NOVEL INTERMEDIATES AND PROCESS FOR THE PREPARATION OF LAPATINIB AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS

FIELD OF THE INVENTION

The present invention relates to a process for the synthesis of Lapatinib comprising novel intermediates and its pharmaceutically acceptable salts thereof.

BACKGROUND OF THE INVENTION

Lapatinib of Formula-(II), was first disclosed by SmithKline Beecham in US Patent No. 6,727,256.

The process for the preparation of Lapatinib of Formula-(II), disclosed in W099/35146, is given in the Scheme-I. Accordingly, 4-chloro-6-iodo-quinazoline of Formula-(IV), is reacted with 3-chloro-4-(3'-fluoro-benzyloxy)-aniline yielding N-[3- chloro-4-{(3'-fluorobenzyloxy) phenyl} ]-6-iodo-quinazoline of Formula-( l). The compound of the Formula-(l) reacts with 5-(l,3-dioxolan-2-yl)-2-(tributylstannyl)furan to get the compound of Formula-(2) which on deprotection with HC1, removes the 1,3- dioxolan-2-yl protecting group and liberates 5-(4-{3-chloro-4-(3-fluoro- benzyloxy)anilino}-6- quinazolinyl)-furan-2-carbaldehyde of Formula-(3). The compound of the Formula-(3) on reaction with 2-methanesulfonylethylamine, followed by reductive amination using sodium (triacetoxy)borohydride as the reducing agent gives the required compound Lapatinib of Formula-(II) as an organic residue, which is purified by column chromatography and subsequently converted into its hydrochloride salt (5).

Subsequently, US 7, 157,466 also discloses the preparation of Lapatinib and its ditosylate salt, which is given in Scheme-II.

Lapatinib ditosylate has been prepared by reacting the tosylate salt of 5-(4-[3- chloro-4-(3-fluorobenzyloxy)-anilino]-6-quinazolinyl)-furan- 2-carbaldehyde of Formula (3) with 2-(methylsulfonyl)ethylamine in the presence of base (diisopropyl- ethylamine) followed by reduction with sodium triacetoxyborohydride to obtain Lapatinib base which is converted to Lapatinib ditosylate anhydrate by adding para- toulenesulfonic acid. Conversion to Lapatinib ditosylate monohydrate is carried out using THF/H ₂ 0. Intercon vers ion to the anhydrate of the ditosylate salt and back to monohydrate is carried out with methanol and water respectively.

(lla)

WO201 1039759, filed by Natco Pharma also describes a process for the preparation of Lapatinib from 2-amino benzonitrile, as given in scheme-Ill. Firstly, 2- aminobenzonitrile (6) is reacted with iodine monochloride in acetic acid medium to form compound of Formula (7) which is recrystallized from mixture of hexane and toluene. The compound of Formula (1) is reacted with N,N-dimethylformamide dimethy|acetal in an organic solvent such as toluene or xylene to form novel compound of Formula (8). The compound of Formula (7) is then coupled with compound of Formula (8) in presence of acid catalyst such as trifluoroacetic acid, formic acid or acetic acid to form compound of Formula (3). The compound of Formula (3) is the subjected to Suzuki coupling with 5-formyl-2-furyl boronic acid in ethereal solvent in the presence of catalyst selected from palladium (II) acetate, palladium (II) chloride, and palladium on carbon to form aldehyde compound of Formula (4). The compound of Formula (4) is reacted with 2-methanesulphonyl ethylamine or its salt to produce imine compound of Formula (VI) which is reduced with sodium borohydride to form Lapatinib base (II). The crude Lapatinib base is purified by crystallization from organic solvents. The purified Lapatinib base is converted into Lapatinib ditosylate anhydrous by treating Lapatinib base in organic solvent with /7-toluenesulfonic acid monohydrate which is then recrystallized from aqueous alcohol to produce pharmaceutically acceptable Lapatinib ditosylate monohydrate. The process is depicted in Scheme-Ill.

