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A Process For Preparation Of Benzodiazepine Compound

Abstract: A PROCESS FOR PREPARATION OF BENZODIAZEPINE COMPOUND The present invention relates to a process for preparation of benzodiazepine compound of Fonnula I or salts thereof. More particularly, the present invention relates to a process for preparation of Rernimazolam besylate. Br 0-0 HO-~ I # II 0 Formula

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Patent Information

Application #
Filing Date
23 September 2022
Publication Number
14/2025
Publication Type
INA
Invention Field
CHEMICAL
Status
Email
Parent Application

Applicants

Enaltec Labs Private Limited
17th Floor, Kesar Solitaire, Plot No. 5, Sector-19, Sanpada, Navi Mumbai 400705, Maharashtra, India

Inventors

1. PATIL, Dilipkumar Jibhau
Enaltec Labs Private Limited, Plot No. W-59 A, Additional MIDC, Ambernath, Thane 421506, Maharashtra, India
2. ATKURU, Venkat Subbarao
Enaltec Labs Private Limited, Plot No. W-59 A, Additional MIDC, Ambernath, Thane 421506, Maharashtra, India
3. PAWAR, Sanjay Sakharam
Enaltec Labs Private Limited, Plot No. W-59 A, Additional MIDC, Ambernath, Thane 421506, Maharashtra, India
4. ZANJE, Prasad Haridas
Enaltec Labs Private Limited, Plot No. W-59 A, Additional MIDC, Ambernath, Thane 421506, Maharashtra, India

Specification

--Q) Q) c.. E 0 -0 s:::: 0 -c.. ·;:: CJ 1/J Q) -c en CIO (0 -::I' 1.1') 0 ..... N N N 0 ~ CIO .......... (0 (""';' N 0 ~ ~ I en I N N FIELD OF THE INVENTION The present invention relates to a process for preparation of benzodiazepine compound(s). More particularly, the present invention relates to a process for preparation of benzodiazepine compound of Formula I, i.e., Remimazolam besylate. Br ~N ~ N) ... ,,,fCOOMe # --N 0-0 ~ II N HO-S I # \._ h II 0 Formula I BACKGROUND OF THE INVENTION Benzodiazepine compounds are known for their potential to bind to a site on a specific receptor/chloride ion channel complex known as the GABAA receptor. The binding of the benzodiazepine compound accelerates the binding of the inhibitory neurotransmitter 7-aminobutyric acid (GABA) to the complex, thereby leading to inhibition of normal functionality of neurons. Benzodiazepine compounds are therapeutically used for treatment of sedation or hypnosis, induction of anxiolysis, induction of muscle relaxation, treatment of convulsions etc. Short-acting benzodiazepines provide faster recovery profiles. A new short-acting benzodiazepine derivative has been developed to provide a superior sedative profile, i.e., more predictable fast onset, short duration of sedative action, and rapid recovery profile. This profile has been achieved by rendering the compound susceptible to metabolism via esterases. Remimazolam of formula II is a medication for the induction and maintenance of procedural sedation in adults for invasive diagnostic or surgical procedures lasting 30 minutes or less is a short-acting benzodiazepine drug, for use in the induction of anesthesia and conscious sedation for minor invasive procedures. Br Formula II 2 .. ., c; i ..L ~... • --CJ) CJ) c.. E 0 -0 s:::: 0 -c.. ·;:: CJ 1/J CJ) -c en CIO (0 -::1' Lt) .0. .. N N N 0 ~ ..C..I..O.. (0 (""';' N 0 ~ c.. " CJ) i. en I N N Several derivatives or salts of Remimazolam of formula II have been prepared. (S)-methyl-3-(8- bromo-l-methyl-6-(pyridin-2-yl)-4H-benzimidazo[l ,2-a][l ,4]diazepin-4-yl] propanoate benzenesulfonate is commonly known as Remimazolam besylate. Remimazolam besylate has the following chemical