FI63936B - ANALOGIFICATION OF FRAMSTATION OF AV 4-AMINO-2- (4- (PHENYL SUBSTITUTES ALCOXY) PIPERIDINO) QUINAZOLINE ANVAENDBARA SAOSOMANTIHYPERTENSIVA MEDEL - Google Patents

Description

Tri M1v advertisement publication s-io-l t

Ma ^ (11) UTLÄGCNINGSSKMFT 6 3936 \ 3§ £ y 1 “3 '3 C 07 D 401/04 (S1) Kv.lk./IncCI. // c 07 D 239/95 FINLAND —FINLAND (21) Pu.nttlK * k.mu.-PK «« ieekmn * 800252 (22) HakemltpUvt —AiwOknlnpdag 29.01.80 '' (23) AlkupUvi —GiMghatadag 29 · 01.80 ( 41) Tullut | ulklMksl - Bllvlt offmcllg qQ Qq PMMtl · |. r.kl «« - lh.llltu.

Patant- och r * gict * rctyr «lMn 'Anukin utlagd och utl.sk Rifton published 31.05.83 (32) (33) (31) Pyr ^ *« y «Tuoikeu» —Begird prloriuc 31.01.79

England-England (GB) 7903398 (Tl) Pfizer Corporation, Calle 151/2, Avenida Santa Isabel, Colon,

Panama (PA) (72) Simon Fraser Campbell, Kingsdown, Deal, Kent, John Christopher Danilewicz, Ash, no. Canterbury, Kent, Colin William Greengrass, Woodnesborough, Sandwich, Kent, England-England (GB) (7l) Qy Kolster Ab (5 * 0 Analogue method for U-amino-2 - [- (phenyl-substituted alkoxy) piperidine] quinazolines used as antihypertensive drugs - Analogifarfarande för framställning av l + -ami-no ^ - ^ - ifenylsubstituerad alkoxy) piperidino7kinazoliner användbara s & som antihypertensiva medel

The invention relates to an analogous process for the preparation of 4-amino-2- [3- (phenyl-substituted alkoxy) piperidino / quinazolines of the formula I or pharmaceutically acceptable acid addition salts thereof for use as antihypertensive drugs,

^ - 0 — X — OR

c “> ° -rr y

CH-Jo-Jv. OF

nh2 wherein X is -CH (phenyl) CH2-, -CH2CH (phenyl) - or 2,63936 -CE2C (CH2) phenyl-, and R is hydrogen, methyl, ethyl or phenyl.

Pharmaceutically acceptable acid addition salts include salts formed from acids having a pharmaceutically acceptable anion, such as hydrochloride, hydrobromide, sulfate or hydrogen sulfate, phosphate or hydrogen phosphate, acetate, maleate, fumarate, lactate, , citrate, gluconate, saccharate or p-toluenesulfonate salts.

The compounds of the invention having one or more centers of asymmetry exist as one or more pairs of enantiomers, and such pairs or individual enantiomers can be separated by physical methods, e.g. by fractional crystallization of the appropriate salts.

Preferred compounds are the compounds of Examples 1 and 3.

Compounds resembling the compounds of the present application are known e.g. FI patent application 783 477.

The compounds of the invention are prepared by reacting a quinazoline of the formula ch30-ch30- (II) nh2 wherein Q is a readily leaving group such as chlorine, bromine, iodine, (C1-C4-alkyl) thio or (C1-C4-alkyl) -alkyl) sulfonyl, is reacted with piperidine of formula (",> HN) -O-X-OR (III) wherein X and R are as defined above, after which the product of formula I is optionally converted into a pharmaceutically acceptable acid addition salt. by reacting it with a non-toxic acid.

3 6 3 9 3 6 Q is preferably Cl or Br.

In a typical process, the reactants are heated together, e.g. at a temperature between 70-130 ° C, preferably at boiling point, in a neutral organic solvent, e.g. n-butanol, for up to about 48 hours. The product can be isolated and purified by conventional methods.

The intermediates of formula II and III are either known compounds or can be prepared according to methods previously known in the art. The preparation of some of the intermediates of formula III is described in the Preparation Examples.

Pharmaceutically acceptable acid addition salts of the compounds of formula I may be prepared by conventional methods, e.g. by mixing the free base with a suitable acid in a suitable solvent, e.g. isopropanol, filtering and, if necessary, recrystallising the salt so prepared. The product is often already in the form of an acid addition salt.

