LV14853B

LV14853B - A method for preparation of 2-methyl-4-(4-methilpiperazin-1-il)-10h-thieno[2,3-b][1,5]benzodiazepine

Info

Publication number: LV14853B
Application number: LVP-12-172A
Authority: LV
Inventors: Aleksandrs ČERNOBROVIJS; Antons ĻEBEDEVS; Jurijs PONOMARJOVS; Diāna BOROVIKA
Original assignee: Latvijas Organiskās Sintēzes Institūts
Priority date: 2012-11-12
Filing date: 2012-11-12
Publication date: 2014-08-20
Also published as: LV14853A

Abstract

The present invention provides a novel and effective method for synthesis of 2-methyl-4-(4-methylpiperazin-1-yl)-10H-thieno[2,3-b]-[1,5]benzodiazepine, also known as antipsychotic drug Olanzapine (INN).

Description

Izgudrojuma pamatsBACKGROUND OF THE INVENTION

Olanzapīns ir labi zināma psihotropa ārstnieciskā viela, jo īpaši kā atipiskais antipsihotiskais līdzeklis, kas ir paredzēts šizofrēnijas un bipolāro traucējumu ārstēšanai.Olanzapine is a well-known psychotropic medicinal product, particularly as an atypical antipsychotic, for the treatment of schizophrenia and bipolar disorder.

1991. gadā pirmoreiz Lilly Industries Limited patentēja (EP454436) Olanzapīhu un tā 15 sintēzes metodi. Šajā patentā tika aprakstīti divi Olanzapīna (4) sintēzes ceļi (shēma 1).In 1991, Lilly Industries Limited patented (EP454436) Olanzapich and its 15 synthesis methods. This patent describes two pathways for the synthesis of Olanzapine (4) (Scheme 1).

Abi sintēzes ceļi ir ar līdzīgu diazepīna cikla veidošanas secību: 1) C-N-C saite tiek veidota 2-amīntiofen-3-karbonskābes atvasinājumiem (1, 5) reakcijā ar 2halogēnnitrobenzolu; 2) veidojot amidīna saiti tiek panākta septiņlocekļu cikla veidošanās. Olanzapīna sintēzi var veikt no starpsavienojuma 3’, nukleofīlas aizvietošanās reakcijā aizvietojot Q uz metilpiperazīna fragmentu.Both synthesis pathways follow a similar diazepine cycle formation sequence: 1) the C-N-C bond is formed by the reaction of 2-aminothiophene-3-carboxylic acid derivatives (1,5) with 2-halogen nitrobenzene; 2) forming an amidine bond results in a seven-membered cycle. Synthesis of olanzapine can be accomplished from the intermediate 3 'by substituting Q for the methylpiperazine moiety in the nucleophilic displacement reaction.

Shēma 1. Olanzapīna sintēzē pēc EP454436.Scheme 1. Synthesis of olanzapine according to EP454436.

Principiāli atšķirīga Olanzapīna sintēzes diazepīna cikla veidošanas shēma ir aprakstītaA fundamentally different scheme for the formation of a diazepine cycle for olanzapine synthesis has been described

W02004065390. Dotajā patentā 1,2-fenilēndiamĪns reaģē ar malonitrilu, veidojot septiņlocekļu bis-amīdīnu 8, kam seko transaminēšanas reakcija ar 1-metilpiperazīnu, un tai sekojoša reakcija ar propanālu un sēru, atšķeļot vienu piperazīna fragmentu bis-amidīnā 9 un veidojot tiofena ciklu (shēma 2).WO2004065390. In the present patent, 1,2-phenylenediamine reacts with malonitrile to form a seven-membered bis-amidine 8, followed by a transaminization reaction with 1-methylpiperazine, followed by a reaction with propanal and sulfur to cleave one piperazine moiety in bis-amidine 9 (forming the thiophene ring). 2).

Shēma 2. Olanzapma sintēze pēc W02004065390.Scheme 2. Synthesis of Olanzapma by WO2004065390.

Vairāki patenti apraksta N-demetil Olanzapīna (11) metilēšanu. N-demetil Olanzapīns var tikt metilēts ar vairākiem metilējošiem reaģentiem kā dimetilsulfats, metiljodīds, formaldehīda-skudrskābes sistēma u.c. (US2006035887) (shēma 3). Cits veids ir N-demetil savienojuma 11 formilēšana ar etilformiātu ar tam sekojošu formilgrupas reducēšanu par metil grupu, veidojot Olanzapīnu (4) (EP1669359) (shēma 4).Several patents describe the methylation of N-demethyl olanzapine (11). N-Demethyl Olanzapine may be methylated with a number of methylating reagents such as dimethyl sulfate, methyl iodide, formaldehyde-formic acid and the like. (US20060358888) (Scheme 3). Another method is the formylation of the N-demethyl compound 11 with ethyl formate followed by reduction of the formyl group to a methyl group to form olanzapine (4) (EP1669359) (Scheme 4).

Shēma 3. Olanzapīna sintēze pēc US2006035887.Scheme 3. Synthesis of olanzapine according to US2006035887.

Shēma 4. Olanzapīna sintēze pēc EP1669359Scheme 4. Synthesis of olanzapine according to EP1669359

Izgudrojuma aprakstsDescription of the Invention

Mēs negaidīti atklājām, ka 2-metil-4-(4-metilpiperazīn-l-il)-10H-tiēn[2,3-b][l,5]benzdiazepūis (4) var tikt iegūts ar augstiem iznākumiem pēc reakciju shēmas parādītas shēmā 5, ietverot sekojošus soļus:We have unexpectedly discovered that 2-methyl-4- (4-methylpiperazin-1-yl) -10H-thieno [2,3-b] [1,5] benzodiazepine (4) can be obtained with high yields according to the reaction scheme shown in Scheme 5 including the following steps:

1. 2-halogēnanilīna acilēšana ar cianoetiķskabes hloranhidridu, veidojot amīdu 13;1. Acylation of 2-haloaniline with cyanoacetic acid chloro anhydride to form amide 13;

2. iegūtam amīdam 13 reaģējot ar sēru un propanālu, tiek iegūts tiofena cikls amīdā 14;2. Reaction of the resulting amide 13 with sulfur and propanal yields the thiophene ring in amide 14;

3. turpmāk amīdam 14 reaģējot ar l-metilpiperazūiu un TiCLj-anizola sistēmu, veidojas amidīnsl5;3. Further reaction of the amide 14 with the l-methylpiperazine and the TiCl3-anisole system produces the amidine15;

4. veicot amidīna 15 iekšmolekulāru ciklizēšanu, tiek iegūts 2-metil-4-(4-metilpiperazīn-1 il)-l 0H-tiēn[2,3-ž>] [1,5]benzdiazepīns (4).4. Internal molecule cyclization of amidine 15 affords 2-methyl-4- (4-methylpiperazin-1-yl) -1H-thieno [2,3-b]] [1,5] benzthiazepine (4).

Saskaņā ar doto atklājumu, C-N-C saišu veidošanas reakcija (ti., ciklizācija, 4 sintēzes posms no uzrādītajiem) notiek karsējot attiecīgā šķīdinātājā bāzes klātienē ar katalizējošo sitēmu, kas ir atkarīga no halogēna veida 2-halogēnanilīna fragmentā.According to this discovery, the C-N-C bond formation reaction (i.e., cyclization, 4 steps of synthesis shown) occurs by heating in the appropriate solvent in the presence of a base with a catalytic system dependent on the halogen type in the 2-haloaniline moiety.

