FI107254B - 5,6,7,8,9,10-hexahydro-8-hydroxy-5,8-dimethyl-5,9- methanobenzocyclooctan-11-one derivatives and process for preparing them - Google Patents

Description

No. 107254 5,6,7,8,9,10-Hexahydro-8-hydroxy-5,8-dimethyl-5,9-meta-nobenzocyclooctane-11-one derivatives and process for their preparation are novel 5,6,7,8,9,10-hexahydro-8-hydroxy-5,8-dimethyl-5,9-methanobenzocyclooctoct-11-one derivatives of formula (II) 10 - (χ) π (v " 15 0 H ch 3 as further defined below, and a process for preparing these compounds.

The compounds of formula II can be used as intermediates in the preparation of hexane and octahydrobenzo [f] quinolinone which are active as steroid 5α-reductase inhibitors.

It is well-known that certain diseases, such as benign prostatic hyperplasia, male ossification, normal acne, hypertrophy of the sebaceous gland

«M

25 secretion, androgenic alopecia, alopecia and prostate: * ·. · Hash cancer is an androgenic disease that is dependent on • · 5α-dihydrotestosterone (DHT).

• M *. . ·. The enzyme 5α-reductase causes the conversion of testosterone to a locally more potent androgen * · t 30 DHT in the target organ. It has been shown and demonstrated that 5α-reductase inhibitors would prevent the formation of DHT and ameliorate the unwanted physiological diseases described above. Recently, two 5α-reductase isozymes (designated as types 1 and 2) have been described in humans, Andershit 35 son et al., Proc. Natl. Acad. Sci. U.S.A .. 87. 3640 - 3644 «« «• · • ·» • t · • ·

Ml • · • · «« · 107254 2 (1990); Andersson et al., Nature. 354. 159-161 (1991). In addition to certain structural differences, the two isoenzymes exhibit minor differences in their biochemical properties, expression patterns, gene-5 drop and pharmacology, Andersson et al., Nature. 351: 159-161 (1991); Jenkins et al., Journal of Clinical Ilves tiat ion. 89. 293-300 (1992). Further studies on the roles of the two 5α-reductase isozymes in the androgenitol mine are currently the subject of intensive research 10. These isozymes are generally described as 5α-reductase 1 or 2, or type 1 or type 2 5α-reductase.

Compounds that have been reported to be useful in inhibiting 5α-reductase are generally female steroid derivative-15, such as the azasteroids in Rasmusson et al., J. Med. Chem. 29 (11): 2298-2315 (1986); and benzoylaminophenoxy-butanoic acid derivatives such as those described in EP 291 245.

Certain benzo [f] quinolinone compounds are known as -20 and. See, for example, Cannon et al., Synthesis. 6: 494-496 (1986); Kiguchi et al., Heterocycles. 18 (Special Number), 217-220 (1982); Cannon et al., J. Med. Chem ..

22 (4), 341-347 (1979); Cannon et al., J. Med. Chem ..

• · ·, * ·· 23, (1), 1-5 (1980); Ninomiya et al., J. Med. Chem. Soc.

25 Perkin Trans. 12, 2911-2917 (1984); and Horri et al., Chem. Pharm. Bull., 16. (4), 668-671 (1968). In general, these references relate to the compounds 4 4 4 4 described therein. and dopaminergic evaluation. These references - • · · ♦♦♦ do not refer to the new hexes of formula I

4 4 4 J

4 4 4 30 octahydrobenzo [f] quinolinones as defined below, or that such compounds would be useful as 44444 steroid 5α-reductase inhibitors.

• 4 · * · * of the present invention. the compounds can be used as intermediates in the preparation. 35 new hexa and octahydrobenzo [f] quinolin-3-ones which are potent selective steroid 5α-reductase inhibitors that are ... ... * 1 • i * · • 4 4 4 4 4 3 107254 useful in the treatment of benign prostatic hyperplasia, male baldness, common acne, increased sebaceous secretion, androgenic calcification, obesity, and prostate cancer.

The aforementioned novel hexa and octahydrobenzo [f] quinolin-3-ones which are potent inhibitors of the steroid 5α-reductase are compounds of formula (I)

15 3 4a · S 7 I

O j z1

R

Wherein the dotted lines represent possible double bonds, wherein the compound may contain up to one of these double bonds; · R * is hydrogen, C 1 -C 6 alkyl or phenyl (C 1 -C 4) alkyl which is unsubstituted or substituted with one or more substituents on the same or different substituents on halo. Gene, alkyl, C 1 -C 4 alkoxy, amino, C 1 -C 4 alkyl. liamino and Cx-C4 dialkylamino; Z is hydrogen or C 1 -C 6 alkyl; * Z1 is hydrogen or C1-C4 alkyl or, in the presence of a 5,6 double bond, Z1 is absent; * * Y is hydrogen or methyl or, in the presence of a 1,10b double bond, Y is absent; R 2 is hydrogen or C 1 -C 6 alkyl; • «, ···. N is 1 or 2; 0 · 0 0 »00 0 0 0 0 0 0 00 0 ·%.

107254 4 X is halogen, NO 2, CF 3, C 1 -C 8 alkyl, C 1 -C 8 alkoxycarbonyl, amino, amido or a group -A-R 6 where A is C 1 -C 8 alkylene, C 2 -C 6 alkenylene or C 2 -C 6 alkynylene and R 6 is carboxy, C 1 -C 8 alkoxycarbonyl, amino, C 1 -C 6 alkylamino, amido or C 1 -C 4 alkylamido.

The activity of the compounds of formula I as 5κ reductase inhibitors is further described and tested in FI patent application No. 923 752 (FI patent 102475), which is the parent strain of this application.

The present invention relates to novel compounds useful as intermediates in the preparation of compounds of formula I having the formula (II) 15 - (X) n .-- (It) 20 ΟΗ ^ η, where X is halogen, NO 2, CF 3, C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy-1,1-cicarbonyl, amino, amido or a group -A-R 6 where A is C 1 -C 8 -alkylene or C 2 -C 6 -alkenylene or C 2 -C 6 alkynylene: 1 · · · and R 6 is carboxy, C 1 -C 8 alkoxycarbonyl, amino, C 1 -C 6 alkyl alkyl, amido or C 1 -C 6 alkylalkylamido, and • · · ·. . ·. n is 1 or 2.

The invention also relates to a process for the preparation of a compound of formula II by hydrolyzing the reaction product obtained by reacting 3,4-dihydro-1M-1-methyl-2- ( 1-phenylethylamino) naphthalene to react with a · S, S-unsaturated carbonyl compound in an inert or predominantly inert solvent or a mixture of solvents. 35 and isolate the compound of formula II. j • t • · t • «· • · * * • • 5 107254

By a process using an intermediate of formula II, a substantially pure optically active compound of formula ίο can be prepared

R

wherein R is hydrogen, C 1 -C 6 alkyl or phenyl (C 1 -C 4) alkyl unsubstituted or substituted with one or more same or different substituents selected from halo, C 1 -C 1 alkyl, C 1 -C 4 alkoxy , amino, C 1 -C 4 alkylamino and C 1 -C 4 dialkylamino; Z is hydrogen or C 1 -C 1 -C 4 alkyl; Z 1 is hydrogen or C 1 -C 4 alkyl, or in the presence of a 5,6 double bond, Z 1 is absent; Y is hydrogen or methyl or in the presence of a 1,10b double bond Y is absent; R 2 is hydrogen or C 1 -C 4 alkyl; • · · .1 ·· n is 1 or 2; X is halogen, NOa, CF 3, C 1 -C 8 alkyl, C 1 -C 8 alkoxycarbonyl, amino, amido or a group -A-R 6 where A is • · C 1 -C 8 alkylene, C 2 -C 6 - alkenylene or C2-C6 alkynylene and ··· «. .% R 6 is carboxy, C 1 -C 8 alkoxycarbonyl, amino, C 1 -C 6 alkyl. liamino, amido or C 1 -C 6 alkylamido.

In this method, a) a-methyl-2-tetralone is reacted with an optically active amine to give the corresponding 1-methyl-1-methylene; ja • «« «• 4 4 ·« 4 4 4 4 · • «♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ j j j

1072H

b) reacting 1-methyleneamine with an α, β-unsaturated carbonyl compound to give the corresponding methanobenzocyclooctoct-4-one; and c) reacting the methanobenzocyclooctane-4-one with an acidic or basic catalyst of the earth to give the corresponding 2,3,4,4a, 9,10-hexahydro-4a-methyl-phenanthren-2-one; and d) cleaving said phenanthrene-1-one by oxidation to give the corresponding 3- [1-methyl-1- (2-keto-1,2,3,4-tetrahydronaphthyl)] propionic acid; and e) reacting said propionic acid with ammonia or a primary amine to counteract 10b-methyl-1,2,3,4,6,10b-hexahydrobenzo [f] quinolin-1-one; and 15 f) reducing said hexahydrobenzo [f] quinolin-3-one to give octahydrobenzo [f] quinolin-3-one as defined above.

As used herein, the term "alkyl" is a straight or branched alkyl group having the indicated number of carbon atoms. Such alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl and, where present, higher homologues and isomers such as n-pentyl, n-hexyl, 2-methylpenic - ·, '·· style and the like.

The term "alkylene" is a divalent branched alkyl chain having a number of carbon atoms, such as · · ··· methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-bu- ···· . titanium diyl, 1,5-pentanediyl, 1,6-hexanediyl. In contrast, "alkenylene" is a bivalent unsaturated hydrocarbon chain having the indicated amount of carbon. liatoms and one carbon-carbon double bond such as vinylene, · · · · ·, 1-propene-1,3-diyl, 2-propylene-1,3-diyl, 2-butene-1,4-diyl, 1-butene-1,4-diyl and the like. You-·*·*; club like "alkynylene" is bivalent straight. ** ·. 35 hydrocarbons ju, showing the number of carbon atoms and »· • · · • | 7,107,254 one carbon-carbon collar bond such as 1,2-acetylene diyl, 1-propyne-1,3-diyl, 2-butyne-1,4-diyl and the like.

The term "phenyl (Cx-C4) alkyl" is a straight or branched alkyl chain group of 1 to 4 carbon moieties substituted with a monosubstituted or substituted phenyl ring having the same or different substituents, such as halogen, C1-C4 alkyl, C 1 -C 6 alkoxy, amino, C 1 -C 4 alkylamino or C 1 -C 4 dialkylamino. Common phenyl (C 1 -C 4 alkyl groups are benzyl, 2-pheneth-1-yl, 10 3-phenprop-1-yl, 4-fenbut-1-yl, 1-pheneth-1-yl, 2-phenprop-1 -yl, 2- (4-halophenyl) et-1-yl, 4-halobenzyl and the like.

The term "alkoxy" is methoxy, ethoxy, n-propoxy, isopropoxy and the like. The terms "halogen" and "halo" are any of fluorine, chlorine, bromine and iodine.

The term "amido" is aminocarbonyl (-C (O) NH 2). The term "alkylamino" is a group -NH (C 1 -C 4 alkyl) and the term "alkylamido" is a group -C (O) NH (C 1 -C 4 alkyl). Where the "C 1 -C 4 -alkylamino" (-N (C 1 -C 4 -alkyl) 2) substituent is shown, each alkyl group independently contains 1-4 carbon atoms.

The octahydrobenzo [f] quinolinones of the formula I are those compounds in which the dotted bonds * · · .1 ·· are single bonds. Correspondingly, the hexahydrobenzo [f] quinolinones of the formula I are those having less than two protons and having one broken chain. the bonds marked with butter have a double bond.

····. . ·. The compounds of formula I have at least one asymmetric carbon which is represented by an asterisk carbon * ♦ ♦ 30 atoms in the following formula Ia, ♦ ♦ · 1 «« 1 1 1 1 107254 8 R3 R1 v-o I £ ΑΑ-ΙγΓ2 RRR® 2 10 wherein R1, R3, R4 and R5 are hydrogen or form part of a possible double bond represented by the dotted line in formula I.

The compounds of formula I also exist as single cis-d and cis-1 stereoisomers, such as myc, trans-d and trans-1 stereoisomers, and mixtures of such isomers. Two cis and two trans configurations are shown in the following formulas Ib-Ie.

20 tl ϊ JMn (X) n f Γ v Πα / A-AA2 An4v ^ -z 0 I R4 Z1 O I R4 I z1 · ;;;. · 25 r r5 ή r5 • · t · · • · ·

'··· Ψ f Y ί ^ ΊΓ1 ^ f f Y

φ 30 r4 ^ tY «h cAy'WV2 ο ^ 'Τγΐ2 * ... ϊ R RS R Rs aa a« aa «« a «« • • • • • • • • • • • aa • aa 107254 9

Correspondingly, the compounds of formula I include not only mixtures of two or more such single isomers, but also single isomers.

In addition, other diastereomers exist depending on the R2, Z and Zx substituents. The compounds of formula I comprise mixtures of two or more diastereomers and single isomers.

The compounds of formula I or their precursors are prepared using methods known to those skilled in the art. The compounds of formula I wherein Y is hydrogen are preferably prepared according to the following Scheme 1.

aCH2COCI 1) Lewis acid catalyst ----- 2) ethylene gas (χ), - ΓΠ 1 x ^ x ^ X ^ q acrylamide N-Ra

20 I

Rb '* / V / s. 1) base. .

(χ) η-ϋ- T] 2) R-EAA {XL-iYl

25 J N-H ^^ y ^ N-R

·: * ^ \) 1) Reducer \ 2) Base

V; \ 3) R-EAA

30 X »• * Λ • · · · * * Reducer (x) n-jr- T V”

--- ► X ^ V ^ N-R

** · '* 35 Hx ^^ 4v

O

Wherein X, n and R are as defined above for Formula I, R-EAA is an electrophilic alkylating agent and R a and R b are independently selected from hydrogen or C 1-6. C 1 -C 4 alkyl or together with the nitrogen atom may form a 5-7-5 membered heterocyclic group which may also contain an oxygen atom, provided that both R a and R b cannot be hydrogen at the same time.

As described in Preparation Scheme 1, delta4a-10b-hexahydrobenzo [f] quinolinones represent intermediates which, after double bond reduction, provide compounds of formula I and / or compounds useful as intermediates in the preparation of compounds of formula I.

Hexahydrobenzo [f] quinolinones are prepared from substituent or appropriately ring-substituted phenacetyl chloride. Phenacetyl chloride is commercially available or is prepared by methods well known to those skilled in the art. Typically, the appropriately substituted phenylacetic acid 20 is reacted with thionyl chloride, phosphorus trichloride, oxalyl chloride or phosphorus pentachloride, preferably thionyl chloride, under conditions well known to those skilled in the art to give the corresponding phenacyl chloride.

• · 1: 25 By Friedel-Crafts acylation reaction of phenacetyl chloride with ethylene in the presence of a Lewis acid catalyst in an inert or predominantly inert solvent or mixture of solvents, the ring closure is accomplished to give 2-tetra- · · * · 1 · 1 ion. Suitable Lewis acid catalysts include AlBr3, AlCl3, GaCl3, FeCl3, SbCl5, ZrCl4, SnCl4, BC13, BF3, SbCl3 and vanadium, preferably AlCl3. Useful solvents for this ··· * ... J reaction include carbon disulfide, methylene chloride, nitromethane, 1,2-dichloroethane, nitrobenzene and polar acids, preferably methylene chloride. Activation with Lewis acid is carried out at temperatures from about -78 ° C to about 25 ° C.

The addition of ethylene is exothermic in nature and the temperatures used are from about -78 ° C to about 30 ° C using standard cooling methods.

The 2-tetralone reaction product is then aminated with a primary or secondary amine, preferably pyrrolidine, in an inert or predominantly inert solvent or mixture of solvents to give the corresponding enamine. In the case of a primary-10 amine, an imine tautomer may also be present. The reaction is completed by removal of water, which may be accomplished by raising the temperature to about 80 ° C to 110 ° C using a suitable azeotropic solvent or at about room temperature using a suitable dehydrating agent such as molecular sieves or magnesium sulfate. Suitable solvents include aprotic organic solvents such as benzene, toluene, THF, CH 2 Cl 2 and ethyl acetate.

The enamine reaction product is then reacted with acrylamide in the presence of an acid and in the presence or absence of an inert or predominantly inert solvent or mixture of solvents to give hexahydro-2- (1H) -benzo [f] -quinolinone. Acids useful in this reaction include strong organic or inorganic acids, preferably p-toluenesulfonic acid (pTSA). Although the reaction may be carried out in a solvent, it is preferable not to use a solvent.

• ·

The reaction is carried out at temperatures of about 90 ° C to about 130 ° C.

] The hexahydro-2 (1H) -benzo [f] quinolinone can then be reduced to the corresponding octahydrobenzo [·] * [f] quinolinones of the formula I. The octahydro [f] quinolinones can then be 30 N-alkylated to give other compounds of formula I.

· *** Alternatively, the hexahydro-2 (1H) benzo [f] -quinolin-1-ol can first be N-alkylated and then reduced to the corresponding N-alkyl-octahydrobenzo [f] quinoline- (3) ).

