DE2217930A1 - Bicycloheptene derivatives - Google Patents

Description

PATENT LAWYERS
DR.-INQ. H. FINCKE DI PL.-ING. H. BOHR DIPL.-ING. S. STAEGER

Telephone: »26 60 00

S MUNICH 5, Müllerslraße 31

1 3 APR 1972

Imperial Chemical Industries Ltd-Loä & on-Gro Rbx-.itaaaios

B: i.cyclab.ep'i; other derivatives

Deeds: 13 April 1971 and 16, Deaeinber 197Ί Qr ο ßbrit aimi en

ö Hj'f Induug looks at bicyclohapten derivatives uad ebeκοΛχ! are on 3iajeloj ^ 2,2 _: 'Uheptenderivate, which values' ο v>n.3ch;3npr-.dy.ktfe; .Cür you Hsrstalluns of prostaslandins .>! ■ yiosta ^ landin - äliüliche: ü represent connections.

2098Λ3 / 1Ί92

In exaev known synthesis of I> rcatiigl & 7i.ü.:. T: $ v uud prosfcaglar .lin-ii'ialichen Ter'bi.r.-dimgan full, the first stages of the synthesis : iie .follows:
(a> Addition of Cy ^ lopeivbadisnyl-sodium to Oklor-oiaethyl-Hi3thyl ~ ä't; hear _:. where 5-M8fch.xi7metb.yl ~ i. ^ cyclopentadiene I.

is obtained, which then
Ob) with 2-Giiloroaorjdonitril der Dieis-Alder-Hsaktion urxtsr-

v / orfan becomes,
(c) That in this way gebildäia bicjcliscuo Cnlororätril II will see 3üm corresponding 'bj, c; / cli ifaton III h; rdroli-

sierfc, which one in it
(el) d.ar Baeyer-Villiger oxidation. is subjected, whereby si frill bicyclischsss lactone IY is obtained *

(0) Las Lacton w5: d ve.t'ßei.ft and, jcdiex't, where sin rearranged iodolactor. V is obtained, which then

(f) is acetylated. The AceboxylactoQ formed on these catfish VI will then

(g) iodized, whereby the ifethoxymethyllactone VII is formed, (h) The Methoxymethjllacton VII is demethylated to the Hydroxyraethyllacton VIII to produce, which daan

(1) Sum aldehyde lactone IX is oxidized.

BAD ORIGINAL 209843/1192

CH ₃ OCH ₂ Cl

CH OCH ₂

CH ₃ OCH ^ Jl

III

CH ₃ OCH

II

IV

Hd

\ ι

( r
1 ) CH ₂ OCH '-Os 192 ^ CH ₂ OCH CH, CO. 1
O I.
/ j CH, CO.O VI • S. 3
O < K Λ \ VIII \ t
\ I 1 "CHO y ₂ OH CH, CO J. I.
I. 3 CH, CO.O A, j
IX 2 09843/1 VII I.

This well-known reaction vessel is for industrial production of prostaglandins and prostaglandin-like ones Connections unusable for various reasons * Three of the more important reasons are as follows:

(1) ^ -Methoxymethyl-i ^ -cyclopentadiene I is subject to slight isomerization ζυ. 1 ~ Ifethoxyinethyl-1 ^ -cyclopentadiene, which is worthless for the purpose of synthesis. ! This isomerization ran be kept low "that the reaction of cyclopentadienylsodium with chloromethyl-methyl-ether at low temperatures of about - 55 ⁰ C executes. However, such a temperature is unsuitable and uneconomical for industrial production.

(2) The Diels-Alder reaction gives a mixture of the bicyclic chloronitrile isomers II and an equal amount of other isomers, mainly 5-chloro-5-cyano-i-methoxymeth / lbicyclo (2 _t 2,1Jhept-2-ene. The desired isomers II must be separated from the other isomers present, namely by column chromatography, by preparative gas / liquid chromatography or by distillation. In addition, the presence of isomers in the reaction product, which are worthless for the purpose of the synthesis, the overall result of isomers II from sodium cyclopentadienide decreased to about 25% (after purification by chromatography).

(3) Demethylation of the Methox / methyllactons VII requires the use of boron tribromide, a reagent _t which its dangerous nature is due particularly unsuitable for industrial production Diss.

209843/1 1 92

) ώί ντί, τΊίΐ .irarikiaehii? ä © .fTHidaB _: that through dia Fervendimg something new! Sc * ilüssöi: 'r; ji £' Ciiesprodmrb3 the drai above-mentioned disadvantage of the ofci ^ en method vex-miedsa be kdzmen,

(1) J & sine- possibility of isomerization of the starting material

(2) ca in the Dis-ls-A3.aer ~ Hsal £ tioa no 1 «- Bicjclof2 _? 2.'ijli.ep1; en = »d®ri" / at formed mrd »imd

(3) cia in the final stage the Schutsgrouppe, weleh © smr manufacture unequal Aldehjäs as d © s Aldahyds Il © stremt verdöB must ί easily with Eaumtomperatiaa? iand Raiamdr-iaek ' o ^ e the Verwsndiiag removed from dangerous heag @ ati © n warders kami *

So according to the Sr-fifödiiBS sin Bicycloh3pt © s-7-S3raiyd the formula

proposed, in which H stands for a halogen atom, radical R stands for Äixi cyano or gax'bamorjrlicadikal ₄ sin alkoxycarboayl-3'udikal with up to 6 carbon atoms or an H-Alky.1-carbamoyl: -? adii: al, where the alkyl radical Ί is up to 6 Kohl'asioaKv e »i'o; holdsj.

: .v, y.a - ^^ döufest einan Sübati biientsn en der salb © ». page α <;; ϊ, 'C-7-Eeü <; ico vjis the .Οοχίρ-a! bond

2 0 9 8 A _3/1 1 9 2 BÄD ORIGINAL

Ss it is pointed out that dzR> dxj wavy lines in the above formula indicate that one of the groups R and

ρ
R is in the exo -. Ko,; aiguration and the other of the groups is in the endo configuration, that is, the formula represents e: in 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 prosteglandin of the natural series.

A suitable value for R, which stands for a Halogenatoin,

ρ isfc the chlorine or bromine atom. A suitable value for R _t when it stands for an alkoxycarbonyl radical is, for example, the Hethoxyearbony! Radical, and a suitable value

2
for R. warn ea stands for an R-alkylcarbamoyl radical, is for example the H-Nefchyicarbamo.ylradikal.

Preferred bicycloheptene-V-syn-carbaldehydes of the invention are those in which R stands for a chlorine or bromine atom and R stands for the cyano, carbaioyl or ffethoxycarbonyl radical, in particular 5-chloro-7-oynformylbioyclo [2.2 , ilhept-2-en-5-carbonitrile _t 5-chloro-7-syn-formylbicyclo [2,2,1] hept-2-en-5-carboxamide and

the 5-chloro »7-syn-formylbicyclo [2 _x 2, i] hept-2-en-5-carboxylic acid methyl ester.

