KR0150566B1 - A process for preparing stereo active 3-amino heterocyclic compound - Google Patents

Abstract

The present invention is a protected 3-aminopiperidine derivative or 3-amino- with optical activity, using as starting materials L-glutamic acid, L-adipic acid or optical isomers thereof, which are a-amino acids which are abundant in nature. A method for producing 3-amino heterocyclic amine derivatives such as 2,3,4,5,6,7-hexahydro-1H-azepine derivative.

Description

Method for preparing 3-amino heterocyclic amine derivative having optical activity

The present invention relates to a method for producing an optically active 3-amino heterocyclic amine derivative using a-amino acid (L- or D-), which is present in abundance in nature, as a starting material.

The optically active 3-amino heterocyclic amine derivatives of the following formula (I) are known compounds or derivatives thereof, and are intermediates of optically active catalysts, synthetic raw materials, agrochemicals or pharmaceutical fields, especially quinolone drugs and anticancer agents. Useful as

Conventionally, 3-amino heterocyclic amine derivatives as optically inactive racemic compounds have been synthesized in various ways and widely used in quinolone-based antimicrobial agents.

Synthesis of 3-amino piperidine derivatives, which are 6-cyclic ring compounds among 3-amino heterocyclic amine derivatives, is a method of synthesizing a 3-amino pyridine compound as a starting material through 3-4 steps as an optically inactive racemic compound, and In the case of synthesis of an optically active 3-amino piperidine derivative, a method of synthesizing L- or D-ornithine chlorate as a starting material through three steps (see Japanese Patent Laid-Open No. 3-95177, European Patent Publication No. 342675 and Heterocycles, 1993, 36 (10), 2383-96) are disclosed, but the production cost is very high or the yield is very low due to the use of metal such as platinum or high pressure reaction.

Accordingly, the present inventors have endeavored to solve the problems of the conventional manufacturing method as described above, and have completed the present invention having better features and advantages than the conventional one.

An object of the present invention is to provide optically active 3-amino hetero via four short synthetic routes using L-glutamic acid and L-adipic acid and their optical isomers, which are very inexpensive optically active α-amino acids present in nature By synthesizing cyclic amine derivatives in a very safe condition, it is to provide a new production method that can solve the problems of the known production methods mentioned above.

The gist of the present invention is a very inexpensive optically active α-amino acid, L-glutamic acid and L-adipic acid and their optical isomers, which are abundant in nature. To synthesize an amino acid derivative of formula (II),

By selective reduction of the carboxyl group to prepare a 2-amino-alkanediol derivative of the general formula (III) having optical activity,

The diol compound of general formula (III) is protected by a protecting group which can easily undergo a nucleophilic substitution reaction, thereby changing to a compound of general formula (IV),

A method of preparing a 3-amino heterocyclic amine derivative of protected general formula (I) which is optically active by reacting a sulfonyl derivative of protected 2-amino-alkanediol of formula (IV) with an amine derivative .

Wherein n is 1 or 2, R ₁ is lower alkyl of 1-6 carbon atoms, R ₂ is hydrogen or lower alkyl of 1-6 carbon atoms, R ₃ is lower alkyl, benzyloxycarbonyl, in particular t-butyloxycarbon Bonyl, R ₄ represents a toluene group or methyl, R ₅ represents hydrogen or benzyl, (R)-or (S) -phenylethyl, benzhydryl group.

The present invention starts from the natural α-amino acid L- glutamic acid and L- adipic acid and their optical isomers as starting materials, to obtain alkyl ester derivatives by reaction with methyl alcohol or ethyl alcohol under an acid catalyst which is a general esterification reaction. Without reaction, benzyloxycarbonyl chloride or di-butyloxycarbonyl is reacted in the presence of a base such as triethylamine or sodium hydroxide to obtain an optionally protected amino acid derivative of the general formula (II). 2-amino-alkanediol of formula (III) was prepared by sodium borohydride in ethyl alcohol solvent in the presence of a chloride chloride, and then the compound of formula (III) was dissolved in a methylene chloride solvent in the presence of a base. General formula (IV) which is a sulfonyl substituent of 2-amino-1,4-butanediol by reacting with polyphenyl or methanesulfonyl chloride Compounds of Formula (IV) were reacted with primary amines or aqueous ammonia and acetonitrile or methylene chloride in the presence of sodium carbonate to prepare the substituted 3-amino heterocyclic amine derivatives of Formula (I). It is a method of manufacturing.

