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Title:
THE METHOD FOR MANUFACTURE OF BREXPIPRAZOLE, INTERMEDIATES USED IN THIS METHOD, AND THE METHOD FOR MANUFACTURE THEREOF
Document Type and Number:
WIPO Patent Application WO/2018/015354
Kind Code:
A1
Abstract:
The invention relates to a method for manufacture of brexpiprazole comprising in step (a) reaction of 4-[(2-oxo-1,2-dihydroquinolin-7-yl)oxy]butanal or a solvate thereof with 1-(1- benzothiophen-4-yl)piperazine or a salt thereof in a solvent, optionally in the presence of a catalyst, and in step (b) reduction of the iminium salt formed in step (a) using a reducing agent in a solvent, optionally in the presence of a catalyst. The invention relates also to the intermediates used for the manufacture of brexpiprazole, and the method for manufacture of these intermediates.

Inventors:
RUSIECKI RAFAŁ (PL)
ŚNIEŻEK MARCIN (PL)
Application Number:
PCT/EP2017/068058
Publication Date:
January 25, 2018
Filing Date:
July 17, 2017
Export Citation:
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Assignee:
ADAMED SP ZOO (PL)
International Classes:
C07D409/12; C07D215/14; C07D409/14
Domestic Patent References:
WO2013015456A12013-01-31
WO2006112464A12006-10-26
WO2013015456A12013-01-31
WO2013035892A12013-03-14
WO2013162046A12013-10-31
WO2006112464A12006-10-26
Foreign References:
CN104447723A2015-03-25
CN104829602A2015-08-12
CN104844585A2015-08-19
CN105061414A2015-11-18
CN105440026A2016-03-30
CN105461704A2016-04-06
CN105461703A2016-04-06
US20150361099A12015-12-17
CN105399736A2016-03-16
US9206169B22015-12-08
Other References:
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 2011, OTANI, TADAAKI ET AL: "Preparation of benzothienylpiperazine compounds as antipsychotic agents", XP002773926, retrieved from STN Database accession no. 2011:876391
PIOTR KOWALSKI ET AL: "An Efficient Synthesis of Aripiprazole, Buspirone and NAN-190 by the Reductive Alkylation of Amines Procedure", ARCHIV DER PHARMAZIE, vol. 345, no. 1, 5 October 2011 (2011-10-05), Weinheim, pages 81 - 85, XP055381549, ISSN: 0365-6233, DOI: 10.1002/ardp.201100112
Attorney, Agent or Firm:
SULIKOWSKI, Daniel (PL)
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Claims:
Claims

1. A method for manufacture of brexpiprazole, comprising the following steps: a) reaction of 4-[(2-oxo-l,2-dihydroquinolin-7-yl)oxy]butanal or a solvate thereof with l-(l-benzothiophen-4-yl)piperazine or a salt thereof in a solvent, optionally in the presence of a catalyst;

b) reduction of the iminium salt formed in step (a) using a reducing agent in a solvent, optionally in the presence of a catalyst.

2. The method according to claim 1, wherein a base catalyst is used in step (a).

3. The method according to claim 2, wherein the base catalyst is sodium acetate.

4. The method according to any one of the preceding claims, wherein in step (a), the reaction is conducted in a solvent selected from toluene, methylene chloride, dichloroethane, methanol, ethanol, 2-propanol, THF, DMF, and acetonitrile.

5. The method according to any one of claim 1 to 4, wherein the solvent is 2-propanol.

6. The method according to any of the preceding claims, wherein in step (a), 1-(1- benzothiophen-4-yl)piperazine is used in the form of a hydrochloride salt, and 4-[(2-oxo-l,2- dihydroquinolin-7-yl)oxy]butanal is used in the form of a hydrate.

7. The method according to any one of the preceding claims, wherein a base catalyst is used in step (b).

8. The method according to claim 7, wherein the catalyst is sodium acetate.

9. The method according to any one of the preceding claims, wherein sodium acetate is used as a catalyst in step (a) and step (b).

