl)ether to the intermediate II is 0.75 to 0.9%.

Description

DETAILED DESCRIPTION OF THE INVENTION

EXAMPLE 1

EXAMPLE 1-1

Preparation of Compound I: 4-tert-butoxycarbonyl-1-(2-aminophenyl)piperazine

(1) ##STR00012##

(2) Ortho-fluoronitrobenzene (14.1 g, 0.1 mol), 4-tert-butoxycarbonyl-1-piperazine (18.6 g, 0.1 mol), and potassium carbonate (13.8 g, 0.4 mol) were added to acetonitrile (140 ml), stirred and heated to reflux. After reacting for 16 h, the reaction system was cooled to room temperature, filtered under reduced pressure to remove inorganic salts. Then, the filter cake was washed with acetonitrile (40 ml), and the filtrate was merged and concentrated to a slurry system under reduced pressure. Ethanol (140 ml) was added and concentrated to obtain a slurry system, after that ethanol (140 ml) was added, and stirred until clarification. Then a wet palladium/carbon (7% palladium) (1.12 g) was added. The system was purged with nitrogen gas (40 psi) for three times and then hydrogen gas (40 psi) for three times. Hydrogenation was carried out, under the pressure of 30 to 40 psi and at the temperature of 35 to 40 C. for 10 h, then cooled to room temperature, and filtered to remove palladium/carbon. The filter cake was washed with ethanol (30 ml), and the filtrate was merged and concentrated to dry under reduced pressure. A pale yellow solid of 25.3 g was obtained, and the yield was 91.2%; MS.sup.+=278.2.

EXAMPLE 1-2

(3) ##STR00013##

(4) 2-acetyl-piperazinylnitrobenzene (24.9 g, 0.1 mol) was added to ethanol (250 ml), and stirred until clarification. A wet palladium/carbon (1.12 g) was added, and hydrogenated (35 to 40 C., 40 psi) for 3 h. The reaction system was cooled to room temperature, and filtered to remove palladium/carbon. The filter cake was washed with ethanol (30 ml), and the filtrate was merged, and concentrated to dry under reduced pressure. Then, a pale yellow solid of 22.0 g was obtained, and the yield was 100%; MS.sup.+=220.3.

EXAMPLE 2

EXAMPLE 2-1: PREPARATION OF COMPOUND II: 4-tert-butoxycarbonyl-1-(2-bromophenyl)piperazine

(5) ##STR00014##

(6) Concentrated sulfuric acid (98%) (7.6 g, 0.077 mol) was dropped slowly into water (180 ml), stirred, and cooled to 0 to 5 C. 4-tert-butoxycarbonyl-1-(2-aminophenyl)piperazine (20.0 g, 0.072 mol) was added slowly into the system and stirred. Sodium nitrite (5.2 g, 0.077 mol) was added into water (20 ml), stirred until clarification, and then slowly dropped into the raw material system while controlling the temperature to 0 to 10 C. After the completion of dropping, the reaction system was raised to room temperature, and stirred for half an hour to form a diazonium salt system. Sodium bromide (41.6 g, 0.288 mol) and cuprous bromide (10.4 g, 0.072 mol) were added into water (80 ml), stirred mechanically, and heated to an internal temperature of about 80 C. Then the aforementioned obtained diazonium salt system was dropped slowly into the system. After the completion of dropping, the reaction was performed for 3 h while maintaining the temperature. Then heating was stopped, and the reaction system was cooled to room temperature. Ethyl acetate (200 ml) was added, stirred for half an hour, and filtered under reduced pressure. The filter cake was washed with ethyl acetate (50 ml). The obtained dark green filtrate was layered. Aqueous phase was extracted with ethyl acetate (200 ml) once. Organic phases were merged, dried with anhydrous sodium sulfate (10.0 g, 0.07 mol), and then filtered under reduced pressure to remove the solids. The filtrates were merged, and distilled to remove acetyl acetate. The residue was distilled under reduced pressure (2 mm Hg), and the distillate in the range of 70 to 80 C. was collected to obtain a pale yellow oil of 18.42 g. The yield was 74.9%; MS.sup.+=341.1.

EXAMPLES 2-2 to 2-19

(7) Referring to example 2-1, the substituent groups R and X as well as halogenating agent are changed, and the results of the yields are shown in table 1.