According to the invention, a process for the production of the bicycloheptene ^ -ayn-carbaldehydes of the formula X is proposed, which is carried out by the fact that
(&) a compound of the formula

209843/1192

CHOIR-

XI

Λ 2.
wherein R and R have the meanings given above

and R * is an alkyl, alkanoyl, alkanesulfonyl or Arenesulfonyl radical with up to 7 carbon atoms, subject to acid hydrolysis under such conditions and using such an acid that that initially formed Bicycloheptene - ^ - anti-carbaldehyde of the formula

H OHO

XII

1 2
in which R and R have the meanings given above, wiil $ or isomerized in the corresponding bicycloheptene ^ -syn-carbaldeh ^ d of the formula X without substantial decomposition

1 (b) that a compound of the formula XII, in which R and R have the meanings given above, in a solvent with an amine of the formula RR ^ HH, in which R and Br

209843/1192

ά «? * Ό.ΐ. ? .s for an alkyl ₁ aralkyl or aryl wheel with up to 1 ^ carbon atoms

A suitable value for Ir is, for example, t-butyl ~, Acetyl, methanesulfonyl or toluene p-aulfonyl radical,

Examples of specific conditions IMD a specific acid used in the above process (a) flocks can _t are the hydrolysis of a compound of formula II wherein R stands for the Chloratoa, Ε ⁴¹ represents the cyano radical and R 'stands for dae acetyl radical, with 2N Salasäure (1 part) in Diorran (M- ^ rush) at 85 ⁰ C acnähernd vährend about 4 days.

The extent of the isomerization of the compound XII to the bicycioheptene X can be followed in an expedient manner by magnetic Kerure3OZianzßspektrosie _t izwdea? maxi followed the occurrence of signals at £ 9 * 50 and 9 _t 57, which are due to the aldehyde proton of the aldehyde X attached to G-? possesses the required stereochemistry.

It wildly pointed out that the invention is the process (b) in two variants, wherein the reaction of the aldehyde with an amine an aldehyde / amine adduct. for example a Schiff * s base, supplies that are isolated and as such can be used in the isomerization reaction, or wherein an aldehyde / amine adduct is formed in situ and not is isolated.

Suitable amines R R-ΈΗ are, for example, aromatic primary nna secondary amines, *? I © for example aniline, p ~ chloroaniline. p-ioluidine and N-methylaniline.

BAD ORiGlNAL 209843/1 192

A suitable solvent, for example, 1st an alkenol, such as AB * methanol, ethanol, isopropanol or t-butanol, or a chlorinated aliphatic hydrocarbon, such as itethylendlchlorid * It is advantageous for the pH of the reaction mixture to less than 6 ₅ preferably between 4 and 5 » by adding an acid _t . such as an alkanoic acid _9, for example glacial acetic acid, to adjust «

The amine H R-IfH can be used in the reaction in an amount between 0.1 and 5 »O equivalents per 1 equivalent of the aldehyde of the formula X. However, 0.5 to 2 _T O equivalents or equivalents of the aldehyde are preferably used,

The reaction should be continued until the isomerization has largely ended, which can be determined by the appearance of a doublet signal between ^ 9 «50 and 9–60 in the nuclear magnetic resonance spectrum of the reaction product. This signal has its origin in the aldehyde proton of the aldehyde X _9, which has the required syn stereochemistry at C-7. A typical response time is 16 to 21 hours.

The compounds of the formula XI, which can be used as starting material in the above process (a), are themselves new compounds. Thus, according to the invention, compounds of the formula XI are also proposed in which R ² ^
sit.

G
wherein R ¹ R ² _s and R ^ are as defined above beGemäß of the invention is finally also proposed a method for preparing the novel compounds of the invention of Fomel XI, which is carried out by reacting a fulvene derivative of the formula

209843/1192

CSOR ⁵

XIII

λ ο 1

with an olefin of the formula CH ₀ : CH R, where R,

H and R have the meanings given above «

It should be noted that of course the various fulvene derivatives of the formula XIII have different reactivities which depend on the nature of the radical R, and that in a similar manner olefins of the formula CH ₂ : CR R

Possess different activities by the nature of the

1 2 Radicals R and R depend. A skilled chemist who Knowing this will therefore not try to be a non-reactive To react fulvene derivative with a non-reactive olafin, but he will select a fulvene derivative and an olefin that will interact with each other under moderate conditions within one respond appropriately. So are 2-chloroacryloyl chloride, 2-bromoacryloyl chloride and 2-chloroacrylonitrile the most reactive olefins and are therefore preferred. Fulvene-6-sulfonate and 6-methoxyfulvene are not very stable and should therefore only be reacted with the more reactive olefins *

The aldehydes of the formula XII, which are used as starting material in above method (b) can be used are in turn novel compounds · So are according to the invention also proposed aldehydes of the above formula XII,

1 2 wherein R and R have the meanings defined above.

According to the invention, a process ssv.r production of the aldehydes of the formula XII is also proposed, which

209843/1192

is carried out by establishing a connection d © x? For-

1 P 5

mel XI, in which B ₄ R and Br have the abovementioned ©: "functions, for example by heating with a mineral acid" such as "3 · Hydrochloric acid®" by treatment with alcoholic ammonia; for example methanolic ammonia, hydrolyzed.

As stated above, compounds of the Forsaol £ are valuable intermediates for use in the synthesis of Frostaglandins and prostaglandin-Äkallehen ¥ © s% ijä & iungen Thus, according to the invention, a method for the production of prostaglandins ^ or prostaglaadia-like compounds is proposed is that nan a compound of lormel H in bicycloheptene ^ -syn-earbaldehyd the Forättel X 'wherein e and H ₉ Br have the meanings indicated above * imter such conditions and using a @ n @ & ole Säur® acid hydrolysis unterwi ft , the ice is initially educated

der fomsl XII ₉ woria H ^J and

R ^{2 have} the meanings given above without ZeraetBung in the Ateprechenden Bicyelohepten «7 isomerized, or that a compound de? Formula XII in a solvent with an Ania of the fetter S rU, where R, R, R and R ^ have the meanings given above, implements "

Suitable conditions and a suitable acid siad ohm ready have been described. Suitable amines 1 IT HE have also been described above.