The antihypertensive effect of the compounds of the invention is demonstrated by their ability to lower blood pressure in conscious spontaneously hypertensive rats and in conscious dogs with renal hypertension when administered orally at doses up to 5 mg / kg.

The following table shows the antihypertensive activity of the compounds of the invention.

Table I

Antihypertensive activity values of the compounds of the invention —-1-— --— -

Compound Percentage of blood pressure- Maximum maximal reduction in blood pressure in maximal rats * (dose 5 mg / kg, elapsed __orally) __ time (hours)

Product of Example 1 93 1 "2" "78 1" 3 "" 100 1 "4" "60 1" 5 "" 81 1 "6" "62 1

Percentage of blood pressure _ Actual decrease in blood pressure (mm) x 100% decrease Blood pressure before administration of test compound (mm) - 130 mm

No adverse toxic side effects were observed after oral administration at 5 mg / kg.

4,63936

The compounds of the invention may be administered alone, but will usually be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and normal pharmaceutical practice. They can be administered, for example, orally in the form of tablets containing excipients such as starch or lactose, or in capsules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents. They can be injected parenterally, for example, intramuscularly, intravenously or subcutaneously. For parenteral administration, they are preferably used in the form of a sterile aqueous solution which may contain other solutes, for example, enough salts or glucose to make the solution isotonic.

The compounds of the invention may be administered to humans for the treatment of hypertension either orally or parenterally, and may be administered orally in dosage ranges of approximately 1-50 mg / day to an adult patient (70 kg) administered in a single dose or in up to three divided doses. Dosage levels for intravenous administration are about 1/5 to 1/10 of the daily oral dose. Thus, the amount of active compound contained in individual doses in the form of a tablet or capsule for administration to a normal adult patient is in the range of 1 to 50 mg. Deviations may be necessary depending on the weight and condition of the patient being treated and the route of administration chosen.

The following examples illustrate the invention.

Example 1 Preparation of 4-amino-6,7-dimethoxy-2- [1- (2-ethoxy-1-phenylethoxy) -piperidino] quinazoline hydrochloride CH 3 N + HN OCH-i \ v_y \ \ _ / NHo. CH_0C_H- i ch2oc2h5 ch3 ° x

II

5,63936 4-Amino-2-chloro-6,7-dimethoxyquinazoline (2.6 g) and 4- (2-ethoxy-1-phenylethoxy) piperidine (3.0 g) were heated to reflux in n-butanol (100 ml). hours. The solution was then cooled, filtered and the filtrate evaporated to dryness in vacuo. The residue was triturated with diethyl ether and recrystallized twice from isopropanol to give 4-amino-6,7-dimethoxy-2- [4- (2-ethoxy-1-phenylethoxy) piperidino] quinazoline hydrochloride (2.0 g). , sp. 229-230 °.

Analysis for C 25 H 32 N 4 O 4 * HCl,%: Found: C 61.0 H 6.9 N 11.5 Calculated C 61.4 H 6.8 N 11.5.

Example 2 Preparation of 4-amino-6,7-dimethoxy-2- [4- (2-phenoxy-1-phenylethoxy) piperidine] quinazoline hydrochloride hydrate CH3 Cl 'li CB, NH2 CH2OPh

V

"VriOrO-.; N CH" 1 2

CH? 0> O

“* 2) -V

4-Amino-2-chloro-6,7-dimethoxyquinazoline (1.44 g) and 4- (2-phenoxy-1-phenylethoxy) piperidine (2.0 g) were heated at reflux in n-butanol (100 ml) for 20 hours. . The solvent was then evaporated in vacuo, the residue triturated with ether and crystallized from isopropanol. The solid was partitioned between chloroform and aqueous sodium carbonate solution soluble / the chloroform extract dried (MgSO 4) and the solvent evaporated in vacuo. The residue was chromatographed on silica (100 g) eluting with chloroform followed by chloroform / methanol (20: 1). The product-containing fractions were combined, the solvent was evaporated in vacuo and the residue was converted into the hydrochloride salt by treating the chloroform solution with ethereal hydrogen chloride solution. The solid hydrochloride salt was collected and recrystallized from isopropanol to give 4-amino-6,7-dimethoxy-2- [4- (2-phenoxy-1-phenylethoxy) -piperidine] quinazoline, hydrochloride hydrate (0.85 g), m.p. 202-204 ° C.

