DD294260A5 - PROCESS FOR THE PRODUCTION OF SUBSTITUTED PYRROL COMPOUNDS - Google Patents

Abstract

The invention relates to a process for the preparation of substituted pyrrole compounds. These pyrrole compounds are potent cyclooxygenase and / or lipoxygenase inhibitors. They are therefore useful in medicine for the prevention of allergically induced diseases and for the treatment of diseases of the rheumatic type. {Method; manufacture; substituted pyrrole compounds; Pharmacy; Medicine; lipoxygenase inhibitors; cyclooxygenase inhibitor; allergic-induced diseases; Diseases of the rheumatic type}

Description

PROCESS FOR THE PRODUCTION OF SUBSTITUTED PYRROL COMPOUNDS

Field of application of the invention

The invention relates to substituted pyrrole compounds, processes for their preparation and their use in pharmacy.

Characteristic of the known state of the art

It is known that the metabolism of arachidonic acid takes place in two different ways. In the cyclooxygenase pathway, the arachidonic acid is metabolized to prostaglandins under the action of the enzyme cyclooxygenase. In the lipoxygenase pathway, arachidonic acid, under the action of lipoxygenases, becomes the so-called leukotrienes met & bolisicrt-

The prostaglandins are involved in the development of inflammation, fever and pain, while the leukotrienes play an important role in the development of asthma, inflammation and allergies. Non-steroidal anti-inflammatory drugs such as arylacetic acid, 2-arylpropionic acid and anthranilic acid derivatives are frequently used to combat these symptoms. These derivatives inhibit cyclooxygenase and thus prevent the formation of prostaglandins from arachidonic acid. However, the use of such derivatives is not safe because of their side effects. However, drugs that inhibit lipoxygenase are not available in the country.

Object of the invention

The aim of the invention is to provide new compounds which are useful for the treatment of rheumatic diseases.

Surprisingly, it has now been found that certain substituted pyrrole compounds are potent cyclooxygenase and / or lipoxygenase inhibitors and are therefore useful for the prevention of allergically induced diseases and for the treatment of rheumatic disorders.

DESCRIPTION OF THE NATURE OF THE INVENTION 15

The invention has for its object to provide a method for producing these substituted pyrrole compounds.

This object is achieved by the process according to the invention for the preparation of the compounds of the formula I. The substituted pyrrole compounds according to the invention have the general formula I:

wherein

R ^{1 represents} a C 1 -C 12 alkyl group;

r2 is a hydrogen atom or a Ci or

R ¹ and R ² together with the carbon atom and the nitrogen atom to which they are attached form a 5- to 8-membered ring which may optionally contain a sulfur heteroatom or a carbonyl group and which may optionally be substituted by 1 to 2 C 1 -C 4 ^ Alkyl groups may be substituted;

3 4 5

in each case two of the radicals R, R and R independently of one another a Wasserstoffato.Ti; a C 1 -C 6 cycloalkyl group; a C ₁ -C ₁₂ alkyl group or an aryl group optionally substituted by one or two groups selected from a halogen atom, a nitro, C ₁ -C ₄ alkoxy, hydroxy, C ₃ -C ₄ or phenoxy group, and

3 4 5 the third of the radicals R, R and R is -CHO, -C0 _? H, -C0SC ₁ -C ₄ -alkyl or AX, where A is a straight-chain or branched Cj-Cg-alkylene group which may be interrupted by an oxygen heteroatom or a carbonyl group, or a C ₂ -Cg-alkenylene group, and X is represents CO ₂ H, SO ₃ H, CHO, OH or SH,

and their pharmaceutically acceptable salts and esters, for use in pharmacy.

The pharmaceutically acceptable salts may in the present case be acid addition or base addition salts. For acid addition salts, use is made of inorganic

see acids, such as hydrochloric acid, sulfuric acid or phosphoric acid, or organic acids, such as tartaric acid, lactic acid, citric acid, malic acid, mandelic acid, ascorbic acid, maleic acid, fumaric acid, gluconic acid and the like.

Base addition salts include salts of the compounds of formula I with inorganic bases such as sodium or potassium hydroxide or with organic bases such as mono-, di- or triethanolamine.

The esters of the compounds of the formula I include, in particular, physiologically readily hydrolysable esters, for example alkyl, pivaloyloxymethyl,

Acetoxymethyl, phthalidyl, indanyl and methoxymethyl esters.

The term "alkyl, alkoxy, etc." includes straight-chain or branched alkyl groups, such as methyl, ethyl, n- and i-propyl, n-, i- or t-butyl, n-pentyl, neopentyl, n-hexyl etc.

10

Unless stated otherwise, "alkyl" is preferably C.-Cn-alkyl and especially C.-C, -alkyl.

Aryl is preferably naphthyl and especially phenyl.

The term "halogen atom" includes a fluorine, chlorine, bromine or iodine atom and in particular a fluorine or chlorine atom.

20

The cycloalkyl radical is preferably a cyclopentyl or cyclohexyl radical.

A preferred embodiment are compounds of the formula Ia:

30

35

wherein R

R ⁴ and R are the ones related to the above

Have formula I and R and R ^{7 are} independently a hydrogen atom or a C ₁ -C ₄ -AlKyIgTUpPe.

Particular preference is given to compounds of the formula Ia in which two of the radicals R, R and R are each a

Phenyl group, the

is optionally substituted by one or two radicals which are selected from a halogen atom, in particular a fluorine or chlorine atom, a

C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, hydroxy and phenoxy

group, and the third radical is AX, wherein A is a C.-C "alkylene group or a C ₁ -C g nylengruppe and X is CO ₂ H.

AX is in particular C ₉ -C, -alkylene-CO-, Η or C ₂ -C ₆ -alkenylene-CO ₂ H and particularly preferably (CH ₂ ) ₂ CO ₂ H, CH ₂ CO ₃ H or CH = CH CO ₃ H.

R and R are preferably in the 2-position of the pyrrolizine skeleton and in particular both are a hydrogen atom or a methyl group.

Particularly preferred embodiments are the compounds of the formulas:

⁶ 13 ¹ IICO

wherein R and R represent a hydrogen atom or a C.-C.- alkyl group, and

R and R represent a phenyl group optionally substituted by one or two groups selected from a halogen atom, a nitro, C 1 -C 4 alkoxy, C 1 -C 4 alkyl or phenoxy group. A-X has the meanings given above in connection with the formula I.

, λ The substituents of the phenyl group ^ are preferably selected from a halogen atom, in particular a fluorine or chlorine atom, a C ₁ -C.-alkyl, C ₁ -C ₄ alkoxy and phenoxy group. The substituents are preferably in the m- and / or p-position.

A is preferably a C ^ -CG-alkylene group or C.-C _ß alkenylene group, in particular a C ₂ -C _f-alkylene. Or C ₃ -C, - alkenylene group X preferably is CC ^ H ,

Another embodiment is the compounds of formula I wherein

R and R independently of one another represent a C.sub.1-C.sub.4 alkyl group,

two of R ³ , R ⁴ and R ^{5 represent} a phenyl group which is optionally substituted by one or two radicals selected from halogen, C ₁ -C ₄ -alkyl. C ₁ -C ₄ -alkoxy, hydroxy and phenoxy, and

the third of the radicals R ³ , R ⁴ and R ^{5 is} a hydrogen atom or AX, where A is a C 1 -C ₆ -alkylene or C ₂ -C ₆ -alkenylene group and X is CO ₂ H or SO H

ro «- _A U. Λ- J

stands.

R ¹ preferably denotes a C ₁ -C ₆ -alkyl group, in particular a C ₁ -C ₆ -alkyl radical, and more preferably a C ₄ -C ₆ -alkyl group.

R ² is preferably a C ₁ -C ₄ -alkyl group and in particular a methyl group.

R and R and R and R are preferably phenyl, and R and R are preferably AX, where A is preferably a C.C.-alkylene group or C _n -C, -alkenylene group.

I. D

Particularly preferred compounds are:

(2,2-dimethy-6,7-diphenyl-2,3-dihydro-IH-pyrrolizine-5-yl) -acetic acid and

3- (2,2-Dimethyl-6- (4-phenoxyphenyl) -7-phenyl-2,3-dihydrol-H-pyrrolizin-5-yl) -propionic acid.

The invention also relates to the compounds of the general formula I and the corresponding abovementioned preferred embodiments per se, wherein R and R together represent a 5- to 8-membered ring which optionally has a sulfur heteroatom or a carbonyl group and which optionally with 1 to 2 C.-C.-

Substituted alkyl groups, and 30

3 4 5 R, R and R have the abovementioned meanings,

however, A is a straight-chained or branched C, -Cg-alkylene group optionally interrupted by an oxygen atom or a carbonyl group, or

a straight-chain or branched C 1 -C 6 -alkenyl group, or

wherein R to R are the meanings given in claim 4.

The synthesis of the compounds of the formula I in which R and R together form a 5- to 8-membered ring is carried out in a first step according to the following equation (1):

_{9CH 9} R ³ \ ^ - ^ + R ⁵ - CH - C - R ⁴

X = Cl, Br η = 1 -

This synthesis step is just like the subsequent air. B ispiel the diphenyl-substituted pyrrolizine compounds explained. The first reaction step is explained in more detail in the following reaction scheme:

Reaction scheme (1):

Ethanol, NaHCO ₃ , H ₂ O _> 40%

-N

CH,

Cl-C

Ethanol, NaHCO ₃ ,

15%

Ethanol, NaHCO ₃ .

20-30%

The reaction conditions for these reactions are known, as described in Chemiker-Zeitung, 110 (1986), No. 7/8, pages 267, 271 and Arch. Pharm. 321, 159-162 (1988).

In a second step, the introduction of a formyl or methylol group in the pyrrole ring and their further conversion to the corresponding acetic acid or ethanol derivatives according to the following reaction scheme (2)

Reaction scheme (2):

UAIH ₄₁ THF POCb. DMF ₁ benzene, Δ

CH ₂ OH

CHO

CHO

A-CH ₂ OH

CHO

CH ₂ OH

11

N ₂ CHCOOC ₂ H ₅ . Cu ⁰ , toluene, Δ

CH ₂ -COOC ₂ H ₅

UAIH ₄ , THF

CH ₂ -CH ₂ OH

CH ₂ -COOC ₂ H ₅

CH ₂ -CH ₂ OH

CH ₂ -COOC ₂ H ₅

CH ₂ -CH ₂ OH

¹²

These reactions and the reaction conditions are known, as described in Chemiker-Zeitung, (1986), Nos. 7/8, 267 to 271 and Arch. Pharm. 321, 159 to 162 (1988).

The preparation of the corresponding formic acid, propionic acid and acrylic acid derivatives is described in Arch. Pharm. 321, 545 to 549. It is carried out according to the following reaction schemes (3) and (4):

Roaction scheme (3);

ClCOSC H _{2. 5} AlQ ₃ . CH ₂ Cl ₂

SC2H5

KOH. Ethanol, Δ

COOH

\ Q --- SC2H5

COOH

14

Reaction scheme (4)

CHO

Wittig ^Raaktlon

HI

C-COOC ₂ H ₅ KOH, // ethanol, Δ

ethanol

(CHO) ₂ -COOH

COOC ₂ H ₅

COOH

¹⁵

The preparation of the corresponding butyric acid derivatives is carried out according to the following Reaction Scheme (5). Initially, Friedel-Crafts acylation with succinic anhydride (E. Berlina, Org. React. 1949, 5, 229-289) prepared the 4-qobutyric acids, which were then purified by the Huang-Minlon variant of the Wolff-Kishner reduction in Diethylene glycol can be reduced with hydrazine / KOH. The reaction conditions are known to the person skilled in the art.

16

Reaction scheme (5):

H ₂ N-NH ₂ , NaOH ₁ Dlethytenglykol, Δ

A) Cl ₃ , CH ₂ Ct ₂

(CH ₂ VCOOH

^ - (CH ₂ J ₂ -COOH

(CH ₂ ) ₂ -COOH

(CH ₂ ) ₃ -COOH

(CH ₂ ) ₃ -COOH

The valeric acid derivatives can be prepared analogously to the corresponding steric acid derivatives via the 5-oxovaleric acids which are obtainable by Friedel-Crafts acylation with glutaric anhydride from the pyrrolizine Gr 3 bodies. Similarly, the Capronsaure derivatives are obtained by Friedel-Crafts acylation of Diphenylpyrrolizine with methyl-5- (chloroformyl valerate / AlCl, and saponification of the obtained 6-üxceapronsäuremethylester derivatives and subsequent reduction of the oxovaleric acid with hydrazine / KOH.

