FI76802C - 3-Iodine Cyclohexylentio and 3-Iodoalkylentio-7-oxo-1-azabicyclo [3.2.0] hep t-2-ene-2-carboxylic acid derivatives and process for their preparation - Google Patents

Description

1 76802 3-Iodocyclohexylenethio- and 3-iodo-alkylenethio-7-oxo-1-azabicyclo [3.2.07] hept-2-ene-2-carboxylic acid derivative and process for their preparation 5 Separated from application 831170

The invention relates to novel carbapenem compounds of formula II

10 0H H

CH 3 = M - <«> O 2 -N-3-COOR 2 '15 wherein A is -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CHCH 2 - or - / CH-3- / 2' Λ and R is ordinary easily removable a protecting group such as p-nitrobenzyl.

These compounds are prepared according to the invention in such a way that

(1) a compound of formula III

OH H H ch3ch__ 25 2 '(HI) * J_N - COOR ^ 2'

wherein R is as defined above, is reacted in a marine organic solvent with diphenyl chlorophosphate 30 in the presence of a base to give a compound of formula IV

OH H 5 ° DOP (OC, HJ, - 6 5 2 2 · (1V>

w _ - COOR

2 '2 76302 wherein R is as defined above; (2) reacting a compound of formula IV in an inert organic solvent and in the presence of a base with a mercaptan compound of formula 5

HS-A-OH

wherein A is as defined above to give a compound of formula V.

10

OH H H

CH-.CH --S-A-OH

i Γ 2. m O ^ -N-1-COOR ^ 15 2 'wherein R is as defined above; (3) reacting a compound of formula V in an inert organic solvent and in the presence of a base with methane or p-toluenesulfonyl chloride or their

With an equivalent functional acylating agent to give a compound of formula VI

OH H H 3. S-A-OSO0 ° CHjCH - ΪΤ "2 25 '1?. (VI)

N - COOR

21 .3 wherein R is as defined above and R is methyl or tolyl; and (4) reacting the compound of formula VI in an inert organic solvent with a source of iodide ion to replace the methanesulfonyloxy group with an iodine group to form the desired compound of formula II.

I! 3 76302

Compounds of formula II may be used as intermediates in the preparation of new antibiotically active compounds of formula I

5 OH H H

ch3ch - S_A- _J M POOR2 10. 2 wherein A is as defined above, R is hydrogen, an anionic charge or a common easily removable carboxyl protecting group, provided that when R is hydrogen or a protecting group, a counter anion is also present; and group

O

is a pyridinium or imidazolium group attached to the group A from the ring nitrogen and which may be substituted by one or two C 1-4 alkyl, C 3-4 alkoxy, hydroxy-substituted C 1-4 alkyl, C 1-4 alkylthio or amino.

The properties of the compounds of formula I and their preparation from the compounds of the invention are described in detail in basic application 831170 of this application.

The above-mentioned ordinary readily removable protecting group means a known ester group which can be used to protect the carboxyl group during the chemical reaction steps described below and which can be removed by methods which do not cause significant cleavage of the remaining moiety, e.g. by chemical hydrolysis or enzymatic treatment. with reducing agents under mild conditions, by irradiation with ultraviolet light or by catalytic hydrogenation. Examples of such ester protecting groups are benzhydryl, p-nitrobenzyl, 2-naphthylmethyl, allylbenzyl, trichloroethyl, silyl such as trimethylsilyl, phenazyl, p-methoxybenzyl, acetonyl, o-nitrobenzyl, 4-pyridylmethyl and C 1 -C 6 alkyl such as ethyl and t-butyl. Such protecting groups also include groups that hydrolyze under physiological conditions such as pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl, and methoxymethyl. Preferred protecting groups are p-nitrobenzyl, which can be easily removed by catalytic hydrogenolysis, and allyl, which can be removed by a Pd (Ρφ ^) ^ -catalyzed reaction.

Preferred compounds of formula II have the absolute configuration 5R, 6S, 8R.

