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(S)-Atenolol

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Figure US06982349-20060103-C00001

(S)-atenolol

  • Description
    Selective β1 adrenoceptor antagonist
  • Biological descriptionSelective β1 adrenoceptor antagonist. Orally active. Limited ability to cross the blood-brain barrier. Antihypertensive activity in vivo.

Properties

  • Chemical name(S)-(-)-4-[2-Hydroxy-3-[(1-methylethyl)amino]propoxy]benzeneacetamide
  • Molecular Weight  266.34
  • Molecular formula  C14H22N2O3
  • CAS Number  93379-54-5
m.p. 152–153° C.
[α]D 25: −17.2 (c=1.0, 1N HCl).
IR: νmax 3352, 3168, 1635, 1242 cm−1.

1H NMR (DMSO-d6): δ 0.99 (d, J=7 Hz, 6H, 2×CH3), 2.60 (m, 1H, CH), 2.74 (m, 2H, CH2), 3.27 (s, 2H, CH2), 3.88 (m, 4H, CH2, CH, NH), 6.83 (d, J=8 Hz, 2H, Ar—H), 7.14 (d, J=8 Hz, 2H, Ar—H), 7.40 (bs, 1H).

13C NMR (DMSO-d6):
22.01, 22.09,
41.26, 48.39, 49.38, 67.73, 70.58, 114.16, 128.41, 129.93, 157.17, 172.59 ppm.

The compound (R,S)-atenolol (4-[2-hydroxy-3-[(1-methylethyl)amino]propoxy]-benzeneacetamide) is useful as a β-adrenegic blocker for the treatment of angina pectoris, arrhythmia and hypertension. It is known that atenolol is a 1-aryloxy-3-aminopropane-2-ol derivative wherein the hydroxy bearing carbon is an asymmetric carbon and hence exists as R- and S-isomers. It is also known that the S-isomer is particularly useful as a β-adrenegic blocker in view of its superior pharmacological activities. It is reported that S-atenolol has hypotensive activity and activity on brachycardia (A. A. Pearson, T. E. Gaffney, T. Walle, P. J. Privitera; J. Pharmacol. Exp. Ther., 250(3), 759, 1989).

In prior art, the optical resolution of racemic atenolol has been studied to obtain the desired optically active atenolol, however, any practical method has not been reported so far. It is also reported that the diastereomers of atenolol having high purity is obtained from racemic mixture by using (R,R)-O,O-di-toluoyltartaric acid anhydride (M. J. Wilson et al., J. Chromatogr. (NLD) 431 (1), 222–227, 1988). However, this method is not suitable for large scale production of optically active atenolol as it requires a large volume of solvent and further it is technically very troublesome to recycle (R,R)-O,O-di-toluoyltartaric acid anhydride.

Another method of preparing optically active atenolol has been proposed in JP-A-50-77331 and DE-A-2453324:

Figure US06982349-20060103-C00003

Wherein Z is halogen atom or sulphonyloxy group, and * means asymmetric carbon.

However, this process has some disadvantages as this process requires several steps for obtaining optically active S-atenolol stating from D-manitol; moreover the yield of S-atenolol by this process is less than 50% and the optical purity is just about 80% ee.

Another method for the preparation of S-atenolol has been reported in U.S. Pat. No. 5,223,646 which consists of reacting sodium salt of 4-carbamoylmethylphenol with R-epichlorohydrin at 0° to 35° C. to obtain an intermediate—an optically active glycidyl ether and then reacting the optically active intermediate glycidyl ether with isopropylamine to obtain S-atenolol (see also EP-435068 A2; EP-605384; JP 03077856 A2).

It has also been reported that the above procedure gives optically active glycidyl ether and atenolol of 90–96% ee optical purity. According to this report, the optical purity of atenolol may be enhanced to 98% or higher, if the intermediate optically active glycidyl ether is repeatedly recrystallised from a suitable solvent.

It has also been reported that the optically active atenolol in an optical purity of 98% or higher can be produced from atenolol of lower optical purity by converting it to its salt with Bronsted’s acid (K. Kazuhiro; T. Yosikazu; F. Yoshiro; Y. Hiroshi; O. Junzo, Chem. Pharm. Bull., 46(3), 505–507, 1998).

The separation of the atenolol salt having higher optical purity (>98% ee) is carried out by dissolving the atenolol salt having lower optical purity in a solvent, precipitating solid materials having a high content of racemic atenolol salt, and then isolating the desired atenolol salt having higher optical purity (>98% ee) by solid-liquid separation method. The optically active salt having high optical purity is then subjected to removal of acid moiety to isolate the desired optically active atenolol in free form. Though this process yields atenolol of higher optical purity, it involves salt formation and tedious separation of racemic salt from an optically active salt, which leads to the lower yields of desired optically active atenolol. Further, the salt has to be converted to free atenolol either by neutralisation or using ion exchange resins. Thus, this process gives lower overall yield of the desired optically active atenolol is low.

There is therefore a need to provide a process whereby S-atenolol may be obtained in high yield and high optical purity.