It should be noted that once dae arf loader laugh Concept of using a compound of formula 1 in a synthesis of a prostaglandin or a proetaglandin-

209843/1192

Similar connection has been established, an experienced organic chemists can easily convert the compound of formula X into the desired product in various ways can, with known standard reactions of the organic Chemistry can be used. Some exemplary alternate reaction sequences that can be used to achieve such conversion are now described below:

5-chloro-5-cyanobicycloJ2 * 2 ₁ 1] hept-2-en-7-carbaldehyde of the formula X (R ¹ »chlorine) is reacted with trimethylorthoforraiate or with methanol and with concentrated hydrochloric acid, the dimethylacetal XIVa being obtained, which on reaction with 1,2-xyIoI-O, α'-diol, the corresponding acetal XIV b results. Bas acetal XIV b is hydrolyzed with potassium hydroxide in dimethyl sulfoxide to give ketone XVb, which is subjected to the Baeyer-Villiger oxidation with m-chloroperbenzoic acid, the lactone XVIb being obtained. Bas lactone XVIb is saponified with sodium hydroxide and neutralized with acetic acid, and the product is treated with potassium triiodide to give an iodohydrin XVIIb which is reacted with p-phenyl likewiseyl chloride to produce the ester XVIIIb. The ester XVIIIb is reacted with TributylBinn-hydria, the deiodinated lactone XIXb being obtained wiz-d. When this is hydrolyzed, the acetal grouping disappears, giving the aldehyde XX (H ⁶ «p-phenylbenzoyl). The aldehyde XX (E = p-phenyl likewiseyl) is then converted into the prostaglandin F ~ a, specifically in the same way as is known for the conversion of the known aldehyde XX (K acetyl) into prostaglandin F ₂ α.

2 0 9 8 Λ 3/1 1 92

X (Ii ¹ = Cl
R = CN)

CH = Y

j HO

i '

CH = Y

XVIII

a) Y = (CH O) ₂ =

b) Y =

Y = CH

Y = CH

XVI

CH = Y

R ⁶ O

XIX

CHO

XX

R = p-phenylbenzoyl

'209 843/1

- 13 -

A modification of this reaction sequence is shown Dimethylacetal ZIVa itself hydrolyzes to the ketone Produce XVa, which by the above-described sequence of actions via the lactone XVIa, the iodohydrin IVIIa and the ester XVIIIa is converted into the decoded lactone XIXa «The lactone XIXa is then selectively converted into a two-phase system of chloroform and concentrated hydrochloric acid hydrolyzed to give the dimethylacetal moiety remove, but the lactone remains intact, so that the aldehyde XX is formed.

The potassium triiodide can of course be replaced by other known Ealogenierungsmittel, such as chlorine, bromine or the corresponding N-halosuecinimide in an aqueous reaction medium or a derivative of hypochlorous acid, such as sodium hypochlorite, a halohydrin corresponding to the iodohydrins X7II , which can be used in the gMchen Weiss like the Jodohydrino XVII. Similarly, when converting the ester Tv ⁷ III into the decoded lactones XlX, other known reducing agents can be used instead of - / on tributyltin hydride, such as, for example, sodium borohydride or sodium yano borohydride (Na.BHjCN) in dimethyl sulfoxide, dimethylformamide, sulfoxide or hexamethylphosphoramide, or Raney nickel.

An alternative reaction sequence begins with 7-acetoxymethylene-5-chloroblcyclo \ 2,. 2 ₁ il hept-2-en-5-carbonyl chloride (XI. R ¹ = chlorine, R ² «chloroformyl, R * · acetoxy) _s which is treated with a methanolic amine, such as, for example, methanolic ammonia, followed by an acid treatment connects to the anti-aldehyde XII (R ¹ - chlorine, R «carbamoyl)

209 843/1192

Ί 2

via a x * of the primary amide ΣΧ (R - ■ = chlorine, R * = carbanioyl) * This anti-aldehyde is produced by the procedure described above for the corresponding cyanoaldehyde in the ketone XVa is converted via the syn-AXdehyde ivad its dimethyl acetal.

Another alternative reaction sequence begins with the 7 ~ acetoxymethylene-5-chiorobicyclo f2,2 ₁ t3hept-2-en-5-carbonoic acid ~ methyl ester (XI, R = chloro »B» ethoxycarbonyl, R * * aoetoxy) which is carried out by similar processes as described above "is hydrolyzed into the anti-aldehyde XII (R» chlorine, R * flethoxycarbonyl), which is then isomerized to the corresponding syn-aldehyde X (R = chlorine, R »methoxycarbonyl). This syn-aldehyde is protected as its dimethyl acetal, and the methoxycarbonyl group is converted into amide by treatment with ammonia, which is hydrolyzed to the ketone XVa as above,

The invention is illustrated by the following examples explained »

example 1

25-, B g (0.16 mol) 7-aoetoxyffle'fenylea-5-ohlorobioycloQ2,2, i] -hcpt-2-en-5-carbonitrile (XI, R ¹ «= chlorine, R ² = cyano, R ^ = Acetal) were dissolved in 360 ml of dioxas, (welslies for the purpose of cleaning c lircJA basic aluminum oxide of Sor-fcs "0 ^ts hindurcli- % fi- \ X: uw urd ai ^ chlenä rinsed with Argoa wordsa v / ar), and - X> ml (0, 'ir ίϊοΐ) 2n SalssäuÄ ⁵ © (^ loiie vqv exercises Vervv; .ud -;, ß3 flushed with argon vroräsn p / ar) vmrden added, where e:, j-3.e bl &Bgel'belS3i2i> .g was obtained <Die Losta & g wurda far? ^^ 5C atx ^; with 4rgos. $ <% rinses uaa dam ?, lid © ia @ a oil bath

209843/1192

SAD OR

'Page ! 8.i: g να .: »ο ?: ei ^ er / rgott ^ iposphapft in dfci- WeS. ac?; rhi τ

that Gine Tßns & töE-p & ^ a.tui: τοπ 85 *:> ° O Dia Diosan wards evaporated under reduced brackets, and the * remaining liquid was saturated with aqueous Sodium bicarbonate solution "basic poured .. Then 200 ml of water and added 120 ml of methylene chloride to the suepsneion obtained wuiie filtered through gelite. The organic sliding * Was separated off and the remaining aqueous solution wards Yieraial with 50 ml of ethylene chloride each time.

The organic layers were combined and dried, and the solvent was removed under reduced pressure. D "-: r residue vairde dried under high vacuum _t v; o ν el 5-t ''-"> - lo3? O-7 - syn-f oriaylbicyclo 1 * 2 »2, i] hept-2-en- 5-carbo

jiifcrJ.l (S ₅ Pt '= chlorine. R ² · cyano) obtained as a brown oil 1, .IrO-. The aldehyde & goaiach showed awei spots Hj, co _? 2 xtid 0.3, when hydrogen chloride was used as an eluent agent \ - 'ri-r> i -' ?. Splashing the Ρ1? .1; 'ΰ (5η with 0 © χ · - (IV) -sulphate and aiiachlassondee heating the plates developed. The nuclear magnetic resonance spectrum of the mixed aldehydes in deuteriochlorite form: f * i.frre the following values (ί -Values):

1.79 and 2.26, 1E, Doubleta, J * 14-Hz ₁ ezidc-tfaaeeratoff at C-6. £ s ^ 8 and. "· _? 84, 1F" double doubl ",; s, J« 14 · and 6Ha ^ earof bi> i C ~ 6 «

3 _t O7 »1H» Singlet, Hydrogen C at C- ?. 5, ^Λ - · ί: · 1Hi broadf3 £ i singlet, bridgehead gas. ?, 56 and 5.80, 1E ₅ wide singlet. Bridging hydrogen. _{6.0-0.6 v} 2H "complex multiplet8 _f oUtfinischo WewRersto 9.50" to 9.57t 1H, doublets, J = IHz, aldehyde waeeeratoff.