(8) TABLE-US-00001 TABLE 1 Halogenating Example R group X group agent Yield (%) 2-2 Cbz Br CuBr and NaBr 60.3 2-3 Ac Br CuBr and LiBr 75.8 2-4 Tfa Br CuBr and LiBr 70.5 2-5 Fmoc Br CuBr and LiBr 66.8 2-6 Ac Br NaBr 62.6 2-7 Ac Br KBr 60.7 2-8 Ac Br LiBr 61.9 2-9 Ac Br MgBr.sub.2 60.0 2-10 Ac Br CuBr 58.6 2-11 Ac Br CuBr and NaBr 60.8 2-12 Ac Br CuSO.sub.4 and NaBr 61.1 2-13 Boc Br CuBr and LiBr 69.5 2-14 Ac Br CuBr.sub.2 and LiBr 62.8 2-15 Ac Cl CuCl and KCl 62.2 2-16 Ac I CuI and KI 62.0 2-17 Ac Cl CuBr and NaBr 75.2 2-18 Ac I CuBr and NaBr 74.3 2-19 Ac Br CuBr and LiBr 75.3

(9) From the examples above, it can be seen that, compared with the method for synthesizing the intermediate IIA reported in the PCT Publication WO2004067703, the method for preparing the intermediate II of Vortioxetine provided by the invention not only has a higher yield, but also avoids the use of expensive and specific palladium reagent and phosphine complex, thereby effectively reducing the cost, and being suitable for industrial production. Moreover, the method for preparing the intermediate II of Vortioxetine provided by the invention avoids the use of expensive and specific palladium reagent and phosphine complex, thus it avoids the extreme process conditions related to the use of palladium reagent and phosphine complex, and is process-friendly.

EXAMPLE 3

EXAMPLE 3-1

Preparation of Compound V: Vortioxetine Hydrobromide

(10) ##STR00015##

(11) 4-tert-butoxycarbonyl-1-(2-bromophenyl)piperazine (24.6 g, 0.07 mol), 2,4-dimethyl-thiophenol (10.0 g, 0.07 mol), sodium tert-butoxide (10.0 g, 0.1 mol), tri(dibenzalacetone)dipalladium (Pd.sub.2(dba).sub.3) (0.78 g, 0.8 mmol) and 1,1-binaphthyl-2,2-bis(diphenylphosphine) (BINAP) (2.2 g, 3.5 mmol) were added into toluene (150 ml), and stirred. It was purged with nitrogen gas for three times and then protected with nitrogen gas. The system was heated to reflux, reacted for 24 h, cooled to room temperature, and filtered to remove insoluble substance. The filter cake was washed with toluene (30 ml), and the filtrate was merged and concentrated to dry under reduced pressure to obtain claret-red oil. The cold (0 to 10 C.) ethyl acetate (100 ml) was dropped slowly and a large amount of orange-yellow solid was precipited. The system was stirred for 2 h while maintaining the temperature, and filtered under reduced pressure. The filter cake was washed with cold ethyl acetate (20 ml) to obtain orange solid, and dried to obtain compound IV. Compound IV was added into methanol (150 ml), and stirred until clarification. 48% hydrobromic acid (20 ml) was dropped slowly, and earthy yellow solid was separated out gradually from the system. The system was heated to reflux and reacted for 2 h, then cooled to 0 to 15 C., and stirred for 16 h. The system was concentrated to about 30 ml under reduced pressure. 200 ml ethyl acetate was added, and concentrated to get a slurry. A large amount of yellow solid was separated out from the system. Methyl tert-butyl ether (100 ml) was added, stirred for half an hour at room temperature and filtered. The filter cake was washed with methyl tert-butyl ether (30 ml) to obtain yellow solid of 18.2 g. The yield was 66.2%. MS.sup.+=299.2.