. ···. The reduction is accomplished by reacting a hexahydrobenzo [35] [f] quinolinone or N-alkyl-hexahydrobenzo [f] quinolino- • mm-mm-mm mm-1 · m 107254 12 ni in an inert or predominantly inert solvent or mixture of solvents. . Suitable reduction methods include hydrogenation with a metal catalyst and use of hydride transition reagents such as ammonium formate with a metal catalyst, preferably triethylsilane / trifluoroacetic acid. Useful solvents include inert or predominantly inert organic solvents, preferably methylene chloride. Temperatures are from about 0 ° C to about 60 ° C, preferably about 25 ° C.

N -alkylation is accomplished by reacting hexahydro-benzo [f] quinolinone or octahydrobenzo [f] quinolinone with the electrophilic alkylating agent R-EAA, wherein R is as defined in Formula I above, in the presence of a base or in an inert solvent. . In this reaction, R 4A is preferably iodine. The base is usually a metal hydride, metal amide or metal alkoxide, preferably sodium hydride. Generally, this reaction is carried out at a temperature of n.

-30 ° C - solvent reflux temperature.

The compounds of formula I wherein Y is methyl are preferably prepared according to Scheme 2 below.

• · * · «« · * 1 • • • • • • • • • • • •: • • • • • • • • • • • - • · · • • • 1 * MI 1 · 4 • · • • • • • «« • «« * 1 1 107254 13

Scheme 2 CHoCOCI Lewis Acid Catalyst 5 -: - 2) Ethylene Gas

1) CH 3-EAA

(X) n_OOl amine1 ~ <x) "- 0Q ^ hydrolysis ^ xo N - Ra acid catalyst ^ acrylamide« Cl · ^ H 0 1) Base 2) R'EAA m rT ^ YY1 20 »Tl 1 - <X>" Ti I ,, „chvl 1 CHs kA.

. '· .; O

• i: /! 25 Reducer Reducer • · · ··· * u

• · · I

• · · ’• · · · · · · ·

30 (Χ) η · χ ^ Τ ^^ Η 1) emäS Wn "X ^ LjcfH

'S> Si!? I !! iisy / ^ N-H 2) R-EAA Vsv ^ Pp ^' N-R

CH3 kJC -CH3

: · Λ O

Wherein X, n and R are as defined in formula I above and R a, R b and R-EAA are as defined in Scheme 1 above.

As depicted in Scheme 2 above, the 5α-methylhexahydrobenzo [f] quinolin-2 (1H) -ones are intermediates which are reduced to provide compounds of formula I and / or compounds useful as intermediates in the preparation of compounds of formula I.

Enamine is prepared according to the methods depicted in Schemes 1 and 2 and described in Scheme 1 above. The enamine is alkylated by reaction with an electrophilic alkylating agent, preferably methyl iodide, in an inert or predominantly inert solvent or mixture of solvents. The temperatures of this reaction are generally in the range of about 0 ° C to about 60 ° C. The reaction mixture of Si: s is subjected to hydrolysis with an aqueous acid, preferably a mixture of sodium acetate: ethyl acetate and acetic acid. In this reaction, temperatures of about 0 ° C to about 30 ° C are used to give 1-methyl-1-2-tetralone.

The 1-methyl-2-tetralone is then further reacted as described in Scheme 2 using the reagents and methods described in Scheme 1 above,

I M

25 to give compounds of formula I wherein Y is methyl.

The compounds of formula I wherein Z, Z1 or both are C1-C4 alkyl are prepared essentially according to the methods of Scheme 1 · · · · · * and Scheme 2, except that fenas-30 ethyl chloride Friedel -Crafts ring closure reaction a: .- * * The appropriate alkene is used * ♦ ♦ '... · rather than ethylene as shown in Schemes 1 and 2. Examples of suitable alkenes for use in this reaction are ···. thio include propylene, 1-butene, 2-butene, isobutylene, 35,3, 3,3-dimethyl-1-butene, 2-pentene, 4-methyl-2-pyrene • · · · · Xylene, 3-methyl-1-butene, 2-methyl-2-butene, 2,3-dimethyl-2-butene, and the like.

Compounds of formula I wherein R 2 is C 1 -C 4 alkyl are prepared from compounds of Schemes 1 and 2, preferably where R is C 1 -C 4 alkyl, unsubstituted or substituted phenylC 1 -C 4 alkyl as in Scheme 3 below. is shown: T 1. Base.

15 P U | B

H R

wherein Y, X, n, R and R 2 are as defined above for Formula I except that R is not hydrogen and R 2 -EAA is an electrophilic alkylating agent wherein R 2 is as defined in Scheme 1. The R- (alkyl or phenalkyl) compound is reacted with a base such as a metal amide or a metal alkali metal oxide, preferably potassium hexamethyldisilazide, in an inert or predominantly inert solvent or at a temperature of about -78 ° C. - n.

· 25 ° C. Alkylation is then accomplished by the addition of • ·· ·. . *. a suitable electrophilic alkylating agent, preferably • ♦ ·. ···. C 1 -C 4 alkyl iodide to give 2- (C 1 -C 4 alkyl) compounds of formula I.

. In compounds of formula I wherein R is H, the nitrogen * # * atom at the 4-position is first blocked with a suitable amino protecting group, such as t-butoxycarbonyl or benzyloxycarbonyl · *: reaction as shown in Scheme 3 above. After alkylation at the 2-position <t *, · 35 nitrogen atoms are deprotected at the 4-position. The deprotection and deprotection reactions are carried out under standard conditions of such reactions.

An alternative method for preparing compounds of formula I wherein Y is methyl 5 is shown in Scheme 4 below.

Figure 4

Chiral amine

(Χ) η ^ ΧΛ liUOtin (X) n_ ^ AvAH

io T Ό I N H

CH3 CH3 \ /

ch / I

c6h5! 15

1) 06, & Saturation / V

basic carbonyl- CH3 / / χ \ li / solvent ° alkali metal ____ / O \ alkoxide 2) Aqueous \) "" "^ 20 acid νΛ ^ / solvent OH ΐΗ3 ^^ ζ3τ (Χ)" oxidant

ν ·! 25 solvent H02C I X I

0 ^ cf ^ NH2R t CH3 ί "jj -" (X) n Reducer • I I Solvent

. 30 X JL J

u 1

· ... = R

• · · • · t O CH3j ^ X- (X) „/. 35

0 / n / vj

° R H

Wherein R, X and n are as defined in formula I above.

In particular, the process shown in Scheme 4 can be used to prepare the optically active isomers of the compounds of formula I. As depicted in Scheme 4 above, 1-methyl-2-tetralone is reacted with a chiral amine, preferably 1-phenylethylamine, in an inert or predominantly inert solvent or mixture of solvents to give the corresponding enamine. If a primary chiral amine is used, the enamine can be obtained together with the imine tautomer. The reaction is carried out by removing water, which may be carried out at a high temperature between about 80 ° C and about 110 ° C using a suitable azeotropic solvent or at about room temperature using a suitable dehydrating agent such as molecular sieves or magnesium sulfate.

The enamine is then reacted with a suitable α, β-unsaturated carbonyl compound, preferably methyl vinyl ketone, in a Michael addition reaction followed by hydrolysis with weak aqueous acid to give 5,6,7,8,9,10-hexahydro-8-hydroxy-5 8-dimethyl-5,9-methanobenzocyclooctoct-11-one. This reaction is carried out in an ethereal solvent such as tetrahydrofuran. in THF, dioxane or the like, inert • · ·. ·. : 25 atmospheres, such as argon or nitrogen, ca.

.j, at 10 ° C to about 50 ° C, preferably at about room temperature. ** In general, this reaction uses reactants from about · stoichiometric amounts to an excess of α, β-saturated The free carbonyl compound and preferably an excess of the α, β-unsaturated carbonyl compound are used Suitable acids are organic carboxylic acids and perchloric acid, and preferably acetic acid.

Methanobenzocyclooctane-11-one is treated with an acid or base catalyst, preferably sodium or potassium ethoxide, in a protic solvent, preferably ethanol. Reflux to give 2,3,4,4a, 9,10-hexahydro-4a-methyl-phenanthren-2-one.

Phenantren-2-one is cleaved by oxidation with a suitable oxidant such as ozone, KMnO 4, CrO 3, i.e. RuO 4, preferably ruthenium tetraoxide, in an inert or predominantly inert solvent or mixture of solvents at about -78 ° C. At 100 ° C, preferably at about -10 ° C. At 10 ° C to give b- [1-methyl-1- (2-oxo-1,2,3,4-te: -hydronaphthyl)] propionic acid. Generally, the solvent is an inert solvent or mixture of solvents, and preferably the solvent is a mixture of two parts carbon tetrachloride, three parts acetonitrile and two parts water.

The propionic acid is reacted with ammonia or a primary amine (NHR where R is as defined in formula I above) in an inert or predominantly inert solvent or mixture of solvents, preferably 2-propanol, at a temperature of about 95 ° C to about 200 ° C, preferably at about 165 ° C to about 180 ° C to give the 10b-methyl-1,2,3,4,6,10b-hexahydrobenzo [f] -20 quinolin-3-one. Preferably, this reaction is carried out in the absence of oxidants such as air, for example in a closed reactor or the like.

The hexahydrobenzo [f] quinolinone can be reduced to · · · 1 · 1 · to the corresponding octahydro compound of the formula I by the same procedures as described above for the formula. defects 1 and 2.

By following the procedures described in Scheme 4, and as described above, substantially pure optically active isomers of the compounds of formula I wherein Y is methyl are obtained.

***** Preferred asymmetry of single enantiomeric compounds of formula I or precursors thereof: .-; v. this preparation is accomplished by placing an enamine with a «0 * ..! formula • ♦ • ♦ *: 1 35 • · • · · • ♦ · ♦ ♦ · «• · •« «» 107254 19

Reaction of γγ'ΥΜΧ, π A-10 with an acryloyl derivative of formula r2vx / .cog X.

Wherein Y, X, R 2 and n are as defined above in formula I; G is a leaving group such as chlorine, bromine, fluorine, iodine, toluenesulfonate, methanesulfonate and symmetric or asymmetric anhydride; and Rc is 1-phenethyl. The 1-Fe-20 methyl substituent is then cleaved using trifluoroacetic acid. It is desirable that the acryloyl derivative -COG radical is the activated form of -COOH which *. I may be activated by other means such as active esters, mixed anhydrides and the like.

The production conditions for the preparation of the preferred single isomers of the schemes are very mild.

····: In most cases, it is noticeable that the best * · «yields are obtained using short periods at ambient temperature. For example, temperatures of about 0 ° C to about 0 ° C are used.

e. 30 to 150 ° C and reaction times from a few minutes to a maximum of several hours * * ... are sufficient. The reaction medium is preferably a two-phase mixture of a suitable organic solvent and an aqueous solution of a weak base. Useful solvents include, for example, haloalkanes, ether-35 ter, including tetrahydrofuran, and nitriles, including acetonitrile. Preferred weak bases include alkali metal carbonates and bicarbonates; in some cases, more basic reagents such as alkali and alkaline earth metal hydroxides and the like can be used, but bicarbonates are usually preferred. The method can also be carried out without a base if desired.

The products of this synthesis are readily isolated by standard production steps. Using this method, a: L-10 provides a particularly pure synthesis of the individual isomeric forms of the reaction product.

It will be appreciated that the products of this process may be used as such, utilizing their biological activity, or may be used as intermediates in further processes for the preparation of active compounds of formula I.

Those hexahydrobenzo [f] quinolin-3-ones of formula I having a delta1 or delta5 carbon-carbon double bond are prepared from the corresponding octahydrobenzo [f] quinolin-3-ones by 20 addition / elimination reactions. The octahydrobenzo [f] quinolin-3-one is reacted with electrophilic sulfur or selenium in the presence of a base in an aprotic solvent. The base is generally a metal hydride or metal amide: preferably a metal hydride such as sodium hydride. Although «% m. ·. In general, one equivalent of base is added for each oct.- * · · hydrobenzo [f] quinoline, for compounds wherein R is hydrogen, another equivalent of base is added. This • · · * · ·

The reaction temperatures of H1 are about 20 ° C to the refluxing temperature of the solvent. The reactive electrophile added contains sulfur or selenium and the reaction is carried out at a temperature of about -50 ° C to about -100 ° C. Suitable sulfur electrophiles • · · are essentially similar to sulfur groups which are useful in: useful in nucleophilic substitutions and skilled in the art, Patai, "The Chemistry of the *; * 35 Thiol Group", Wiley, New York (1974); Reid, "Organic Che- • · * · · * * ·« «· 107254 21 Mistry of Bivalent Sulfur," Chemical Publishing Company,

New York (1958, 1963); Kharasch, “Organic Sulfur

Compounds, ”Perganon, New York (1961).

Suitable selenium compounds include phenyl selenylene dichloride, phenyl selenylene enyl bromide, N- (phenyl selenium) phthalimide, diphenyl disiselenide, benzene selenic anhydride, and selenium oxides. Specific conditions for a particular reactive selenium are well known or readily apparent to one skilled in the art, Clive, Tetrahedron.

10, 34, 1049-1132 (1978); Aldrichimica Acta. 11. 43-49 (1978); and Miyoshi et al., Tetrahedron Lett., 23, 4813 (1982).

The elimination reaction is generally carried out under oxidizing conditions in an aprotic solvent. March, "Advanced Organic Chemistry", 3rd Edition, pp. 912-914, Wiley-Inter- science, New York (1985).

The delta10b compounds of formula I are obtained by rearrangement (isomerization) of the corresponding delta1b compounds when Y is hydrogen. This reaction is carried out in an aprotic solvent in the presence of an acid or base catalyst under conditions well known or readily known to those skilled in the art.

The delta4a compounds of Formula I are prepared as intermediate products by the methods described in Scheme 4 and are isolated rather than reduced to the corresponding octahydro- * · 25 benzo [f] quinolin-3-one.

• · · • ·

The compounds of formula (II) are used as follows. . ·. for the preparation of the compounds of formula (I): - 30 ° |) r2 Tl lp »» ··· * 35 ° I H z1 • · "

. * ** · R

• · • · ·! Wherein R, Z, Z1, Y, R2, n and X are as defined above.

This method provides a 1-methyl-2-tetrailone compound of formula 5

Xn

10 I

ch3 to react with an optically active amine to afford the corresponding 1-methylamine; and b) the resulting 1-methylenamine compound of the formula 15

Xn n 20 0113 h ch 3 C 6 H 5. * ·. · Is reacted with an α, β-unsaturated carbonyl compound in the presence of the corresponding methanobenzocyclooctane-4-one. : 25 missions; and c) the resulting methanobenzocyclooctane-4-one compound of formula (II) • H HC - (X) n

• · · · · I

* * I

* * / Nyl '35 OH CH 3 O' 107254 23 is reacted with an alkali metal alkoxide to give the corresponding 2,3,4,4a, 9,10-hexahydro-4a-methylphenanthren-2-one compound of formula <and d ) cleaving said phenanthrene-2-one under oxidative conditions to provide the corresponding 3- [1-methyl-1- (2-oxo-1,2,3,4,4-tetrahydronaphthyl)] propionic acid compound of formula ch3 (X) rv

H 2 C °

• · • · ·. ·. And (e) reacting said propionic acid compound with ammonia or a primary amine, the corresponding *** 10b-methyl-1,2,3,4,6,10b-hexahydrobenzo [f] quinolin-3- • · · * · * 'To obtain an oni compound of formula 30f ··,

35 J

R

Wherein R, X and n are as defined above.

The following examples further illustrate the present invention as well as methods for preparing the compounds of formula I. The examples are not intended to limit the scope of the invention in any way.

Example 1

Preparation of cis-d1- and trans-d1 -8-bromo-4-methyl-1,2,3,4,4ar-5,6,10b-octahydrobenzo [f] quinolin-3-one A. 4-Bromophenylacetyl chloride 10 To a 250 mL round bottom flask equipped with a magnetic stirrer was added 4-bromophenylacetic acid (: 1-00.0 g; 0.465 moles) and 100 mL thionyl chloride (163.1 g; 1.37 moles). The resulting slurry was stirred at room temperature for 22.5 hours. Excess thionyl chloride was evaporated in vacuo to give 108.5 g of the subtitle compound as a brown liquid.

B. 6-Bromo-2-tetralone j

To a cold (-78 ° C; ice-ice / isopropanol bath) suspension of AlCl 3 (125 g; 0.94 mol) in 1400 mL of CH 2 Cl 2 was added the acid chloride from Step A (108.5 g, 0.47 mol). dissolved in 400 ml of dry CH 2 Cl 2 with stirring for one hour. The carbonic acid / isopropanol bath was removed and the solution was allowed to warm to -10 ° C. Ethylene was then bubbled into a flask. : 25 with vigorous stirring. The reaction warmed exothermically to 20 ° C, at which time the addition of ethylene was stopped.

The mixture was stirred at room temperature for three hours, then cooled to 0 ° C and ice was added until no exotherm was observed. The reaction mixture was diluted with 1 L of ice-cold water and stirred until all of the '*** solid had dissolved. The resulting layers were separated and

the organic layer was washed twice with 1 L portions of 1 N

; ·) ·, HCl and then once with 1 L of saturated Na 2 HCO 4. Orgaa - • · \.! The aqueous layer was dried over Na 2 SO 4 and concentrated in vacuo to give a pale yellow crystalline solid.

The 107-crystals of 6-bromo-2-tetralone were recovered in a minimum amount of ether. Hexane was carefully added until the solution became cloudy. The mixture was cooled for 4 hours, filtered and washed with cold hexane 5 to give 75.6 g of the subtitle compound as pale yellow crystals (71% yield), m.p. 71-73 ° C.