20 9 8 A3 / ei, 19 2

_i ₇ - 2217330

Example 2

61 s (0.45 McI) of crude ar-acetoxyfulvene (ZIII, R ⁵ »acetyl) were dissolved in 450 ml of Be & sol The solution obtained was heated to reflux for 21 hours in an argon atmosphere. The solvent was evaporated off under reduced pressure to give a dark brown oil which was purified by purifying it through a column of IPloriail (1 kg) using methylene chloride as eluent * was passed through to give 7 ~ acetoxymethylene - ^ - chlorobicyclo [2,2,1] hept-2-ene-5-carbonitrile as a pale yellow oil obtained "which in thin echiahtchromatographie on Msrck silica gel plates using ethylene chloride as the eluent gave an R ^ = 0" * "The magnetic nuclear sonan spectrum? .iB of the product 1.5 D '* uteriochloroforia shows" the following characteristics; -value):

1.7 ^ 5.3 2.9 «2H _f complex» protons at 0-6 2, C8 usA 2.09 »3H, complex, methyl _{protons 3.3 to 4.2 {} 2H _V complex, bridgehead protons 6.1 to 6, 7, 2H, complex, olefinic ring protons 6,81 wkä 6j82 .. 1H, complex, olefinic acetosomethylene provons

15 % (0.08 hol) 5'-chloro "7 ~ 37n-forraylbicyclor2,2, i3hept-> 2-e £ _5 ~ urbonitrile (X, R ¹ = chlorine, R ² = cyano), 26 g (0, 25Mo Wr-jλ.atiiflorthoforaiiat and 7 ^ 0 ag (4 MLllimol) toluene-p-

209 843/1 192

BATH

sulfonic acid were dissolved in 500 ml of methanol, and the solution was heated to reflux for 20 hours. The solvents were evaporated under reduced pressure and the remaining Oil was dried under Roch vacuum using an oil pump from a mixture of epimeric dimethylacetalone was obtained

The crude dimethylacetal mixture was dissolved in 550 ml of Benaol (which had been dried over 4A molecular sieves), and then 11 g (0.08 Hol) of i ^ -Xylene-OjOo'-diol and 560 mg of toluene-p-sulfonic acid® were added issued. The solution was heated for 13 hours, allowing benzene to slowly evaporate and maintaining volume by adding more dried benzene. The solution was cooled, washed with 100 ml of saturated aqueous sodium bicarbonate solution and dried, and the solvent was removed under reduced pressure. The residue was purified by chromatography on Florisil (420 g) using methylene chloride as the eluent to give the 1,2-xylene-O ₉ o / diylacetal (XIVb) as a pale yellow solid. It showed an Rp * 0.3 on Merek silica gel plates by thin layer chromatography using methylene chloride as the eluant. The nuclear magnetic resonance spectrum of the mixed acetals (XIVb) in deuteriochloroform had the following characteristics (& values) j

1.6 to 2.8, 3H, multiple signals, C ~ 6 ~ and C ~ 7 hydrogens 3.10, 1H, broad singlet, C-1 hydrogen 3.36 and 3 »50, 1H, broad singlets, σ-4-hydrogen 4.6 to 5 * 0.5H, multiplet,> 0H-0-

6.0 to 6.5, 2H, multiplet, olefinic 7.14, 4H _t singlet, aromatic

209843/1192

19j '· ¹ - S (0.06 mol) of acetal (ZITb) vmrden in 100 ml of dimethyl sulfoxia ( then purified by distillation over Ealai \ önhydr5.a and stored over molecular sieves t-; o:? The what?) Dissolved * and the solution was 4 st laic argon purged "Simultaneously, a solution of 13 6 Ealiisiöiydroxi'ä was dissolved in 10 ml of water au :: 50 ⁰ C. and H- st purged with argon. The Ealiumhydroxidlösung was then stirred οι solution au of the acetal added _t, and the mixture vmrde "is room temperature 20 st rater argon stirring, a white solid during which precipitated. The reaction mixture tvurde in 500 ml of 1N hydrochloric acid, poured *, and the mixture was washed four times, each with 200 ml of methylene chloride are extracted. The combined organic layers are dried, and the solvent is evaporated under reduced pressure to obtain the ketone (XVb) as a white plague. Thin-layer chromatography on Merck silica gel plates and under water, 3 of ethyl acetate / Meth ^ l ehlorid (3:97) as an eluent an R ^ * 0.25 was obtained The Maipietic Esx ^ rssonansspektrum of the ketome (XVb) Dev.tariochloroform aeigta the following Mercuials (t

1.99 _t 2E, singlet ■; - doublet, -OH ₂ .CO- 2J ¹ S ₁ 1H. Doublet, J = SHz _t . C-7 hydrogen 5 ^ 2 and 3.72, 2H-iTultipleta, bridgehead hydrogen 4 ,? up to 5 »0 _t 5H ₁ » altiplet,> OH-O-6.0 and 6.5, 2H, hultiplete, olefinic 7 »15, HE _t singlet, aromatic

14 * * € I (57 millimoles) of the ketone (XTb) was dissolved in 250 ml of Heth; <'> Θ33 chloride (that is, by stirring it up over anhydrous bicarbonate). Then Q ,, ^ 6 ·; (11 / r Millimol) Weseer-free Sodium Bicarbonate '. ■ nee ^ -'- u ^ ii yoraiif sich der Susav.?, Of 12.5 S (68 MLllimol)

209843/1192

8AD

IQ

mC & icroperbeixiioeseure connected, lias mixture wurai? whose. Stirred for 20 hours at room temperature. The bio-organic content was diluted with 750 ml of methylene chloride and washed successively with 50 ml of saturated sodium sulfite solution and with 50 ml of saturated sodium bicarbonate solution each time. The ablated organic solution was dried and the solvent evaporated to give the lactone (SVIb) as a white solid. It showed an R _{F on tin-layer chromatography on Merck silica gel plates using Äbher / Benfccl (1t5) as the eluant} * 0.25.

