AU607437B2 - Resolution of dl-methyl 3-(4-(2-hydroxy-3-isopropylamino) propoxy)phenylpropionate((dl-esmolol)) - Google Patents

Description

I

AU-AI-79114/ 87 IL PCT WORLD IN4TELLECTUAL PROPERTY 0I OA31TIO INTERNATIONAL APPLICATION PUIS.~Y DE4& THE'AT T OPERATION TREATY (PCT) (51) Iternational Patent Classification 4 (11) International Publication Number: WO 88/ 01614 C07C 101/30, 99/12 Al (43) International Publication Date: 10 March 1988 (10.03.88) ('21 Inerntionl Apliatio Nuber PCTUS8/026-0(81) Designated States: AU, DE (European patent), FR (Eu- (22) International Filing Date: 25 August 1987 (25.08.87) ropean patent), GB (European paterit), IT (European patent), JP.

(31) Priority Application Number: 902,806 Published (32) Priority Date: 2 September 1986 (02.09.86) With international search report.

(33) Priority Country: us F11Tlitia)U2-nit C1t u'V -1.

(71) Applicant: E.I. DU PONT DE NEMOURS CO., V' dlLc. it (INC.) EUS/USI; 1007 Market Street, Wilmington, DE f~lit 19898 (US).

(72) Inventors: PATIL, Ohanshyamn 340 Albert Drive, Ver- 28AR18 non Hills, IL 60061 MAI, Khuong, X. 108 EL 2-8AR18 South Orchard, Waukegan, IL 60095 (US).

(74) Agent; FATO, Gildo, Du Pont Critical Care, Subsi- ASRIA diary of EI. Du Pont de Nemnours Co., IZ600 I AJ~AA Waukegan Road, Waukegar,, IL 60085 1 2 4tiAR'i988 jPATENT OFFICE (54) Title: RESOLUTION OF dt-METHYL 3-4-(2-HYD ROXY-3-ISO PRO PYLAMINO)PRO POXYiPH EN YLPRO Pl- ONATE (di-ESMOLOL)l (57) Aibstract A process for the resolution of di-methyl 3-4-(2-hydroxy-3-isopropylamino)propoxylphenylpropionate (dl-esmo- 101)] into a dextro and a levo isomer.

.'V88/01614 PCT/US87/02068 1 RESOLUTION OF dl-METHYL 3-E4-(2-HYDROXY-3-ISOPROPYLAMINO)PROPOXY] PHENYLPROPIONATE [(dl-ESMOLOL)1 BACKGROUND OF THE INVENTION Isomeric compounds are generally obtained as racemates.

Oftentimes, it is desirable to obtain one of the isomers, usually the 1-isomer. Consequently, various methods have been devised for resolving racemic mixtures. Two methods are asymmetric synthesis or optical resolution. A representative process for optical resolution is described in U.S, Patent 3,649,691.

The preparation and use of methyl 3-[4-(2-hydroxy-3isopropylamino)propoxy]phenylpropionate (dl-esmolol) is described in U.S. Patent 4,387,103, issued June 7, 1983. This compound is a short-acting beta-adrenergic-blocking agent used in the treatment or prophylaxis of cardiac disorders. Since the 1-isomer is more active than the dl-mixture, an effective method for resolving the racemic mixture is desirable.

The present invention relates to a novel process for the optical resolution of dl-methyl 3-C4-(2-hydroxy-3-isopropy1amino)propoxy]phenylpropionate (dl-esmolol) having the following structural formula 0 j--

CO

2

CH

3 into its and isomers. The isomer is about twice as potent as a beta-adrenergic-blocking agent than the racemate -1-1-1_ PCT/US87/02068 WO 88/01614, The above compound is an important beta-adrenergicblocking agent, its preparation and use is more fully described in the U. S. Patent Number 4,387,103.

According to the present invention, a novel process whereby this therapeutically important agent is further resolved into its optically active components is illustrated in the following schematic diagram.