The preparation of the compounds substituted on the phenyl group is carried out in an analogous manner. The hydroxy-substituted derivatives are thereby by ether cleavage

with BBr, prepared from the corresponding alkoxy derivatives (Tetrahedron, 1968, 24, 2289-2292).

In the following the preparation of the compounds of formula I is described, in which R and R ^{2 is} a

Are ^C l ^"c i2 ~ ^Alkvl 9 PP ^{ru e.} Starting product for the synthesis of these compounds are the corresponding 2,3,4 or 2,3,5-substituted pyrrole compounds, their preparation is described in Aust. J. Chem. 1966, 2 ^{rj 19} ' ¹⁹⁷¹ - 1885. The further synthetic steps are explained below by way of example starting from 2-methyl-2,3-diphenylpyrrole and 5-methyl-2,3-diphenylpyrrole. 7)

 30

Reaction scheme ( 6);

Toluenesulfonate methyl ester or

Alkyibromld

Verb. R H H CH ₃ S C ₂ H ₅ d Pi-C ₃ H ₇ sl n-W f HC ₅ H ₁₁ Q HC ₆ H ₁₃ H ISO-C ₄ Hg i neopentyl

CH ₂ -CHCOOCH ₃ , BF ₃ , CH ₂ CICH ₂ Q

COOCH ₃

KOH

 Ethanol, Δ

COOH

Reaction scheme (7)

Toluol sulfonic acid methyl ester or

Alkyibromld

Verb. R H a CH ₃ b C ₂ H ₅ nC ₃ H ₇ IQ. nC ₄ H _g e HC ₅ H ₁₁ f nC ₆ H, 3 G nc ₈ H ₁₇ H ISO-C ₄ H ₉ I neopentyl i

N ₂ CHCOOC ₂ H ₅ . Cu ⁰ . Toluene, Δ

KOH, ethanol, Δ

The first step is an alkylation of the pyrrole nitrogen atom. This reaction is carried out in a conventional manner, for example using the corresponding alkyl halides in the presence of a base, e.g. Alkali metal alcoholates such as sodium methylate, sodium ethylate or potassium t-butylate in an inert solvent such as DMSO, ethylene glycol ethyl ether and the like. The alkylation can also be carried out heterogeneously with the corresponding toluenesulfonic acid alkyl esters or alkyl halides using phase transfer catalysts in a conventional manner (see, for example, Can. J. Chem. 1977, 55, 4112-4116). The introduction of the acid side chains then takes place analogously to the syntheses of the corresponding pyrrolizinylcarboxylic acids, as described above.

The compounds according to the invention have proven to be potent cyclooxygenase and / or lipoxygenase inhibitors. They are therefore useful in the treatment of rheumatic diseases and in the prevention of allergic-induced diseases. Thus, the compounds of the present invention are potent antiphlogistics, analgesics, antipyretics, antiallergics and broncholytics and are useful for thromboprophylaxis and prophylaxis of anaphylactic shock and for the treatment of dermatological disorders such as psoriasis, urticaria, acute and chronic rashes of allergic and non-allergic origin.

The compounds of the invention can be administered either as individual therapeutic agents or as mixtures with other therapeutic agents. They may be administered alone, but are generally administered in the form of pharmaceutical agents, that is, as mixtures of the active ingredients with suitable pharmaceutical carriers or diluents. The compounds or agents can be administered orally or parenterally,

however, they are preferably given in oral dosage forms.

The type of pharmaceutical agent and the pharmaceutical carrier or diluent will depend on the desired mode of administration. Oral agents may, for example, be in the form of tablets or capsules and may contain common excipients such as excipients (eg syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone), fillers (eg lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine), lubricants (eg, magnesium stearate, talc, polyethylene glycol, or silica), disintegrating

agent (e.g., starch) or wetting agent (e.g., sodium lauryl sulfate). Oral liquid preparations may be in the form of aqueous or oily suspensions, solutions, emulsions, syrups, elixirs or sprays, etc., or may be presented as a dry powder for reconstitution with water or other suitable vehicle. Such liquid preparations may contain conventional additives, for example suspending agents, flavorings, diluents or emulsifiers. For parenteral administration, solutions or suspensions may be employed with conventional pharmaceutical carriers.

The compounds or agents of the present invention can be administered to a mammal (human and animal) at doses of from about 0.5 mg to about 100 mg per kg of body weight per day. You can administer 3Q in a single dose or in multiple doses.

The effectiveness of the compounds of the invention can be determined by the inhibition of 5-lipoxygenase or cyclooxygenagg se. The investigations were carried out as follows:

Test system for the determination of the inhibition of 5-lipoxygenase

Bovine granulocytes, which, like the human granulocytes, are capable of producing leukotrienes were chosen as the source of 5-lipoxygenase. By stimulation with calcium ionophore (see Biochem Biophys Acta 1984 , 795, 499 to 503) are mainly LTC ₄ (leukotriene C, ) and LTB.

^ q, B.) are formed from endogenous arachidonic acid. The isolation of the granulocytes and the performance of the enzyme reaction are carried out by known methods (see Biochem., Biophys Acta 1984 , 795, 499-503). The blood protected with EDTA from coagulation is first centrifuged and the platelet-rich supernatant is removed. After lysis of the erythrocytes with water, lymphocytes and monocytes are separated from the granulocytes by means of a Ficoll gradient. The granulocytes are adjusted to a specific cell number. The enzyme reaction is then started in the presence or absence of the test substances after addition of Ca with calcium ionophore. The synthesis of the leukotrienes is stopped after 5 minutes by addition of a mixture of methanol and acetonitrile containing PGB2 as internal standard and NDGA as antioxidant. The samples are then diluted in water and purified as described in J. Chromatogr. 1986 , 378, 208-214, worked up. The measurement of LTB. takes place in the absorption maximum at 270 nm. The arachidonic acid metabolytes are recovered approximately quantitatively in this investigation.

Test system for determining the inhibition of cyclooxygenase

In this test system, the amount of 12-HHT produced by bovine thrombocytes after addition of calcium ionophore becomes 12-hydroxyheptadeatrienoic acid or prostaglandin E2 ~ amount

determined by UV detection after HPLC separation. Doing 35

The thrombocytes are obtained after centrifugation of the bovine blood from the supernatant obtained. The enzyme reaction and the isolation of the formed

²³ ι

Metabolites are as in the determination of 5-lipoxy • genase inhibition, but the incubation time was one minute 5. The detection of 12-HHT after HPLC separation takes place at 232 nm.

The results obtained in the testing of the compounds of the invention are summarized in Tables 1 and 10 below. The test substances were used at a concentration of 10 μΜ.

Table 1: Inhibition of .5-lipoxygenase and cyclooxygenase by pyrrolidine compounds

(10 μΜ)

Ver bind. No. R ³ R ⁴ R ⁵ R ⁶ R ⁷ Inhibition% lipoxy-cyclooxygenase genase 99 phenyl (CH ₂ J ₄ CO ₂ H phenyl H H 82 97 phenyl (CH ₂ J ₅ OO ₂ H phenyl H H 80 (CH ₂ J ₄ CO ₂ H phenyl phenyl H H 86 (CH ₂ J ₅ CO ₂ H phenyl phenyl H H 86 91 phenyl phenyl CH ₂ CO ₂ H CH ₃ CH ₃ 94 phenyl phenyl (CH ₂ J ₂ OO ₂ H CH ₃ CH ₃ 91 (CH ₂ J ₂ OO ₂ H phenyl phenyl CH ₃ CH ₃ 93 (CH ₂ J ₅ OO ₂ H phenyl phenyl ^ 3 CH ₃ 96 phenyl phenyl CH ₂ OO ₂ H H H phenyl phenyl CH = CH-CO ₂ H H H 80 Ql = CHCO ₂ H phenyl phenyl CH ₃ CH ₃ 91 70 phenyl ^C 6 ^H 13 CH = CHCO ₂ H H H 82 93 (3.3 μΜ) phenyl m-chlorophenyl (CH ₂ J ₂ CO ₂ H H H 89 93 (3.3 μΜ) phenyl p-chlorophenyl (CH ₂ J ₂ OO ₂ H H H 98 phenyl p-tolyl (CH ₂ J ₂ OO ₂ H H H 92 Phenyl phenyl phenyl p-methoxyphenyl ρ phenoxyphenyl-naphthyl 9 9 9 NJ NJ NJ NJ NJ 8 8 8 NJ NJ NJ XXX XXX XXX 91 98 94 phenyl p-fluorophenyl (CH ₂ J ₂ CO ₂ H ^ 3 CH ₃ phenyl p-tolyl (CH ₂ J ₂ OO ₂ H CH ₃ CH ₃ phenyl p-Fncp.oxy- phenyl (CH ₂ J ₂ CO ₂ H CH ₃ CH ₃ 98 (3.3 μΜ

25

Table 2: Inhibition of 5-lipoxygenase by 2-methyl-1-diphenyl pyrrole acetic acid

R ³ R ⁴ Il \

10 μΜ)

R ¹ R ² R ³ R ⁴ (CH ₂ R ⁵ Inhibition (%) (Lipoxygenaso'j HC ₄ H ₉ ^OT 3 phenyl phenyl (CH ₂ J ₂ CO ₂ H 94 nC ₅ H _n phenyl phenyl (CH ₂ J ₂ CO ₂ H 99 HC ₆ H ₁₃ ^ffl 3 phenyl phenyl (CH ₂ J ₂ OO ₂ H 99 Neopentyl CH ₃ phenyl phenyl J ₂ CX) ₂ H 97

26

Ausführunysbeispiele

The following examples illustrate the invention. All temperatures are uncorrected. Unless otherwise stated, the IR spectra were recorded with KBr pellets. Unless otherwise indicated, the NMR spectra are 90 MHz spectra recorded in CDCl with tetramethylsilane (TMS) as the internal standard.

The preparation and characterization of the compounds used as starting materials in some cases for the following reactions and compiled in Tables 3, 4 and 5 below are described in:

Arch. Pharm. 312, 896-907 (1979)

Arch. Pharm. 319, 500-505 (1986)

Arch. Pharm. 321, 159-162 (1988)

Arch. Pharm. 321, 545-549 (1988)

Chemiker Zeitung, 110 (1986), 7/8, 267 -

27

¹ SVZGO

table

Example no. R H R 'H CH ₃ 1 CHO la IIJ 2 CH ₂ OH £ a £ b_ 3 CH ₂ COOC ₂ H ₅ 2a 4 (CH ₂ ) ₂ OH 1ΖΆ J2b_ 5 COOH 15a 15b 6 CH ₂ COOH 18a 18b 7 (CH ₂ ) ₂ COOCH ₃ 23a 23b 8th (CH ₂ ) ₂ COOH 26a 26b 9 CH = CHCOOC ₂ H ₅ (E) 2Za 2Zb. 10 CH = CHCOOH (E) 3Q 11 33

28

table

Example no. R H R 'H CH ₃ 12 CHO 2E 2h 13 CH ₂ OH Za 7h 14 CH ₂ COOC ₂ H ₅ .1Qa 10b 15 (CH ₂ ) ₂ OH 13a 13b 16 COSC ₂ H ₅ 16a 16b 17 COOH 19a 19b 18 CH ₂ COOH 2ia 21b 19 CH = CHCOOC ₂ H ₅ (E) 24a 24b 20 CH = CHCOOH (E) 2S 21 (CH ₂ ) ₂ COOH 3JJ 22 52

29

table

Example no. R R 'H CH ₃ 23 H & 3J2 24 CHO fia fib 25 CH ^ H iia lib. 26 CH ₂ COOC ₂ H ₅ 14a 14b 27 (CH ₂ ) ₂ OH Iza IZl ₂ 28 COSC ₂ H ₅ 20a 20b 29 COOH 22a 22b 30 CH ₂ COOH 25a 25b 31 CH = CHCOOC ₂ Hs (E) 29a 29b 32 CH = CHCOOC ₂ H ₅ (Z) 29b ' 33 CH = CHCOOH (E) 31a 31b 34 CH = CHCOOH (Z) 31b ' 35 (CH ₂ J ₂ COOH 33a 33b

General work on the preparation of 4- (diphenyl-2,3-dihydro-1H-, pvrrolizinvlH-oxobutyric acids

To dissolve 4 mmol of diphenyl-2,3-dihydro-1H-pyrrolizine and 4 mmol (0.40 g) of succinic anhydride in 16 ml of absol. CH.sub.2Cl.sub.2 are added in portions with 8.8 mmol (1.17 g) of AICI.sub.3 while cooling with ice and while stirring within 5 minutes. Then it is stirred for 45 min at RT. The mixture is then poured into 150 ml of ice water. After adding 4 ml of 8% H3PO4, it is extracted three times with CHCl3, the organic phases are dried over Na2SO4 and the solvent is distilled off. The product is isolated by means of SC (silica gel, 1.Ether, 2.Ether / THF 1 + 1). The product fractions are concentrated, the residue is dissolved in a little CHCl 3. After addition of n-hexane and renewed concentration, the product precipitates.

