DK142053B - Process for preparing racemic or optically active indane or perhydronaphthalene derivatives. - Google Patents

Description

(11) PUBLICATION WRITING 1U2053 DENMARK lntc '· 3 c II c «S / βΓ i (21) Application No. 15 ^ 5/72 (22) Filed Done 29 * Mar. 1972 (23) Race day 2. Qkt. 19 ^ 9 (44) The application presented and the Q ^ publication published on * O * »Ug * 1 yOv THE PATENT AND TRADEMARKETS Woritet begs« from ^ n

Oct 4 i960, 7o5Q22, US

(71) F. HOFFMA.NN-LA ROCHE & CO. AKTIENGESELLSCHART, Grenzacherstraøe 124 “184, Post Box CH-4002 Basal, CH, (72) Inventor: Zoltan George Hajos, 24 ^ Highland Avenue, Upper Montclair, N. J., US.

(74) Plenipotentiary in the proceedings:

Plougmann & Vlngtoft Patent Bureau · (54) Process for the preparation of racemic or optically active in-dan or perhydronaphthalane derivatives.

The present invention relates to a particular process for the preparation of novel racemic or optically active indane or perhydronaphthalene derivatives of the general formula I

R4

CH2

where R4 represents hydrogen or alkyl of 1-7 carbon atoms, Z represents carbonyl, alkylenedioxymethylene of 1-6 carbon atoms or CH (OR), R represents hydrogen, alkyl of 1-7 carbon atoms, alkoxyalkyl of 1-7 carbon atoms. each alkyl moiety, phenylalkyl having 1-7 earh atoms in the alkyl moiety, alkanoyl having 1-6 earh atoms, benzoyl, nitrobenzoyl having 1 or 2 nitro groups, trifluoroacetyl or camphorsulfonyl, and m represents 1 or 2. In the formulas shown herein, the various substituents are attached to the cyclic nucleus by either a fully drawn line, indicating a substituent which is in the β position, i. above the plane of the paper, or by a dashed line, indicating a substituent which is in the α position, i. under the plan of the paper.

Examples of alkyl groups having 1-7 earhone atoms include methyl, ethyl, isopropyl, n-propyl and tert-butyl. Examples of alkoxyalkyl groups having 1-7 earhone atoms in each alkyl moiety are 2- ethoxyethyl and 3-propoxy propyl. Examples of alkanoyl groups having 1-6 earhone atoms are acetyl and propionyl. Examples of alkylene dioxide groups whose alkylene moiety contains 1-6 earhone atoms are 1,2-ethylenedioxy, 2,2-dimethyl-1,3-propylenedioxy, 1,2-propylenedioxy and 2,3-butylenedioxy. Examples of nitrobenzoyl groups having 1 or 2 nitro groups are 4- & itrobenzoyl and 3,5-dinitroben = zoyl.

The process according to the invention for the preparation of the compounds of the general formula I shown above is characterized by hydrogenating one. compound of the general formula III

R4 Z '«f2> m

III

COOH

wherein R 4, Z and m have the above meanings, in the presence of a noble metal catalyst in an inert organic solvent, the compound obtained with the general formula II dissolves

3 142053 Η4 H \ CH2 ^ m, A | A- '

! H

COOH

4 wherein R, Z and m have the above meanings as racemate or an optical enantiomer in an aprotic polar solvent which is preferably "dimethylsulfoxide or a mixture of dimethylsulfoxide and another aprotic polar solvent, and then to reaction * the mixture substitutes formaldehyde in the presence of a primary amine or a secondary amine or acid addition salts thereof.

The reaction sequence, which is based on the novel compounds of general formula III and which leads to the novel compounds of general formula I, is part of a completely new, economically valuable total synthesis of steroids. It has not been proposed in the prior art to use compounds of the general formula I as intermediates in such a total synthesis. The hydrogenation of bicyclic β-ketoacid esters to form trans-substituted bicyclic compounds is described by Lominé et al., Bulletin de la Société Chimique de France, 9 »3664 (1968).

However, the conversion of a compound of general formula III into a compound of general formula II in high yield by catalytic hydrogenation is, however, surprising because strong decarboxylation under the reaction conditions used when the free acid is to be expected.

