DE2217930C2 - Bicycloheptene derivatives and processes for their preparation - Google Patents

Description

a) a compound of the formula Xl
CH-OR ³

(XI)

where R ¹ and R ^{2 have} the meanings given above and R ^{1 is} an alkyl, alkanoyl, alkanesulfonyl or arylsulfonyl radical having up to 7 carbon atoms

b)

Use of an acid such as 2N hydrochloric acid from acid hydrolysis at about 85 ° C subject, so that the initially formed bicycloheptene-7-anti-carboxaldehyde of the formula

CHO

(XII)

R,

wherein R ¹ and R- have the meanings given above, is isomerized to the corresponding bicyclo-hepten-7-svn-carboxaldehyde or

that a compound of the formula XII, in which R 'and R ^{2 have} the meanings given above, in a solvent with an amine of the formula R ⁴ R ^ NH, in which R ⁴ and R ⁵ each represent an alkyl, aralkyl or aryl radical with up to 15 carbon atoms and R ^{5 can} also stand for hydrogen, converts.

5. The method according to claim 4, characterized in that the amine used is R ⁴ R ^ NH aniline, p-chlorani-Hn, p-toluidine or N-methylene aniline.

6. The method according to claim 4 or 5, characterized in that the amine R ⁴ R ¹ WII in the reaction mixture in an amount between 0.1 and 5.0 equivalents, preferably 0.5 to 2.0 equivalents, per I equivalent of the aldehyde of the formula XII is present.

7. The method according to claim 4 to 6, characterized in that the solvent is isopropanol or t-butanol is used.

The invention relates to bicyclohcptcndcrivatc and more particularly to bicyclo [2.2.1] -ncptcndcrivate, the valuable intermediates for the production of prostaglandins and prostaglandin-like compounds represent.

In a known synthesis of prostaglandins and prostaglandin-like compounds they take place first stages of synthesis as follows:

(a) Addition of cyclinpcntadicnyl-nairium to chlorinethylmethyl-uiher, where 5-methoxyniethyl-1,3-vyclopcntadicn I get which one then

(b) with 2-chloroacrylonitrile of the Diels-Alder reaction is subjected.

fcl Diis formed in this way (acyclic chloronitrile II becomes the corresponding acyclic ketone III hydrolyzed, which then

(d) is subjected to the Baeyer-Villigcr oxidation, whereby a bicyclic lactone IV is obtained.

(e) The lactone is saponified and iodized to obtain a rearranged [odolactone V which

M) then

(f) is acetylated. The acctoxylactone Vl formed in this way is then

(^) dcjodicrt. whereby the Melhoxymethyllactnn VII

realizes.
f> 5 (h) The methoxymelhyllactone VII is demetliylieri.

mn to produce the hydroxymethyllactone VIII.

which then
(i) is oxidized to the Aklehydlactone IX.

CH ₂ OCH ₃

aj) Na® + CH ₃ OCHjCl

α)

CH ₃ OCH, H

(III)

CH ₃ OCH ₂ H

CH ₃ OCH ₂ H

(IV)

Cl

CN

(Π) O

CH ₂ OCH ₃

HO

(V)

CH ₃ CO.O

(VII)

CH ₂ OCH ₃

CH ₃ CO-O (VI)

CH ₂ OCH ₃

ΓΗ, CO.O

(VIII)

CH, CO. O

(IX)

CHO

This known reaction sequence is used for the industrial production of prostaglandin and prostaglandin-like ones Connections unusable for various reasons. Three of the more important reasons are that following:

(1) S-methoxymethyl-IrS-cyclopentadiene (I) is subject a slight isomerization to 1-methoxymethyl-!, S-cyclopentadten, which for the purposes of Synthesis is worthless. This isomerization can be kept low by the fact that Reaction of cyclopentadienyl sodium with chloromethyl methyl ether at low temperatures of about -55 "C. Such a temperature is, however, for industrial production inexpedient and uneconomical.

(2) The Diels-Alder reaction gives a mixture of the bicyclic chloronitrile isomers of the formula II, and from an equal amount of other isomers, mainly S-chloro-S-cyano-1-methoxymethylbicyc! o [2,2,1] -hept-2-ene. The desired isomers of the formula II must be separated from the other isomers present, and by column chromatography, by preparative gas / liquid chromatography: or by distillation. In addition, the presence of isomers in the reaction product, soft are worthless for the purposes of synthesis, avoid the total yield of isomers of formula II Sodium cyclopentadienide decreased to approximately 25% (after purification by chromatography).

(3) The demethylation of the methoxymethyllactone of the formula VII requires the use of Boron tribromide, a reagent which due to its dangerous nature for technical Production is particularly unsuitable.

It has now been found that through the use of a new key intermediate the three disadvantages of the above method mentioned above; rens can be avoided because

(1) no possibility of isomerization of the starting material consists,

(2) since no! -Substituted ι in the Diels-Alder reaction Bicyclo [2,2,1] -heptene derivative is formed and

(3) Ha in the final stage, the protective group which is used to produce an aldehyde, such as the aldehyde Formula IX, must be removed easily at room temperature and normal pressure without the. Use of hazardous reagents can be removed.

The invention thus relates to bicycloheptene-7-syn-carboxaldehydes (syn means a substituent on the same side of the C-7 bridge as the double bond) the formula

HCO

(X)

where R ^{1 represents} chlorine or bromine and R ^{2 represents} a cyano or carboxamide radical, an alkoxycarbo-

nyl radical with up to 6 carbon atoms or one N-Alkylcarboxamidrest, where the Mkylrest I to Contains 6 carbon atoms.

It should be noted that the wavy lines in the above formula indicate that one of the groups Ri and R ^{3 is} in the exo configuration and the other of the groups is in the endo configuration, ie the formula represents a mixture of compounds which are isomeric at carbon atom 5. It should also be noted that the above formula and the following formulas represent racemates, which, however, can be separated to give a natural series prostaglandin precursor.