EXAMPLE 3-2

Preparation of Compound V: Vortioxetine Hydrobromide

(12) ##STR00016##

(13) 4-acetyl-1-(2-bromophenyl)piperazine (19.8 g, 0.07 mol) prepared in example 2-3, 2,4-dimethyl-thiophenol (10.0 g, 0.07 mol), sodium tert-butoxide (10.0 g, 0.1 mol), tri(dibenzalacetone)dipalladium (Pd.sub.2(dba).sub.3) (0.78 g, 0.8 mmol) and 1,1-binaphthyl-2,2-bis(diphenylphosphine) (BINAP) (2.2 g, 3.5 mmol) were added into toluene (150 ml), and stirred. It was purged with nitrogen gas for three times and protected with nitrogen gas. The system was heated to reflux and reacted for 10 h, then cooled to room temperature, and filtered to remove insoluble substance. The filter cake was washed with toluene (30 ml), and the filtrate was merged, and concentrated to dry under reduced pressure to obtain claret-red oil. The cold (0 to 10 C.) ethyl acetate (100 ml) was dropped slowly, and a large amount of orange-yellow solid was separated out. The system was stirred for 2 h while maintaining the temperature, and then filtered under reduced pressure. The filter cake was washed with cold ethyl acetate (20 ml) to obtain orange-yellow solid, and dried to obtain compound IV. Compound IV was added into methanol (150 ml), and stirred until clarification. 48% hydrobromic acid (20 ml) was dropped slowly, and earthy yellow solids were separated out gradually from the system. The system was heated to reflux and reacted for 2 h, then cooled to 0-15 C., and stirred for 5 h. The system was concentrated to about 30 ml under reduced pressure. 200 ml ethyl acetate was added, and concentrated to get a slurry. A large amount of yellow solid was separated out from the system. Methyl tert-butyl ether (100 ml) was added, stirred for half an hour at room temperature, and filtered. The filter cake was washed with methyl tert-butyl ether (30 ml) to obtain yellow solid of 18.2 g. The yield was 67.2%. MS.sup.+=299.2.

EXAMPLE 3-3

Preparation of Compound V: Vortioxetine Hydrobromide

(14) ##STR00017##

(15) Vortioxetine hydrobromide was prepared in the same manner as that in example 3-2, except that 4-trifluoroacetyl-1-(2-bromophenyl)piperazine prepared in example 2-4 was used instead of 4-acetyl-1-(2-bromophenyl)piperazine. The yield was 66.9%.

EXAMPLE 3-4

Preparation of Compound V: Vortioxetine Hydrobromide

(16) ##STR00018##

(17) Vortioxetine hydrobromide was prepared in the same manner as that in example 3-2, except that 4-acetyl-1-(2-chlorophenyl)piperazine prepared in example 2-17 was used instead of 4-acetyl-1-(2-bromophenyl)piperazine. The yield was 67.8%.

EXAMPLE 3-5

Preparation of Compound V: Vortioxetine Hydrobromide

(18) Vortioxetine hydrobromide was prepared in the same manner as that in example 3-2, except that 4-acetyl-1-(2-iodophenyl)piperazine prepared in example 2-18 was used instead of 4-acetyl-1-(2-bromophenyl)piperazine. The yield was 66.8%.

EXAMPLE 3-6

Preparation of Compound V: Vortioxetine Hydrobromide

(19) Vortioxetine hydrobromide was prepared in the same manner as that in example 3-2, except that 4-carboxybenzyl-1-(2-bromophenyl)piperazine prepared in example 2-2 was used instead of 4-acetyl-1-(2-bromophenyl)piperazine. The yield was 66.4%.

EXAMPLE 3-7

Preparation of Compound V: Vortioxetine Hydrobromide

(20) Vortioxetine hydrobromide was prepared in the same manner as that in example 3-2, except that 4-(9-fluorenylmethoxycarbonyl)-1-(2-bromophenyl)piperazine prepared in example 2-5 was used instead of 4-acetyl-1-(2-bromophenyl)piperazine. The yield was 66.1%.