Dotā izgudrojuma vienā gadījumā, kad X = Cl, Br vai I, kā katalizatori ciklizācijas reakcijā var tikt izmantoti palādija kompleksi ar fosfiha ligandiem; palādija avots ietver, bet nav ierobežots arIn one case of the present invention, when X = Cl, Br or I, palladium complexes with phosphich ligands can be used as catalysts in the cyclization reaction; The source of palladium includes but is not limited to

Pd(0Ac)2, Pd2(dba)3_s Pd(dba)2, u.c, un fosfmu saturošie ligandi ietver, bet nav ierobežoti ar PPI13, rac-BINAP, Xantphos, X-Phos, S-Phos, John-Phos, ieskaitot karbēna tipa ligandus.Pd (0Ac) 2, Pd2 (dba) 3 _s Pd (dba) 2, etc. and fosfmu containing ligands include, but are not limited PPI13, rac-BINAP, Xantphos, X-Phos, S-Phos, John-Phos, including carbene-type ligands.

Shēma 5. Olanzapīna iegūšana pēc dotā izgudrojuma.Scheme 5. Preparation of olanzapine according to the present invention.

xx

NH,NH,

Dotā izgudrojuma citā gadījumā, kad X=Br vai I, vara-fosfina kompleksi var tikt izmantoti kā katalizatori cildizācijas reakcijai, ietverot, bet neaprobežojoties ar Cu(PPh3)3l vai Cu(PPli3)3Br.In another embodiment of the present invention, where X = Br or I, copper-phosphine complexes may be used as catalysts for the cationation reaction including, but not limited to, Cu (PPh 3) 3 L or Cu (PPli 3) 3 Br.

Savukārt, dotā izgudrojuma citā gadījumā, kad X=F, Cl, Br vai I, vairāk vēlams kad Hal = Cl, 10 niķeļa kompleksi ar N-heterociklisko karbēnu ligandiem var tikt izmantoti kā katalizatori ciklizācijas reakcijai, ietverot, bet neaprobežojoties ar Ni(cod)2.In another embodiment of the present invention, where X = F, Cl, Br or I, more preferably Hal = Cl, 10 nickel complexes with N-heterocyclic carbene ligands can be used as catalysts for the cyclization reaction, including but not limited to Ni (cod). ) 2.

Savukārt, dotā izgudrojuma citā gadījumā, kad X = F, var tikt izmantotas ciklizācijas reakcijas veikšanai spēcīgas bāzes, ietverot, bet neaprobežojoties ar n-BuLi, NaH, LiHMDS, un nātrija vai litija 1-metilpiperazīdu.In another embodiment of the present invention, when X = F, strong bases can be used to carry out the cyclization reaction, including but not limited to n-BuLi, NaH, LiHMDS, and sodium or lithium 1-methylpiperazide.

Saskaņā ar doto izgudrojumu, ciklizācijas reakcijā var tikt izmantotas neorganiskas vai organiskas bāzes, ietverot, bet neaprobežohoties ar NaiCCh, K2CO3, CS2CO3, K3PO4,According to the present invention, inorganic or organic bases may be used in the cyclization reaction including, but not limited to, NaiCCh, K2CO3, CS2CO3, K3PO4,

NaO-/-Bu, LiHMDS un DBU. Saskaņā ar doto izgudrojumu, ciklizācijas process ir veicams temperatūru intervālā 80-140°C atbilstošā šķīdinātājā, vēlams toluolā.NaO - / - Bu, LiHMDS and DBU. According to the present invention, the cyclization process can be carried out at a temperature in the range of 80-140 ° C in a suitable solvent, preferably toluene.

Dotais izgudrojums piedāvā jaunu un efektīvu metodi farmaceitiski aktīvas vielas Olanzapīna sintēzei no 2-halogēnanilīniem. Metode ļauj iegūt arī dažādus Olanzapīna atvasinājumus. Ekonomiski pamatotāka ir vara katilzatoru izmantošana dotās sintēzes shēmas gala ciklizācijas nodrošināšanai.The present invention provides a novel and effective method for the synthesis of a pharmaceutically active substance olanzapine from 2-haloanilines. The method also yields a variety of Olanzapine derivatives. It is economically more feasible to use copper boilers for the final cyclization of the given synthesis scheme.

Sintēzes ceļš pēc shēmas 5 ir ilustrēts sintēzes piemēros, kas doti zemāk. Izgudrojuma apmērs nav ierobežots ar zemāk minētiem sintēžu aprakstiem, kas doti kā piemēri. Jebkurš, kas ir prasmīgs nozarē var atkārtot dotos sintēžu aprakstus.The synthesis pathway according to Scheme 5 is illustrated in the synthesis examples given below. The scope of the invention is not limited to the following synthesis descriptions which are given by way of example. Anyone skilled in the art may repeat the given synthesis descriptions.

PiemēriExamples

Piemērs 1. 2-Ciano-N-(2-iodfenil)acetamīda (13a) iegūšanaExample 1. Preparation of 2-Cyano-N- (2-iodophenyl) acetamide (13a)

Cianoetiķskābi (15.00 g, 176.3 mmol) suspendē sausā dihlormetanā (150 ml), tad pievieno oksalilhlorīdu (33.57 g, 22.7 ml, 264.5 mmol) un sauso dimetliformamīdu (0.4 ml). Reakcijas maisījums tiek maisīts inertajā atmosfērā 20-25°C, kamēr izšķīst cianoetiķskābe un beidzas gāzes izdalīšanās (3-5 h). Reakcijas maisījumu ietvaicē pazeminātā spiedienā temperatūrā, kas nepārsniedz 25°C un šķidrais atlikums tiek šķīdināts sausā dihlormetāna (50 ml) un šo šķīdumu piepilina pie 2-jodanilīna (38.61 g, 176.3 mmol) un trietilamīna (19.62 g, 27.0 ml, 193.9 mmol) šķīduma sausā dihlormetānā (200 ml), maisot un dzesējot 0-5°C. Reakcijas maisījumu maisa 20-25°C 3 h. Reakcijas kontrole: PSH, etilacetāts heksāns 1:2, /(/-produktam = 0.4). Reakcijas beigās, maisījumu ietvaicē pazeminātā spiedienā, atlikumu šķīdina etilacetātā, radušās nogulsnes (trietilamīna hidrohlorīds) filtrē un skalo ar etilacetātu (3 χ 50 ml). Filtrātu skalo ar 0.5M HCI (3 ><50 ml), tad piesātinātu NaHCO₃ ūdens šķīdumu (3x50 ml) un žāvē uz bezūdens Na₂SC>4. Pēc šķīduma ietvaicēšanas produktu pārkristalizē no izopropanola. Iznākums: 38.29 g (76%) 2-ciano-N-(2-jodfenil)acetamīda, tīrība 97.5% (AEŠH). *H KMR spektrs (CDC1₃,400 MHz), δ: 3.598 (s, 2H); 6.921 (ddd, 1H,Cyanoacetic acid (15.00 g, 176.3 mmol) is suspended in dry dichloromethane (150 mL), then oxalyl chloride (33.57 g, 22.7 mL, 264.5 mmol) and dry dimethylformamide (0.4 mL) are added. The reaction mixture is stirred under an inert atmosphere at 20-25 ° C until cyanoacetic acid is dissolved and gas evolution ceases (3-5 h). The reaction mixture is evaporated under reduced pressure at a temperature not exceeding 25 ° C and the liquid residue is dissolved in dry dichloromethane (50 ml) and this solution is added to 2-iodanyline (38.61 g, 176.3 mmol) and triethylamine (19.62 g, 27.0 ml, 193.9 mmol). solution in dry dichloromethane (200 mL) with stirring and cooling at 0-5 ° C. The reaction mixture is stirred at 20-25 ° C for 3 h. Reaction control: PSH, ethyl acetate hexane 1: 2, / (/ - product = 0.4). At the end of the reaction, the mixture is evaporated under reduced pressure, the residue is dissolved in ethyl acetate, the resulting precipitate (triethylamine hydrochloride) is filtered off and rinsed with ethyl acetate (3 × 50 ml). The filtrate is washed with 0.5M HCl (3 x 50 mL) then saturated aqueous NaHCO ₃ ( ₃ x 50 mL) and dried over anhydrous Na ₂ SC> 4. After evaporation of the solution, the product is recrystallized from isopropanol. Yield: 38.29 g (76%) of 2-cyano-N- (2-iodophenyl) acetamide, purity 97.5% (AESH). 1 H NMR Spectrum (CDCl ₃ , 400 MHz), δ: 3.598 (s, 2H); 6.921 (ddd, 1H,