When the reaction procedure of the present invention is represented by the reaction scheme as follows.

Wherein n is 1 or 2, R ₁ is lower alkyl of 1-6 carbon atoms, R ₂ is hydrogen or lower alkyl of 1-6 carbon atoms, R ₃ is lower alkyl of 1-6 carbon atoms, benzyloxycarbonyl, in particular t-butyloxycarbonyl, R ₄ represents a toluene group or methyl, and R ₅ represents hydrogen or benzyl, (R)-or (S) -phenylethyl, benzhydryl group.

Step 1 of the present invention synthesizes methyl ester or ethyl ester by esterification which is a common method of carboxyl groups such as glutamic acid and adipic acid in L- or D- form, and the amine group is separated by di-butyloxycarbonyl or The amino groups were protected in basic conditions such as benzyloxycarbonyl chloride and triethylamine and in tetrahydrofuran solvent or dioxane-distilled solvent. R ₁ , R ₂ and R ₃ which can be applied to step 1 have been described above, in particular, when R ₁ is methyl or ethyl, the yield is good, when R ₂ is hydrogen, methyl or ethyl and R ₃ is Good results were obtained with t-butyloxycarbonyl.

Step 2 of the present invention is a step of reducing the ester to prepare an alcohol, showing a high yield and fast reaction by adding calcium chloride and the like to lithium-aluminum hydride or sodium borohydride. Tetrahydrofuran may be used as a solvent under lithium aluminum hydride conditions, and lower alcohols such as methyl alcohol, ethyl alcohol and isopropyl alcohol may be used as a solvent under sodium borohydride conditions. The reaction temperature is very fast even at room temperature, or cooled to 0 ℃ it is preferable to react.

Step 3 of the present invention is a step of converting the diol derivative of formula (III) into a sulfonyl compound, using 2.5 to 5 equivalents of alkylsulfonyl chloride or arylsulfonyl chloride and the like, and inert solvent such as methylene chloride. It is preferable to use a solvent. At this time, organic bases such as triethylamine and pyridine may be used as the base, and 3 equivalents to 5 equivalents may be used.

Step 4 of the present invention shows the preparation of 3-amino heterocyclic amine derivative of formula (I) by cyclolation reaction, wherein the amines of cyclolation reaction are ammonium chloride, ammonium carbonate, ammonium hydroxide, benzylamine, phenylethylamine , Diphenylmethylamine and the like are used and show different yields depending on the type of amine. At this time, the base used is ammonia, potassium carbonate or sodium carbonate, and the solvent used is water, methanol, acetonitrile or dichloromethane or the like is usefully used alone or as a mixed solution. The reaction temperature shows a good yield even at room temperature, or can be heated to about 50 ℃ to obtain 3-amino heterocyclic amine derivatives of the general formula (I) in a high yield.

The present invention has the following features and advantages compared to the existing methods. Firstly, we developed a very economical method by obtaining 3-amino heterocyclic amine derivatives of general formula (I) through a short manufacturing process starting from cheap and abundant α-amino acids and their optical isomers. Second: Since the optical activity of the starting material is maintained as it is, it shows the optical activity of the target compound, and thus, more pure chiral compounds can be synthesized than the conventional methods. Or to reduce environmental pollution.

Hereinafter, the present invention will be described in more detail with reference to Examples. The present invention is not necessarily limited to the following Examples.

Example 1

Preparation of (L)-(-)-N-t-butyloxycarbonylglutamic acid dimethyl ester

(L) -Glutamic acid (0.1 mol) is suspended in methyl alcohol anhydride (100 ml), followed by dropwise addition of concentrated sulfuric acid (10 ml) and stirring under reflux for 18 hours. The solution was concentrated under reduced pressure, and the obtained residue was dissolved in water: dioxane (1: 1, 100 ml), cooled to 0-5 ° C, and triethylamine (0.5 mol) was added dropwise, followed by 5 minutes at the same temperature. Stir. To this solution was added dropwise a solution of di-t-butyloxycarbonyl (0.13 mol) in water: dioxane (1: 1, 50 ml) at the same temperature, followed by stirring at room temperature for 3 hours. After completion of the reaction, the organic solvent was removed under reduced pressure, extracted with dichloromethane (100 ml x 2), washed with saturated brine, dried over magnesium sulfate, and the organic solvent was removed under reduced pressure (L)-(-)-Nt-butyl. Oxycarbonyl glutamic acid dimethyl ester is obtained.