C. 2-Pyrrolidinyl-6-bromo-3,4-dihydronaphthalene To a 250 mL round bottom flask was added 5.00 g (22.21 mmol) of the 6-bromotetralone from Step B above; 70 ml of dry toluene and 3.1 g (3.7 ml) of pyrrolidine.

The flask was equipped with a Dean-Stark water trap, a condenser, a nitrogen inlet, and a magnetic stirrer, and the reaction was refluxed for four hours. The solvent was evaporated in vacuo to give 6.02 g (97.4%) of the subtitle compound 15 as brown crystals which were used without further purification.

D. 8-Bromo-1,2,3,4,5,6-hexahydrobenzo [f] quinolin-3-one

Enamine (2.15 g; 7.73 mmol) from Step C, ac-20-aryl amide (1.10 g; 15.46 mmol) and 100 mg p-toluene sulfonic acid (pTSA) were thoroughly mixed in mortars. The mixture was transferred to a 250 mL round bottom flask equipped with a magnetic stirrer and a nitrogen inlet. Using a mineral oil bath, the mixture was heated. : 25 to 89 ° C, whereupon the blend turned black and melted. The temperature was kept constant at 89 ° C for 1.5 hours,

at this point the temperature was raised to 130 ° C and maintained at · · · M

"Stir at this temperature for 0.5 hours. The oil bath was removed • · · * · 1 L and 60 mL of water was carefully added. The resulting gray matter was thoroughly mixed with a spatula and 80 mL of water was added to facilitate filtration. Brown crystals ··· (1 The crystals were taken up in CHCl3 and activated charcoal was added and the mixture was stirred for 15 minutes, filtered and evaporated in vacuo.

T 35 Residue was recovered in minimum amount of ethyl acetate ........................ ---------------- h ------- 107254 26 in a steam bath and transferred to an Erlenmeyer flask fitted with a magnetic stirrer and immersed in a dry ice / acetone bath, stirring to give the subtitle concentrate as a white crystalline solid (m.p. 215-5177 ° C, dec.). First yield 940 mg; second yield 175 mg (55% yield).

E. 8-Bromo-4-methyl-1,2,3,4,5,6-hexahydrobenzo [f] quinolin-3-one

Following essentially the above procedure, 5.17 g of 8-bromo-1,2,3,4,5,6-hexahydrobenzo [f] quinolin-3-one were obtained. Hexahydrobenzoquinolinone (5.17 g; 19.6 mmol) was dissolved in 60 mL of dry diethyl ether in a 250 mL round bottom flask. To the solution was added 1.2 g of sodium hydride (60% dispersion in mineral oil). The flask was fitted with 15 reflux condenser arms and the mixture was refluxed for 2 hours. The mixture was then cooled to room temperature and 7.35 mL of methyl iodide was added. After the addition, the reaction mixture was refluxed for another three hours. After cooling, the reaction mixture was quenched by the careful addition of 5 mL of water.

The mixture was then concentrated in vacuo to give light crystals which were taken up in ethyl acetate / water and the resulting layers were separated. The organic layer was washed · * '*; twice with water and once with brine and then dried over MgSO4 and evaporated in vacuo to give 5.22 g of yellow crystals. The solid was recrystallized from acetone to give 3.55 g (62%) of the subtitle compound as a light yellow solid. Melting point 126 ° C · 128 ° C.

30 F. 8-Bromo-4-methyl-1,2,3,4,4a, 5,6,10b-octahydro- * * benzo [f] quinolin-3-one • · ·

To a solution of hexahydrobenzoquinolinone (1.17 g; 4.0 mmol) prepared in Step E above in 10 mL of dry dichloromethane was added tri-T 35 ethylsilane (1.37 g; 11.8 mmol). The resulting mixture was stirred for 10 minutes at room temperature. The reaction mixture was cooled in an ice bath and trifluoroacetic acid (5 mL) was added. The resulting mixture was stirred at room temperature for four days. The reaction mixture was concentrated in vacuo. The oily residue was taken up in CH 2 Cl 2 and washed with saturated NaHCO 3. The organic layer was dried over sodium sulfate and concentrated in vacuo to give an orange oil. Flash chromatography on SiO 2 (eluting with 0.5% methanol / CH 2 Cl 2) gave 1.14 g of a light brown oil. Proton 10 NMR spectroscopy revealed a trans: cis ratio of 3.2: 1.

G. Cis-trans and trans-d1-8-bromo-4-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3-one Cis- and trans- the isomers were separated by HPLC on SiO 2 (gradient of ethyl acetate in hexane-15 account). The trans isomer (Example IA) first came in, giving 631 mg; and the cis isomer (Example IB) came second giving 192 mg. The trans isomer was recrystallized from diethyl ether / hexane to give 176 mg; mp 103-104.5 ° C.

20 Elemental Analysis: C H N

trans (IA)

Calculated: 57.16 5.48 4.76

Found: 57.57 5.53 4.64 .1 · 1. cis (IB) 25 Calculated: 57.16 5.48 4.76 • · ·

Found: 57.46 5.67 4.59 ··· '1' * · 1: Example 2 • · · *? 2 Trans-dl-8-bromo-1,2,3,4,4a, 5,6 Preparation of 10b-octahydrobenzo · · ·so [f] quinolin-3-one Compound 8-bromo-1,2,3,4,5,6-hexahydrobenzo [f] quinolin-3-one was prepared according to Example 1. according to the production methods described in steps A, B, C and D.

The title compound was prepared according to the production procedure described in Example 1, Step '...' F to give 84 mg of · · *; · 35 white crystals (29% yield), followed by? • · 2 • · 28 107254 Recrystallization from ethyl acetate; mp 252-254 ° C, dec.

Elemental Analysis: C H N

Calculated: 55.73 5.04 5.00 5 Found: 55.47 5.07 4.89

Example 3

Preparation of trans-d1-8-iodo-4-methyl-1,2,3,4,42,5,6,10b-octa-hydrobenzo [f] quinolin-3-one

The compound trans-dl-8-bromo-4-methyl-2,3,4,4a, 5,5, 10,10b-octahydrobenzo [f] quinolin-3-one was prepared in Steps A, B, C, D of Example 1. , E, F and G according to the described production methods.

To a stirred solution of the trans isomer (475 mg; 1.614 mmol) in 3.5 mL of dry dioxane was added hexamethyldithine and 54 mg (3 mol%) of tetrakis (triphenylphosphine) palladium. The reaction mixture was refluxed for 2.5 hours, cooled to room temperature, filtered through celite (CeliteR) and concentrated to give a pale yellow oil. The material was then concentrated under high vacuum overnight at room temperature to give 677 mg of the corresponding 8-trimethyltin compound as a pale yellow oil which was used without further purification.

• ·

To a cold solution (-78 ° C) of 8-trimethyl-tin: 25 tin compound prepared above in 5.0 mL of CH 2 Cl 2 was added 1.6 mL of 1.0 M mono chloride. The reaction mixture was allowed to warm to room temperature over 1.5 hours. The mixture was quenched with 1 mL of water, filtered and the volatiles evaporated in vacuo to give a black oily substance. The black oily substance * · * '· was chromatographed on SiO 2 (eluted with 5% isotope *, #> propanol / CH 2 Cl 2) to give a yellow crystalline solid, m.p. which was recrystallized from ethyl acetate / hexanes 4 to give 141 mg (86% yield) of the title compound as a white crystalline solid; mp: 103-104.5 ° C.

* ·!

Elemental Analysis: C H N

Calculated: 49.28 4.73 4.11

Found: 49.48 4.72 3.96 • · · 107254 29

Example 4

Preparation of trans-dl-8,9-dichloro-1,2,3,4,48,5,6,10b-octahydro-benzo [f] quinolin-3-one

The title compound was prepared using 3,4-dichloro-5-phenylacetic acid as the starting material according to the methods described in Steps A, B, C, D and F of Example 1 above to give 567 mg of the title compound as a light, highly crystalline material. Melting point 267-268 ° C, dec.

Elemental Analysis: C H N

Calculated: 57.80 4.85 5.18

Found: 58.22 5.04 5.18

Example 5

Preparation of trans-d1-8,9-dichloro-4-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3-one Following Steps A, B, C of Example 1 , D and F, followed by recrystallization from ethyl acetate, were prepared trans-d1-8,9-dichloro-1,2,4,4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3- onion using 3,4-dichlorophenylacetic acid as starting material.

The title compound was prepared from trans-dl-8,9-dichlorooctahydrobenzo [f] quinolinone according to the procedures described in Example 1, Step E to give 117 mg (35% yield) of a beige solid. Melting point «» ·. **. 168-169 ° C.

• ·

. ·. : 25 Elemental Analysis: C H N

• · ♦ '. · * Calculated: 59.17 5.32 4.93 *' *! Found: 59.45 5.08 4.83 • · · • * · *** Example 6 • e ·

Preparation of trans-d1-8-chloro-4-methyl-1,2,3,4,4a, 5,6,10b-ox-30 tachydrobenzo [f] quinolin-3-one

The title compound, together with the cis-dl isomer * w! (Example 7), prepared in Steps A, B, ··) of Example 1. c, D, E, and F using β-chlorophenylacetic acid as starting material. Example- • • · * • «•» * • «· 9 ·« · · • • • *! 107 725) 4 k by Step 1 separation gave 500 mg of the title compound. Melting point 82 ° C.

Elemental Analysis: C H N

Calculated: 67.33 6.46 5.61 5 Found: 67.60 6.63 5.67

Example 7

Preparation of Cis-d1-8-chloro-4-methyl-1,2,3,4,4a, 5,6,10b-oct i-hydrobenzo [f] quinolin-3-one

The title compound, together with the trans-d1 isomer 10 (Example 6), was prepared according to the production procedures described in Steps A, E, C, D, E and F of Example 1 using p-chlorophenylacetic acid as starting material. Separation according to Step G of Example 1 gave 200 ng of the title compound as an oil.

15 Elemental Analysis: C H N

Calculated: 67.33 6.46 5.61

Found: 67.57 6.82 5.70

Example 8

Preparation of trans-dl-4,8-dimethyl-1,2,3,4,4a, 5,6,10b-octahyd-20 robenzo [f] quinolin-3-one

The title compound, together with the cis-d1 isomer (Example 9), was prepared in Example 1, Steps A, Br. . C, D, E, and F using p-tolylacetic acid as starting material. Separation of step * G * of Example * · * ··· * gave 400 mg of title · *. *: compound. Melting point 115-116 ° C.

Elemental Analysis: C H N

: Calculated: 78.56 8.35 6.11

Found: 78.79 8.32 6.11 Example 9

Cis-dl-4,8-dimethyl-l, 2,3,4,4a, 5,6,10b-octahydro. ···. Preparation of benzo [f] quinolin-3-one

The title compound, together with the trans-d1 isomer, · · ·: * (Example 8), was prepared according to the preparation procedures of Steps A, B, 35 C, D, E and F of Example 1.

• 31 107254 p-tolylacetic acid as starting material. Separation according to Step G of Example 1 gave 290 mg of the title compound. Melting point 78 ° C.

Elemental Analysis: £ H N

5 Calculated: 78.56 8.35 6.11

Found: 78.26 8.56 5.87

Example 10

Preparation of trans-d1-8-fluoro-4-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3-one The title compound, together with the cis-d1-isomer ( Example 11) was prepared according to the procedures described in Steps A, B, C, D, E and F of Example 1 using p-fluorophenylacetic acid as starting material. Separation according to Step G of Example 1 gave 244 mg of the title compound. Melting point 108-109 ° C.

Elemental Analysis: C H N

Calculated: 72.80 6.91 6.00

Found: 72.07 6.89 6.09

Example 11 Preparation of Cis-dl-8-Fluoro-4-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3-one

The title compound, together with the trans-d1 isomer (pre · ·: sign 10), was prepared according to the procedures described in Example 1, Steps A, ♦ · ♦, ··· [B, C, D, E and F]. . 25 o-fluorophenylacetic acid as starting material. Separation according to Step 1 of ♦ ♦ * * ♦ ♦ *. * Of Example 1 gave 130 mg of the title compound. Melting point 136-137 ° C.

* ♦!. * Elemental Analysis: £ H N

Calculated: 72.08 6.91 6.00 30 Found: 72.30 7.04 6.06 *: ··· Example 12 (not according to the invention) · * '*. Preparation of trans-dl-4-methyl-1,2,3,4,4a, 5,6,10b-octahydro-4 · benzo [f] quinolin-3-one

The title compound, together with the cis-d1 isomer (Example '<··· 353), was prepared in Steps A, B, C, Example 107 D, E and F of Example 1 using the phenyl acetic acid as starting material. Separation according to Step G of Example 1 gave 200 mg of the title compound. Melting point 128-129 ° C.

5 Elemental analysis: C H N

Calculated: 78.10 7.96 6.51

Found: 77.87 7.85 6.46

Example 13 (not according to the invention)

Preparation of Cis-dl-4-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenz-10so [f] quinolin-3-one

The title compound, together with the trans-d1 isomer (Example 12), was prepared according to the preparation procedures described in Steps A, B, C, D, E and F of Example 1 using phenylacetic acid. as starting material. Separation according to Step 15 of Example 1 gave the title compound. Melting point 129-130 ° C.

Elemental Analysis: C H N

Calculated: 78.10 7.96 6.51

Found: 78.32 7.04 6.58 Example 14 (not according to the invention)

Preparation of cis-dl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [e] quinolin-3-one. : The compound 1,2,3,4,5,6-hexahydrobenzo [f] quinolin-1-one was prepared according to the production procedures described in Steps A, B, C and D of Example 1 using phenyl. / acetic acid as starting material.

* 1 2 ··· 1 In 94 ml of acetic acid was added 1,2,3,4,5,6-hexahydrobenzo [f] quinolin-3-one (3 g; 15 mmol) and 3 g of V · 5 % palladium / activated carbon. The mixture was allowed to stand at room temperature for 30 days for 3 days at 60 psi hydrogen on:. The catalyst was removed by filtration. Soda la: .- • 3; was taken up in ethyl acetate and basified with NaHCO 3 saturated with ethyl acetate. The resulting layers were separated, and the organic layer was dried over MgSO 4 and concentrated to give an? 2 • ia! 3 * 1 1 * 1 1 107254 33 countries 1.4 g (46% yield) of the title compound. Melting point 178-179 ° C.

Elemental Analysis: £ H N

Calculated: 77.58 7.51 6.96 5 Found: 77.88 7.52 6.05

Example 15

Preparation of trans-dl-8-fluoro-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3-one

The title compound was prepared according to the preparation procedures described in Steps A, B, C, D, F and G of Example 1 using p-fluorophenylacetic acid as the starting material to give 14.2 mg of the title compound. Sp. 262-263 ° C. Elemental Analysis: £ H N

Calculated: 71.21 6.44 6.39 15 Found: 71.17 6.48 6.29

Example 16

Preparation of trans-d1-8-ethoxycarbonyl-ethylenediyl-4-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [e] quinolin-3-one Compound trans-d1-8-bromo 4-Methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3-one was prepared as described in Steps A, B, C, D, E, F and G of Example 1. ·. according to the methods. This compound (1.52 g; 5.17 mmol) and palladium (II) acetate (12 mg; 0.052 mmol / l), tri- (o-tolyl) phosphine (64 mg, 0.28 mmol), Ethyl acrylate (647 mg; 6.46 mmol) and triethylamine (2.8 ml) were combined in a thick-walled tube fitted with a magnetic, non-stick teflon-coated stirring bar. The reaction mixture was heated to 100 ° C in a sealed tube and allowed to be · *: ··· overnight. After cooling, 1N HCl and. *** were added. the green solid was gently mixed with a spatula. The solids were collected by filtration and dissolved in ethanol with heating. The solution was filtered through diatomaceous earth (Celite) and washed several times with ethanol. Volatile • «« ------ -----------------------------------—--- I ------- ------- 107251 34 were evaporated in vacuo to give a solid yellow residue. Recrystallization of the residue from 3% ethyl acetate / hexanes gave 1.24 g of the title compound as a foamy yellow substance (88% yield).

Melting point 115.5 - 116.5 ° C. High Resolution Mass Spectrometer: 313.1659 C19H23NO3.

Example 17

Preparation of trans-dl-8-chloro-1,2,3,4,4a, 5,6,10b-octahydrothiophen [f] quinolin-3-one The title compound was prepared in Steps A, B, C, D of Example 1. F and G using p-chlorophenylacetic acid as starting material. Melting point 231-232 ° C.

Elemental Analysis: C H N

Calculated: 66.24 5.97 5.94

Found: 66.44 6.17 6.06

Example 18 (not according to the invention)

Preparation of trans-d1-8-methoxy-1,2,3,4,4a, 5,6,10b-octahydro-benzo [f] quinolin-3-one The title compound was prepared in Steps A, B, C, D and Example 1. F following the production procedures described, followed by recrystallization from ethyl acetate. . using p-methoxyphenylacetic acid as a starting material to give 198 mg (38%) of an off-white highly crystalline substance. Mp 216-217 ° C.

