United States Patent
`B21-an et al.
`
`[19]
`
`nu Patent Number:
`[45] Date of Patent:
`
`4,499,289
`Feb. 12, 1985
`
`[54] OCTAHYDRONAPTHALENES
`
`['I:'>]
`
`Inventors:
`
`John S. Baran, Winnetka; Chi-Dean
`Li3“E= G1‘=“"iC"'* 55”‘ 01° 111-
`-
`.
`-
`~
`G‘ D‘ Same & C0" Skohe’ H1‘
`D] Assign“
`1] Appl. No.1 549,534
`
`—
`
`[
`
`22
`
`1
`
`F1 d,’
`1e
`
`N _ 7! 1933
`W
`Related U.S. Application Data
`
`[63]
`
`Continuation-in-part of Ser. No. 446.546, Dec. 12,
`1933‘ abandonm
`
`Int. Cl.‘
`[51]
`C07D.309/3|}
`
`[52] US. Cl.
`549/292
`[S8}
`Field of Search
`549/292
`
`[56]
`
`.
`
`References Cited
`
`U.S- PATENT DOCUMENTS
`3,953,140 9/1976 Endo at al.
`4.232.155
`321931 Smith et al.
`4,450,171
`5,/1934 Hoffman et al.
`
`549/292
`
`.. 549x292
`.................. .. 549/292
`
`Primary Examir1er—N0rn:1a S. Milestone
`Auomey, Agem. or F:'rm—John J. McDonnell
`
`[57]
`
`ABSTRACT
`
`_
`,
`,
`The ll'l\.-’el'ltiOl'1 relates to octahyclronapthalenes whl-:11
`are useful in antiatherosclerotic agents.
`
`1 Claim, No Drawings
`
`1 of 7
`
`PENN EX. 2192
`CFAD V. UPENN
`IPR2015-01836
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`
`1
`
`OCTAHYDRONAPTHALENES
`
`4,499,289
`
`2
`obtained by cultivation oft: microorganism of the genus
`Pet-ticillium. useful as an inhibitor in vivo of the bi-
`osythesis of cholesterol. Further, Monaghan, et. ai.
`(U.5. Pat. No. 4,231,933), described certain lactones as
`well as their free hydroxy acids useful in the treatment
`of hypcrcholesteremia and hyperlipernia.
`SUMMARY OF THE INVENTION
`
`Accordingly it has been discovered that
`pounds of present invention of the formula:
`
`the Com-
`
`xxvi
`
`CH]Cl'l3R5
`R3
`
`R4
`
`at
`R2
`
`wherein R1, R1, R3 and R4 are hydrogen, alkyl of l to 6
`atoms inclusive or fluorine. R1, R3. R3 and R4 each
`being the same or difi'erent.
`Wherein R5 is:
`
`Ilia
`—(|IH—CH1—(]IH—(|I—CO2R to; or
`OH
`OH R’;
`
`OH
`R
`Rs9
`
`0
`
`ll0
`
`(al
`
`(bl
`
`wherein R5. R7, R5, R9 and R19 are hydrogen, alkyl of l
`to 6 carbon atoms, inclusive or fluorine, R5, R7, R5 and
`R9 each being the same or different and the pharmaco-
`logically
`acceptable
`salts
`are
`useful
`for
`their
`hypobetalipoproteinemic activity.
`Examples ofalkyl of l to 6 carbon atoms inclusive are
`methyl, ethyl, butyl, propyl, pentyl, hexyl and the iso-
`meric forms thereof.
`The test procedure used to determine hypobeta—lipo—
`proteinernia is as follows:
`Hepatic 3-hydroxy-,6-mcthylglutaryl-coenzyrne A Re-
`dtictase [HMG COA reductase) inhibition is measured
`in the rat. Rats used are males weighing from 180-220 g
`pretreated with 2% diethylaminoethanolamine in diet
`using reversed lighting. I Millimolar final concentration
`of test compound is used in liver in vitro testing. Activ-
`ity for each compound is reported as a percent inhibi-
`tion based on control. A compound is considered active
`if it inhibits the conversion of 1‘lC-Hydroxymethylglutw
`ryl-CoA to MC-mevalonolactone in the prescribed
`assay by 40% or more.
`If significant activity is ob-
`served, a titration will be done to determine potency
`and affinity for enzyme relative to substrate. HMG
`CoA reductase is the rate controlling enzyme in the
`synthesis of cholesterol. An agent which inhibits the
`enzymatic activity would be expected to reduce con-
`version of precursors to cholesterol. Therefore, an
`agent which inhibits this enzyme should be beneficial in
`the treatment of hyperlipoproteinemia with enhanced
`cholesterol biosynthesis.
`The term “pharrriaceutically acceptable salts” refers
`to cationic salts such as sodium potassium, calcium,
`magnesium. aluminum, ammonium, etc.
`
`This is a continuation—in-part of application Ser. No.
`446.546 filed Dec. I2, 1982, now abandoned.
`
`5
`
`BACKGROUND OF THE INVENTION
`
`10
`
`15
`
`20
`
`30
`
`(:1) Field of the Invention
`The present invention provides novel compounds. In
`particular,
`this
`invention relates
`to novel octahy—
`dronaphthalenes of Formula XXVI.