General working method for the preparation of 4- (Diphenvl-2.3-dihvdro-1H-pvrrolizinvD-butyric acids

0.5 mmol of 4- (diphenyl-2,3-dihydro-1H-pyrrolizinyl) -4-oxobutyric acid are mixed with 10 ml of diethylene glycol, 50 mmol (2.8 g) of KOH and 30 mmol (1.5 g) of hydrazine hydrate. The mixture is heated for 1 h to reflux (bath temperature about 17O ⁰ C). Then you replace the reflux condenser through a distillation bridge and continue to heat until an internal temperature of about 21O ⁰ C is reached. This temperature is then maintained for 2 hours. After cooling, the mixture is poured into 150 ml of H 2 O, acidified with 8% H 3 PO 4 and extracted three times with ether. The extracts are washed with H 2 O, dried and concentrated. The product is isolated by SC (silica gel, ether / THF 4 + 1 at 3_ £, diisopropyl ether at 4Q ₁ ether at 41a and ether / n-hexane 4 + 1 at 4_ib_)

and precipitated with η-hexane.

General procedure for the preparation of 5- (diphenyl-2,3-dihydro-1H-pvrrolizinvn-5-oxovaleric acids

4 mmol of diphenyl-2,3-dihydro-1H-pyrrolizine are absol in 16 ml. CH2Cl2 reacted with 4 mmol (0.46 g) glutaric anhydride and 8.8 mmol (1.17 g) AICI3 analogously to the AAV to prepare the 4- (diphenyl-2,3-dihydro-1H-pyrrolizinyl) -4-oxobutyric acids (see S. 222). By way of derogation, the mixture is poured into ice water immediately after the addition of AlC.sub.1 and worked up further. The product is purified by column chromatography (silica gel / ether).

In general, a protocol for the preparation of 5- (Diphenvl-2.3-dihvdro-1H- pyrrolizinvn-5-valeric acids

0.5 mmol of 5- (diphenyl-2,3-dihydro-1H-pyrrolizinyl) -5-oxovaleric acids are reacted analogously to the AAV to prepare the 4- (diphenyl-2,3-dihydro-1H-pyrrolizinyl) -4-oxobutyric acids. The product is isolated by SC (silica gel, ether) and precipitated with η-hexane.

General procedure for the preparation of the 6- (Diphenvl-2.3-dihvdro-1H-

pvrrolizinvl) -6-oxocapronsäuremethvlester

To dissolve 10 mmol of diphenyl-2,3-dihydro-1H-pyrrolizine and 10 mmol (1.79 g) of methyl 5- (chloroformyl) -va! Erat in 50 ml absol. CH 2 Cl 2 are added under ice-cooling and with stirring within 5 min portionwise 22 mmol (2.93 g) AICI3. Immediately thereafter, the batch is poured into 150 ml of ice-cooled 10% NaCl solution. After addition of 4 ml of 8% H3PO4, it is extracted three times with ether, the organic phases are dried over Na9SO4

and distilling off the solvent. The product is isolated by means of SC (silica gel, 1 n-hexane / ether 3 + 2, 2 n-hexane / ether 1 + 4 at 4 l, 5JIa and 50Ji or 1 toluene, 2nd hexane / ether 1 +4 at 49.). The eluates are first concentrated to about 100 ml, washed twice with 0.05N NaOH and twice with 10% NaCl solution and finally dried over Na 2 SO 4. The products precipitate upon concentration of the solution or crystallize after distilling off the solvent.

32 Z9UZ0O

General work description of the 6- (diphenyl-2,3-dihydro -1H- pyrrolizinyl) -6- capronic acids

The solution of 1 mmol of methyl e-l-diphenyl-.S-dihydro-IH-pyrrolizine O-S-oxocaproate in 10 ml of ethanol is heated to boiling. Then added dropwise 5 ml of 10% aqueous KOH, which have been previously degassed by boiling, and heitit still 15 min under reflux. After cooling, the mixture is poured into 100 ml of 5% NaCl, acidified with 8% H3PO4 and extracted three times with ether. The organic phases are dried over Na 2 SO 4 and concentrated. The residue is reacted with 50 mmol (2.8 g) of KOH and 30 mmol (1.5 g) of hydrazine hydrate in 10 ml of diothylene glycol analogously to AAV to prepare 4- (diphenyl-2,3-dihydro-1H-pyi-tolizinyl) -butyric acids

and purified by column chromatography on silica gel.

The compounds obtained and some physical data of these compounds are summarized in Tables 6 to 8 below.

33

table

Example no. R 3 £ Schmp. "C IR ¹ ) 36 CO (CH ₂ J ₂ COOH 32 187-188 1710, 1635 37 (CH ₂ ) ₃ COOH 42 166-167 1705 38 CO (CH ₂ J ₃ COOH 45 142-143 1710, 1635 39 (CH ₂ ) ₄ COOH 4fi 146 1710 40 CO (CH ₂ ) ₄ COOH £ 1 99 1740, 1630 41 (CH ₂ ) ₅ COOH £ 4 - * 42 CH (CH ₃ ) COOC ₂ H ₅ se - 1730 43 CH (CH ₃ ) COOH 173 1705 -Band ^X) (C = O)

1 H NMR: δ (ppm) = 1.06-1.78 (m, 6H, - (Cu ₂ ) S-CH ₂ -CO-), 2.10-2.40 (m, 2H ₁ -CH ₂ -CO-), 2.40-2.76 (m, 4H, PyC-CH ₂ ^{and c} " ² ) * ³⁰² ^ - ^2H * ^{J = 17 Hz} * C-1), 3.94 (t, 2H ₁ J = 7 Hz ₁ C-3), 6.97-7.31 ( m, 1OH, Arom.)

Table 7

15 20 25

Example no. R Schmp. • c IR ¹ ^ 44 CO (CH ₂ J ₂ COOH 2Z 231-234 1715, 1680 45 (CH ₂ J ₃ COOH 4Q 176-178 1715 46 CO (CH ₂ ) ₃ COOH 43 128 1710.1660 47 (CH ₂ J ₄ COOH 4 lbs 126-127 1700 48 CO (CH ₂ J ₄ COOCH ₃ 42 112 1745.1658 49 (CH ₂ ) ₅ COOH £ 2 63 1710

30

(C = O) band

35

30

Table 8

10

20

Be.Lsp no. R R '- ^H I = 38b M.p. a ⁰ C b a D b 50 CO (CH ₂ J ₂ COOH 38a 41b 190-191 187-188 1715, 1665 1645 1715-1645 51 (CH ₃ ) ₃ COOH 41a 44b 146-148 192-194 1705 1710 52 CO (CH ₂ J ₃ COOH 44a 47b 109 167 1720, 1660 1715, 1660 53 (CH ₂ J ₄ COOH 47a 50b 111-112 1705 129-130 1715 54 CO (CH ₂ ) ₄ COOCH ₃ 50a 53b 92 1735, 1645 1740, 1655 55 (CH ₂ ) ₅ COOH 53a 123 1710 122 1710

(C = O) band

35

General work description of 2- (Diphenvl-2,3-dihvdro1H- p- rrolizinvlVproDionsäureethylester

5 mmol of diphenyl ^. S-dihydro-IH-pyrrolizine, dissolved in 4 ml of absolute. Toluene, with 7.5 mmol (0.96 g) 2-Diazopropionsäureethylester, dissolved in 2 ml of absolute. Toluene, analogous to the AAV for the preparation of diphenyl-2,3-dihydro-1H-pyrrolizinylessigsäureethyester implemented. The reaction time is 2 h. The purification is carried out by SC (Al ₂ O ₃ , n-hexane / ether 9 + 1).

The products are precipitated with ethanol.

General procedure for the saponification of 2- (Diphenvl-2,3-dihvdro-1H-pyrronzinylD-propionic acid ethyl ester

1.6 mmol 54 or 0.5 mmol 5_5_a and 55b. dissolved in 12 ml or 9 ml of ethanol, with 8 ml or 2.5 ml of 10% aqueous KOH analogous to the AAV for saponification of diphenyl-2,3-dihydro-1H-pynOlizinylessigsäureethylester

implemented. The saponification time is 5_4_15 min, 5_5_a and 5_5_b_ 60 min. The purification is carried out by means of SC (silica gel, 1. N-hexane / ether 1 + 1, 2.

Ether). After concentrating the eluates, the products are precipitated with η-hexane.

The compounds obtained and some physical data of these compounds are summarized in Table 6 and Table 9 below.

37

table

R '

Example no. R R H CH ^ ScY a imp. b IR a (C = O) b 56 CH (CH, iCOOC-.H, - 55a 55b 133 136 1730 1740 57 CH (CH ₃ ) COOH 57a 57b 190 1705 226 1710

example

5- (1- (5-6-diphenv ^ -2,3-dihydro-1H-pv ^ τolizine "7-vl) -ethvl) -2-dimethy-1-dodecane- 4,6-dione (52a) The solution of 4 mmol (1.04 g) 3a, 4 mmol (0.58 g) of 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid) and 8 mmol (0.35 g) of freshly distilled acetaldehyde in 40 ml of acetonitrile 24 h allowed to stand at 3O ⁰ C. After cooling in an ice bath the precipitated product is filtered. yield:. 0.44g (26%) m.p .: 169 ⁰ C (with dec.)

1790 (C = O), 1755 (C = O) ₁ 1605 (C = C)

38 W160

Example 59

5- (1- (2,2-Dimethyl-5,6-di-phenyl-2,3-dihydro-1H- pi-iTli-2-yl-7-vl) -ethyl) -2,3- dimethyl- 1,3 -dioxane- 4,6 -dione (59_bJ

4 mmol (1.15 g) of 3b_ are reacted with acetaldehyde and MeWrum's acid as described in 59ji.

Yield: 1.35 g (74%)

IR: v _max -1790 (CO),

Example 60

3- (5.6-Diphenvl-2.3-dihydro-1H-dibrolizin-7-vl) -butyrate (60a ) 1 mmd 5_9_a is dissolved in a mixture of 5 ml absolute. Pyridine and 1.0 ml abso). Ethanol dissolved. After addition of some copper powder is heated to reflux for 3 h. The copper powder is filtered off with suction and the solvent is distilled off in vacuo. From the residue, the product is isolated by means of SC (silica gel, n-HeXBfVCH ₂ Cl ₂ 1 + 2)

 Yield: 95 mg (25%)

IR: vmax »1735 (C = O) ₁ 1605 (C = C) cnr" »

Example 61

3- (2.2-Dimethvl · 5.6-diDhenvl-2 3-dihydro-1H-pvrrolizine-7-vl) -butyrate (60b)

2.5 mmd 5_9_b_ in a mixture of 20 ml absol. Pyridine and 2 ml absolute. Ethanol dissolved uno 'after addition of some copper powder as described in 6jQa implemented. The purification is carried out by SC (silica gel, n-hexane / CH ₂ Cl ₂ 2 + 1) isolated

 Yield: 0.68 g (68%)

IR: vmax - 1745 (C = O), 1605 (C = C) cnr *

³⁹ a to zto

Example 62

3- (5.6-Diphenyl-2,3-dihydro-1H- pyrrolizine-7-vn-butyric acid (61a) The eluates are concentrated, the product is crystallized with a little ether and then largely precipitated by the addition of η-hexane . yield: 63 mg (36%) m.p .: 157 ⁰ C (with dec.)

IR: v _max = 3300-2400 (OH) ₁ 1710 (C = O), 1605 (C = C) crrri

Example 63

3- (2,2-dimethyl-5,6-di-dhenyl-2,3-dihydro-1 H -pyrroli7- in-7- yn-butyric acid

(filh) '.

The product precipitates on concentration of the eluates. Yield: 0.26g (46%), m.p .: 202-208 ⁰ C (with dec.)

General working procedure for

Preparation of trimethylphenyl-2,3-dihydro-1H-oyrrolizine 0.05 mol (5.6 g) 2,4,4-trimethyl-A1-pyrroline dissolved in 25 ml absolute. Ethanol, with 0.05 mol (10.7 g) of 1-bromo-1-phenylacetone (at 6_3J or a-bromopropiophenone (at £ 4) analogously to the synthesis of 3.1 implemented .Davincn after addition of the NaHCO3 solution (0.06 mol in 40 ml of H 2 O) is heated to reflux for only 4 h and purified by means of SC (Al 2 O 3, n-hexane / ether 9 + 1) .After evaporation of the eluates, an oil remains.