Analysis for C 29 H 32 N 4 O 4 • HCl • * H 2 O,%: Found: C 62.8 H 6.1 N 10.0

Calculated: C 62.8 H 6.4 N 10.1.

Examples 3-6

The following compounds were prepared in the same manner as in the above examples using 4-amino-2-chloro-6,7-dimethoxyquinazoline and the appropriate piperidine as starting material: The product of Example 3 was prepared in the same manner as in Example 1, and the products of Examples 4, 5 and 6 were prepared in the same manner as in Example 1. in Example 2, but the product of Example 5 was not converted to the hydrochloride salt.

63936 CH'3 (\ ^ VsV ^ 'N ^ I- ^ N_OCH C - OR2 I' V7 'o 5 2

Eg R R Isolation Form and Analysis,% m.p. (° C) (Theoretical values in brackets)

C H N

3 H H hydrochloride 241-243 59.7 6.3 12.0 (59.9 6.3 12.2) 4 H C-H hydrochloride 234-235 61.3 6.7 11.0 ^ S (61, 4 6.8 11.5) Έ?

ch3Q. N / \ I

'y ^ -? y— ° ch2— c or2

JLJL * »w I

ό ς 2

Eg R R Isolation Form and Analysis,% m.p. (° C) (Theoretical values in brackets)

C H N

5 CH, H free base, monohydrate 63.0 6.8 12.2 J, 146-148 (63.1 7.1 12.3) 6 CH, C, Hr hydrochloride 231-233 61.9 7, 0 11/1 J 1 b (62.1 7.0 11.1) 8 63936

The following preparation examples illustrate the preparation of some starting materials:

Preparation Example A

Preparation of 4- (2-hydroxyphenylethoxy) piperidine A solution of N-acetyl-4-hydroxypiperidine (5.0 g) in tetrahydrofuran (THF) (50 mL) was added to a stirred suspension of sodium hydride (1.84 g, 50 mL). -% mineral oil dispersion) in tetrahydrofuran (THF) (25 ml) under a nitrogen atmosphere. After boiling, styrene oxide (4.6 g) in THF (25 mL) was added; then the reaction mixture was diluted with dimethylformamide (DiMF) (25 mL) and stirred at 60 ° C for 18 hours. After isopropanol was added to the cooled solution, the solvent was removed in vacuo, the residue was treated with water, the pH was adjusted to 4 with 2N hydrochloric acid, and extracted with chloroform. The chloroform extract was dried (Na 2 SO 4) and the solvent evaporated in vacuo to give N-acetyl-4- (2-hydroxyphenylethoxy) piperidine. This product was heated by boiling in ethanol (50 ml) and 5N sodium hydroxide solution (100 ml) for three hours. The solvent was then removed in vacuo, the residue was dissolved in water, extracted with chloroform, dried and the solvent was evaporated in vacuo. The product was converted into the hydrochloride salt in chloroform by treatment with ethereal hydrochloric acid and evaporation of the solvent.

The residue was dissolved in methanol, treated with ether, the precipitated solid separated and recrystallised from isopropanol to give 4- (2-hydroxyphenylethoxy) piperidine hydrochloride (0.6 g), m.p. 174-175 °.

Analysis for C 10 H 11 N 2 O 2 -HCl, found: C 60.1 H 7.8 N 5.2 calculated: C 60.6 H 7.8 N 5.4.

Comparative Example B

Preparation of 4- (2-ethoxyphenylethoxy) piperidine N-acetyl-4- (2-hydroxyphenylethoxy) piperidine (8.0 g) (prepared as in Preparation Example A) and 1,2-dimethoxyethane (0.3 g) dissolved in dry DMF (50 ml) was added dropwise to a stirred suspension of sodium hydride (2.96 g, 50% mineral oil dispersion) in dry DMF (50 ml). The suspension was stirred at room temperature for 3.5 hours, cooled to 0-5 ° C, then a solution of 9,63936 ethyl iodide (9.6 g) in DMF (25 ml) was added dropwise. The mixture was allowed to warm to room temperature (20 ° C) and then stirred for two hours at room temperature. Isopropanol (75 ml) was added, the solvent was removed in vacuo and the residue was partitioned between chloroform and water. The chloroform layer was dried and the solvent was evaporated in vacuo to give N-acetyl-4- (2-ethoxyphenylethoxy) piperidine (5.2 g).