`The compounds ofthe present invention are useful as
`hypobetalipoproteinemic agents which are used to treat
`a mammal suffering from or susceptible to the develop-
`ment of an atherosclerotic disease.
`Atherosclerosis in mammals is a disease characterized
`by the deposition of atherosclerotie plaque on arterial
`walls. Atherosclerosis exhibits many various forms and
`consequences. Typical consequences of atherosclerotic
`diseases include angina pectoris, mycardial infarction,
`stroke and transient cerebral ischemic attacks. Other
`forms of atherosclerotic diseases include certain periph-
`eral vascular diseases and other ischemias (e.g., bowel
`and renal).
`Medical science now recognizes that certain forms of 25
`atherosclerosis may be preventable or
`reversible.
`Agents capable of preventing or reversing atherosclero-
`sis are characterized as exhibiting antiatherosclerotic
`activity. Since serum lipids have a recognized associa-
`tion with atherogenesis, an important class of antis-
`therosclerotic agents are those with serum lipid-modify
`ing effects. Serum lipids implicated in atherogenesis
`include serum cholesterol, serum triglycerides, and
`serum lipoproteins.
`three
`least
`With respect
`to serum lipoproteins, at
`different classes of these substances have been charac-
`terized; high-density lipoproteins (HDL's}, low density
`lipoproteins [LDL‘s) and very low-density lipioproteins
`(VLDL’s). HDL's are betalipoproteins. The control of
`LDL and VLDL levels (hypobetalipoproteineinic ac- 40
`tivity} is postulated to have a direct antiatherosclerotic
`effect. See Goodman and Gilman, The Pharmacological
`Basis of Therapeutics,
`fifth Ed.
`7"4»4—?'52 (l9?'5). The
`importance of lowering cholesterol levels may further
`be demonstrated by the availability of several commer- 45
`cial prescription products that are designed to lower
`cholesterol by several routes. See Physicians Desk Ref-
`erence I981, deittrothyroxine sodium pg. 898, clofibrate
`pg. 605, and cholestyramine pg. H49. Several mecha-
`nisms of action have been described. for example, stimu-
`lation of the liver to increase catabolism and excresion
`of cholesterol, blocking the absorption of cholesterol in
`the intestine. and elimination by emulsification. The
`compounds of the present invention inhibit the produc-
`tion of cholesterol directly by interfering with HMG
`CoA reductase. This is beneficial in that serum Iiprotein
`levels of cholesterol are kept low without the need to
`elinlinale excess cllolcslcrol. The compounds of the
`invention are therefore also beneficial in cases of hyper-
`eholesterol production.
`(b) Prior Art
`The relationship between high blood cholesterol,
`atherosclerosis and medicament to control cholesterol
`are well known as described above. In addition it
`is
`known that 3-hydroxy-3-Inethylglutaryl-Coenzyme A
`reduczase is the rate—limiting enzyme in the cholesterol
`synthetic pathway. Endo et al., described [U.S. Pat.
`Nos. 4.049,-195 and 3,983,140] a fermentation product
`
`50
`
`65
`
`201"?
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`PENN EX. 2192
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`CFAD V. UPENN
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`
`

`
`4,499,289
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`3
`The mammals susceptible to the development of ath-
`erosclerotic diseases and the untoward consequences
`thereof are particularly those physically asymptomatic
`patients manifesting one or more risk factors known to
`predispose one to disease development. Such risk fac-
`tors are high serum cholesterol and serum triglycerides,
`hypertension, obesity, diabetes, and genetic predisposi-
`tion. Mammals manifesting two or more risk factors are
`deemed to be especially susceptible to atherosclerotic
`diseases. Accordingly,
`in using the compound of the
`invention for the instant purposes, an oral route of ad-
`ministration.‘ either by conventional oral dosage forms
`or by mixture with food or feed, represents the pre-
`ferred method oftheir systemic administration. Alterna-
`tively, however, these compounds may be administered
`by other convenient routes of administration whereby
`systemic activity is obtained. These other routes of
`administration would, accordingly, include rectal, vagi-
`nal, subcutaneous, intravenous, and like routes.
`Liquid dosage forms for oral administration include
`pharmaceutically acceptable emulsions, solutions, sus-
`pension, syrups, and elixirs containing inert diluents
`commonly used in the art, such as water. Besides, such
`inert diluents, compositions can also include adjuvants,
`such as wetting agents, emulsifying and suspending
`agents. and sweetening. flavoring and perfuming agents.
`Preparations according to this invention for paren-
`teral administration include sterile aqueous or non—aque-
`ous solutions, suspensions. or emulsions. Examples of
`non—aqueous solvents or vehicles are vegetable oils,
`such as olive oil, and injectable organic esters such as
`eth yl oleate. Such dosage forms may also contain ad_ju-
`vants such as preserving, wetting, emulsifying, and
`dispersing agents. They may be sterilized, for example,
`by filtering through a bacteria-retaining filter, by incor-
`porating sterilizing agents into the compositions. by
`irradiating the compositions, or by heating the composi-
`tions. They can also be manufactured in the form of
`sterile solid compositions which can be dissolved in
`sterile water, or some other sterile injectable medium
`immediately before use.