R ² is, for example, the methoxycarbonyl radical or the N-methyicarboxamide radical.

Preferred bicycloheptene ^ -syn-carboxaldehydes of the invention are those in which R ^{1 is} chlorine and R- is the cyano, carboxamide or methoxycarbonyl radical, namely chloro-Z-syn-formyibicyclo [2.2, l] -hept -2-en-5-carbonitrile, 5-chloro-7-synformylbicycio [2 ^, 1] -hept-2-en-5-carboxamide and 5-chloro-7-syn-formylbicyclo [2 " _/ l] -hept -2-en-5-carbonic acid methyl ester.

According to the invention there is also a process for the preparation of the bicycloheptene-7-syn-carboxaldehydes according to the invention proposed the formula X, which is characterized in that one

(a) a compound of the formula
CHOIR ³

(XI)

R.

wherein R ¹ and R ² have the above meanings angegebenea and R ³ is an alkyl, alkanoyl, alkanesulphonyl or arylsulphonyl having up to 7 carbon atoms, using an acid such as 2N hydrochloric acid to acid hydrolysis conveniently at about 85 ⁰ C , so that the initially formed bicycloheptene-anti-carboxaldehyde of the formula

CHO

(XH)

R ₁

in which R ¹ and R ^{2 have} the meanings given above, is isomerized to the corresponding bicycloheptene-7-syn-carboxaldehyde of the formula X without substantial decomposition; or that a compound of the formula XII, in which R ¹ and R ^{2 have} the meanings given above, in a solvent with an amine of the formula R ⁴ R ^ NH, in which R ¹ and R 'are each an alkyl, aralkyl - or aryl radical with up to 1? Are carbon atoms and R ^r · i'can also stand for hydrogen.

A suitable value for R ¹ is, for example, HtIIyI-, acetyl-, Meihansulfoinl- or toluene-p-sulfonylresl.

The hydrolysis of a compound of formula Xl. where R ^{1 stands} for the chlorine atom, R- for the cyano radical and R 'for the acetyl radical, takes place with 2N hydrochloric acid ( 1 part) in dioxane (4 parts) at approximately 81 (' while el wa A were.

The extent of isomerization of the compound of the formula XII to the bicycloheptene of the formula X can be monitored in an expedient manner by nuclear magnetic resonance spectroscopy by following the occurrence of signals at <) 9.50 and 9.57, which are based on the aldehyde proton of the aldehyde of the formula X. , which has the required stereochemistry at carbon atom 7.

It should be noted that the invention comprises process (b) in two variants, the reaction of the aldehyde with an amine yielding an aldehyde / / ~ \ rriin - / - AuOüKi, uCiSpiCiSWCisC C'iiiC SCnm'sCnO ΓΪ-ιλΟ which can be isolated and used as such in the isomerization reaction, or wherein an aldehyde / amine adduct is formed in situ and is not isolated.

Suitable amines R ¹ R ¹⁵ NH are, for example, aromatic primary and secondary amines, such as aniline. p-chloroaniline, p-toluidine and N-methylaniline.

A suitable solvent is, for example, an alkanol. such as methanol, ethanol, isopropanol or t-butanol, or a chlorinated aliphatic hydrocarbon, like methylene dichloride. It is advantageous to keep the pH of the reaction mixture below 6. preferably between 4 and 5. by adding an acid such as an alkanoic acid, e.g. to adjust.

The amine R ¹ R ⁵ NH can be used in the reaction in an amount between 0.1 and 5.0 equivalents per 1 equivalent of the aldehyde of the formula XII. Preferably, however, 0.5 to 2.0 equivalents are used per equivalent of the aldehyde. j

The reaction should be continued until the isomerization has largely ended, which can be determined by the appearance of a doublet signal between ό 9.50 and 9.60 in the nuclear magnetic resonance spectrum of the reaction product. This J signal has its origin in the aldehyde proton of the aldehyde of the formula X, which has the required syn stereochemistry at carbon atom 7. A typical response time is 16 to 21 hours.

The compounds of the formula XI, which as ί Starting material in the above process (a) can be used, si-.rd in turn new compounds. she can be prepared by using a fulvene derivative of the formula

Possess activities by the Nnliir of the residues R um! R- depend. I will be skilled chemist who knows this therefore don't try a non-reactive fulvene derivative to implement with a flour lekaiiven olefin.

ι but it will be a FiiKenderival and an olefin choose that with each other in moderate conditions respond within a reasonable time. So are 2-chloro-ryloy I-chloride. 2-bromoacrylo> l-chloricl and 2-ChloraiTylnitril the most reactive olefins and become

ι therefore preferred. Fulven b sulfonate and b Mei.howfiilven are not very stable and should therefore only be reacted with more reactive olefins.

The aldehydes of formula XII. as a starting material can be used in the above method (b)

• can are also new connections. They can be prepared by adding a compound of the formula Xl, in which R ¹ , R- 'and R ^{1 have} the meanings given above, for example by heating with a mineral acid such as hydrochloric acid.

> uiiC-f iiiii'tn »iMirtikmiMg mit, ilkuiiolnciiCMii ammonia, for example methanolic ammonia, hydrolyzed.