• · · * · Example 19 (not according to the invention) ... f 'Trans-d1-8-methoxy-4-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinoline Preparation of -3-one • · · ί.ί: The title compound was prepared according to the production procedures described in Steps 30A, B, C, D, F of Example 1.

recrystallization from ethyl acetate and then step E

. ···. using p-methoxyphenylacetic acid as starting material to give 38 mg of a yellow powder. Melting point: V 102 - 103 ° C.

35 Elemental Analysis: C H N

Calculated: 72.20 7.40 6.05 ···! Found: 72.61 7.59 5.94 ♦ * · 107254 35

Example 20

Preparation of trans-dl-8-methyl-1,2,3,4,4a / 5,6,10b-octahydro-benzo [f] quinolin-3-one

The title compound was prepared according to the preparation procedures described in Steps A, B, C, D, F and G of Example 1 using p-tolylacetic acid as starting material. Melting point 226-227 ° C.

Elemental Analysis: C H N

Calculated: 78.10 7.96 6.51 10 Found: 78.39 8.19 6.27

Example 21 (not according to the invention)

Preparation of trans-dl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3-one

The title compound was prepared according to the preparation procedures described in Example 1 Steps 15A, B, C, D and F using phenylacetic acid as the starting material to give 327 mg (30% yield) of the title compound after four recombinations from ethyl acetate. Melting point 227 228 ° C.

20 Elemental Analysis: C H N

Calculated: 77.58 7.58 6.96

Found: 77.29 7.74 6.99. . EXAMPLE 22 Trans-dl-8-ethoxycarbonylethanediyl-4-methyl-4-methyl-25-l, 2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3-one • · · * · 1! manufacturing

The compound trans-d1-8-ethoxycarbonylethylenediyl-4-ϊ, ϊ, ϊ methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3-one was prepared according to the procedure for ti. This compound (424 mg; 1.35 mmol) was combined with 50 mg of 5% palladium on activated carbon in 50 mL. ethanol in a sealed reactor at room temperature at an initial pressure of 60 psi. After 4 hours, catalyst * 14: was removed by filtration. The filtrate was concentrated in vacuo.

The residue was subjected to flash chromatography on SiO2 and eluted with 1072p4 36 (5% methanol / CH2Cl2) to give 308 mg (72%). -%) of the title compound as a light yellow oil which crystallized on standing. Melting point 86-88 ° C. High Resolution Mass Spectrometer; 315.1840 C19H25N03.

5 Example 23

Preparation of trans-dl-8-methoxycarbonylethyldiediyl-4-methyl L-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3-one

The title compound was prepared according to the preparation procedures of Example 16, except that methyl acrylate was used rather than ethyl acrylate to give 1.18 g (94% yield). Melting point 172-174 ° C.

Elemental Analysis for C H N 15 Calculated: 72.22 7.07 4.68

Found: 71.97 7.87 4.72

Example 24

Preparation of trans-d1-8-carboxyethenediyl-4-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3-one

The compound trans-d1 -8-ethoxycarbonylethylenediyl-4-methyl-1,2,3,4,5,6,10b-octahydrobenzo [f] quinolin-3-one. : was prepared according to the preparation procedures described in Example 16. To a solution of KOH (436 mg; 7.77 x 12.12 mmol) 3: 1 (v / v) in a mixture of methanol and water was added ethyl ester (1.22 g; 3.89 · · · mmoles). The reaction mixture was heated under reflux with stirring for one hour. The methanol was removed in vacuo and? M?: The remaining mixture was acidified with 5N HCl. The resulting white precipitate was collected by filtration and washed with water. la. Recrystallization from ethanol gave 741 mg (67% · *** yield) of the title compound as a white crystalline solid.

• · ·

Melting point 311 ° C, dec.

«« ·

: it1 'Elemental Analysis: C H N

35 Calculated: 71.56 6.71 4.91

Found: 71.82 6.57 4.88 • · i 1 i 2 • · 107254 37

Example 25

Preparation of trans-dl-8-t-butylaminocarbonyl-xetenediyl-4-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3-one 5 A. Trans-dl-8 - (2-Thiopyridylcarbonylethylenediyl) -4-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3-one

Trans-d1-8-carboxyethenediyl-4-methyl-1,2,3,4,43,5,6,10b-octahydrobenzo [f] quinolin-3-one was prepared according to the preparation procedures described in Example 24. A suspension of this acid (1.99 g, 6.97 mmol), triphenylphosphine (3.66 g, 13.95 mmol) and 2,2'-dithiodipyridine (3.07 g, 13.95 mmol) in 30 ml anhydrous toluene, stirred at room temperature overnight. The reaction mixture was filtered and the precipitate was washed with 100 mL of diethyl ether and dried to give 2.2 g of the subtitle compound as a light yellow solid (81%).

B. Trans-d1-8-t-Butylaminocarbonylethylenediyl-20-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3-one

To a stirred suspension of pre-. of thiopyridyl ester from Step A (440 mg; * .. * 1/13 mmol) in dry THF (11.0 mL) was added tert-butyl acetate (0.95 mL, 9.04 mL). mmol). The reaction mixture stirred * · *! at room temperature for 24 hours. The mixture was filtered and the solids washed with hexanes to give 256 mg (66.5% yield) of the title compound. Melting point 243-245 ° C, dec.

30 Elemental Analysis: C H N

Calculated: 74.08 8.29 8.23 ···. Observed: 74.21 8.39 8.11 «·« * · • t • ♦ · • • • • • • • • • • • • • • • • • • • • • • • • • • 38 1072 ^ 4

Example 26

Preparation of trans-d1-8-chloro-2- (a and B) -methyl-4-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3-one Trans-d1-8-chloro-4-methyl-1,2,3,4,4a, 5,6-6,10b-octahydrobenzo [f] quinolin-3-one was prepared according to the preparation procedures described in Example 6.

To a cold (-78 ° C; carbonated ice / isopropanol bath) stirred solution of trans-d1-8-chloro-10R-4-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] Quinoliu-3-one (759 mg; 2.88 mmol) in 45 mL of dry THF, 17.6 mL of 0.5 M potassium hexamethyldisilazide (1.1 eq; 8.81 mmol) in toluene was added dropwise. After complete addition, the reaction mixture was stirred in cold for an additional 45 minutes. An excess (5.0 equivalents) of methyl iodide (2.5 mL) was added to the reaction mixture. The ice caps were removed and the reaction mixture was allowed to warm to room temperature over two hours. The reaction mixture was quenched by careful addition of water and transferred to a separatory funnel. Ethyl acetate and 1 N HCl were added to the mixture and the layers were separated. The organic layer was washed with 1N HCl, once with saturated NaHCO 3 and then suc-. : solution. The organic material was dried over MgSO 4 and evaporated in vacuo to afford 2.11 g of the title compound Γ1. 25 as a yellow solid.

The α and β isomers * were separated by HPLC on silica gel using a gradient of 0 to 75% ethyl acetate / toluene (v / v) to give 414 mg of α-iso - · · · V2 mer (Example 26A; melting point 166-167 ° C) as a white solid and 199 mg of β-isomer (Example ·; ··· 26B; melting point 82-83 ° C) as a colorless solid. *** Well.

• · ·

Elemental analysis: 1 · 1 · a · isomer C H N! • · · 35 Calculated: 68.30 6.88 5.31!

Found: 68.09 6.93 5.20 * · «« «i i · 2 • ·« 107254 39

Elemental analysis:

&lt; C &gt; C H N

Calculated: 68.30 6.88 5.31

Found: 68.05 6.68 5.55 Example 27

Preparation of trans-d1-8-bromo-6,6-dimethyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3-one 4,4-dimethyl-6-bromo 2-Tetralone was prepared according to the preparation procedures described in Steps A and B of Example 1 except that isobutylene was used in Step B instead of ethylene and a 1: 1 mixture of regioisomeric tetralones of 4,4-dimethyl and 3,3-dimethyl was obtained. , was separated by HPLC on silica gel using a 0 to 7.5% ethyl acetate / hexanes (v / v) gradient to give the desired 4,4-dimethyl-6-bromo-2-tetralone. The title compound was prepared from this tetraion according to the preparation procedures described in Steps C, D and F of Example 1, and then recrystallized from ethyl acetate to give 109.3 mg of a white solid. Melting point 281-282 ° C.

Elemental Analysis: C H N

Calculated: 58.45 5.89 4.54: Found: 58.68 5.77 4.44 • «·

Example 28 t · • «! * '. Trans-d1-8-bromo-4,6,6-trimethyl-1,2,3,4,4a, 5,6,10,6-trimethyl-10b-octahydrobenzo [f] quinolin-3-one manufacture ** * ···! A mixture of trans- and cis -d1-8-bromo-6,6-dimethyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinoline · · · was obtained. Σ · lin-3-one, by concentration of the filtrates trans-d1-8-bromo-6,6-dimethyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3 · · : ··:. (Example 27) by recrystallization with ethyl acetate. The title compound was prepared from this material in association with the cis-d1 isomer (Example 29) using the preparation procedures described in Steps E and G of the pre-4% • '

IM

• i

I

«• • • · i t t% t t • •%

Mt 107254 40 to give 67.2 mg of white solid. Melting point 133-136 ° C.

Elemental Analysis: C H N j

Calculated: 59.64 6.26 4.35 5 Found: 59.50 6.21 4.55

Example 29

Preparation of cis -dl-8-bromo-4,6,6-trimethyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3-one

A mixture of trans- and cis -dl-8-bromo; L-10 6,6-dimethyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinoline-3 was obtained. -one, by concentrating the filtrates from recrystallization of trans-dl-8-bromo-6,6-dimethyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3-one (Example 27) with ethyl acetate . The title compound was prepared from this material together with the 15 trans-d1 isomers (Example 28) using the preparation procedures described in Steps E and G of Example 1 to give 67.2 mg of a white solid. Melting point 177-180 ° C.

Elemental Analysis: C H N

Calculated: 59.64 6.26 4.35

Found: 59.85 6.16 4.28

Example 30

Preparation of trans-dl-8-t-butyl-1,2,3,4,4a, 5,6,10b-octahydro- · · · · · · · · · · · · · · · · · · benzoff] quinolin-3-one 25 A. 6-tert. butyl-2-naphthol

To a 2 liter round bottom flask were charged the correspondingly zinc chloride (45.0 g), β-naphthol (150.0 c; · ***. 1.04 mol) and hexane (450 ml). The mixture was stirred vigorously while adding t-butyl chloride (150.0 c; • 30 1.62 moles) dropwise over 30 minutes. When reacting. the mixture was gradually heated to reflux, no solution was obtained. The reaction mixture was cooled to room temperature and 100 mL of CH 2 Cl 2 was added. The reaction mixture was refluxed overnight, cooled, and concentrated in vacuo to give a white solid. The solid was refluxed with 1800 mL of 10% NaOH, filtered and allowed to cool. The precipitated white sodium salt was collected by filtration. The solid collected by filtration was mixed with 5.0 M excess HCl and the resulting phenol was collected by filtration and washed with 2 L of water. Recrystallization from heptane gave 30.67 g of the subtitle compound as a white solid.

B. 6-t-Butyl-2-methoxynaphthalene In a 2 L round bottom flask was added 6-t-butyl-2-naphthol 10 (30.67 g; 0.153 mmol) and 550 mL of 15% KOH in water.

The solution was stirred while adding dimethyl sulfate (6.0 equivalents) dropwise over 30 minutes. After complete addition, the mixture was allowed to stir for two hours. The solids were collected on a filter and washed with water to give 28.97 g (88% yield) of the subtitle compound.

C. 6-t-Butyl-2-tetralone

To a stirred solution of 6-t-butyl-2-methoxynaphthalene (28.97 g; 0.135 mmol) in 20 350 mL of anhydrous ethanol was added sodium chips (36 g; 11.5 equivalents) over 2 hours at poor reflux was maintained. The viscous reaction mixture was stirred until all the sodium was dissolved. The mixture was cooled and 140 ml of water was added carefully ... ** 25. Concentrated HCl (275 ml) was added and the reaction mixture was cooled to reflux. After cooling, the reaction mixture was filtered and the aqueous layer was extracted three times with toluene. Evaporation of the volatiles in vacuo gave 28.1 g of a red vis-30 oil. ml of diethyl ether and stirred with 50 ml of saturated aqueous NaHSO 3 overnight The resulting white precipitate was collected by filtration and washed several times with hexanes. This solution was partially dissolved in 500 ml: H 2 O and 200 mL of diethyl ether were added and the mixture was stirred vigorously and 107 mL of saturated aqueous Na 2 CO 3 was added. The mixture was stirred for one hour, the layers were separated and the aqueous layer was extracted three times with diethyl ether. The combined organic layers were combined, washed with brine, dried over MgSO 4, and concentrated in vacuo to give 5.74 g of the subtitle compound as an orange oil which crystallized slowly upon standing.

D. 6-t-Butyl-2-pyrrolidinyl-3,4-dihydronaphthylene To a stirred solution of 6-t-butyl-2-tetralone (5.74 g, 28.37 mmol) in 100 mL toluene, 1.5 equivalents of pyrrolidine (3.56 mL; 42.56 mmol) were added. A 100 mg portion of p-toluenesulfonic acid was added and the mixture was refluxed. Water from the pol-15 reaction was collected in a Dean Stark water trap. After refluxing for 3.5 hours, the volatiles were concentrated in vacuo to give 7.31 g of the subtitle compound as a purple solid.

E. 8-t-Butyl-1,2,3,4,5,6-Hexahydrobenzo [f] quin-20-lin-3-one 6-t-butyl-2-pyrrolidinyl-3,4-dihydronaphthalene (7.25 g; 28.37 mmol) was added 3.0 equivalents of acrylamide (6.05 g; 85.11 mmol). The reaction mixture was stirred. ·: Stirred at 89 ° C overnight. The temperature was then raised to 130 ° C and held for 20 minutes. Vet (100 mL) was carefully added and the reaction mixture was cooled to room temperature. The resulting solid was ground in water • «·«. and collected on the filter to give a brown solid.

• · ·

The solid was recrystallized twice from dimethylformamide (DMF) / H2O to give the subtitle compound. A melting. mp 265-268 ° C, dec.

... F. Trans-dl-8-t-butyl-1,2,3,4,4a, 5,6,10b-octahydro-· ·; · '

To a cold (0 ° C) stirred solution of 35-8-t-butyl-1,2,3,4,5,6-hexahydrobenzo [f] quinolin-3 '·' · 4 '·' 107254 43 on ( 4.00 g; 15.66 ramoles) and triethylsilane (7.29 g; 62.66 mmol) in 90 mL of CH 2 Cl 2 were added 45 mL of trifluoroacetic acid. The cold bath was removed and the mixture was stirred at room temperature for 24 hours. The reaction mixture was poured carefully into saturated NaHCO 3, shaken and the layers separated. The organic layer was washed once with NaHCO 3, dried over Na 2 SO 4, and concentrated in vacuo to give 5.86 g of a brown solid. Recrystallization from ethyl acetate gave the subtitle compound 10 (2.5 g, 62% yield) as a beige crystalline solid.

Melting point greater than 280 ° C.

Elemental Analysis: C H N Calculated: 79.33 9.01 5.44

Found: 79.36 9.16 5.49 Example 31

Preparation of trans-d1-8-t-butyl-4-methyl-1,2,3,4,5,6,10b-octahydrobenzo [f] quinolin-3-one The title compound was prepared in Example 30, Steps A, B, C, D , E and F, and then N-methylated according to the procedures described in Example 1, Step E using 1,2-dimethoxyethane as the solvent to give 1.14 g (73% yield) of a tan solid. Melting point 183-184 ° C. ·. * ·: Elemental Analysis: C H N

25 Calculated: 79.66 9.29 5.16

Found: 80.08 9.31 4.99 • · ·· Example 32 ····. Preparation of trans-dl-8-fluoro-4,10b-dimethyl-1,2,3,4,4a, 5,6, · · · · 10b-octahydrobenzo [f] quinolin-3-one. 6-fluoro-2-pyrrolidinyl-3,4-dihydronaphthalene

The subtitle compound was prepared according to the production procedures described in Steps A, B and C of Example 1 using p-fluorophenylacetic acid as starting material.

B-6-fluoro-1-methyl-2-pyrrolidinyl-3,4-dihydro-naphthalene 6-fluoro To 2-pyrrolidinyl-3,4-dihydronaphthalene (13 g; 60.8 mmol) in 200 r of dry tetrahydrofuran? 5 (THF) was added methyl iodide (30 mL; 482 mmol) and the mixture was refluxed for 2 hours. The reaction mixture was allowed to cool with stirring while crystallization occurred. The solids were collected by filtration to give the subtitle compound.

10 C. To 6-fluoro-1-methyl-2-tetralone 6-fluoro-1-methyl-2-pyrrolidinyl-3,4-dihydronaphthalene obtained from the preceding step) in 1700 ml of ethyl acetate was added sodium acetate. (10.2 g; 124.4 mmol), acetic acid (10.2 mL; 178.2 15 mmol) and 102 mL of water. The reaction mixture was stirred at room temperature for four hours. The layers were separated and the organic layer was washed with brine, 5% NaHCO 3, and brine. The organic layer was dried over MgSO 4 and concentrated to give 7.9 g of subtitle compound 20 as a dark orange-red oil (60% yield).