Example 2

Preparation of (L)-(-)-N-t-butyloxycarbonyladipic acid dimethyl ester

(L) -adipic acid (0.1 mol) is suspended in methyl alcohol anhydride (100 ml), and then concentrated sulfuric acid (10 ml) is added dropwise and stirred under reflux for 18 hours. The solution was concentrated under reduced pressure, and the obtained residue was dissolved in water: dioxane (1: 1, 100 ml), cooled to 0-5 ° C, and triethylamine (0.5 mol) was added dropwise, followed by 5 minutes at the same temperature. Stir. To this solution was added dropwise a solution of di-t-butyloxycarbonyl (0.13 mol) in water: dioxane (1: 1, 50 ml) at the same temperature, followed by stirring at room temperature for 3 hours. After completion of the reaction, the organic solvent was removed under reduced pressure, extracted with dichloromethane (100 ml x 2), washed with brine, dried over magnesium sulfate, and the organic solvent was removed under reduced pressure (L)-(-)-N) t. -Butyl oxycarbonyl glutamic acid dimethyl ester is obtained.

Example 3

Preparation of (D)-(+)-N-t-butyloxycarbonylglutamic acid dimethyl ester

D-(+)-N-t-butyloxycarbonyl glutamic acid dimethyl ester is obtained by the same method as in Example 2 using D-form α-glutamic acid.

Example 4

Preparation of (D)-(+)-N-t-butyloxycarbonyladipic acid dimethyl ester

D-(+)-N-t-butyloxycarbonyl adipic acid dimethyl ester is obtained by the same method as in Example 2 using D-form α-adipic acid.

Example 5

Preparation of (L)-(-)-N-t-butyloxycarbonyl-N-methylglutamic acid dimethyl ester

1 equivalent of (L)-(-)-Nt-butyloxycarbonyl glutamic acid dimethyl ester is dissolved in anhydrous tetrahydrofuran solution, 1.1 equivalent of sodium hydride is added, and then 1.5 equivalent of methyl iodide is added to the solution at room temperature. Stir. After the reaction, the mixture was extracted with sodium hydrogencarbonate solution, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain a product. The solid can be used as it is for the following reaction, and recrystallized as necessary to give L-(-)-N-t-butyloxycarbonyl-N-methylglutamic acid dimethyl ester.

Example 6

Preparation of (L)-(-)-N-t-butyloxycarbonyl-N-methyladipic acid dimethyl ester

Dissolve 1 equivalent of (L)-(-)-Nt-butyloxycarbonyl adipic acid dimethyl ester in anhydrous tetrahydrofuran solution, add 1.1 equivalent of sodium hydride, add 1.5 equivalents of methyl iodide to this solution, and then room temperature Stir in After the reaction, the mixture was extracted with sodium hydrogencarbonate solution, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain a product. The solid can be used as it is for the following reaction, and recrystallized as necessary to give L-(-)-N-t-butyloxycarbonyl-N-methylglutamic acid dimethyl ester.

Example 7

Preparation of S-(-)-2-t-butyloxycarbonylamino-1,5-pentanediol

2-4 equivalents of calcium chloride powder was dispersed in anhydrous ethyl alcohol, cooled to 0 ° C., and then 3-5 equivalents of sodium borohydride were added and stirred at the same temperature for 1 hour. A solution of 1 equivalent of N-protected glutamic acid dimethyl ester in anhydrous ethyl alcohol was added dropwise at the same temperature, followed by stirring for 1 hour, followed by stirring at room temperature for 3 hours. After adding excess water, the organic solvent was removed under reduced pressure, saturated with sodium chloride, extracted with ethyl acetate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a white solid. The obtained white solid was dissolved in a small amount of dichloromethane, n-hexane was added at 0 ° C., stirred for 1 hour at the same temperature, the produced white solid was filtered and dried under reduced pressure to obtain pure white solid S-(-)-2. -t-butyloxycarbonylamino-1,5-pentanediol is obtained.