7=1.1, 7.7, 7.8 Hz); 7.369 (ddd, 1H, J= 1.1, 7.8, 7.8 Hz); 7.814 (dd, 1H, J= 1.1, 8.1 Hz); 8.047 (s, 1H); 8.116 (dd, 1H, J= 1.1, 8.3 Hz)m.d.7 = 1.1, 7.7, 7.8 Hz); 7.369 (ddd, 1H, J = 1.1, 7.8, 7.8 Hz); 7.814 (dd, 1H, J = 1.1, 8.1 Hz); 8.047 (s, 1H); 8.116 (dd, 1H, J = 1.1, 8.3 Hz) m.d.

ESI- MS (m/z, %): 44.7 (100); 61.6 (2); 90.7 (3); 126.8 (3); 193.0 (2); 239.0 (4); 284.9 (67); 286.2 (3) [M]'.ESI-MS (m / z,%): 44.7 (100); 61.6 (2); 90.7 (3); 126.8 (3); 193.0 (2); 239.0 (4); 284.9 (67); 286.2 (3) [M] '.

Elementanalīze, aprēķināts: C 37.79%; H 2.47%; 144.36%; N 9.79%; O 5.59%.Elemental Analysis: Calculated: C 37.79%; H, 2.47%; 144.36%; N, 9.79%; O, 5.59%.

C₉H₇IN₂O. Iegūts: C 37.91%; H 2.38%; N 9.96%.C ₉ H ₇ IN ₂ O. Found: C 37.91%; H, 2.38%; N, 9.96%.

Piemērs 2, N-(2-Bromfenil)-2-cianoacetamīda (13b) iegūšanaExample 2 Preparation of N- (2-Bromophenyl) -2-cyanoacetamide (13b)

Metode analoģiska aprakstītai Piemērā 1. Iznākums 29.77 g (71%) N-(2-bromfenil)-210 cianoacetamīds, tīrība 99.4% (AEŠH). ’H KMR spektrs (CDC1₃, 400 MHz), δ: 3.601 (s, 2H), 7.059 (ddd, 1H, J= 1.1, 7.7, 7.7 Hz), 7.342 (ddd, 1H, J= 1.1, 7.8, 7.9 Hz), 7.573 (dd, 1H, J= 1.1, 8.1 Hz), 8.237 (dd, 1H, J= 1.1, 8.1 Hz), 8.246 (s, lH)m.d.Method analogous to that described in Example 1. Yield 29.77 g (71%) of N- (2-bromophenyl) -210 cyanoacetamide, purity 99.4% (AESH). 1 H NMR Spectrum (CDCl ₃ , 400 MHz), δ: 3.601 (s, 2H), 7.059 (ddd, 1H, J = 1.1, 7.7, 7.7 Hz), 7.342 (ddd, 1H, J = 1.1, 7.8, 7.9) Hz), 7.573 (dd, 1H, J = 1.1, 8.1 Hz), 8.237 (dd, 1H, J = 1.1, 8.1 Hz), 8.246 (s, 1H) md

ESI- MS (m/z, %): 34.5 (2); 39.7 (6); 44.7 (63); 61.6 (2); 65.6 (5); 78.6 (3); 96.7 (2); 193.0 (4); 236.9 (92); 239.0 (100) [M]'.ESI-MS (m / z,%): 34.5 (2); 39.7 (6); 44.7 (63); 61.6 (2); 65.6 (5); 78.6 (3); 96.7 (2); 193.0 (4); 236.9 (92); 239.0 (100) [M] '.

Elementanalīze, aprēķināts: C 45,22 %; H 2.95 %; Br 33.42 %; N 11.72 %; 0 6.69 %.Elemental Analysis: Calculated: C, 45.22%; H, 2.95%; Br 33.42%; N, 11.72%; 0 6.69%.

C₉H₇BrN₂O. Iegūts: C 45.34 %; H 2.77 %; N 11.65 %.C ₉ H ₇ BrN ₂ O. Found: C, 45.34%; H, 2.77%; N, 11.65%.

Piemērs 3. 2-Ciano-N-(2-hlorfenil)acetamīda (13c) iegūšanaExample 3. Preparation of 2-Cyano-N- (2-chlorophenyl) acetamide (13c)

Metode analoģiska aprakstītai Piemērā 1. Iznākums 26.8 g (78%) 2-ciano-N20 (2-hlorfenil)acetamīda, tīrība 98.6% (AEŠH). *H KMR spektrs (CDC1₃, 400 MHz), δ: 3.605 (s, 2H), 7.124 (ddd, 1H, J= 1.1, 7.7, 7.8 Hz), 7.300 (ddd, 1H, 7= 1.1, 7.8, 7.9 Hz), 7.407 (dd, 1H, 7= 1.1, 8.2 Hz), 8.242 (s, 1H), 8.253 (dd, 1H, 7= 1.1, 8.5 Hz) m.d.Method analogous to that described in Example 1. Yield 26.8 g (78%) of 2-cyano-N 2 O (2-chlorophenyl) acetamide, purity 98.6% (AESH). 1 H NMR Spectrum (CDCl ₃ , 400 MHz), δ: 3.605 (s, 2H), 7.124 (ddd, 1H, J = 1.1, 7.7, 7.8 Hz), 7.300 (ddd, 1H, 7 = 1.1, 7.8, 7.9) Hz), 7.407 (dd, 1H, 7 = 1.1, 8.2 Hz), 8.242 (s, 1H), 8.253 (dd, 1H, 7 = 1.1, 8.5 Hz) md

ESI- MS (m/z, %): 39.6 (8); 44.6 (45); 61.5 (2); 65.6 (8); 96.7 (2); 177.0 (2); 193.0 (100); 194.9 (38) [M]'; 196.2 (3).ESI-MS (m / z,%): 39.6 (8); 44.6 (45); 61.5 (2); 65.6 (8); 96.7 (2); 177.0 (2); 193.0 (100); 194.9 (38) [M] '; 196.2 (3).