It should be noted that once the inventive concept of using a compound

Formation of the formula X in a synthesis of a prostaglandin or a prosiaglandin-like one Connection has been established. a skilled organic chemist can easily find the compound's formula X on ve. i different ways into the desired product can convert, known standard reactions of organic chemistry are used. Some exemplary reaction sequences in which such further processing can be achieved are now presented described below:

5-chloro-5-cyanbicyclo [2,2.l] -hept-2-en-7-carboxaldehyde of the formula X (R '= chlorine, R' = CN) is reacted with trimethyl orthoformate or with methanol and with concentrated hydrochloric acid, wherein the dimethylacetal of the formula XIVa (Y = (CH ₁ O) ₂ ) is obtained, which in the reaction with 1,2-xylene-AA-diol, the corresponding acetal of the formula XIVb

Y =

CH ₂ O-CH ₂ O-

; R "= p-phenylbenzoyl

CHOIR ³

results. The acetal of the formula XIVb is converted into the ketone with potassium hydroxide in dimethyl sulfoxide Hydrolyzed formula XVb, which is subjected to the Baeyer-Villiger oxidation with m-chloroperbenzoic acid is obtained, the lactone of formula XVIb being obtained. The lactone of formula XVIb is made with sodium hydroxide saponified and neutralized with acetic acid, and the product is treated with potassium iodide, whereby a Iodohydrin of formula XVIIb

(XIII)

with an olefin of the formula CH ₂ : CR'R ² , where R ¹ , R ² and R ^{3 have} the meanings given above.

It is pointed out that of course the various fulvene derivatives of the formula XIII have different reactivities, which ^{depend on the nature of the radical R 3} , and that in a similar manner olefins of the formula CH ₂ : CR ¹ R ^{2 are} different

γ ₌

α CH ₂ O-CH ₂ O-

R ⁶ = p-phenylbenzoyl

is obtained, which with p-phenylbenzoyl chloride is reacted to give the ester of formula XVIIIb

-CH ₂ O-

; R ⁶ = p-P'nenyibenzoyi

308 111/25

liemislellen. The Hster tier formula XVIIIb is reacted with tribiityl / inn-imbride, whereby chi ¹ · dcindierte I .iiclon the I ormel XIXb

> CHO--

; R 'p-i'henyihen / m!

K)

will echo. If this is hydrolyzed, go away! the Aceüilgnippicnin: ¹ whereby the aldehyde of the formula XX (R ^1- ■ p-l'lieinlbeti / oyl) is obtained. The aldehyde of the loniiel XX (K '- |) -l'henylben / oyl) becomes iliinn in dns Prostayliinclin I λ nberj-'efülirl, and / was on the same Wi'p. as he did for the I Ibcrfi'ihriintr des hckiinnicii \ ldeh \ dsdcr l'ormel XX (K '- ■ -acetyl) in l'rosiiigliiiulin l ^; .> \ is known.

V = -CH

X (K ¹ = Cl
R ¹ = CN)

Y - C Il

(XiV)

(XV)

= CH H

CH = Y (XVI)

CH = Y CH = Y

a) Y (CH ₁ O); -

η) V

C! LO

H, O -

R "- p-phenylhinoyl

CIIO

In a modification of this reaction sequence, the dimethyl acetal of the formula XIVa is hydrolyzed to give the To produce ketone of the formula XVa, which by the reaction sequence described above via the lactone of the formula XVIa, the | odhydrin of the formula XVIIa and the Ester of formula XVIIIa in the dejodieite lactone of Formula XIXa is transferred. The lactone of Formula XIXa is then selective in a two phase system hydrolyzed from chloroform and concentrated hydrochloric acid to remove the dimethyl acetal group, but the lactone remains intact, so that the aldehyde Formula XX is created.

The potassium triiodide can of course be replaced by other known halogenating agents, e.g. R. by chlorine. Bromine or the corresponding N-halosuccinimide in an aqueous reaction medium or a derivative of hypochlorous acid, e.g. B. sodium hypochlorite, in a known manner a halohydrin, which corresponds to the iodohydrins of the formula XVIII. which is obtained in the same way as the iodohydrins of formula XVII can be used. Similarly, when converting the Esters of the formula XVIIi in the deiodinated lactones of the formula XIX use other known reducing agents instead of tributyltin hydride can be used, e.g. B. Sodium borohydride or sodium cyanoborohydride (NaBHiCN) in dimethyl sulfoxide. Dimethylformamide. Sulfolane or hexamethylphosphoramide. or Raney-Nickei.

Another reaction sequence begins with 7-acetoxymethylene-5-chlorobicyclo [2.2,1] -hept-2-en-5-carbonyl chloride (Xl, R ¹ = chlorine. R ² = chloroformyl. R '= acetoxy). which with a methanolic amine. z. B. methanolic ammonia, is treated, followed by an acid treatment to the anti-aldehyde of the formula XII (R '= chlorine, RJ = -CONH.) Via the primary amide of the formula Xl (R' = chlorine. R ² = -CONH ₂ ). This anti-aldehyde is converted into the ketone of the formula XVa by the process described above for the corresponding cyanaldehyde, specifically via the syn-aldehyde and its dimethyl acetal.

Another reaction sequence begins with the 7-acetoxymethylene-5-ehlorbicyclc {2,2J] -hept-2-en-5-carboxylic acid methyl ester (X I. R ^ = chlorine. R ^: = methoxycarbonyl, R ³ = acetoxy ), which is hydrolyzed to the anti-aldehyde of the formula XII (R '= chlorine. R-' = methoxycarbonyl) by methods similar to those described above, which is then hydrolyzed to the corresponding syn-aldehyde X (R ¹ = chlorine. R - = Methoxycarbonyl) is isomerized.

This syn-aldehyde is converted into its dimethylacetal, and the metho \ ycarbony! Group becomes converted by treatment with ammonia into da «, amide, which as above / around ketone of the formula XVa is hydrolyzed.

The invention is illustrated in more detail by the following examples.