(+)-Esmolol salt (+)Esmolol salt 59 (c 10.0, MeGH) (+)-Esmolol HCl (CI' 5 +19.1 [aQ -90.4 (c 1.0, MeGH) 1. BASE (-)Esmolal HCI C %C -19.6 (c 1.0, MeOH) (c MeCH) di-Esmalol, as a free base, 'is treated. with *-isopropylidene-2-keto-L-gulonic acid employing

L

WNO 88/01614 PCT/US87/02068 3 aqueous acetone and water as a solvent, preferably in a ratio of 1:1 to 1:10 of acetone to water. The resulting (+)-esmolol (-)-OA'-salt has the following optical rotations: 25 -3.0 (c 10.0, MeOH) 589 The free base is recovered by treating the above (+)-esmolol (-)-OAG-salt with an inorganic base, sodium hydroxide, the (+)-esmolol hydrochloride salt of this base has the following optical rotation in methanol: 25 +19.1 (c 1.0, MeOH) 689 Similarly, the isomer of esmolol is resolved as follows: dl-esmolol, as a free base, is treated with toluoyl-L-tartaric arid employing acetone as solvent. The resulti *ng (-)-eimolol TT-(-)salt has the following optical rotation: 2 -90.4 (c 1.0, MeOH) 589A The free base ii~ recovered by treating the above (-)-esmolol salt with an inorganic base, sodium hydroxide, the (-)esmolol -hydrochloride salt of this base has the following optical rotations: Cal 25 -19.6 (c 1.0, MeOH).

589 pharmacevotically acceptable non-toxic C- Aaetlon salts by conventional procedures. d -adiion salts may be prepared 1 '-Caventional m~anner by treating a solution or

VI'

3a The invention claimed herein is concerned with the use of to separate the isomers.

The compounds of the invention may be converted into their pharmaceutically acceptable non-toxic acid addition salts by conventional procedures. The acid addition salts may be prepared in the conventional manner by treating a solution or suspension of the free base in an organic solvent with the e

S*

*0 i **I S 0 WO88/01614 PCT/US87/0208 4 desired acid and then recovering the salts which form by crystallization techniques. The desired non-toxic acids are the following: acetic, maleic, fumaric, succinic, tartaric, citric, malic, cinnamic, sulfonic, hydrochloric, hydrobromic, sulfuric, and phosphoric acid.

The compounds of the invention, and particularly the 1isomer, can be used in the treatment or prophylaxis of cardiac disorders. In Clinical Research, Vol. 33, No. 3, 1985, p, 748A, M. Schwartz et al. report on Efficacy and Safety of Esmolol for Postoperative Atrial Fibrillation/Flutter. As reported, for the racemic mixture (esmolol), a therapeutic response was obtained in 9/15 patients, the median effective dose being 100 mcg/kg/ minute with a mean time to response of 22 minutes. In Clinical Research, Vol. 33, No. 2, 1985, p. 167A, J. Askenazi et al.

report on The Effect of Esmolol on Cardiac Hemodynamic Function.

A 4 minute loading dose of 500 ug/kg/minute was given followed by a 16-24 minute,infusion at 300 ug/kg/minute.' In Drug Intelligence and Clinical. Pharmacy, Vol. 19, June 1984,'p. 446, P. E. MacCosbe et al. repGrt on Antiarrhythmic Efficacy and Safety of Esmolol in Supraventricular Tachycardia and a mean effective dose of 97.2 5.5 ug/kg/minute. J. Kirshenbaum et al. in Circulation, Vol. 72, No. 4, October 1985, pps. 873-880, report on the use of esmolol in patients with acute myocardial ischemia wherein eimolo was titrated to a maximum dose of 300 ug/kg/minute, infused for up to 420 rinutes.

For the l-isomer, dosage ranges of one-half those reported in the above publications can be used for the same indications.

s, i; 1- -r-1 11-: C11- ~--_lili -Ii i ii _i iY li WO 088/01614 PCT/US87/020 68 f-AMW-E I.

Preparation of (-)-esmolol salt dl-Esmolol (-)-Esmolol Salt A mixture of esmolol freebase (3.0 g, '10.16 mmole) and C) Di-p-toluoyl-L-tartaric acid monohydrate (4.10 g, 10.16 mmole) in acetone (20 mQL was warmed to di-ssolve and allowed to cool to 22'C. This clear solution was allowed to stand at 22'C for 16 hours, the crystalline prodLc' formed was diluted with acetone mL) and filtered, was~ied with acetone (20 mQL, then acetone:ether 30~ mQL followed by ether and air dried to give the white crystalline salt (1.9 g, m.p. 158-1590C, [(II 58 -90.4 (c 1.0, MeOH)* Anal1ysis calculated for C 36

H

43 N0 12 C, 63.42, H, 6.36, N, .12.05 4-Zound-C. Gj=3a P i WO 88/01614 PCT/US87/02068 EXAMPLE a: Preparation of (-)-esmolol HC1 1. NaOH/EtOAC (-)-Esmolol Salt (-)-Esmolol HC 2. MEK/HC1 (-)-Esmolol(-)-DTT (2 C, 2.86 mmole) was suspended in water (100 mL) and to this, IN NaOH (15 mL) and ethyl acetate (100 mL) were added with vigorous stirring. The ethyl acetate layer was separated and washed with brine (2 X 100 mL), dried (MgS04), filtered and evaporated to an oil. This was dissolved in methyl ethyl ketone (12 mL), acidified with hydrogen chloride, treated with ether (10 mL) and allowed to stand at 22 0 C for 16 hours.

