AU747690B2 - Naphthyl intermediates - Google Patents

Description

S&F Ref: 447377D1

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

ORIGINAL

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Name and Address of Applicant: Actual Inventor(s): Address for Service: Invention Title: Eli Lilly and Company Lilly Corporate Center Indianapolis Indiana 46285 United States of America Henry U Bryant Thomas A Crowell Charles D Jones Alan D Palkowitz Spruson Ferguson St Martins Tower 31 Market Street Sydney NSW 2000 Naphthyl Intermediates The following statement is a full description of this invention, including the best method of performing it known to me/us:- 5845c Naphthyl Intermediates Osteoporosis describes a group of diseases which arises from diverse aetiologies, but which are characterised by the net loss of bone mass per unit volume. The consequence of this loss of bone mass and resulting bone fracture is the failure of the skeleton to provide adequate support for the body. One of the most common types of osteoporosis is associated with menopause. Most women lose from about 20% to about 60% of the bone mass in the trabecular compartment of the bone within 3 to 6 years after the cessation of menses. This rapid loss is generally associated with an increase of bone resorption and formation. However, the resorptive cycle is more dominant and the result is a net loss of bone mass. Osteoporosis is a common and serious disease among postmenopausal women.

This invention relates to novel intermediates in the manufacture of the naphthyl compounds of application 43284/97 which are useful in the treatment of osteoporosis. The disclosure of application 43284/97 is incorporated herein in its entirety.

The invention provides compounds of the formula I which are useful for preparing the pharmaceutically active compounds of application 43284/97:

R

2 a R3a la/R

S

R

I

wherein: R l a is -H or -OR 5 in which R 5 is a hydroxy protecting group; R 2 a is H, OH, O(C14alkyl), OCOAr where Ar is phenyl or substituted phenyl, OCO(Ci.alkyl), O(CO)O(Ci.alkyl), or OSO 2

(C

4 6. alkyl); R 3a is H, or OR 7 in which R 7 is a hydroxy protecting group; R 4a is H, CH3, OH, O(C14alkyl), S. 20 OCOAr where Ar is phenyl or substituted phenyl, O(CO)OAr where Ar is phenyl or substituted phenyl, OCO(Ci.alkyl), O(CO)O(Ci-6alkyl), or OSO2(C46alkyl); with the proviso that both R 3 a and

R

4 a cannot be hydrogen.

The invention also provides compounds of the formula II which are useful for preparing the pharmaceutically active compounds of application 43284/97:

R

2 a R R 3 a RA la V V 3 [R:\LIBVVI02528speci.doc:NJC 1la wherein: Ria is H or OR 6 in which R 6 is a hydroxy protecting group; R 2 a is H, OH, O(Cl.~alkyI), OCOAr where Ar is phenyl or substituted phenyl, OCO(C.6alkyl), O(CO)O(Ci-6alkyI), or 0S0 2

(C

4 6alkyl); R 3 a is H, or OR 7 in which R 7 is a hydroxy protecting group; R 4 a is H, CH 3 OH, O(C,4.alkyl), OCOAr where Ar is phenyl or substituted phenyl, OCO(Ci.6alkyl), O(CO)O(Ci-6alkyI), or 0S0 2

(C

4 6alkyl), with the proviso that only one of R 2 a, RUa and R 4 a can be hydrogen; R 8 is OH or OCO(CI.

6alkyl); wherein the dotted line represents optional unsaturation; or a pharmaceutically acceptable salt or solvate thereof.

[R:\LIBVV]02528speci.doc:NJC General terms used in the description of compounds herein described bear their usual meanings. For example, "Ci.4alkyl" refers to straight or branched aliphatic chains of 1 to 4 carbon atoms including methyl, ethyl, propyl, iso-propyl, n-butyl, and the like; and "Cl-6alkyl" encompasses the groups included in the definition of "Ci-4alkyl" in addition to groups such as pentyl, iso-pentyl, hexyl, and the like.