Elementanalīze, aprēķināts:C 55.54 %; H 3.63 %; Cl 18.22 %; N 14.39 %; O 8.22 %.Elemental Analysis: Calculated: C 55.54%; H, 3.63%; Cl, 18.22%; N, 14.39%; O, 8.22%.

C₉H₇C1N₂O. Iegūts: C 55.58 %; H 3.53 %; N 14.29 %.C ₉ H ₇ ClN ₂ O. Found: C 55.58%; H, 3.53%; N, 14.29%.

Piemērs 4. 2-Ciano-N-(2-fluorfenil)acetamīda f!3d) iegūšanaExample 4. Preparation of 2-Cyano-N- (2-fluorophenyl) acetamide (3d)

Metode analoģiska aprakstītai Piemērā 1. Iznākums 26.5 g (84%) 2-ciano-N-(2fluorfenil)acetamīda, tīrība 98.7% (AEŠH). ‘H KMR spektrs (CDC1₃, 400 MHz), δ: 3.593 (s, 2H), 7.077-7.192 (m, 3H), 7.875 (s, 1H), 8.111-8.191 (m, 1H) m.d.Method analogous to that described in Example 1. Yield: 26.5 g (84%) of 2-cyano-N- (2-fluorophenyl) acetamide, purity 98.7% (AESH). 1 H NMR Spectrum (CDCl ₃ , 400 MHz), δ: 3.593 (s, 2H), 7.077-7.192 (m, 3H), 7.875 (s, 1H), 8.111-8.191 (m, 1H) md

ESI- MS (m/z, %): 39.6 (10); 44.6 (87); 61.6 (3); 65.6 (9); 156.9 (2); 177.0 (100); 178.2 (6) [M].ESI-MS (m / z,%): 39.6 (10); 44.6 (87); 61.6 (3); 65.6 (9); 156.9 (2); 177.0 (100); 178.2 (6) [M].

Piemērs 5. 2-Amīn-N-(2-iodfenil)-5-metiltiofen-3-karboksamīda (14a) iegūšanaExample 5. Preparation of 2-Amine-N- (2-iodophenyl) -5-methylthiophene-3-carboxamide (14a)

2-Ciano-N-(2-jodfenil)acetamīdu (13a) (36.00 g, 125.8 mmol), propanālu (8.4 g,2-Cyano-N- (2-iodophenyl) acetamide (13a) (36.00 g, 125.8 mmol), propanal (8.4 g,

10.5 ml, 144.7 mmol) un sēru (4.03 g, 125.8 mmol) suspendē dimetilformamīdā (75 ml), un pievieno trietilamīnu (6.36 g, 8.8 ml, 62.9 mmol). Reakcijas maisījumu maisa 6 h pie 5560°C. Reakcijas kontrole: PSH, etilacetāts - heksāns 1:4,Ā/produktam = 0.4). Reakcijas maisījumu ietvaicē pazeminātā spiedienā, tad pievieno heksānu (50 ml), kas veicina kristalizāciju. Nogulsnes filtrē, žāvē un pārkristalizē no toluolā. Iznākums 27.54 g (61%) 2-amih-N-(2-jodfenil)-5-metiltiofen-3-karboksamīda, tīrība 94.1% (AEŠH). ‘H KMR spektrs (CDC1₃, 400 MHz), δ: 2.327 (s, 3H); 6.072 (s, 2H); 6.583 (s, 1H); 6.810 (ddd, 1H, J= 1.2, 7.4, 7.8 Hz); 7.341 (ddd, 1H, J= 1.2, 7.8, 8.2 Hz); 7.718 (s, 1H); 7.776 (dd, 1H, J= 1.2,7.8 Hz); 8.315 (dd, 1H, J= 1.2, 8.6 Hz) m.d.10.5 mL, 144.7 mmol) and sulfur (4.03 g, 125.8 mmol) are suspended in dimethylformamide (75 mL) and triethylamine (6.36 g, 8.8 mL, 62.9 mmol) is added. The reaction mixture is stirred for 6 h at 5560 ° C. Reaction control: PSH, ethyl acetate - hexane 1: 4, A / product = 0.4). The reaction mixture is evaporated under reduced pressure, then hexane (50 ml) is added to facilitate crystallization. The precipitate is filtered off, dried and recrystallized from toluene. Yield: 27.54 g (61%) of 2-amyl-N- (2-iodophenyl) -5-methylthiophene-3-carboxamide, purity 94.1% (HPLC). 1 H NMR Spectrum (CDCl ₃ , 400 MHz), δ: 2.327 (s, 3H); 6.072 (s, 2H); 6.583 (s, 1H); 6.810 (ddd, 1H, J = 1.2, 7.4, 7.8 Hz); 7.341 (ddd, 1H, J = 1.2, 7.8, 8.2 Hz); 7.718 (s, 1H); 7.776 (dd, 1H, J = 1.2,7.8 Hz); 8.315 (dd, 1H, J = 1.2, 8.6 Hz) md

ESI+ MS (m/z, %): 140.0 (100); 142.0 (4); 194.1 (2); 359.0 (54) [M+H]⁺; 360.2 (6).ESI + MS (m / z,%): 140.0 (100); 142.0 (4); 194.1 (2); 359.0 (54) [M + H] ⁺ ; 360.2 (6).

Elementanalīze, aprēķināts:C 40.24%; H 3.10%; 135.43%; N 7.82%; O 4.47%,Elemental Analysis Calculated: C 40.24%; H, 3.10%; 135.43%; N, 7.82%; O 4.47%

S 8.95%. Ci₂H„IN₂OS. Iegūts: C 40.66%; H 2.95%; N 7.61%.S, 8.95%. Ci ₂ H IN ₂ OS. Found: C, 40.66%; H, 2.95%; N, 7.61%.

Piemērs 6. 2-Amīn-N-(2-bromfenil)-5-metiltiofen-3-karboksamīda (14b) iegūšanaExample 6. Preparation of 2-Amine-N- (2-bromophenyl) -5-methylthiophene-3-carboxamide (14b)

Metode analoģiska aprakstītai Piemērā 5. Iznākums 22.66 g (67%) 2-amīn-N-(2bromfenil)-5-metiltiofen-3-karboksamīda, tīrība 96.5% (AEŠH). ^JH KMR spektrs (CDC1₃,Method analogous to that described in Example 5. Yield 22.66 g (67%) of 2-amine-N- (2-bromophenyl) -5-methylthiophene-3-carboxamide, purity 96.5% (AESH). ¹ H NMR Spectrum (CDCl ₃ ,

400 MHz), δ: 2.323 (s, 3H), 6.060 (s, 2H), 6.524 (s, 1H), 6.943 (ddd, 1H, /= 1.2, 7.7, 7.8 Hz),400 MHz), δ: 2.323 (s, 3H), 6.060 (s, 2H), 6.524 (s, 1H), 6.943 (ddd, 1H, / = 1.2, 7.7, 7.8 Hz),

7.313 (ddd, 1H, 7= 1.0, 7.8, 7.9 Hz), 7,537 (dd, 1H, J= 1.1, 8.0 Hz), 7.911 (s, 1H), 8.416 (dd,7.313 (ddd, 1H, J = 1.0, 7.8, 7.9 Hz), 7.537 (dd, 1H, J = 1.1, 8.0 Hz), 7.911 (s, 1H), 8.416 (dd,

1H, J= 1.3, 8.3 Hz) m.d.1H, J = 1.3, 8.3 Hz) m.d.

