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INTERCHAPTER Medicinal Chemistry - Problems in Organic Synthesis

The synthesis of most of the drugs in this problem set can be found in one or the other of the following references. The Organic Chemistry of Drug Synthesis, Vol. 1-6, by D. Lednicer et al., John Wiley & Sons, Inc. 1980 - 1999. Pharmaceutical Chemistry, Volume 1, drug synthesis, by H. J. Roth and A. Kleemann, Ellis Horwood Series in Pharmaceutical Technology, Halsted Press, 1988.

MC.1 Following is an outline for this synthesis of diazepam.

H N Cl 4-Chloro-Nmethylaniline

O CH3 Ac2 O (1) Cl N CH3

O PhCCl, AlCl3 (2)

O N Cl CH3 O

NaOH, H2 O (3)

CH3 N H Cl (B) O

O Cl (4) Cl Cl (A)

CH3 O N O Cl NH3 (5)

CH3 O N Cl O NH2 (6) Cl Diazepam

CH3 O N N

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Step 1: The amine nitrogen is first protected by treatment with acetic anhydride (Section 18.7B). Whereas a 2 amine is a good nucleophile and will react with benzoyl chloride to give an amide (Section 18.7A), the nucleophilicity of an amide nitrogen is so reduced that it will no longer react with an acid chloride. Step 2: Friedel-Crafts acylation (Section 21.1C) is directed by the amide nitrogen, which is activating and ortho, para directing (Section 21.2A). Chlorine is also ortho, para directing but it is deactivating and, therefore, the amide nitrogen takes precedence in directing the position of further electrophilic aromatic substitution. Step 3: The acetyl protecting group is removed by treatment with aqueous NaOH (Section 18.5D) to give (B). Step 4: Treatment of the amino group of (B) with chloroacetyl chloride results in acetylation (Section 18.7A) to form the amide group of (A). Step 5: Treatment of (A) with ammonia results in nucleophilic displacement of chlorine by an SN2 reaction (Section 8.3) to form a primary amine. Step 6: Intramolecular reaction of the ketone and 1 amine of (A) results in formation of an imine (a Schiff base, Section 16.10A) and completes this synthesis of diazepam.

MC.2 Following is an outline of this synthesis of lorazepam. NH2 Cl O Cl Et OOC COOEt H2N Cl (1) NH2 N Cl OEt C O COOEt Cl (A) H N CH3 OH Cl (3) (C) H N N Cl O COOEt

H N Br2 (2) Cl (B)

O COOEt N Br Cl

O COOEt N OCH3 Cl

hydrolysis and decarboxylation of the -ketoacid (4)

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draft.3.whb H N Cl (D) N H N BBr 3 (5) Cl N Cl Lorazepam

-3-

O OCH3 Cl

O OH

Step 1: This step is divided into two parts. In the first part, reaction of the 1 amino group of diethyl 2-aminopropanedioate with the carbonyl group of the diaryl ketone gives an imine (a Schiff base, Section 16.10A). In the second part of this step, reaction between the 1aromatic amine and an ester group gives an amide by nucleophilic acyl substitution (Section 18.7C). Step 2: Bromination of this -ketoester proceeds by way of keto-enol tautomerism (Section 16.11) followed by reaction of the enol with bromine (Section 16.12C). Step 3: Solvolysis of the tertiary bromide proceeds by an SN1 mechanism (Section 8.3). Step 4: Hydrolysis of the ester to a carboxylic acid (Section 18.5C) followed by heating results in decarboxylation of the -ketoacid (Sections 17.9A and 19.3D). Step 5: Boron tribromide, BBr3, is widely used to cleave ethers under very mild conditions. This reagent is a colorless liquid most commonly supplied as a 1.0 M solution in CH2Cl2 or hexane. It is highly sensitive to moisture and reacts rapidly with water to give B(OH)3 and HBr. Cleavage of an ether requires one mole of BBr3 per mole of ether.