Furthermore, the formation of the compounds of the general formula 1 from compounds of the general formula II was surprisingly under the conditions of a Mannich reaction, since it has been stated that the reaction was expected to lead to the corresponding β aminoketone, cf. eg. C. Mannich et al., Chem. Ber., 57, 1108 (1924) and Marshall et al., J. Org. Chem., 30, 3475 (1965).

The conversion of a compound of general formula II to the 4-methylene trans-fused compound of general formula 4 is carried out by a modified Mannich reaction. The conversion can be carried out using formaldehyde in the presence of primary or secondary amino acid addition salts. Suitable salts are those derived from strong mineral acids or organic acids, e.g. hydrogen halides, preferably hydrogen chloride, sulfuric acid or oxalic acid. The reaction is conveniently carried out at a temperature in the range of 0 ° C to approx. 80 ° C. A preferred temperature range according to the invention for this reaction is 15 - 40 ° C, as it is the most convenient and gives the best results. Although the amount ratio of the reactants used for this reaction is not critical, it has been found advantageous to use a molar ratio of formaldehyde to keto acid of approx. 10: 1 and a mole ratio of amine to keto acid of 0.1: 1 to 1: 1.

The reaction is best carried out in such an aprotic solvent which acts both as a solvent for the reaction and as a carboxylating agent. Particularly good results are obtained when the compound of general formula II is allowed to react with the Mannich system formed by the addition of formaldehyde and a primary or secondary amine salt in dimethyl sulfoxide; the anion of the compound of general formula II is first formed in the dimethyl sulfoxide and it is suppressed in situ by the Mannich = system. Aqueous formalin (37 - 40 µs) is a generally satisfactory source of formaldehyde for this reaction. Examples of the amines suitable for this reaction are secondary amines such as diethylamine, morpholine, piperidine and pyrrolidine, and primary amines such as methylamine, butylamine and benzylamine. A particularly preferred amine for this reaction is piperidine. internal aprotic solvents, e.g. dimethylformamide and hexamethylphosphorus amide, which are inert to the reactants, may be used in conjunction with the dimethyl sulfoxide. One dimethyl sulfoxide-containing solvent promotes decarboxylation which induces enolization at the position where the carboxy group is attached; the suppression with the Mannich system in dimethylsulfoxide does not allow the enol to equilibrate toward the preferred position in the trans-fused bicyclic system.

5 142053

It is a particular advantage that the hydrogenation of the compounds of the general formula III to form a trans-fused bicyclic structure can be carried out to obtain extremely high yields. The hydrogenation is carried out in the presence of a precious metal catalyst such as palladium, rhodium, iridium or platinum. In particular, a palladium catalyst is preferred. The precious metal catalyst can be used with or without carrier, and if carrier is used, conventional carriers are suitable. It is preferred to use palladium on barium or calcium sulfate, and according to the invention, it is particularly preferred to use palladium on barium sulfate, as this common and readily available catalyst has been found to give good results in practice. Particularly preferred is P10 / BaSO4. The pore ratio of catalyst to substrate is not critical and can be varied, but it has been found advantageous to use a weight ratio of catalyst to substrate of from approx. 1: 1 to approx. 1:10.

In particular, a ratio of 1: 3 is preferred. The hydrogenation is carried out in the presence of an inert organic solvent for the particular compound of the general formula III which is hydrogenated, e.g. a lower alkanol such as methanol, isopropanol or octanol, ketones, e.g. lower dialkyl ketones such as acetone or methyl ethyl ketone; lower alkyl esters of lower alkanoic acids, e.g. ethyl acetate, lower alkyl ethers such as diethyl ether or tetrahydrofuran and aromatic hydrocarbons such as toluene or benzene. It is particularly preferred to carry out the hydrogenation using a lower alkanol as solvent, and the hydrogenation is preferably carried out under non-acidic conditions, suitably carried out under neutral conditions. The hydrogenation can be carried out at atmospheric pressure or at or below atmospheric pressure, e.g. at as high pressures as approx. 50 atmospheres. In addition, hydrogenation can be carried out at room temperature or at temperatures below or above (room temperature '; hydrogenation is conveniently carried out at room temperature. when an equivalent hydrogen is taken up, it is advantageous then to add more catalyst and hydrogenation further.It is understood that another essential feature of this hydrogenation step is that the hydrogenation of the compound of the general formula III to form the compound with the% The general formula II proceeds without substantial decarboxylation of the substituted compound of the general formula III, depending on the hydrogenation conditions used, the group Z of the compound of the general formula III may be modified during the hydrogenation. (OR2) where R2 is alkoxyalkyl can 2 the group R under the hydrogenation conditions described above is decomposed during the hydrogenation. A preferred group R for carrying out the hydrogenation is alkyl, especially tert-butyl. According to the invention, it is preferred that R 2 is tert-butyl and that R 1 is methyl or ethyl, the tert-butoxy 2 protecting group being particularly easily introduced and again cleaved, and R 2 = methyl or ethyl corresponding to the most interesting steroids. prepared from compounds I, cf. below.