structure of formula 1: Br Formula I Related prior arts: Remimazolam of formula II and pharmaceutically acceptable salt thereof is disclosed in W00069836. The synthesis of Remimazolam of formula II is disclosed in example Ic-8 of W0'836 patent. The process described in below scheme I. Scheme I The process disclosed in W0'836 involves swem oxidation, which needs to carry out in the presence of dimethyl sulfoxide (DMSO) and oxalyl chloride and requires extremely low temperature of -78°C, therefore this process is not industrially viahle. •- ...... . I ! ..... 1 ..... --Q) Q) c. E 0 -0 s:::: 0 -c. ·;:: CJ 1/J Q) -c en CIO (0 -::1' Lt) .0. .. N N N 0 ~ ..C..I..O.. (0 (""';' N 0 ~c. .., ,. , .. , ,.,.. Q) 1. i"' I I en I N N W02021256679 discloses a preparation of Remimazolam wherein the compound of Formula J reacted with nitrous acid in the presence of acid and organic solvent to obtain the compound of Formula H which is further reacted with amino-alkanol in the presence of organic solvent to obtained compound of Formula G. The compound of formula G further oxidised in the presence of acid and organic solvent to obtained Remimazolam of formula II. The process disclosed in W0'679 is depicted in below scheme II: Nitrous acid, D H N N- Organic acid, ' N N- """ N) Inorganic acid, """ ) ... ,\_ Br --"" """\_ Organic solvent ~N COOMe Br """' ~N COOMe ""'N ""'N ""'- I I ""'- Formula J Formula H lAm;""'"''""'· Organic solvent Oxidizing agent, HO YN Organic acid, ~__)-- """N)"'"\_ Inorganic acid, """ N) Organic solvent ""'"\_ Br --"" ~N COOMe Br """' ~N COOMe ""'N ""'N ""'- I I ""'- Formula II Formula G Scheme II However, Remimazolam besylate of formula I obtained by using prior art process contains impurities listed in below table 1: Sr. No. 1 2 Br Chemical Structure N ~I Impurity-A; (S)-methyl 3-(7-bromo-2-oxo -5-(pyridin-2-yl)-2,3- dihydro-1H-benzo[e][1,4]diazepin-3-yl) propanoate (starting material) Impurity-B; (S)-3-(8-bromo-l-methyl-6-(pyridin-2-yl)-4Hbenzo[ fJimidazo[1 ,2-a] [1 ,4]diazepin-4-yl)propanoic acid. (Acid impurity)) .---. (J 'i) ·:·· .. ,_. .. ,, .-.. ~. 14 .-::, -~::. ' ;j, "•i ~ j __ ~:.... ..,::___ '· .' CAS No 308242-23-1 960305-91-3 --Q) Q) c. E 0 -0 s:::: 0 -c. ·;:: CJ 1/J Q) -c en CIO (0 -::1' Lt) .0. .. N N N 0 ~ ..C..I..O.. (0 (""';' N 0 ~ ·r c. J_ Q) en I N N r:~. ,._.,, ,..... ~ i ~- ' .' Sr. No. 3 4 Chemical Structure Impurity-C; (S)-ethyl 3-(8-bromo-1-methyl-6-(pyridin-2-yl)-4Hbenzo[ f]imidazo[1 ,2-a ][1 ,4]diazepin-4-yl)propanoate. (Ethyl ester impurity) 0 Impurity-D; (R)-methyl 3-(8-bromo-1-methyl-6 -(pyridin-2-yl)-4Hbenzo[ f]imidazo[ 1 ,2-a] [ 1 ,4]diazepin-4-yl)propanoate benzenesulfonate. (Chiral Isomer) Table I CAS No 1860899-55-3 1449295-46-8 There are several method disclosed in prior art for purification of Remimazolam besylate of formula I to remove process impurities and other genotoxic impurities. IN202017038957 discloses a crystalline form of the hydrochloride of a benzodiazepine derivative of Formula D or its ethanolate, Br 0 I Formula D wherein R is methyl or ethyl. The crystalline form of the hydrochloride of a benzodiazepine derivative of Formula D can be further converted into the compound of formula I which remove genotoxic impurities. However smce the method described in IN'957 involve the synthesis of hydrochloride of a benzodiazepine derivative and its further conversion into pharmaceutically acceptable salt of compound of formula I, which adds extra step in the process becoming the process tedious and lengthy. 