This product in ethanol (50 mL) and sodium hydroxide solution (50 mL, 5-n) were heated at reflux for 3.5 hours. The organic solvent was removed in vacuo and the aqueous residue was extracted with chloroform. The organic extract was dried (Na 2 SO 4), evaporated to dryness in vacuo, then the residue was partitioned between 2N hydrochloric acid and ether. The aqueous phase was then basified with sodium carbonate solution and extracted with chloroform. The chloroform extract was dried (Na 2 SO 4), the solvent evaporated in vacuo, then the residue was dissolved in ether and converted into the oxalate salt. Recrystallization from isopropanol gave 4- (2-ethoxyphenylethoxy) piperidine, oxalate salt (1.6 g), m.p. 136-137 °.

Analysis for 5 ^ 3 ^ 2 * C 2 H 2 O 4 'found: C 60.3 H 7.4 N 4.1 calculated; C 60.2 H 7.4 N 4.1.

10 63936

Preparation Example C

Preparation of 4- (2-ethoxy-1-phenylethoxy) piperidine 1. NaH

^ o OH 2 ‘ΤΓ l“ ochco2c2h5

BrCKCOjH, _x

3. EtOH, H + \ N / c = 0 i = 0 ch3 CH2

LiBH.

4

V

Q 0 OCHCH2OC2H5 ochch2oh 1 · NaH .Ax.

I i 2. C, HKI r A

J <—-

ANA 3. NaOH / CH3OH

H I

C = O CH 3 (i) α- (N-acetyl-4-piperidinoxy) phenylacetic acid, ethyl ester N-acetyl-4-hydroxypiperidine (27.5 g) in dry DMF (100 ml) was added slowly to a stirred suspension of was sodium hydride (25 g, 50% mineral oil dispersion) in DMF (150 mL) and 1,2-dimethoxyethane (10 mL). The suspension was stirred at room temperature for three hours. O-Bromophenylacetic acid (45 g) in 11,63936 DMF (250 ml) was then added slowly with ice / water cooling. The mixture was stirred at room temperature for 20 hours, then isopropanol was added and the solvent was evaporated in vacuo. The residue was dissolved in water, acidified to pH 1 with 2N hydrochloric acid and extracted four times with chloroform (300 ml). The combined chloroform extracts were washed with water and brine, dried (MgSO 4) and the solvent evaporated in vacuo. The residue in dry ethanol (450 ml) was heated by boiling with concentrated sulfuric acid (9 ml) for eight hours. The cooled solution was carefully neutralized with aqueous sodium carbonate solution and the organic solvent was evaporated off in vacuo. The pH of the aqueous residue was adjusted to 10 with sodium carbonate solution and extracted twice with chloroform. The combined chloroform extracts were dried (MgSO 4) and evaporated to dryness in vacuo. Distillation of the residue gave o- (N-acetyl-4-piperidinoxy) -phenylacetic acid, ethyl ester (37.2 g), b.p. 190-194 ° C / 0.18 mm.

Analysis for c 17 H 23 NO 4%: Found: C 66.4 H 7.8 N 4.5 Calculated: C 66.9 H 7.6 N 4.6.

(ii) N-Acetyl-4- (2-hydroxy-1-phenylethoxy) piperidine Lithium borohydride (3.24 g) was added portionwise to a solution of c <- (N-acetyl-4-piperidinyloxy) phenylacetic acid, ethyl ester ( 11.2 g) in dry THF (200 ml). After the evolution of hydrogen ceased, the reaction mixture was heated to reflux for four hours. Water was added to the cooled solution, the solvent was evaporated in vacuo, then the residue was dissolved in chloroform (200 ml) and washed with dilute hydrochloric acid, water and brine. The chloroform extract was dried (MgSO 4) and the solvent evaporated in vacuo. Thin layer chromatographic analysis of the product showed incomplete reduction, so the product was treated with a portion of lithium borohydride (3.24 g) added in THF (100 ml) and heated at reflux for 4 hours. as above to give N-acetyl-4- (2-hydroxy-1-phenylethoxy) piperidine (9.5 g) as an oil which gradually became a solid, the sample crystallized from ether, mp 92-94 ° C.