Compounds of general formula III can be prepared from compounds of general formula V '

Xt> where R 1, Z and m have the above meanings.

Many of the starting materials of general formula V in which Z is a carbonyl compound are known compounds. The indanone starting compounds of general formula Y, wherein Z is a carbonyl compound, may conveniently be prepared by known methods, e.g. by Michael addition of methyl vinyl ketone to 2-alkyl-cyclopentane-1,3-dione. The cyclization can be carried out using pyrrolidine in a benzene solvent under reflux conditions (cf. U.S. Pat. No. 3,321,488).

If desired, other derivatives of the compounds of general formula Y. may be prepared. Thus, to prepare the derivatives wherein OR is a hydroxy group, the corresponding oxo group can be selectively reduced with a lithium aluminum tri (lower alkoxy) = hydride. or alkali metal borohydride, e.g. sodium or potassium = 2 umbohydride, at low temperatures. Derivatives wherein OR is an alkoxy group of 1-7 carbon atoms, e.g. tert-butoxy, can be prepared from the corresponding hydroxy derivative by reaction under acidic conditions with isobutyl ether by methods known per se.

7 142053

Other derivatives corresponding to the definition of Z can be prepared by methods known per se.

The bicyclic ketone of general formula V can be converted to acidic compounds of general formula III by reaction with a base sufficiently strong to form the corresponding anion of the bicyclic compound via formation of conjugatenolate. Examples of bases suitable for this reaction are alkali metal amides such as sodium amide, alkali metal alkoxides such as lithium metal oxide and alkali metal hydrides such as sodium hydride. It is generally preferred to carry out this reaction at room temperature, although temperatures of approx. -40 ° C to the reaction boiling point. The reaction is conveniently carried out in liquid ammonia or in the presence of an organic solvent which is inert to reactants, e.g. dimethyl ', sulfoxide or dimethylformamide, hydrocarbons, e.g. benzene or toluene, or ethers, e.g. diethyl ether or tetrahydrofuran. A preferred solvent for this reaction is dimethyl sulfoxide. This reaction product, the bicyclic enolate "" intermediate, can be isolated by conventional "methods, e.g. by removal of the solvent using vacuum dehydrogenation.

The anion thus obtained in the residue can be carboxylated by reaction with excess carbon dioxide to give the carboxylic acid of general formula III. The carboxylation may conveniently be carried out using solid carbon dioxide ("dry ice") or by passing gaseous carbon dioxide into the reaction mixture. Examples of suitable solvents for this reaction are any of the aforementioned solvents which can be used to prepare the anion, with the exception of liquid ammonia which is basic and dimethyl sulfoxide which appears to promote decarboxylation. In cases where liquid ammonia or dimethylsulfoxide is used to prepare the anion, they should be replaced with an inert solvent when carrying out the carbon dioxide treatment. Suitable reaction temperatures range from -60 ° C to approx. 40 ° C. The reaction is preferably carried out initially at the lower end of this range for a period of approx. 6 hours, after which the reaction mixture is allowed to warm to approximately room temperature over 4 hours and then left at room temperature for another 12 hours. The separation of the desired reaction product from the reaction mixture can be carried out by extraction. The extraction is conveniently carried out from a hydrocarbon solvent having a dilute base such as sodium hydroxide or lithium carbonate to form the corresponding water-soluble salt of the acid. Base extraction is used to remove the desired product from the starting material. The aqueous phase is separated and gently acidified to a pH of between 2.5 and 4.5 with dilute mineral acid, after which the desired product is obtained by conventional methods. Although the reaction can be conveniently carried out at atmospheric pressure, higher yields can be obtained by carrying out the reaction under higher pressure, e.g. pressure in the range of 30 - 40 kg / cm 2.