-IH

Lapatinib (II) WO2010017387, filed by Teva relates to Lapatinib intermediates and process for the preparation of Lapatinib base and Lapatinib ditosylate. The application relates to highly pure intermediate of Formula (2), 3-chloro-4-(3-fluorobenzyloxy)aniline which is prepared by reducing a compound of Formula (1), 3-chloro-4-(3- fluorobenzyloxy)nitrobenzene, with iron and ammonium chloride system in the presence of a C1 -C4 alcohol and water at refluxing temperature. The application also relates to highly pure intermediate of Formula (3), N-[3-chloro-4-(3-fluorobenzyloxy)- phenyl]-6-iodoquinazolin-4-amine, which is prepared in one-pot process from compound of Formula (1 ) by reduction using iron and ammonium chloride system in presence of C1 -C4 alcohol and water. The compound of Formula (3) is reacted with 5- formyl-2-furanboronic acid in the presence of a palladium catalyst and a base in a polar organic solvent to obtain Lapatinib aldehyde base, compound of Formula (4). Optionally, Lapatinib aldehyde base is combined with /? oluenesulfonic acid to obtain Lapatinib aldehyde monotosylate, compound of Formula (5). The invention further provides a process for the preparation of Lapatinib base. Lapatinib aldehyde base or its salt is combined with methylsulfonylethylamine or its hydrochloride salt, acetic acid, an inorganic base in an organic solvent and a reducing agent (sodium triacetoxyborohydride) to form Lapatinib base. Lapatinib base is further purified by using organic solvents. Lapatinib base obtained is further converted to Lapatinib ditosylate. The process is depicted in scheme-IV.

Scheme-IV

Purification Organic solvent

Pure Lapatinib base

Palladium catalyst: palladium (II) acetate, palladium (II) chloride and palladium tetrakistriphenylphosphine

Organic base: trialkylamine

Reducing agent: alkali borohydride or alkali cyanoborohydride

Inorganic base: alkali carbonates, alkali bicarbonates, alkali phosphates and alkali acetate

Reducing agent: sodium rriacetoxyborohydride

Organic solvent: C ₅ -C ₇ ketones preferably acetone, acetonitrile, ethyl acetate, methyl acetate, isobutyl acetate, and dichloromethane From the foregoing, it would be apparent that the reported methods for the preparation of Lapatinib ditosylate suffer from one or more of the following disadvantages or limitations viz.

a)multiple steps involved in the process.

b)lack of Industrial applicability

In their endeavor to provide an improved process for the manufacture of Lapatinib or its salt, the present inventors found that most, if not all of the limitations of the prior art could be addressed through utilization of

a) novel intermediates for the synthesis of the object compounds;

b) a robust process having industrial applicability

SUMMARY OF THE INVENTION

First aspect of the present Invention provides intermediate compound of Formula (I), wherein R is selected from CHO or CH=NR' S0 ₂ R ² , where R ¹ is CH ₂ CH ₂ , R ² is CH ₃ .

Second aspect of the present Invention provides intermediate compound of Formula (la)

Third aspect of the invention provides a process for preparing a compound of Formula (la) comprising reacting 2-chloro-4-(6-iodoquinazolin-4-ylamino)-phenol (III)

(HI)

with Formylfuran-2-yl boronic acid in basic medium in the presence of palladium catalyst at ambient temperature in a mixture of organic solvent.

Fourth aspect of the Invention provides intermediate compound of Formula (lb)

(lb)

Fifth aspect of the invention provides a process for preparing a compound of Formula (lb) comprising treating compound of Formula (la) with >-toluenesulfonic acid.

Sixth aspect of the invention provides intermediate compound of Formula (Ic)

(Ic)

Seventh aspect of the invention provides a process for preparing a compound of Formula (Ic) comprising reacting compound of Formula (la)

or (lb)

(lb)

with 2-(Methylsulfonyi)ethanamine or its salts in presence of base and an organic solvent.

Eight aspect of the present Invention provides a process for the preparation of Lapatinib of Formula (II)

or its ditosylate salt

(Ha)

which comprises:-

(i) reacting 2-chloro-4-(6-iodoquinazolin-4-ylamino)phenol (HI)

(III)

with Formylfuran-2-yl boronic acid in basic medium in the presence of palladium catalyst at ambient temperature in a mixture of organic solvent to obtain 5-(4-(3-chloro-4-hydroxyphenylamino)quinazolin-6-yl)furan-2- carbaldehyde of Formula (la)

(lb)

reacting compound of Formula (la) or Formula (lb) with 2- (Methylsulfonyl)ethanamine or its salts in presence of base and an organic solvent to obtain 2-chloro-4-(6-(5-((2-