Example I.

a) 25.8 g (0.1b mol) of 7-ace (oxymethylene-5-chlorobicycrlo [2.2.1) -hcpt-2-cn-5-carboxylic acid nitrile (Xl. R ^: = chlorine. R- '= cyano, R ¹ = Acetyl) were dissolved in 3M) ml of dioxane (which had been passed through basic aluminum oxide of the type "0" for purification and then flushed with argon), and 80 ml (0.16 mol) of 2 II hydrochloric acid (which had been washed with argon before use rinsed) were added to give a pale yellow solution. The solution was purged with argon for a further JO min and then heated in an oil bath for 4 days under an argon atmosphere in such a way that an internal temperature of 85 + JC was maintained. The dioxane was evaporated under reduced pressure and the remaining liquid made basic with saturated aqueous sodium bicarbonate solution. 200 ml of water and 120 ml of methylene chloride were then added and the suspension obtained was filtered through kieselguhr. The organic layer was separated and the remaining aqueous solution was extracted four times with 50 ml of methylene chloride each time. The organic layers were combined and dried and the solvent was evaporated under reduced pressure. The residue was dried in a high vacuum, giving α-chloro-7 · syn-formylbicyclo [2.2, l] -hept-2-en-5-carboxylic acid nitrile (X, R '= chlorine, Ri = cyano) as a brown oil became. _{The aldehyde mixture showed two spots R F} = 0.2 and OJ on thin layer chromatography on 0.25 mm Merck silica gel plates when methylene chloride was used as the eluent. The spots were developed by spraying cerium (IV) sulfate onto the plates and then heating the plates. The nuclear magnetic resonance spectrum of the mixed aldehydes in deuterochloroform showed the following values ((5 values):

1.79 and 2.26, IH, doublets, J = HHz,

endo hydrogen on carbon atom 6,

2.48 and 2.84, in, double doubles, j = i4 and 6Hz,

■■ «! • Wii. "Crstoif at carbon atom 6.

2.8) and 3.07. 1 H.:Single! t. hydrogen on carbon atom 7.

3.42. 111th broad singlet.

UriKcnkupf Hydrogen.

3.66 and 3.80.111. wide singlet.

Hr tick en head water toff,

b.O- 6.6. 211, complex multiple! Ts.

olefinic hydrogens,

9.50 and 9.57. 111. Doublets. I = III /.

Hydrogen Hydrogen.

The original material used in the above procedure Bcoligtc carboxylic acid nitrile of the formula Xl was manufactured as follows:

61 g (0.45 mol) of crude Λ-Acctoxyfulvcn (XIII. R '= acetyl) were in 450 ml of benzene which had been dried over 4 molecular sieves. dissolved, and 235 g (2.68 mol) of freshly distilled 2-chloroacrylonitrile and 2 *) 0 ml of hydroquinone were added. The solution obtained was refluxed for 2 hours in an agitator. The solvent was evaporated under reduced pressure to give a dark brown oil which was purified by passing it through a column of M.igncsilimilica gel (1 kg) using methylene chloride as the solvent. Ls became 7-acel-

oxy-methylene-5-chlorobicyclo [2,2,1] -hcpt-2-cn-5-carboxylic acid nitrile Preserved as a pale yellow oil, weld.ι ι iiei Thin-layer chromatography on Me rck silica gel plates Using v -.- n methylene chloride as the eluent resulted in a Ri = 0.4. The magnetic one Nuclear resonance spectrum of the product in deuterochloroform showed the following characteristics (n-valuec):

1.7 to 2.9, 2H, complex. Protons on carbon atom 6,

2.08 and 2.09.3H. complex. Methyl protons. 3.3 to 4.2.2H. complex. Bridgehead protons. 6.1 to 6.7.2H, complex, olefinic ring protons,

6.81 and 6.82, IH. complex, olefinic Acetoxymethylene protons.

The 5-chloro-syn-formylbicyclo [2,2,1] -hept-2-en-5-carboxylic acid nitrile obtained according to Example 1 a) was converted into the known prostaglandin intermediate of the formula XX (R ^b = p- Phenylbenzoyl) converted:

A) 15 g (0.08 mol) of 5-chloro-7-syn-formylbicyclo [2.2.1] -hcpt-2-en-5-carboxylic acid; .itri! (X, R '= chlorine,

R ^: = cyan). 26 g (0.25 mol) of trimethyl orthoformate and 710 mg (4 millimoles) of toluene-p-sulfonic acid were dissolved in 500 ml of methanol, and the solution was refluxed for 20 hours. The solvents were evaporated under reduced pressure and the remaining oil dried under high vacuum using an oil pump to give a mixture of epimeric dimethylacetals.

The crude dimethylacetal mixture was dried in 550 ml of benzene (which was dried over 4A molecular sieves had been resolved. Then 11 g (0.08 mol) 1,2-xylene- * A'-diol and 560 mg of toluene-p-sulfonic acid admitted. The solution was heated for 13 hours, whereby Benzene slowly evaporated and the volume increased by adding more dried benzene was maintained. The solution was cooled, washed with 100 ml of saturated aqueous sodium bicarbonate solution

washed and dried and this oil solution minel removed under reduced pressure. The residue was determined by chromatography over magnesium silica (42Og) using methylene chloride as! • '!. !! c'riiiiHel fiereirv; "« cIai dii'i', .2-XvIoI v \ '- diylacel, ii tic ι I ormcl XIVb

/\-αι.o-l

^v ■ L Cc ,,.

,O-

; \ ls pale gray clbcr F-cstsloff was obtained. On Merck silica gel plates he showed at Dünnschk-hlchromatographic using methylene chloride as the fluidizing agent a Ri = 0.3. The magnetic resonance space of the mixed acetals of I'ormcl XIVb

^Y ■ (XcZ '

in deuterochloroform had the following characteristics ((VWcrtc):

1.6 to 2.8,311. multiple signals. C-6 and C "^ hydrogens.
3.10. 111, broad singl. C-1 hydrogen, 3.36 and 3.50. IH. broad singletis, in C-4 hydrogen,

4.6 to S.O.SH.Mulliplett.

CH-O -

r. /

6.0 to 6.5. 211. Multiple, olefinic. 7,14.4 H. Singlet. aromatic.