`Compositions for rectal or vaginal administration are
`preferably suppositories which may contain, in addition
`to the active substance, excipients such as cocoa butter
`or a suppository wax.
`Compositions for nasal or sublingual administration
`are also prepared with standard excipients well known
`in the art.
`The compounds of the present invention are useful
`hypobetalipoproteinemic agents at dosages from 100
`mg/kg to 2 g/kg daily preferably in divided dosages.
`The dosage of active ingredient in the compositions of
`this invention may be varied; however,
`it
`is necessary
`that the amount of the active ingredient shall be such
`that a suitable dosage form is obtained. The selected
`dosage depends upon the desired therapeutic effect, on
`the route of administration, and on the duration of the
`treatment.
`
`The compounds ofthis invention are prepared from
`3.4-dihydro-6-alkoxy-l(2H)-naphthalenes. Formula I,
`by the methods illustrated in the attached Charts A
`through C. Alkylation of] with an alkyl acetate, under
`strongly basic conditions in an inert organic solvent,
`affords substituted octahydronaphthalenes of Formula
`II. Preferred alkylating conditions employ’ ethyl acetate
`and lithium isopropylmethyl amide (prepared in situ by
`reaction of isopropylmethylamine and butyl lithium) in
`tetrahydrofuran. Catalytic hydrogenation of It removes
`
`4
`the I-hydroxyl group, giving compounds of Formula
`Ill. Typical hydrogenation conditions include hydro-
`gen gas at about 60 psi, an alcoholic solvent, and a
`transition metal catalyst. Preferred conditions employ
`ethanol solutions of Forrnula [I over palladium on car-
`bon as catalyst. Esters of Formula III can further be
`converted to corresponding alcohols. Formula IV. by
`reduction with an active metal hydride, preferably lith-
`ium aluminum hydride, in an inert organic solvent. such
`as diethyl ether. Compounds of Formula V are pre-
`pared from Formula IV by partial reduction in ammo-
`nia using a dissolving alkali metal, such as lithium or
`sodium, preferably lithium. Hydrolysis of Formula V
`under acidic conditions affords hexahydronaphthale-
`nones of Formula VI. Preferred hydrolytic conditions
`include a strong acid, such as hydrochloric or sulfuric
`acid, in an aqueous alcoholic medium, such as aqueous
`methanol or ethanol.
`Ketone intermediates Formula VI are converted to
`corresponding octahydronaphthalenes, Formula XII,
`by reaction with ethancdithiol under acidic conditions
`to form corresponding dithiolanes, Formula X],
`fol-
`lowed by reductive dcsulfuration. Preferred conditions
`for the dithiolane formation include borontritluoride
`etherate in methanol. Preferred conditions for the desul—
`furation include Raney nickel in refluxing absolute etha-
`nol. Thc side-chain hydroxyl group of Formula XII is
`replaced by iodine for subsequent reactions. A pre-
`ferred method involves reaction of Formula XII with
`p-toluenesulfonyl chloride in pyridine, which forms an
`intermediate tosylate ester that can be converted to
`compound XII) by reaction in refluxing acetone with an
`alkali metal iodide. such as sodium or potassium iodide.
`The extended side-chain compound, Formula XV,
`is
`prepared from XIII by reaction with the lithium salt,
`Formula XIV, of a 2-(2,2-dialkoxyethyl)-I,3-dithiane,
`prepared according to the method of Seebach and
`Corey, J. Org. Chem. 40, 231 (1975). A preferred com-
`pound XIV is 2-(2,2-dimethoxyethyl)—l,3—dithiane. The
`dithiane group of XV is removed to give corresponding
`ketones, Formula XVI. A preferred method for remov-
`ing the dithiane group involves heating in aqueous ace-
`tone with cadmium carbonate and mercuric chloride,
`followed by treatment with potassium iodide.
`Ketone intermediates XVI are reduced to the corre-
`sponding secondary alcohols, which are then silylated
`to form Compounds of Formula XXI. Suitable reducing
`conditions include active metal hydrides, such as so-
`dium borohydride (or boron-substituted derivatives
`thereof} and lithium aluminum hydride (or aluminum-
`substituted derivatives thereof). A preferred reducing
`procedure employs sodium borohydride in refluxing
`anhydrous ethanol. Suitable silylatirtg conditions in-
`clude hindered trialkylsilyl halides in dry unreactivc
`organic Solvents, using a base to scavenge liberated
`hydrogen chloride. A preferred silylating procedure
`employs t-butyldiphenylsilyl chloride in dimethyIform-
`amide in the presence ofirnidazole. Under acidic condi-
`tions, intermediates of Formula XXI are converted to
`aldehydes of Formula XXII. Suitable acidic conditions
`include solutions of formic acid in aqueous dioxane.
`Alkylation of XXII with alkyl acetate, under strongly
`basic conditions in an inert organic solvent, affords
`extended side-chain compounds of Formula XXIII.