RCH2 OCH3 + BBr 3 RCH2 OBBr 2 + 3 H2 O

RCH2 OBBr 2 + CH3 Br RCH2 OH + B(OH) 3 Boric acid

The first step in this ether cleavage reaction is an acid-base reaction between boron tribromide (a Lewis acid) and the ether (a Lewis base) followed by loss of bromide ion. Bromide ion then participates in an SN2 reaction, attacking the methyl carbon and displacing oxygen to give an alkylborate ester. Hydrolysis of this ester gives the alcohol.

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RCH2 -O-CH3

Br + B Br Br

Lewis acidbase reaction Br B + :Br RCH2 -O CH3 Br

Br RCH2 -O

Br B Br CH3

loss of bromide ion

MC.3 The synthesis of clonazepam is very similar to that of diazepam (MC.1) and lorazepam (MC.2).

SN 2

RCH2 -O-B
:

Br Br + CH3 Br

HO

O Cl SOCl2 (1)

Cl

O Cl AlCl3 (3) O NHCCH3 O NHCCH3 NaOH O2N O Cl (4)

2-Chlorobenzoic acid NH2 O2N p-Nitroaniline Ac2 O (2) O2N

NH2 O2N O

O Cl (5) Cl Cl O2N

H N

O O Cl Cl NH3 (6)

H N O2N

O O NH2 Cl

O HN (7) N O2N Cl

Clonazepam

Step 1: 2-Chlorobenzoic acid is treated with thionyl chloride to give an acid chloride (Section 17.8).

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Step 2: p-Nitroaniline is treated with acetic anhydride to form an amide (Section 18.7B), thus protecting the amino group. Step 3: Friedel-Crafts acylation (Section 21.1C) gives a diaryl ketone. Step 4: Removal of the amine protecting by hydrolysis of the amide in aqueous base (Section 18.5D) gives the free amine. which is then treated in Step 5: Treatment of the amine with chloroacetyl chloride (Section 18.7A) gives an -chloroamide. Step 6: Nucleophilic displacement of the primary chloride by ammonia (Section 8.3) gives a primary amine. Step 7: Reaction of the primary amine with the nearby ketone gives an imine (Section 16.10A) and closes the seven-membered ring of clonazepam.

MC.4 The synthesis of gabapentin involves two carbon-carbon bond forming steps. The first involves condensation of an enolate anion (Section 19.2A) and ketone. The second involves a Michael addition (Section 19.8A).

COOEt O+ Cyclohexanone COOEt Diethyl malonate

NaOEt (1)

OH COOEt COOEt Tetrahedral carbonyl addition intermediate (1)

COOEt COOEt

(i) NaOH/ H2O (ii) HCl/ H2 O (2)

COOH COOH

heat (3)

Et OH, H+ (4) COOH

ester hydrolysis (7)

COOEt

NaCN (5)

CN COOEt

Pt / C (6)

NH2 COOEt

NH2 COOH Gabapentin

Step 1: When treated with sodium ethoxide, diethyl malonate is converted to its enolate anion (Section 19.7) and then, in a carbonyl condensation related to the aldol reaction (Section 19.2) and the Claisen condensation (Section 19.3), adds to the carbonyl carbon of cyclohexanone to

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give a tetrahedral carbonyl addition compound. Dehydration of this addition compound gives an ,-unsaturated diester. Step 2: Base-promoted hydrolysis of the diester in aqueous base followed by acidification with HCl (Sections 18.5C and 19.7) gives an ,-unsaturated dicarboxylic acid. Step 3: Heating the -dicarboxylic acid results in decarboxylation (Section 17.9B) and gives an ,unsaturated carboxylic acid. Step 4: Treatment of the carboxylic acid with ethanol in the presence of a p-toluenesulfonic acid catalyst (Fischer esterification, Section 17.7A) converts the carboxyl group to an ethyl ester. Step 5: Michael addition (Section 19.8A) of cyanide ion to the ,-unsaturated ester gives a cyanoester. Step 6: Treatment of the cyano group with hydrogen over a platinum-on-charcoal catalyst reduces the cyano group to a primary amine. Step 7: Hydrolysis of the ester group (Section 18.5C) using either aqueous NaOH or HCl gives gabapentin.