D. 8-Fluoro-10b-methyl-1,2,3,4,6,10b-hexahydro-benzo [f] quinolin-3-one for 6-fluoro-1-methyl-2-tetralone (7.06 g; 39.6 (· ·, · · · · mmol) in a round bottom flask was added p-toluenesulfonic acid • **: 25 (1.23 g, 6.5 mmol) and the mixture was stirred at room temperature under nitrogen pressure for 15 minutes. Acrylamide (5.62 g, 79.2 mmol) was added and the reaction mixture was heated. at 90-90 ° C under nitrogen pressure for three days.

• · ·

The mixture was diluted with ethyl acetate and water and stirred at room temperature for 1 hour. The resulting layers were separated. The organic layer was washed three times with .....

*, dried over MgSO 4 and concentrated to a viscous oil. The crude product was crystallized from ethyl acetate to give * '· *; 1.59 g (17% yield) of the subtitle compound. Melting point ···. Mp 202 ° C.

• · t «· * ♦« «·» · • «j 107254 45

Elemental Analysis: C H N Calculated: 72.71 6.10 6.06

Found: 72.45 6.14 6.03 E. 8-Fluoro-4,10b-dimethyl-1,2,3,4,6,10b-hexahydro-benzo [f] quinolin-3-one 8-fluoro -10b-Methyl-1,2,3,4,6,10b-hexahydrobenzo [b] quinolin-3-one (1.38 g; 6 mmol) was added to a suspension of NaH (475 mg; 20 mmol) 1, In 2-dimethoxyethane (15 mL). The mixture was refluxed for 1.5 hours and rapidly cooled to room temperature. Methyl iodide (15 ml) was added and the mixture was refluxed for 4 hours, then allowed to cool to room temperature. After the addition of water, the mixture was concentrated to near dryness. The residue was partitioned between ethyl acetate and water. The organic layer was washed three times with water, dried

MgSO 4 and concentrated in vacuo. Recrystallization from hexane gave 737 mg (56% yield) of the subtitle compound. Melting point 110-111 ° C.

Elemental Analysis: C H N

Calculated: 73.45 6.57 5.71

Found: 73.72 6.84 5.86 F. 8-Fluoro-4,10b-dimethyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3-one Triethylsilane (1 mL; 6.12 mmol) was added · 8 · fluoro-4,10b-dimethyl-1,2,3,4,6,10b-hexahydrobenzo · · · [f] quinolin-3-one (500 mg, 2.04 mmol) in CH 2 Cl 2 4: 15 (15 mL) at room temperature. The reaction mixture was cooled to 0 ° C and trifluoroacetic acid (2.6 mL) was added.

· · ·

After stirring for 4 days at room temperature, the reaction mixture was diluted with CH 2 Cl 2 and treated with saturated NaHCO 3. The resulting layers were separated and the organic layer was washed with saturated NaHCO 3, dried over MgSO 4, and concentrated in vacuo to give a yellow oil.

4 4 · «« • «« 1 1 1 1 25 25 25 25 107254 46 G. Trans-dl-8-Fluoro-4,10b-dimethyl-1 , 2,3,4,4a, 5, 6,10b-octahydrobenzo [E] quinolin-3-one

The mixture obtained in Step F was separated by column chromatography on SiO 2 (elution with ethyl acetate / hexanes: 5: 9: 1 (v: v)). Appropriate distributions containing the desired product were evaporated to near dryness and diluted with hexanes. The resulting crystals were collected by filtration to give 190 mg of the subtitle compound :. Melting point 130-131 ° C.

10 Elemental Analysis: C H N

Calculated: 72.85 7.34 5.66

Found: 72.71 7.48 5.73

Example 33

Preparation of Cis-dl-8-fluoro-4,10b-dimethyl-1,2,3,4,4a, 5,6,10h-15 octahydrobenzo [f] quinolin-3-one

The title compound was prepared in conjunction with the trans-d1 isomer according to the preparation procedures described in steps A to F of Example 32.

The mixture obtained in Step F of Example 32 was separated by flash chromatography on SiO 2 with SiO 2 (elution with ethyl acetate / hexanes 9: 1 (v / v)). Appropriate fractions containing the desired product, evaporated to near dryness and diluted with hexanes. The resulting crystals were collected by filtration to give the title compound.

* ... ** 25 Example 34 * · · .1 ·· Trans-dl-8-chloro-4,10b-dimethyl-1,2,3,4,43,5,6, ..) · 1 Preparation of 10b-octahydrobenzo [f] quinolin-3-one: The title compound was prepared in combination with the cis-d1 isomer (Example 35) following the preparation procedures described in Steps 30A, B, C, D, E and F of Example 32 using p-chlorophenylacetic acid. as starting material. The column chromatography of Step 12 of Example 12 gave 523 mg of the title compound. Melting point 94 ° C.

• \ · Elemental Analysis: C H N

35 Calculated: 68.30 6.88 5.31; Found: 68.51 6.67 5.36 «· •« «·« · * »107254 47

Example 35

Preparation of cis -dl-8-chloro-4,10b-dimethyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3-one

The title compound was prepared in conjunction with the trans-d1-iso-5 monomer (Example 34) according to the production procedures described in Steps A, B, C, D, E and F of Example 32 using p-chlorophenylacetic acid as starting material. Flash chromatography according to Example 32, Step G provided 145 mg of the title compound.

10 Elemental Analysis: C H N

Calculated: '68, 30 6.88 5.31

Found: 68.09 6.76 5.11

Example 36 (not according to the invention)

Preparation of trans-dl-10b-methyl-1,2,3,4,4a, 5,6,10b-octahydro-15 benzo [f] quinolin-3-one A. 10b-methyl-1,2,3,4 , 6,10b-hexahydro-benzo [f] quinolin-3-one

Following the preparation procedures described in Steps A, B, C and D of Example 32, except that phenyl-acetic acid was used as starting material and silica gel chromatography rather than recrystallization from ethyl acetate, the subtitle compound was prepared as a white crystalline solid. Melting point 123-124 ° C.

• «

·, 1 ·· Elemental analysis: C H N

25 Calculated: 78.84 7.09 6.57: 2 · · Found: 78.82 6.95 6.58 · · B. Trans-dl-10b-methyl-1,2,3,4,6, 10b-octahydro- ····. . ·. benzoff] quinolin-3-one • · 10b-methyl-1,2,3,4,6,10b-hexahydrobenzo [f] quinolin-3-one (500 mg; 2.3 mmol) In 50 ml of acetic acid was added 500 mg of 5% palladium on carbon. The reaction mixture • · · · · 1 was stirred overnight at room temperature under an initial pressure of 60 psi hydrogen · · 2. The reaction mixture was filtered and concentrated to 1 · 1; dryness. The residue was partitioned between ethyl acetate and water.

• ·. ***. The organic layer was washed twice with saturated NaHCO 3 · 9 9 9 2 • 99 107254 48 and then dried over MgSO 4 and concentrated in vacuo. The residue was triturated in ether to give 180 mg (36% yield) of the subtitle compound. Melting point 178-179 ° C. |

5 Elemental analysis: C H N

Calculated: 78.10 7.96 6.51

Found: 78.38 8.02 6.36

Example 37 (not according to the invention)

Preparation of trans-dl-4,10b-dimethyl-1,2,3,4,4a, 5,6,10b-octn-10 hydrobenzo [f] quinolin-3-one

Following the preparation procedures described in Example 36, trans-d1-10b-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3-one was prepared. To 4 mL of 1,2-dimethoxyethane was added NaH (31 mg; 1.26 mmol) and trans-dl-15 10b-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [ f] quinolin-3-one (130 mg; 0.6 mmol). The reaction mixture was refluxed for 1.5 hours. After cooling to room temperature, 10 ml of methyl iodide was added and the reaction mixture was refluxed for 3 hours. Water was added and the mixture was concentrated to near dryness. The residue was partitioned between ethyl acetate / water. The organic layer was washed several times with water, dried over MgSO 4, and concentrated in vacuo. The residue was triturated in petroleum ether to give 60 ng (44% yield) of the title compound. Melting point 93 ° C.

• ««

25 Elemental analysis: C H N

\ ** l Calculated: 78.56 8.35 6.11 * i · Found: 78.29 8.16 6.03 • · · t: Example 38 • t

Preparation of trans-d1-8-chloro-10b-methyl-1,2,3,4,4a, 5,6,101 → 30-octahydrobenzo [f] quinolin-3-one

Following Example 32, Steps A, B, C, D and F

• · ... except that * 1 *; · 'p-chlorophenylacetic acid was used as a starting material, the compound 8-chloro-10b-methyl-1,2,3,4,4a, 5,6,10b-octahydro was prepared. -: ***: 35 Benzo [f] quinolin-3-one as a mixture of cis and trans isomers.

• · • • · 1 * 1 1 49 107254

The mixture was purified by HPLC (reverse phase, CN) eluting with THF: isooctane (48% THF) to give 32 mg of the title compound.

Elemental Analysis: C H N

5 Calculated: 67.33 6.46 5.61

Found: 67.53 6.35 5.73

Example 39

Preparation of Cis-d1-8-chloro-10b-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3-one The title compound was prepared together with trans-d1-iso- with the mer (Example 38) according to the production methods described in Example 38. The cis-d1 isomer was also obtained by HPLC purification using the preparation procedures described in Example 38, followed by trituration in diethyl ether.

Example 40

Preparation of Trans and cis-R (-) - 8-Chloro-10b-methyl-1,2,3,4,4a -5,6,10b-octahydrobenzo [f] quinolin-3-one 20 A. 6- chloro-l-methyl-2-tetralone

Following the procedures described in Steps A, B and C of Example 32, ·,; except that p-chlorophenyl acetic acid was used as the starting material, the subtitle compound was prepared.

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · 25 · B. v: Tetralone (50.0 g; 0.256 mol) and (R) - (+) - 1-phenylethylamine (35 ml; 0.27 mol). The mixture was heated at ♦: ··· 30 reflux for four hours, removing water with azeotropic »· * ·. pisesti. The solvent was removed in vacuo to give 79 g of the subtitle compound together with the imine tautomer, m.p. · As an oil used without further refining.

• · • · «tl« «« «· * · · • ·

<t I

107254 50 C. (5S) -5,6,7,8,9,10-Hexahydro-8-hydroxy-2-chloro-5,8-dimethyl-5,9-methanobenzocycloocten-11-ol

To a stirred solution of 1-methyl-2- (α-methylbenzylamino) -6-chloro-1,2-didehydrotetra-5 (79 g; 0.25 mol) in 500 mL of THF was added methyl vinyl ketone (23 ml; 0.28 mol). The solution was stirred at ambient temperature under argon in the dark for 96 hours. Aqueous acetic acid (20%, 500 mL) was added and the mixture was stirred for two hours. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with saturated Na 2 CO 3 and dried over Na 2 SO 4. The solvent was removed in vacuo to give 82 g of the subtitle compound as a brown oil which was used without further purification.

15 D. (R) - (+) - 8-Chloro-10b-methyl-1,2,3,5,6,10b-hex: sahydrophenanthrene-3-one

To a stirred solution of sodium ethoxide prepared from sodium (6.5 g) in ethanol (500 ml) was added the subtitle compound (82 g) from -20 ° C. The solution was heated at 50 ° C for 3 hours under a nitrogen atmosphere. The solution was cooled to ambient temperature. . and partitioned between diethyl ether and water. The organic phase was washed with brine and dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified «· *. ·: 25 by chromatography on SiO 2 (eluting with 25% ethyl acetate in hexanes) to give 34 g of the subtitle compound as a brown oil which solidified on standing.

E. (R) -3- [1- (1-Methyl-6-chloro-2-tetralone)] -propanoic acid In a stirred mixture of RuCl3.nH2O · · · · ·. (620 mg, 2.99 mmol) in a solvent mixture (200 mL) of two parts of carbon tetrachloride, three parts of acetonitrile and two parts of water were added periodic acid (20.45 g, 89.7 mmol). ). The mixture was cooled to 0 ° C and stirred. ; 35 minutes. To the mixture was slowly added the sub-title compound (? 107254 51 of the title compound from Step D (3.7 g; 14.95 mmol) in acetonitrile and the mixture was stirred at 0 ° C for 3 hours. 2-Propanol (20 mL) was added and The reaction mixture was partitioned between ethyl acetate and water and the aqueous phase was extracted three times with ethyl acetate The combined organic layers were filtered through diatomaceous earth and the filter cake was washed with ethyl acetate.

10 F. (R) (+) - 8-Chloro-10b-mefcyl-1,2,3,4,6,10b-hexahydrobenzo [f] quinolin-3-one

To a stirred solution of the subtitle compound of Step E (1.74 g; 6.457 mmol) in 15 mL of 2-propanol was added ammonia (1 mL) and the tube reactor 15 was closed. The reaction mixture was heated at 180 ° C for 15 minutes. The mixture was cooled to room temperature and concentrated in vacuo to a brown glassy solid. The solid was taken up in ethyl acetate, filtered through SiO 2 and eluted with ethyl acetate to give the subtitle compound as a light solid. The sample was crystallized from diethyl ether / hexane to give 219 mg of the sub-title compound. Melting point 61-63 ° C.

. ···. Elemental Analysis: C H N

V. Calculated: 67.88 5.70 5.65 «· · ** / 25 Found: 67.54 5.65 5.44« · »Optical Rotation: 589 nm = -40.32 ° ( C = 1, methanol) 365 nm = -185.48 ° ··· 5 °: * G. 8-chloro-10b-methyl-1,2,3,4,4a, 5,6,10-octahydrobenzo [f] Quinolin-3-one *: **: To a stirred solution of the subtitle compound from Step F (776 mg; 3.1 mmol) and triethylsilane (4.95 mL; 31 mmol) in CH 2 Cl 2 At ° C, li- · · · t <; ' trifluoroacetic acid (4.82 mL, 6.26 mmol) was added.

The solution was slowly warmed to room temperature and stirred for 48 hours. The reaction mixture was diluted with ethyl acetate, neutralized with Na 2 CO 3, extracted with ethyl acetate, and concentrated in vacuo to give 790 mg of crude product containing the subtitle compound.

H. Trans-8-Chloro-10b-methyl-1,2,3,4,4a, 5,6,1 (i-octahydrobenzo [f] quinolin-3-one

Chromatography of the crude product of Step G on SiO 2 (ethyl acetate as eluent) gave 341 mg of the subtitle compound. Melting point 135-137 ° C.

Elemental Analysis: C H N

Calculated: 67.33 6.46 5.61

Found: 67.41 6.55 5.36

Optical rotation: 589 nm = + 113.86 ° (C = 1, CHCl3) 365 nm = + 371.29 °

Example 41 Preparation of Cis-8-Chloro-10b-methyl-1,2,3,4,4a, 5,6,10-octahycrobenzo [f] quinolin-3-one

The title compound was prepared in conjunction with the trans isomer (Example 40) according to the preparation procedures described in Steps A through G of Example 30. Chromatography of the crude product of Example 40, Step G with SiO 2 (ethyl acetate as eluent) gave 91 mg of the title compound. Molten-*. mp 178-181 ° C.

_ ···. Elemental Analysis: C H N

Calculated: 67.33 6.46 5.61 '* / 25 Found: 66.73 6.73 5.36 • · #

Optical rotation: 589 nm = + 199.10 °: λ: (C = 1, CHCl3) 365 nm = + 660.63 °. Example 42 (not according to the invention)

Trans-4-ethyl-10b-methyl-1,2,3,4,4a, 5,6,10b-octa-; ··; Preparation of hydrobenzo [f] quinolin-3-one

· *** · Following Example 40, Steps A, B, C, D, E, and F

using phenylacetic acid as starting material and using ethylamine rather than ammonia and di-1,2-dimethoxyethane rather than: * ·, · 35 ethylene glycol in step F was prepared with 4-ethyl-10b. -? · 53 107254 Methyl-1,2,3,4,6,10b-hexahydrobenzo [f] quinolin-3-one.

This hexahydrobenzo [f] quinolin-3-one was hydrogenated following the preparation procedures described in Example 22 except that the reaction was carried out at 70 ° C for 7 hours to give a crude reaction mixture. The reaction mixture was filtered and the solvents evaporated in vacuo to give a glassy solid residue. The crude product was purified by chromatography on SiO 2 (gradient elution from 100% hexane to 100% CHCl 3) to give 92 mg of the title compound as a colorless oil.

Elemental Analysis: C H N

Calculated: 78.97 8.70 5.76

Found: 79.07 8.90 5.56

Example 43 (not according to the invention) Preparation of Trans-4-n-Butyl-10b-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [e] quinolin-3-one Following the steps of Example 40. Preparations A, B, C, D, E, and F using phenylacetic acid as the starting material and using n-butylamine rather than ammonia and dimethoxyethane in step F rather than ethylene glycol gave 4-n-butyl. 10b-Methyl-1,2,3,4,6,10b-hexahydrobenzo [f] quinolin-3-h · * .. * one. This hexahydrobenzo [f] quinolin-3-one was hydrogenated following the procedures described in Example 22 except that the reaction was carried out at 60 ° C for 7 hours and treated 61 mg of the title compound as a colorless oil according to the methods described in Example 42.

Elemental Analysis: C H N

Calculated: 77.10 9.35 5.00 30 Found: 77.44 9.28 4.95 • · • · * * * • • • • • • 54 107254

Example 44

Trans-4- (4-methoxybenzyl-8-chloro-10b-methyl; L-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3-one: Preparation of Ln 5 A. (R) -3- [1- (1-Methyl-6-chloro-2-tetralone)] -propanoic acid

Following Example 40, Steps A, B, C, D and E

Using p-chlorophenyl: acetic acid as the starting material, the compound 3- [1- (? - 10-methyl-6-chloro-2-tetralone)] -propanoic acid was prepared.