The term "substituted phenyl" refers to a phenyl group having one or more substituents selected from the group consisting of C1-4alkyl, C1.3alkoxy, hydroxy, nitro, chloro, fluoro, tri(chloro or fluoro)methyl, and the like. "C-4alkoxy" refers to a C-4alkyl group attached through an oxygen bridge, such as methoxy, ethoxy, n-propoxy, and isopropoxy, butoxy, and the like. Of these C14alkoxy groups, methoxy is highly preferred.

Compounds of formula I where at least two of the R 2 a, R3a, and R 4 a substituents are hydrogen are well known in the art and are prepared essentially as described by Boyle et al., in US. 4 910 212 which is herein incorporated by reference. See, also, Collins, et al., Aust. Chem., 41:745-756 (1988); and Collins, et al., Aust. J. Chem., 37:2279-2294 (1984).

15 The following examples are provided to better elucidate the practice of the present invention and should not be interpreted in any way as to limit the scope 25 of same. Those skilled in the art will recognise that various modifications may be made while not departing from the spirit and scope of the invention. All publications and patent applications mentioned in the specification are indicative of the S level of those skilled in the art to which this invention pertains.

Examples NMR data for the following Examples were generated on a GE 300 MHz NMR instrument, and anhydrous d-6 DMSO was used as the solvent unless otherwise indicated.

Preparation 1 2,4-di-(3-methoxyphenyl) butyric acid A solution of 50.68g (305mmol) of 3-methoxyphenylacetic acid in 1.4L of anhydrous THF was prepared and cooled to -70 0 C under a nitrogen atmosphere. Slowly, 400mL of 1.6M (640mmol) of nbutyl lithium was added and the solution was allowed to stir for two hours at -70 0 C. A solution of 72.1g (335mmol) of 2-(3-methoxyphenyl)ethylbromide in 100mL of THF was added and the reaction was allowed to proceed for sixteen hours, while slowly warming to ambient temperature. The solvent was removed by evaporation in vacuo. The residue was dissolved in a solution of 50mL of 5N NaOH and 450mL of water and stirred for one hour. The aqueous solution was extracted three times with ether. The aqueous solution was acidified with the addition of 150mL of 5N HCI and the product extracted three times with CHCI 3 The organic extracts were combined, washed with brine and dried by filtration through anhydrous Na 2

SO

4 The solvent was removed by evaporation. This yielded of the title compound as a clear oil.

Example 1 2-(3-methoxyphenyl)-6-methoxy-1 -tetralone A solution of 90g (300mmol) of 2,4-di-(3-methoxyphenyl)butyric acid in 1.5L of CH 2

CI

2 was prepared and 62.4g (300mmol) of PC15 was slowly added. The reaction mixture was refluxed under a nitrogen atmosphere for four hours. The solvent was removed by evaporation. The residue was C08226 slurried with 100mL of aqueous NaHCO3 and the slurry extracted three times with CHCI 3 The combined organic extracts was washed with brine, dried with Na 2 SO4, and evaporated to dryness.

The product was crystallised from 2-propanol at -700C and then twice from MeOH at -70 0 C. This yielded 65g of the title compound as a tan solid, mp 81-82 0

C.

Example 2 1-Acetyloxy-2-(3-methoxyphenyl)-6-methoxy-3,4-dihydronaphthalene A suspension was prepared of 47g (167mmol) of 2-(3-methoxyphenyl)-6-methoxy-1-tetralone and 4.7g of p-toluenesulfonic acid mono-hydrate in 470mL of isopropenylacetate. The reaction mixture was refluxed for 48 hours under a nitrogen atmosphere. The reaction was allowed to cool and 10g of NaHCO 3 was added, the solution was poured into 500mL of an aqueous solution of NaHCO 3 The aqueous solution was extracted three times with 200mL portions of EtOAc. The combined organic extract was washed with brine, dried with Na2SO4, and evaporated to a dark oil. This yielded 52.7g of the title compound.