The crystalline solid was filtered, washed with methyl ethyl ketone: ether 50 Im), followed by ether and air dried to give 300 mg of the title compound, m.p. 93-94 0

C,

589 -19.6 (c 1.0, MeOH)*

A

p, j WO 88/01614 PCT/US87/02068 7 The relative potency of 1-esmolol and dl-esmolol was determined in the following manner. Mongrel dogs of either sex were anesthetized with a combination of nembutal and sodium barbital.(15.0 and 300 mg/kg, respectively). A femoral artery and both femoral veins were cannulated for measurement of diastolic blood pressure and administration of drugs, respectively. Rectal temperature was monitored and maintained at 36-38*C. The vagus nerves were cut. Heart rate was measured from the arterial blood pressure signal with a Beckman cardiotachometer. Following surgical preparation, one hour was allowed for equilibration prior to initiating the experiment.

The relative potency of levo-esmolol and esmolol was determined utilizing ten-minute intravenous infusions of each compound at increasing doses. Each animal received both levoesmolol and esmolol but the order of administration was randomized and a period of time for complete recovery from the effects of the first compound was'allowed before initiating infusion of the other compound. Beta-blockade was assessed at the end of each ten-minute infusion period using bolus isoproterenol Injections (0.5 ug/kg, i.v. bolus). The reduction in control hypotension and tachycardia responses to isoproterenol by each compound was expressed as percent inhibition, calculated as (Control-Treated)/Control X 100.

Percent inhibition values between 15 and 85 inclusive were related to the log of infusion rate, via least square regression and the LD50 was determined (infusion rate producing reduction of isoproterenol response).

The levo-isomer of esmolol (LD 50 29.3 1.7 ug/kg/minute) was approximately two-fold more potent than the racemic mixture (LD50 56.1 2 ug/kg/minute) in blocking isoproterenol tachycardia. Neither esmolo nor levo-esmolol modified baseline diastolic arterial blood pressure or diastolic arterial blood pressure responses to isoproterenol at any dose.

LD50 dl-Esmolol 56.1 1-Esmolol 29.3

Claims (4)

1. A method for resolving dl-methyl 3-[4-(2-hydroxy-3- isopropylamino)propoxy]phenylpropionate which method comprises: reacting dl-methyl 3-[4-(2-hydroxy-3-isopropylamino)propoxyphenylpropionate, as the free base, with (-)-O,O'-di-p-toluoyl-L-tartaric acid in acetone as a solvent to obtain the (-)-methyl 3-[4-(2-hydroxy-3- isopropylamino)propoxy]phenylpropionate (-)-O,O'-di-p-toluoyl-L-tartaric acid salt; and treating said salt with an inorganic base to obtain the (-)-isomer of methyl 3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate as the free base.

2. The method of Claim 1 wherein the inorganic base is sodium hydroxide. 3, The method of Claimp wherein the methyl 3-[4-(2-hydroxy-3- isopropylarino)propoxy]phenylpropionate free base is treated with an appro p r iate acid to obtain a pharmaceutically acceptable salt. *0 4 3 4, The method of ClaimA4 wherein the acid is hydrochloric acid. (-)-Esmolol or a non-toxic pharmaceutically acceptable acid addition salt thereof, when prepared by the process claimed in any one of the preceding claims.