Example 8

Preparation of S-(-)-2-t-butyloxycarbonylamino-1,6-hexanediol

2-4 equivalents of calcium chloride powder was dispersed in anhydrous ethyl alcohol, cooled to 0 ° C., and then 3-5 equivalents of sodium borohydride were added and stirred at the same temperature for 1 hour. A solution of 1 equivalent of N-protected adipic acid dimethyl ester in anhydrous ethyl alcohol was added dropwise at the same temperature, followed by stirring for 1 hour, followed by stirring at room temperature for 3 hours. After adding excess water, the organic solvent was removed under reduced pressure, saturated with sodium chloride, extracted with ethyl acetate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a white solid. The obtained white solid was dissolved in a small amount of dichloromethane, n-hexane was added at 0 ° C., stirred for 1 hour at the same temperature, the produced white solid was filtered and dried under reduced pressure to obtain pure white solid S-(-)-2. -t-butyloxycarbonylamino-1,6-hexanediol is obtained.

Example 9

Preparation of R-(+)-2-t-butyloxycarbonylamino-1,5-pentanediol

R-(+)-2-t-butyloxycarbonylamino-1,5-pentanediol was obtained by the same method as Example 7 using D-(+)-Nt-butyloxycarbonyl glutamic acid dimethyl ester. Lose.

Example 10

Preparation of R-(+)-2-t-butyloxycarbonylamino-1,6-hexanediol

R-(+)-2-t-butyloxycarbonylamino-1,6-hexanediol was prepared by the same method as in Example 8 using D-(+)-Nt-butyloxycarbonyl adipic acid dimethyl ester. Obtained.

Example 11

Preparation of S-(-)-2-t-butyloxycarbonylamino-1,5-pentanediol

S-(-)-2-t-butyloxycarbonylamino-1,5- by the same method as in Example 7 using L-(-)-Nt-butyloxycarbonyl-N-methylglutamic acid dimethyl ester Pentanediol is obtained.

Example 12

Preparation of S-(-)-2-t-butyloxycarbonylmethylamino-1,6-hexanediol

S-(-)-2-t-butyloxycarbonylmethylamino-1, by the same method as in Example 8 using L-(-)-Nt-butyloxycarbonyl-N-methyladipic acid dimethyl ester 6-hexanediol is obtained.

Example 13

Preparation of S-(-)-2-t-butyloxycarbonylamino-1,5-dimethanesulfonoxy-pentane

1 equivalent of N-protected 1.5-pentanediol is dissolved in methylene chloride, cooled to -10 ° C-0 ° C, and then 3 equivalents of triethylamine are added dropwise and stirred at the same temperature for 5 minutes. 2.5 equivalents of methanesulfonyl chloride was added to the solution, followed by stirring at the same temperature for 1 hour. After completion of the reaction, the resultant was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a slightly yellow solid. The obtained solid is again dissolved in a small amount of methylene chloride, hexane is added at 0 ° C., and then stirred at the same temperature for 1 hour. The resulting white solid was filtered and dried under reduced pressure to obtain pure white solid S-(-)-2-t-butyloxycarbonylamino-1,5-dimethanesulfonoxy-pentane.

Example 14

Preparation of S-(-)-2-t-butyloxycarbonylamino-1,6-dimethanesulfonoxy-hexane

1 equivalent of N-protected 1.6-hexanediol is dissolved in methylene chloride, cooled to -10 ° C-0 ° C, and then 3 equivalents of triethylamine are added dropwise and stirred at the same temperature for 5 minutes. 2.5 equivalents of methanesulfonyl chloride was added to the solution, followed by stirring at the same temperature for 1 hour. After completion of the reaction, the resultant was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a slightly yellow solid. The obtained solid is again dissolved in a small amount of methylene chloride, hexane is added at 0 ° C., and then stirred at the same temperature for 1 hour. The resulting white solid was filtered and dried under reduced pressure to obtain pure white solid S-(-)-2-t-butyloxycarbonylamino-1,6-dimethanesulfonoxy-hexane.