40

General protocol for the preparation of trimethyl-phenyl-SS-dihydro-IH-pvrrolizinvlessiic acid ethyl ester 5 mmol (1.13 g) £ 3 or £ 4, respectively. dissolved in 5 ml absolute. Toluene, with 7.5 mmol (0.86 g) of ethyl diazoacetate, dissolved in 4 ml of absolute. Toluene, analogous to

general procedure for the preparation of diphenyl-2,3-dihydro-IH-pyrroliziny1-ethyl acetate reacted. The products are obtained after SC (Al ₂ O ₃ , 1. n-

Hexane / ether 9 + 1, 2. η-hexane / ether 3 + 2) as oils.

Verification of the trimethyphenols vl-2,3-dihydrodyl -1 H- pyrrolizine ylacetic acid and hylester 1.5 mmol £ 5. BZV /. 0.5 mmol of oil, dissolved in 4 ml or 12 ml of ethanol, are treated with 2.5 ml or 7.5 ml of 10% aqueous KOH analogously to the general procedure for saponification of Dj.phenyl-2,3-dihydro-lH-pyrrelizinyl-acetic acid ethyl ester

implemented. The purification is carried out by column chromatography

The compounds obtained and some physical data of these compounds are given in Tables 10 and 11 below.

41

Table 10

10

15 20

Example no. R 6J3 Mp. IR ^1} 64 H 65 - 1605 65 CH ₂ COOC ₂ H ₅ 62 - 1735 66 CH ₂ COOH 168 1715

25

30

35

table 11 R H ₃ C / = H ₃ C \ CH ₃

r * " R ü 66 68 Mp. IR ¹¹ 67 68 69 H CH ₂ COOC ₂ H ₅ CH ₂ COOH 58-60 141 1595 [C = C] 1740 1710

(C = O) band, unless stated otherwise

ISH IGO

Example 70

5- (n- Hexyl) -7-phenyl-2.3 <lihy dro-1H- di-tolizin (£ 9.) To the solution of 36 mmol of n-octanal in 15 ml of ether and 5 ml of dioxane is added the solution of 35 mmol (5.6 g) of bromine in 5 ml CH 2 Cl 2 slowly added dropwise. Then it is mixed with 50 ml of ether and washed twice to neutralize HBr twice with 5% NaHCC ^ solution. The organic phase is dried over Na 2 SO 4 and concentrated. The residue is dissolved in 50 ml of ethanol and added to a mixture of 35 mmol of 2-benzyl-1-pyrroline, 50 ml of ethanol and 50 ml of 10% NaHCO.sub.3 solution After stirring at RT for 24 h, the mixture is poured In 500 ml of 10% NaCl and extracted twice with ether, the organic phases are dried over Na 2 SO 4, the solvent is distilled off and the resulting Pyrrolizine Mouth ZQ is isolated by SC (Al 2 O 3, n-hexane / ether 9 + 1)

 The two isomeric pyrrolizines are then dissolved in 60 ml of dichloroethane and admixed four times at intervals of 15 minutes with 17 mmol each of methyl acrylate and 1.0 ml of BF 3 etherate. The mixture is extracted twice with ether after adding 200 ml of 5% NaCl solution. After drying over Na 2 SO 4, the solvent is distilled off and the unreacted fiS is isolated by SC (Al 2 O 3, n-hexane / ether 9 + 1). The eluates are concentrated. The remaining oil solidifies after some time

Bulge: 1.23 g (16%) MP: 46-47 ⁰ C C19H25N (224.1) IR: vmax-1610 (OC)

₁ H-NMR: 6 (PPm) -OJS-LOe (Fn ₁ SH ₁ -CH ₃ ), 1.06-1.76 (m, 8H ₁ -CH ₂ -), 2.33-2.72 (m 4H, C-2 and pyridine) CHjr), 3.04 (t 2H ₁ J-7 Hz ₁ C-1), 3.83 (t, 2H ₁ J = 7 Hz. C-3). 6.20 (see 1H ₁ C-5), 6.95-7.56 (m, 5H ₁ flavor)

Example 71 5- (5- ( n-Hexyl) -7-phenyl-2.3-clihydro-1H-ovrr-6-chloro-6-vl) -5-oxovaleric acid

5 mmol 5- (n-hexyl) -7-phenyl-2,3-dihydro-1H-pyrrolizine 9 lbs. are reacted in 20 ml CH 2 Cl 2 with 5 mmol (0.5 g) glutaric anhydride and 11 mmol (1.47 g) AICI 3 analogous to AAV to prepare the 5- (diphenyl-2,3-dihydro-1H-pyrrolizinyl) -5-oxovaleric acids. The product is purified by means of SC (silica gel, 1N-hexane / ether 1 + 1, 2 nd ether.) After concentrating the eluates, Zl remains as an oil

 Yield: 0.40 g (21%) C24H31NO3 (381.5)

₁ H NMR: δ (ppm) -0.69-1.07 (m.H 3H ₁ -CH ₃ ). 1.07-1.98 (m, 10H ₁ -CH ₂ -), 1.98-2.65 (m.H 6H ₁ C-2 and -CO-CHo-CHp-CHg-CO-). 2.65-2.95 (m 4H ₁ C-1 UfXi Pyr-CH 2 -), 3.91 (t 2H ₁ J = 7 Hz ₁ C-3). 7.07-7.47 (m, 5H ₁ Ar om.)

Example 72

5- (5- (n-Hexy-y-7-phenyl-2,3-dihydro-1H-dyrrolizine-6yl) valeric acid (72) 1 mmol Z1 is dissolved in 10 ml diethylene glycol 50 mmol (2.8 g) KOH and 30 mmd (1.5 g) of hydrazine hydrate analogously to the AAV for the reduction of 4- (diphenyl-2,3-dihydro-1H-pyrrolizinyl) -4-oxobutter acid .. The product is purified by means of SC (silica gel / diisopropyl ether After concentration of the eluates, IZ remains as an oil

 Yield: 0.20 g (54%) C24H33NO2 (367.5)

IR: ν, * * - 3600-2400 (OH) ₁ 1710 (C = O) ₁ 1605 (OC) cm-1 1 H-NMR: δ (ppm) - 0.72-1.12 (m 3H, -CH ₃ ), 1.12-1.78 (m, 12H, -CH ₂ -), 2.08-2.70 (m, 8H ₁ C-2. -CH ₂ -CO- and 2x PyT-CH ₂ -). 2.90 (t 2H ₁ J = 7 Hz "OD.3.87 (t 2H J = 7 Hz C-3), 6.95-7.44 (m 5H ₁ A / om)

Example 73 and 74

5-fn-Hexyl) -7-prienyl-2,3-dihydro- 1H- pyrrolidin-e-yl-carb aldehyde (Z3) S-fn-HexvD-T-phenyl ^, S-dihydro-IH-ovrrolizine-S yl-carbaldehy d (74) Each 35 mmol of OdanaJ, bromine and 2-benzyl-A1-pyrroline are reacted analogously to the preparation of 9 9_ and ZQ. The isolated pyrrolizines are then absol. In 35 ml. Benzene and with 105 mmol (7.7 g) absolute. DMF and 35 mmol (5.4 g) of POCl3 reacted analogously to the AAV for the Vilsmeier formylation of the diphenyl-2,3-dihydro-1H-pyrolytic acid. The two

Products are separated by SC on silica gel, eluting first with n-hexane / diisopropyl ether Z3_ and then with diisopropyl ether JA . Both products accumulate as oils after concentration of the eluates. Structural proof of Z3: at the Vilsmeier-Forrnylierung of £ 9. The same product is created.

Yield: 1.74 g

C20H25NO (295.4)

IR: v _max - 1660 (C = O), 1610 (C = C) cm * i

₁ H NMR: δ (ppm) = 0.73-1.07 (m, 3H ₁ -CH ₃ ), 1.07-1.86 (m, 8H ₁ -CH ₂ -). 2.30-2.70 (m, 2H, C-2), 2.74-3.05 (m, 4H, C-1 and PyT-CH ₂ -), 3.91 (t, 2H, J = 7Hz, C-3), 7.05- 7.46 (m, 5H, Arom.), 9.87 (s, 1H, -CHO)

Yield: 2.13 g

C20H25NO (295.4)

IR: vnvax -1655 (C = O) ₁ IeIO (C = C) CnTi

₁ H NMR: δ (ppm) = 0.68-1.01 (m, 3H ₁ -CH ₃ ), 1.01-1.74 (m, 8H ₁ -CH ₂ -), 2.30-2.67 (m, 2H, C-2), 2.67 -3.C0 (m, 4H ₁ C-1 and PyT-CH ₂ -). 4.32 (t 2H, J 7 Hz ₁ C-3), 7.19-7.46 (m, 5H ₁ flavor), 9.67 (s, 1H, -CHO)

Example 75

3- ( 6- (r »-Hexyl) -7-phenyl-2,3-dihydro-1H-pyrrolizine-5-vl) -acrylic acid ester (Z5J

5 mmol (1.48 g) of JA are reacted analogously to the AAV to prepare the diphenyl-2,3-dihydro-IH-pyrrolizinylacrylsäureethylester. The purification is carried out by means of SC (silica gel, petroleum ether 50-70 / ethyl acetate 7-M). The product precipitates after concentration of the eluate as oil. Yield: 0.45 g (25%)

(365.5)

IR: v _max - 1705 (C = O), 1610 (C = C) cm ^-1 .

₁ H NMR: δ (ppm) 0.62-1.02 (m 3H ₁ -CH ₃ ), 1.02-1.78 (m, 11H, -CH ₂ -and-O-CH ₂ -CU ₃ ), 2.23-3.01 (m , 6H ₁ C-2, Py ^ CH ₂ - and C-1), 3.93-4.39 (m, 4H ₁ C-3 and -O-CH ₂ -), 5.89 (AB, 1H, J = 16.1 Hz, = CH-CO-), 7.04-7.48 (m, 5H ₁ flavor). 7.68 (AB ₁ 1H, J = 16.1 Hz, Pyr-CH =)

Example 76

3- (6- (n-Hexyl) -7-Dhenvl-2.3-dihydro-1H-pyrrolizine-5-yl) -acrylic acid (76)

1.0 mmol (0.37 g) Z5 is reacted analogously to the AAV for the saponification of the diphenyl-2,3-dihydro-IH-pyrrolizine-acrylic acid ethyl ester.

Yield: 0.20 g (59%)

M .: 14O ⁰ C (under Zers.)

C22H27NO2 (337.5)

IR: v _ma x * 3300-2200 (OH) ₁ 1670 (C = O) ₁ 1595 (OC) ατΗ

¹ H-NMR (cfe-DMSO): δ (ppm) = 0.58-0.96 (m, 3H ₁ -CH ₃ ). 0.96-1.60 (m, 8H ₁ -CH ₂ -), 2.18-2.73 (m, 4H, C-2 and Pyr-CH ^), 2.86 (t 2H, J = 7Hz, C-1). 4.15 (t 2H, J = 7 Hz, C-3), 5.85 (AB, 1H, J = 15.8 Hz, = CH-CO-), 7.02-7.53 (m 5H ₁ Arom.), 7.50 (AB ₁ 1H ₁ J = 15.8 Hz, Pyr-CH =)

At game 72

(ZZ)

To dissolve 50 mmol (6.3 g) of cyclohexylmethylketone in 40 ml of CCI4, 50 mmol of Br ₂ , dissolved in 10 ml of CCI ₄ , are slowly added dropwise with the exclusion of light and with stirring. It is then mixed with 50 ml of CH ₂ Cl ₂ and washed twice to neutralize HBr twice with 5% NaHCO ₃ solution. The organic phase is dried over Na ₂ SO ₄ and concentrated. The residue becomes it; Dissolved 30 ml of ethanol and treated with the solution of 50 mmol of 2-benzyl-Ai-pyrroline in 20 ml of ethanol. The mixture is stirred for 24 h at RT. After addition of 25 ml of saturated NaHCO ₃ solution is stirred for a further 24 h. Connect »:; add 500 ml of 10% NaCl and extract twice with ether. The organic phases are dried (Na 1 SO 4). The solvent is distilled off and the product is isolated by SC (Ai ₂ Os, n-hexane / ether 9 + 1). The residual oil after concentration of the eluates (3.0 g) is not pure. It will continue to be used without additional purification.