ESI+ MS (m/z, %): 102.0 (3); 140.0 (100); 142.0 (4); 180.1 (2); 251.2 (2); 312.0 (22) [M+H]⁺; 313.0 (23).ESI + MS (m / z,%): 102.0 (3); 140.0 (100); 142.0 (4); 180.1 (2); 251.2 (2); 312.0 (22) [M + H] ⁺ ; 313.0 (23).

Piemērs 7. 2-Amīn-N-(2-hlorfenil)-5-metiltiofen-3-karboksamīda (14c) iegūšanaExample 7. Preparation of 2-Amine-N- (2-chlorophenyl) -5-methylthiophene-3-carboxamide (14c)

Metode analoģiska aprakstītai Piemērā 5. Iznākums 23.05 g (70%) 2-amīn-N-(2hlorfenil)-5-metiltiofen-3-karboksamīda, tīrība 96.8% (AEŠH). *H KMR spektrs (CDCI3, 400 MHz), δ: 2.316 (s, 3H), 6.050 (s, 2H), 6.501 (s, 1H), 7.003 (ddd, 1H, 1.2 Hz, 7.7 un 7.8 Hz),Method analogous to that described in Example 5. Yield 23.05 g (70%) of 2-amine-N- (2-chlorophenyl) -5-methylthiophene-3-carboxamide, purity 96.8% (AESH). 1 H NMR Spectrum (CDCl 3, 400 MHz), δ: 2.316 (s, 3H), 6.050 (s, 2H), 6.501 (s, 1H), 7.003 (ddd, 1H, 1.2 Hz, 7.7 and 7.8 Hz),

7.269 (m, 1H), 7.367 (dd, 1H, J= 1.2, 7.9 Hz), 7.909 (s, 1H), 8.426 (dd, 1H, J= 1.2, 8.3 Hz)7.269 (m, 1H), 7.367 (dd, 1H, J = 1.2, 7.9 Hz), 7.909 (s, 1H), 8.426 (dd, 1H, J = 1.2, 8.3 Hz)

m.d.m.d.

ESI+ MS (m/z, %): 140.0 (100); 142.0 (4); 251.1 (19); 267.1 (1) [M+H]⁺.ESI + MS (m / z,%): 140.0 (100); 142.0 (4); 251.1 (19); 267.1 (1) [M + H] ⁺ .

Elementanalīze, aprēķināts: C 54.03 %; H 4.16 %; Cl 13.29 %; N 10.50 %; 0 6.00 %,Elemental Analysis calculated: C 54.03%; H, 4.16%; Cl, 13.29%; N, 10.50%; 0 6.00%,

S 12.02 %. C12H11CIN2OS. Iegūts: C 54.12 %; H 3.85 %; N 10.48 %.S, 12.02%. C12H11CIN2OS. Found: C, 54.12%; H, 3.85%; N, 10.48%.

Piemērs 8. 2-Amīn-N-(2-fluorfenil)-5-metiltiofen-3-karboksamīda (14d) iegūšanaExample 8. Preparation of 2-Amine-N- (2-fluorophenyl) -5-methylthiophene-3-carboxamide (14d)

Metode analoģiska aprakstītai Piemērā 5. Iznākums 24.42 g (72%) 2-amīn-N-(2fluorfenil)-5-metiltiofen-3-karboksamīda, tīrība 98.5 % (AEŠH). ’H KMR spektrs (CDC1₃,Method analogous to that described in Example 5. Yield 24.42 g (72%) of 2-amine-N- (2-fluorophenyl) -5-methylthiophene-3-carboxamide, purity 98.5% (AESH). 1 H NMR Spectrum (CDCl ₃ ,

400 MHz), δ: 2.308 (s, 3H), 5.996 (s, 2H), 6.482 (s, 1H), 6.981-7.074 (m, 1H), 7.057-7.157 (m, 2H), 7.539 (s, 1H), 8.329 (ddd, 1H, J= 1.3, 8.1, 8.1 Hz) m.d.400 MHz), δ: 2.308 (s, 3H), 5.996 (s, 2H), 6.482 (s, 1H), 6.981-7.074 (m, 1H), 7.057-7.157 (m, 2H), 7.539 (s, 1H). ), 8.329 (ddd, 1H, J = 1.3, 8.1, 8.1 Hz) md

ESI+ MS (m/z, %): 44.6 (3); 52.7 (2); 67.7 (20); 77.7 (42); 84.8 (43); 86.7 (2); 111.9 (54); 113.9 (5); 140.0 (100); 142.0 (6); 166.1 (2); 251.1 (1) [M+H]⁺.ESI + MS (m / z,%): 44.6 (3); 52.7 (2); 67.7 (20); 77.7 (42); 84.8 (43); 86.7 (2); 111.9 (54); 113.9 (5); 140.0 (100); 142.0 (6); 166.1 (2); 251.1 (1) [M + H] ⁺ .

Elementanalīze, aprēķināts: C 57.59 %; H 4.43%; F 7.59 %; N 11.19 %; 0 6.39; S 12.81 %. C₁₂HnFN₂OS. Iegūts: C 57.66 %; H 4.47 %; N 10.82 %.Elemental Analysis calculated: C 57.59%; H, 4.43%; F, 7.59%; N, 11.19%; 0 6.39; S, 12.81%. C ₁₂ HnFN ₂ OS. Found: C, 57.66%; H, 4.47%; N, 10.82%.

Piemērs 9. N- Γ (2-amino-5 -metiltien-3-il)f 4-metilpiperazīn-1 -il)metilēnļ -N-(2-j odfenibam 1 n a (15a) iegūšanaExample 9. Preparation of N- (2-amino-5-methylthien-3-yl) -4-methylpiperazin-1-yl) methylene-N- (2-iodophenibam 1 n a (15a)

Titāna(IV) hlorīdu (17.45 g, 10.1 ml, 92.0 mmol) lēnām pievieno pie anizola (49.74 g, 50 ml, 0.46 mol) šķīduma sausā toluolā (100 ml) inertā atmosfērā intensīvi maisot. Iegūto TiCLļ-anizola kompleksu (tumši violets šķidrums) pilinot pievieno pie 2-amīn-N-(2-jodfenil)5-metiltiofen-3-karboksamīda (25.00 g, 65.7 mmol) un 1-metilpiperazīna (6.58 g, 7.3 ml,Titanium (IV) chloride (17.45 g, 10.1 mL, 92.0 mmol) is slowly added to a solution of anisole (49.74 g, 50 mL, 0.46 mol) in dry toluene (100 mL) under vigorous stirring. The resulting TiClCL-anisole complex (dark purple liquid) is added dropwise to 2-amine-N- (2-iodophenyl) 5-methylthiophene-3-carboxamide (25.00 g, 65.7 mmol) and 1-methylpiperazine (6.58 g, 7.3 mL,