US6982349

Emcure Pharmaceuticals Limited

http://www.google.com/patents/US6982349

Satish Ramanlal Mehta, Baburao Manikroa Bhawal, Vishnu Hari Deshpande, Mukund Keshav Gurjar

Accordingly, the present invention provides a process for the preparation of (S)-atenolol (1), which comprises the steps of:

    • a) reacting a phenol of formula 2:
      Figure US06982349-20060103-C00004

      with an (R)-epichlorohydrin of formula (3):

      Figure US06982349-20060103-C00005

      in presence of an alkali metal hydroxide and a quaternary ammonium salt as phase transfer catalyst (PTC) in an aqueous solution at a temperature in a range of −10° C. to 0° C. to obtain optically active intermediate glycidyl ether of formula 4:

      Figure US06982349-20060103-C00006
    • b) reacting the optically active intermediate glycidyl ether (4) with isopropylamine at 10° to 40° C. to obtain (S)-atenolol of the formula 1:
      Figure US06982349-20060103-C00007

      in good chemical yield and high optical purity (>99 ee).

One major advantage of this process is that S-atenolol may be obtained directly without going through the cumbersome step of recrystallization or additional salt formation step, as in the prior art.

The aqueous alkali metal hydroxide used in the process is selected from sodium hydroxide or potassium hydroxide and is used as aqueous solution in 1 to 1.5 moles to 1 mole of the phenol 2. The (R)-epichlorohydrin (3) used in the process is preferably of high optical purity and used in an amount of 1 to 3 moles, more preferably 1 to 1.6 moles, to 1 mole of phenol (2).

The quaternary ammonium salt has the formula:
R1R2R3R4N+X

Wherein R1, R2, R3 and R4 are same or different, each an alkyl group having 1 to 16 carbon atoms (e.g. methyl, ethyl, propyl butyl etc), phenyl or benzyl, X is chlorine, bromine, iodine, hydrogen sulphate or hydroxyl group. The amount of quaternary ammonium salt used is 0.001 to 2% by weight of phenol (2).

The Applicant studied the reaction temperature extensively and found that it plays an important role in deciding optical purity of (S)-atenolol (1) formed via optically active glycidyl ether. When the reaction of phenol (2) and (R)-epichlorohydrin is carried out at 5° C. or at any other higher temperature, (S)-atenolol (1) of a lower optical purity was obtained via optically active glycidyl ether, as for example in EP 435068.

The Applicant, after studying the prior art processes found that during the course of these reactions, the phenoxide (or phenol) attacks the C-1 carbon atom of (R)-epichlorohydrin with the expulsion of chloride to yield (R)-glycidyl ether, which on reaction with isopropyl amine gives (R)-atenolol. The original epoxide ring remains unchanged in the reaction.

Figure US06982349-20060103-C00008

Thus, the reaction of phenol (2) at carbon centre C-1 of (R)-epichlorohydrin by nucleophilic displacement of chlorine leads to the formation of undesired (R)-atenolol via optically active (R)-glycidyl ether as a side product, which accounts for the low yield of optically active S-atenolol in the prior art.

The Applicant then conducted this reaction at a lower temperature and found to their surprise that S-atenolol could be obtained in high yield. The reason is that during the course of reaction, the phenoxide (or phenol) ion attacks the C-3 carbon atom of (R)-epichlorohydrin and opens the epoxide ring. The new epoxide ring formation takes place by the attack of O on C-3 carbon with expulsion of chloride to give (S)-glycidyl ether, which on reaction with isopropyl amine gives (S)-atenolol. Thus, the reaction of phenol (2) at carbon centre C-3 of (R)-epichlorohydrin leads to the formation desired (S)-atenolol (1) as a major product via optically active glycidyl ether (4).

Figure US06982349-20060103-C00009

The lower optical purity in (S)-atenolol formation in the prior art may therefore be on account of the slow reaction rate at carbon atom 1 and the high yield of S-atenolol obtained by the process of the present invention may be due to the reaction at carbon atom 3 of (R)-epichlorohydrin (3). Both these reactions occurring on different atoms are shown as path ‘a’ and path ‘b’ in the following scheme herebelow.

Path ‘a’ is the process of the present invention whereas path ‘b’ is the process of the prior art.

Figure US06982349-20060103-C00010

EXAMPLE 1A mixture of (R)-epichlorohydrin ([α]D 25: −35.1 (neat), 138.75 g, 1.5 mole) and water (82 ml) was cooled to −7° C. and to this cold reaction mixture is added a solution of 4-hydroxyphenyl acetamide of formula 1 (151.00 g, 1 mole) and benzyltrimethylammonium chloride (1.3 g) in sodium hydroxide [40 g, 1 mole; dissolved in water (670 ml)] with stirring over a period of 3 hrs. maintaining the temperature at −7° C. to −5° C. The reaction mixture is then stirred further at −7° C. to −5° C. for 50 hrs. The precipitated solid is filtered, washed with water and dried at 60° C. to give 176 g of a mixture of S-glycidyl ether of formula 4 and S-chlorohydrin of formula 5 in about 3:2 ratio. m.p. 159–161° C.