The optical antipodes of the subject compounds can be obtained either by cleavage of the corresponding racemic final product or by cleavage of racemic starting material or, if the racemic starting material is used directly, by cleavage of any one. intermediate won race food. The invention provides a simple synthesis for optically active end products due to the fact that the optical specificity is maintained throughout. the synthesis due to the stereoselectivity of the individual conversions occurring in the process, of which the above reactions are examples. The cleavage can be carried out by conventional known cleavage methods. Thus, e.g. racemates of compounds wherein the part symbolized 'by the symbol' Z is hydroxymethylene, or a group which can be converted to hydroxymethylene, for example carbonyl (which can be converted to hydroxymethylene by reduction) or an ether or ester of the hydroxymethylene (which can be converted to hydroxymethylene by hydrolysis) is cleaved by reacting the compound containing the hydroxymethylene moiety with a tobacic acid, for example with a tobasic lower alkanoic carboxylic acid such as oxalic acid, malonic acid, succinic acid, glutaric acid or Adipic acid, or an aromatic tobasic acid such as phthalic acid, reacting the thus-formed half-ester with an optically active base such as brucine, ephedrine or quinine, and separation of the resulting diastereoisomeric products. Alternatively, the hydrosymethylene group can be esterified with an optically active acid, e.g. camphor sulfonic acid and the resulting diastereoisomeric esters can be separated. Conventionally, the optical antibodies can be recovered from the separated diastereoisomeric salts and esters.

The present compounds are useful intermediates in the total synthesis of known and novel pharmacologically valuable steroids, e.g. 19-nor-steroids as described in the examples in Danish Patent Application No. 5252/69. The reaction scheme below illustrates the further conversion of a compound of general formula I to 19-norsteroids, e.g. 19-nor-testosterone. In this reaction scheme, R 2 and R 2 have the meanings given above, and W represents the rest of the ketal moiety, e.g. an alkylene group.

α η ηΛ 142053 Η 10 ·> Η ^ Μ & / - ^ W / -1 — W.

<Μ / - Μ / 7 \ §_ί. · Η (“7- \ / \ 'w νΛ / / O o \ <0 \ / N-' o o \ / ^ <M / - - ° - (

~ ^ pj \ ----- M

1 jP i / H s / ΜΛ

1. ^ 81 · vU- «/ (V

Ϊ r \ v / \ a * SC s H \ v a o \ ° \

v A

. o o + w

+ fe H

H

/ - H

CJ / i> W_ / O \ '% i —— U-w w r— / W-Λ--.

^ - \ «8 \ / w V - V-a ^ cM h

No / \ o o

V

11 142053

By the Michael addition, process step (a) of the above reaction scheme, the precursors of steroid rings A and B are built up in a single ring formation reaction. The reaction is carried out in the presence of a base sufficiently strong to form the anion of the β-keto ester. Examples of suitable bases are lower alka =. limetal alkoxides, e.g. sodium methoxide, sodium ethoxide, potassium methoxide or potassium tert.butoxide, alkali metal hydroxides such as sodium hydroxide, alkali metal hydrides such as sodium hydride and lithium hydride, alkali metal amides such as lithium amide and sodium amide, and methylsulfinylcarbanion (i.e. In particular, the lower alkali metal alkoxides are preferred. The reaction can be carried out in a temperature range of approx. -5 ° C to • for approx. 100 ° C, but it is particularly advantageous to carry out the reaction in a temperature range from 0 ° C to 25 ° C. Furthermore, the reaction is conveniently carried out in the absence of oxygen, e.g. in an atmosphere of inert gas such as nitrogen or argon. It is convenient to carry out the reaction in the presence of an organic solvent which is inert to the reactants and to the intermediates of the general formula VII. Such solvents are e.g. dimethylformamide, dimethyl sulfoxide and aromatic hydrocarbons, e.g. benzene, toluene and xylene.