Example 3 1-Acetyloxy-2-(3-methoxyphenyl)-6-methoxynaphthalene A solution was prepared of 52.7g (162mmol) of 1-acetyloxy-2-(3-methoxyphenyl)-6-methoxy- 3,4-dihydronaphthalene and 36.9g (162mmol) of DDQ in 500mL of p-dioxane. The solution was heated to reflux for two hours under a nitrogen atmosphere. The reaction was allowed to cool and the solvent removed by evaporation. The residue was extracted by stirring in CHCI 3 for sixteen hours, then filtering to remove the insoluble material. The CHCI 3 extract was further purified by chromatography on a silica gel column eluted with CHCI 3 This resulted in a red oil, which was suspended in MeOH and crystallised at -70 0 C. This yielded 46.5g of the title compound as a low melting solid.

Example 4 25 1-Hydroxy-2-(3-methoxyphenyl)-6-methoxynaphthalene A suspension was prepared of 46.5g of 1-acetyloxy-2-(3-methoxyphenyl)-6methoxynaphthalene and 40mL of 5N HCI in 400mL of MeOH. The reaction mixture was heated to reflux for eleven hours. The reaction mixture was evaporated to a clear oil. This yielded 38.6g of the title compound. PMR: (CDCI 3 8.19ppm J=9.1Hz, 1H); 7.51-6.94ppm 5 8H); 5.91ppm 1H); 3.94ppm 3H) MS: mle=280 FD EA: Calc. for C 18

H

16 0 3 C, 77.12; H, 5.75 Found: C, 76.91; H, 5.81.

Example 1-Hydroxy-2-(3-methoxyphenyl)naphthalene In a manner analogous to Preparation 1 and Examples 1 to 4, the title compound was prepared.

PMR: 8.30ppm 1H); 7.80ppm 1H); 7.57-7.45ppm 4H); 7.40ppm J=7.1Hz, 1H); 7.35ppm J=6.0Hz, 1H); 7.06ppm 1H); 6.97ppm (dd, J=6.0Hz, 1H); 6.00ppm 1H); 3.90ppm 1H) MS: m/e=250 FD EA: Calc. for C 1 7

H

1 4 0 2 -0.21mol EtOAc: C, 79.52; H, 5.93 Found: C, 79.72; H, 5.63 C08226

Claims (4)

1. A compound of formula I: R 2 a R R 3 a a R 4 a wherein: R la is -H or -OR 5 in which R 5 is a hydroxy protecting group; R 2a is H, OH, O(C-4alkyl), OCOAr where Ar is phenyl or substituted phenyl, OCO(Ci-6alkyl), O(CO)O(Ci-6alkyl), or OS0

2 (C 4 6alkyl); R3a is H, or OR 7 in which R 7 is a hydroxy protecting group; R 4 a is H, CH 3 OH, O(Cl-alkyl), OCOAr where Ar is phenyl or substituted phenyl, O(CO)OAr where Ar is phenyl or substituted phenyl, OCO(Ci.alkyl), O(CO)O(Ci-6alkyl), or OSO2(C 4 6alkyl); with the proviso that both R 3 a and R 4 a cannot be hydrogen. t10 2. A compound of formula I, substantially as hereinbefore described with reference to any one of the examples.

3. A compound of formula II: R2a R 8 R 3 a O R4a SRla R SR II C wherein: Ria is H or OR 6 in which R 6 is a hydroxy protecting group; R 2a is H, OH, O(Ci4alkyl), 15 OCOAr where Ar is phenyl or substituted phenyl, OCO(Ci-6alkyl), O(CO)O(Ci-6alkyl), or OS0 2 (C 4 e•6alkyl); R 3 a is H, or OR 7 in which R 7 is a hydroxy protecting group; R 4 a is H, CH 3 OH, O(C-4alkyl), OCOAr where Ar is phenyl or substituted phenyl, OCO(Ci-6alkyl), O(CO)O(C1.6alkyl), or OS0 2 (C 4 6alkyl), with the proviso that only one of R 2a R 3 a and R 4 a can be hydrogen; R 8 is OH or OCO(C1. 6alkyl); wherein the dotted line represents optional unsaturation; or a pharmaceutically acceptable salt or solvate thereof.

4. A compound of formula II, substantially as hereinbefore described with reference to any one of the examples. Dated 4 March 2002 ELI LILLY AND COMPANY -Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON [R:\LIBVV]02528speci.doc:NJC