10. The method according to claim 9, wherein sodium acetate is used at an amount of 0.5-1.5 equivalents in relation to the aldehyde, preferably 0.8 equivalent.

11. The method according to any of the preceding claims, wherein the reducing agent in step (b) is selected from a group consisting of NaBH(OAc)3,NaBH3CN, NaBH4 and H2/Pd.

12. The method according to claim 11, wherein the reducing agent is NaBH(OAc)3.

13. The method according to any one of the preceding claims, wherein the reduction reaction in step (b) is conducted in a solvent selected from toluene, methylene chloride, dichloroethane, methanol, ethanol, 2-propanol, THF, DMF, and acetonitrile.

14. The method according to claim 13, wherein the solvent is 2-propanol.

15. The method according to any one of the preceding claims, wherein both step (a) and step (b) are conducted at room temperature.

16. A compound of the formula:

17. A compound of the formula:

18. A compound of the formula:

wherein R1, R2 independently are alkyl groups comprising 1 to 5 carbon atoms, or R1 and R2 together with the -(CH2)n- group, where n=2 or 3, constitute a ring.

19. The method for manufacture of the compound as defined in claim 18, comprising a reaction of 7-hydroxyquinolin-2(lH)-one with a compound of the formula:

wherein R1 and R2 are as defined in claim 19, and X is a leaving group.

in the presence of a solvent, in the present of a base, and optionally in the presence of a catalyst.

20. The method according to claim 19, wherein the reaction is conducted in DMSO.

21. The method according to claim 19 or 20, wherein the reaction is conducted in the presence ofNa2C03.

22. The method according to claim 20-22, wherein the reaction is conducted in the presence of a catalyst in the form of tetraalkylammonium halogen.

23. The method according to claim 22, wherein the tetraalkylammonium halide is tetra-n- butylammonium bromide.

Description:
The method for manufacture of brexpiprazole, intermediates used in this method, and the method for manufacture thereof

The present invention relates to the method for manufacture of brexpiprazole, intermediates used in this method, and the method for manufacture thereof.

Brexpiprazole and its synthesis was disclosed for the first time in WO2006112464. The synthesis consisted in a construction of a brexpiprazole molecule from two fragments 3 and 4 by nucleophilic substitution reaction between the leaving group X 1 in the form of a halogen and a secondary amine group of a piperidine ring.

In turn, a substrate for this reaction, compound 3, was obtained from the reaction of 7- hydroxyquinolin-2(lH)-one 1 with an appropriate disubstituted compound 2 under basic conditions, with the X 2 group also being a halogen.

The identical transformation using a halogen derivative as the leaving group X 1 was disclosed in WO 2013015456, WO 2013035892, WO 2013162046, CN 104447723, CN 104829602, CN 104844585, CN 105061414, CN105440026, CN 105461704, CN 105461703, using a sulfate derivative as the leaving group X 1 in US2015361099, using a mesylate derivative as the leaving group X 1 in CN 105399736.

The main problem associated with the methods known in the prior art is primarily the formation of hardly removable impurities which are formed via uncontrolled nucleophilic substitution reactions. Thus, in the process of manufacture of compound 3, the main side reaction is a secondary alkylation reaction of compound 3 with another molecule of compound 1. The separation of reactivities of groups X 1 and X 2 through the use of various leaving groups with different reactivities produces no satisfactory results.

Additionally, at the stage of the reaction between compounds 3 and 4, due to the need for conducting the reaction in alkaline medium and at an elevated temperature, a secondary reaction occurs between these compounds, which also leads to the formation of impurities that are very difficult to remove using simple purification techniques such as crystallization.

Due to the difficulties in purifying the brexpiprazole obtained by the methods known in the prior art, final yields of this compound with purities appropriate for being used in pharmaceutical preparations are usually unsatisfactory.

Therefore, it is necessary to develop a new method for manufacture of brexpiprazole, which, on the one hand, yields a final product in a very pure form, without the need for performing complex purification procedures, and on the other hand, with high yield.