`Preferred alkylating conditions include the method
`described above and illustrated in Chart A for convert-
`ing I to II. Silyl-protected compounds XXIII are de-
`blocked with suitable reagents. preferably tetrabutylam-
`
`10
`
`I5
`
`20
`
`25
`
`30
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`33
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`40
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`45
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`50
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`60
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`65
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`sort"
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`PENN EX. 2192
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`CFAD V. UPENN
`IPR2015-01836
`
`

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`4,499,289
`
`5
`moniuni fluoride. and chromatographed preferably on
`silica gel
`to give compounds of Formula XXIV and
`XXV. the title compounds of this invention.
`Some of the reactions described above form com-
`pounds having asymmetrically substituted carbon
`atoms. For those compounds having more than one
`asyrnrnetric carbon center, partially or completely sepa-
`rated components may be obtained using separation
`methods, such as recrystallization and chromatography,
`known to those skilled in the art.
`
`DESCRIPTION OF THE PREFERRED
`
`The operation of this invention is further elaborated
`by the representative examples below.
`EXAMPLE 1
`
`6
`bisulfite solution. The organic phase was washed with
`water until neutral. then dried over magnesium sulfate.
`Removal of the solvent gave 250 mg of crude mate-
`rial, which was used in the next step without further
`purification. Structure amignment was confirmed by
`the proton nmr spectrum.
`5l.5—2.|
`(iii, 6H), 3.73 [1, 21-1), 3.75 (5, 3H), 6.5-71.3
`(tn, 3H}.
`IR, {CHC1_1) 3600 ern—l.
`
`mm [__m_,
`Found
`Theory
`C
`756.;
`74,94
`
`it
`shit;
`ti.-is
`
`5
`
`in
`
`[5
`
`go
`
`EXAMPLE 4
`l.2.3.4.5,8-he-xahydro-6-methoxy-1-naphtha1enee-
`thaw]
`
`Ethyl
`]"2’3"4_mrahydr°_ I 'h"°l,"?"3j"5"“‘“h°"3"""“"“”“"°“'
`eacetate.
`.
`A solution of i.4l g (19 mmoles] of isopropylme—
`froijsglfiignlgglif](:‘fn;'":E::2_£f tgfoigllszzol
`thylamine in 10 ml of tetrahydrofuran was cooled to
`I
`{Pb I] 11’ h]
`]dt 13'
`h
`0“ and 45
`-78”, and 6.6 ml1.1equ1v-«1.6Tr' M [11 mmoles) of
`1,”;
`of d_ “,l-‘E Ego 9d was C00,:
`0 553‘ a”Th'_a“
`n-butyllithiunt was added dropwise. After fifteen min-
`15“ C hlqm .£immOma was added‘
`1?’ was 0 '
`utes at —'t'B°, a solution of 0.88 g (10 mmoles) of ethyl 25 :3
`acetate in 3 ml of tetrahydrofuran was added dropwise.
`owedfiby t 5 addm_°"_ W“ a ”’“'m'“““’ P""°d of 600
`After stirring for ten minutes at —78° a solution of L76
`mg isddmgflcghof mhltlim’ All? thrEet.}l70%rS’b’1nethaI]10l
`g (10 mmoles) of 6-methoity—l~tetralone in 5 ml oftetra-
`glfas 3
`3 do S 1:13‘: 10“ m”‘_ M9 untlht E
`U3 C0 0;
`hydrofuran was added. After ten minutes the mixture
`'5§PP°‘“° Manf
`_
`"3
`a"‘m_lE’l_rl1'a W35
`en :_"aP1°ra£?
`was acidified with 10% hydrochloric acid and concen- 3'3 un era Stream 0 nitrogen;
`e_re'51 us was
`1530
`1“
`trateci to dryness. The residue was extracted into di-
`5 Pillar Water’ ‘3"”"’°t°_d wlih dleihyl “he? and amdlfied
`ethyl ether, and the organic phase was washed with
`with 5% ‘hydmchlonc’ acid‘ The Organic phase was
`brine’ drifid over magnesium sulfate’ filtered and Com
`washed with water, dried over magnesium sulfate, fil-
`centrated. The crude material was chromatographed on
`‘fled! and Concentiaiiiffl lo d1'Y“e§5' The residue ‘’_‘’as
`silica gel ‘0 give 2_,; g of the title compound as an oil_ 35 chromatographed on silica gel to give 1.26 g of the title
`Structure assignment was confirmed by the proton nmr
`“_°"‘P°““d= Coniamlnaied with “bl-‘l3“0l' smlclure 35'
`SpeCUum_
`signment was confirmed by the proton nmr spectrum.
`HNMR (CDCIB): 5125 (I, 1:71.12, 31.1); 1_6_,2_2 (m,
`5l.6—2.4 UH), 2.4-3.0 (m, 7H), 3.4-4.0 (m, 3H}, 3.5 (5,
`31-1), 2.5-2.9 (111, 31-1), 3.'1’8(d,J=7H;,2H), 3.73 (S, 3H), 40 3H)-
`IR, (C1-1c1,~.)’1735 cm—1.