Example 15

Preparation of R-(+)-2-t-butyloxycarbonylamino-1,5-dimethanesulfonoxy-pentane

R-(+)-2-t-butyloxycarbonylamino-1,5-di by the same method as in Example 13 using R-(+)-2-t-butyloxycarbonylamino-pentanediol Methanesulfonoxy-pentane is obtained.

Example 16

Preparation of R-(+)-2-t-butyloxycarbonylamino-1,6-dimethanesulfonoxy-hexane

R-(+)-2-t-butyloxycarbonylamino-1,6-di by the same method as in Example 14 using R-(+)-2-t-butyloxycarbonylamino-hexanediol Methanesulfoneoxy-hexane is obtained.

Example 17

Preparation of S-(-)-2-t-butyloxycarbonylmethylamino-1,5-dimethanesulfonoxy-pentane

S-(-)-2-t-butyloxycarbonylmethylamino-1,5 by the same method as Example 13 using S-(-)-2-t-butyloxycarbonylmethylamino-pentanediol -Dimethanesulfonoxy-pentane is obtained.

Example 18

Preparation of S-(-)-2-t-butyloxycarbonylmethylamino-1,6-dimethanesulfonoxy-hexane

S-(-)-2-t-butyloxycarbonylmethylamino-1, S-(-)-2-t-butyloxycarbonylmethylamino-1, by the same method as in Example 14 using hexanediol 6-dimethanesulfoneoxy-hexane is obtained.

Example 19

Preparation of S-(-)-3-t-butyloxycarbonylaminopiperidine

One equivalent of dimethanesulfonoxy pentane derivative is dissolved in ammonia water (28%): acetonitrile (1: 1) and then reacted, or 1 to 3 equivalents of sodium carbonate or potassium carbonate are added and stirred at room temperature for 2-3 days. The reaction mixture was filtered and the organic layer was separated and the aqueous layer was extracted with chloroform. The extract and the organic layer were dried over a mixture of anhydrous potassium carbonate, and then the solvent was removed under reduced pressure, or a salt was formed with a hydrochloride to obtain crystals. The hydrochloride was removed to remove S-(-)-t-butyloxycarbonylaminopi. Got ferridine.

Example 20

Preparation of S-(-)-3-t-butyloxycarbonylamino-2,3,4,5,6,7-hexahydro-1H azepine

1 equivalent of dimethanesulfonoxy pentane derivative is dissolved in ammonia water (28%): acetonitrile (1: 1) and then reacted or 1 to 3 equivalents of sodium carbonate or potassium carbonate are stirred at 30-35 ° C. for 2-3 days. do. The reaction mixture was filtered and the organic layer was separated and the aqueous layer was extracted with chloroform. Combine the extract with the organic layer, dry over anhydrous potassium carbonate, remove the solvent under reduced pressure, or form a salt with hydrochloride to obtain crystals. Remove hydrochloride to remove S-(-)-t-butyloxycarbonylamino- 2,3,4,5,6,7-hexahydro-1H-azepine was obtained.

Example 21

Preparation of R-(+)-3-t-butyloxycarbonylamino piperidine

R-(+)-3-t-butyloxycarbonylamino piperidine by the same method as in Example 19 using R-(+)-2-t-butyloxycarbonylamino-dimethanesulfonoxypentane Is obtained.

Example 22

Preparation of R-(+)-3-t-butyloxycarbonylamino-2,3,4,5,6,7-hexahydro-1H-azepine

R-(+)-3-t-butyloxycarbonylamino-2, by the same method as in Example 20 using R-(+)-2-t-butyloxycarbonylamino-dimethanesulfonoxyhexane 3,4,5,6,7-hexahydro-1H-azepine is obtained.

Example 23

Preparation of S-(-)-3-t-butyloxycarbonylmethylaminopiperidine

S-(-)-3-t-butyloxycarbonylmethylamino pi using the same method as in Example 19 using S-(-)-2-t-butyloxycarbonylmethylamino-dimethanesulfonoxypentane Ferridine is obtained.