Analysis for c 15 H 21 NO 3 'found: C 68.1 H 8.1 N 5.7 Calculated: C 68.4 H 8.1 N 5.3.

12 $ 39 3 6 (iii) 4- (2-ethoxy-1-phenylethoxy) piperidine This compound was prepared in the same manner as in Preparation Example B using N-acetyl-4- (2-hydroxy-1-phenylethoxy) piperidine as starting material / prepared as in part (ii) above and ethyl iodide, followed by hydrolysis of the N-acetyl group with a base. The sample is characterized by its oxalate salt, m.p. 137-139 °.

Analysis for c 15 H 23 N® 2 "C 2 H 2 O 4 'found: C 59.9 H 7.4 N 4.0 calculated: C 60.2 H 7.4 N 4.1.

Preparation Example D

4- (2-phenoxy-1-phenylethoxy) piperidine

A mixture of N-acetyl-4- (2-hydroxy-1-phenylethoxy) -piperidine (5.29 g) / prepared as in Preparation Example C (ii / 7, diethyl azodicarboxylate (4.2 g), triphenylphosphine (6.3 g) g) and phenol (2.25 g) in dry tetrahydrofuran (100 ml), stirred at 0 ° C for two hours and then left at room temperature for 48 hours The solvent was evaporated in vacuo, the residue dissolved in boiling diethyl ether (50 ml) and left in the refrigerator overnight The precipitated by-products were removed by filtration and the filtrate was evaporated to dryness, the residue was redissolved in ether, cooled and the solid precipitate was filtered off, the ether filtrate was evaporated to dryness and the residue was heated in methanol (50ml) and sodium hydroxide solution (30ml, 5g). the solvent was removed in vacuo, the aqueous residue was acidified to pH 3 with 2N hydrochloric acid and extracted twice with ether, the organic extracts were discarded. sodium hydroxide solution to 12, extracted with ether (3 x 100 ml), the ether extracts combined, dried (MgSO 4) and the solvent evaporated in vacuo to give 4- (2-phenoxy-1-phenylethoxy) piperidine (3.55 g) as an oil. A sample was converted to the oxalate salt, which was recrystallized from isopropanol and m.p. was 170-172 °.

Analysis for c 19 H 23 NO 2 found: C 64.9 H 6.6 N 3.8 calculated: C 65.1 H 6.5 N 3.6.

li 13 63936

Preparation Example E

Preparation of 4- (2-hydroxy-2-phenyl-n-propoxy) piperidine οϊ3 OH 1 '““' if \ <χά2 / - oh, 2. BrCH, c A Λ 2 'vi' '^ l.Hg (Cec ), I 2 f J -> Y_ / ^ CH3ce

c = 0 c = 0 H

(i) N-acetyl-4- (2-phenylallyloxy) piperidine

A solution of N-acetyl-4-hydroxypiperidine (13.6 g) in DMF (50 ml) was added dropwise to a stirred suspension of sodium hydride (10 g, 50% mineral oil dispersion) in DMF (50 ml). ) protected under nitrogen. The mixture was stirred at room temperature for three hours, then c * - (bromomethyl) styrene (20 g) in DMF (50 ml) was added dropwise. The mixture was stirred at room temperature for 4 hours, then diluted with water and extracted with chloroform (3 x 200 mL). The combined chloroform extracts were dried (Na 2 SO 4), evaporated to dryness in vacuo, and distilled to give N-acetyl-4- (2-phenylallyloxy) piperidine (25 g), b.p. 170-180 ° C / 0.3 mm, NMR spectrum according to this structure.