This goal is solved by the method according to the present invention using a method including steps of the formation of an iminium ion and its subsequent reduction with a reducing agent. The method is shown on the following scheme:

Accordingly, in the first aspect, the present invention relates to the method for manufacture of brexpiprazole, comprising the following steps: (a) reaction of 4-[(2-oxo-l,2-dihydroquinolin-7-yl)oxy]butanal 5 or a solvate thereof with l-(l-benzothiophen-4-yl)piperazine 4 or a salt thereof in a solvent, optionally in the presence of a catalyst;

(b) reduction of the iminium salt formed in step (a) using a reducing agent in a solvent, optionally in the presence of a catalyst. l-(l-Benzothiophen-4-yl)piperazine 4, used in this process, is a known compound, and it may be obtained according to the procedures known in the prior art. For example, a procedure described in Reference Example 30 included in WO2006112464A1 may be applied.

Preferably, a base catalyst is used in step (a). Particularly preferably, the base catalyst is sodium acetate. Alternatively, an acid catalyst is used in step (a). Preferably, the acid catalyst is acetic acid.

Preferably, in step (a), the reaction is conducted in a solvent selected from toluene, methylene chloride, dichloroethane, methanol, ethanol, 2-propanol, THF, DMF, and acetonitrile. More preferably, the solvent is either methanol or 2-propanol. Particularly preferably, the solvent is 2-propanol.

Preferably, in step (a), l-(l-benzothiophen-4-yl)piperazine is used in the form of a hydrochloride salt, and 4-[(2-oxo-l,2-dihydroquinolin-7-yl)oxy]butanal is used in the form of a hydrate.

Preferably, a base catalyst is used in step (b). Particularly preferably, the base catalyst is sodium acetate. Alternatively, an acid catalyst is used in step (b). Preferably, the acid catalyst is acetic acid.

Good results were obtained where acetic acid is used as a catalyst in step (a) and step (b). Good yields of the final products were obtained using acetic acid at an amount of 1-3 equivalents, particularly preferably 1.2 equivalent in relation to the amount of the aldehyde used.

Particularly good results were obtained where sodium acetate is used as a catalyst in step (a) and step (b). Excellent yields of the final product were obtained using sodium acetate at an amount of 0.5-1.5 equivalents, particularly preferably 0.8 equivalent in relation to the amount of the aldehyde used. Preferably, in step (b), the reducing agent is selected from a group consisting of NaBH(OAc)3, NaBH 3 CN, NaBH 4 , and H 2 /Pd. A particularly preferable reducing agent is NaBH(OAc) 3 .

Preferably, the reduction reaction in step (b) is conducted in a solvent selected from toluene, methylene chloride, dichloroethane, methanol, ethanol, 2-propanol, THF, DMF, and acetonitrile. More preferably, the solvent is either methanol or 2-propanol. Particularly preferably, the solvent is 2-propanol.

In the preferred embodiment, the method of the invention comprising the generation of an iminium ion and the reduction thereof, is performed in one vessel. Iminium salts are relatively unstable intermediates, therefore preferably no separation or purification thereof is conducted. This enables the maximization of the yield of the entire process while maintaining high purity of the final product.

Preferably, all reactions i.e. the reactions in step (a) and step (b) are conducted at room temperature. Aldehyde 5 used in the reaction may be obtained by using alkylation of 7- hydroxyquinolin-2(lH)-one 1 with an appropriate n-butanal derivative 7, protected in the form of an acetal, which comprises a leaving group at the opposite end in relation to the protected aldehyde group, and then by hydrolyzing the obtained product 8, under acidic conditions, according to the following scheme:

« 5

wherein R 1 , R 2 independently are alkyl groups comprising 1 to 5 carbon atoms, or R 1 and R 2 together with the -(CH 2 ) n - group, where n=2 or 3, form a ring. Preferably, both groups R 1 , and R 2 are methyl or ethyl group, particularly preferably both groups are ethyl groups. Said alkylation reaction is preferably conducted in an appropriate solvent such as DMSO, DMF, acetonitrile, acetone, toluene, THF, water, or mixtures thereof. Preferably, either DMSO or a mixture of water and DMF is used. More preferably, a 1 :1 ratio (v/v) mixture of water and DMF, or DMSO is used. Most preferably, DMSO is used. Said alkylation relation is conducted in the presence of a base. Both organic bases such as triethylamine, diisopropylethylamine, pyridine, DMAP, and DBU, and inorganic bases such as KOH, NaOH, K2CO3, and CS2CO3 may be used as the base. Reactions with organic bases proceed with a much lower yield. The use of KOH and NaOH leads to the formation of large amounts of impurities. Most preferably, either K2CO3 or Na 2 C03 is used. Additionally, a catalyst can be used in this process. A quaternary ammonium salt such as tetraalkylammonium halide, and preferably tetrabutylammonium bromide, can be used.

The obtained 4-[(2-oxo-l,2-dihydroquinolin-7-yl)oxy]butanal acetal is then hydrolyzed using an acid to yield 4-[(2-oxo-l,2-dihydroquinolin-7-yl)oxy]butanal. Preferably, aqueous solutions of organic acid such as formic acid, acetic acid, TFA, sulfonic acids, or mineral acids such as HC1, H2SO4, HCIO4, or acid resins such as Amberlyst 15 are used. Preferably, hydrochloric acid is used.

The solvent used in this step may be selected from water, THF, acetone, DCM, methanol, acetonitrile, diethyl ether, ethanol, 2-propanol, toluene, and mixtures thereof. Preferably, mixtures of water and the solvents mentioned are used. The aldehyde is usually isolated in a form of a solvate. In the preferable embodiment, when mixture with water is used as a solvent, the aldehyde is isolated as a hydrate. The hydrate can be directly used in the next reaction or can be dried to obtain the anhydrous aldehyde. Preferably, it is used as the hydrate.

A further aspect of the present invention is an intermediate in the form of an iminium salt in which the cation is the iminium cation has the following formula:

Still a further aspect of the present invention is an intermediate of the following formula:

Moreover, an additional aspect of the present invention is an intermediate of the following formula:

wherein R 1 , R 2 independently are alkyl groups comprising 1 to 5 carbon atoms, or R 1 and R 2 together with the -(CH 2 ) n - group, where n=2 or 3, form a ring.

Preferably, the intermediate is obtained by reaction of 7-hydroxyquinolin-2(lH)-one with a compound of the formula:

wherein R 1 and R 2 are as defined above, and X is a leaving group.

in the presence of a solvent, in the present of a base, and optionally in the presence of a catalyst.

Preferably, the reaction is conducted in DMSO. Preferably, the reaction is conducted in the presence of Na 2 C03.

Preferably, the reaction is conducted in the presence of a catalyst in the form of tetraalkylammonium halogen. Most preferably, the tetraalkylammonium halide is tetra-n- butylammonium bromide.

This compound is a particularly preferred intermediate in the synthesis of 4-[(2-oxo- 1 ,2- dihydroquinolin-7-yl)oxy]butanal, since when subjected to hydrolysis in the presence of an acid, it gives the aldehyde with very high, practically quantitative yields, and with high purity.

Thanks to the method of the invention, brexpiprazole is obtained with high yields and very high purities. An additional advantage of the method of the invention is that both steps i.e. the step of iminium salt formation and the step of reduction of this salt to brexpiprazole may be conducted at room temperature. EXAMPLES

I. Synthesis of acetals

(a) 7-(4,4-diethoxybutoxy)quinolin-2(lH)-one 8, R 1= R 2 =Et (Method 1-1)

13 mL (74 mmol) 4-chloro-l,l-diethoxybutane, 2 g (6 mmol) TBAB, and 10 g (74 mmol) potassium carbonate were added successively to a suspension of 10 g (62 mmol) 7- hydroxyquinolin-2(lH)-one in 40 mL DMSO. The mixture was heated to 120°C and maintained at this temperature for one hour. After cooling it to 30°C, the suspension was poured onto 300 mL water. It was stirred at room temperature overnight, and then the precipitate was filtered off and rinsed with water. It was crystallized from ethanol, yielding 11 g of the product 7-(4,4- diethoxybutoxy)quinolin-2(lH)-one with HPLC/MS purity of over 99%, m/z 305. 58% yield.