15/ : --Q) Q) c.. E 0 -0 s:::: 0 -c.. ·;:: CJ 1/J Q) -c en CIO (0 -::1' Lt) 0 ..... N N N 0 ~ CIO .......... (0 (""';' N 0 ~ T c. 1 Q) en I N N IN7241/CHENP/2008 discloses a process for preparation of crystalline Remimazolam besylate of formula I, which comprises of reaction of free base of a compound of formula I with benzene sulphonic acid in solvent selected from toluene, ethanol, ethyl acetate, MTBE, dichloromethane, isopropyl acetate, ethyl formate, methanol or acetone. IN'241 also discloses the purity of Remimazolam besylate of formula I obtained by using different solvent summarised in below table II: Sr. Lab book salt solvent XRPD Yield% Purity/% Purity post No. reference area 400C/75% RH for 4 weeks 1 LJC-039-067 -2 besylate acetone Form 1 38 98.4 98.1 2 LJC-039-067 -4 besylate iPrOAc Form 1 79 97.7 95.9 3 LJC-039-067 -6 besylate Ethyl Form 1 40 98.6 98.3 formate 4 LJC-039-067 -8 besylate MeOH Single crystal. Not 98.1 Not recorded Form2 recorded Table II Therefore Remimazolam besylate produced from prior art process is having purity less than 99% and contains individual impurity more than 0.15%. In recent years, more and more serious medical accidents are occurred due to traces of impurities found in the marketed drugs as these impurities pose a strong threat to the drug safety. Therefore, regulatory agencies have more specific requirements for impurities. As per ICH guideline limit of individual impurity of Rernimazolam besylate is less than 0.15%. Therefore more and more pharmaceutical companies are focusing on the control and removal of impurities in the development of drug. Therefore there is a need of efficient process for the preparation of Rernimazolam besylate of formula I which avoid the formation of impurities and effectively remove the impurities providing the product with high yield, purity and with known individual impurity less than 0.15% which meets the regulatory requirement. Inventors of the present invention developed novel process for synthesis of Remimazolam besylate by using novel intermediate to obtain crude Remimazolam besylate which is further purified to obtain pure Remimazolam besylate with individual impurity less than 0.15%. ,:''.'•- -·'-,_ ..... ,, 1-~-~ L -- --Q) Q) c. E 0 -0 s:::: 0 -c. ·;:: CJ 1/J Q) -c en CIO (0 -::1' Lt) .0. .. N N N 0 ~ ..C..I..O.. (0 (""';' N 0 ~c .TF~t) Q) en I N N OBJECT OF THE INVENTION An object of the invention is to provide a simple, economic, safe and industrially viable and one pot process for preparation of Remimazolam besylate of structural formula I having HPLC purity > 99.70% and Chiral HPLC Purity> 99.90% without chromatographic purification. Another object of the present invention is to provide a process for preparation of Remimazolam besylate of formula I by using novel intermediate. Yet another object of the present invention is to provide a process for preparation of pure Remimazolam besylate of formula I having individual impurity less than 0.15%. SUMMARY OF THE INVENTION: An aspect of the present invention is provide an improved process for preparation of Remimazolam besylate of formula I comprising the steps of; a) reacting Br "\N;-N-{ ~ J""'""fCOOMe # --N 0-0 ~ II I IN HO-S _o? \._ II II 0 Formula I (S)-methyl-3-(7 -bromo-2-oxo-5-(pyridin-2-yl)-2,3-dihydro-1 H -benzo[ e] [ 1 ,4] diazepin-3-yl) propanoate of Formula V Formula V with 2-bromopyridine in the presence of at least one carbonyl activating agent to obtain a compound of Formula N; :.: .... _, ... , ./ L •'"> j"7'j· -·:·~~ ..;,....._ ·~_.! ...:.::.... ~N ~~ Formula IV 17 --Q) Q) c. E 0 -0 s:::: 0 -c. ·;:: CJ 1/J Q) -c en CIO (0 -::1' Lt) .0. .. N N N 0 ~ ..C..I..O.. (0 (""';' N 0 6_ I Q) en I N N wherein R is selected from -CH3, p-toluene and phenyl b) reacting compound of Formula IV with amino ketal compound to obtain (S)-methyl-3-(7- bromo-2-( (2,2-dimethoxypropyl)amino )-5-(pyridin-2-yl)-3H-benzo[ e] [1 ,4 ]diazepin-3-yl) propanoate of Formula III; Formula III c) deprotecting and cyclizing the obtained (S)-methyl-3-(7 -bromo-2-( (2,2- dimethoxypropyl)amino )-5-(pyridin-2-yl)-3H-benzo[ e ][1 ,4] diazepin-3-yl)propanoate of Formula III to obtain Remimazolam base of Formula II; Formula II d) converting Remimazolam base ofFom1ula II into crude Remimazolam besylate of Formula I; e) purifying the crude Remimazolam besylate of Formula I to obtained pure Remimazolam besylate of Formula I. The process for preparation of pure Remimazolam besylate of Formula I is represented in below scheme HI. .~~. >-, . .::~ .L --Q) Q) c. E 0 -0 s:::: 0 -c. ·;:: CJ 1/J Q) -c en CIO (0 -::1' Lt) .0. .. N N N 0 -N ..C..I..O.. (0 -""' M N 0 N T i--~. cI . i'"'' t''.i Q) en I N N Br carbonyl activating H 0 . ""' N--{) . ,,r COOM agent, e 2-Bromopyridine --7 ~N MDC ------- Formula V Br Formula IV R= -CI-13, p-toluene and phenyl] Ethyl acetate Mexo- ( D~ NI-12 Formula VI TEA, NI-14Cl, Toluene Benzene sui phonic acid Br Br Formula I (Crude Remimazolam Besylate) MDC, Sodium Bicarbonate, (Purification) I P A,Ethyl acetate, Water, Benzene sulphonic acid Scheme III Br Formula Ill Methanol, Methanolic HCI, Na2C03,MDC, Ethyl acetate Formula II (Remimazolam Base) Another aspect of present invention is to provide novel intermediate of Remimazolam besylate of formula IV: Formula IV -~~. .·---~ C.i <~i .,.~L fi'"i. ... ,, ·• ····;;< - ·1. :;:;.. ·' .. .. ... ... , ~ / " J:. ..<'"~ ~ ~ ~ •._! ~ '-·' --Q) Q) c. E 0 -0 s:::: 0 -c. ·;:: CJ 1/J Q) -c en CIO (0 -::1' Lt) .0. .. N N N 0 ~ ..C..I..O.. (0 (""';' N 0 ~ ,.. ... ,. .... c. l.. t· .. · i:_,l Q) en I N N wherein R is selected from -CH3, p-toluene and phenyl. Yet another aspect of the present invention is to provide pure Rernimazolam besylate of formula I having known individual impurity less than 0.15%. Br ~N ~ N--) .. ,,,fCOOMe # --N 0-0 ~ II I IN HO-S # \._ II II 0 Formula I which is prepared by the process comprising the steps of: 1. Reacting the solution of Rernimazolam besylate with base to obtain Remimazolam; n. converting Remimazolam into pure Rernimazolam besylate in presence of alcoholic solvent. DETAILED DESCRIPTION OF THE INVENTION The present disclosure is not to be limited in scope by the specific embodiments described herein, which are intended for the purposes of exemplification only. Functionally equivalent products and processes are clearly within the scope of the disclosure, as described herein. Accordingly the present invention is provide an improved one pot process for preparation of Rernimazolam besylate of structural formula I with individual impurity less than 0.15%, comprising the steps of; a) reacting Br ~N ~ N) . ,,fCOOMe # ...--oN ~ t H0-~-0 \._ ~ Formula I (S)-methyl-3 -(7 -bromo-2-oxo-5-(pyridin-2-yl)-2,3-dihydro-1 H -benzo[ e] [ 1 ,4] diazepin-3-yl) propanoate of Formula V Formula V •·•·•• •'''L L ..:::: .•···, ,:'"L ·""•, , .. ~. L l.~.i L .