65.7 mmol) šķīduma sausā toluolā (150 ml). Reakciju veic pie 110-115°C 18hinertā atmosfērā. Reakcijas kontrole: PSH, metanols - dihlormetāns 1:4, R/produktam = 0.5). Rekacijas maisījumu atdzesē līdz 40-50°C un izlej ūdens un ledus maisījumā (320 g), maisā 5 min, pievieno etilacetātu (640 ml), maisījumu maisa 10 min un filtrē. Nogulsnes skalo ar etilacetātu (2 χ 320 ml) un acetonu (2 χ 120 ml). Augšējais (organiskais) filtrātā slānis tiek atdalīts, skalots ar piesātinātu NaCl ūdens šķīdumu, žāvēts uz bezūdens Na₂SO₄ un filtrēts. Pie fīltrāta pievieno silikagēlu (40 g), maisa 15 min, filtrē, uz filtra silikagēlu mazgā ar etilacteāta -toluola maisījumu (150 ml + 30 ml). Filtrātu divreiz skalo ar 5% HC1 (pirmāporcija: 26 ml konc. HC1 + 156 ml H₂O, otra porcija: 5.2 ml konc. HC1 + 31 ml H₂O). Ūdens slāņus, kas satur produktu hidrohlorīda sāls formā apvieno un skalo ar etilacetātu (65 ml). Organiskā fāze un etilacetāts pēc skalošanas satur anizolu un blakusproduktus. Ūdens slāni neitralizē ar piesātinātu NaHCO₃ (65 g šķīdina minimālā ūdens daudzumā) un ekstraģē ar etilacetātu (3 χ 320 ml). Organiskos ekstraktus apvieno, žāvē uz bezūdens Na₂SO₄ un ietvaicē. Sauso atlikumu suspendē etilacetātā (60 ml), maisa istabas temperatūrā 20 min, atdzesē līdz -20°C, filtrē, mazgā ar minimālu auksta etilacetāta daudzumu un žāvē pazeminātā spiedienā.65.7 mmol) of a solution in dry toluene (150 mL). The reaction is carried out at 110-115 ° C under an 18 hertz atmosphere. Reaction control: PSH, methanol - dichloromethane 1: 4, R / product = 0.5). The reaction mixture is cooled to 40-50 [deg.] C. and poured into a mixture of water and ice (320 g) in a bag for 5 min, ethyl acetate (640 ml) is added, the mixture is stirred for 10 min and filtered. The precipitate is washed with ethyl acetate (2 x 320 ml) and acetone (2 x 120 ml). The upper (organic) filtrate layer is separated, rinsed with saturated aqueous NaCl solution, dried over anhydrous Na ₂ SO ₄ and filtered. Silica gel (40 g) is added to the filtrate, stirred for 15 min, filtered, and the filter is washed with ethyl acetate-toluene (150 ml + 30 ml). Wash the filtrate twice with 5% HCl (first portion: 26 ml conc. HCl + 156 ml H ₂ O, second portion: 5.2 ml conc. HCl + 31 ml H ₂ O). The aqueous layers containing the product in the form of the hydrochloride salt are combined and rinsed with ethyl acetate (65 mL). The organic phase and ethyl acetate after rinsing contain anisole and by-products. The aqueous layer is neutralized with saturated NaHCO ₃ (65 g dissolved in a minimum amount of water) and extracted with ethyl acetate (3 x 320 mL). The organic extracts are combined, dried over anhydrous Na ₂ SO ₄ and evaporated. The dry residue is suspended in ethyl acetate (60 ml), stirred at room temperature for 20 min, cooled to -20 ° C, filtered, washed with a minimum amount of cold ethyl acetate and dried under reduced pressure.

Iznākums 12.1 g (42%) N-[(2-amino-5-metiltiēn-3-il)(4-metilpiperazīn-l-il)metilēn]-N(2-jodfenil)amīna, tīrība 96.9% (AEŠH). Ή KMR spektrs (CDC1₃,400 MHz), δ: 2.165 (s,Yield: 12.1 g (42%) of N - [(2-amino-5-methylthien-3-yl) (4-methylpiperazin-1-yl) methylene] -N (2-iodophenyl) amine, purity 96.9% (AESH). Ή NMR spectrum (CDC1 _3, 400 MHz) δ: 2165 (s,

3H); 2.327 (s, 3H); 2.491 (t, 4H); 3.556 (t, 4H); 3.932 (d, 2H); 6.023 (s, 1H); 6.444 (dd, 1H, J= 1.4, 8.1 Hz); 6.557 (ddd, 1H, J= 1.4, 7.6 un 7.8 Hz); 7.026 (ddd, 1H, J= 1.4, 7.6 Hz); 7.705 (dd, 1H, /= 1.4, 7.9 Hz) m.d.3H); 2.327 (s, 3H); 2.491 (t, 4H); 3.556 (t, 4H); 3.932 (d, 2H); 6.023 (s, 1H); 6.444 (dd, 1H, J = 1.4, 8.1 Hz); 6.557 (ddd, 1H, J = 1.4, 7.6 and 7.8 Hz); 7.026 (ddd, 1H, J = 1.4, 7.6 Hz); 7.705 (dd, 1H, / = 1.4, 7.9 Hz) ppm.

ESI+MS (m/z, %): 116.2 (3); 341.1 (12); 407.2 (4); 441.2 (100) [M+H]⁺; 442.4 (16).ESI + MS (m / z,%): 116.2 (3); 341.1 (12); 407.2 (4); 441.2 (100) [M + H] ⁺ ; 442.4 (16).

Piemērs 10. N-r(2-amino-5-metiltiēn-3-il)(4-metilpiperazīn-l-il)metilēn]-N-(2bromfenil)amīna (15b) iegūšanaExample 10. Preparation of N-r (2-amino-5-methylthien-3-yl) (4-methylpiperazin-1-yl) methylene] -N- (2-bromophenyl) amine (15b)

Metode analoģiska aprakstītai Piemērā 9. Iznākums 9.96 g (41%) N-[(2-amino-5metiltiēn-3-il)(4-metilpiperazīn-l-il)metilēn]-N-(2-bromfenil)amīna, tīrība 89.3% (AEŠH).Method analogous to that described in Example 9. Yield 9.96 g (41%) of N - [(2-amino-5-methylthien-3-yl) (4-methylpiperazin-1-yl) methylene] -N- (2-bromophenyl) amine, purity 89.3 % (Ash).

^]H KMR spektrs (CDC1₃, 400 MHz), δ; 2.159 (s, 3H), 2.332 (s, 3H), 2.479 (t, 4H), 3.538 (t, 4H), 3.910 (s, 2H), 6.034 (s, 1H), 6.380-6.548 (m, 1H), 6.611-6.763 (m, 1H), 7.387-7.471 (m, 1H) m.d. ¹ H NMR Spectrum (CDCl ₃ , 400 MHz), δ; 2.159 (s, 3H), 2.332 (s, 3H), 2.479 (t, 4H), 3.538 (t, 4H), 3.910 (s, 2H), 6.034 (s, 1H), 6.380-6.548 (m, 1H) , 6.611-6.763 (m, 1H), 7.387-7.471 (m, 1H) md

ESI+ MS (m/z, %): 116.1 (8); 295.1 (23); 296.3 (24); 393.2 (85); 395.2 (100) [M+H]⁺; 396.64 (12).ESI + MS (m / z,%): 116.1 (8); 295.1 (23); 296.3 (24); 393.2 (85); 395.2 (100) [M + H] ⁺ ; 396.64 (12).