Example 24

Preparation of S-(-)-3-t-butyloxycarbonylmethylamino-2,3,4,5,6,7-hexahydro-1H-azepine

S-(-)-3-t-butyloxycarbonylmethylamino- by the same method as in Example 20 using S-(-)-2-t-butyloxycarbonylmethylamino-dimethanesulfonoxyhexane 2,3,4,5,6,7-hexahydro-1H-azepine is obtained.

Example 25

S-(-)-1-benzyl-3-t-butoxycarbonylamino piperidine

After dissolving 1 equivalent of dimethanesulfonoxy pentane derivative in dichloromethane, 2-5 equivalents of benzylamine and 1-3 equivalents of sodium carbonate are added and stirred at 50-55 ° C. The reaction mixture was filtered, washed three times with saturated aqueous sodium hydrogencarbonate solution, dried over anhydrous magnesium sulfate: potassium carbonate (1: 1), and the organic solvent was removed under reduced pressure. The obtained residue was separated by column chromatography (hexane: ethyl acetate = 4: 1), or a salt was formed with a hydrochloride to obtain crystals. The hydrochloride was removed to remove S-(-)-3-t-butyloxycarbonylamino Obtained piperidine.

Example 26

Preparation of S-(-)-1-benzyl-3-t-butoxyoxycarbonylamino-2,3,4,5,6,7-hexahydro-1H-azepine

One equivalent of dimethanesulfonoxy hexane derivative is dissolved in dichloromethane, and then 2 to 5 equivalents of benzylamine and 1 to 3 equivalents of sodium carbonate are stirred under reflux at 50 to 55 ° C. The reaction mixture was filtered, washed three times with saturated aqueous sodium hydrogencarbonate solution, dried over anhydrous magnesium sulfate: potassium carbonate (1: 1), and the organic solvent was removed under reduced pressure. The obtained residue was separated by column chromatography (hexane: ethyl acetate = 4: 1), or a salt was formed with a hydrochloride to obtain crystals. The hydrochloride was removed to remove S-(-)-1-benzyl-3-t-butyl Oxycarbonylamino-2,3,4,5,6,7-hexahydro-1H-azepine was obtained.

Claims (5)

L-glutamic acid and L-adipic acid and their optical isomers are protected by amino and carboxyl groups by a selective protection method to synthesize amino acid derivatives of general formula (II), Preparing a 2-amino-alkanediol derivative of general formula (III) having optical activity by selective reduction of the general formula (II) with a carboxyl protecting group, The diol compound of general formula (III) is changed to a compound of general formula (IV) by changing into a protecting group that can easily undergo a nucleophilic substitution reaction, A process for preparing 3-amino heterocyclic amine derivative of protected general formula (I) having optical activity by reacting a sulfonyl derivative of protected 2-amino-alkanediol of general formula (IV) with an amine derivative. Wherein n is 1 or 2, R ₁ is lower alkyl of 1-6 carbon atoms, R ₂ is hydrogen or lower alkyl of 1-6 carbon atoms, R ₃ is lower alkyl, benzyloxycarbonyl, in particular t-butyloxycarbon Bonyl, R ₄ represents a toluene group or methyl, R ₅ represents hydrogen or benzyl, (R)-or (S) -phenylethyl, benzhydryl group. The 3-amino heterocyclic amine of formula (I) according to claim 1, wherein the reducing reagent used in the preparation of the compound of formula (III) is lithium aluminum hydride or a mixture of calcium chloride and sodium borohydride. Process for the preparation of derivatives. The 3-amino heterocyclic amine derivative of the general formula (I) according to claim 1, wherein a triethylamine, pyridine or the like is used in an organic halide solvent such as methylene chloride in the preparation of the compound of the general formula (IV). Manufacturing method. 3. The compound of formula (I) according to claim 1, wherein a base used for ring-closing the compound of formula (IV) to the compound of formula (I) uses ammonia, potassium carbonate or sodium carbonate. Method for preparing amino heterocyclic amine derivative. The method of claim 1, wherein the solvent used when the compound of formula (IV) is closed with the compound of formula (I) is water, ethanol, acetonitrile, dichloromethane, or the like. A method for producing the 3-amino heterocyclic amine derivative derivative of (I).