~·r --Q) Q) c. E 0 -0 s:::: 0 -c. ·;:: CJ 1/J Q) -c en CIO (0 -::1' Lt) 0 ..... N N N 0 ~ CIO .......... (0 (""';' N 0 N T I 1- Q. ~ Q) en I N N with 2-bromopyridine in the presence of at least one carbonyl activating agent to obtain a compound ofFormula IV; Formula IV wherein R is selected from -CH3, p-toluene and phenyl b) reacting compound of Formula IV with amino ketal compound to obtain (S)-methyl-3-(7- bromo-2-( (2,2-dimethoxypropyl)amino )-5-(pyridin-2-yl)-3H -benzo[ e] [ 1 ,4 ]diazepin-3 -yl) propanoate ofFonnula III; Formula III c) deprotecting and cyclizing the obtained (S)-methyl-3-(7 -bromo-2-( (2,2- dimethoxypropyl)amino )-5-(pyridin-2-yl)-3H-benzo[ e ][1 ,4] diazepin-3-yl)propanoate of Formula TU to obtain Remimazolam base ofFonnula U; Br Formula II d) Converting Remimazolam base ofFormula II into crude Remimazolam besylate of Formula I; e) purifying the crude Remimazolam besylate of Formula I to obtained pure Remimazolam besylate of Formula I. The present invention relates to the process for preparation of Remimazolam besylate of Formula I wherein preparation of can be carried out without isolating the intermediate of step (V), (IV) and (III). Starting material of process; benzo[ e ][1 ,4]diazepin-3-yl)propanoate disclosed in the prior art. -~·-\.., .,·.,, i' ,' L.._ .. :.... (S)-methyl-3-(7 -bromo-2-oxo-5-(pyridin-2-yl)-2,3-dihydro-1 Hof Formula V may be prepared by following the methods --Q) Q) c. E 0 -0 s:::: 0 -c. ·;:: CJ 1/J Q) -c en CIO (0 -::1' Lt) .0. .. N N N 0 ~ ..C..I..O.. (0 (""';' N 0 N, ·y c. l.. Q) en I N N In step (a), (S)-methyl-3-(7-bromo-2-oxo-5-(pyridin-2-yl)-2,3-dihydro-1H-benzo[e] [1,4] diazepin-3- yl) propanoate of Formula V is reacted with 2-bromopyridine at a temperature in a range of -30°( to - 1 ooc in an solvent in the presence of at least one carbonyl activating agent to obtain a reaction mass of Formula IV. The carbonyl activating agent used in the step (a) is selected from benzene sulfonic acid, toluene sulfonic acid and methane sulfonic acid. In step (b), to the obtained reaction mass ofF ormula IV the solution of amino ketal compound added m presence of solvent, acid and base to obtain (S)-methyl-3-(7-bromo-2-((2,2- dimethoxypropyl)amino )-5-(pyridin-2-yl)-3H-benzo[ e] [1 ,4]diazepin-3-yl) propanoate of Formula III. The amino ketal compound used in step (b) is selected from 2,2-dimethoxypropan-1-amine, (2,5,5- trimethyl-1 ,3-dioxan-2-yl)methanamine and 1-amino-2,2-dimethoxypropane. The solution of amino ketal compound prepared by dissolving amino ketal compound in organic solvent at room temp. The organic solvent used for dissolution of amino ketal compound is selected form methylene chloride, methanol, isopropyl alcohol, ethyl acetate, toluene hexane and acetone. The acid used in step (b) is hydrochloric acid. In step (c), (S)-methyl-3 -(7 -bromo-2-( (2,2-dimethoxypropyl )amino )-5-(pyridin-2-yl)-3Hbenzo[ e][1,4] diazepin-3-yl)propanoate of Formula TU deprotected followed by cyclized by adding acidic alcoholic solution and a base in presence of solvent to obtain Remimazolam base of Formula H. The acidic alcoholic solution used in step (c) is methanolic-HCl solution. The base used in step (b) and (c) is selected from triethylamine, trimethylamine, sodium carbonate and sodium bicarbonate. In step (d), Remimazolam base of Formula II converted into crude Remimazolam besylate of Formula I by adding a benzene sulphonic acid solution to the Rernimazolam base of Formula ll. The benzene sulphonic acid solution prepared by dissolving benzene sulphonic acid in solvent. The solvent used in the step (a), (b), (c) and (d) is. selected form methylene chloride, methanol, isopropyl alcohol, ethyl acetate, toluene, hexane, acetone and water. :>-..