Piemērs 11. N-r(2-amino-5-metiltiēn-3-il)(4-metilpiperazīn-l-il)metilēnļ-N-(2hlorfenil)amīna (15c) iegūšanaExample 11. Preparation of N-r (2-Amino-5-methylthien-3-yl) (4-methylpiperazin-1-yl) methylene-N- (2-chlorophenyl) amine (15c)

Metode analoģiska aprakstītai Piemērā 9. Iznākums 13.53 g (51%) N-[(2-amino-5metiltiēn-3-il)(4-metilpiperazīn-l-il)metilēn]-N-(2-hlorfenil)amīna, tīrība 96.2% (AEŠH).Method analogous to that described in Example 9. Yield 13.53 g (51%) of N - [(2-amino-5-methylthien-3-yl) (4-methylpiperazin-1-yl) methylene] -N- (2-chlorophenyl) amine, purity 96.2 % (Ash).

’H KMR spektrs (CDC1₃, 400 MHz), δ: 2.155 (s, 3H), 2.330 (s, 3H), 2.475 (t, 4H), 3.529 (t, 4H), 3.937 (s, 2H), 6.023 (s, 1H), 6.536 (dd, 1H, 1.3, 8.0 Hz), 6.774 (ddd, 1H, J= 1.4, 7.6,1 H NMR Spectrum (CDCl ₃ , 400 MHz), δ: 2.155 (s, 3H), 2.330 (s, 3H), 2.475 (t, 4H), 3.529 (t, 4H), 3.937 (s, 2H), 6.023 (s, 1H), 6.536 (dd, 1H, 1.3, 8.0 Hz), 6.774 (ddd, 1H, J = 1.4, 7.6,

7.6 Hz), 6.965 (ddd, 1H, J= 1.3, 7.6, 7.6 Hz), 7.235 (dd, 1H, J= 1.3, 8.0 Hz) m.d.7.6 Hz), 6.965 (ddd, 1H, J = 1.3, 7.6, 7.6 Hz), 7.235 (dd, 1H, J = 1.3, 8.0 Hz) m.d.

ESI+ MS (m/z, %); 101.1 (3); 116.1 (5); 233.2 (2); 240.3 (9); 249.2 (38); 251.1 (15); 252.4 (2); 333.3 (4); 349.2 (100) [M+H]⁺; 351.2 (36); 352.0 (4).ESI + MS (m / z,%); 101.1 (3); 116.1 (5); 233.2 (2); 240.3 (9); 249.2 (38); 251.1 (15); 252.4 (2); 333.3 (4); 349.2 (100) [M + H] ⁺ ; 351.2 (36); 352.0 (4).

Piemērs 12. N-[(2-amino-5-metiltiēn-3-il)(4-metilpiperazīn-l -il)meti1ēn]-N-(2fluorfeniDamīna (T5dj iegūšanaExample 12. Preparation of N - [(2-Amino-5-methylthien-3-yl) (4-methylpiperazin-1-yl) methylene] -N- (2-fluorophenamidine (T5dj)

Metode analoģiska aprakstītai Piemērā 9. Iznākums 10.12 g (46%) N-[(2-amino-5metiltiēn-3-il)(4-metilpiperazm-l-il)metilēn]-N-(2-fluorfenil)amīha, tīrība 92.7% (AEŠH).Method analogous to that described in Example 9. Yield 10.12 g (46%) of N - [(2-amino-5-methylthien-3-yl) (4-methylpiperazin-1-yl) methylene] -N- (2-fluorophenyl) amine, purity 92.7 % (Ash).

*H KMR spektrs (CDC1₃, 400 MHz), δ: 2.151 (s, 3H), 2.330 (s, 3H), 2.471 (t, 4H), 3.513 (t, 4H), 3.882 (s, 2 H), 6.013 (s, 1H), 6.628-6.950 (m, 3H), 7.481-7.759 (m, 1H) m.d.1 H NMR Spectrum (CDCl ₃ , 400 MHz), δ: 2.151 (s, 3H), 2.330 (s, 3H), 2.471 (t, 4H), 3.513 (t, 4H), 3.882 (s, 2H), 6.013 (s, 1H), 6.628-6.950 (m, 3H), 7.481-7.759 (m, 1H) md

ESI+ MS (m/z, %): 201.2 (3); 233.2 (100); 234.3 (11); 245.2 (6); 273.2 (44); 274.4 (4); 287.2 (2); 333.3 (53) [M+H]⁺.ESI + MS (m / z,%): 201.2 (3); 233.2 (100); 234.3 (11); 245.2 (6); 273.2 (44); 274.4 (4); 287.2 (2); 333.3 (53) [M + H] ⁺ .

Piemērs 13. 2-Metil-4-(4-metilpiperazīn-l-il)-10H-tiēnl~2.3-l>][1.5]benzdiazepīna 64) iegūšanaExample 13. Preparation of 2-Methyl-4- (4-methylpiperazin-1-yl) -10H-thiene-2.3-l]] [1.5] benzothiazepine 64)

N- [(2-amino-5-metiltiēn-3 -il)(4-metilpiperazīn-1 -il)metilēn] -N-(2-j odfenil)amīnu (15a) (440 mg, 1.00 mmol), Pd(OAc)₂ (11 mg, 5 mol%), rac-BINAP (31 mg, 5 mol%) un cēzija karbonātu (977 mg, 3.00 mmol) sausā toluolā (10 ml) maisa 110°C inertā atmosfērā 5 dienas. Reakcijas kontrole: PSH, metanols - dihlormetāns 1:4,7?/produkta = 0.4. Reakcijas beigās maisījumu atdzesē līdz istabas temperatūrai, filtrē, nogulsnes skalo ar acetonu, un filtrātu ietvaicē. Produktu attīra ar šķidruma hromatogrāfiju, lietojot kā eluentu metanola dihlormetānā (1:5) sistēmu. Iznākums 243 mg (78%) 2-metil-4-(4-metilpiperazīn-l-il)-10Htiēn[2,3-ž»][l,5]benzdiazepma. Tīrība 98.5% (AEŠH). Ή KMR spektrs (CDC1₃,400 MHz), δ: 2.299 (s, 3H); 2.368 (s, 3H); 2.552 (t, 4H); 3.577 (t, 4H); 5.227 (s, 1H); 6.281 (s, 1H); 6.627 (dd, 1H, J= 1.1,7.7 Hz); 6.871 (ddd, 1H, J= 1.3, 7.5,7.6 Hz); 6.956 (ddd, 1H, J= 1.1,7.4,N - [(2-Amino-5-methylthien-3-yl) (4-methylpiperazin-1-yl) methylene] -N- (2-iodophenyl) amine (15a) (440 mg, 1.00 mmol), Pd ( OAc) ₂ (11 mg, 5 mol%), rac-BINAP (31 mg, 5 mol%) and cesium carbonate (977 mg, 3.00 mmol) in dry toluene (10 mL) were stirred at 110 ° C for 5 days. Reaction control: PSH, methanol - dichloromethane 1: 4.7 / product = 0.4. At the end of the reaction, the mixture is cooled to room temperature, filtered, the precipitate is washed with acetone and the filtrate is evaporated. The product is purified by liquid chromatography using methanol in dichloromethane (1: 5) as eluent. Yield: 243 mg (78%) of 2-methyl-4- (4-methylpiperazin-1-yl) -10H-thieno [2,3-b] [1,5] benzodiazepine. Purity 98.5% (AESH). Ή NMR spectrum (CDC1 _3, 400 MHz) δ: 2299 (s, 3H); 2.368 (s, 3H); 2.552 (t, 4H); 3.577 (t, 4H); 5.227 (s, 1H); 6.281 (s, 1H); 6.627 (dd, 1H, J = 1.1,7.7 Hz); 6.871 (ddd, 1H, J = 1.3, 7.5.7.6 Hz); 6.956 (ddd, 1H, J = 1.1,7.4,