B. 4- (4-Methoxybenzyl) -8-chloro-10b-methyl: -1,2,3,4,6,10b-hexahydrobenzo [f] quinolin-3-one To 40 ml of dimethoxyethane was added 3- [1- (1-Methyl-6-chloro-2-tetralone)] -propanoic acid (2 g) 3α-p-methoxybenzylamine (5 ml) in a sealed tube reactor. The solution was heated at 120 ° C overnight. After allowing the reaction mixture to cool to room temperature, the solvent was removed in vacuo. The residue was dissolved in CHCl 3, washed sequentially with 1N HCl, water, sat. NaHCO 3, and brine. The organic phase was dried over Na 2 SO 4 and concentrated in vacuo. Residue krc- *. was chromatographed on SiO 2 (concentration gradient elution from 1 · 100 · 100% hexanes to 100% ethyl acetate) 1 to give 394 mg of the subtitle compound as an oil.

C. Trans-4- (4-methoxybenzyl) -8-chloro-10b-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f ] quinolir-3-one • · · * Triethylsilane (1.4 mL) was added to a stirred solution of the subtitle compound from Step B (693 mg) in CH 2 Cl 2 (2.5 mL) under nitrogen: 2: 30. The reaction mixture was stirred for 15 minutes. To the solution was added 1.5 ml of trifluoroacetic acid and the reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between CHCl 3 * ··· 'and saturated NaHCO 3. The organic phase was dried over Na 2 SO 4 and the solvent removed in vacuo. The residue was purified by chromatography on SiO 2 (25% ethyl acetate in hexanes as eluent). Evaporation of the product containing the fractions in vacuo gave 459 mg of the subtitle compound as a foam. Melting point 55-60 ° C.

5 Elemental analysis: £ H N

Calculated: (+1/2 mole H 2 O) 69.74 6.65 3.70

Found: 70.27 6.49 3.68

Example 45 (not according to the invention) Preparation of Trans-4-methyl-10b-methyl-1,2,3,4,4,4a, 5,6,10b-oc-10 tachydrobenzo [f] quinolin-3-one

Following the manufacturing procedures described in Steps A, B, C, D, E, and F of Example 40 using phenylacetic acid as the starting material and using methylamine rather than ammonia and di-1,2-dimethoxyethane in step F rather than ethylene glycol, 4-methyl-10b was prepared. -methyl-1,2,3,4,6,10b-hexahydrobenzo [f] quinolin-3-one. This hexahydrobenzo [f] quinolin-3-one was hydrated following the procedures described in Example 22 except that the reaction was carried out at 60 ° C for 7 hours. The reaction mixture was filtered and the solvent evaporated in vacuo. The residue was purified by chromatography on SiO 2 (CHCl 3 / J as eluent) followed by recrystallization from ethyl acetate. acetate / hexanes to give 154 mg of the title compound.

. · /; Melting point 111-113 ° C.

25 Elemental Analysis: C H N

* · · ••• i Calculated: 78.56 8.35 6.11 '··· * Found: 78.33 8.62 6.14 • · ·: Example 46

Preparation of trans-dl-9-nitro-1,2,3,4,4a, 5,6,10b-octahydrobenz-30so [f] quinolin-3-one '***: Compound trans-d1- 1 The trans-octahydrobenzo [f] quinolin-3-one was prepared according to the production procedures described in Example 21. To this compound (8.0; · 1 g; 39.75 mmol) in 320 mL of a mixture of 1: 1 (v / v) glacial acetic acid and concentrated sulfuric acid , 1.4 equivalents of 90% concentrated nitric acid was added at a rate that did not raise the temperature to above 10 ° C. The mixture was stirred for 30 minutes at 0 ° C and then poured onto ice. The resulting solid was collected by filtration and recrystallized in DMF / water to give 5.40 g (55%) of the title compound as a yellow solid. Melting point> 300 ° C.

Elemental Analysis: C H N

Calculated: 63.40 5.73 11.38 10 Found: 63.61 5.97 11.39

Example 47

Preparation of trans-d1-9-nitro-4-methyl-1,2,3,4,4a, 5,6,10b-octylhydrobenzo [f] quinolin-3-one

The compound trans-dl-4-methyl-1,2,3,4,4a, 5,6,10b-octa-15 hydrobenzo [f] quinolin-3-one was prepared according to the production procedures described in Example: .2. The title compound was prepared according to the preparation procedures described in Example 46 using trans-dl-4-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3-one as starting material, except: -20 si the reaction was quenched with water and the product recrystallized from ethyl acetate / hexanes. Melting point: 172-172.5 ° C.

• «·

# ·. / Elemental Analysis: C H N

Calculated: 64.60 6.20 10.76 i ** / 25 Found: 64.80 6.34 10.85 • · «

Example 48 * * Trans-d1-9-amino-4-methyl-1,2,3,4,4a, 5,6,10b-oct * .- · · · · hydrobenzo [f] quinolin-3 -one preparation

Trans-d1-9-nitro-4-methyl-1,2,3,4,4a, 5,6, - *: ··· 10b-octahydrobenzo [f] quinolin-3-one was prepared according to the procedure 'according to the manufacturing methods described in 47. This compound (700mg, 2.69mmol) was dissolved in 100% ethanol and 100mg of 10% palladium on carbon was added.

The reaction mixture was hydrogenated for one hour at 42 psi of hydrogen at 35 psi. The mixture was filtered and the filtrate was concentrated in vacuo to give a light tan solid which was recrystallized from ethyl acetate / hexanes to give 308 mg of the title compound as a white solid. Melting point 213-2144.5 ° C.

5 Elemental analysis: C H N

Calculated: 73.01 7.88 12.16

Found: 73.22 8.02 12.20

Example 49

Preparation of trans-d1-9-chloro-4-methyl-1,2,3,4,4a, 5,6,10b-ox-10 tachydrobenzo [f] quinolin-3-one

The compound trans-d1-9-amino-4-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3-one was prepared according to the production procedures described in Example 48. To a 0 ° C solution of this compound (74 mg, 15.321 mmol) in 0.3 mL of concentrated HCl was added sodium nitrite (23 mg, 0.324 mmol) in 0.15 mL of water. The reaction mixture was stirred at 0 ° C for 30 minutes, then water was added to a 0 ° C solution of copper (I) chloride (35 mg, 0.353 mmol) in 0.2 mL concentrated HCl. The reaction mixture was allowed to warm gradually to room temperature over 2.5 hours, then heated to 60 ° C for 30 minutes. After cooling, the mixture • ·. ···. was partitioned between CHCl3 and saturated NaCl. The organic layer was dried over Na 2 SO 4 and concentrated in vacuo to give 25 mg of a solid. The title compound was obtained as a light solid (59 mg) by flash chromatography on SiO 2 (10% isopropanol / ethyl acetate).

· · · V * Melting point 228-230 ° C.

Elemental Analysis: £ H N

*: 1: 30 Calculated: 67.33 6.46 5.61 · 2: Found: 67.19 6.57 5.53 ··· ·· · * · · ♦ *. · · • · «· • • t · ·« «• •« «*« 2 10725 {4 58

Example 50

Trans-d1-8-chloro-3,4,4a, 5,6,10b-hexahydrobenzo [f] quinolin-3-one and trans-d1-8-chloro-2,3,4,4ar-5,6 Preparation of -hexahydrobenzo [f] quinolin-3-one 5 A. Trans-dl-4-t-butyloxycarbonyl-8-chloro; 1,2,3,4,43,5,6,10b-octahydrobenzo [f] quinolin-3-one Compound trans-dl-8-chloro-1,2,3,4,4a, 5,6,10b- oct; i-hydrobenzo [f] quinolin-3-one was prepared according to the preparation procedures described in Example 7. To this compound (1.56 g, 6.62 mmol) in 40 mL of anhydrous 1,2-dimethoxyethane (1,2-DME) was added 380 mg of sodium hydride as a 60% dispersion in mineral oil. The mixture was refluxed for one hour under a nitrogen atmosphere and then cooled to room temperature. A solution of di-t-15 butyl dicarbonate (1.74 g, 7.94 mmol) in 10 mL of anhydrous 1,2-DME was added and the mixture was refluxed for one hour. The mixture was cooled and water was carefully added followed by diethyl ether. The layers were separated and the aqueous layer was extracted with diethyl ether. The combined organic layers were washed with saturated

NaCl, dried over Na 2 SO 4 and concentrated to give ·. : an orange semi-solid which was purified by column chromatography (SiO 2, 1: 1 ethyl acetate / hexanes) to give 1.2 g (54%) of the subtitle compound as a white solid.

# · · 2: B. Trans-d1-4-t-Butyloxycarbonyl-2-phenylsulfonyl-:: -ene-8-chloro-1,2,3,4,4a, 5,6,10b-octahydrobenzo-V * [ f] quinolin-3-one

To the protected lactam from Step A (1.2 g, ·: * ··· 3.58 mmol) in 20 mL of anhydrous THF at -78 ° C was added dropwise a 0.5 M solution of potassium hexamethyldisilazide ( 14.3 mL, 7.16 mmol) in toluene. After 1 hour at -78 ° C, a solution of phenylselenyl chloride (755 mg, 3.94 mmol) in 5 mL of anhydrous THF was added. The reaction mixture was allowed to warm to room temperature at room temperature and stirred for 2 hours before quenching with 5 mL of saturated NH 4 Cl. The mixture was partitioned between saturated NH 4 Cl and ethyl acetate. The organic layers were dried over Na 2 SO 4 and concentrated in vacuo to give 2.197 g of the subtitle compound as an orange oil.

C. Trans-d1-4-t-Butyloxycarbonyl-8-chloro-3,4,4a, 5,6,10b-hexahydrobenzo [f] quinolin-3-one and trans-d1-4-t-butyloxycarbonyl-8 -chloro-2,3,4,4a, 5,6-hexahydrobenzo [f] quinolin-3-one 10 To a solution of the selenide prepared in Step B above (2.197 g, 4.48 mmol) in 20 mL of THF 0 ° At C, buffered with excess solid NaHCO 3, 1.2 equivalents of 30% hydrogen peroxide (610 mg) in 4 mL of THF was added. After 30 minutes, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated NaHCO 3, dried over Na 2 SO 4, and concentrated in vacuo to give 645 mg of a mixture of olefins. Separation of delta1,2-olefin from delta10b, 1-olefin was carried out by column chromatography on SiO2 with 2: 1 hexanes: ethyl acetate. 293 mg of delta-1,2-olefin was obtained as a white solid (Example 50A). 149 mg of the polar, *,, delta 10b, 1-olefin isomer was obtained as a white solid (Example 50B).

· ,; D. Trans-dl-8-chloro-3,4,4a, 5,6,10b-hexahydrobenzo-4,2,10so [f] quinolin-3-one and d1-8-chloro-2,3, 4.4a, 5,6-hex- ***; sahydrobenzo [f] quinolin-3-one »* · * · * * solution of protected C · · · * · * * delta1,2-olefin from step C (290 mg, 0.869 mmol) in 20 mL of CH2Cl2, trifluoroacetic acid (0.14 mL, 1.74 mmol) was added. *! '* · 30 The reaction mixture was stirred at room temperature for 1 hour · *] ** and then partitioned between CH 2 Cl 2 and saturated NaHCO 3.

The organic layer was dried over Na 2 SO 4 and concentrated in vacuo. The resulting crude product was recrystallized from ethyl acetate * to afford 142 mg (70%) of white crystalline trans-4-hydroxy-1-hydroxypropyl-3-hydroxypropyl-3-ol.

dl-8-chloro-3,4,4a, 5,6,10b-hexahydrobenzo [f] quinolin-3-one (Example 50A). Melting point 227-228 ° C. Elemental Analysis: C H N

Calculated: 66.81 5.18 5.99 5 Found: 67.09 5.18 6.22

The protected delta 1,10b-olefin (149 mg, 0.446 mmol) was treated in the same manner as described above for the protected delta1,2-olefin except that the crude product was purified by column chromatography on SiO 2 (5% isopropanol / -10 CHCl 3) to give 65 mg (62%) of dl-8-chloro-2,3,4,4a, 5,6-hexahydrobenzo [f] quinolin-3-one (Example 50B) as a white solid. Melting point 241-243 ° C. Elemental Analysis: C H N

Calculated: 66.81 5.18 5.99 15 Found: 67.06 5.35 5.93

Example 51

Preparation of trans-d1-8-bromo-4-methyl-3,4,4a, 5,6,10b-hexahydro-benzo [b] quinolin-3-one

Trans-d1-8-bromo-4-methyl-1,2,3,4,4a, 5,6,10b-oct-20 hydrobenzo [f] quinolin-3-one was prepared according to the preparation procedures described in Example 1. This compound was converted to the title compound in Example 50, Steps B and. C, followed by recrystallization from ethyl acetate / hexanes. Melting point 136-138 ° C.

»· ♦

'• * i Elemental analysis: C H N

... T Calculated: 57.55 4.83 4.79

Found: 57.81 4.74 4.81: Γ: Example 52 30 Trans-dl-8-chloro-4-methyl-3,4,4a, 5,6,10b-hexahydrobenzo [f] quinoline- Production of 3-one ···. Trans-d1-8-chloro-4-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3-one was prepared in Example 6; according to the production methods described. This compound 35 was converted to the title compound according to the preparation procedures described in Steps 50 to 61 107254 C of Example 50, followed by column chromatography on SiO 2 (ethyl acetate). Melting point 124-125 ° C.

Elemental Analysis: C H N

5 Calculated: 67.88 5.70 5.65

Found: 67.77 5.77 5.38

Example 53 Preparation of dl-8-chloro-4-methyl-2,3,4,4a, 5,6-hexahydrobenzo [f] quinolin-3-one 10 Trans-dl-8-chloro-4-methyl-3 , 4,4a, 5,6,10b-Hexahydrobenzo [f] quinolin-3-one was prepared according to the production methods described in Example 52. To this compound (250 mg, 1 mmol) in 30 mL of anhydrous THF was added 800 mg (6.8 mmol) of pyridine hydrochloride. The reaction mixture was stirred at room temperature for 7 days and then partitioned between ethyl acetate and 1N HCl. The organic layer was washed with 1N HCl, followed by water, then dried over MgSO 4 and concentrated in vacuo to a volume of 10 mL. The title compound was crystallized from this solution and collected by filtration. Melting point 99 ° C. Elemental Analysis: C H N Calculated: 68.16 5.31 5.67 .φ. Found: 67.95 5.48 5.64

EXAMPLE 54 Trans-d1 -8-Chloro-2-a-methyl-4-methyl-1,2,3,4,4-trans-1,1,2,4-trans-d1 -8-chloro-2-α Preparation of 4a, 10b-hexahydrobenzo [f] quinolin-3-one

Mixture of trans-d1-8-chloro-2- (a and b) -methyl; .beta.-4-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3-ones were prepared according to the production procedures described in Example 26. To a solution of this mixture (759 mg, 2.88 mmol) at -78 ° C in 15 mL anhydrous. With 2.0 equivalents of THF in hexamethylphosphoric triamide (HMPA), 11.6 ml of a 0.5 M solution of potassium? · ·: · · · Hexamethyldisilazide (5.76 mmol) in toluene was added. The reaction mixture was stirred at -78 ° C for 90 minutes before stirring.

--- -------—---— "...- - I

107254 62 of a solution of phenylselenyl chloride (607 mg, 3.17 mmol) in 5 mL of anhydrous THF. The solutions were allowed to warm to room temperature over 2 hours, quenched with NH 4 Cl solution and extracted with ethyl 5 acetate. The combined organic layers were washed with saturated NH 4 Cl, dried over Na 2 SO 4 and concentrated in vacuo to give 1.42 g of a brown oil. The crude product was purified by flash chromatography on SiO 2 (ethyl acetate) to give 252 mg of 6-phenylselenide. To a solution of 10 of selenide in 10 mL of THF was added 100 mg of NaHCO 3 and r.

1.1 equivalents of 3-chloroperoxybenzoic acid (m-CPBA) (142 mg 80-85% pure m-CPBA, 658-700 mmocl). After 15 minutes, the reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with saturated NaHCO 3 solution, dried over Na 2 SO 4 and concentrated in vacuo. The crude oil thus obtained was purified by flash chromatography on SiO 2 (70% ethyl acetate / hexane) to give 114 mg of the title compound as a white solid. 1 H NMR analysis showed that the delta 5.6 olefin was formed and that the 2-methyl group was α-oriented. Melting point 130-132 ° C.