Other suitable solvents are the ethers such as diethyl ether and tetrahydrofuran and lower alkanols such as methanol and ethanol. The concentration of the reactants is not critical, but it is preferred to use a 1: 1 molar ratio of the reactants of formulas Ia and VI. The side chain of the reaction intermediate VII assumes the thermodynamically favorable equatorial configuration under the equilibrium reaction conditions. The side orientation α orientation is extremely important for the construction of ring B with the right stereochemistry.

Due to the preferred enolization of the keto group towards the ester function, no cycling occurs at this stage.

Following the Michael addition of the β-keto ester of the general formula VI to the bicyclic trans-indanone of the general formula la hys, the compounds thus obtained with the general formula VII are drolyzed to remove the ester group and then cyclized after step (b). ) in the reaction scheme. The cyclization should be carried out under reaction conditions which do not result in cleavage of the cyclic ketal group. Examples of basic cyclizing agents are e.g. a dilute aqueous solution of alkali metal hydroxides 12. 142053 or alkaline earth metal hydroxide. The cyclization is conveniently carried out in an inert organic solvent, e.g. carbon = hydrides such as benzene and toluene, and ethers such as tetrahydrofuran. The cyclization can be carried out at room temperature or at temperatures above room temperature, but it is preferable for convenience reasons to carry out the reaction at approximate room temperature. The ester group of the bicyclic intermediate of the general formula VII can be removed by hydrolysis of the ester following step (b) of the reaction scheme to form the corresponding acid of general formula VIII (after acidification) and decarboxylation to compounds with the general formula IX, e.g. in refluxing toluene under inert atmosphere, e.g. nitrogen, according to step (c) of the reaction scheme.

The hydrogenation of the ³ - double bond forbind compounds of the general formula IX to form compounds of the general formula X can be carried out by step (d) of the reaction scheme in a lower alcohol solvent, e.g. ethyl alcohol, in the presence of a base, preferably triethylamine. 19-Ror testosterone may be prepared from the compounds of the general formula X by hydrolysis and refluxing in a mineral acid such as hydrochloric or sulfuric acid in a lower alkanol solvent such as methanol according to step (e) of the reaction scheme.

It should be noted that the process steps shown in the reaction scheme can be used to prepare norgestrel. This may be accomplished by preparing the 7 αβ-ethyl analogs of the compound of formula Ia using the reaction steps (a), (b), (c), (d) and (e) of the reaction scheme followed by oxidation using e.g. . Jones reagent and ethynylation. It will further be understood that by using the optically active 7ap-ethyl = -enanthiomers of compounds of the general formula Ia in the reaction scheme, optically active norgestrel can be prepared.

The method according to the invention is illustrated in more detail by the following example.

13 142053

Example.

A.

45 ml of dimethyl sulfoxide distilled over calcium hyuride is added to a $ 53 dispersion of 1.05 g of sodium hydride in mineral oil, which is already washed with anhydrous ether and dried under nitrogen = atmosphere. The mixture is stirred at 20 ° Cr and a solution of 5.0 g of ip-tert.butoxy ~ 5,6,7,7a-tetrahydro = - * 7ηβ-ηΐθΐ1 ^ 1 · -5-οχο-1η1ηη is added at once. 45 ml of dimethyl sulfoxide. The reaction = the mixture is stirred until the hydrogen evolution is stopped and thereafter = for approx. 4 hours. The dimethyl sulfoxide is then distilled off under high vacuum using a bath maintained at a temperature of 75 ° C. The residue (conjugate anion of ip-tert.butoxy-5,6,7,7a = * -tetrahydro-7a6-methyl-5-oxo · -indane) is dissolved in 90 ml of anhydrous ether and added as soon as possible (during 2 minutes) into a 1 liter flask containing a thick slurry of anhydrous solid carbon dioxide in 225 ml of anhydrous ether. The reaction mixture is stirred vigorously. The slurry is prepared by cooling 2 - 5 ml

f - J

anhydrous ether with a cooling mixture of dry ice and methanol and then adding anhydrous solid carbon dioxide from an inverted container containing "crushed" carbon dioxide. The container stands by means of rubber pressure pipes in connection with the flask. 2 departures are connected to it with two dry towers filled with anhydrous calcium sulfate. After the hand as the slurry is formed and thickens, little by little dry ether is added from a drip funnel until a total of 225 ml is added. The reaction mixture is stirred for 6 hours in a cooling bath of dry B and methanol and left for 16 hours at 20 ° 0. To the ether solution is added 200 ml of water containing 50 ml of 0.1 R sodium hydroxide and stirred for 1 hour under a nitrogen atmosphere. The ether phase and water phase are separated and the ether phase is washed twice with water.