19.4 g (0.06 mol) of the acetal of the formula XIVb

4 <i, in 100 ml of dimethyl sulfoxide (obtained by distillation purified over calcium hydride and stored over molecular sieves), and the solution was purged with argon for 4 hours. At the same time, a solution of 13 g of potassium hydroxide in 10 ml of water heated to 50C and flushed with argon for 4 hours. The potassium hydroxide solution then became the stirring Given a solution of the acetal and the mixture was stirred at room temperature for 20 hours under argon, meanwhile a white solid separated out. The reaction mixture was dissolved in 500 ml of 1N hydrochloric acid poured and the mixture extracted four times with 200 ml of methylene chloride each time. The united organic Layers were dried and the solvent was evaporated under reduced pressure, wherein the ketone of the formula XVb

γ ₌

CH ₂ O-CH, O

as a white solid. With thin layer chromatography on Merck silica gel plates and using ethyl acetate / methylene chloride (3:97) an R | .- = 0.25 was obtained as the eluant. The nuclear magnetic resonance spectrum of the ketone the Formula XVb in deuterochloroform showed the following characteristics (o-values):

1.99.2H ₁ SiHgIeIi + doublen, -CH. CO-.
2.48.1H, doublen, J = 81 Iz, C-7 hydrogen.
3.12 and 3.72.2H, multiplets,
Bridgehead hydrogens,
4.7 to 5.0.5H, multiples,

CH-O-

6.0 and 6.5.2H, multiplets, olefinic,
7.15.4H, singlet. aromatic.

14.6 g (57 millimoles) of the ketone of the formula XVb were dissolved in 250 ml of methylene chloride (which had been purified by stirring over anhydrous bicarbonate). Then 935 grams (114 millimoles) of anhydrous sodium bicarbonate was added, followed by the addition of 12.5 grams (68 millimoles) of m-chloroperbenzoic acid. The mixture was then stirred at room temperature for 20 hours. The reaction mixture was diluted with 750 ml of diethylene chloride and washed successively with 50 ml of saturated sodium sulfite solution and twice with 50 ml of saturated sodium bicarbonate solution each time. The separated organic solution was dried and the solvent evaporated to give the lactone of formula XVIb as a white solid. In thin-layer chromatography it showed 8 ¹ Jf Merck silica gel plates using ether / benzene (1: 3) as the eluent and an R _F = 0.25.

The nuclear magnetic resonance spectrum of the lactone of the formula XVIb

in deuterochloroform showed the following characteristics (O values):

2,48,1H, doublet, J = 8Hz, C-7 hydrogen,
2,4-2,9,2H ₁ MULTIPLEIT, -CH ₂ CO-,
3.0. IH ₁ wide singlet,
Bridgehead hydrogen near C.

- O

- O —CH-

O-,

added to the stirred reaction mixture in order to destroy the excess iodine. The suspension obtained was filtered off and the solid was washed three times with 50 ml of water and finally three times with 25 ml of acetone washed. The solid was then dried in vacuo, the iodohydrin of the formula XVIIb

4,80.4H ₁ SiHgIeIT ₁ -CH ₂ ■
5,07,1H ₁ wide singlet,
Bridgehead hydrogen near C,
6.2-6.5.2H, multiple, olefinic.
7.2.4H. Singlet, aromatic.

14.6 g (54 millimoles) of the lactone of Formula XVIb were dissolved in 153 ml of dioxane; then a solution of 6.5 g (162 millimoles) of sodium hydroxide in 68 ml of water were added at room temperature with stirring. Stirring was continued for 6 hours, whereupon acetic acid was added to bring the solution to approximately pH 7.5. Eventually became a Solution of 40.8 g (161 millimoles) iodine and 82 g (48J Millimoles) Kaliiimjodid in 181 ml water added, whereupon the mixture is 21 hours at room temperature geriilirl became. Then solid sodium sulfite became

as a white solid. Thin layer chromatography on Merck silica gel plates using of methanol / benzene (5:95) as the eluent gave an Rp = 0.4.

The nuclear magnetic resonance spectrum of the iodohydrin of the formula XVIIb in ds-pyridine showed the the following characteristics (ό values):

2,4,1H, multiple, C-4 hydrogen,

2.73.2H, doubles. J = 8Hz, C-3 hydrogens.

3.03.1H. Multiple, C-3a hydrogen.

3,53,1H, singlet, hydroxy,

4.42.2H, multiples, C-5 and C-6 hydrogens,

4,82,4H. Multiple, -CH ₂ · O-,

5,08,1H ₁ multiple, C-6a hydrogen,

530, IH, doubles, J = 4Hz.

- O

- O

O —CH-

7.13.1H ₁ singlet, aromatic.

16.3 g (39 millimoles) of the iodohydrin of formula XVIIb were in 60 ml of pyridine. that had been dried over potassium hydroxide cookies. solved; then 9.7 g (44 millimoles) p-phenylbenzoyl chloride added, and finally the solution was heated to 50 ° C. under argon for 27 hours. The solution was at room temperature cooled down. 0.2 ml of water was added and the mixture was stirred at room temperature for 30 minutes. The pyridine was evaporated under reduced pressure and the residue in 500 ml of methylene chloride solved. This solution was successively three times with 100 ml of 2η-hydrochloric acid each time, three times with each time 100 ml of saturated sodium bicarbonate solution and 100 ml Water washed. The organic layer was dried and the solvent evaporated, with a white solid was obtained which crystallized from a mixture of methyl chloride and ether was, wherein the p-Phcnylbenzoat-ester of the formula XVIIIb

γ ₌

α CH ₁ O-CH ₁ O-

p-phenylbenzoyl

as a white solid. Diinnseliichtcliromatographic on Mcrck silica gel plates for use of methylene chloride as l-fluoride gave a R, = 0.2.