`
`EXAMPLE 2
`
`4,-lo,5,6,7.3-hexahydro-5-(2-hydroxyethyl)-2(3H]-naph-
`thalenone
`
`A solution of 1.26 g of the crude product compound
`Elhyl
`45 of Exampte 4 in 50 mi of methane] and 50 m1 of 3N
`I,2,3.4—tetrahydro-6-methoxy-1-naphthaleneacetate.
`hydrochloric acid was heated at 60° for thirty minutes.
`A solution of 0.95 g (35 mm015}0f1h¢ product com-
`After the solution was stirred at room temperature for
`pound of Exampm 1
`in 40 mi of ethangl was hydmge-
`one hour, 50 ml of water was added. The methanol was
`Rated at 50° using 50 psi of hydrogcn gas ova, 10%
`palladitim on carbon catalyst. After filtration, the reac- 50 C"'3P‘3"1'3I‘?d and the Pmd“°_'‘ “'35 Cxlracfed mm Chlom‘
`tion mixture was concentrated to dryness. The crude
`f9l'l'I1. which W35 Washed With Water. dried OW-‘T magne‘
`matei-531 was cl-lromatographed on gflica £5] to git,-.3 0_5
`slum sulfate.-filtered and concentrated to dryness. The
`g of the title compound. Structure assignnient was con-
`Cflldfi material was Ch1"°ma‘°STaPh5d 0” 511163 S51 10
`firmed by the proton nmr spectrum.
`SW5 0-74 8 Of fl“? ‘ill? C0mP011T1d-
`01.24 (t, J:'.?1-1;, 31-I), 1.6-2.0 (in, 31-1), 2_4—3_D (m, 55
`Structure assignment was confirmed by the proton
`SH), 3.1-3.5 (m, 11-1), 3.73 (5, 31-1), 4.15 (q-,1, 2H), 6.5—7.3
`nmr spectrum.
`l4-H), 3.6-4.0 (rn, 3H], 5.85 (m, lH).
`(m, 3H)_
`8|-2.6 ppm (tn,
`IR, (CHCI3) 1670 0111*‘ 1620 (W), 3620 (S), 3640 (W).
`EX MPLE 3
`U.v 7t,,,,,,,239 mp. (G 15,000).
`A
`-
`—
`—
`EXAMPLE 6
`tetrahfydro 6 meghoxy 1 I)1Zl}Z;‘l';tl'11-€l.!leI1Ct3ll]21110l
`.I
`,
`1,
`ium aluminum
`A so ution o 24 mg (0. mmo e o it
`I’2‘3‘+'6'7’8‘8a‘0ctahydm'I inaphthaleneethaml
`hydride in 10 ml of dicthyl ether was added dropwise to
`A solution of 4 g (0.02 mole) of the compound of
`a solution of 250 mg (1 mmole) of the product com-
`Example 5 and 3.5 g (0.037 mole} of ethanedithiol in 200
`pound of Example 2 in 10 ml of ether. The reaction
`mixture was stirred at room temperature for one hour 65 ml ofrrtethanol was cooled to 0° C., and a solution of2.5
`and then heated to reflux for thirty minutes. After cool-
`ml (0.02 mole) of boronlrifluctride etherate in 20 rtil of
`ing the reaction. a 30% ethyl acetate in ether solution
`methanol was added dropwise.
`'1"he reaction mixture
`was added dropwise, followed by a saturated sodium
`was stirred at 0° for four hours, then 5 ml of sodium
`
`.
`
`60
`
`2 3 4-
`
`—
`
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`‘T
`bicarbonate solution was added. The methanol was
`evaporated and the product was extracted into ether,
`which was then washed with water, dried over magne-
`sium, sulfate, filtered and concentrated to dryness. The
`crude material was chromatographed on silica gel to 5
`give 4.5 g of the intermediate 4‘,4a’, 5',6’, ?’,8'-hcxahy-
`drospiro
`[1.3-dithiolane-2,2‘(3’I-I)-naphthalene]-5'-
`ethanol, an oil having the expected nmr spectrum.
`A mixture of350 mg (1.3 mmole) of the intermediate
`compound and 2.6 g of a slurry of W-2 Raney nickel in
`ethanol in an additional 26 ml of absolute ethanol was
`heated as reflux for sixteen hours. After the reaction
`mixture was cooled, the catalyst was filtered and the
`solvent was evaporated. The product was extracted
`into diethyl ether and dried over magnesium sulfate.
`Chromatography on silica gel afforded 220 mg of the
`title compound. Structure assignment was confirmed by
`the proton nmr specturm.
`803-16 (m, 16H], 3.4-4.0 (in, 3H), 5.39 (in, 11-1).
`
`I0
`
`15
`
`20
`
`8
`fil-
`tracted into ether, dried over magnesium sulfate,
`tered, and concentrated. The crude material was chro-
`matographed on silica gel to give 1.5 g of the title com-
`pound. Structure assignment was confirmed by the
`proton nmr spectrum.
`50.6—2.4 (tn, 22H), 2.6-3.0 (m, 41-1), 3.36 (S, 6H) 4.64
`(t, J=4 Hz, 1H), 5.44 (m. IH).