EXAMPLE 4

EXAMPLE 4-1

Preparation of Compound V: Vortioxetine Hydrobromide

(21) ##STR00019##

(22) 4-tert-butoxycarbonyl-1-(2-bromophenyl)piperazine (24.6 g, 0.07 mol), 2,4-dimethyl-thiophenol (10.0 g, 0.07 mol), sodium tert-butoxide (10.0 g, 0.1 mol), tri(dibenzalacetone)dipalladium (Pd.sub.2(dba).sub.3) (0.78 g, 0.8 mmol) and 1,1-binaphthyl-2,2-bis(diphenylphosphine) (BINAP) (2.2 g, 3.5 mmol) were added into toluene (150 ml), and stirred. It was purged with nitrogen gas for three times and then protected with nitrogen gas. The system was heated to reflux and reacted for 24 h, then cooled to room temperature, and filtered to remove insoluble substance. The filter cake was washed with toluene (30 ml), and the filtrate was merged, and concentrated to dry under reduced pressure to obtain claret-red oil. Methanol (150 ml) was added, and stirred to clarification. 48% hydrobromic acid (20 ml) was dropped slowly, and earthy yellow solids were precipitated gradually from the system. The system was heated to reflux and reacted for 2 h, then cooled to 0 to 15 C., and stirred for 16 h. The system was concentrated to about 30 ml under reduced pressure. 200 ml ethyl acetate was added, and concentrated to get a slurry. A large amount of yellow solid was separated out from the system. Methyl tert-butyl ether (100 ml) was added, and stirred for half an hour at room temperature. The system was filtered, and the filter cake was washed with methyl tert-butyl ether (30 ml) to obtain yellow solid of 20.6 g. The yield was 75.3%.

EXAMPLE 4-2

(23) 4-acetyl-1-(2-bromophenyl)piperazine (19.8 g, 0.07 mol) prepared in example 2-3, 2,4-dimethyl-thiophenol (10.0 g, 0.07 mol), sodium tert-butoxide (10.0 g, 0.1 mol), tri(dibenzalacetone)dipalladium (Pd.sub.2(dba).sub.3) (0.78 g, 0.8 mmol) and 1,1-binaphthyl-2,2-bis(diphenylphosphine) (BINAP) (2.2 g, 3.5 mmol) were added into toluene (150 ml), and stirred. It was purged with nitrogen gas for three times and then protected with nitrogen gas. The system was heated to reflux and reacted for 10 h, then cooled to room temperature, and filtered to remove insoluble substance. The filter cake was washed with toluene (30 ml), and the filtrate was merged, and concentrated to dry under reduced pressure to obtain claret-red oil. Methanol (150 ml) was added, and stirred to clarification. 48% hydrobromic acid (20 ml) was dropped slowly, and earthy yellow solids were percitated gradually from the system. The system was heated to reflux and reacted for 2 h, then cooled to 0 to 15 C., and stirred for 5 h. The system was concentrated to about 30 ml under reduced pressure, and 200 ml ethyl acetate was added and concentrated to get a slurry. A large amount of yellow solid was separated out from the system. Methyl tert-butyl ether (100 ml) was added, and stirred for half an hour at room temperature. The system was filtered, and the filter cake was washed with methyl tert-butyl ether (30 ml) to obtain yellow solids of 20.6 g. The yield was 78.3%.

EXAMPLE 4-3

(24) Vortioxetine hydrobromide was prepared in the same manner as that in example 4-2, except that 4-trifluoroacetyl-1-(2-bromophenyl)piperazine prepared in example 2-4 was used instead of 4-acetyl-1-(2-bromophenyl)piperazine. The yield was 76.9%.

EXAMPLE 4-4

(25) Vortioxetine hydrobromide was prepared in the same manner as that in example 4-2, except that 4-acetyl-1-(2-chlorophenyl)piperazine prepared in example 2-17 was used instead of 4-acetyl-1-(2-bromophenyl)piperazine. The yield was 77.8%.

EXAMPLE 4-5

(26) Vortioxetine hydrobromide was prepared in the same manner as that in example 4-2, except that 4-acetyl-1-(2-iodophenyl)piperazine prepared in example 2-18 was used instead of 4-acetyl-1-(2-bromophenyl)piperazine. The yield was 76.8%.

EXAMPLE 4-6

Preparation of Compound V: Vortioxetine Hydrobromide

(27) Vortioxetine hydrobromide was prepared in the same manner as that in example 4-2, except that 4-carboxybenzyl-1-(2-bromophenyl)piperazine prepared in example 2-2 was used instead of 4-acetyl-1-(2-bromophenyl)piperazine. The yield was 76.4%.