7.6 Hz); 7.038 ppm (dd, 1H, /= 1.1, 7.8 Hz) m.d. ¹³C KMR spektrs (CDC1₃,400 MHz), δ: 15.314; 45.762; 46.770; 54.836; 119.159; 122.788; 122.990; 124.200; 124.805; 128.233;7.6 Hz); 7.038 ppm (dd, 1H, J = 1.1, 7.8 Hz) md ¹³ C NMR spectrum (CDCl ₃ , 400 MHz), δ: 15.314; 45,762; 46,770; 54,836; 119.159; 122,788; 122,990; 124,200; 124,805; 128,233;

129.442; 142.952; 157.672 m.d.129,442; 142,952; 157,672 m.d.

ESI+ MS (m/z, %): 83.9 (12); 101.0 (3); 256.2 (11); 257.3 (2); 313.2 (100) [M+H]⁺;ESI + MS (m / z,%): 83.9 (12); 101.0 (3); 256.2 (11); 257.3 (2); 313.2 (100) [M + H] ⁺ ;

314.4 (11); 315.3 (4).314.4 (11); 315.3 (4).

Elementanalīze, aprēķināts: C 65.35%; H 6.45%; N 17.93%; S 10.26%. C17H20N4S. Iegūts: C 65.11%; H 6.54%; N 10.15%.Elemental Analysis Calculated: C 65.35%; H, 6.45%; N, 17.93%; S, 10.26%. C17H20N4S. Found: C, 65.11%; H, 6.54%; N, 10.15%.

Piemērs 14, 2-Metil-4-(4-metilpiperazm-l-il)-10H-tiēn[2₁3-Z>irE51benzdiazepīna (4) iegūšanaExample 14 2-Methyl-4- (4-metilpiperazm-l-yl) -10H-thieno [2 ₁ 3-Z> irE51benzdiazepīna (4) obtaining

N-[(2-amino-5-metiltiēn-3-il)(4-metilpiperazīn-l-il)metilēn]-N-(2-jodfenil)amīnu (15a) (2.20 g, 5.00 mmol), Cu(PPh₃)₃I (0.98 g, 1.00 mmol) un cēzija karbonātu (2.44 g, 7.5 mmol) sausajā toluolā (50 ml) maisa 90°C 3 dienas. Reakcijas kontrole: PSH, metanols dihlormetāns 1:4, ///produkta = 0.4. Reakcijas beigās maisījumu atdzesē līdz istabas temperatūrai, filtrē, nogulsnes skalo ar acetonu, un filtrātu ietvaicē. Produktu šķīdina etilacetātā, nogulsnes filtrē. Produktu ekstraģē no etilacetāta filtrātā ar 0.5 M HC1. Ūdens ekstrakts tika neitralizēts ar piesātinātu NaHCO₃ šķīdumu un ekstraģēts ar etilacetātu. Organisko slāni žāvē virs bezūdens Na₂SO4 un ietvaicē. Produktu pārkristalizē no toluola. Iznākums 1.14 g (73%) 2-metil-4-(4-metilpiperazīn-l-il)-10H-tiēn[2,3-5][l,5]benzdiazepīna. Tīrība 97.3 % (AEŠH).N - [(2-Amino-5-methylthien-3-yl) (4-methylpiperazin-1-yl) methylene] -N- (2-iodophenyl) amine (15a) (2.20 g, 5.00 mmol), Cu (PPh) ₃ ) ₃ L (0.98 g, 1.00 mmol) and cesium carbonate (2.44 g, 7.5 mmol) in dry toluene (50 mL) are stirred at 90 ° C for 3 days. Reaction control: PSH, methanol dichloromethane 1: 4, /// product = 0.4. At the end of the reaction, the mixture is cooled to room temperature, filtered, the precipitate is washed with acetone and the filtrate is evaporated. The product is dissolved in ethyl acetate and the precipitate is filtered off. The product is extracted from ethyl acetate into a filtrate with 0.5 M HCl. The aqueous extract was neutralized with saturated NaHCO ₃ solution and extracted with ethyl acetate. The organic layer is dried over anhydrous Na ₂ SO 4 and evaporated. The product is recrystallized from toluene. Yield: 1.14 g (73%) of 2-methyl-4- (4-methylpiperazin-1-yl) -10H-thieno [2,3-5] [1,5] benzodiazepine. Purity 97.3% (AESH).

Claims

1. Preparation of 2-methyl-4- (4-methylpiperazin-1-yl) -10H-thieno [2,3-b] [1,5] benzodiazepine

5 techniques consisting of the following steps:

(a) acylation of 2-haloaniline with cyanoacetic anhydride;

b) reaction of the resulting amide with sulfur and propanal to form a thiophene ring;

c) reaction of the resulting amide with 1-methylpiperazine in the TiCl ₄ -anisole system;

d) Internal solvent cyclization of the resulting amidine in a solvent base and a catalyst

In the presence of 10.

2. A process according to pl, wherein the cyclization is catalyzed by a palladium catalyst with a ligand selected from the group consisting of PPh ₃ , BINAP, Xantphos,

X-Phos and John-Phos.

3. The process according to claim 1, wherein the catalyst is a copper-containing catalyst.

15th

A process according to pl, wherein the catalyst is a copper-containing catalyst selected from the group consisting of Cu (PPh ₃ ) ₃ I and Cu (PPh ₃ ) ₃ Br.

5. A process according to claim 1, wherein the catalyst is a nickel-containing catalyst.

6. A process according to claim 1, wherein the catalyst is Ni (cod) 2.

A process according to claim 1, wherein the catalyst is a base selected from the group consisting of

20 includes n-BuLi, NaH, LiHMDS, l-methylpiperazine sodium and l-methylpiperazine lithium.

A process according to claim 1, wherein the cyclization of the amidine is carried out in a solvent selected from the group consisting of benzene, toluene, xylene and dioxane.

9. The process after p. 1. characterized in that the cyclization of the amidine is carried out in the presence of a base which

25 is selected from the group consisting of Na ₂ CO ₃ , K ₂ CO ₃ , Cs ₂ CO ₃ , K ₃ PO ₄ , NaO 2 -Bu, LiHMDS and DBU.