`EXAMPLE 9
`
`1.l—dimethoxy—5—(1,2,3.4.6,‘l’,8,8a-octahydro-l-naph-
`tha1enyl)—3~pentar1one
`A solution of 5.0 g (29 mmolc) of cadmium carbonate
`and 5.0 g (18.4 mmo1e)ofmercuric chloride in 125 ml of
`acetone and 23 ml of water was heated to 50°, and a
`solution of 1.3 g (4.9 mmole) of the product compound
`of Example 3 in 25 ml of acetone was added. The reac-
`tion mixturc was heated at 50“ for fifteen minutes and an
`additional 2.5 g (14.5 mmole) of cadmium carbonate
`was added. The mixture was heated at 50° an additional
`30 minutes and 6.3 g (39 mmolc) of potassium iodide
`was added. After stirring at room temperature for 30
`minutes, the solvent was evaporated and the product
`was extracted into diethyl ether. The organic phase was
`washed with water, dried over magnesium sulfate, F11-
`tered, and evaporated to dryness. Chromatography of
`the crude material on silica gel afforded the title com-
`pound. Structure assignement was confirmed by the
`proton nmr spectrum.
`60.8—2.6 (In, 18H), 2.68 (d, J=5.5 Hz, 2H), 3.34 (s.
`6H), 4.8 (t. J=5.5 Hz, 1H}, 5.43 (in, 1H}.
`EXAMPLE 10:
`
`[3,3-dimethoxy-1-[2-(1,2,3,4,6,7,8,8a—octahydro—l—naph—
`tha1enyl_)ethyl]propoxy](1.1-dirnethy1ethy1)dipheny|si-
`lane
`
`A mixture of 1.45 g of the product compound of
`Example 9 and 250 mg of sodium borohydride in 5 ml OF
`ethanol was heated to reflux for thirty minutes and then
`stirred at room temperature for thirty rninlites. The
`reaction mixture was cooled to 0° and a 10% aqueous
`acetic acid solution was added dropwise until no further
`reaction occurred. The solution was made basic with
`sodium bicarbonate solution and the ethanol was evapo-
`rated. The intermediate product ct-(2,2-dirnethoxye-
`thy1)-1,2,3.4,6.7.3,8a-octahydro-1-naphthalenepropanol
`was extracted into diethyl ether, and the organic phase
`was washed with water, dried over magnesium sulfate,
`filtered. and concentrated to dryness. The intermediate
`product, without further purification, was dissolved in 4
`ml ofdimethylformamide and 1.5 g o['t-buty1dipheny1si-
`lyl chloride was added. The reaction mixture was
`cooled to 0° and 350 mg of imidazole was added. After
`stirring at room temperature for Five hours, the reaction
`mixture was extracted with ether, washed with water,
`dried over magnesium sulfate,
`filtered, and concen-
`trated to dryness. Chromatography on silica gel af-
`forded 1.4 g of the title compound. Structure assign-
`ment was confirmed by the nmr spectrum.
`30.6-2.4 (m, 131-I),
`3.16 (5. 1H),
`3.6-4.3 (rn, 1H),
`4.4-4.6 (rti, 1H),
`5.36 (m, 1H),
`7.2-8.0 (m. 10H).
`
`
`
`C
`H
`
`Theory
`T994
`1 1. 18
`
`Found
`319.03
`1 1.06
`
`EXAMPLE 7
`
`1,2,3,4,6,'l,3,So-octahydro-1-(2-iodoethyl) naphthalene
`A solution of 350 mg (1.9 mmole) of the product
`compound of Example 6 in 1 ml of pyridine was cooled
`to 0°, and a solution of 400 mg (2.1 mmole) of p-
`tolueneslllfonyl chloride (190.65) in 2 ml of pyridine
`was added dropwise. An additional 1 ml of pyridine was
`used as a rinse for the p—toluenesulfonyl chloride. The
`reaction mixture was stirred at 0" for 24 hours and ex-
`tracted with ether. The organic phase was washed with
`cold 1% hydrochloric acid until
`the aqueous phase
`remained aicidic and,
`then washed three times with
`water, dried over magnesium sulfate. filtered, atid con-
`centrated to dryness. A 40% yield of the tosylate deriv-
`ative,
`1.2,3,4,6,7,3a—octahydro—1—naphtha1eneethano1,4
`methylbenzenesulfonate, having the expected nmr spec-
`trum was obtained.
`A solution of 700 mg (2.1 mmole) of the tosylate
`derivative and 1.3 g (12 mmolc) of sodium iodide in 30
`ml of acetone was heated on a steam bath for three
`hours. The reaction mixture was cooled to room tem-
`perature and the solvent was removed under a stream of
`nitrogen. The product was extracted into Skelly B,
`dried over magnesium sulfate, filtered and concentrated
`to dryness. Chromatography on silica gel afforded 600
`mg of the title compound. Structure assignment was
`confirmed by the nmr spectrum.