The magnetic chain reaction spectrum of lactones (XVIb) in Deuteriochloroform showed the following characteristics (£ values):

2.48, 1H, doublet, J = 6Hz, C-7-Vaeeeretoff 2.4-2.9, 2H ₅ multiplet, -Cg ₂ .CO-

3 * 0, 1H, broad Sj, nglet _t BräckeultopfKasserstofi * in the MLe of C

4.43, IH. Doublet, JaBH *, -O-CH-

4.80, 4H. Singlet, ₂

5.0 ?, 1H ₉ wide singlet, Brüekeiikopi'vranae.vatcfl in dor MLe vcn C 6 _t 2--6 _r 5i 2H _? iMultiplat, olefinic.
7.2, 4H, singlet, cromatisoh

14.6 g (5 ^ fBLllinoj.) Des LsctoDfe (XVIb) v / urdc.r: i..n 153 «1 Dioxaa dissolved ₄ '- ■> · &<? clanr. was, an Itönxms of ·· .. 6.5 g (162 MilllBiol) KatrSuiähydroxid in (58 nl water at: - i &untöEr>) € i: atur added under Rütee'i. The throne was 6 rt fo.ft ^ esf.tn ¹ ;, whereupon E £? Igiiäur>. ZugV ^ ebea. ·; ■ -.?.:?.; .. «·, uj; the L «: cn; u.»? sui "amrfhenul χΕ 7.5 to l: riüigeD 3chX: U.iU.; i; ίΛ '« αβ f: L ^ q LÖ £ \ ire vca ίί-Ο, ε (■: f "^ 1 iLMlimo :.) uoö. wni. Bi; g; 4B5 ΜΠΓλϊβοΙ) Ealiiw ,, Viiijd je ! oil ml './asor-.? ?. ■ »e'Sf:" ^ · '·. ·. ■: d /. Ö .-? S Ιϊ2 ^; -; .- i? 1 et ί · Μ Hauuit-aiüpt caiiv. · - (.ri ^ din ^; - v / vr. '·;'.

209843/1192

BATH ORIGINAL

₅ suspension was filtered and the solid "mrde three times with 50 ml of water and finally washed three times with 23 ial acetone» The solid was then ,, wherein the Jodohydrin (XVIIb) was dried as a white solid in vacuo. Dünnschichtchromatograpßie on Merck Silicegelplatten using Mstfeanol / Beftsol (5 * 95) as JSluiermittel gave a Η. '~ 0 _t4.

The magnetic resonance spectrum of iodohydrin (XVIIb) in de-pyridine the following iterkaal (S-values) showed j

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

2.73 "2H, doublet, J" 8Hz, 0-3 wa3ser3toffe 3.03, 1H, multiplet, 0-3a-V / aseeratoff 3.53 »* IH, Singlet, Hydros

4.42, SH, Mttitiplat, C-5 and G-6 hydrogens 4.82, 4H, hultiplet, -CHp.O «

5.08, 1H ₄ Multiplet, O-eä-Vasaeratoff

;: · .Ίθ »IE ₅ doublet, J * 4H3, CH

Siuglet, aromatiscii

16.3 S (39 KilXiraoX) of the iodohydrin (XVIIb) in 60 ml of pyridine, which was viorden over laliurahydroiridplätschan gatrocisnst, aufaeiöetp there were 9 * 7 S (44 Hlllimol) p-Pheaylbensoy-lchlorid sugegeban, finally the solution 27 was heated in argon to 50 ° C. The solution was brought down to raw temperature _and 0.2 ml of the vase were poured in, and the mixture was stirred for 30 min at the fiairafe temperature

see 500 pil helylcine chloride aufgsluei

i ·

209843/1192 _{B. n}

■ © AD

losing -was succeeded by threeBa.l each with 100 al 2a hydrochloric acid, three times with 100 ml of saturated sodium bicarbonate solution each time and washed 100 ml of water. The organic layer was dried and the solvent was evaporated » a white solid was obtained which crystallized from a mixture of methylene chloride and ether was) the p-phenylbenzoate ester (XVIIIb) being white Solid was obtained. Thin layer chromatography on Merek silica gel plates using methylene chloride as an eluant, the result was an E «* 0.2.

The magnetic resonance spectrum of the p-phenylbenzoate theater (XVIIIb) in deuteriochloroform showed the following Features (& values):

2.42, 1H, multiplet, 0 3a water 2.72, 2H, singlet + doublet, C-3 hydrogens 3.25, 1H, multiplet, C-4 hydrogen 4,4-1, 1H, double doublet, J = 3 and 5Hz, C-6 hydrogen * j7-4.91 4H, multiplet, -OHg-O-

5.1 »2H, multiplet G-6a hydrogen 5.73; 1H ₉ triplet, J-5Hss _f σ-5-Vaaeeretoff 7.0-8.1, 13H. Cult, aromatic

A xezaic mixture of 14.0 g (24 milliraoles) of the p-benzyl benzoate (XVIIIb) in 500 ml of benzene (dried over 4A molecular sieve) was obtained under pressure until the solution was grounded. The refluxing solution was flushed with argon for 0 min, and then a solution of 8.6 g (29 millimoles) of titanium-butyl-synn-hydride in 10 ml of benzene was added. The reaction mixture wv.r-de 20 st heated to reflux and cleared; . ^. Αρβπιtür ahkvüileß, and then the benzene was evaporated off under reduced pressure. The received one Pest substance was drsiraal with! l'O ml of n-peatan grated and mixed

209843/1192

of methylene chloride and ether crystallized, with the decoded ester (XIXb) as a white crystalline solid a bp of 188-189 ° 0 was obtained. Using Dünttschlchtchronatographie on Merck silica gel plates a mixture of ethyl acetate and pentane (1: 1) as the eluent gave an H «· 0.3.

Nuclear Magnetic Resonance Spectrum of the Decoded Ester (XIXb) in deuteriochloroform showed the following features (& values) t

2.5-3.2, 6H, complex, C-3H 3bi% 4- and 6-Waeeeretoffe 4.86, 4H, Hultiplet, -OT ₃ .0-

V 5105, 2Ej Hultiplet, C-6a- and -O-ÖH-Waeeerstoffe 5.50, 1H, tiltiplet, C-5 hydrogen 7.1-8.1, 13H, KuItiplet, aromatic

142 mg of the decoded ester (XIXb) were suspended in 30 ml of methanol which contained a drop of concentrated perchloric acid. 67 ng of palladium oxide were then added, whereupon the suspension was shaken in a hydrogen atmosphere for 24 hours. The reaction agemiscb was diluted with 100 ml of ethylene chloride and filtered through gelite. The filtrate was washed with 10 ml of saturated sodium bicarbonate solution, the organic layer was separated and dried, wid. the solvent was evaporated. The shell was purified by chromatography to give the aldehyde (XX). Thin-layer feromatography on Ferck gel-gel plates using a mixture of ethyl acetate and methylene chloride (1: 1) as the eluent, whatever an Rp => 0.5 'The magnetic resonance spectrum of the aldehyde (XX) in general Deiiterlochloroform showed the following characteristics ( i values):

209843/1192

BATH

1i9 ~ 3f5i 6Η, complex, 0-3-, Ja- »4- ~ and G-Waeoerstoffe 5j15» 1H * triplet »J * 6Hz« C-6a ~ vase fabric 5.79 »1H * multiplej, C-5-Waeeerßtott "7.3-8 * 2, 9H _? Ifultlplet, aromatic 9.84, 1H, singlet, aldehyde