Note that although gabapentin is shown in the problem as containing primary amino and carboxyl groups, it is better represented as an internal salt resulting from proton transfer from the acidic carboxyl group to the basic amino group.
NH2 COOH Gabapentin intramolecular acid/base reaction NH3 + COO-

MC.5 Following is the outline for this synthesis of phensuximide.

+ CN COOEt Ethyl cyanoacetate NaOEt H CN COOEt (A) KCN NC (B) CN COOEt

CHO Benzaldehyde

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1 . NaOH, H2 O 2 . HCl, H2 O 3. heat HOOC (C) COOH

Et OH, H+ Et OOC (D) COOEt

CH3 NH2 O N CH3 Phensuximide O

(a) As shown in the following table, a cyano group has about the same acid-strengthening effect on an -hydrogen as does an ester group. Thus, the acidity of an -hydrogen of ethyl cyanoacetate is comparable to that of an -hydrogen in diethyl malonate (pKa 13, Section 19.7).

pK a O RCH2 COEt RCH2 C N 24-25 25 O O Et OCCH2 COEt N CCH2 C N

pK a 13 11

When treated with sodium ethoxide, ethyl cyanoacetate is converted to its enolate anion (Section 19.7) and then, in a carbonyl condensation related to the aldol reaction (Section 19.2) and the Claisen condensation (Section 19.3), adds to the carbonyl carbon of benzaldehyde to give a tetrahedral carbonyl addition compound. Dehydration of this addition compound gives an ,-unsaturated cyanoester. (b) Treatment of (A) with KCN results in Michael addition (Section 19.8A) of cyanide ion to the carbon of the ,-unsaturated cyanoester. (c) Treatment of (B) with NaOH, H2O results in base-promoted hydrolysis of the ester and cyano groups (Sections 18.5C and 18.5E)) to carboxylic salts. Acidification with HCl and heating results in decarboxylation of the -dicarboxylic acid (Section 17.9B). (d) Treatment of the dicarboxylic acid with ethanol in the presence of an acid catalyst such as ptoluenesulfonic acid (Fischer esterification, Section 17.7A) converts each carboxyl group to an ethyl ester.

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(e) Treatment of the diester with methylamine results in conversion of one ester and then the other to an amide (Section 18.7C). Each reaction is an example of nucleophilic acyl substitution (Section 18.4).

In an even more direct route to phensuximide, phenylsuccinic acid is treated with methylamine to give an ammonium salt and then heated to form the imide.

CH3 NH2 , heat HOOC COOH

O N CH3 Phensuximide O

+ H2 O

(f) For the synthesis of methsuximide, use acetophenone as the starting carbonyl compound. For the synthesis of ethosuximide, use 2-butanone as the starting material and ammonia as the amine to form the five-membered imide ring.
same steps as for phensuximide O N CH3 Methsuximide O

+ O Acetophenone

CN COOEt

Ethyl cyanoacetate

+ O 2-Butanone

CN COOEt

same steps as for phensuximide Et OOC COOEt

NH3 O N H O

Ethyl cyanoacetate

Ethosuximide

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(g) Only ethosuximide has a hydrogen on the imide nitrogen. It is the most acidic and has an acidity comparable to that of succinimide (pKa 11, Section 18.2). The imide anion is stabilized by resonance interaction with the carbonyl groups on either side of it.

MC.6 The synthesis of diethylcarbamazine can be accomplished in five steps. Key to forming each new C-N bond is the nucleophilicity of nitrogen.