`
`25
`
`30
`
`-'10
`
`45
`
`50
`
`_35
`
`EXAMPLE 8
`2-(2,2-dimcthoxyethyl)-2-[2—(1,2,3,4.5,6.8.8a-octahydro-
`1-naphtha1eny|)ethyl]-l,2—dithio1ane.
`A solution of 2 g (9.6 mmole) of in 20 ml of tetrahy—
`drofuran was cooled to -78“ and 5 ml (106 mmole) of
`n-butyl lithium was added dropwise. The reaction mix— 60
`ture was stirred at 0“ for three hours and recoolcd to
`—73°. A solution of 2.0 g (6.9 mmole) of the product
`compound of Example ‘I in 5 ml oftctrahydrofuran was
`added dropwise over a five minute period. The reaction
`mixture was stirred at —7S° for one hour and at -20‘
`for two hours, then quenched with 15 rr11ol'5% aqueous
`hydrochloric acid and warmed to room temperature.
`The solvent was evaporated and the product was ex-
`
`65
`
`CFAD V. UPENN
`IPR2015-01836
`
`
`501”?
`
`PENN EX. 2192
`
`

`
`9
`EXAMPLE I
`
`l
`
`4,499,289
`
`10
`
`SC-J50?! tluctunei
`Theory
`Found
`1"]-.35
`73.67
`9.4]
`9.5]
`
`C
`H
`
`5tJ.Ei—1..‘~ tnt. 23113
`2.5 {(17, J-6.5 H14. 2|-l}
`3.5-4.1 tm. EH}
`4.37 [L]. 3H]
`5.43 lm. iHl
`
`SC—397l3
`80.'t5—2.5 (m. 201-1), 2.5-2.8 (m, 2H}, 2.33 (m, 1H),
`2.65 (m. 1H), 5.75 (m, 11-l).
`EXAMPLE 13
`
`Ethyl
`1,2.3.4,6,7,8,Sa-octahydro-,8,8-dihydroxy-l-naph-
`thaleneheptanoate, component B, and
`tetrahydro-4-hydroxy-6-[(1,2,3,4.6,T,8,8a-octahydro-l-
`naphthalenyl)ethyl]-2H-pyran-2-one, component B.
`
`The silyl group was removed from 550 mg (0.98
`rnmoles) of component B of Ex. ll in the same manner
`as for component A (see Ex. 12). Chromatography on
`silica
`gel
`ethyl
`l.2,3,4,6.?,8,8a—octahydro—,8,5-dihy-
`droxy—1—naphthalene—heptanoate, afforded 220 mg of
`the open chain form of the product and tetrahydro-4»
`hydroxy-6-[(1,2,3,4,6,7,8,8a—octahydro—l-naphthalenyl-
`)ethyl]-211-pyran-2-one. 42 mg of the lactone form of
`the product. Structure assignments were confirmed by
`proton nmr spectra and by elemental analyses.
`Open Chain Compound
`
`Found
`59.75
`9:?
`
`IR 3620 cm-1
`2300-3050 cm-‘
`1730 cm-1
`
`C
`H
`
`Theory
`10.34
`9.94
`SC—356T8
`.su.r5—2.5 (m, 20H)
`2.5-2.3 (m, an)
`2.38 (m. 11-n
`2.05 t. IH}
`5.T5(n't. 11-{J
`SC-35?39
`'<i0.3~2.3 [m. 23H}
`2.5 (d. J=a.s Hz. 2H)
`1.5.4.1 (111.21-I)
`43': (1_ EH]
`s.42(m. lHJ
`
`CHART A
`
`o
`
`1
`
`I I
`
`1):
`
`ID
`
`15
`
`20
`
`25
`
`30
`
`35
`
`45
`
`St}
`
`55
`
`Ethyl 8[[l,1—dimethylethyl)
`diphen}-lsily1]oxy]—1,2,3,4,6,?,3,Sa—octahyclro——
`-hydroxy-l -naphthaleneheptanoate
`
`A solution of L5 g (2.9 mmole} of the product com-
`pound ofE:-zample 10 in 1.5 ml of dioxane was cooled to
`10‘. and a mixture of 15 ml of formic acid, 1.25 ml of
`water and 1.25 ml dioxane was added dropwise. The
`reaction mixture was stirred at room temperature for
`ninety minutes, then 30 ml of diethyl ether was added.
`The reaction mixture was made basic with saturated
`aqueous sodium bicarbonate, and then washed with
`water until neutral, dried over magnesium sulfate, fil-
`tered, and concentrated to give l.3 g of the crude alde-
`hyde intermediate, 6-[[(l _.l—dimetliylethyl)dip]ienylsilyl-
`]0xy]—l.2,3.4,6,7,8,8a—octahydro—l—naphthalenepentanal.