The aldehyde (XZ) was not identical in any way to a sample: that had been prepared by a known method was *

example

116.7 B 5-chloro-5-cyanobicyolo [2 _$ 2 _l 1Jhapt-2-en "-7-anti-carbo) caldehyde and 93.2 g of p-chloroaniline were dissolved in 116 tablespoons of ice cream and 950 ml of isopropunol, and the Lösrag was 2C ot at RäumteFrperatur under a ßtiokatoffatmosphäre göiilhrt. the Löeungöaittel was evaporated ",, ml 2t 500th ßalMäuxO were sum .Rückstand added, and since β Gemificb vairde once ait 400 ml and once * the combined with 200 ml of methylene dichloride © xtrebiert Extracts were washed successively with 250 ml of 2N hydrochloric acid, to acidity with aqueous sodium bicarbonate solution and twice with 300 ml of water each time, and dried over magnesine meulia. The solvent was evaporated to give oin viscous Cl which was more than 90% pure 5-chloro 7-syn-formyl-bicyclo £ 2 "2,1jhept ~ 2 ~ en ~ 5-cerbonitril insisted was _t which used without further purification"

SAD 209843/1192 ^ß

Using the method τοζι Example 4 _f , but the p-chloroaniline was replaced by 0.3 equivalent of p-toluidine, when a reaction time of 18 hours was used, a 90% isomerization of the ayn-aldehyde was achieved.

Example 6

The procedure iron Example 4 was repeated, but with the glacial acetic acid was dumped and nrobei di © ia the consequence

Amines and solvents were used * Es receive the following hssultata;

2.0 equivalents of Sf-Hethylanilia in ffethanol for 18 sbj This became a 40% ig® isomerization. © rhalteaj

2.0 iguivalents K-diethylaniline iaa ethanol during 18 et; © o - became one 65 / äigö IsoOerlaati-on © rhaltenj

1.2 equivalents of aniline in isopropanol during 16 rij obtained a 73% 3- '£ 3 isomrisation;

si aniline ia Ksthaaol during 16 atj "for aiae 3S% isomerization obtained,

2 "Ο il.qr.iva.l6atö .iliiilia la t-B'atauoi währead 20 stj äs vjtirdc: ainij Kehr als 90 ^ ige IsomariaabioK. receive

At. · 3 oil? X 7

^-:!:> Ώ p-Ohlorcv ^ ^ ^ yj ^^ dliaevlicj L'ithyn ^ ic.

(JIYa) w-ils / s L »'i? 0 al ethanol containing 50 ml

209843/1192 _ßÄD

was dissolved), 16.8 g of sodium hydroxide were added and the solution was _t st in an atmosphere inertan 20 erhitst under reflux. The solution was then cooled, diluted with 500 ml of water and extracted four times with 250 μl of ethylene 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 gave the ketone (XVa) on crystallization from pentane", mp 45 ° C., Ry = 0.4 (5% ethyl acetate in methylene dichloride). The nuclear magnetic resonance spectrum of the ketone (ZYa) in prey chloroform gave the following characteristic features (&values);

1.9S, 2H _t Mnltiplet, -Og ₂ .CO-2.52, 1H, Doublst, G-7-P.eoton

and C-4- »ProtoÄön

3.00, 1H, multiplet)

) C-I-

5.10, 1H, multiplet)
3.2 ^, 3H, singlet

3 »30, 3H, singlet

4.38, 1H, doublet, (OH ₅ O) ₂ .CS-

5.98, 1H, multiple *)

) olefinic protons 6.44, 1H ₁ maltiplet)

111 g of the ketone (X ^ a) was dissolved in 550 ml of ither, 39.7 ml of a 10% aqueous sodium hydroxide solution was added and the mixture was stirred and cooled to ^{0 ° O.} Then 186 ml of hydrogen peroxide (27% strength (Q / V) solution) were added in coppers to the stirred mixture, the temperature of which was kept at ^{10 3 O.} When the addition was complete, the mixture was stirred for 3 hours, the ether layer was separated, and the aqueous layer was

209843/1192

BATH

twice with 100 al ether Ci3rtrs.hi.ert - the aqueous layer was adjusted to pH 7.4 old liseesig, and ^{cooled to 0 0} C, and dent? A concentration of 887 K potassium iodide and 451 g iodine in 1758 JaI Vaeeer was added. The mixture was stirred for 20 hours at O ⁶ C, and then the excess iodine was decomposed by adding solid sodium sulfate. The aqueous suspension was dissolved in 500 ml of ethylene dichloride. , the combined organic extracts were dried f and the solvent was evaporated under reduced pressure to obtain the uobei Jodohydrin (XVXIa) as an oil, B ^ '0.3 (5% Äthylaeetat in methylene dichloride). The magnetic Eemreeonan spectrum in Deuteriochloroforii tended to have the following characteristic Herkaale ζ S values):

3.59, 6H, singlet, ffethoxy

4.0, 2H _{ hultiplet; C-5 « vaaä. C-6 protons 4 _t 40, 1H, doublet, (GH ₃ O) ₂ GH-

4.96, 1H _for r & iltiplet, G-6 £ proton

iifi! © followed the procedures described in Example 3 • was repeated. % Obei instead of iodohydria (ZViIb) the tloaob.ydi * in (21QIa) was used, Ea vrurden di © inferring intermediates:

Ester (XVIIIa), m.p. 159-141 ° C, Rj ₁ = 0.6 (15% methanol in benzene) D & a magnetic nuclear freeonane spectrum in Deuterio chlcrnforas showed the following characteristic features *)

3, JC and 5? 52, ei ₅ singlets, methoxy ^ -J ^ A 1H ₄ quartets G-6 proton
4.31. 1H, doublet »

OHlQINAL

2098A3 / 1192

5ι10, 1H, quartet, 0-6a proton
5.62, 1H, triplet, C * -5 ~ proton

1, 9Η, multiplet, aromatic protons

decoded ester (XIX), Ip 114 to 116 ⁰ C, Ej, * O _t 3 (50% Ithylacttat in Pe & ten). The magnetic resonance spectrum in deuteriochloroform showed the following characteristic features (S values) j

3.38 uiid 5 * ^ 1, 6H, Singlet, Bethoxy 4.34, 1H, Doublet, (OH ₅ O) ₂ Cg-

5 * 04, 1H, Mttltiplet, O ~ 6a proton

5.42, 1H »i & atiplet, C-5 proton

7.4-8.1, 9H, maltiplet, aromatic protons

39 "5 6 ^dee decoded ester (XIXa) were dissolved in 1980 ml of chloroform," which spell 2 Vol. ~ # Isopropanol containing "were 495 el Salt concentrated acid was added, and the Zweiphaaeneysten was stirred st at Rauatentperatur 1 1/2" The Chloroforssobloht was then separated and the aqueous layer was extracted with 50 ml of chloroform. * 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 50 ml of ethyl acetate was extracted, the combined extracts were dried and the solvent was evaporated under reduced pressure until crystallization began. The solvent was then left behind until crystallization was over and the product was filtered off and dried, * It was 2 _s 3i3r-a 3,6 (* ß-Tetrahydro-5o (p-phenylbenj5oyl oacy) -2-oxocyclopenteno £ b3 f \ äran "4ß-carbaXdehyde (H) which was identical in all respects to a sample prepared by a known method