Example 78 e-Cy clohexvl-Zp henvl ^ .S-dihy dro-IH-pvrTQlizin-Sv l-carbaldehyde (ZS) 3.0 g of contaminated ZZ are dissolved in 5 ml of absolute. Benzene dissolved and with 12 mmol absolute. DMF (0.88 g) and 4 mmol (0.61 g) of POCl3 reacted analogously to the AAV for Vilsmeier formylation of diphenyl-2,3-dihydro-1H-pyrrolizines.

The purification is carried out by SC (silica gel, ether / n-hexane 3 + 1). The product is then precipitated with ethanol.

Yield: 0.66 g (4.5% based on Cydohexylmethylketon) m.p .: 135 ⁰ C.

C ₂₀ H ₂₃ NO ₂ (293.4)

IR: v _max - 1645 (C = O) ₁ 1610 (C = C) cm-1

n ^j -NMR: 5 (ppm) = 1.01-2.13 (m, 10H ₁ -CH ₂ -dos cyclohexyl ring), 2.24-3.03 (m, 5H ₁ C-1, C-2 and Pyr-CH <), 4.35 (t, 2H, J = 7 Hz ₁ C-3). 7.07-7.51 (m 5H ₁ flavor). 9.93 (see 1H ₁ CHO)

Example 79

S-fe-Cvdohexvl ^ -Dhenvl ^ .S-dihydro-IH-pyrrolizine-S-vD-acrvlsäureethvlester

2 mmol ZS. dissolved in 4 ml absolute. CH ₂ Cl ₂ , with the solution of 2 mmol (0.86 g) of ethoxycartoxymyttriphenylphosphinium bromide in 3.5 ml absol. Ethanol and one of 6 mmol (0.14 g) of sodium and 3 ml of absolute. Ethanol prepared solution of Na-ethanolate analogous to the AAV for the preparation of diphenyl-2,3-dihydro-IH-pyrrolizJnvlacrylsäureothylester implemented. The cleaning

carried out by means of SC (silica gel, petroleum ether 50-70 / ethyl acetate 7 + 2). The oil remaining after concentration of the eluates solidifies after some time. Yield: 80 mg (11%) M.p .: 109 ⁰ CC ₂₄ H ₂₉ NO ₂ (363.5) IR: Vm _4x - ^ IS (C = O) ₁ IEOs (C = C) cm ^-1 1 H-NMR: δ ( ppm) = »0.99-1.99 (m, 1OH, -CH ₂ - of the cyclohexyl ring), 1.31 (t, 3H ₁ J = 7 Hz ₁ -Q-CHrCHO 2.27-2.93 (m. 5H, C-1, C-) 2 and Pyr-CH <), 4.17 (t, 2H> 7 Hz, C-3), 4.23 (q 2H, J = 7 Hz ₁ -0-CH ₂ -).

5.85 (AB ₁ 1H ₁ J = 16.2 Hz, = CH-CO-). 7.04-7.48 (m, 5H ₁ flavor), 7.91 (AB, 1H ₁ J = 16.2 Hz, Pyr-CH =)

Example 80

3- (6-Cyclohexylyl-7- phenyl-2,3-dihydro-1H-pyrrolizine- 5 -yl ) -acryric acid 0.22 mmol (80 mg) 7_9_ dissolved in 5 ml of ethanol are analogous with 3 ml of 10% aqueous KOH the AAV was reacted to saponify the diphenyl-1,2,3-dihydro-1H-pynrolizylacrylic acid ethyl ester (sS219)

Yield: 37 mg (50%) M.p .: 201 ⁰ C (with dec.) C22H25NO2 (335.4)

IR: v _max - 3200-2400 (OH) ₁ 1660 (C = O) ₁ 1585 (C = C) cm ^{-1 1} H-NMR: δ (ppm) - 0.98-2.05 (m, 1OH. -CH ₂ - des Cyclohexyl ring), 2.29-2.98 (m, 5H ₁ O ₁ , C-2 and pyr-CH <). 4.21 (t, 2H, J = 7 Hz ₁ C-3), 5.87 (AB ₁ 1H ₁ J = 16.0 Hz ₁ -CH-CO-), 7.02-7.55 (m, 5H ₁ Arom.), 8.01 (AB. 1H ₁ J = 16.0 Hz. Pyr-CH =)

General Procedure for the N-Acquisition of 2 -Methyl-3,4-diphylpyrrole 2 mmol (0.47 g) 2-Methyl-3,4-diphenylpyrrole

(Aust. J. Chem. 1966, 19, 1871-1885) 2.2 mmol p-TolUOlSUlfonsäuremethylester (at 81b) or alkyl bromide (at restl.Verb.) And 1 mmol (0.32 g) Tetrabutylarnmoniumbromid be with 10 ml of ether and 5 ml 50% aqueous NaOH. The mixture is heated with vigorous stirring for 8 h to a weak boil. The mixture is then poured into 100 ml of H 2 O and extracted twice with ether. The ether phasers. are washed with 1% H 3 PO 4 and H 2 O, dried over Na 2 SO 4 and concentrated. The product is isolated by means of SC (Al ₂ C _1- n-hexane / ether 9 + 1).

48

The compounds obtained and physical data of these compounds are summarized in Table 12 below:

table

I Ex. No. R Schmp. ⁰ C IR (C = C) 81- ^l> CH ₃ 81b 82 C ₂ H ₅ 81c 1600 83 nC ₃ H ₇ 81d 80 1605 84 n-C H 81e 4 9 1610 85 ^{2) n} " ^C 5 ^H ll ^81f 86 ^{2) n} " ^C 6 ^H 13 ^81g 87 ISO-C ₄ H ₉ 81h 116 1605

2)

Tetrahedron Lett. 1969, 55, 4875-4878 Chem. Pharm. Bull. 1974, 22, 61-69

Mixture with alkyl bromide; it is reacted without further purification

⁴⁹ atf 160

Example 88

i-Neo- pentyl-methyl -S-diphenvylpyrrole (SIi) The compound is not available with the above synthesis. However, it can be made as follows:

2 mmol (0.46 g) of 2-methyl-3,4-diphenyl-pyrrole, 2.6 mmol of potassium t-butoxide and 3 mmol (0.45 g) of neopentyl bromide are absol in 6 ml. DMSO heated to 130-14O ⁰ C for 45 min. After cooling, 100 ml of H2O are added, acidified with dil. H3PO4 and extracted twice with ether. The ether phases are washed with H 2 O, dried over Na 2 SO 4 and concentrated. The product is isolated from the residue by SC (Al 2 O 3, n-hexane / ether 9 + 1) and precipitated with ethanol (analogous to 81 h).

Yield: 0:31 g (51%) M.p .: 132 ⁰ C.

C22H25N (303.4) Ber. C 87.1 H 8.30 N 4.6

Gef. C 86.9 H 8.21 N 4.5 IR: vmax = 1605 (OC) cnri MS: m / z (rel.lnt.) = 303 (89%, M ⁺ -). 288 (9%, M ⁺ -CH ₃ , * 273.74), 247 (58%, M ⁺ -Ca * 201.34), 246 (100%, 247-H)

1 H NMR: δ (ppm) = 1.02 (s, 9H, -CH ₃ ), 2.19 (s, 3H, Pyr-CH ₃ ), 3.66 (s, 2H,> N-CH 2 -), 6.75 (s, 1H ₁ C-5), 7:06 to 7:33 (m, 1 OH, arom.)

General Rule for Preparation of 3- (5- Methyl- 3,4-diphenvil-tr-2-yl) -propionic Acid Esters

1 mmol of 2-methyl-3,4-diphenylpyrrole or 1-alkyl-2-methyl-3,4-diphenylpyrrol fi b_d [and 1.5 mmol (0.13 g) of methyl acrylate are in 4 ml of absolute. Dichloroethane dissolved After addition of 0.06 ml of 8F ₃ -Ethylether complex is geu'hrt 1 h at RT, after each 15 min again the same amounts of Acfylsäuremethylester and BF ₃ -Ethylether complex are added. Then it is mixed with 50 ml of H2O and extracted twice with ether. The ether phases are washed with H 2 O, dried over Na 2 SO 4 and concentrated. From the residue, the product is isolated by SC (Al 2 O 3, r, hexane / ether. M (82a) and 1 + 1 (82b.c) and 3 + 2 (rest! Verb.)). After concentration of the eluates remains an oil.

ίο

20 25

The compounds obtained and some physical data of these compounds are listed in Table Ij.

Table 13

COOCH ₃

30

Example no. R IR (C = O) 89 H 82a 1730 90 CH ₃ 82b 1740 91 C ₂ H ₅ 82c 1740 92 nC ₃ H ₇ 82d 1740 93 nC ₄ H ₉ 82e 1745 94 ⁿ " ^C 5 ^H ll ^82f 1740 95 NC ₆ H ₁₃ 82g 1740 96 ISO-C ₄ H ₉ 82h 17Ί0 97 Neopentyl 82i 1740

35

General procedure for the saponification of 3- (5-methyl-3,4-diphenvl-pyrrol-2-vinyl) -propionic acid methyl ester

The solution of 0.4 mmol of methyl 3- (2-methyl-3,4-diphenylpyrrol-5-yl) -propionate Ł 2a. Methyl 3- (1-alkyl) -methyl-S-diphenylpyrrole-S-y-O-propionate 82b-i in 3 ml of ethanol is heated to boiling point followed by the dropwise addition of 2 ml of 10% aqueous KOH, which has been previously boiled After cooling, the mixture is refluxed for a further 5 minutes and, after cooling, is poured into 100 ml of 5% NaCl solution and washed twice with 50 ml of ether The aqueous phase is acidified with dilute H 3 PO 4 and washed twice 50 ml of ether are extracted, the ether phases are washed with 100 ml of H 2 O, dried over Na 2 SC> 4, the solvent is distilled off and the product is precipitated with hexane, if necessary.

The compounds obtained and some physical data of these compounds are summarized in Table 14.

52

table

14

COOH

Example no. R Schmp. ⁰ C IR (C = O 98 H 60 1710 99 CH ₃ 108 1710 100 C ₂ H ₅ 157 1715 101 HC ₃ H ₇ 128 1705 102 nC ₄ H ₉ > 49 ° (ZersJ 1715 104 HC ₅ H _n - 1715 105 HC ₆ H ₁₃ - 1715 106 ISO-C ₄ H ₉ 50 1715 107 neopentyl 48 1710

53 i

General procedure for r N -alkylation of 5-methyl-P? - ^ iph $ n ylpvrrrol

5 mmol (1.17 g) of 5-methyl-2,3-diphenylpyrrole (Aust. J. Chem. 1966, 19, 1871-1885), 5.5 mmol of toluenesulphonate or alkylbromide and 1 mmol (032 g) of tetrabutylairanonium bromide are mixed with 10 ml of ether and 5 ml of 50% aqueous NaOH. Further reaction is carried out in accordance with the general procedure for the N-alkylation of 2-methyl-3,4-diphenylpyrrole.

The obtained compounds and physical data of these compounds are shown in Table 15.

54

table

15

10

15

No. R Schmp. ⁰ C IR (C = C) 108 CH ₃ 84b 149 1605 109 C ₂ H ₅ 84c 68-69 1605 110 111 n-C H 84d n-C H 84e - 1605 1605 112 HC ₅ H ₁₁ 84f 1605 113 UC ₆ H ₁₃ 84g 1605 114 nC ₈ H ₁₇ ^1} 84h 115 iso-C.Hg 84i 107 1600 116 Neopentyl 84 j 89 1605

30 η

Mixture with nC _R H. ₇ Br, which is reacted without further purification

35

55

General procedure for the preparation of (5- methyl-4,5-diphenylpyrrole

3-vO-essi gsä'ureethvlester

2.5 mmol of 5-methyl-2,3-diphenylpyrrror (Aust. J., formerly 1966, 19, 1871-1885) or 1-alkyl-S-methyl-1,3-diphenylpyrrole 84b-j. dissolved in 2.5 ml of absoI. Toluene, with 3.75 mmol (0.43 g) of ethyl diazoacetate, dissolved in 2 ml of absol. Toluene, analogous to the AAV for the preparation of diphenyl-2,3-dihydro-1H-pyrrolizinylessigsäureethylester implemented. The products are obtained as oils according to SC (silica gel, n-hexane / ether 1 + 1 in Ex. 117 or Al ₃ O ₃ , n-hexane-ether 9 + 1.5 in the other verbs).

The compounds obtained and IR data of these compounds are summarized in Table 16.

Table 16

H ₅ C ₂ OOC--.