The magnetic core reservoir.iiM / spectrum of the p-l'he-

.10R 111 ? 'J

Nylbenzoate ester of the formula XVIlIb in deuterochloroform showed the following characteristics (O values):

2,42,1H, multiple », C-3a-hydrogen,

2,72,2H, singlet + double «, C-3 hydrogens,

3,25,1H, multiple, C-4 hydrogen,

4,41,1H, double doublet, J = 3 and 5 Hz,

C-6 hydrogen,

4,7-4,9,4H, multiple, -CH ₂ -O-,

5,1,2H, multiple, C-öa-hydrogen,

5,73.1H, triplet, J = 5Hz, C-5 hydrogen,

7.0-8.1.13H, multiple, aromatic.

A mixture of 14.0 g (24 millimoles) of the p-phenylbenzoate ester of the formula XVIiIb in 500 ml of benzene (dried over 4A molecular sieves) was refluxed until dissolution was complete. The refluxing solution was flushed with argon for 30 minutes; then a solution of 8.6 g (29 millimoles) of tri-n-butyltin hydride in 10 ml of benzene was added. The reaction mixture was refluxed for 20 hours and cooled to room temperature. Then the benzene was evaporated under reduced pressure. The solid obtained was triturated three times with 50 ml of n-pentane and crystallized from a mixture of methylene chloride and ether, the deiodinated ester of the formula XIXb (R ⁶ = p-phenylbenzoyl) being a white crystalline solid with a melting point of 188 to 189 ° C was obtained. Thin layer chromatography on Merck silica gel plates using a mixture of ethyl acetate and pentane (I: I) as the eluent gave an Rf = 03-

The nuclear magnetic resonance spectrum of the deiodicrte Esters of the formula XIXb in deuterochloroform showed the following characteristics (ό values):

2.3 - 3.2.6H, complex. C-3-. -3a-, -4- and
-6 hydrogens.

4.86.4H. Multiple, -CH ₂ O-,
5.05.2H, multiples. C-6a- and

1.9-3.5.6H, complex, C-3-, -3a-, -4- and

-6 hydrogens,

5,15,1H, triplet, I = 6Hz, C-6a-hydrogen,

5,79,1H, multiple », C-5 hydrogen,

7.3 - 8.2.9H, multiple, aromatic,

9.84.1H, singlet, aldehyde.

The aldehyde of Formula XX was identical in all respects to a sample obtained by a known Procedure had been established.

B) 45.5 g of S-chloro ^ -syn-dimethoxymethylbicyclo [2 ^, l] -hept-2-en-5-carboxylic acid nitrile of the formula XIVa (Y = (CHiO) ₃ ) were in 450 ml of ethanol, the 50 mi Dimethyl sulfoxide (which had been dried over 4A molecular sieves) was dissolved, 16.8 g sodium hydroxide was added, and the solution was refluxed in an inert atmosphere for 20 hours. The solution was then cooled, with 50. » Diluted i-nl of water and extracted four times with 250 ml of methylene dichloride each time. The combined extracts were washed four times with 500 ml of water and dried, and the solvent was removed under reduced pressure. An oil was obtained which, on crystallization from pentane, gave the ketone of the formula XVa (Y = (CHjO)>), melting point 45 ° C., R _F = 0.4 (5% ethyl acetate in methylene dichloride). The nuclear magnetic resonance spectrum of the ketone of the formula XVa in dcuterochloroform gave the following characteristic features (δ values):

1.96, 2H,

2.52, IH,

3.00, IH,

3.10. IH,

3.24.3H,

3.30. 3 H,

4.38, IH,

5.98, IH,

6.44, IH,

Multiple, —CH ₂ -CO -

Doublet, C-7 proton

Multiples)

Multiple I

Singlet)

Singlet I.

Doublet, (COjO) ₂ - OH-

Multiples

C-I and C-4 protons, methoxy,

Multiple I

olefinic protons.

- O - CH Hydrogen

5.50.1H. Multiplctl.CS hydrogen,
7.1 -8.1.13H. Multiple, aromatic.

142 mg of the deiodinated ester of the formula XIXb were suspended in 30 ml of methanol, which is a Drops of concentrated perchloric acid contained. Then 67 mg of palladium oxide was added, followed by the suspension was shaken in a hydrogen atmosphere for 24 hours. The reaction mixture was diluted with 100 ml of methyl chloride and filtered through kieselguhr. The filtrate was 10 ml saturated sodium bicarbonate solution, the organic layer was separated and dried, and the solvent was evaporated. The residue was purified by chromatography, whereby the Udehvc! the form! XX (R * - ρ phenylbene / ny!) was echoed. Thin layer chromatography on Mcrck silica gel plates using a for A mixture of ethyl acetate and methyl chloride (I 1) as the inner mixture gave a Ki = 0.5.

The core magnetic resonance spectrum of the aide hvds of the formula XX m Deutcrochloroform showed the following features (iVWcrtr):

IHg of the ketone of formula XVa were dissolved in 550 ml of ether. 39.7 ml of IO% aqueous sodium hydroxide was added, and the mixture was stirred and cooled to 0 ⁰ C. Then, 186 ml of hydrogen peroxide (27% (w / v) solution) was added dropwise to the stirred mixture was added, keeping the temperature thereof at 1O ⁰ C. After the addition had ended, the mixture was stirred for 3 hours, the ether layer was separated off and the aqueous layer was extracted twice with 100 ml of ether each time. The aqueous layer was adjusted to pH 7.4 with glacial acetic acid and cooled to 0 ° C. Then a solution of 887 g of potassium iodide and 451 g of iodine in 1758 ml of water was added. The mixture was stirred at O'C for 20 hours. The excess iodine was then replaced by the addition of solid sodium sulfite. The aqueous suspension was heated four times with 500 ml of methylene chloride each time. The combined organic extracts were dried, and the oil solution was evaporated off under reduced pressure, the odhvdrin of the formula XVIIa (Y - (CI I, O).,) being obtained as an oil. K ₍ = 0.Ϊ ( ^r >% Alhylaietal in methylene dichloride). Has nuclear magnetic resonance spectrum in deutcrochloroform showed the following characteristic features (Λ values):

3,39,6H, singlet, methoxy,
4,0,2H, multiple, C-5 and C-6 protons,
4.40,1H, doublet !, (CHjO) ₂ CH -,
4,96,1H, multiple, C-Ba proton.

