WO2020084389A1

WO2020084389A1 - Ribociclib intermediate and process for preparation thereof

Info

Publication number: WO2020084389A1
Application number: PCT/IB2019/058774
Authority: WO
Inventors: Rohidas Shivaji SULAKE; Yuvraj Dadasaheb SUDRIK; Rajinder Singh Siyan; Nandu Baban Bhise; Girij Pal Singh
Original assignee: Lupin Limited
Priority date: 2018-10-23
Filing date: 2019-10-15
Publication date: 2020-04-30

Abstract

The present invention relates to the process for the preparation of ribociclib succinate by making use of novel intermediates. The invention also relates to the process for the preparation of novel intermediates.

Description

RIBOCICLIB INTERMEDIATE AND PROCESS FOR PREPARATION THEREOF

Field of the invention

The present invention relates to novel intermediates for preparation of ribociclib intermediates and process for preparation thereof.

Background of the invention

Ribociclib is a pyrrolopyrimidine compound represented by Formula (I), known as inhibitors of cyclin dependent kinases (CDK). Chemically it is known as 7-cyclopentyl-2-(5- piperazin-l-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide. Ribociclib, as the succinic acid salt of the Formula (II), has been approved by for the treatment of FIR-positive, H ER2-negative advanced or metastatic breast cancers.

Formula (II)

US patent no. 8,415,355 discloses a manufacturing process for Ribociclib from 2-chloro-7- cyclopentyl-7H-pyrrolo [2,3-d]pyrimidine-6-carboxylic acid dimethylamide of Formula (III) and 5-piperazin-l-yl-pyridin-2-ylamine of Formula (IV).

Formula (III) Formula (IV)

Furthermore, US patent no. 9,193,732 discloses manufacturing processes for 2-chloro-7- cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide of Formula (III) and the N-protected compound ferf-butyl 4-(6-aminopyridin-3-yl)piperazine-l- carboxylate of the Formula (VI).

Formula (VI)

The above mentioned manufacturing processes produces product of low yield and purity. The processes are suitable for commercial scale manufacturing due to their complexity like involving chromatographic purification and use of hazardous reagent / reactant.

Therefore, there is a need to provide an alternate synthetic process for the manufacture of ribociclib and salts that would be commercially viable. Objective of the invention

In one aspect, the present invention provides novel compounds ethyl-2-bromo-3-(2,4- dioxo-l,2,3,4-tetrahydropyrimidin-5-yl)acrylate, ethyl-2-bromo-3-(2,4-dichloropyrimidin- 5-yl)acrylate and ethyl-2-bromo-3-(2-chloro-4-(cyclopentylamino)pyrimidin-5-yl)acrylate of formula (XII), (XIII) and (XIV), respectively along with its process for preparation.

In another aspect, the present invention provides novel compounds of Formula (XII), (XIII) and Formula (XIV) useful for the preparation of intermediate compounds of formula (V) and (VII), which are useful for preparation of ribociclib and salts thereof.

In yet another aspect, the present invention provides a process for the manufacture of ribociclib of Formula (I).

In further aspect, the present invention provides a process for the manufacture of ribociclib succinate of Formula (II).

Detailed description of the Invention

The present invention relates to an efficient process for the synthesis of ribociclib using novel intermediates.

In accordance with the present invention, described herein is a process for the preparation of ethyl 2-chloro-7-cyclopentyl-7FI-pyrrolo[2,3-d]pyrimidine-6-carboxylate of formula (Va) and ethyl 2-((5-(4-(tert-butoxycarbonyl) piperazin-l-yl) pyridin-2-yl)amino)- 7-cyclopentyl-7FI-pyrrolo[2,3-d]pyrimidine-6-carboxylate of formula (Vlla)using novel intermediates of formula (XII), (XIII) and (XIV).

Formula (XII) Formula (XIII) Formula (XIV) The synthetic scheme of the present invention for preparation of intermediate compounds of Formula (Va), (Vila) and preparation of Ribociclib and its salts thereof is as depicted in Scheme-1.