(ii) 4- (2-hydroxy-2-phenyl-n-propoxy) piperidine

A solution of N-acetyl-4- (2-phenylallyloxy) piperidine (4.0 g) in dry THF (60 ml) was added dropwise to a stirred solution of mercuric acetate (6.35 g) in water (60 ml). and the solution was stirred at room temperature for one hour. To the stirred solution at 0 ° C were then added dropwise sodium hydroxide solution (40 ml, 3-n) and sodium borohydride (0.75 g) in sodium hydroxide solution (40 ml, 3-n). The gray suspension was stirred at 0 ° C for 1 hour, glacial acetic acid was added until pH 6, then the suspension was filtered and the filtrate was extracted with chloroform i4 63936 (3 x 150 ml). The combined chloroform extracts were dried (Na 2 SO 4) and evaporated to dryness in vacuo to give N-acetyl-4- (2-hydroxy-2-phenyl-n-propoxy) piperidine (2.1 g). This product, dissolved in methanol (30 mL), and sodium hydroxide solution (20 mL, 5-n) were heated at reflux for four hours. The organic solvent was evaporated and the aqueous solution was extracted with chloroform (3 x 20 ml), dried (Na 2 SO 4) and the solvent evaporated in vacuo to give 4- (2-hydroxy-2-phenyl-n-propoxy) piperidine (1.8 g) as an oil. The properties of the sample were characterized by an oxalate salt which was recrystallized from ethyl acetate and its m.p. was 132-134 ° C. Analysis for C 14 H 21 NO 2 * O 2 •%, found: C 58.8 H 7.1 N 4.8 Calculated: C 59.1 H 7.1 N 4.3.

Preparation Example F

Preparation of 4- (2-ethoxy-2-phenyl-n-propoxy) piperidine A solution of N-acetyl-4- (2-phenylallyloxy) piperidine (7.0 g) (prepared as in Preparation Example E) in ethanol (10 ml) , was added to a stirred suspension of mercuric acetate (9.2 g) in ethanol (50 ml) at room temperature. The mixture was stirred at room temperature for 1 hour and then cooled to 0 ° C. To the stirred suspension was added sodium hydroxide solution (20 ml, 5-n) followed by sodium borohydride (1.03 g) in sodium hydroxide solution (20 ml, 5-n), and after 10 minutes glacial acetic acid was added until pH 6. The suspension was filtered, the filtrate evaporated to dryness. and the residue was partitioned between chloroform and water. The organic layer was dried (Na 2 SO 4) and the solvent was evaporated in vacuo. Gas-liquid chromatographic (GLC) analysis of the product showed that the conversion to the desired product was incomplete, so the oxymercurization procedure was repeated as above to give N-acetyl-4- (2-ethoxy-2-phenyl-n-propoxy) piperidine (7.4 g). ); Purity by GLC: 84%. A solution of the product in ethanol (100 ml) and sodium hydroxide solution (30 ml) was heated at reflux for 11 hours. The organic solvent was evaporated and the aqueous solution was extracted with chloroform (3 x 30 ml). The combined chloroform extracts were dried (Na 2 SO 4) and the solvent evaporated in vacuo to give 4- (2-ethoxy-2-phenyl-n-propoxy) piperidine as an oil (3.8 g). A sample of this was converted to the oxalate salt, which was recrystallized twice from ethyl acetate and then from acetone and its m.p. was 126-127 ° C.

Analysis for C 18 H 25 NO 2 * C 2 H 2 O 4 · H 2 O / Found: C 60.4 H 7.6 N 4.1 Calculated: C 60.4 H 7.3 N 3.9.

Claims (3)

An analogous process for the preparation of 4-amino-2- / 4- (phenyl-substituted alkoxy) piperidine-quinazolines of the formula I or their pharmaceutically acceptable acid addition salts, which are used as antihypertensive drugs, wherein X is -CH (phenyl) CH 2, CH 2 CH (phenyl) - or -CH 2 C (CH 3) (phenyl) -, and R is hydrogen, methyl, ethyl or phenyl, characterized in that the quinazoline of the formula CH 0 -L 1 N (II) ch 3 cr-nh 2 wherein Q is a readily leaving group such as chlorine, bromine, iodine, (C 1 -C 4 alkyl) thio or (C 1 -C 4 alkyl) sulfonyl is reacted with piperidine of the formula H1 / N-OX-OR ( III) wherein X and R are as defined above, after which the product of formula I is optionally converted into a pharmaceutically acceptable acid addition salt by reacting it with a non-toxic acid. Process according to Claim 1, characterized in that X is -CH (phenyl) CH 2 -, R is C 2 H 1 - and Q is Cl. Process according to Claim 1, characterized in that X is -CH 2 CH (phenyl) -, R is H and Q is Cl. Il