(methylsulfonyl)ethylimino)methyl)furan-2-yl) quinazolin-4- ylamino)phenol of Formula (Ic)

(Ic)

reacting 2-chloro-4-(6-(5-((2-(methylsulfonyl)ethylimino)methyl)furan -2- yl) quinazolin-4-ylamino)phenol of Formula (Ic) with 3- Fluorobenzylbromide in presence of a base in an organic solvent at ambient temperature to obtain a compound of Formula (VI)

(VI)

(iv) carrying out reduction of compound of Formula (VI) in presence of a sodium triacetoxy borohydride in an organic solvent at ambient temperature to obtain a compound of Formula (II)

(v) optionally converting Lapatinib of Formula (II) to its ditosylate salt (Ila).

ED DESCRIPTION OF THE INVENTION

reaction Scheme of the present invention is depicted in the following

Scheme-V.

Scheme-V

(VI) (!la)

The reaction of 2-chloro-4-(6-iodoquinazolin-4-ylamino)phenol of Formula (III) with Formylfuran-2-yl boronic acid may be carried out in the presence of suitable base. Suitable base may be selected from the group comprising of metal carbonate such as lithium carbonate, sodium carbonate, potassium carbonate, barium carbonate, calcium carbonate and magnesium carbonate; metal bicarbonate such as sodium bicarbonate, potassium bicarbonate, barium bicarbonate, calcium bicarbonate and magnesium bicarbonate and metal hydroxide such as sodium hydroxide, potassium hydroxide, barium hydroxide, calcium hydroxide and magnesium hydroxide. The base may also be selected from the group comprising of C1-C4 alkyl ammonia; mono, di or tri C I- C4 alkyl amine such as triethyl amine, diisipropropyl ethyl amine; mono, di or tri hydroxy C1-C4 alkyl amine; morpholine; thiomorpholine; piperidine; N,N-dimethylaniline; pyridine; hydrazines and pyrrolidine.

The ambient temperature employed is in the range of 20-60°C and more preferably from about 45 to 50°C.

Organic solvent may be selected from the group comprising of water; alcohols, such as methanol, ethanol and isopropanol; nitriles, such as acetonitrile; chlorinated hydrocarbons, such as methylene chloride, ethylenedichloride; dipolar aprotic solvents, such as dimethylsulfoxide, dimethyacetamide and dimethylformamide; esters, such as ethyl acetate and isopropyl acetate; cyclic ethers, such as dioxane and tetrahydrofuran; ketone such as acetone, diisobutyl ketone, cyclohexanone, methylcyclohexanone, methyl ethyl ketone, methyl isobutyl ketone, acetylacetone or mixtures thereof.

5-(4-(3-chloro-4-hydroxyphenylamino)quinazolin-6-yl)furan-2- carbaldehyde of Formula (la) may be converted to its. salt (lb) by treating it with an acid. Examples of acid include inorganic acids resulting in forming salts such as but not limited to hydrohalides (e.g.hydrochloride and hydrobromide), sulfate, nitrate, phosphate, diphosphate, carbonate, bicarbonate, and the like; and organic monocarboxyhc or dicarboxylic acids resulting in forming salts such as, for example, acetate, propanoate, hydroxyacetate, 2-hydroxypropanoate, 2-oxopropanoate, lactate, pyruvate, oxalate, malonate, succinate, maleate, fumarate, malate, tartrate, citrate, methanesulfonate, ethariesulfonate, benzoate, 2-hydroxybenzoate, 4-amino-2-hydroxybenzoate, benzenesulfonate, p-toluenesulfonate, salicylate, p-aminosalicylate, pamoate, bitartrate, camphorsulfonate, edetate, l,2ethanedisulfonate, fumarate, glucoheptonate, gluconate, glutamate, hexylresorcinate, hydroxynaphtoate, hydroxyethanesulforlate, mandelate, mefhylsulfate, pantothenate, stearate, as well as salts derived from ethanedioic, propanedioic, butanedioic, (Z)-2-butenedioic, (E)2-butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxybutanedioic, 2-hydroxy-l,2,3-propanetricarboxylic and cyclohexanesulfamic acids and the like. Preferably, a p-toluenesulfonate salt of 5-(4-(3- chloro-4-hydroxyphenylamino)quinazolin-6-yl)furan-2-carbalde hyde of Formula (la) may be prepared by using /?-toluenesulfonic acid.