2,4-dioxo-l,2,3,4-tetrahydropyrimidine-5-carbaldehyde,the compound of formula (XI) is prepared by reaction of commercially available uracil of formula (X) with paraformaldehyde in the presence of an organic base such as trimethylamine, diisopropyl ethyl amine, DBU followed by oxidiation with an alkali metal persulfate such as potassium persulfate or sodium persulfate in the presence of silver nitrate.

Ethyl -2-bromo-3-(2,4-dioxo-l,2,3,4-tetrahydropyrimidin-5-yl)acrylate, the compound of formula (XII) is prepared by wittig reaction of compound of formula (XI) with the bromo ylide, ethyl a-bromo(triphenylphosphoranylidene)acetate. The reaction can be performed in solvents like THF, 2-methyl THF, ethyl acetate, alcoholic solvents like methanol, ethanol. Reaction of compound of formula (XII) with a chlorinating agent such as phosphorous oxychloride in the presence of organic base like diisopropyl ethyl amine or triethyl amine or pyridine or cyclopentyl amine yields ethyl -2-bromo-3-(2,4-dichloropyrimidin-5- yl)acrylate of formula (XIII). The reaction is carried in the solvents like tetrahydrofuran or 2-methyl tetrahydrofuran.

The compound of formula (XIII) is reacted with cyclopentylamine in the presence of base like diisopropylethylamine (DIPEA) to yield ethyl -2-bromo-3-(2-chloro-4- (cyclopentylamino)pyrimidin-5-yl)acrylate, compound of formula (XIV).

The reaction of compound of formula (XIV) with palladium acetate in the presence of (2,2'- bis(diphenylphosphino)-l,l'-binaphthyl) (BINAP) followed by stepwise or in situ reaction with tert-butyl 4-(6-aminopyridin-3-yl)piperazine-l-carboxylate, compound of formula (VI) yields compound of formula (Vi la) [Method-A, Scheme-1] The base used for the reaction can be selected from potassium carbonate, cesium carbonate, tripotassium phosphate, acetates, hydroxides etc.

Alternatively, the reaction of compound of formula (XIV) with palladium acetate in the presence of (2,2'-bis(diphenylphosphino)-l,l'-binaphthyl) (BINAP) yields the cyclized compound of formula (Va) which upon reaction with compound of formula (VI) yields compound of formula (Vila) [Method-B, Scheme-1]

The compound of Formula (Vila), upon hydrolysis yields the corresponding carboxylic acid derivative - 2-((5-(4-(fert-butoxycarbonyl) piperazin-l-yl)pyridin-2-yl)amino)-7- cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid - the compound of Formula (VIII) [Method-C, Scheme-1]

The compound of Formula (VII I) is then converted to tert-butyl 4-(6-((7-cyclopentyl-6- (dimethylcarbamoyl)-7FI-pyrrolo [2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-l- carboxylate of Formula (IX). Alternatively, the compound of Formula (Vila) is converted to ferf-butyl 4-(6-((7- cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)pyridin-3- yl)piperazine-l-carboxylate of Formula (IX) by reaction with dimethyl amine in a single step with a peptide coupling reagent like l-[Bis(dimethylamino)methylene]-lFI-l,2,3- triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, N-[(Dimethylamino)-lFI-l,2,3- triazolo-[4,5-b]pyridin-l-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (FIATU) in presence of a HOnig's base like N, N-Diisopropylethylamine (DIPEA) [Method-D, Scheme-1]

Alternatively, the compound of Formula (IX) is prepared from 2-((5-(4-(tert- butoxycarbonyl)-piperazin-l-yl)pyridin-2-yl)amino)-7-cyclopentyl-7FI-pyrrolo[2,3- d]pyrimidine-6-carboxylic acid via activation of the carboxylic acid group, i.e., by preparing the corresponding acid halide derivative of the compound (VIII) followed by reaction with dimethylamine.