6. The compound according to Claim 5 wherein said salt is hydrochloride salt, A T E D this 29 day of August 1990. 6 DU PONT DE NEMOURS AND COMPANY by their Patent Attorneys CALLINAN LAWRIE ;Pt %4 INTERNATIONAL SEARCH REPORT International Application N OPC1T /TT 8 026 1. CLASSIFICATrION OF SUBJECT MATTER (if several classification symbols apply, indicate all)3 According to International Patent Classification (iPC) or to both National Classification and IPC IPC(4): C07C 101/30, 99/12 U.S.Cl.: 560/42 III FIEWLS SEARCHED Minimum Documentation Searcned Classification System i Classification Symnols U.S.C1. 560/421,106 Documentation Searched other than Minimum Documentation to the Extent that such Documents are IncludWd In the Fields Searched6 Databases: CAS online, Fle CA, structure of RN 81147-92-4 or esmolol;APS, File USPAT., esmolol il1, DOCUMENTS CONSIDERED TO BE RELEVANT" Categoryj Citation of Document, I$ with Indication, where appropriate, of the relevant passageas I Relevant to claim No,.t X EP, Al, 0041491 (HASSLE) 09 December 11-12 Y 1981, see pages 4-7 and 26-27. X US, A, 4i387,103 (ERHARDT ET AL) 7 June 11,12 Y 19$3f see column 6, lines 65-67 and co~lumn 7, lines 1-49. X US, R, 4,593,119 (ERHARDT ET AL) 3 June 1L,12 y1986, see column 7, lines 1-59 and claims 1-6.1 Journal of Pharmaceutical Sciences, 1-15, Volume 68, No. 9, September 1979, 11,12 Washin1gton# Yost et al, "Resoluti.on of (+)-Propanolol", pp

1181-1182, see t~e entire article. A WO, Al, 85/04168 (BODOR) 26 September 11,12 1985, see pages 3-26. spzecial categories of cited documentat is later document published athar the international filing date docmen deinng he enealstae o th at wichisnot or priority date and not in conflict with the application but 'Alldcr tdnigtegnra tt fteatwihI cited to understanid the principle or theory underfying the considered to be of particular relevance Invention U11 earlier document bit published on or after the International "II document of particular relevancei the claimed Iinvnton fifing data cannot be considered novel or cannot be conalclated to "Ll' doc~ument which may throw doubts on priority cialm(sl or involve an inventive step which Is cited to establish the Publication date of another 1YI document of particular relevance: the claimed Invention citation or other special reaicon las specified) cannot bes considered to Involve an Inventive step whin the 1011 document ref erring t, an oral disclosure, use, exhibition or document is combined with one or more other such docU, othter means ments, such combination being obvious to a person skilledi I" document Published prior to thbi International filing date but iWIn the art. later than the priority date cla'med '"document member of the some patent family IV, CERTIFICATION Date of the Actual Completion of the International Search I Date of Malling If this International Search Report I 4 NOVEMBER 1987 3 0 NOV 198 Internationtal Searching Authority tSignature of Authorf ted Officer 11:SA./US. ruce D. Gra Forfm FiCT11SAiMt (second sheet) (bOte 1981) salt; and treating said salt with an inorganic base to obtain the (--isoimer of~ mnethyl 3 -[4-(2-hydroxy-3-isopropylammno)propoxy]phenylpropionate as the free base. E~kUE-inMinUh'L 5 -N International Aoniication No. PCTJ/US 87 02068 FURTHER INFORMATION CONTINUED FROM THE SECOND SHEET Y-I] OBSERtVATbONS WHERE CERTAIN CLAIMS WERE FOUND UNSEARCHA13LE iO Ihis international search report has not been established in respect of certain claims under Article 17(2) for the following reasons: Ll Claim numbers because they relate to subject matter tJ not required to be searched by this Authority, namelyl claim numbers because they relate to parts ot the International application that do not Comply with the prescribed require- -tents to such an extent that no meaningful International search can be carried out W, apeclilcally: VIX7i OBSERVATIONS WHERE UNITY OF INVENTION IS LACKING It This International Searching Autl,.vtlty tound multiple Inventions In this lnlernifional application as tollowsl, 1. Claims 1-5, 11 and 12 drawn to a method for resolving di-esmolol by reaction with and (-)-esmolol. 11. Claims 1 and 6-10 drawn to a method for resolving di-esmolol by reaction with for reasons stated in prior Form PCT/ISA/206. 1,]As all required additional search fees were timely pald by the applicant, this International search report covers all searchabl, claims of the International application, 2M As only some of the required additional search fees Were timely paid by the applicant, this International search report Covers only those claims of the International application fot which tees were paid, 3peciflcally claims: 3.FNo required additional search fees were timely paid by the applicant. Consequently, this International search report 1s restricted to the Invention firs, mentioned In the claims', it Is covered by claim numberst 1-5t, 1 1 and 1 2 4.7As all searchtable claims could be searched Without effort justifying an additional fee, the internationall Searching Authority dId not invite Payment of any additional tee, Remark on Protest SThe additional search fees were Accompanied by applicant's protest, SNo protest accompanied the payment of additional search fees. Form PCTIISA/210 (Supplemental Shoet (Octubr 081) t