`A solution of 424 mg (3 mmole) of cyclohexyl iso-
`propylamine in 50 ml of tetrahydrofuran was cooled to
`-3'8‘, and 1.3 ml (5.2 rnrnoles) of It-butylithiurn was
`added dropwise. After stirring the reaction mixture for
`fifteen minutes at —?8‘', a solution of 270 mg (3 mmole)
`of ethyl acetate in 25 ml of tetrahydrofuran was added
`dropwise. The reaction mixture was stirred at -78” for
`an additional thirty minutes and a solution of 1.3 g (2.8
`mmole] of the aldehyde intermediate (prepared above)
`in 10 ml of tetrahydrofuran was added. After thirty
`minutes of stirring at -20“, the reaction mixture was
`neutralized with 5% aqueous hydrochloric acid. The
`solvent was removed and the product extracted into
`ether. The organic phase was washed with water, dried
`over magnesium sulfate, filtered, and concentrated to
`dryness. Chromatography on silica gel gave the title
`compound as two separate components which were
`identical by proton nmr spectrum except for the chemi-
`cal shift of the methine proton adjacent to the silyloxy
`group. Isotner A weighed 0.68 and isomer B weighed
`0.53 g.
`80.8-2.6 (m, 36H), 3.24.45 (m, 1H}, 4.04.2 (m, 3H),
`5.2-5.4 (m_. 1H), 12.30 (m, 10H).
`EXAMPLE l2
`
`Ethyl
`1,2,3,4,6,2,8,Ba-octahydro—,G.8—dihydroxy—l—naph—
`thaleneheptanoate, component A, and
`tetrahydro—4—hydroxy-6-[(l.2,3,4,6.7.8,
`Sa-octal1ydro-1-naphthaler1yl)ethyl]2}-I-pyran-2-one,
`component A.
`
`A solution of 0.68 g (1.2 mmole) of component A
`from Example ll
`in 25 ml of tetrahydrofuran was
`treated dropwise with 2 ml (2 mmoles) ofa IM solution
`of tetrabtitylammonium fluoride in tetrahydrofi.iran_
`The reaction mixture was stirred for two hours, after
`which 5 ml of water was added. The solvent was evapo-
`rated and the product extracted into diethyl ether. The
`organic phase was dried over magnesium sulfate, fil-
`tered, and concentrated to dryness. The crude material
`was chromatographed several times on silica gel to give
`120 mg ethyl l,2,3,4,6,7,8.Sa-octahydro-B,8-dihydroxy
`l—naphthalencheptanoatc, of the open chain form ofthc
`product as an oil and 100 mg tetrahydro~4-hydroxy-6-
`[(1.2.3,4,I5.7.8.8a—octahydro—l—naphthalenyl)ethyl]-2H-
`pyran—2one. of the lactone form of the product as a
`white solid. The lactorte prod uet was recrystallized
`from Skelly B to afford 80 mg of compound. Structure
`assignments were confirmed by proton nmr spectra and
`by elemental analyses.
`
`RT)
`
`65
`
`R‘O
`
`Jl I..lCHgCO1R_1_
`
`H0
`
`(I?
`cox;
`
`\L I-{ydrogenolysis
`
`601'’?
`
`PENN EX. 2192
`
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`_
`
`12
`['
`E9lL_Al§lJ%d
`I
`
`A
`
`s
`
`s Li+
`\E<0R3OR;
`
`S
`
`\.__/
`
`X111
`
`DR}
`
`_
`_
`.\\r
`
`J’ Hydrolysis
`
`XVI
`
`H
`0
`
`OR“OR
`_\
`
`11
`-C0nIir1ue::l
`CHARTA
`
`«l?
`COR;
`
`mo‘ : i
`
`_
`LIAIH4
`
`®R'O
`\L
`
`Nu/NH;
`
`RT)
`
`J’ Hydrolysis
`
`8
`
`OH
`
`on
`
`OH
`
`CHART B
`
`VI
`
`\L HSCH3CH3SH
`
`on(.6
`
`\L Rm-y Ni
`
`OH
`
`OH
`
`(11 pTT>.C':
`
`J/‘31 53'
`
`4,499,289
`
`111
`
`W
`
`‘V
`
`VI
`
`XI
`
`K"
`
`5
`
`10
`
`I5
`
`20
`
`25
`
`30
`
`-1-U
`
`45
`
`50
`
`up Ut
`
`60
`
`[I5
`
`XVI
`
`(I) NzzBH.;
`
`CHART C
`$(.’_',l I-‘L,R_-R¢,SiC[
`
`OSiR4R5R°
`OR.\
`OR;
`
`l
`
`Hydrolysis
`
`DSiR4R5R;-_.
`H
`
`II
`ll L1'CI-I;CO3R1OSiR4R_iR(;
`
`0
`
`OH
`
`COR1
`
`OH
`
`J’ Bu..1~:-F-ll,
` OH + as
`
`XXIV
`
`xxv
`
`EOR:
`0
`Cl-l3CH3R_<
`R:
`
`R4
`
`XX]
`
`XXII
`
`XXIII
`
`O
`
`é
`
`0
`
`OH
`
`xx\'1
`
`R1
`R:
`What I claim is:
`
`I.
`
`Tctrahydrov4-hydr0xy-6-[2-l.2,3,4,6,T,3,3a-0c[a-
`
`hydro-I-naphIhalene)ethyI]—2H—p§1ran-2-one.
`*
`BF
`1‘
`i
`:&
`
`7 of 7
`
`PENN EX. 2192
`CFAD V. UPENN
`IPR2015-01836