The combined aqueous fraction is extracted with ether. The combined ether extracts are dried over sodium sulfate and evaporated in vacuo to give the starting material, tβ-tert. ::: butoxy-5,6,7,7η-ΐθΐηη1 ^ ηο-7ηβ-: αΐθ1] ^ Γΐ ··· · 5- οχο-1η1ηη. The aqueous solution is filtered and gently acidified with 2N hydrochloric acid to pH 2.5 at a temperature of approx. 0 ° 0th The mixture is extracted twice with benzene and then with ether, and the extract is washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated in vacuo to give the β-ketosyrene, β-tert, in the form of a dry solid. butoxy-5,6,7,7a-tetrahydro-7aP-methyl-5-oxo-4-indanecarloxylic acid, m.p. 153-160 ° 0. In trituration with ether, ip-tert.butoxy-5β, 7,7a-tetrahydro-7aP = -methyl-5-QXo-4-indanecarboxylic acid, mp 156 ° C.

Recrystallization of acetone gives an analytically pure sample of Ιβ-tert.butoxy - $, 6,7,7a-tetrahydro-7aP-methyl-5-oxo-4-indane = carboxylic acid, mp 159.5 ° C.

B.

1.84 g of unsaturated β-keto acid, 1β-tert.butoxy-5,6,7,7a-tetrahydro = -7ηβ-methyl-5-oxo-4-indanecarboxylic acid, dissolved in 92 ml of absolute ethanol and hydrogenated at atmospheric pressure and room temperature in the presence of 184 mg of 10 wt $ 1 s palladium / barium sulfate catalyst. The. theoretical amount of hydrogen is consumed over 20 mi = nuts. The solution is filtered and evaporated in vacuo to give iP-tert.butoxy-3aa-4P-5,6,7, α-hexahydro-7aP-methyl-5-oxo = -4a-indanecarboxylic acid, mp 107.5 - 109 ° C. An analytically pure sample of β-tert-butoxy-3aa, 4β, 5,6,7,7a-hexahydro-7aβ = -methyl-5-oxo-4a-indanecarboxylic acid is obtained by recrystallization from ether and has a melting point of 114 - 114.5 ° C.

G.

2.95 g of Ιβ-tert, butoxy-Ja «^ 5,6,7,7η-ηβΧθ1ητάηο-7ηβ-πιβΐ1] $ -1-5- = methyl sulfoxide and 12.2 ml of 36 - 38 $ * aqueous formaldehyde solution.

1.35 g of piperidine hydrochloride is added and the mixture is stirred under nitrogen for 3 hours. To the above-mentioned mixture is added 9.35 mg of sodium bicarbonate χ οο ml of water, then the mixture is extracted 3 times with benzene. The extract is washed with water and a saturated sodium chloride solution, dried over magnesium sulfate and filtered and evaporated formation of crude lp-tert.butoxyactax, 7,7a-tetrahydro-7aP-methyl = -4 ~ methylene-indan-5 (4H) -one in the form of an oil.

Claims (1)

A process for the preparation of racemic or optically active indane or perhydronaphthalene derivatives of the general formula I S4 ο'ίίίί [ί H ch 2 wherein R 4 represents hydrogen or alkyl of 1-7 carbon atoms, Z represents carbonyl, alkylenedioxymethylene with 1-6 carbon atoms. the alkylene moiety or CH (OR), R represents hydrogen, alkyl of 1-7 carbon atoms, alkoxyalkyl of 1-7 carbon atoms in each alkyl moiety, phenylalkyl of 1-7 carbon atoms in the alkyl moiety, alkanoyl of 1-6 carbon atoms, benzoyl, nitrobenzoyl of 1 or 2 nitro groups, trifluoroacetyl or camphorsulfonyl, and m represents 1 or 2, characterized by hydrogenating a compound of the general formula III