CH3 NH2 + Methylamine

O Ethylene oxide
O

OH (1) OH N SOCl2 (2) N

Cl Cl NH3 (3) N N

N-Methylpiperazine
O N N N Diethylcarbamazine

O OEt N N OEt

N (5)

Cl

(4)

Step 1: Treatment of methylamine with two moles of ethylene oxide results in nucleophilic opening of the highly strained epoxide ring (Section 11.9B). Step 2: Treatment of the diol with two moles of thionyl chloride (Section 9.5C) gives a dichloride. Step 3: Treatment of the dichloride with one mole of ammonia results in nucleophilic displacement of first one chloride and then the second to form a six-membered nitrogencontaining ring. Note that the dichloride has the structural characteristics of a nitrogen mustard (Section 8.5) and displacement of chlorine most probably involves neighboring group participation by the tertiary amine of the mustard. Step 4: Nucleophilic displacement of chlorine from ethyl chloroformate by nitrogen (Section 18.7A) gives the carbamic ester; that is, a derivative of carbonic acid that is both an amide and an ester. Note that, in the reaction of the amine with ethyl chloroformate, it is -Cl that is displaced and not the -OEt group; chloride is a more stable anion than ethoxide ion and, therefore, is more readily displaced from ethyl chloroformate than ethoxide ion.

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Step 5: Treatment of the carbamide with diethylamine (Section 18.7C) gives diethylcarbamazine by nucleophilic acyl substitution.

In an alternative synthesis, N-methylpiperazine is treated with phosgene, the diacid chloride of carbonic acid, to give a carbamoyl chloride. This acid chloride is then treated with diethylamine to give diethylcarbamazine.

O N N
N- Methylpiperazine

O OEt N N Cl

H Cl (4')

N N (5') N

O N

Diethylcarbamazine

MC.7 Following is an outline for this synthesis of amitriptyline.

1. H3 PO4 (1) COOH (A) O (B)

Cl, Mg

2. H3 O+ (2)

HO (C)

HBr (3) Br (D)

(CH3 ) 2 NH (4) N Amitriptyline

Step 1: This step is a type of electrophilic aromatic substitution resulting in acylation of the aromatic ring. The electrophile is an acyl cation.

+ H-O-PO3 H2 C OH O :

+ C O H O H

+ -:O-PO3 H2

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+ H-O-PO3 H2 C+ O An acyl cation O H

-:

O-PO3 H2

Step 3: This transformation is initiated by proton transfer to the -OH group of the 3 alcohol to give an oxonium ion followed by loss of H2O to give a tertiary carbocation. What must be done next is opening of the highly-strained three-membered ring and formation of a primary bromide. Because it is not acceptable to propose a primary carbocation, propose that opening of the three-membered ring and formation of the primary bromide are concerted (simultaneous).

Br-H

HO

H O + H

In an alternative synthesis of amitriptyline, the ketone (B) is treated with the Grignard reagent formed from 3-dimethylaminopropyl bromide to give a tertiary alcohol. Acid-catalyzed dehydration of the alcohol gives amitriptyline.
BrMg O (B) (2') N HCl HO N (3') Amitriptyline N

MC.8 Following is an outline for this given synthesis of fluoxetine.

+ :Br
-

Br

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O H (A) N (1)

N NaBH4 (B)

HO

N SOCl2 (C)

Cl

(D)

OH F3 C CH3 ONa F3 C (E) 1 . NaOH, H2 O 2 . HCl, H2 O F3 C An N-substituted carbamic acid O N Cl

O O OEt F3 C O

OEt C N

(F) COOH N F3 C Fluoxetine H N

(a) Conversion of (A) to (B) involves a Michael addition (Section 19.8A) of dimethylamine to the ,-unsaturated ketone. (b) Conversion of (B) to (C) is a two-electron reduction of the carbonyl group of the ketone to a primary alcohol. Suitable reducing agents are H2 in the presence of a transition metal catalyst such as Pt or Pd (Section 16.14A), or a metal hydride reduction using NaBH4 (Section 16.14B). (c) To convert (C) to (D) treat the secondary alcohol group with thionyl chloride, SOCl2 (Section 9.5C). (d) The first step in the conversion of (E) to (F) is nucleophilic addition of the tertiary amine nitrogen to the carbonyl group of ethyl chloroformate to give a tetrahedral carbonyl addition intermediate (TCAI) followed by its collapse to give a quaternary amide with a positive charge on the nitrogen of the amide. Nucleophilic attack of chloride (an SN2 reaction, Section 8.3) on one of the two methyl group and displacement of nitrogen gives the ethyl carbamide and chloromethane.