~- ;, l- h>lt- t~·~< .,-,._, , ... I"'i J. ~ p-;· t"\ t---lo I ' ' ._, " !_ ...... ' < -'- :.;,, _,.,, L. ..::::_ '- '· '· .. f.~J :j ... ~ -·t ;:~:; 1 c~ --Q) Q) c.. E 0 -0 s:::: 0 -c.. ·;:: CJ 1/J Q) -c en CIO (0 -::1' Lt) 0 ..... N N N 0 ~ CIO .......... (0 (""';' N 0 ~ ..L c.. Q) en I N N In step (e), wherein crude Remimazolam besylate of Formula I obtained in step (d) is converted into highly pure Remimazolam besylate of Formula I. In another aspect of present invention is to provide novel intermediate of Remimazolam besylate of formula IV: Formula IV wherein R is selected from -CH3, p-toluene, phenyl. It is observed that addition of carbonyl activating agent such as benzene sulfonic acid, toluene sulfonic acid and methane sulfonic acid to the compound of formula III converts carbonyl group of compound of formula III to better leaving group, providing novel intermediate of formula IV which is highly reactive and converted to compound V immediately by addition of amino ketal compound avoiding unreacted starting material in the product. Remimazolam besylate obtained by process of present invention, by using novel intermediate, can be further purified and converted into more pure form ofRemimazolam besylate. Yet another aspect, preparation of highly pure Remimazolam besylate of Formula I comprises step of: 1. Reacting the Remimazolam besylate of Formula I with base in an organic solvent to obtain Remimazolam base of Formula II; 11. isolating Remimazolam base of Formula II; 111. and converting Remimazolam base of Formula II into pure Remimazolam besylate of Formula I in presence of alcoholic solvent. The organic solvent used in step (i) is selected form ethyl acetate, Benzyl benzoate, acetone, toluene and hexane. The base used in step (i) is inorganic base selected from sodium bicarbonate, sodium carbonate, sodium hydroxide and potassium hydroxide. The step (ii), wherein Remimazolam base IS isolated by distillation of solvent, filtration and centrifugation method. In step (iii), Remimazolam base of Formula II converted into pure Remimazolam besylate of Formula I by addition of a benzene sulphonic acid solution to the Remimazolam base ofF onnu Ia II. .,~,. :,.~, .•' ... .<:...-- ..d.~ --Q) Q) c.. E 0 -0 s:::: 0 -c.. ·;:: CJ 1/J Q) -c en CIO (0 -::1' Lt) .0. .. N N N 0 ~ ..C..I..O.. (0 (""';' N 0 ~ l c.. Q) en I N N The alcoholic solvent used in step (iii) 1s selected from methanol, n-propanol, iso-propanol and butanol, preferably iso-propanol. The present invention provides a process for preparation of Remimazolam besylate, wherein Remimazolam besylate of formula I is having HPLC purity> 99.70% and Chiral HPLC Purity> 99.90% and the high purity is achieved without column chromatography purification. In an embodiment, Remimazolam besylate obtained by using process of present invention having individual impurity less than 0.15%. In preferred embodiment, Remimazolam besylate obtained by using process of present invention having individual impurity less than 0.1 %. In more preferred embodiment, Remimazolam besylate obtained by using process of present invention having individual impurity less than 0.05%. The Remimazolam besylate obtained by the process of the present invention have advantageous properties selected from at least one of: chemical or polymorphic purity, flowability, solubility, dissolution rate, bioavailability, morphology or crystal habit, stability - such as chemical stability as well as thermal and mechanical stability with respect to polymorphic