209843 / Π 92

A 5% solution of 5-chloro «7-anti-formylblcyclop _t 2 _i i3-hept-2» e3a-5-6arb03caffiid (III, R ^ * GhIoS ¹ SR ² * carbamoyl) in methylene dichloride, which is 1.5 equivalents p ~ chloroaniline, stirred over Haoht, washed twice with 5% hydrochloric acid and filtered. The solvent was then evaporated. The residue was dissolved in ethyl acetate and the solution; was to low to E entfexnen by a Xieselgelkissen hindurchlaufea gelasseni impurities ^ * d © s Abdaapfung solvent gave 5 ~ Chl6ro-7-sy "- ^^^ fonBylbiöyclo iJ ^ P ^^^^^ - fcarboxamid (X, R ¹ * Chlorine, R ^ * Oarbamoyl) · The magical Eerm? Eaonanaspekt2? Um in deuteriohaloroform showed a doublet at fr «9 * 6 (J« 2Has), which is characteristic of the 7-S "yn-formyl group«

The starting material in the above process vexii / ends © 5-chloro-7 ~ anti-formylbicyclo [* 2.2 _$ i3h © pt-2-en-5-carbox: amide -was obtained wi 3 follows jj

7-acetosymethylene-5-chlorobicyclo p, 2, ΐ] hept ~ 2- © n «5-carboiijl-

chloride (H § R ¹ '= R ² chloro ^ ■ _{Ghloroforsoyl%} B?' Acetoacy) was au eiasrs About Schus you saturated with ammonia Hethanol added Uach · 1/2 st ^1, the resulting solution was acidified with 3N hydrochloric acid and extracted with Kethylandlchlorid " resolved the extract was evaporated to dryness, the residue wurds la Sinea small volume Kethjleadichlorid _Φ U && di © solution win? de violently with 3a hydrochloric acid for 2 st gexiihrt long "the organic phase was separated, filtered and evaporated to dryness to give crude 5-chloro -7- ° antiformylbicyclo | ^ 2.2 _t iJ [hept ~ 2-'Sa-5-carboxamide, 1 ^ 0.52 (ithyl acetate / silica oil) was obtained. The magnetic E®rn- ^ ösonanizspektruHi in deuteriochloroform showed a P- \ nglet at ^ «9.7 ·» which is characteristic of the 7 ~ "ejati-Formylg3? Uppe '.

209843/1192

Example 9

The procedure of Example β was repeated, using 5-chloro-7 ~ anti ~ formylbicyclo (2,2, "Qhept-2-®n-5-carbons & treaethyl ester (Xi R» chlorine, H * methoxycarbonyl) instead of 5-chloro «7-anti-foruylbicyolo [2,2, ohept-2-en-5-carbonitrile was used» Bs was the 5 "Ohloro-7-eya-ioraylbicyolo ^^ iijhept ^ -en ^ -carbonic acid-aethyleeter. (X ₁ H · Ohlor, H · methoxycarbonyl) obtained, Y _Me «17 * 5 ca" * ¹ (PiIa- Methyl ester). The magnetic nuclear reaction spectrum in Deuterioohlorofora shows characteristic bands which were similar to those of the corresponding nitrile from Example Λ . There was also an additional 3H singlet at S * 7 »75 due to the ester methyl group.

The ala Auegangaomaterial used 5 ** 0hloro-7-anti-forBiylbicyclo [2,2, Ühept-2-en-5-carboxylic acid methyl ester can be obtained by the process described in the last part of Example 8, 7 ~ acetoxymethylene-5-chlorobicyclo £ 2.2, i3hept ~ 2 ~ ene-5-carboxylic acid methyl ester instead of 7-acetoacymethylene-5-chlorobicyclo ~ [2,2, ilhept-2 ~ en ~ 5-carbonyl chloride was used »

Example 10

2.75 g of 2-chloroacryloyl chloride were added to a solution of 2.72 g of £, ~ acetoxyfulvene in 10 ml of cyclohexane, and the mixture was stirred for four times at room temperature. The reaction mixture was filtered and the solvent was evaporated, yielding 7-acetoxymethylene-5-chlorobicylo- [2.2 _t i] ^le P * "2-eE-5-carbonyl chloride, which was obtained without further purification in the process. j uses wuz'ae, which is described in the second part of & Bslepial 8. Das

209843/1192

Nuclear Magnetic Resonance Spectrum In Deuteriochlorofore showed the following characteristic features (b values):

2.0? and 2.10, JH, singlet »methyl (2 isomers at 0-5) 6.1-6.7 "2H" multiplet, olefinic ring protons 6.6? » 1B, singlet, olefinic β acetoxymethylene proton

In similar catfish, using methyl 2-chloroacryloyl ester instead of 2-chloroacryloyl chloride, methyl 7-acetosylethylene-5-chlorobicyclo £ 2,2, 2-hept-2-ene-carboxylate was obtained XexnresonanBspectrum In carbon tetrachloride showed Similar characteristic bands as the spectrum of the acid chlorides described above, with a useful one 3H singlet at S «5.69 and 3.72 due to the Eeteraethylgruppe (isomers at 0-5) was« ''

Example 11 .

The procedure described in the first paragraph of Example 3 was repeated using 5-chloro-7-syn-foraylbicycloJ2.2 _$ 1J hept-2-en-5-carboxamide instead of 5-chloro-7-syn-formylbicyclo [2.2 _t i \ hept-2-en-5 * -oarbonitrile was used. 5-Chloro-7-syn- (dimethoxymethyl) bioyclo f2,2, Λ \ hept-2-en-5-carboxaaid was obtained , 6H, 2 Methoay ^, 88, 1H, (OH ₅ O) ₂ OH-CH <. (J «9H *)

20984-3 / 1192

iyl) b icyclo [2 _f 2 / f
carboacamide was hydrolyzed by the process described in the first part of Example 7, with 7-Β7ο ~ Β1.Εΐε ^}. κ) 3 ^ - methylbieyclo [2,2.ijb.ept-2-en ~ 5- "0n (XVa) was obtained _t dae with the la. example 7 hergeetftlltfcn product was identical "

The 5-chloro-7-syn ~ (diKGthoxjmethyl) bicyelo [2.2 »i} hopt> - £? - βη-5-carbonic acid-metliyleötör ifU3? De converted into a similar Veiee ijr dae ketone IVa,