(b) 7-(4,4-diethoxybutoxy)quinolin-2(lH)-one 8, R 1= R 2 =Et (Method 1-2)

124 mL (684 mmol) 4-chloro-l,l-diethoxybutan, 10 g (31 mmol) TBAB, and 50 g (350 mmol) potassium carbonate were added successively to a suspension of 50 g (310 mmol) 7- hydroxyquinolin-2(lH)-one in a mixture of 100 mL DMF and 100 mL water. The mixture was heated to 100°C and maintained in this temperature for 4 hours. After cooling it to 60°C, 300 mL of 30%) isopropanol solution was added, and then the mixture was cooled to 25°C, stirred at this temperature for 5 hours, cooled to 3°C, stirred for 2 hours, filtered off, and rinsed with water. It was crystallized from a hexane/isopropanol mixture, yielding 70 g of the product 7- (4,4-diethoxybutoxy)quinolin-2(lH)-one with HPLC/MS purity of over 99%, m/z 305. 74% yield.

(c) 7-(4,4-diethoxybutoxy)quinolin-2(lH)-one (Method 1-3, most preferable method)

A reactor was charged with 700 g (4.34 mol, 1.0 eq) 7-hydroxyquinolin-2(lH)-one, 920 g (8.68 mol, 2.0 eq) Na 2 C0 3 , 140 g (0.43 mol, 0.1 eq) TBAB, and 2170 mL DMSO. The stirring was turned on, temperature of bath was set on 110°C. After temperature of reaction mixture reached 100°C, 1180 g (6.53 mol, 1.5 eq) 4-chloro-l,l-diethoxybutane was added. Reaction was conducted for 3 hours in 110°C. Next, 1075 mL 2-propanol was added, and reaction mixture was cooled to 40°C. Solid was separated on Schott funnel and washed with 1075 mL 2-propanol. Filtrate was transfered to another reactor, and 4400 mL water followed by 6500 mL heptane was added. The mixture was heated to 50°C and then slowly cooled down to 0°C. Suspension was filtered and washed with 3000 mL heptane. The solid was placed in the air flow dryer for 18 hours at 60°C. After drying, crude 7-(4,4-diethoxybutoxy)quinolin-2(lH)- one was loaded to reactor followed by 1100 mL 2-propanol and 9900 mL heptane. Mixture was heated to reflux and than slowly cooled down to 0°C. A solid was filtered and washed with 4000 mL heptane. The solid was placed in the dryer for 18 hours at 60°C. 1032 g (3.38 mol, 78% yield) 7-(4,4-diethoxybutoxy)quinolin-2(lH)-one was obtained. (d) 7-(4,4-dimethoxybutoxy)quinolin-2(lH)-one, 8, R 1= R 2 =Me

The dimethyl derivative was obtained analogously as in example I - Method 1-1 but using 4-chloro-l,l-dimethoxybutane instead of 4-chloro-l,l-diethoxybutane. 52% yield.

II. Synthesis of 4-[(2-oxo-l,2-dihydroquinolin-7-yl)oxy]butanal 5 (a) Method II-l 20 mL of 3M HC1 solution was added to 2.02 g (6.6 mmol) 7-(4,4- diethoxybutoxy)quinolin-2(lH)-one from Method 1-3 in 20 mL DCM. The mixture was stirred vigorously for 12 hours at room temperature. The precipitate was filtered off, then rinsed with water and aqueous sodium hydrogen carbonate solution. After drying, 1.5 g 4-[(2-oxo-l,2- dihydroquinolin-7-yl)oxy]butanal hydrate was obtained. HPLC/MS purity: 99.95%). 91%> yield. (b) Method II-2