Ribociclib of Formula (I) is prepared from ferf-butyl 4-(6-((7-cyclopentyl-6- (dimethylcarbamoyl)-7FI-pyrrolo [2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-l- carboxylate of the Formula (IX) by deprotecting the t-butoxycarbonyl group attached to the piperizine moiety by treatment with an acid like hydrochloric acid.

Ribociclib of Formula (I) so obtained provides the corresponding succinate salt of Formula (II) upon treatment with succinic acid as per methods known in the art or by a novel method. Ribociclib of Formula (I) is also converted to pharmaceutically acceptable salts known in the art or to a novel salt.

Ribociclib and salts thereof prepared according to the present invention can be used in the preparation of pharmaceutical composition indicated in combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of postmenopausal women with hormone receptor (FIR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer. Such pharmaceutical composition can be prepared using one or more pharmaceutically acceptable carriers, excipients or diluents by methods known in the literature. The present invention is further illustrated by the following non-limiting examples without restraining the scope of the same.

Examples

Example-1: Preparation of 2,4-dioxo-l,2,3,4-tetrahydropyrimidine-5-carbaldehyde (Formula XI)

To a solution of uracil (50.0 g, 0.44 mol) in water (400 mL), triethylamine (91.22 mL, 0.66 mol) and paraformaldehyde (33.47 g, 1.33 mol) was added. The reaction mixture was stirred at 65°C -70 °C for 8 to 10 hrs. Thereafter the reaction mixture was cooled to 25°C - 30°C and stirred for 10-12 hrs and concentrated. The residue obtained was diluted with 95% ethanol (130 mL) and stirred at 0°C -5°C for 1-2 hrs. The solid obtained was filtered; suck dried and dissolved in water (1200mL) and silver nitrate (2.15 g, 0. 012 mol) was added. Sodium persulfate (183 g, 0.77 mol) was added portion wise at 45 °C and stirred for 1 hr. Thereafter the reaction mixture was cooled to ambient temperature and filtered. The solid obtained was dried under vacuum to give 2, 4-dioxo-l, 2, 3, 4- tetrahydropyrimidine-5-carbaldehyde (40.0 g). ¹H NMR (500 MHz, DMSO-d6): d 11.90 (s, 1H), 11.50 (s, 1H), 9.74 (s, 1H), 8.14 (s, 1H).

Example-2: Ethyl -2-bromo-3-(2, 4-dioxo-l,2,3,4-tetrahydropyrimidin-5-yl)acrylate (Formula XII)

To a mixture of 2, 4-dioxo-l, 2, 3, 4-tetrahydropyrimidine-5-carbaldehyde (20.0 g, 0.14 mol) in tetrahydrofuran (400 ml), ethyl a-bromo (triphenylphosphoranylidene)acetate (67.5 g, 0.15 mol) was added. The reaction mixture was stirred for 24 hrs at reflux. Thereafter the reaction mixture was cooled, filtered and dried under vacuum to give Ethyl -2-bromo-3-(2, 4-dioxo-l, 2, 3, 4-tetrahydropyrimidin-5-yl)acrylate (27.5 g). ¹H NMR (500 MHz, DMSO-d6): d 11.61 (brs, 2H), 8.56 (s, 1H), 8.14 (s, 1H), 4.26 (q, 2H), 1.27(t, 3H); MS: 288.9 [M-H]⁺.