conversion, stability towards dehydration and/or storage stability, a lower degree of hygroscopicity, low content of residual solvents, adhesive tendencies and advantageous processing and handling characteristics such as compressibility, and bulk density. EXAMPLES The following examples are set forth to illustrate the process of the present invention. These examples are not intended to be inclusive of all aspects of the subject matter disclosed herein, but rather to illustrate representative methods and results. These examples are not intended to exclude equivalents and variations of the present invention, which are apparent to one skilled in the art. Example-1: Synthesis of (S)-methyl-3-(8-bromo-1-methyl-6-(pyridin-2-yl)-4H -benzo-[ fl imidazo [1,2-a][1, 4]diazepin-4-yl)propanoate benzenesulfonate (Remimazolam besylate): In RBF, (S)-methyl-3-(7 -bromo-2-oxo-5-(pyridin-2-yl)-2,3-dihydro-1 H-benzo[ e ][1 ,4]diazepin-3- yl)propanoate of Formula V (200 gm) was charged in of methylene dichloride (2000 ml) to obtain a clear solution. To the clear solution, 2-bromopyridine (236 g) and benzene sulfonic acid (211 gm) added to obtained reaction mass containing compound of formula IV. To the reaction mass of formula IV, solution of 2,2-dimethoxypropan-1-amine (119 g) in methylene dichloride ( 100 ml) added in presence of trimethylamine, ammonium chloride solution (160.09 g of ammonium chloride in 800 ml ··-. -:·\ ·····~ .. --~._ -~~. _,..,, -1· ;;::-;. ,.:::: L ... .:: t:~J ..:.~ .~:r- l._ () --Q) Q) c. E 0 -0 s:::: 0 -c. ·;:: CJ 1/J Q) -c en CIO (0 -::1' Lt) 0 ..... N N N 0 ~ CIO .......... (0 (""''"; N 0 ~ Q.; Q) -" en I N N of purified water) and toluene (400 ml) to obtain (S)-methyl-3-(7-bromo-2-((2,2- dimethoxypropyl)amino )-5-(pyridin-2-yl)-3H-benzo[ e][1 ,4]diazepin-3-yl) propanoate of Formula III. To the obtained (S)-methyl-3-(7 -bromo-2-((2,2-dimethoxypropyl)amino )-5-(pyridin-2-yl)-3Hbenzo[ e][1,4]diazepin-3-yl) propanoate of Formula III, methanol (200 ml), methanolic HCl (400 ml) solution, sodium bicarbonate solution (50g sodium bicarbonate in 2000ml of purified water) and methylene dichloride (500 ml) were added to obtain reaction mass containing Remimazolam base of Formula II. To the reaction mass containing Remimazolam base of Formula II, benzene sulphonic acid solution (79 g of benzene sulphonic acid in 200rnl ethanol) was added to obtain crude Remimazolam besylate of Formula I which is further purified to get pure Remimazolam Besylate of Formula I. The 1H-NMR spectrum; 1H-NMR (CDC13, 400 MHz)

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1 202221054689-TRANSLATIOIN OF PRIOIRTY DOCUMENTS ETC. [23-09-2022(online)].pdf 2022-09-23
2 202221054689-STATEMENT OF UNDERTAKING (FORM 3) [23-09-2022(online)].pdf 2022-09-23
3 202221054689-PROVISIONAL SPECIFICATION [23-09-2022(online)].pdf 2022-09-23
4 202221054689-PROOF OF RIGHT [23-09-2022(online)].pdf 2022-09-23
5 202221054689-FORM 1 [23-09-2022(online)].pdf 2022-09-23
6 202221054689-DECLARATION OF INVENTORSHIP (FORM 5) [23-09-2022(online)].pdf 2022-09-23
7 202221054689-FORM-26 [28-09-2022(online)].pdf 2022-09-28
8 202221054689-Form 5-220923.pdf 2023-10-10
9 202221054689-Form 3-220923.pdf 2023-10-10
10 202221054689-Form 2(Title Page)-220923.pdf 2023-10-10
11 202221054689-Description(Complete)-220923.pdf 2023-10-10
12 202221054689-Correspondence-220923.pdf 2023-10-10
13 202221054689-Claims-220923.pdf 2023-10-10
14 202221054689-Abstract-220923.pdf 2023-10-10
15 202221054689-ORIGINAL UR 6(1A) FORM 26)-301123.pdf 2023-12-08