The procedure described in the last part of procedure A) was repeated, wherein instead of the iodohydrin of the formula XVUb, the iodohydrin of the formula XVIIa was used. It became the receive the following intermediates:

Esters of formula XVIIIa (Y = (CH ₁ O) ₂ ;
R ⁶ = p-phenylbenzoyl), m.p. 139-14TC,
R _F = 0.6 (15% methanol in benzene).

The nuclear magnetic resonance spectrum in deuterochloroform showed the following characteristic features (6 values):

3.30 and 3.32.6H, singlets, methoxy,

4,41,1H ₁ square, C-6 proton,

4, bl, 1H, doubles, (CH jOfcCH -,

5.10, IH, quartet, C-63 proton,

5,62,1H ₁ triplet, C-5 proton,

7.4-8,1,9H, multiple, aromatic protons;

deiodinated ester of the formula XlXa (Y = (CH ₁ O) ₂ ;

R ⁶ = p-phenylbenzoyl),

Mp 114 to 116 ° C.

Rf = 03 (50% ethyl acetate in pentane).

The magnetic nuclear resonance spectrum in deuterochloroform showed the following characteristic features (d-values):

338 and 3.41, 6H ₁ singlet, methoxy,

434.1H ₁ DOUBIEIT ₁ (CHiO) ₂ CH-,

5,04,1H, multiple, C-6a proton,

5,42,1H, multiple, C-5 proton,

7.4-8.1.9H, multiple, aromatic protons.

393 g of the deiodinated ester of the formula XIXa were dissolved in 1980 ml of chloroform which contained 2% by volume of isopropanol. Then 495 ml of concentrated hydrochloric acid were added, and the resulting two-phase system was _{stirred at room temperature for 1/2} hour. The chloroform layer was then separated and the aqueous layer was extracted with 50 ml of chloroform twice. The combined extracts were washed with 200 ml of saturated sodium bicarbonate solution and the organic solvent was evaporated under reduced pressure in the presence of 50 ml of sodium bicarbonate solution. The suspension obtained was then extracted three times with 50 ml of ethyl acetate each time, the combined extracts were dried and the solvent was evaporated off under reduced pressure until crystallization began. When the crystallization had ended, the product was filtered and dried. 2,3,3-txβ, b <xβ- Tetrahydro-5 "- (p-phenylbenzoyloxy) -2-oxocyclopentcnofbj-fiiran ^ -carboxaldehyde of the formula XX (R ⁶ = ρ Phcnylbcn / oyl), obtained in was identical in every respect to a sample. which had been produced by a known method

Example 2

b) I 16.7 g of 5-Chli> r-5-cyanbicyclo [2.2, IJ-hepl-2-en-7-anti-cirboxaldehyde and 98.2 g of p-chloroaniline were in

116 ml of glacial acetic acid and 950 ml of isopropanol dissolved and the The solution was stirred for 20 hours at room temperature under a nitrogen atmosphere. The solvents were evaporated, 500 ml 2 η-hydrochloric acid were to. Residue was added and the mixture was once extracted with 400 ml and once with 200 ml of methylene dichloride. The combined extracts were sequential with 250 ml of 2 η-hydrochloric acid until it is acid free with aqueous sodium bicarbonate solution and two in washed times with 300 ml of water each time and dried over magnesium sulfate. The solvent was evaporated to give a viscous oil which to more than 90% from 5-chloro-7-syn-formyl-bicyclof2,2,1] -hept-2-en-5-carboxonitrile existed which: ■ cl »it was used without further purification.

Example 3

b) Using the procedure of Example

2b), but the p-chloroaniline by 0.5 equivalents

- ■ · te p-toluidine was replaced and a reaction time of Was maintained for 18 hours, a 90% isomerization of the anti-aldehyde was achieved.

Example 4

b) The procedure of Example 2b) was repeated, but the glacial acetic acid was omitted and the amines and solvents given below were used. It became the get the following results:

2.0 equivalents of N-methylaniline in methanol for 18 hours; it became a 40% isomerization

obtain;
2.0 equivalents of N-methylaniline in ethanol for 18 hours; it became a 65% isomerization

obtain;
1.2 equivalents of aniline in isopropanol for 16 hours; it became a 75% isomerization

obtain;
2.0 equivalents of aniline in methane! for 16 hours; there was an 88% isomerization

obtain;
2.0 equivalents of aniline in t-butanol for 20 hours; greater than 90% isomerization was obtained.

Example 5

b) A 5% solution of 5-chloro-7-anti-formylbicyclo [2.2.l] -hept-2-en-5-carboxamide (XII, R '= chlorine,

"■ · ■■ R ² CONH ₂ ) in methylene dichloride, which 1.5

Containing equivalents of p-chloroaniline, the mixture was stirred overnight, washed twice with 3η hydrochloric acid and filtered. The solvent was then evaporated. The residue was dissolved in ethyl acetate and the

"Solution passed through silica gel in order to to remove low Rp impurities. Evaporation of the solvent gave S-chloro-Z-syn-formylbicyclo [2.2, l] -hept-2-en-5-carboxamide (X,

R '= chlorine, R ² = -CONH ₂ ). The magnetic core rc

■■ "sonance spectrum in deuterochloroform showed a Doublctl at O * = 9.6 (J = ZH?), Which is characteristic for the 7-syn-formyl group is ;.