209843/1192

Claims (1)

■ 53 the lor-mel HGO rla R stands for sin halogen atom and B "for sin Öyaao- or EIA Alkoz ^ rcarbojsylradlkal inftbie to 6 Eohlan- or EIA n-Alkylcarbamoylradikal "into which the alkyl" fcal 1 to 6 _t is Sofclenatoffatosa -contains, 2, Yarbinduagen- according to claim 1, characterized gekenaaeichnet that R '~ stands for dna öyan.oradikal * 3- »/ compounds according to claim 1 or 2, characterized in that H stands for a chlorine or bromate. irarbiadungea marked according to claim 1 or 3, characterized j that R is for d?
carls amoyl radical, aötj that R stands for ethoxy carbonyl or H-methyl , 5 *? 3r "i) indunge; a according to claim 1 or 3» thereby gekean · Ί 2 ßfi5.a. "aiiat _t DAB R represents a chlorine or bromine atom ateht and H .for lai Garbamoyl ·" or Methaxycarteo & y! radically stands · 2 0 9 8 A3 niW2 BAD 6. The connection 7 «The compounds 3-ghloro ~ 7-syit" -foriaylbicyclo and 5 * - 8. Method sur production of the bioyclohepten-7-eyncarbalde & yde according to claim I ₁ thereby gekennaaichaai; _t that one has a variant dji formula CHOIR ³ II Ί 2
wherein H and R have the meanings given in claim 1 Bit ζ in and R *, alkanoyl, alkanesulphonyl or Arenaulfonylradikal old up to 7 carbon atoms stands for an alkyl, under such conditions and using such Säurj the acidic Hydrolyae subjected formed ₄ da3 the "unächsb © bicycloheptene - ^ - anti -earbaldehyde the formal OHO XII 209843/1 192 bad original 1 p R xmfi. ?. the obsn 0r.gegeDea.en significant ones, besitsezi, ohi3.ß essential. © Zürnet s & ung sum corresponding Bicj? oloheptan · -? - B ^ n ^ car-buj ciföhfd iisoiasrisierc 9 "Y & ^ fahreä r.a" Ii expression 8 * dsigned by The ede Yerbia & unj of the Formiil H with 1 rope 2n Saleßüure and M- ^{parts Dioxax · is heated to 85 C} C annually for about 4 days, whereby the ntinächgi; Bicycloheptene-7-afi.ti- <;a.T'br.ldehyde formed is dissolved into the corresponding 7-ej-n-0arbaldebyd without substantial decomposition. 10 * Yerfahjien i; ur.Hs »creation of the bicyclob, epten-7 ~ syn- ce.rbaldehyde on claim 1 "characterized in that _t eiae compound of formula X * wherein E and R t, the above Eedeutimgen '&r4t'zen _t in a LPs"np;snitt;c> l 4 5 k- '** with an Aaisi der Foriael ilE ^ RH, where H and R 'each "tehe-n for an alkyl, aralkyl ori radical with up to z \ x 15 carbon atoms", 11 ν method according to Aiiapruct. 10 _? through this 4 5
that as Aatin HR ^ M an eromatic primary or eelom- (lär. {: ß Amin vsrwfeßiat becomes * 12 "Verfahiwn according to claim 11 wherein _t denotes g *. daP as aromatic primary or secondary axain aniline, p-OLlorcaniline, p-toluidine or N-methylaniline -ior uses v; ird. 13 'Procedure according to Anepructi 10, 11 or 12 »thereby g3keameiehnet _t öa3 the amine E rSH ita reaction mixture in a range between 0 _v 1 and 5.0 equivalents per fc the aldehyde of the formula 2 is present. 209843/1192 ^{8ÄD 0RIGINAL} 14 * The method according to claim 13, characterized in that g, that the amine R IrHH in an amount of 0.5 to 2.0 equivalents Every equivalent of the aldehyde is present « 15 «The method according to any one of claims 10 to 14, characterized in that the solvent is an alkanol or a chlorinated aliphatic hydrocarbon is used * 16. The method of claim 15 characterized in that _t * is used as solvent methanol * Ithanol, Isopiopanol, t-butanol or methylene dichloride, 17 »Compounds of the formula CHOIR ⁵ 1 3 wherein R has the meaning given in claim 1, R ^ has the meaning given in claim θ and R represents a cyano, carbamoyi or chloroforiBylradikal ^ a Alkoxycarbonyl radical with up to 6 carbon atoms or an H-alkylcarbamoyl radical, wherein the alkyl radical is 1 to 6 Contains carbon atoms, stands. 18. Compounds according to claim 1 ?, characterized in that ■ that 'R is a chlorine or bromate * 19. Connections according to claim 1? or ^ 8, thus identified 209843/1192 _wgMWl aelehnet that R stands for Mathoxyearbonyl- or N-Methyl ~ carbamoylraöikal stands. 20, connections according to claim 17 »18 or 19 * thereby gekennss®lehnet ,, that Ir stands for t-butyl-, acetyl-, mathanaulfonyl- or toluene-p-aulfoHylradikal is The compound 7 ~ aceto3Qrmethylene-5-chlorobicycloj [252 _i 1 ^ - hept ~ 2- © a-5-carboni, tril * 22 ο The compounds 7-aceto: aym0thylen-5-chXorobicyclo- ^, Ssi ^ hept ^ -en-J-carbonyl chloride and 7-acetoxymethylene-5-chlorobieycloj ^ 2,2 "Fj hept ^ -en-J-carboxylic acid methyleeter" 23 «Process aur the preparation of the compounds according to claim 17s characterized» that one is a filling derivative the forael CHOIR ⁵ XIII with an olefin of the formula OHgtOR H, where R and R have the meanings given in claim 1 and Ir has the meaning given in claim 8, 24 «Process for the production of prostaglandins or of proataglandin-like compounds, characterized in that a compound of the formula XI for the production of a bicycloheptene ^ -syn-carbaldehyde of the formula X _t wherein 1 2
.. and H the specified in one of claims 1 to 5 Be · Have interpretations and R ^ those specified in claim 8 209843/1192 Has meaning "subject to acid hydrolysis under such conditions and when using such an acid is that the initially formed Byoyclohepten-7-antiearbaldehyde of the formula XII, wherein R and R have the meanings given above, without substantial decomposition isomerized into the corresponding bioyclohepten ~ 7 ~ eyn ~ earbaldehyd. 25. Process for the production of prostaglandins! * Or of prostaglandin-like compounds, characterized in that a compound of the formula HI ₁ Wherein R and R have the meanings given in one of claims 1 to 5, in a solvent with a « Amine of the formula S R * HH, wherein R ^ and R * are in claim have given meanings, implements * 26. The method according to claim 24, characterized in that the acidic hydrolysis is carried out in that the compound of formula XI is heated ^{to approximately 65 0 O for about 4 days with 1 part of 2N hydrochloric acid and 4 parts of bioxane.} 209843/1192