The base used for the reaction of 5-(4-(3-chloro-4- hydroxyphenylamino)quinazolin-6-yl)furan-2-carbaldehyde of Formula (la) or Formula (lb) with 2-(Methylsulfonyl)ethanamine or its salts may be selected from the group comprising of metal carbonate such as lithium carbonate, sodium carbonate, potassium carbonate, barium carbonate, calcium carbonate and magnesium carbonate; metal bicarbonate such as sodium bicarbonate, potassium bicarbonate, barium bicarbonate, calcium bicarbonate and magnesium bicarbonate and metal hydroxide such as sodium hydroxide, potassium hydroxide, barium hydroxide, calcium hydroxide and magnesium hydroxide. The base may also be selected from the group comprising of C1-C4 alkyl ammonia; mono, di or tri CI- C4 alkyl amine such as triethyl amine, diisipropropyl ethyl amine; mono, di or tri hydroxy C1-C4 alkyl amine; morpholine; thiomorpholine; piperidine; N,N-dimethylaniline; pyridine; hydrazines and pyrrolidine. Organic solvent may be selected from the group comprising of water; alcohols, such as methanol, ethanol and isopropanol; nitriles, such as acetonitrile; chlorinated hydrocarbons, such as methylene chloride, ethylenedichloride; dipolar aprotic solvents, such as dimethylsulfoxide, dimethyacetamide and dimethylformamide; esters, such as ethyl acetate and isopropyl acetate; cyclic ethers, such as dioxane and tetrahydrofuran; ketone such as acetone, diisobutyl ketone, cyclohexanone, methylcyclohexanone, methyl ethyl ketone, methyl isobutyl ketone, acetylacetone or mixtures thereof.

The base used for the reaction of 2-chloro-4-(6-(5-((2- (methylsulfonyl)ethylimino) methyl)furan-2-yl) quinazolin-4-ylamino)phenol of Formula (Ic) with 3-Fluorobenzylbromide may be selected from the group comprising of metal carbonate such as lithium carbonate, sodium carbonate, potassium carbonate, barium carbonate, calcium carbonate and magnesium carbonate; metal bicarbonate such as sodium bicarbonate, potassium bicarbonate, barium bicarbonate, calcium bicarbonate and magnesium bicarbonate and metal hydroxide such as sodium hydroxide, potassium hydroxide, barium hydroxide, calcium hydroxide and magnesium hydroxide. The base may also be selected from the group comprising of C1-C4 alkyl ammonia; mono, di or tri C I- C4 alkyl amine such as triethyl amine, diisipropropyl ethyl amine; mono, di or tri hydroxy C 1-C4 alkyl amine; morpholine; thiomorpholine; piperidine; Ν,Ν-dimethylaniline; pyridine; hydrazines and pyrrolidine.

Organic solvent may be selected from the group comprising of water; alcohols, such as methanol, ethanol and isopropanol; nitriles, such as acetonitrile; chlorinated hydrocarbons, such as methylene chloride, ethylenedichloride; dipolar aprotic solvents, such as dimethylsulfoxide, dimethyacetamide and dimethylformamide; esters, such as ethyl acetate and isopropyl acetate; cyclic ethers, such as dioxane and tetrahydrofuran; ketone such as acetone, diisobutyl ketone, cyclohexanone, methylcyclohexanone, methyl ethyl ketone, methyl isobutyl ketone, acetylacetone or mixtures thereof.

The ambient temperature employed is in the range of 20-40°C and more preferably from about 20 to 25°C.

The organic solvent used for the reduction of compound of Formula (VI) in presence of a sodium triacetoxy borohydride may be selected from the group comprising of water; alcohols, such as methanol, ethanol and isopropanol; nitriles, such as acetonitrile; chlorinated hydrocarbons, such as methylene chloride, ethylenedichloride; dipolar aprotic solvents, such as dimethylsulfoxide, dimethyacetamide and dimethylformamide; esters, such as ethyl acetate and isopropyl acetate; cyclic ethers, such as dioxane and tetrahydrofuran; ketone such as acetone, diisobutyl ketone, cyclohexanone, methylcyclohexanone, methyl ethyl ketone, methyl isobutyl ketone, acetylacetone or mixtures thereof.