A reactor was charged with 956 g (3.13 mol, 1.00 eq) 7-(4,4-diethoxybutoxy)quinolin- 2(lH)-one, 2800 mL water and 3800 mL 2-propanol. The stirring was turned on and 950 mL (11.4 mol, 3.64 eq) of 36%> hydrochloride acid was added. Upon addition the bath temperature was set to 20°C. After 60 minutes, reactor was cooled down to 0°C and stirring was continued for 1 hour. Precipitate was filtrated and washed with 3600 mL water, 3600 mL saturated sodium carbonate solution, and next again with 3600 mL water. The solid was placed in the dryer for 18 hours at 60°C. 756 g (3.03 mol, 97% yield) 4-[(2-oxo-l,2-dihydroquinolin-7-yl)oxy]butanal hydrate was obtained.

III. Synthesis of brexpiprazole

(a) Method III-l

1.5 g (6.0 mmol) 4-[(2-oxo-l,2-dihydroquinolin-7-yl)oxy]butanal hydrate from Method II- 1 was suspended in 65 mL methanol. 746 μΐ acetic acid (13 mmol) and 2 g (7.8 mmol) 1-(1- benzothiophen-4-yl)piperazine hydrochloride were added. The mixture was stirred for 2 hours at room temperature. 1.65 g (7.8 mmol) sodium triacetoxyborohydride was added in one portion. After 1 hour of stirring at room temperature, another 1.65 g portion (7.8 mmol) of sodium triacetoxyborohydride was added. The reaction was conducted for another hour at room temperature. It was poured onto 120 mL 1M HC1; the precipitate was formed, which was filtered off and rinsed with water. 2.4 g of a raw product with HPLC/MS purity of 93% was obtained. After crystallisation from 70% ethanol, 1.72 g brexpiprazole with HPLC/MS purity of 99.3%, m/z=433, was obtained. 66.2% yield.

(b) Method III-2

1.5 g (6.0 mmol) 4-[(2-oxo-l,2-dihydroquinolin-7-yl)oxy]butanal hydrate from Method II- 1 was suspended in 50 mL methanol. 559 μΐ acetic acid (9.7 mmol) and 1.65 g (6.5 mmol) 1- (l-benzothiophen-4-yl)piperazine hydrochloride were added. The mixture was stirred for 15 minutes at a temperature of 35°C. 1.38 g (6.5 mmol) sodium triacetoxyborohydride was added in one portion. After 5 minutes of stirring at 35°C, another portion of 1.38 g (6.5 mmol) of sodium triacetoxyborohydride was added, and after 5 minutes, another 1.38 g (6.5 mmol) portion thereof was added. The reaction was conducted for another 15 minutes in room temperature. It was poured onto 100 mL 1M HC1; a precipitate was formed, which was filtered off and rinsed with water. 2.7 g of a raw product with HPLC/MS purity of 96% were obtained.

The product was crystallised twice. First, using 70%> ethanol, and next using 50%> ethanol with addition of 1.2 equivalent NaOH. A product with purity of 99.84%> and yield of 68.2% was obtained.

(c) Method III-3 (large-scale method) Step I: Reactor was loaded with 756 g (3.03 mol, 1.00 eq) 4-[(2-oxo-l,2-dihydroquinolin-7- yl)oxy]butanal hydrate, 749 g (2.94 mol, 0.97 eq) l-(l-benzothiophen-4-yl)piperazine hydrochloride, 194 g (2.36 mol, 0.78 eq) sodium acetate and 7400 mL 2-propanol. The stirring was turned on and the bath was heated to 70°C. Upon mixture temperature reached 65°C, 936 g (4.42 mol, 1.46 eq) sodium triacetoxyborohydride was added in 30 minutes period of time. The temperature of reaction mixture was maintained between 65-68°C for time of addition of sodium triacetoxyborohydride. After 10 minutes, 11000 mL water was added followed by 510 mL (6.06 mol, 2 eq) 36%> hydrochloric acid. The mixture was cooled down to 0°C and the suspension was filtered. The solid was washed with 12000 mL water cooled down to 5°C, and next it was placed in the air flow dryer for 18 hours at 60°C. 1234 g (2.63 mol) of crude brexpiprazole hydrochloride was obtained. Step II: Crude brexpiprazole hydrochloride 1234 g (2.63 mol) was loaded to a reactor followed by 16300 mL methanol and 4100 mL water. The stirring was turned on and the bath was heated to 100°C. After the mixture was refluxed for 10 minutes at 70°C, 124 g of activated charcoal was added. 30 minutes after addition of coal, suspension was filtered through celite pad and filtrate was transferred to the reactor. Mixture was slowly cooled down to 0°C, suspension was filtered and precipitate was washed with 6800 mL methanol. The solid was placed in the air flow dryer for 18 hours at 60°C. 1028 g (2.19 mol) of brexpiprazole hydrochloride was obtained as a white solid.

