A new approach to the synthesis of Atenololusing Coherent Synthesis™™™™™

This report describes the efficient two-step synthesis ofAtenolol from p-hydroxyphenylacetamide, using microwavedielectric heating. In both steps, significant acceleration ofreaction rates and a slight increase in the yield were achievedcompared to conventional procedures.

INTRODUCTIONAtenolol (2-[4-[2-hydroxy-(isopropylamino)propoxy]phenyl]acetamide) is a β1-selective(cardioselective) adrenoreceptorblocking agent that is used fortreatment of hypertension and angina.Atenolol, in a formulation containingthe racemic mixture, was one of thetop-selling drugs in the US market inthe year 2000.1

The most straightforward method ofpreparing Atenolol involves thereaction of commercially available 4-hydroxyphenylacetamide (1) withepichlorohidrin, followed by theaddition of isopropylamine2,3 atelevated temperatures for a long

period of time. In this report, wedescribe a versatile new approach forthe synthesis of Atenolol employingCoherent Synthesis™ technologybased on microwave dielectric heating.The use of microwave dielectricheating as an efficient tool for en-hancing reaction rates, especially fortransformations that require longperiods of time and high temperatures,has been well described.4 It issuggested that the synthesis ofAtenolol in the solution phase undermicrowave conditions would provide aspeedy source not only of thisimportant drug but also of a library ofits analogues.

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OHNH2

O

O

ONH2

OH

NH

OCl

BnNMe3Cl

NH2

Atenolol

1) a)

b)

2)

H2O

a)

b)

EXPERIMENTAL PROCEDUREStep 1Preparation of 1-[p-(carbamoyl-methyl)phenoxy]-2,3-epoxy-propane (2):A process vial was charged withepichlorohydrin (5) (2.5 mL),4-hydroxyphenylacetamide,1, (302 mg,2.0 mmol) and benzyltrimethyl-ammonium chloride (13.0 mg, 0.07mmol). The resulting mixture washeated for 300 sec. at 180oC. Aftercooling, the precipitate was filtered off.The crude products 2 and 3 wereseparated by recrystallization fromMeOH to give 2 in 70% yield (287 mg),mp: 166-167oC, Rf=0.55, CHCl3/MeOH(5/1).

Step 2Preparation of Atenolol (4):A process vial was loaded withisopropyl amine (6) (2.3 mL), water (0.2mL) and 2 (207 mg, 1.0 mmol). Themixture was heated for 600 sec. at130oC. After cooling, solvents wereevaporated and the residue wasdissolved in 1 mL of 2N HCl and filtered.The pH of the filtrate was adjusted to11—12 using 30% NaOH solution. Theresulting suspension was cooled to 5oC,the precipitate was filtered and washedwith a small amount of cold water. Afterdrying, 250 mg (93% yield) of Atenololwas obtained. mp:148-149oC, Rf=0.09CHCl3/MeOH (5/1).

NH2O

OHNH2

O

O OH

NH

OCl

NH2NH2

O

O OH

Cl

O

NH2O

O

+1

2

3

45

6

Step 1 Step 2

Coherent Synthesis™ Conventional2 Conventional3

Step 1 Temp/°C 180 95 – 100 90

Time 5 min 6 h 3 h

Step 2 Temp/°C 130 110 40

Time 10 min 12 h 2 h

Total Yield 65% NA 62%

RESULTSAfter investigating the proceduresdescribed in the literature2,3 undermicrowave conditions, it was foundthat benzyltrimethylammoniumchloride was a better catalyst thanmorpholine or piperidine for synthesisof the epoxy derivative (2). A hightemperature and a relatively shortreaction time is necessary (180oC, 300sec.) to reach complete conversion ofthe initial amide (1) with this catalystunder microwave irradiation. Uponwork up and recrystallisation frommethanol, the epoxide (2) wasobtained with a 70% yield. Accordingto literature2,3, Atenolol can beproduced from the epoxy derivative(2) and chloride (3), with an excess ofisopropyl amine at an elevatedtemperature and pressure. However,when the conditions described by S.M.Jang et al.3

(40-60oC/1–2 h) were tried in ourlaboratories, conversion of reagent 2resulted in a low yield of Atenolol(62%). In fact, from our experience, itrequires a 12-hour reaction at 50oC(conventionally) for full conversion of 2to Atenolol.

The addition of isopropyl amine (6)

to the epoxy derivative (2) undermicrowave conditions at 130oC for 600sec. resulted in 93% isolated yield ofAtenolol. The presence of water asco-solvent is essential to improve theyield of the product (98% vs. 83%HPLC yields). The total yield ofAtenolol from the amide (1) was 65%.

CONCLUSIONSAn efficient, 2-step synthesis ofAtenolol from p-hydroxyphenylacetamidewas carried out in a SmithSynthesizer™.In both steps, significant accelerationof the reaction rate were achievedcompared with the rates achievedusing conventional literatureprocedures. The present approch canbe applied for general use, since thereaction of phenols with epichlorohidrinand the subsequent treatment withamines can be applied not only to thesynthesis of Atenolol but also to thepreparation of other α-amino alcoholbased drugs, such as Propranolol,Metoprolol, Propafenon and theirderivatives.

OOH

NH

OO

OH

NH

O OOH

NH

MetoprololPropranolol Propafenon

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REFERENCES

1.http://www.rxlist.com/top200.htm. Source:Scott-Levin, Newton PA -Based on more than 2.04billion prescriptionsdispenses in US.

2.Barrett, A. M et al., USpatent US 3,934,032, 20Jan 1976.Barrett, A. M et al., USpatent US 3,836,671, 17September 1974.

3. Jang, S. M. et al., USPatent US 5,290,958, 1March 1994.

4. Lidström, P., Tierney, J.,Wathey, B. and Westman,J. Tetrahedron, 2001, 57,9225-9283.

Coherent SynthesisTM is anintegrated approach tochemical synthesis,combining the benefits offast synthesis withadvanced lab automation,knowledge-based systemsand convenience products.

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