Example no. R IR (C = O) 117 H 85a 1730 118 CH ₃ 85b 1740 119 C ₂ H ₅ 85c 1735 120 nc ₃ H _? 85d 1740 121 nC ₄ H _g 85e 1735 122 ⁿ " ^C 5 ^H ll ^85f 1740 123 n-C.H.-, 85g 0 IJ 1740 124 nC _Q H._ 85h 1740 125 ISo-C ₄ H ₉ 85i 1735 126 Neopentyl 8 5 j 1735

General working manual for the saponification of the te-methyl- [S-diphenvlpvrrol- 3-yl) -acetic acid esters

The solution of 0.6 mmol of (2-methyl-4,5-diphenylpyrrol-3-yl) -acetic acid ethyl ester or (1-alkyl-2-methyl-4,5-diphenylpyi-to-3-yl) -acetic acid ethyl ester in 5 ml of ethanol heated to boiling. Then added dropwise 3 ml of 10% aqueous KOH, which has been previously degassed by boiling, and heated for a further 1 h under reflux. After cooling, the mixture is poured into 100 ml of 5% NaCl solution, acidified with 8% H 3 PO 4 and extracted three times with ether. The or-

ganic phases are dried over Na2SO4 and concentrated. The product is purified by means of SC (silica gel, 1 n-hexane / ether 1 + 1 at

Examples 127-131 and 2 + 1 in Ex. 132-136, 2.Ether) The eluates are concentrated to a few ml. After addition p. of η-hexane and re-concentration, the product precipitates.

The obtained compounds and physical data of these compounds are shown in Table 17.

57

table

17

Example no. R • Mp. ⁰ C IR (C = O) 127 H 86a 110 1710 128 CH ₃ 86b 161 1710 129 ^C 2 ^H 5 ^86C 177 1705 130 nC ₃ H ₇ 8 <5d 172 1700 131 HC ₄ H ₉ 86e 129 1705 132 HC ₅ H _n 86f 121 1710 133 HC ₆ H ₁₃ 86g 127 1710 134 HC ₈ H ₁₇ 86h 45 1715 135 ISO-C ₄ H ₉ 86i 168 1710 136 Neopentyl 86 y 163 1710

A AV (General Working Procedure ) for the initial reaction of 6-aryl-7-phenyl-2,3-dihydro-1H-pyrrolizines or 6-phenyl-7-aryl-2,3-dihydro-1H-pyrrolizines 20 mmol of aromatic-substituted * or unsubstituted α-bromoacetophenone dissolved in 25 ml of CH _? C1_ are added to the solution of 20 mmol unsubstitui ^ rtem or aromatensubstituiertem ** 2-Senzyl-Al-pyrroline in 50 ml of ethanol and stirred for 24 h at RT. Then, 20 ml of saturated aqueous NaHCO.sub. Solution are added and the mixture is stirred at RT for a further 24 h. The batch is poured into 500 ml of 5% NaCl solution and extracted three times with 100 ml of ether / CH ₂ Cl ₂ 3 + 1. The organic phases are over Na ^ SO

 dried and worked up as indicated below.

* α-Bromo-S-chloroacetophenone, α-Bromo-3,4-dimethoxyacetophenone, α-bromo-3,4-dichloroacetophenone and α-bromo-4-phenoxyacetophenone are not commercially available. They are made as follows:

To dissolve 20 mmol of 3-chloroacetophenone, 3,4-dimethoxyacetophenone, 3,4-dichlorofacetophenone or 4-phenoxyacetophenone in 15 ml of CH 2 Cl 2 and 10 ml of dioxane, the solution of 20 mmol (3.2 g) of bromine in 10 ml of CH 2 Cl 2 is slowly added dropwise , It is then mixed with 50 ml of CH 2 Cl 2 and twice carefully washed with 5% NaHCO 3 solution to remove HBr. The organic phase is dried over Na 2 SO 4 and concentrated. The residue is reacted directly as described above with 20 mmol of 2-benzyl-Ai-pyrroline

"2- (4-chlorobenzyl) -A1 -pyrroline

Preparation analogous to 2-benzyl-A1-pyrroline (j, Amer.chem.soci932, 54

3971-3976)

" 2- (4-methylbenzylVA1 -pyrroline

From 0.15 md (3.6 g) of Mg and 0.15 mol (21.1 g) of 4-methylbenzyl chloride is dissolved in 150 ml of absolute. Ether prepared a Grignard reagent. After dropwise addition of 0.15 mol (15.5 g) of 4-chlorobutyronitrile dissolved in 100 ml of absol. Ether, is heated to reflux for 2 h. Then distilled off the ether and gives 200 ml of absolute. Xylene too. After a further 2 h of refluxing, the mixture is admixed with 100 ml of H 2 O with ice cooling and acidified with dil. H 3 PO 4. The

aqueous phase is concentrated under ice-cooling with conc. NH3 alkalized, sucked the resulting precipitate. The filtrate is extracted three times with 50 ml of CH 2 Cl 2 and the precipitate is washed with 100 ml of CH 2 Cl 2. The CH 2 Cl 2 solutions are combined, dried over Na 2 SO 4, and concentrated. From the remaining residue, the product is isolated by distillation (boiling point 1170c at 0.1 torr).

Yield: 3.7 g (14%) C12H15N (173.3) IR: v _m ax - 1640 (ON). 1605 (C = C) cm ^-1

"2- (4-methoxybenzyl ) -A1 -pyrroline

From 3.0 mol (72.9 g) of Mg and 0.15 moi (23.5 g) of 4-methoxybenzyl chloride in 500 ml absol. Ether 4-Methoxybenzylmagnesiumchlorid, This is with 0.15 mol (15.5 g) of 4-chlorobutyronitrile

further reacted and purified by distillation (boiling point 142 ⁰ C uei 0.1 Ton-).

Yield: 2.4 g (8%) C12H15NO (189.3) IR: vmax-1640 (ON), 1610 (C-C) cm-1

⁶⁰ 194110

General procedure for the preparation of 3- (6-chlorophenyl- and 6-nitrophenyl-7-phenyl-2,3-dihydro-1H-pyrrolizine-5-yl) -propionic acid methyl ester

4 mmol of 6-chloro or 6-nitrophenyl-7-phenyl-2,3-dihydro-1H-pyrrolizine and 6 mmol (0.52 g) of methyl acrylate are absol in 16 ml. Dissolved dichloroethane. After addition of 0.24 ml BF3-ethyl ether complex is stirred for 1 h at RT, after each 15 min again the same amounts of methyl acrylate and BF3-ethyl ether complex are added. The mixture is then poured into 100 ml of 10% NaCl solution and extracted twice with ether / CH 2 Cl 2 3 + 1. The organic phases are dried over Na 2 SO 4 and concentrated. The residue will be as below

stated worked up.

General procedure for the saponification of methyl 3- (6-chlorophenyl- and 6-nitrophenyl-7-phenyl-2,3-dihydro-1H-pyrrolizine-6-yl) -propionic acid

The solution of 1 mmol of the corresponding Pyrrolizinylpropionsäuremethylesters in 10 ml of ethanol is heated to boiling. Then added dropwise 5 ml of 10% aqueous KOH, which has been previously degassed by boiling, and heated for a further 5 min under reflux. After cooling, the mixture is poured into 100 ml of 5% NaCl solution, acidified with 8% H 3 PO 4 and extracted three times with ether / CH ₂ Cl ₂ 3 + 1. The organic phases are dried over Na ₂ SO ₄ , concentrated and worked up as indicated.

General e procedure for the Vi J ^ ₁ SnTeJeJr form y lie run aromatensubstituierter g 6,7-Di phenyl-2 ^ dihyd ro-lH-pyrrolizi ne

6 mmol of the corresponding pyrrolizine, dissolved in 6 ml absol. Benzene, with 18 mmol (1.32 g) absolute. DMF and 6 mmol (0.92 g) POCI3 reacted analogously to the AAV for the Vilsmeier formylation of diphenyl-2,3-dihydro-1H-pyrrolizines.

General procedure for the preparation of aromatic- substituted ethyl 6,7-diphenyl-2,3-dihydro-1H-pyrrolizinyl acrylate

2.5 mmol of the corresponding carbaldehyde, dissolved in 5 ml absol. CH2Cl2. with the solution of 2.5 mmol (1.08 g) ethoxycarbonylmethyltriphenylphosphonium bromide in 4 ml absol. Ethanol and one of 7.5 mmol (0.17 g) of sodium and 3 ml of absolute. Ethanol prepared solution of Na-ethanolate analogous to the AAV for the preparation of the diphenyl ^ .S dihydro-IH-pyrrolizinylacrylsäureethylester implemented.

General procedure for the saponification of aromatic-substituted 3- (b _f 7-diphenyl-2,3-dihydro-1H-pyrrolizin-5-yl) -

acrylic acid esters 25

1.2 mmol of the corresponding pyrrolizinylacrylsäureethylesters, dissolved in 50 ml of ethanol, with 10 ml of aqueous KOH analogous to the AAV for the saponification of 3- (diphenyl-2,3-dihydro-1H-

pyrrolizin-5-yl) -acrylsäureethylester reacted

 30

General work plan for the hydrogenation of aromatic-substituted acids , 3 - (6 _t 7-diphenyl-2,3-dihydro-1H-pyrrolizine-5-yl) -acryric acids

0.9 mmol of the corresponding Pyrrolizinylacrylsaure be in 30 ml of absolute. THF solved. After addition of 10 ml absol. Ethanol and a spatula tip PtO ₂ (alternatively palladium can be used) is hydrogenated in an autoclave for about 4 h at 15 bar. It is several times a spatula tip fresh PtO _? (or palladium) zugesetrt. After complete reaction (TLC: silica gel, THF), the catalyst is filtered off with suction, the solvent is distilled off and the product is isolated.

General work schedule for the cleavage of the arylmethyl ether 0.5 mmol of the corresponding methoxy compound, dissolved in 5 ml of absolute. CH ₂ Cl ₂ , are

absol at -80 ⁰ C to the solution of 0.20ml BBra in 3 ml. CH2CI2 zugetroft. The mixture is allowed to warm to RT for about 8 h. After addition of 30 ml of H2O, it is extracted three times with ether. The organic phases are washed twice with saturated NaCl solution, dried over Na 2 SO 4 and worked up.

The obtained compounds and physical data of these compounds are shown in Tables 18 to 27 below.

63

Table 18

10

para

met "

ipar "

152025

Example no. meta R para R ¹ para Mp. ° C IR (C = C) 138 Cl H H 1600 139 ^Χ) H Cl H 140 NO ₂ H H 117 1605 141 H NO ₂ H 132 1595 142 H H CI 156 1605

30

^1J Chemist's Gazette 1986, 110, 267-271

35

64

table

19

par"

meta

(CH ₂ ) ₂ -COOCH ₃

Example no. R meta R para R ¹ para Schmp. ⁰ C IR (C = O; 143 Cl H H 99 1735 144 H Cl H 98 1730 145 NO ₂ H H 1740 146 H NO ₂ H 1740 147 H H Cl 111 1730

65

table

para

(CH ₂ J ₂ -COOH

Example no. R _t meta R para R ¹ para Schmp. ⁰ C IR (C = O) 143 Cl H H 99 1735 144 H Cl H 98 1730 145 NO ₂ H H 1740 146 H NO ₂ ri 1740 147 H H Cl 111 1730

Table 21

10

2025

Example no. R H Schmp. ⁰ C IR (C = O) 153 CHO 1605 (C = C) 154 CH = CHCOOC ₂ H ₅ (E) > 84 1650 155 CH = CHCOOH (E) 122 1715 156 (CH ₂ ) COOH 229 1660 157 157 1710

3035

67

Table 22

10

15 20 25 30

Example no. meta para R ¹ para Schmp. ⁰ C OR (C = C) 158 CH ₃ H H 1605 159 H CH ₃ H 1605 160 OCH ₃ H H 1605 161 ^1J H OCH ₃ H 162 ¹ ' OCH ₃ OCH ₃ H 163 ² > H ° - ^C 6 ^H 5 H 164 Cl Cl H 119 1605 165 H H CH ₃ 104 1610 166 H H OCH ₃ 1605

Chemist's Gazette 1986 110, 267-271

The product is not pure; it is reacted without further purification.