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CH3 O + N OEt CH3 Cl

Cl

O: OEt CH3 CH3

R +N

OEt C CH3 R +N CH3 O O R OEt C N CH3

:Cl-

(f) (F) is converted to fluoxetine by base-promoted hydrolysis of the ester (Section 18.5C) using aqueous NaOH to give the N-substituted carbamic acid followed by its decarboxylation.

An alternative synthesis of fluoxetine begins with nucleophilic aromatic substitution (Section 21.3) of the fluorine atom of 4-trifluoromethylfluorobenzene. Removal of the phthalimide protecting group by hydrazinolysis followed by alkylation of the amino group gives fluoxetine.
O F + F3 C 4-Trifluoromethylfluorobenzene Na+ -O N O (1) F3 C O O N O

N2H4 (2)

A TCAI

+ CH3 Cl

O F3 C

NH2

O Cl OEt (3) F3 C

H N O

OEt

O LiAlH4 (4) F3 C

H N Fluoxetine

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MC.9 Following is an outline for this synthesis of venlafaxine.

O + CH3 O Anisole Cl Cl AlCl3 (1) CH3 O Cl N O (2) CH3 O H N O

Chloroacetyl chloride

O NaBH4 (3) CH3 O N OH SOCl2 (4) CH3 O N Cl Mg , (5) CH3 O Venlafaxine N OH

Step 1: Synthesis begins with a Friedel-Crafts acylation (Section 21.1C) of anisole. Step 2: Nucleophilic displacement of the primary chloride by dimethylamine (SN2, Section 8.3) gives the tertiary amine. Step 3: Metal hydride reduction of the ketone (Section 16.14B) gives the secondary alcohol. Catalytic reduction using H2 and a transition metal catalyst such as Pd or Pt (Section 16.14A) may also be used to reduce the ketone. Step 4: Treatment of the secondary alcohol with thionyl chloride (Section 9.5C) converts the alcohol to a chloride. Step 5: The final step in the synthesis is a Grignard reaction with cyclohexanone followed by treatment of the magnesium alkoxide salt with aqueous acid (Section 16.6A).

MC.10 The synthesis of moclobemide can be carried out by the following scheme.

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N O Morpholine (1) N O OH H

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O Ethylene oxide N KN3 SOCl2 (2) O N O (4) NH3 (3) O (7) Cl HO O SOCl2 (6) Cl Cl O N O H N O Moclobemide Cl (5) N3 H2 / Pt N NH2

Cl

Step 1: Treatment of ethylene oxide with morpholine results in nucleophilic opening of the highly strained three-membered ring (Section 11.9B) and formation of a primary alcohol. Step 2: Treatment of the primary alcohol with thionyl chloride (Section 9.5C) converts the alcohol to a chloride. Steps 3, 4, and 5: The most direct way to convert the primary halide to a primary amine is displacement of chloride by ammonia (SN2, Section 8.3). However, as pointed out in Section 22.8A, unless reaction conditions are very carefully controlled, there is formed a complex mixture of primary, secondary, tertiary amines as well as a quaternary ammonium salt. An alternative strategy is to use azide ion, N3-, as the nitrogen-containing nucleophile (Section 22.8B). The resulting alkyl azide is no longer a nucleophile. Reduction of the alkyl azide to the desired primary amine is accomplished using H2/Pt. Step 6: The carboxylic acid is converted to its acid chloride by reaction with thionyl chloride (Section 17.8). Step 7: The synthesis is completed by reaction of the acid chloride and amine (Section 18.7A) to give the amide group of moclobemide.

An alternative synthesis of moclobemide begins with aziridine, the nitrogen analog of ethylene oxide. Acylation of the amine nitrogen with 4-chlorobenzoyl chloride (Section 18.7A) gives an

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aziridine amide. Treatment of the aziridine ring with morpholine results in nucleophilic opening of the ring to give moclobemide.

Cl NH + Cl Aziridine N O O

Cl

N O

N O

H N O Moclobemide

Cl

MC.11 Following are steps in this synthesis of nabumetone.