Lapatinib of Formula (II) may be converted to its Ditosylate salt (Ila) by treating it with^?-toluenesulfonic acid.

Detailed experimental parameters suitable for this novel process of making Lapatinib or its ditosylate salt are provided by the following examples, which are intended to be illustrative and not limiting of all possible embodiments of the invention.

EXAMPLES

Example- 1

Preparation of 2-chloro-4-(6-iodoquinazolin-4-ylamino)phenol

To a stirred mixture of 4-Chloro-6-iodoquinazoline ( 10.0 g) and 4-Amino-2- chlorophenol (4.94 g) in Acetonitrile (100 ml) was refluxed for 1 hour. Reaction was monitored by TLC. On completion of reaction the reaction mixture was cooled to 20- 25°C and the solid was filtered. Crude 2-chloro-4-(6-iodoquinazolin-4-ylamino)phenol hydrochloride so obtained was dissolved in demineralized water and neutralized with Sodium carbonate (3.65 g). Solid was filtered and dried under vacuum at 60-65°C till constant weight.

Weight: 13 g

Yield: 94.5 %

MS (ES+) m/z: 398 [M+H] ⁺ & 400 [M+H+2] ⁺

1H NMR (400 MHz; DMSO-d6): 7.06 (d, J=8.8 Hz, 1H), 7.47 (d, J=8.8 Hz, 1H), 7.64 (d, J=8.8 Hz, 1H), 7.77 (s, 1H), 8.28 (d, J=8.8 Hz, 1H), 8.84 (s, 1H), 9.13 (s, 1H), 10.39 (s, 1H, OH), 1 1.06 (s, ΙΗ, ΝΗ).

Examp e-2

Preparation of 5-(4-(3-chloro-4-hydroxy phenyl amino) quiriazoIin-6-yl) furan-2- carbaldehyde

To a stirred mixture of demineralized water (10 ml), 2-chloro-4-(6- iodoquinazolin-4-ylamino)phenol (10 g), triethylamine (10.6 ml) in DME/MeOH (300 ml, 2: 1) was added 5-Formylfuran-2-ylboronic acid (5.28 g) followed by 10% Pd/C (1 g). The resulting mixture was heated at 45-50°C for 5-6 hours. Reaction was monitored by TLC. On completion of reaction the solid was filtered and the filtrate was diluted with demineralized water (30 ml) to obtain

5-(4-(3-chloro-4-hydroxy phenyl amino)quinazolin-6-yl) furan-2-carbaldehyde in solution.

Example-2a

Preparation of 5-(4-(3-chloro-4-hydroxy phenyl amino) quinazolin-6-yl) furan-2- carbaldehyde tosylate

To solution of 5-(4-(3-chloro-4-hydroxy phenyl amino)quinazolin-6-yl) furan-2- carbaldehyde obtained in Example-2 was added p-Toluenesulfonic acid (19.14 g) in 20 ml demineralized water. The reaction solution was stirred for 14-15 hours at 20-30°C.

The solid obtained was filtered and dried under vacuum at 65-70°C till constant weight.

Weight: 9.8 g

Yield: 72.4 %

MS (ES+) m/z: 366 [M+H] ⁺ & 368 [M+H+2] ⁺

Ή NMR (400 MHz; DMSO-d6): 2.28 (s, 3H), 7.08-7.1 1 (m, 3H), 7.47 (m, 4H), 7.76

(br s, 2H), 7.92 (d, J=8,4 Hz, l H), 8.51 (d, J=8.4 Hz, 1H), 8.88 (s, 1H), 9.1 1 (s, 1H),

9.70 (s, 1H), 10.44 (s, 1H, OH), 1 1.43 (s, 1H, NH).

ExampIe-3

Preparation of 2-chloro-4-(6-(5-((2-(methyIsulfonyl)ethylimino)methyI)furan -2-yl) quinazoIin-4-ylamino)phenoI

To a stirred mixture of 5-(4-(3-chloro-4-hydroxyphenylamino)quinazolin-6- yl)furan-2-carbaldehyde tosylate (1 g) and 2-(Methylsulfonyl)ethanamine hydrochloride (0.36 g) in methanol (10 ml) was added diisopropylethylamine (DIPEA) (0.81 ml). The reaction mixture was stirred at 20-25°C for 20 hours. The solid obtained was filtered and dried under nitrogen.