EXAMPLE 2A mixture of isopropylamine (1.1 kg) and water (200 ml) is cooled to 10° C. and a mixture of S-glycidyl ether of formula 4 and S-chlorohydrin of formula 5 obtained in Example 1 (176 g) is added to it in lots maintaining temperature between 10 to 15° C. over a period of 3 hrs. The reaction is then stirred further for another 10 hr. The excess of isopropylamine is removed by distillation and the residue was treated with the water. The slurry so obtained is acidified with 5N HCl to pH 2.0. The resulting solution is then filtered, washed with water. The filtrate is basified with 2N NaOH to pH 11.7 and precipitated solid is filtered washed with water and dried to get (S)-atenolol (206 g, 91%) in 99.1% ee when analysed by using Chiracel OD column.

m.p. 152–153° C.

[α]D 25: −17.2 (c=1.0, 1N HCl).

IR: νmax 3352, 3168, 1635, 1242 cm−1.

1H NMR (DMSO-d6): δ 0.99 (d, J=7 Hz, 6H, 2×CH3), 2.60 (m, 1H, CH), 2.74 (m, 2H, CH2), 3.27 (s, 2H, CH2), 3.88 (m, 4H, CH2, CH, NH), 6.83 (d, J=8 Hz, 2H, Ar—H), 7.14 (d, J=8 Hz, 2H, Ar—H), 7.40 (bs, 1H).

13C NMR (DMSO-d6): 22.01, 22.09, 41.26, 48.39, 49.38, 67.73, 70.58, 114.16, 128.41, 129.93, 157.17, 172.59 ppm.

OTHER INFO

Despite both optical isomers being bioactive, as briefly mentioned in the Physical section, recent studies have shown that the S-ATENOLOL isomer was found to avoid the occasional side effect of an excessively lowered heart rate sometimes encountered with the racemate. The following steps are involved with the isolation of each enantiomer from 1-[p-[ (butoxy-carbonyl)methyl]phenoxy]-3-chloropropan-2-ol (7) using Lipase Catalysis.

The subsequent step highlights the production of S-ATENOLOL via (S-)1-[p-[ (butoxy-
carbonyl)methyl]phenoxy]-3-chloropropan-2-ol (8). This is fundamentally achieved using lipase from Pseudomonas Cepacia in a mixture of acetic anhydride and DIPE.

STEP 4 (b)

Whereas lipase from Pseudomonas Cepacia was used to isolate the S-ATENOLOL ISOMER, lipase from Candida Cylindracea is utilised in the production of the R + ATENOLOL ISOMER. The same principle applies in each isomeric scenario as demonstated below.

STEP 5 (a)

Acetic anhydride may also be used as a substitute for 1-butanol however, its inherent toxicity led to one opting for 1-butanol. Even though 1-butanol is harmful in its own right, on a relative scale is was the most suitable and effective alternative evolving an approximate 94 %conversion.

STEP 5 (b)

Yet again, greater than 95 % conversion is achieved after purifying the precipitate by treating(R) 1-[p-[(butoxy-carbonyl)methyl]phenoxy]-3-chloropropan-2-ol (10) with 2-methyl-ethanamine. This is then followed by addition of ammonium hydroxide in methanol and finally single recrystallisation in ethyl acetate.

References for (S)-(-)-Atenolol (ab120856)

This product has been referenced in:
  • Agon P  et al. Permeability of the blood-brain barrier for atenolol studied by positron emission tomography. J Pharm Pharmacol 43:597-600 (1991). Read more (PubMed: 1681079) »
  • Tsuchihashi H  et al. Characteristics of 125I-iodocyanopindolol binding to beta-adrenergic and serotonin-1B receptors of rat brain: selectivity of beta-adrenergic agents. Jpn J Pharmacol 52:195-200 (1990). Read more (PubMed: 1968985) »
Cited Patent Filing date Publication date Applicant Title
US4085136 Jun 9, 1976 Apr 18, 1978 Imperial Chemical Industries Limited Adrenergic blocking agents
US5223646 Apr 21, 1992 Jun 29, 1993 Daiso Company, Ltd. Process for producing optically active atenolol and intermediate thereof
JPH0377856A Title not available
JPH01102072A * Title not available
JPH04198175A * Title not available
Cited Patent Filing date Publication date Applicant Title
US4085136 Jun 9, 1976 Apr 18, 1978 Imperial Chemical Industries Limited Adrenergic blocking agents
US5223646 Apr 21, 1992 Jun 29, 1993 Daiso Company, Ltd. Process for producing optically active atenolol and intermediate thereof
JPH0377856A Title not available
JPH01102072A * Title not available
JPH04198175A * Title not available
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1 Comment

  1. rahulchaudhary_22@yahoo.com says:

    Dear Sir,
    At present Atenolol is used in racemic form or in isomeric I.e. In s-form?
    Sent on my BlackBerry® from Vodafone

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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