68

MV160

table

para

meta

CHO

Example no. meta R para R ¹ para Schmp. ⁰ C IR (C = O 167 CH ₃ H H 128 1645 168 H CH ₃ H 142 1645 169 OCH ₃ H H 117 1635 170 ^1} H OCH ₃ H 171 ¹ » OCH ₃ OCH ₃ H 172 H 0-C ₆ H ₅ H 135 1635 173 Cl Cl H 162 1640 174 H H CH ₃ 102 1645

¹⁾ Chemiker-Zeitung 1986 110, 267-271

69

{99160

table

para

Example no. meta R para R ¹ para Schmp. ⁰ C IR (C = O) 175 CH ₃ H H 142 1710 176 H CH ₃ H 158 1710 177 OCH ₃ H H 119 1710 178 H OCH ₃ H 164 1705 179 OCH ₃ OCH ₃ H 133 1705 180 H 0-C ₆ H ₅ H 173 1705 181 Cl Cl H 122 1715 182 H H CH ₃ 222 1705

70

table

par"

English subtitles

Example no. meta F. pol egg R ¹ para Schmp. ⁰ C IR (C = O) 133 CH ₃ H H 216 1660 184 H CH ₃ H 221 1680 185 OCH ₃ H H 205 l>: 70 186 H OCH ₃ H 216 167 5 187 OCH ₃ OCH ₃ H 216 1660 188 H 0-C ₆ H ₅ H 221 1660 189 Cl Cl H 229 1660 190 H H CH ₃ 118 1665

71

table

pan

meta

(CH ₂ J ₂ -COOH

No. Ex. No. meta R para R ¹ para Schmp. ⁰ C IR (C = O) 191 CH ₃ H H 125 1710 192 H CH ₃ H 122 1710 193 OCH ₃ H H 111 1710 194 H OCH ₃ H 73 1710 195 OCH ₃ OCH ₃ H 152 1725 196 OH H H 87 1710 197 H OH H 187 1700 198 OH OH H 76 1710 199 H ° - ^C 6 ^H 5 H 178 1705 200 Cl Cl H 144 1710 201 H H CH ₃ 182 1705

72

IS ff ZOO

2530

Table 27

10

15 20

Example no. R H para Schmp. ⁰ C IR (CiO) 202 (CH ₂ ) ₂ COOCH Cl 118 1605 (C = C) 203 (CH ₂ J ₂ COOH ₃ Cl 113 1735 204 Cl 207 1720

35

Example 205

2.2-dimethyl-6- (4-fluoro) -7-phenvct-2,3-dihydro-1H-pyrroli2 in 20 mM a-chloro-fluoroacetophenone dissolved in 25 ml of CH 2 Cl 2 are mixed with the solution of 20 mmol of 2-benzyl-4, 4-dimethyl-A1-pyrroline 25 ml of ethanol and stirred for 24 h at 7O ⁰ C bath temperature. Subsequently, 20 ml of saturated aqueous NaHCQj solution and stirred for a further 24 h at the same temperature. The batch is poured into 500 ml of 5% NaCl solution and extracted three times with 100 ml of ether / CH ₂ Cl ₂ 3 + 1. The organic phases are dried over Na 2 SO 4. The product precipitated by scrubbing with SC (Al2O3, n-hexane / ether 9 + 1) as an oil

 Yield: 3.1 g (51%) of C21H20FN (305.4) IR-vm -1605 (OC) cm-1

1H-NMR: δ (ppm) - 1.28 (s, 6H ₁ -CH ₃ ), 2.78 (s, 2H ₁ CD, 3.71 (see 2H, C-3)

6.64 (see 1H ₁ C-5). 6.75-7.60 (m, 9H, Arom.)

Example 206

2,2-dimethyl-6- (4-fluoro) -7-phenyl-2.3-dihydro-1H-pvrrolizine-5α-carbaldehyde (cf.

9 mmd Iy, dissolved in 9 ml absolute. Benzene, with 27 mmol (1.97 g) absoi. DMF and 9 mmol (1.38 g) POCb analogous to the AAV for the Vilsmeier Formyüerung of diphenyl-2,3-dihydro-1H-pyrrolizines implemented. The purification is carried out by SC (silica gel, n-hexane / ether 2 + 1). The product precipitates on concentration of the eluates

Yield: 0.9 g (30%) mp: 186 ⁰ CC ₂₂ H ₂ OFNO (333.4)

- 1645 (C = O) ₁ 1610 (C = C) cnr1

₁ H NMR: δ (ppm) - 1.33 (s, 6H, -CH ₃ ), 2.83 (s, 2H ₁ C-1), 4.18 (s, 2H ₁ C-3).

6.90-7.44 (m, 9H, Arcm), 9.38 (s, 1H, -CHO) Example 207

3- (2.2-Dimethvt-6- (4-fluoro) -7-phenyl-2.3- <lihvdro-1H-pvrTolizin-5-yl) -acfvl acid ethers (34v)

2 mmol Sy, dissolved in 15 ml absolute. CH ₂ C ^, with the solution of 2 mmoJ (0.86 g) ethoxycarbonylmethyltriphenylphosphoniumbroniid in 4 ml absol.

Ethanol and one of 6 mmol (0.14 g) of sodium and 3 ml of absolute. Ethanol prepared solution of Na-ethanolate analogous to the AAV for the preparation of

Implemented diphenyl ^. S-dihydro-IH-pyrrolizinylaciylsäureethylester

Purification is carried out by SC (silica gel, CH 2 Cl 2). The product remains as foam after concentration of the eluates.

Yield: 0.33 g (41%)

Mp .: 152 ° C

C26H26FNO2 (403.5)

IR: vmax - 1715 (O = O), 1620 (C = C) cm-1

1H-NMR: δ (ppm) - 1.27 (t, 3H ₁ J = 7 Hz, -Q-CHo-CHs). 1.33 (see 6H ₁ -CH ₃ ), 2.86 (S, 2H ₁ C-1). 4.00 (s, 2H ₁ C-3). 4.19 (q, 2H ₁ J = 7 Hz ₁ -0-CiJ ₂ -CH ₃ ).

5.90 (AB, 1H, J-16.4Hz, -CH-CO-), 6.87-7.34 (m, 9H, Arom.). 7.48 (AB, 1H, J «16.4Hz, Pyr-CH-)

Example 208

3- (2,2-Dimethv ^ -6- (4-fluoro) -7-phenyl · 2 3 → <jihvdro-1H-pvrrolizine-5vl) -acrostate (35v)

0.6 mmol 34y_, dissolved in 30 m! Ethanol, are reacted with 6 ml of 10% aqueous KOH analogous to the AAV for the saponification of the diphenyl-2,3-dihydro-1H-pyrrolizinylacrylsäureethylester.

Yield: 0.20g (89%) M.p .: 242 ⁰ C.

C24H22FNO2 (375.4) Ber. C 76.8 H 5.91 N 3.7

Gef. C 76.1 H 5.81 N 3.3

IR: vmax - 3300-2200 (OH), 1685, 1670 (CO). 1600 (OC) CRRR ¹ 1 H-NMR (de-DMSO): δ (ppm) - 1.27 (3. 6 H, _-CH3), 2.84 (s, 2H, C-1), 4:06 (s, 2H, O3) , 5.92 (AB, 1H ₁ J = 16.4 Hz ₁ -CH-CO-), 6.87-7.41 (m. 9H, Arom. And Pyr-CH »)

⁷⁵ Wf 160

Mi play 209

3- ( 2,2 -dimethyl-6- (4- fluoro-FV7-phenyl-2,3-dihydro-1H-pvfroli2in- 5-yl ) -propyl) acid (2Zy)

0.3 mmol 3_5y_ are reacted analogously to the AAV for the hydrogenation of the aromatic-substituted 3- (6,7-diphenyl-2,3-dihydro-1H-pyrrolizin-5-yl) -acrylic acids. The catalyst used is palladium. The product is precipitated with n-hexane

 Yield: 0.08 g (71%) mp: 182 <> C

C24H24FNO2 (377.5) Ber. C 76.4 H 6.41 N 3.7

Get. C 75.8 H 6.56 N 3.3

IR: v _max 3300-2400 (OH), 1710 (CO), 1605 (C = C) cnrri 1 H NMR: δ (ppm) -1.30 (s, 6H, -CH ₃ ), 2.28-2.58 (m, 2H ₁ -CH ₂ -CO-), 2.73-3.03 (m, 2H, PyT-CH ₂ -), 2.81 (see 2H, C-1), 3.68 (s, 2H, C-3), 6.76-7.28 (m, 9H, flavor)

Example 210

2.2-dimethyl-6- (4-phenoxyphenyl) -7-phtnyl-2.3-dihydro-1H-pyrrolizine Qw) 20 mmol 2-benzyl-4 _l 4-dimethyl-A1-pyrroline Ik ₃ are reacted with 20 mmol a-Bronrv 4 -chloroacetoohenone in 50 ml of ethanol analogously to the AAV for the preparation of 6-A / yl-7-phenyl-2,3-dihydro-1H-pyrrolizine implemented. The cleaning

is carried out by means of SC (Al ₂ Oa, n-hexane / ether 9 + 1). After concentration of the eluates Jw, as oil back

 Yield: 2.7 g (36%) C27H25NO (379.5)

IR: Vm _4x - 1605 and 1595 (OC) CfTTi

1 H-NMR: δ (ppm) - 1.28 (s, 6H, -CH ₃ ), 2.78 (s, 2H, C-1), 3.71 (s, 2H, C-3), 6.65 (see 1H, C-) 5). 6.78-7.57 (m, 14H, A / om.)

Example 211

2,2-dimethyl-6- (4-phenoxyphenyl-7-phenyl-2,3-dihydro-1 H -pyrroline) 7- in-5-yl carbaldehyde (βwj

6 mmol ^ l dissolved in 6 ml absol. Benzene, with 18 mmol (1.32 g) absolute.

DMF and 6 mmol (0.92 g) POCb analogous to the AAV for the Vilsmaier formylation

tion of diphenyl-2,3-dihydro-1H-pyrrolizine implemented. The

Purification is carried out by SC (silica gel, CH ₂ Cl ₂ ). The product is precipitated with ethanol

Yield: 0.94 g (38%) M.p .: 139 ⁰ C C28H25NO2 (407.5)

IR: vmax - 1645 (C = O) ₁ 1605 and 1590 (C = C) cmr ^{1 1} H-NMR: δ (ppm) - 1.30 (s, 6H, -CH ₃ ), 2.81 (s, 2H ₁ C-1 ), 4.17 (s, 2H ₁ C-3), 6.84-7.47 (m, 14H, Arom.), 9.40 (s, 1H ₁ -CHO)

Example 212

3- (2,2-Dimethyl-6- (4-phenoxy-phenyl) -7-phenyl-2,3-acrylic acid ether (34w)

2 mmol ßw., Dissolved in 5 ml of absolute. CH 2 Cl 2, are mixed with the solution of 2 mmol (0.86 g) of ethoxycarbonylmethyltriphenylphosphohium bromide in 4 ml of absolute. Ethanol and one of 6 mmol (0.14 g) of sodium and 3 ml of absolute. Ethanol prepared solution of Na-ethanolate analogous to the AAV for the preparation of the diphenyl-2,3-dihydro-1H-pyrrolizinyl-acrylic acid ethyl ester implemented. Purification is carried out by SC (silica gel, CH 2 Cl 2). The product remains as foam after concentration of the eluates

 Yield: 0.33 g (35%) mp: from 69 ° C C32H31NO3 (477.6)

IR: ν ™ - 1705 (C = O), 1610 (C = C) cnr ¹

₁ H-NMR: 5 (ppm) - 1.28 (t, 3H, J = 7 Hz, -O-CH ₂ -Cb), 133 (s, 6H ₁ -CH ₃ ), 2.86 (s, 2H, C-1) , 4.00 (s, 2H, C-3). 4.19 (q, 2H, J = 7Hz ₁ -O-CJk-CH ₃ ), 5.92 (AB, 1H ₁ J-16Hz ₁ -CH-CO-), 6.83-7.44 (m, 14H, Arom.). 7.56 (AB, 1H, J »16Hz, Pyr-CH =)

Example 213

3- (2,2-dimethyl-6- (4-phenoxyphenyl) -7-phenyl-2.3 <fihydro-1H-pyrrolizin-5yl) -acryic acid (35w)

0.6 mnn 34w. dissolved in 30 ml of ethanol, are reacted with 6 ml of 10% aqueous KOH analogously to the AAV for the saponification of diphenyl ^ -dihydro-IH-pyrrolizine-S-yl-acrylic acid ethyl ester.

Yield: 0.23 g (85%) M.p .: 198 ^° C.

C3OH27NO3 (449.5) Ber. C 80.2 H 6.05 N 3.1

Gef. C 79.9 H 6.07 N 2.7 IR: vmax - 3300-2200 (OH), 1675 (C = O) ₁ 1590 (OC) cnri

₁ H-NMR (de-DMSO): δ (ppm) - 1.27 (s, 6H, -CH ₃ ), 2.83 (see 2H ₁ C-1), 4.06 (s, 2H ₁ C-3). 5.92 (AB, 1H ₁ J-16.2 Hz ₁ -CH-CO-), 6.86-7.57 (m, 15H, Arom., And Fy-CH = O

Example 214

3- (2,2-Dime -1-yl-G- (4-ph6noxydhenvl) -7-phenyl-2,3-dihydro-1H-dibrol-2-yn-5-yl- propionic acid (27w)

0.3 mmol 35w are reacted analogously to the AAV for the hydrogenation of the aromatic-substituted 3- (6,7-diphenyl-2,3-dihydro-1H-pyrrolizin-5-yl) -acrylic acids. The catalyst used is palladium. The product is precipitated with n-hexane

Yield: 0.10 g (74%) M.p .: 149 ⁰ C.