Weight: 0.85 g

Yield: 97.1 %

MS (ES+) m/z: 471 [M+H] ⁺ & 473 [M+H+2] ⁺

1H NMR (400 MHz; DMSO-d6): 3.04 (s, 3H), 3.50 (t, J=6.4 Hz, 2H), 3.97 (t, J=6.4 Hz, 2H), 7.01 (d, J=8.8 Hz, 1H), 7.18 (br s, 1H), 7.26 (br s, 1H), 7.53 (d, J=8.8 Hz, 1H), 7.82 (d, J=8.8 Hz, 1H), 7.83 (s, 1H), 8.20 (d, J=8.8 Hz, 1H), 8.33 (s, 1H, -N=CH- ), 8.53 (s, 1H), 8.85 (s, 1H), 9.93 (s, 1H, NH), 10.10 (s, 1H, OH). Exam le-4

Preparation of N-(3-chIoro-4-(3-fluorobenzyIoxy)phenyI)-6-(5-((2-

(methylsulfonyl)- ethylimino)methyl)furan-2-yl)quinazolin-4-amine

To a stirred mixture of 2-Chloro-4-(6-(5-((2- (methylsulfonyl)ethylimino)methyl)furan-2-yl)quinazolin-4-yl amino)phenol (0.5 g) and Sodium hydroxide (0.42 g) in Methanol (5 ml) was added 3-Fluorobenzylbromide (0.13 ml). The reaction mixture was stirred until completion at 20-25°C for 20 hours. The solid obtained was filtered and dried under nitrogen till constant weight.

Weight: 0.3 g

Yield: 48.8 %

MS (ES+) m/z: 579 [M+H] ⁺ & 581 [M+H+2] ⁺

1H NMR (400 MHz; DMSO-d6): 3.05 (s, 3H), 3.50 (t, J=6.4Hz, 2H), 3.97 (t, J=6.4 Hz, 2H), 5.26 (s, 2H), 7.16-7.34 (m, 6H), 7.47 (m, 1 H), 7.72 (d, J=8.8 Hz, 1H), 7.84 (d, J=8.8 Hz, 1 H), 8.00 (s, 1H), 8.22 (d, J=8.8 Hz, 1 H), 8.33 (s, 1 H, -N=CH-), 8.57 (s, 1H), 8.85 (s, lH) 10.02 (s, NH).

Example-5

Preparation of Lapatinib Ditosylate

To a stirred mixture of Sodiumtriacetoxyborohydride (0.21 g) in Tetrahydrofuran (THF)(2.4 ml) was added N-(3-Chloro-4-(3-fluorobenzyloxy)phenyl)-6-(5-((2- (methylsulfonyl)ethylimino)- methyl)furan-2-yl)quinazolin-4-amine (0.2 g) in THF. The reaction mixture was stirred for 1 hour at 20-25 °C. Reaction was monitored by TLC and on completion of reaction, aqueous NaQH (0.16 g NaOH to 0.8 g demineralized water) was added. The organic layer was separated and added p- Toluenesulfonic acid (0.42) in THF (0.6 ml) and stirred for 3 hours. The solid was filtered and dried under vacuum at 60-65°C till constant weight.

Weight: 0.15 g

Yield: 46.9 %

Purity by HPLC: 96.16%

MS (ES+) m/z: 581 [M+H] ⁺ & 583 [M+H+2] ⁺

1H NMR (400 MHz; DMSO-d6): 2.28 (s, 6H), 3.14 (s, 3H), 3.44 (t, J=8.0 Hz, 2H), 3.55 (t, J=8.0 Hz, 2H), 4.46 (s, 2H), 5.31 (s, 2H), 6.89 (br s, 1H), 7.10 (d, J=7.2 Hz, 4H), 7.20 (m, 1H), 7.23 (br s, 1H), 7.31- 7.36 (m, 3H), 7.47 (d, J=7.2 Hz, 4H), 7.63 (d, J=8.8 Hz, IH), 7.89 (br s, IH), 7.92 (d, J=8.8 Hz, IH), 8.39 (d, J=8.8 Hz, IH), 8.89 (s, IH), 8.98 (s, IH), 9.28 (s, IH, NH), 11.18 (s, IH, NH).