EXAMPLE 4-7

Preparation of Compound V: Vortioxetine Hydrobromide

(28) Vortioxetine hydrobromide was prepared in the same manner as that in example 4-2, except that 4-(9-fluorenylmethoxycarbonyl)-1-(2-bromophenyl)piperazine prepared in example 2-5 was used instead of 4-acetyl-1-(2-bromophenyl)piperazine. The yield was 76.1%.

EXAMPLE 5

EXAMPLE 5-1

Preparation of Compound V: Vortioxetine Hydrobromide

(29) ##STR00020##

(30) 4-acetyl-1-(2-bromophenyl)piperazine (30.0 g, 0.106 mol) prepared in example 2-3, 2,4-dimethyl-thiophenol (14.7 g, 0.106 mol), potassium tert-butoxide (35.67 g, 0.318 mol), tri(dibenzalacetone)dipalladium (Pd.sub.2(dba).sub.3) (0.243 g, 0.27 mmol) and bis(2-diphenylphosphino phenyl)ether (DPEphos) (0.428 g, 0.8 mmol) were added into toluene (300 ml), and stirred. It was purged with nitrogen gas for three times and then protected with nitrogen gas. The system was heated to reflux and reacted for 10 h, and cooled to room temperature. 150 ml water was added, stirred for 30 min, and filtered to remove insoluble substance. The filter cake was washed with toluene (30 ml), and the filtrate was merged. Toluene layer was separated, and toluene phase was concentrated to dry under reduced pressure to obtain claret-red oil. Methanol (120 ml) and an aqueous solution (60 ml) of KOH (29.7 g, 0.53 mol) were added. The system was heated to reflux and reacted for 24 h. The system was concentrated to about 90 ml under reduced pressure, and 300 ml toluene and 90 ml water were added. Toluene phase was separated. 26.8 g (0.159 mol) of 48% hydrobromic acid was dropped into the toluene phase. A large amount of solid was separated out. The system was stirred for 2 h at 0 to 20 C., and filtered. The filter cake was washed with 15 ml toluene once to obtain yellow solid of 35.1 g. The yield was 87.4%.

EXAMPLE 5-2

Preparation of Compound V: Vortioxetine Hydrobromide

(31) ##STR00021##

(32) Vortioxetine hydrobromide was prepared in the same manner as that in example 5-1, except that 4-trifluoroacetyl-1-(2-bromophenyl)piperazine prepared in example 2-4 was used instead of 4-acetyl-1-(2-bromophenyl)piperazine. The yield was 85.2%.

EXAMPLE 5-3

Preparation of Compound V: Vortioxetine Hydrobromide

(33) ##STR00022##

(34) Vortioxetine hydrobromide was prepared in the same manner as that in example 5-1, except that 4-acetyl-1-(2-chlorophenyl)piperazine prepared in example 2-17 was used instead of 4-acetyl-1-(2-bromophenyl)piperazine. The yield was 67.4%.

EXAMPLE 5-4

Preparation of Compound V: Vortioxetine Hydrobromide

(35) Vortioxetine hydrobromide was prepared in the same manner as that in example 5-1, except that 4-acetyl-1-(2-iodophenyl)piperazine prepared in example 2-18 was used instead of 4-acetyl-1-(2-bromophenyl)piperazine. The yield is 81.7%.

EXAMPLE 5-5

Preparation of Compound V: Vortioxetine Hydrobromide

(36) Vortioxetine hydrobromide was prepared in the same manner as that in example 5-1, except that 4-carboxybenzyl-1-(2-bromophenyl)piperazine prepared in example 2-2 was used instead of 4-acetyl-1-(2-bromophenyl)piperazine. The yield is 77.6%.

EXAMPLE 5-6

Preparation of Compound V: Vortioxetine Hydrobromide

(37) Vortioxetine hydrobromide was prepared in the same manner as that in example 5-1, except that 4-(9-fluorenylmethoxycarbonyl)-1-(2-bromophenyl)piperazine prepared in example 2-5 was used instead of 4-acetyl-1-(2-bromophenyl)piperazine. The yield is 80.5%.

(38) The description of examples above is only used for helping to understand the processes and core concepts of the invention. It is pointed out that for the person having ordinary skill in the art, various improvements and modifications can be also made in the present invention without departing from the principle of the present invention, and these improvements and modifications are fallen into the protection scope of the claims of the present invention.