O
3 2 4 5 6

CH3 O

CH2 O, HCl (1) 7

Cl CH3 O

NaOEt , COOEt (2)

2-Methoxynaphthalene

O NaOH, H2 O CH3 O COOEt (3) CH3 O

O HCl, H2 O COO- Na+ (4)

O COOH heat (5)

CH3 O

CH3 O

Nabumetone

(a) Chloromethylation is initiated by proton transfer to formaldehyde to give a resonancestabilized cation.

H H O: + H-Cl H H +H O H + H H O : + : Cl-

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This cation is sufficiently electrophilic to react with 2-methoxynaphthalene to give a resonance-stabilized cation. Comparing contributing structures for attack and positions 6 and 7 of the aromatic ring, we see that if attack occurs at carbon 6, oxygen of the methoxyl group can participate in stabilizing the cation. If attack occurs at carbon 7, oxygen of the methoxyl can not participate in stabilizing the cation. Because cation 6 is more stable, there is a lower energy of activation for its formation and it is the preferred cation intermediate.

H
6

CH2 OH CH3 O +

H
6

CH2 OH

CH3 O
6

+ CH3 O
7

H H

+H O + CH3 O
7

+ CH2 OH CH3 O
7

CH2 OH

Proton transfer from cation 6 to chloride ion completes the electrophilic aromatic substitution and gives the hydroxymethyl group.
H
6

CH2 OH

:ClCH3 O

CH2 OH

CH3 O +

Chloromethylation is completed by proton transfer to oxygen of the CH2OH group to give an oxonium ion, loss of H2O to give a resonance-stabilized benzylic carbocation, and finally reaction of the benzylic carbocation with chloride ion.

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CH2 OH CH3 O + H-Cl CH3 O CH2 + CH3 O

:Cl-

+ CH2 -OH2

(b) The steps in the acetoacetic ester synthesis (Section 19.6) are shown in the outline for the synthesis. (c) Following are structural formulas of 6-methoxynaphthylacetic acid, ibuprofen, and naproxen.

CH3 O 6-Methoxynaphthylacetic acid

MC.12 Following is an outline of this synthesis of racemethorphan.

O Cl NC LiAlH4 (1) (A) (B) H2N CH3 O (2) CH3 O (C) H O N H3 PO4 (3)

CH2 Cl CH3 O

COOH Ibuprofen

COOH CH3 O Naproxen

COOH

N NaBH4 (4) CH3 O (D) CH3 O

H N (redraw)

H N H3 PO4 (5) CH3 O (E)

(E)

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O H N H O Et O Cl (6) Et O N H

-19H3 C N LiAlH4 (7) CH3 O (G) CH3 O Racemethorphan H

CH3 O

(F)

(a) Lithium aluminum hydride reduction of the nitrile gives a primary amine (Section 18.11C). (b) The reagent is 4-methoxybenzoyl chloride. Reaction of this acid chloride with the primary amine gives an amide (Section 18.7A). (c) This intramolecular cyclization is initiated by protonation of the carbonyl group of the amide. The resulting cation (a Lewis acid) reacts with the carbon-carbon double bond of the alkene (a Lewis base) to give a carbocation intermediate, loss of a proton from which gives the carboncarbon double bond of the newly formed six-membered ring. Loss of H2O from the -amino alcohol gives the imine (Schiff base). In this mechanism, phosphoric acid is represented by HA.

H A-H
:O N

H + N H O

H HO N H +
:A N -H2 O

CH3 O

(C)

CH3 O
HO N H

CH3 O

CH3 O

CH3 O

(D)

(d) Conversion of (E) to (F) involves an electrophilic aromatic substitution like that described in Section 21.1D. In this case, the attacking electrophile is the carbocation generated by protonation of the carbon-carbon double bond of the substituted cyclohexene ring.

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H N H-A

N H +

CH3 O

(E)

CH3 O

N H

N H

CH3 O

+ H
:A -

CH3 O

(F)

(e) The reagent is ethyl chloroformate. (f) The reagent is lithium aluminum hydride.