. . Elemental Analysis r C H N

Calculator 68.83 6.16 5.35 * ··· 1 '25 Found: 68.35 6.15 4.92 • · *. 1: Example 55.1-1 Trans-dl-8-t-butylaminocarbonyl-ethanediyl-4-ylmethyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinoline. Preparation of 3-one Compound trans-d1-8-t-butylaminocarbonylethylenediyl-4-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinoline-3-one. oni was prepared according to the methods described in Example 25. To a solution of this compound •, · '(122 mg, 0.358 mmol) in 150 mL of anhydrous ethanol: 15 mg of 10% palladium on carbon was added. Mixture hydrat - • 1 · «·« «« · • * * • ♦ · 107254 63

was carried out at room temperature for six hours at an initial hydrogen pressure of 40 psi. The catalyst was removed by filtration through celite (Celite) and the filtrate concentrated to give a white solid. Proton NMR spectroscopy showed that the reaction was incomplete, thus subjecting the substance again to the same reaction conditions for another 6 hours. Purification of the resulting solid was accomplished using column chromatography on SiO 2 (20% isopropanol / ethyl acetate) to give the title compound as a white solid. Melting point 178-179 ° C. Elemental Analysis: C H N

Calculated: 73.65 8.83 8.18

Found: 73.21 8.69 8.32

Example 56 Preparation of Trans-d1-8-phenyl-4-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3-one

The compound trans-d1-8-bromo-4-methyl-1,2,3,4,4a, 5,6, -10b-octahydrobenzo [f] quinolin-3-one was prepared according to the preparation procedures described in Example 1. A mixture of this compound (160 mg, 0.54 mmol) and tetrakistriphenylphosphine palladium (0) (19 mg, 0.02 mmol) in 1.2 mL of toluene under nitrogen was added. . 0.6 mL of a 2 M aqueous solution of Na 2 CO 3 followed by phenylboronic acid (80 mg, 0.653 mmol). The reaction mixture was heated at 80 ° C for 18 hours. An- * of the mixture. The mixture was cooled to 1 and then partitioned between 75 mL of CH 2 Cl 2 (75 mL) and 25 mL of 2M aqueous Na 2 CO 3 and 2 mL of conc. The organic layer was dried over MgSO 4 and concentrated to give a tan solid. The title compound (106 mg, 67%) was obtained as a white crystalline material after flash chromatography on SiO 2 (5% isopropyl · propanol / CHCl 3) and the product was triturated in hexane. Melting point 186.5-187.5 ° C.

• · «

: V Elemental Analysis: C H N

35 Calculated: 82.44 7.26 4.81. : Observed: 82.38 7.12 5.08 * «· *« · · • • • • • · · 107254 64

Example 57

Preparation of trans-dl-8-vnynyl-4-methyl-1,2,3,4,43,5,6,10b-octahydrobenzo [f] quinolin-3-one

The compound trans-d1-8-bromo-4-methyl-1,2,3,4,4a, 5,6, -105b-octahydrobenzo [f] quinolin-3-one was prepared according to the preparation procedures described in Example 1. To the stopper was added 8-bromo-benzoquinolinone (1.00 g, 3.4 mmol), palladium (II) acetate (7.6 mg, 0.034 mmol), tri-o-tolylphosphine (41 mg, 0.136 mmol / 10 l). ), vinyl tributyltin (1.24 mL, 4.25 mmol) and 5 mL anhydrous dioxane. Argon was bubbled through the mixture for 15 minutes. The reaction tube was sealed and heated at 100 ° C with stirring for 18 hours. The reaction mixture was cooled and filtered through celite (CeliteR). The filtrate was concentrated in vacuo and the residue analyzed by gas chromatography (G.C.), which revealed that the material was a 4.7 / l mixture of the desired product relative to the starting material.

Column chromatography of this mixture with SiO 2 (7% methanol / CHCl 3) gave 212 mg of the title compound as a white solid. Melting point 89-90 ° C.

Elemental Analysis: C H N Calculated: 79.63 7.94 5.80 ..; Found: 79.39 7.98 5.56 • · ·

EXAMPLE 58 Preparation of Trans-d1-8-Ethoxycarbonyl-4-methyl-1,2,3,4,4a, -? · '* * 5,6,10b-octahydrobenzo [f] quinolin-3-one

The compound trans-dl-8-iodo-4-methyl-1,2,3,4,4a, 5,6, -10b-octahydrobenzo [f] quinolin-3-one was prepared in pre-3 according to the production methods described. To a solution of iodide (1.0034 g, 2.94 mmol) in 280 ml of ethanol was added tetrakistriphenylphosphine -. ···. palladium (II) chloride (160 mg) and 1.0 mL of triethylamine.

The mixture was degassed with nitrogen for 30 minutes followed by carbon monoxide. The reaction mixture was equilibrated with 35 CO and refluxed for 48 hours. The reaction mixture was refluxed for 48 hours. After filtration of the 65 thiose mixture through diatomaceous earth (Celite R), the filtrate was concentrated in vacuo to give an orange viscous oil. Proton NMR spectroscopy revealed that the reaction was incomplete. The oil was re-exposed to 5 conditions above for 48 hours. showed that the reaction was 85% complete The resulting material was purified by column chromatography on SiO 2 (10% methanol / CHCl 3) followed by HPLC reverse phase on a CN column to give 122 mg of the 10 title compound Melting point 140-140.5 ° C.

Elemental Analysis: C H N Calculated: 71.06 7.37 4.87

Found: 70.97 7.17 4.60

Example 59 15 (R) (+) - Trans-4-Methyl-8-chloro-10b-methyl-1,2,4,4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3-one manufacturing

Following the preparation procedures described in Example 40, Steps A, B, C, D, E and F using p-chlorophenyl-20 acetic acid as the starting material and in Step F using methylamine rather than ammonia and 2-propanol rather than ethylene glycol, (R) - . ; (+) -4-Methyl-8-chloro-10b-methyl-1,2,3,4,6,10b-hexahydro-robenzo [f] quinolin-3-one. This hexahydrobenzo [f] quinolin-3-one was reduced according to the procedure for * · <'· [· in Example 40, Step G. The crude product was purified by chromatography on SiO 2 (ethyl acetate as eluent) to give 5.6 g of the title compound as a light oil which solidified on standing. Melting point 60-61 ° C.

30 Elemental Analysis: C H N

Calculated: 68.30 6.88 5.31. **. Found: 68.14 6.94 5.27 / Optical rotation: 589 nm = + 76.16 °: (C = 1, CHCl3).

Example 60 Preparation of (R) (+) - Trans-4-Methyl-8-chloro-10b-methyl-3,4,4a, 5,6,10b-hexahydrobenzo [f] quinolin-3-one. (R) (+) - trans-4-methyl-8-chloro-10b-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinoline-3 oni (4: 1, trans: cis) with its cis isomer. A stirred, cooled (-78 ° C) solution of 1.4 g (5.56 mmol) of this mixture in THF (25 mL) was treated with a solution of potassium hexamethyldisilazide (12.2 mL; 6.12 mmol) in toluene. The solution was stirred for 10 minutes and treated with a solution of phenylselenyl chloride (1.17 g; 6.117 mmol) in 5 mL of THF.

The solution was warmed to ambient temperature for one hour and then quenched with 20 mL of saturated NH 4 Cl solution. The mixture was partitioned between ethyl acetate and water and the aqueous phase was dried over Na 2 SO 4 and concentrated to give a diastereomeric mixture of phenyl selenides. The crude phenylselenides were dissolved in 10 mL of ethyl acetate and cooled to 0 ° C. Saturated NaHCO 3 solution (2 mL) was added to the solution followed by 0.4 mL of 30% H 2 O 2.

. The mixture was warmed to ambient temperature and stirred for 2 hours. The mixture was extracted with ethyl acetate and the residue was chromatographed on SiO 2 (ethyl acetate as eluent) to give 611 mg of the title compound as a waxy solid. Melting point 45-48 ° C.

Elemental Analysis: C H N

: T: Calculated: 68.83 6.16 5.35 30 Found: 69.26 6.48 5.08

Optical rotation: 589 nm = + 87.38 ° (C = 1, CHCl 3) • Example 61 (R) (+) - trans-8-chloro-10b-methyl-3,4,4a , 5,6,10b- 35 Hexahydrobenzo [f] quinolin-3-one Preparation: Following Example 40, Steps A, B, C, D, E, F and. G The manufacturing methods used were to prepare the compound.

107254 67 (R) (+) -8-Chloro-10b-methyl-1,2,3,4,4a, 5,6,10-octahydro-benzo [f] quinolin-3-one as a mixture of trans and cis isomers (4: 1). The mixture (1.02 g; 4.07 mmol) was dissolved in 15 mL of dioxane and treated with dichloro-dicyanoquinone 5 (1.02 g; 4.45 mmol) followed by bis (trimethylsilyl) trifluoroacetamide (4.8 mL; 17 mL). , 9 mmol). The solution was stirred at ambient temperature for 4 hours and then heated to 100 ° C for 14 hours. The reaction mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic phase was concentrated in vacuo and the residue was gas chromatographed on SiO 2 (ethyl acetate as eluent) to give 670 mg of the title compound as an oil. A sample was crystallized from diethyl ether to give 60 mg of the title compound as a light solid. Melting point 15151-154 ° C.

Elemental Analysis: C H N

Calculated: (+1/2 mole H 2 O) 65.50 5.89 5.46

Found: 65.67 6.06.40

Optical rotation: 589 nm = + 51.33 ° 20 (C = 1, CHCl 3) 365 nm = -85.55 °

Example 62

Preparation of trans-d1-8-trifluoromethyl-4-methyl-1,2,3,4,4a, -5,6,10b-octahydrobenzo [f] quinolin-3-one Trans-d1-8-bromo-4- methyl 1,2,3,4,4a, 5,6,10b-octa- *% *; | The hydrobenzo [f] quinolin-3-one was prepared according to the preparation procedures described in Example 1 a. A mixture of bromide (1.2 g, 4.1 mmol), sodium trifluoroacetate (2.22 g, 16.3 mmol) and copper iodide (1.55 g, T: 8.1) mmol) in 25 mL of N-methyl-2-pyrrolidinone, heated at 180 ° C for 18 hours under argon. After cooling, the mixture was filtered through silica gel and. the silica gel plug was washed with ethyl acetate. The combined organic layers were washed twice with water and once with brine, dried over MgSO 4 and evaporated in vacuo to give 1.14 g of a black oil which crystallized on standing. «« «· • · 107254 68 Weather. The crude product was purified by flash chromatography on silica gel (ethyl acetate) followed by reverse phase chromatography (1: 1 water / acetonitrile) to give 312 mg of a white solid (27% yield).

5 High resolution mass spectrometer calculated for C 15 H 13 F 3 NO (283.118480); found 283.119620.

Example 63 Preparation of (+) - (4aR) - (10bR) -8-Chloro-1,2,3,4,4a, 5,6,10b-octa.hydrobenzo [f] quinolin-3-one. (S) - {-) - 8-Chloro-4- (α-methylbenzyl) -1,2,3,4,5,6-hexahydrobenzo [f] quinolin-3-one

toluene A, »HiO

I J (2) C 2 H 3 ClOCl, CHCl 3 Jl J

0 ^^ / NaHCO 3 (, q) O

20

To a stirred solution of 6-chloro-#; 2-Tetralone (1.0 equivalents, 100.0 mmol, 18.06 g of «* in toluene (300 mL) was treated with (S) - (-) -? - methylbenzyl), · equivalents, 100.0 mmol, 12.9 mL) «« * '· The mixture was heated under reflux for three hours. ·. *: * with azeotropic removal of water (Dean-Stark). The cooled reaction mixture was concentrated in vacuo to give the enamine, (S) -6. ··· · ··········································································eded (() to a chloroform · · ·: 150 ml) and saturated aqueous sodium bicarbonate. ···, thia was added (150 mL) under vigorous stirring.

The t * · * mixture was treated with acryloyl chloride (1.05 eq., 105.0 mmol, 8.5 mL) dropwise for 5 minutes.

• · * · '... · 35. The reaction mixture was allowed to stir at ambient temperature at 69 107254 for 20 minutes, diluted with chloroform and the layers separated. The aqueous layer was extracted with chloroform (1x). The combined organic layers were washed with brine (1x), dried (Na 2 SO 4) and concentrated in vacuo to give 37.9 g of a black oil. The crude oil was subjected to HPLC on silica gel (gradient elution from hexane to 25% ethyl acetate / hexanes) to give 19.03 g of a purple oil which was further purified by flash chromatography on silica gel 10 (eluting with 20% ethyl acetate / hexane). 96 g, 53% yield, title compound as a brown glass which was homogenized by HPLC analysis (reverse phase, C18, mobile phase: 60% acetonitrile / 0.5% aqueous ammonium acetate buffer), thin layer chromatography (silica gel, Rf = about 0.5, with 40% ethyl acetate / hexanes) and 300 MHz * Η NMR analysis.

FDMS: m / e = 337. Ä [D] 5e9 = -24.75 (c = 1.0, CHCl3).

B. (-) - (4aR) - (10bR) -8-Chloro-4- (5a-methylbenzyl) -1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinone 20 lin-3-one

25 NaBH3CN

'* · *: A HCOOH A. 1 J

·: · O n ^ ···· a n 2

. I H

... Ph ^ -ph ::: 'Ph 30. · ♦ ·. A stirred solution (12.0 g; 35.4 mmol) of the product of Step A in 96% formic acid • (175 mL) was treated with solid sodium cyanoborohydride (2.0 mL). equivalents, 70.98 mmol, 4.46 g) which is known as 107254 70 ti over 5 hours (total 10 equivalents, 354.9 mmol, 22.3 g). The mixture was allowed to stir overnight (about 14 hours) at ambient temperature. The reaction mixture was concentrated to give a pale yellow paste which was taken up in dichloromethane and washed with 1N sodium hydroxide (1x). The aqueous layer was extracted with dichloromethane (2x). The combined organic layers were washed with brine (1x), dried (Na 2 SO 4), and concentrated in vacuo to give 12.0 g of a colorless foam. Preparation of the residue by -10 va HPLC on silica gel (elution gradient from dichloromethane to 1% ethyl acetate / dichloromethane) and combining fractions more than 90% diastereomerically pure gave 1.63 g of the title compound as a crystalline solid (15%). HPLC analysis: reversed phase, C18, 230 nm, mobile phase: 60% acetonitrile / 40% 0.5% ammonium acetate buffer). Recrystallization of the solid from ethyl acetate gave the title compound in diastereomerically pure form as colorless needles (greater than 99 in 20: 1 diastereomeric purity, HPLC analysis). The fractions enriched with the title compound were then combined and concentrated in vacuo to give 3.0 g of a colorless foam. Here. , crystallization of the material from ethyl acetate (three crystallizations) gave an additional 870 mg of the pure title compound, 2.50 g, 21% yield. Sp. 176-177 ° C. FDMS: m / <; *. 1 D = 339. a [D] 589 = -126.63 (c = 1.0, CHCl 3). The absolute configuration of the title compound,. ', V was interpreted by examining X-ray powder diffraction patterns of a single crystal.

Theoretical Observed 30 C 74.21 74.07 H 6.52 6.59 • ·, ···, N 4.12 4.04 «* tt $« «i I ·« «• · ♦ {M« 4 • ♦ 1 * · • · 107254 71 C. (+) - (4aR) - (10bR) -8-Chloro-1,2,3,4,4a, 5,6,10b-octacahydrobenzo [f] quinoline-3- one

I H I H

Ph H

10

A mixture of the product of Step B (1.0 equiv., 4.09 mmol, 1.39 g) and trifluoroacetic acid (35 mL) was combined in a round bottom flask. The stirred mixture was refluxed for 2 hours.

The cooled reaction mixture was concentrated in vacuo, taken up in dichloromethane and washed with saturated aqueous sodium bicarbonate solution (1x). The layers were separated and the aqueous layer was extracted with dichloromethane (1x). The combined organic layers were washed with brine (1x), dried (Na 2 SO 4), and concentrated in vacuo to give a white solid. Recrystallization from ethyl acetate gave 0.81 g, 84% yield, of the title compound as colorless needles. Sp. 241.5-242 ° C.

FDMS: m / e = 235. α [D] 589 = 32.61 (c = 1.0, THF).

25 Theoretical Observed «· ·: C 66.24 66.35 • · · H 5.99 6.10 *” N 5.94 5.83 • · ♦ ''

Example 64 • · · * · * 30 (-) - (4aR) - (10bR) -8-Chloro-4-methyl-1,2,3,4,4a, 5,6-6,10b-octahydrobenzo [f] quinolin-3-one 1: Γ \ *: ^ (1) NaH, DME, Δ

O \ (2) Mel, A ^ I I T

I fi 0:: Me • · · 107254 72

To a stirred solution of the product of Example 63, Step C (1.0 equivalents, 0.288 mmol, 98 mg) in dry 1,2-dimethoxyethane (5 mL) was added 60% (w / w) sodium hydride (26 mg) in an oil dispersion. -5 blessings. The mixture was heated at reflux under nitrogen with stirring for 1 hour, cooled and treated with methyl iodide (5.0 equivalents, 1.44 mmol, 0.09 mL). The mixture was refluxed for an additional 1.5 hours. The cooled reaction mixture was quenched with water (1 mL) and extracted with dichloromethane (3x). The combined organic extracts were washed with brine (1x), dried (Na 2 SO 4) and concentrated in vacuo to give an orange oil. Preparative thin layer chromatography on silica gel (2 mm plate, developed with ethyl acetate) gave 50 mg of a colorless solid, 60% yield. Sp. 71.5-73 ° C. α [D] 589 = -74.80 (c = 1.0, CHCl3). HRMS (FABs) calcd for C 14 H 17 NOCl: 250.1003. Found 250.0999. Example 65 (+) - (4aS) - (10bS) -8-Chloro-4- (methyl) -1,2,3,4,4a, -20 5,6,10b-octahydrobenzo [f] quinoline-3 Preparation of A. (+) - (4aS) - (10bS) -8-Chloro-4- (5-methyl-benzyl) -1,2,3,4,4a, 5,6,10b-octahydrobenzo [f ] quinolin-3-one * ·: 3 25 _χΎσ «

... 11 NaBH3CN

; · 1: / k HCOOH Ji J

::: 0 n

'2 30 l H

A stirred solution of the product of Step A of Example 63 in 96% formic acid (20 ml) was treated with sodium cyanoborohydride in portions of 8 · · · · · · · · · · · · · · · · · · 107254 over a period of 73 hours (30 equivalents, 88.8 mmol, 5.58 g) at ambient temperature. The mixture was then heated at 50 ° C for two hours. The cooled reaction mixture was concentrated in vacuo to give a colorless foam. The residue was taken up in dichloromethane and washed with water (1x). The aqueous layer was extracted with dichloromethane (2x). The combined organic extracts were washed with 1N sodium hydroxide (1x), brine (1x), dried (Na 2 SO 4), and concentrated in vacuo to give a colorless foam. Semi-pressure liquid chromatography on silica gel (elution with 10% ethyl acetate / dichloromethane) gave 201 mg of the product of Example 63, Step B. Further elution gave 129 mg of the title compound as a colorless solid, 13% yield. HPLC analysis of this material (reverse phase, C18, 230 nm, 60% acetonitrile / 40% 0.5% aqueous ammonium acetate buffer) revealed that the material was more than 99% diastereomerically pure.