The 5-chloro-7-anti-formylbicyclo [2.2.I J-hepi-2 en-Vcarbonsäurcamid was obtained as follows:

Z-Aceioxymethylene-Vchlorbicyclo ^ ZlJ-hepi ^ -en · 5-carbonyl chloride (Xl. R '= C.'hlor, R · = chloroformyl. R '= acetoxy) was / u an excess of with

Ammonia was added to saturated methanol. After ¹ 1/2 hour, the resulting solution was acidified with 3N hydrochloric acid and extracted with methylene dichloride. The extract was evaporated to dryness, the residue was dissolved in a small volume of methylene dichloride and the solution was stirred vigorously with 3N hydrochloric acid for 2 hours. The organic phase was separated, filtered and evaporated to dryness, with crude S-chlorine ^ -anti-for-

mylbicyclo [2,2,1] -hept-2-en-5-carboxamide,
Rf = 0.52 (ethy acetate / silica gel). The nuclear magnetic resonance spectrum in Deulerochloroform showed a singlet at ό = 9.7, which is characteristic of the 7-anti-Formy! Group.

The 7-acetoxymethylene-5-chlorobicyclo [2,2, I] -hept-2-en-5-carbenzylchio- rid is obtained as follows:

2.75 g of 2-chloroacryloyl chloride became a solution of 2.72 g of a-acetoxyfulvene in 10 ml of cyclohexane, and the mixture was 4 hours at Room temperature stirred. The reaction mixture was filtered and the solvent evaporated, whereby 7-Acctoxymethy! En-5-ch! Orbicyclo [2,2,1] -hept-2-en-5-carbonyl chloride which oMe further purification was used in the process described in second part of Example 5 is described. The nuclear magnetic resonance spectrum in deuterochloroform showed the following characteristic features (o-values):

2.07 and 2.10.3H, singlet, methyl 3υ

(2 isomers at C-5),

6.1-6.7.2H, multiple, olefinic

Ring protons,

6,67,1H, singlet, olefinic

Acetoxymethylene proton.

Similarly, using methyl 2-chloroacrylate instead of 2-chloroacryloyl chloride the 7-acetoxymethylene-5-chlorobicyclo [2,2,1] -hept-2-en-5-carboxylic acid methyl ester obtain. The nuclear magnetic resonance spectrum in carbon tetrachloride showed characteristic bands similar to the spectrum of the one described above Acid chloride, with an additional 3H singlet at 0 = 3.69 and 3.72 due to the ester methyl group (Isomers at carbon atom 5) was present.

Example 6

The procedure of Example 5 was repeated using 5-chloro-7-anti-formylbicyclo [2,2,1] -hept-2-en-5-

-to

methyl carboxylate (X, R '= chlorine, R ² = metboxycarbonyl) was used instead of 5-chloro-7-anti-formylbicyelo [2,2, l] -hept-2-en-5-carboxylic acid nitrile. The 5-chloro-7-syn-formylbicyc! O [2,2,1] -hept-2-en-5-carboxylic acid methyl ester (X, R ¹ = chlorine, R ² = methoxycarbonyl) was obtained,> w = 1745 cm - '(film methyl ester). The nuclear magnetic resonance spectrum in deuterochloroform shows characteristic bands which were similar to those of the corresponding nitrile from Example 1. There was also an additional 3H singlet at δ = 7.73 due to the ester methyl group.

The 5-chloro-7-antiformylbicyclo ^ Älj-hept ^ -en-S-carboxylic acid methyl ester used as the starting material could be obtained by the method described in the last part of Example 5, using 7-acetoxymethylene-5-chlorobicyclo [2.2, l] -hept-2-en-5-carbon- methyl acid ester instead of 7-acetoxymethylene-5-chlorobicyclo [2.2, l] -hept-2-en-5-carbonyl chloride was used.

Example 7

The procedure described in the first paragraph of procedure A) of Example 1 was repeated, using 5-chloro-7-syn-formylbicyclo [2 ^, 1] -hept-2-en-5-carboxamide instead of 5-chloro-7- syn-formylbicyclo [I _r 2, t] -hept-2-en-5-carboxylic acid nitrile was used. 5-chloro-7-syn- (dimethoxymethyl) -bicyclo [2,2,1] -hept-2-en-5-carboxamide was obtained. The nuclear magnetic resonance spectrum in deuterochloroform showed additional characteristic bands at

3.2-3.38, 6H, 2 methoxy, _/

4.88, IH, (CH ₃ O) ₂ CH-CH (J = 9Ha)

Example 8

5-chloro-7-syn- (dimethoxymethyl) -bicyclo [2 ^, 1] -hept-2-pn-5-carboxamide was by that described in the first part of procedure B) of Example 1 Process hydrolyzed to give 7-syn-dimethoxy-methylbicyclo [2,2,1] -hept-2-en-5-one (XVa) was obtained which is identical to the product prepared in Example IB) was.

The 5-chloro-7-syn- (dimethoxymethyl) -bicyclo [2,2,1] -hept-2-eri-5-carboxylic acid methyl ester was similarly converted to the ketone of formula XVa.

Claims (4)

Patent claims: 1. Bicyclohepten ^ -syn-carboxaldehyde of general formula HCO R ₃ where R ^{1 stands} for chlorine or bromine and R ^{2 stands} for a cyano or carbamoyl radical, an alkoxycarbonyl radical with up to 6 carbon atoms or an alkylcarbamoyl radical in which the alkyl radical contains 1 to 6 carbon atoms. 2. 5-Chloro-7-syn-formylbicyclo [2,2.1] -hept-2-en-5-carboxylic acids! iril. 3. 5-Chior-7-syii-ionriyibicycio [2.2,!] - hcp! -2-en-5-carboxamide. 4,5-Chloro-7-syn-formylbicyclo [2.2.1] -hept-2-cn-5-carboxylic acid methyl ester. 4. Process for the preparation of Bicyclohcpten-7-syn-carbaldehyde according to claim 1 to 3, characterized in that one