Example-3: Preparation of ethyl-2-bromo-3-(2-chloro-4-(cyclopentylamino)pyrimidin-5- yl)acrylate (Formula XIV)

Phosphorous oxychloride (65 mL) was added to ethyl -2-bromo-3-(2,4-dioxo-l,2,3,4- tetrahydropyrimidin-5-yl)acrylate (6.5 g, 0.022 mol) thereafter diisopropylethylamine (8.7 g, 0.067 mol) was added slowly to the reaction mixture at 0°C. The resulting reaction mixture was stirred at 110 °C for 5 hrs. Phosphorous oxychloride was distilled off and the residue was diluted with ethyl acetate (100 mL). Then the reaction mixture was added gradually to water at 0°C-5 °C. The layers were separated and the organic layer was washed with aqueous saturated sodium bicarbonate solution (100 mL). The Organic layer was filtered through silica bed and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (50 mL) and cooled to -20 °C and cyclopentylamine (3.9 g, 0.046 mol) was added. The reaction mixture was stirred and then quenched with water

(30 mL) and extracted with ethyl acetate (100 mL). The organic layer was separated and concentrated. The residue obtained was crystallized from ethyl acetate:hexane mixture to give ethyl-2-bromo-3-(2-chloro-4-(cyclopentylamino)pyrimidin-5-yl)acrylate (4.2 g). ¹H NMR (500 MHz, DMSO-d6): d 8.24 (s, 1H), 7.90 (s, 1H), 7.63 (d, 1H), 4.32 (m, 3H), 1.94 (m, 2H), 1.68 (m, 2H), 1.54 (m, 4H), 1.31 (t, 3H); MS: 375.8 [M+H]⁺.

Example-4: Preparation of ethyl 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6- carboxylate (Formula Va)

To a solution of ethyl-2-bromo-3-(2-chloro-4-(cyclopentylamino) pyrimidin-5-yl) acrylate (3.0 g, 8 mmol) in methyl isobutyl ketone ( MI BK) (30 mL) under nitrogen atmosphere,

Pd(OAc)₂ (0.04 g, 1.6 mmol), BI NAP 0.2 g, 3.2 mmol) and K2CO₃ (5.53 g, 40 mmol) was added. The reaction mixture was stirred at 80 °C for 2 hrs. Thereafter it was washed with water and then concentrated to give ethyl 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3- d]pyrimidine-6-carboxylate (2.1 g). *H N M R (500 MHz, DMSO-d6): d 9.10 (s, 1H), 7.40 (s, 1H), 5.68 (m, 1H), 4.34 (q, 2H), 2.25 (m, 2H), 2.03 (m, 4H), 1.67 (m, 2H), 1.32 (t, 3H); MS: 294 [M+H]⁺.

Example-5: Preparation of ethyl 2-((5-(4-(tert-butoxycarbonyl) piperazin-l-yl) pyridin- 2-yl)amino)-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate (Formula Vila)

To a solution of ethyl-2-bromo-3-(2-chloro-4-(cyclopentylamino) pyrimidin-5-yl) acrylate (3.0 g, 8 mmol) in MIBK (30 mL) under nitrogen atmosphere, Pd (OA (0.04 g, 1.6 mmol), BINAP (0.2 g, 3.2 mmol) and K2CO3 (5.53 g, 40 mmol) was added. The reaction mixture was stirred at 80 °C for 2 h and then tert-butyl 4-(6-aminopyridin-3-yl) piperazine-1- carboxylate (2.33 g, 8.4 mmol) was added. Thereafter the reaction mixture was stirred for 4 hrs at 95 °C, cooled and concentrated under reduced pressure; residue obtained was stirred in ethyl acetate: hexane (30 mL) mixture. The solid obtained was filtered and dried at 60 °C to afford ethyl 2-((5-(4-(tert-butoxycarbonyl)piperazin-l-yl)pyridin-2-yl)amino)-7- cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate (5.3 g).

Example-6: Preparation of 2-((5-(4-(tert-butoxycarbonyl)piperazin-l-yl)pyridin-2- yl)amino)-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (Formula VIII)

To a solution of ethyl 2-((5-(4-(ferf-butoxycarbonyl)piperazin-l-yl)pyridin-2-yl)amino)-7- cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate (5.0 g, 9.6 mmol) in THF (50 mL) in methanol (20 mL) aqueous sodium hydroxide (1.15 g in 20 mL) was added. Reaction mixture was stirred for 4 h at ambient temperature. The organic solvents were removed the residue and was diluted with water (50 mL) and was acidified with 1 N HCI to give solid material. The solid was filtered and then dried at 50 °C to afford 2-((5-(4-(ferf- butoxycarbonyl)piperazin-l-yl)pyridin-2-yl)amino)-7-cyclopentyl-7H-pyrrolo[2,3- d]pyrimidine-6-carboxylic acid (4.7 g).