B. (+) - (4aS) - (10bS) -8-Chloro-4-yl-ethyl-1,2,3,4,4a, - 5,6,10b-octahydrobenzo [E] quinolin-3-one

Cl cj | oi) tfa »δ

· "· 25 (2) NaH 'DME' Δ I I J

I h ~ C3) Mel, Δ N

: · * ·: I H

'Ph Me

(• M

• · · • # ·

A stirred solution of step A

* · · 30 products (1.0 equivalents, 0.359 mmol, 122 mg) tri-1. in fluoroacetic acid (6 mL) was heated under reflux for 1.5 hours. The cooled reaction mixture was concentrated in vacuo to give a yellow solid which was taken up in dichloromethane and washed with saturated sodium carbonate solution (1x). The aqueous layer was extracted with dichloromethane (1x). The combined organic extracts were washed with brine (1x), dried (Na 2 SO 4) and concentrated in vacuo to give (-) - (4aS) - (10bS) -8-chloro-1,2,3,4,4a, 5,6, 10b-Octahydrobenzo [f] quinolin-3-one as a pale yellow solid. The residue was dissolved in dry 1,2-dimethoxyethane (5 mL) and treated with sodium hydride (19 mg, 60% dispersion in mineral oil, washed three times with pentane). The mixture was heated at reflux for 1.5 hours, cooled and treated with Melo Style Iodide (5.0 equivalents, 1.80 mmol, 0.2 mL).

The reaction mixture was heated for an additional 1.5 hours. The cooled reaction mixture was quenched with water and extracted with dichloromethane (3x). The combined organic extracts were washed with brine (1x), dried (Na 2 SO 4), and concentrated in vacuo to give an orange oil. Preparative thin layer chromatography on silica gel (2 mm plate, developed with ethyl acetate) gave the title compound (56 mc, 62% yield) as a colorless solid. Sp. 71.5-73 ° C. α [D] 589 = + 79.00 (c = 1.0, CHCl 3). HRMS (FAB +): calculated for C14H17NOCl, 250.0999. Found 250.1002.

The following abbreviations were used in Examples 66-69, "HPLC System A": 40% acetonitrile in water and? ·, 1 ··· 0.5% ammonium acetate in Waters Nova-Pak C-8R, 25 at 220 nm: at 2.00 ml / minute, 25 ° C.

• HPLC system B: 50% acetonitrile in water and • 0.5% ammonium acetate DuPont Zorbax R C-18: Llar. 220 nm, 2.00 ml / minute, 25 ° C.

· · · “HPLC System C”: 10% isopropyl alcohol in hexane at 0 · 50 ° C with Chiralcel 0DR at 254 nm, 1.00 ml / min and 25 ° C.

"HPLC System D": 10% Isopropyl Alcohol Hex ···· m; in Chiralcel ODR at 220 nm, 2.00 ml / min :.

v. and 40 ° C.

• «« «* · 1 # · • ♦ t 107254 75

Example 66 Preparation of (+) - (4aS) - (10bS) -4-methyl-8-chloro-1,2,3,4,4a, 5,6 -10,10b-octahydrobenzo [f] quinolin-3-one aa «ΓΥ f Hrra hv« »PA · ™, sjfY r ^ fY __ m-MV ,, ΓΎΎ

«-> · J I J„ I I cHj-Q ^ coo co, h <·> · J I I

CH 3 H CH 3 10 A. Di-p-toluoyl tartaric acid salt of 1- (2-methoxycarbonylethyl) -2- (methylamino) -6-chloro-1,2,3,4-tetrahydronaphthalene

A solution of trans- (dl) -4-methyl-8-chloro-1,2,3,4,43,5,6,10b-octahydrobenzo [f] quinolin-3-one (1/5 g) which was prepared essentially as in Example 6 in methanol (30 ml) with concentrated sulfuric acid (3.5 g) was refluxed for 144 hours. The solution was concentrated to ca. 20 mL and diluted with ether (50 mL), water 20 (100 mL) and saturated sodium bicarbonate (20 mL, pH = 9). The phases were separated and the aqueous phase was further extracted with ethyl acetate (100 mL) and methylene chloride (100 mL). The combined organic phases were dried at 4 ° C. And through a solution of (-) - p-toluoyl-L-tartaric acid (DTTA) monohydrate (2.00 g) in methanol (10 mL). All volatiles were removed under vacuum and the residual foam dissolved in about 40 ml of methanol. lia. The solids were filtered and dried to give • 1 l of 1.01 g (50% of theory) salt with 6.3% * · · 30 non-hydrolyzed trans-dl-8-chloro-4-methyl-1,2, 3,4,4a, -5,6,10b-octahydrobenzo [f] quinolin-3-one. Sp. 126-130 ° C.

TLC (silica gel with toluene - ethyl acetate - acetic acid - methanol (7: 4: 1: 4)): Rf = 0.34 (phosphomolybenzene acid observation).

aa · · • aa aa • aa · · · · aaa 107254 76 HPLC (System A): tr (min): 0.48 (43%, DTTA), tr = 1.33 (53%, free amino ester) , tr = 3.36 (3.15%, racemate).

HPLC (System B): tr (min) 1.06 (48.1%, DTTA), 2.775 (1.2%, unknown), 3.73 (46.1%, free amino ester, δ). 54 (4.5%, (title compound)) 1 H NMR (CDCl 3): δ 5.43 (s, 2H), 3.57 (s, 3H), 2.38 (s, 6H. UV (methanol): lambda (epsilon) 276 (30,100).

IR (CHCl 3): 1723 cm -1.

10 B. (+) - (4aS) - (10bS) -4-Methyl-8-chloro-1,2,3,4,4a, -5,6,10b-octahydrobenzo [f] quinolin-3-one

A solution of the preceding DTTA salt (100 mg!) Was mixed with toluene (5 ml), water (10 ml) and sodium bicarbonate (50 ml) for 20 minutes at 25. The toluene-15 ethylene layer was separated, dried (sodium sulfate), was heated (90-100 ° C, 18 hours) and evaporated to give the title compound.

1 H NMR (Benzene-d 6): 6.99 (dxd, 1H), 6.83 (d, 1H), 6.57 (d, 1H), 2.67 (3H, s), 2.40 (dxt, 2H).

20 1 2 H NMR (Benzene-d 6 with 2 equivalents of R - (-) - 2,2,2-trifluoro-1- (9-anthryl) ethanol (TFAE): d 2.14 (3H, s), observed in the methyl islet at 2.10 for 5-6% of the (-) - enantiomers.

HPLC (System A): tr (min) 3.36 (title compound).

; 3. HPLC (System B): tr (min) 5.68 (title compound).

• · ·. ·. : HPLC (System D): tr (min.) 13.85 (92%, title compound), 15.8 (8%, (-) enantiomer).

1 H NMR (CDCl 3): 3.07 (3H, s).

**; 'Example 67' · 11,30 (+) - (4aS) - (10bS) -4-methyl-8-chloro-1,2,3,4,4a, 5,6-6,10b-octahydrobenzo [ f] quinolin-3-one • i • ♦

Hl I II H IB HOjS. OCOCeHi-CHj H I [I

: V. ΓίΤ - Meo ^ -slAJ »η. ^ .- η 35 awco ° c ° 2H" KL ·; ^ H Λ 0 H CH, CHs • · · • · · · 2 * · 3 • · 107254 77 A. 1 - (2-Methoxycarbonylethyl) -2- (methylamino) -6-chloro-1,2,3,4-tetrahydronaphthalene di-p-toluoyl tartaric acid salt

A solution of trans-d, 1-8-chloro-4-methyl-5 1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3-one (2.3 g). 0.85 N hydrochloric acid in methanol was allowed to reflux for 168 hours, after which concentrated sulfuric acid (3.00 ml) and additional methanol (100 ml) were added. After 96 hours, the mixture was concentrated and treated with solid sodium bicarbonate (20 g). A mixture of 1- (2-methoxycarbonylethyl) -2- (methylamino) -6-chloro-1,2,3,4-tetrahydronaphthalene was partitioned between ethyl acetate (100 mL) and water (100 mL). The phases were separated and the aqueous layer was extracted with 250 mL of methylene chloride. The organic phases were combined and filtered through 3A molecular sieves (15 g) to a solution of 5.9 g of (-) - p-toluoyl-L-tartaric acid monohydrate in methanol. All volatiles were removed in vacuo and the white foam dried in vacuo for 30 hours to give the di-20 astereomeric salt (6.1 g, 99%, containing 5.0% non-hydrolyzed trans-dl-8-chloro-4). methyl 1,2,3,4,4a, 5,-6,10b-octahydrobenzo [f] quinolin-3-one) m.p. 126-130 ° C.

The preceding foam (DTTA salt) (5.69 g) was dissolved in «· · .1 ·; ' methanol (43 ° C, 32 ml) and the resulting solution was cooled to 25 ° C. The mixture was filtered and vacuum dried to give 2.92 g of DTTA salt. Recrystallization of this salt ··· (2.28 g) from 30 ml of methanol gave 2.12 g of essentially pure salt (47%, 94% of theory).

· (HPLC) (system A): 0.48 (46%, DTTA), 1.28 (54% amino- • · 30 esters), no other impurities were observed.

B. (+) - (4aS) - (10bS) -4-Methyl-8-chloro-1,2,3,4,4a, -5,6,10b-octahydrobenzo [f] quinolin-3-one The preceding salt (1.50 g) was stirred (25 ° C, 10 minutes) with toluene (30 ml), saturated aqueous sodium bicarbonate (10 ml) and water (40 ml). The phases were separated and the toluene layer was dried (3-D molecular sieves). The resulting solution was heated (16 hours, 92 ° C) and evaporated to give 0.55 g of (+) - (4a R) - (10b R 4 - methyl-8-chloro-1,2,3,4,4a, 5), 6,10b-octahydrobenzo [f -5-quinolin-3-one together with 5-7% enantiomer (- - (4aR) - (10bR) -8-chloro-4-methyl-1,2,3,4) , 4a, 5,6,10b-octa-hydrobenzo [f] quinolin-3-one.

HPLC (System A): 3.36 (97.9%, title compound).

HPLC (System B): 5.76 (99.9%, title compound).

HPLC (System C): 93% of the title compound and 7% of the enantiomer.

UV (methanol) 204 (24100).

Example 68 Preparation of (-) - (4aR) - (10bR) -8-Chloro-4-methyl-1,2,3,4,4a, 5 (-15,6,10b-octahydrobenzo [f] quinolin-3-one OH \ jf

I n H f T HO: C OCOC6H, -CHj ysrAJ

,. flY—- Η „7Γ ^ · Η - {-yJ ^ jT Ji

20 HN ^ JcHrC, H.COO COsH

CH3 093

Isolated A. 1- (2-Methoxycarbonylethyl) -2- (methylamino) -25 6-chloro-1,2,3,4-tetrahydronaphthalene di-p-toluoyl tartaric acid salt ··· A solution of 90.4 g trans-dl -8-chloro-4-methyl ····. l-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3-one (about 95% pure by HPLC analysis) was prepared essentially as in Example 6. . , was stirred at reflux under nitrogen pressure in anhydrous methanol (4 L) and sulfuric acid (98%, 200.0 mL) for 160 hours (<1.5% trans-dl-8-chloro-4-methyl-1,2,3, 4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3: * ··· 35 onions remained by HPLC). The solution was concentrated in vacuo and extracted at 10-15 ° C using methylene chloride, sodium bicarbonate (700 g) and water. (2 1). 4 Treatment of organic extracts with (+) - p-toluoyl-D-tartaric acid (DTTA) monohydrate (derived from non-naturally occurring tartaric acid (S, S isomer), 132.9 g) in methanol (700 mL) and three crystallizations gave 48.2 g of purified salt (mp 125-130 ° C, suitable for analytical standard).

HPLC (System A): 0.48 (DTTA), 1.28 (amino ester).

UV (methanol): 204 (51200), 239 (31400), 270 (2500).

B. (-) - (4aR) - (10bR) -8-Chloro-4-methyl-1,2,3,4,4a, -5,6,10b-octahydrobenzo [f] quinolin-3-one

The preceding DTTA salt (500 mg) was mixed with 10 mL of toluene, 5 mL of water, and 5 mL of saturated aqueous sodium bicarbonate (25 ° C). The aqueous layer was separated and re-extracted with toluene (5 mL). The combined toluene extracts were washed once with saturated sodium bicarbonate (5 mL), dried (4 Å molecular sieves), and heated at 95 ° C-105 ° C (18 hours). The toluene was removed under a stream of nitrogen at 40 ° C and the resulting oil was triturated with hexane-ether to give the subtitle compound.

TLC (silica gel, toluene-ethyl acetate-acetic acid, 7: 4: 1): Rf = 0.68.

HPLC (System A): 3.25 minutes (> 99% of the title compound) • · • Ϊ. HPLC (System C): 31.12 min. (> 99% of the title compounds • · · ·), 28 min. (<1% of the (+) enantiomer).

1 H NMR (CDCl 3): 3.22 (dxd).

IR (CHCl 3): 1620 cm -1 UV (methanol): 205 (20800).

• · • · t • »'<<1 1 <1 f <I« • · «« «• · * 10725 ^ 80

Example 69 Preparation of 1- (2-methoxycarbonyl-ethyl) -2- (methyl-amine) -? 5-chloro-1,2,3,4-tetrahydronaphthalene di-p-toluoyl-1-butyric acid salt 5 -

Mother liquors o o ^ H02c p ocoq ^ -ch, Example 68 Η "^ Γ" {,, Η

MeO I j-1 J CH3-QH4COO CO2h resolination- HNvlv ^. . · CH. CH3 from process 3 10 Isolated

The original resolvation isolation filtrates and the mother liquor from the first recrystallization of Example 68 were combined and evaporated at 25 ° C in vacuo to give 15 as a white foam (190.4 g). This salt (180.4 g) was extracted with cold methylene chloride, water and sodium bicarbonate as described in Example 68. Extraction of the extracts with (-) - p-toluoyl-L-tartaric acid monohydrate (92.7 g) in methanol (450 ml) and three crystallizations from antis 20 pure DTTA salt (57.0 g). Sp. 126-130 ° C).

HPLC (System A): 0.48 min. (47%, DTTA), 1.28 (53%, amino ester).

IR (CHCl 3): 1720 cm -1.

UV (methanol): 204 (46200), 239 (28000), 270 (4200).

• ♦ ♦ · · «♦ ♦ ♦ · · e e ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦. t «« «·« · »*» • · • ·

Claims (4)

107254 81 A compound of the formula: wherein: X is halogen, NO 2, CF 3, C 1 -C 8 alkyl, C 1 -C 8 alkoxycarbonyl, amino, amido or a group -A-R 6 wherein A is C 1 -C 6 alkylene or C 2 -C 6 alkenylene or C 2 -C 6 alkynylene 15 and R 1 is carboxy, C 1 -C 6 alkoxycarbonyl, amino, C 1 -C 6 alkylamino, amido or C 1 -C8 alkylamido, and n is 1 or 2. 2. A process for the preparation of a compound of the formula 25 OH ΐΗ3: *.! wherein ··· X is halogen, NO 2, CF 3, C 1 -C 6 alkyl, C 1 -C 6 alkoxy; * · cicarbonyl, amino, amido or a group -A-R 6 where A is • · · C 1 -C 8 alkylene or C 2 -C 6 alkenylene or C 2 -C 6 alkynylene 30 and R 6 is carboxy, C 1 -C 8 alkoxycarbonyl, amino, C 1 -C 6 alkylamino, amido or C 1 -C 4 alkylamido and n is 1 or 2 ; characterized in that the reaction product obtained by reacting 3,4-dihydro-1-methyl-2- (1-phenylethylamino) naphthalene with an α, β-unsaturated carbonyl compound is hydrolyzed. in an inert or predominantly inert solvent or mixture of solvents and isolating the compound of formula II. • · • · • · 107254 82