Step III: Next, a reactor was loaded with 1028 g (2.19 mol) brexpiprazole hydrochloride, 13900 mL ethanol 96% and 8400 mL water. The stirring was turned on and bath was heated to 130°C. Mixture was refluxed for 30 minutes at 80°C, than cooled to 75°C, and 525 g (3.28 mol, 1.5 eq) 25% sodium hydroxide solution was added. Temperature 70-75°C was kept for another 30 minutes. Next, 3200 mL water was added and mixture was cooled down to 0°C. This temperature was kept for 1 h. Next, the suspension was filtrated through a Buchner funnel with paper filter and washed with 13200 mL water. Light yellow solid was placed in the air flow dryer for 18 hours at 60°C. 886 g (2.04 mol, 67%> yield) of brexpiprazole as light yellow solid was obtained. HPLC Purity 99.81%.

Total yield after 3 steps: 51 >.

IV. Comparison of brexpiprazole obtained by the method of the invention and brexpiprazole obtained by the method known in the prior art.

Brexpiprazole was also obtained according to the procedure disclosed in WO 2006112464A1, Example 1. According to the procedure, workup of the reaction mixture consisted in pouring the mixture onto water, filtering off the product, and then crystallisation from 70% ethanol. The yield of the process was 52%. The HPLC purity of brexpiprazole was 93.91%.

Furthermore, brexpiprazole was obtained according to US Patent US9206169 (Step I - reference example 9, col. 27; Step II - example 4, col. 27) in a slightly larger scale. The total yield after 2 stages and purification was 45%>, and the HPLC purity was 99.21%>.

Analogously, crude brexpiprazole obtained in the above Method III- 1 was crystallized from 70% ethanol, and brexpiprazole was obtained in a total yield of 61% and with the HPLC purity of 99.70%. In addition, brexpiprazole obtained in Method III-3 (large scale method) was analyzed. Total yield after 3 stages was 51%, and the HPLC purity was 99.81%).

The results clearly show that the method of the invention not only gives brexpiprazole with higher yield but also with a significantly higher purity: 99.70%) vs 93.91%). Similarly, while manufacturing brexpiprazole on a large scale. In a comparative method,

41% yield was obtained (2 steps and purification), while in the method of the invention, the yield was 51%. In addition, it should be noted that the HPLC purity of brexpiprazole obtained on a large scale according to the invention was 99.81%, while for the comparative method it was 99.21%. HPLC analysis conditions:

Instrument: HPLC WATERS 2695 with Det. UV WATERS 2498 and

Det. PDA WATERS 2996

Analytical Column: SymmetryShield RP8, 150 mm x 4.6 mm, 5 μιη

(or equivalent)

Phase A: 750 mL 10 mmol SDS solution, 250 mL ACN and 5 mL

CHsCOOH

Phase B: 100% acetonitrile

Flow rate: 1.0 ml/min

Column temperature: 25°C

Autosampler temperature: 20°C

Detection: 230 nm

Injection: 30 μΐ

Time of analysis: 30 min

Diluent: Acetonitrile : water (1 :1, v/v)

Gradient: Time Mobile Mobile

Gradient curve [min] phase A [%] phase B [%]

- 93 7 -

10 60 40 Linear (6)

20 30 70 Linear (6)

25 93 7 Immediate (11)

30 93 7 Immediate (11)