Example-7: Preparation of tert-butyl 4-(6-((7-cyclopentyl-6-(dimethylcarbamoyl)-7H- pyrrolo[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-l-carboxylate (Formula IX) Method A: From 2-((5-(4-(tert-butoxycarbonyl)piperazin-l-yl)pyridin-2-yl)amino)-7- cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (Formula VIII)

To a solution of 2-((5-(4-(ferf-butoxycarbonyl)piperazin-l-yl)pyridin-2-yl)amino)-7- cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (4.5 g, 8.86 mmol) in DMF (30 mL), HATU (4.04, 10.6 mmol), and DIPEA (3.19 g, 26.5 mmol) were added and stirred for 10 min at ambient temperature. Dimethyl amine (2N) solution (13.9 mmol) was added and stirred at ambient temperature for 2 hrs. Thereafter the reaction mixture was poured into ice-cooled water and extracted with EtOAc (2 X 50 mL).The organic layer was concentrated to give ferf-butyl 4-(6-((7-cyclopentyl-6-(dimethylcarbamoyl)-7H- pyrrolo[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-l-carboxylate (4.4 g)

Method B: From ethyl 2-((5-(4-(te/t-butoxycarbonyl)piperazin-l-yl)pyridin-2-yl)amino)- 7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate (Formula Vila)

To a solution of ethyl 2-((5-(4-(ferf-butoxycarbonyl)piperazin-l-yl)pyridin-2-yl)amino)-7- cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate (1.0 g, 1.86 mmol) in methanol, dimethyl amine was added and stirred for 10 hrs at ambient temperature. After completion, the reaction mixture was concentrated to give ferf-butyl 4-(6-((7- cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)pyridin-3- yl)piperazine-l-carboxylate( 1.0 g)

Example-8: Preparation of 7-cyclopentyl-N, N-dimethyl-2-((5-(piperazin-l-yl)pyridin-2- yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (Formula I)

To a cooled solution of ferf-butyl 4-(6-((7-cyclopentyl-6-(dimethylcarbamoyl)-7H- pyrrolo[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-l-carboxylate (4.0 g, 7.48 mmol) in toluene (20 mL), 6N aqueous hydrochloric acid (6 mL) was added over 10 min at a temperature of 15±3 °C. The resulting biphasic reaction mixture was warmed to 25±3°C and stirred at this temperature for 1 hr until the remaining starting material was consumed. The toluene layer was separated and the aqueous layer was diluted with water (30 mL) and basified with NaOH solution (2N) to give solid material. The solid was filtered and then dried to give 7-cyclopentyl-N,N-dimethyl-2-((5-(piperazin-l-yl)pyridin-2- yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (3.2 g)

Example-9: Preparation of Ribociclib succinate (Formula II)

To a solution of 7-cyclopentyl-N,N-dimethyl-2-((5-(piperazin-l-yl)pyridin-2-yl)amino)-7H- pyrrolo[2,3-d]pyrimidine-6-carboxamide (3.5g, 8.05 mmol) in isopropanol (150 mL) at 70 °C succinic acid (1.0 g, 8.46 mmol) was added portion wise. The reaction mixture was stirred for 1 h and then cooled to ambient temperature. Solid obtained was filtered and dried at 60 °C to give Ribociclib succinate (3.8 g).