C30H29NO3 (451.6) Ber. C 79.8 H 6.47 N 3.1

Get. C 79.5 H 6.61 N 2.7

IR: vrnax - 3300-2400 (OH) ₁ 1710 (C = O) ₁ 1605 and 1595 (C = C) cm ^-1 1H NMR: δ (ppm) - 1.29 (see 6H ₁ -CH ₃ ) 2.34 2.63 (m 2H ₁ -CH ₂ -CO-) 2.77-3.06 (m, 2H ₁ PyT-CH ₂ -) 2.83 (see 2H, C-1) 3.69 (see 2H, C-3 ), 6.85-7.47 (with 14H ₁ aroma)

Example 215

2- (2,2-Dimethv-6- (4-phenoxyphenvl) -7-ohenvl-2,3-dihydro-1H-pyi-tolizin-5-vl) -propionic acid ester (54a)

2.5 mmol 6- (4-phenoxyphenyl) -7-phenyl-2 _l 3-dihydro-1H-pyiTolizin Iw ₁ dissolved in 3 ml absol. Toluene, with 4 mmol (0.51 g) 2-Diazopropionsäureethylester, dissolved in 3 ml of absolute. Toluene, analogous to the AAV for the preparation of diphenyl-2,3-dihydro-1H-pyrrolizinylessigsäureethylester (sS201) implemented. The isolation is carried out by SC (Al ₂ O ₃ , n-hexane / ether 9 + 1). The nati · concentration of the eluates remaining oily product (0.45 g) is not pure. It will continue to be used without additional purification.

Example 216

2- (2,2-Dimethyl-6- (4-phenoxyphenyl) -7-phenyl-2.3-dihydro-1H-pyitolizin-5-vP-propionic acid (5_6_a)

The contaminated 5Ya (0.45 g), dissolved in 10 ml of ethanol, is treated with 5 ml of 10% aqueous KOH analogously to the AAV for the saponification of the phenyl-2,3-dihydro-1H-

⁷⁸

pyrrolizinyl-ethyl acetate implemented. The saponification time is min. The purification is carried out by means of SC (silica gel, diisopropyl ether).

Yield: 90 mg m.p .: 186 ⁰ C C3OH29NO3 (451.6) IR: vmax - ^ 300-2400 (OH), 1710 (C = O), 1605 and 1595 (C = C) cm-1

₁ H-NMR: δ (ppm) - 1.23 (s, 3H ₁ -CH ₃ ), 1.32 (s, 3H, -CH ₃ ), 1.48 (d, 3H, J = 7 Hz ₁ CH ₃ -CH <), 2.72, 2.91 (Aβ, 2H, J = 15.5 Hz ₁ C-1). 3.81 (s, 2H, C-3). 3.96 (q 1H ₁ J = 7 Hz ₁ -CH <). 6.81-7.50 (m, 10H ₁ aroma)

Claims (7)

claims 1. Process for the preparation of the substituted pyrrole compounds of the general formula I: (I) R ² ^ N- wherein R is a C.-C, ₂ ~ alkyl group; 2 R is a hydrogen atom or a C.-C - alkyl group means or R and R together with the carbon atom and the nitrogen atom to which they are attached form a 5- to 8-membered ring which may optionally contain a sulfur heteroatom or a carbonyl group and which optionally substituted with 1 to 2 Cj-C ^ alkyl groups can be; or »3 4 5 Each two of the radicals R, R and R independently represent a hydrogen atom; a Cg-Cg cycloalkyl group; a C 1 -C 4 alkyl group or an aryl group which is optionally substituted by one or two radicals selected from a halogen atom, nitro, C ₁ -C ₄ -AIkOXy-, hydroxy, ^C l ~ ^C ~ 4 ~ ^{alkyl or} phenoxy,
mean and -to- the third of the radicals R ³ , R ⁴ and R is -CHO, -CO ₃ H, -COSC-C-alkyl or AX, where A is a straight-chain or branched C.-Cg-alkylene group which is optionally substituted by an oxygen heteroatom or a carbonyl group may be interrupted, or a C ₂ -C _fi alkenylene group and X is CO ₂ H, SO ₃ H, CHO, OH or SH, 10 and the pharmaceutically acceptable salts and esters thereof, 20 characterized in that A) a compound of general formula II; in which one of the CH2 ~ groups in the ring is replaced by a sulfur atom or a carbonyl group may be replaced and in 26 where η is an integer from 1 to 3, Rg and R7 independently of one another represent a hydrogen atom or a C 1 to C 1 -j-alkyl group, with a compound of general formula III: R ⁵ - CH - C - R ⁴ (HD I
X ° 35 implements, ISHlGO wherein X is Cl or Br and wherein in these formulas each two of R ₃ , R 4 and R 5 independently represent a hydrogen atom, a C5 to Cg cycloalkyl group, a C ₁ to C ^ alkyl group or an aryl group, optionally is substituted by one or two radicals which are selected from a halogen atom, a nitro, C ₁ to C ₄ alkoxy, hydroxy, C ₁ to C ₄ alkyl or phenoxy group, and the third of the radicals R 3, R 4 and R5 is a hydrogen atom, to obtain a compound of general formula IV: R'-v ^ / ^ z in which the radicals R3 to R7 and η have the meanings mentioned above own, una if desired, introducing into one of the compounds thus obtained a residue in an optionally multistage reaction, the meanings of the third of the radicals R ³ , R ⁴ and R ⁵ corresponds to 25 wherein a compound of formula I is obtained, wherein R ¹ and R ^ together with the carbon atom and the nitrogen atom to which they are attached form a 5- to 8-membered ring which may optionally contain a Schwefelhetero- ₃ q atom or a carbonyl group and optionally substituted with 1 to 2 C ^ C ^ Alkyl groups can be substituted and R ³ to R ^{7 have} the meanings mentioned; or B) that a compound of the general formula: 35 3 4 RR ^H 1 H - η- wherein in each case two of the radicals R ³ , R ⁴ and R ^{5 are} independently a Wasssrstoffatom; a C5 to Cg cycloalkyl group; a C 1 to C 1 alkyl group or an aryl group optionally substituted by one or two radicals selected from a halogen atom, a nitro, C 1 to C 1 alkoxy, hydroxy, C 1 to C 4 -Alkyl or phenoxy group, and the third of the radicals R ³ , R ^ and R ^ represents a hydrogen atom, with a compound of the general formula R ^ -X, wherein R * is a C ^ to C ^ alkyl group and X is a suitable leaving group, alkylated and, if desired, a radical in an optionally multi-step reaction, the meanings of the third of the radicals R ³ , R ^ and R ^, wherein a compound of the general formula I: R ³ R ⁴ N
ι gets wherein R ^ is a C ^ to C ^ 2 ".AIkV] .9 ^ru PP ^e and R '' to R- * have the meanings given above. 2. The method according to claim 1, characterized in that for the preparation of the compounds mentioned in claim 1 h i) a compound of general formula II: 35 , Q in which η is an integer from 1 to 3, R ⁶ and R ^{7 represent} a hydrogen atom or a C 1 to C ⁴ alkyl group and R represents a hydrogen atom; a C5 to Cg cycloalkyl group; a C 1 to C 1 alkyl group or an aryl group optionally substituted by one or two radicals selected from a halogen atom, a nitro, C 1 to C 4 alkoxy, hydroxy, C 1 to C 4, Alkyl or phenoxy group, with a compound of general formula III: 20 R ⁵ - CH - C - R ⁴ wherein X is Cl or Br and R ^{4 has} the meanings given for R ³ and R ^ is a hydrogen atom means to a compound of general formula IV: 30 < ^C "£ J / Vr ⁴ (IV) _R 6 - <^ N ^ R ⁵ in which R ³ , R ⁴ , R, R ⁷ and η have the meanings mentioned and R- * represents a hydrogen atom, ii) a compound of general formula II, wherein R ³ , R ⁶ , R ⁷ and η have the meanings mentioned under point i), with a compound of general formula III, wherein R ^ is a hydrogen atom; a C ₅ to Cg-cycloalkyl group; a C ₁ to C ₁₂ alkyl group or an aryl group, which is optionally substituted by one or two radicals selected from a halogen atom, a nitro, C ₁ to C ₄ alkoxy, hydroxy, C ₁ to C ^ - R4 represents an alkyl or phenoxy group, and R4 represents a hydrogen atom, to give a compound of general formula IV in which R ³ , R 5, R 6, R ⁷ and η have the meanings given and R 1 represents a hydrogen atom, iii) a compound of general formula II wherein R 1, R ⁷ and η are as defined and R ^{3 is} hydrogen, with a compound of general formula III wherein R ⁴ and R ^{5 represent} a hydrogen atom; a C5 to Cg cycloalkyl group; a C ₁ to C 1 alkyl group or an aryl group optionally substituted by one or two radicals selected from a halogen atom, a nitro, C ₁ to C ₄ alkoxy, hydroxy, C ₁ to C ₄ -Alkyl or phenoxy group, to give a compound of general formula IV, wherein R ^, R ^, R ^, R ⁷ and η have the meanings given and R ^{3 is} a hydrogen atom, and if desired, in one of the compounds obtained according to i), ii) or iii), a methylol group, ethyl acetate group, formic acid thioester group or an acyl group and, if desired, these by reduction, ester cleavage, Wittig reaction, hydrogenation or by a combination of these measures in - IS- the desired meaning of 'radicals R ³ , R ⁴ or R ⁵ leads over. • 3rd A process according to claim 1, characterized in that after the alkylation according to claim IB an alkyl ester radical is introduced and, if desired, by reduction, ester cleavage, Wittig reaction or hydrogenation or by a combination of these measures into the desired meaning of the radicals R ³ , R ⁴ or R ⁵ transferred.
10 4. The method according to any one of the preceding claims, characterized in that the compounds of the formula Ia: (la) wherein R ³ , R ⁴ and R ^ have the meanings given in claim 1 and R ^ and R ^ independently represent a hydrogen atom or a C ^ -CJ alkyl group. 5. The method according to claim 4, characterized in that one obtains the compounds of formula Ia, wherein two of the radicals R ³ , R ⁴ and R ^ is a phenyl group which is optionally substituted by one or two Radicals selected from a halogen atom, 30 in particular a fluorine or chlorine atom, a C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy and phenoxy group, and the third radical is AX, wherein A is a C 1 -C 6 alkylene group or a C ^ -Cp alkenylene group and X is COoH. ^£ 6. The method according to any one of claims 1 or 3, characterized in that one obtains the compounds of formula I, wherein 1 2
R and R independently of one another represent a C.-C.-j-alkyl group, 3 4 5
two of the radicals R, R and R represent a phenyl group which is optionally substituted by one or two radicals selected from the group consisting of halogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, hydroxy and phenoxy group, and the third of the radicals R, R and R 'represents a hydrogen atom or AX, where A is a C.-C, alkylene or C_-C means ₆ alkenylene group and X is CCKH or SCKH. 7. The method according to any one of the preceding claims, characterized in that one obtains one of the following compounds: (2,2-Dimethy1-6,7-diphenyl-2,3-dihydro-1H-pyrrolizine-5-yl) -c-acetic acid and 3- (2,2-Dimethyl-6- (4-phenoxyphenyl) -7-phenyl-2,3-dihydrol-H-pyrrolizin-5-yl) -propionic acid. 8. The method according to any one of claims 1 to 3, characterized 3t characterized in that the compounds of general formula I: R ³ R ⁴ R ¹ 60 ι receives, wherein R and R together represent a 5- to 8-membered ring which may optionally have a sulfur heteroatom or a carbonyl group and which may optionally be substituted by 1 to 2 C 1 -C 4 -alkyl groups, and in each case two of the radicals R, R and R have the meanings given in one of claims 1 to 3, and the third is AX, where A is a straight-chain or branched C ₃ -C ₉ -alkyl radical optionally substituted by an oxygen atom or a carbonyl group may be interrupted, or a straight-chain and branched C, -Cg-alkenylene group, and X has the meanings given in claim 1, or wherein R - have the meanings ^u to R ^ the Be specified in claim 6 - *.