Claims

1) A process for the preparation of ribociclib succinate comprising the steps of a) reaction of uracil of formula (X) with paraformaldehyde in the presence of an organic base followed by oxidiation with an alkali metal persulfate to give 2,4- dioxo-l,2,3,4-tetrahydropyrimidine-5-carbaldehyde of formula (XI),

b) reaction of compound of formula (XI) with the bromo ylide, ethyl a- bromo(triphenylphosphoranylidene)acetate to giver ethyl -2-bromo-3-(2,4-dioxo- l,2,3,4-tetrahydropyrimidin-5-yl)acrylate of formula (XII),

c) reaction of compound of formula (XII) with a chlorinating agent in the presence of organic base to give ethyl -2-bromo-3-(2,4-dichloropyrimidin-5-yl)acrylate of formula (XIII),

d) reaction of compound of formula (XIII) with cyclopentylamine in the presence of base to yield ethyl -2-bromo-3-(2-chloro-4-(cyclopentylamino)pyrimidin-5- yl)acrylate of formula (XIV),

e) reaction of compound of formula (XIV) with palladium acetate in the presence of (2,2'-bis(diphenylphosphino)-l,l'-binaphthyl) (BINAP) with tert-butyl 4-(6- aminopyridin-3-yl)piperazine-l-carboxylate of formula (VI) to give compound of formula (Vila) or the reaction of compound of formula (XIV) with palladium acetate in the presence of (2,2'-bis(diphenylphosphino)-l,l'-binaphthyl) (BINAP) to give the cyclized compound of formula (Va) which upon reaction with compound of formula (VI) gives compound of formula (Vila),

f) hydrolysis of the compound of formula (Vila) to give the corresponding carboxylic acid derivative - 2-((5-(4-(fert-butoxycarbonyl) piperazin-l-yl)pyridin-2-yl)amino)- 7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid of formula (VIII), g) conversion of compound of formula (VIII) to tert-butyl 4-(6-((7-cyclopentyl-6-

(dimethylcarbamoyl)-7H-pyrrolo [2,3-d]pyrimidin-2-yl)amino)pyridin-3- yl)piperazine-l-carboxylate of formula (IX) or conversion of compound of formula (Vila) to ferf-butyl 4-(6-((7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3- d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-l-carboxylate of formula (IX), h) preparation of ribociclib from ferf-butyl 4-(6-((7-cyclopentyl-6-

(dimethylcarbamoyl)-7H-pyrrolo [2,3-d]pyrimidin-2-yl)amino)pyridin-3- yl)piperazine-l-carboxylate of the formula (IX) and

1) preparation of succinate salt of ribociclib from ribociclib.

2) The process of claim 1, wherein step a is carried in the presence of organic base selected from group consisting of triethyl amine, diisopropyl ethyl amine, DBU.

3) The process of claim 1, wherein step a is carried in the presence of alkali metal persulfate such as potassium persulfate or sodium persulfate.

4) The process of claim 1, wherein step a is carried in the presence of silver nitrate.

5) The process of claim 1, wherein step b is carried in the presence of solvents selected from a group consisting of tetrahydrofuran, 2-methyl tetrahydrofuran, ethyl acetate, alcoholic solvents such as methanol, ethanol.

6) The process of claim 1, wherein step c is carried in the presence of a chlorinating agent such as phosphorous oxychloride.

7) The process of claim 1, wherein step d is carried in the presence of organic base selected from a group consisting of diisopropyl ethyl amine, triethyl amine, pyridine or cyclopentyl amine.

8) A compound of formula (XII) with *H NMR (500 MHz, DMSO-d6): d 11.61 (brs, 2H), 8.56 (s, 1H), 8.14 (s, 1H), 4.26 (q, 2H), 1.27(t, 3H).

Formula (XII) 9) A compound of formula (XIV) with *H NMR (500 MHz, DMSO-d6): d 8.24 (s, 1H), 7.90 (s, 1H), 7.63 (d, 1H), 4.32 (m, 3H), 1.94 (m, 2H), 1.68 (m, 2H), 1.54 (m, 4H), 1.31 (t, 3H).

Formula (XIV)

10) A compound of formula (XIII)

Formula (XIII)