The compounds of formula III used as starting materials for the preparation of the compounds of formula II are described, for example, in European Patent Application 38 869 (compound 7) and can be prepared by the general methods described therein.

The compound of formula III is reacted in an inert organic solvent such as methylene chloride, acetonitrile or dimethylformamide with approximately an equimolar amount of diphenyl chlorophosphate in the presence of a base such as diisopropylethylamine, triethylamine, 4-dimethylamine, pyridine or intermediate. The acylation to obtain the leaving diphenylphosphoryloxy group at the 2-position of the compound of formula III is preferably carried out at a temperature of about -20 to + 40 ° C, most preferably at about 0 ° C. The intermediate of formula IV can be isolated if desired, but for convenience it is generally used in the next step without isolation or purification.

Il 5 76302

Next, the compound of formula IV is converted to the compound of formula V by a conventional substitution reaction. In this case, the compound of formula IV can be reacted with approximately an equimolar amount of the mercaptan-5 compound HS-A-OH wherein A is as defined above in an inert organic solvent such as dioxane, dimethylformamide, dimethylsulfoxide or acetonitrile and a base such as diisopropylethylamine, triethylethylamine, triethyl , in the presence of potassium carbonate or 4-10 dimethylaminopyridine. Temperature is not critical to the substitution reaction, but the preferred temperature range is from about -40 ° C to + 25 ° C. More conveniently, the reaction is carried out under cooling, e.g. at about 0 ° C.

The compound of formula V is then acylated with methane- or p-toluenesulfonyl chloride, or an equivalent reactive acylating agent such as methanesulfonic anhydride, in an inert organic solvent and in the presence of a base to give the toluene-leaving methane or p-methylate of the compound of formula VI. -sulfonyylioksiryhmä. The acylation is performed in an inert organic solvent such as tetrahydrofuran, methylene chloride, acetonitrile or dimethylformamide and in the presence of a suitable base such as diisopropylethylamine, triethylamine, 4-dimethylaminopyridine and the like. The reaction may be carried out over a wide range of temperatures, e.g. from -40 ° C to + 40 ° C, but is most preferably carried out under cooling, e.g. from about -30 ° C to -40 ° C.

Next, a substitution reaction of a compound of formula VI is carried out to give a leaving iodine substituent in a compound of formula II. This iodine substituent has been found to greatly facilitate the preparation of carbapenem end products of formula I. The novel intermediates of formula II therefore form a primary object of the present invention.

6 76302

The leaving methanesulfonyloxy group is replaced with iodine by reacting a compound of formula VI with a source of iodide ion in an inert organic solvent such as acetone, dimethylformamide or di-methylsulfoxide. In this case, any compound which ionizes in the solvent used can be used to produce iodide ions, e.g. an alkali metal ethanol iodide such as NaJ or KJ. The temperature of the substitution reaction is not critical, but temperatures of 10 ° C or above are most preferred to complete the reaction within a perfectly reasonable time. The source of iodide ions is used to such an extent that iodide ions are formed in an amount approximately equivalent to or in excess of the compound of formula VI.

From the compound of the formula II thus obtained, the antibiotically active compounds of the formula I can be prepared by the methods described in FI patent application 831170.

The following examples illustrate the invention.

Example 1 3- [2- (1-Pyridinium) ethyl] -7-6L-ZT- (R) -hydroxyethyl-7--oxo-1-azabicyclo [5.2.2] hept-2-ene-2- preparation of carboxylate 25

OH

V'X- s-ch2ch2-® / J ^ -Leo® A. p-Nitrobenzyl-3- (2-hydroxyethylthio) -6d- [j- (R) -hydroxyethyl] N-oxo-1-azabicyclo (3.2 .0) hept-2-ene-2-carboxylate 35

II

7 76302

OH

0 Jr- N

5 CO2pNB

OH

1 H

4Γ ^ ^ SCH0CH-OH

10 - ^

^ ^ -CO-pNB

O Δ 2 15 pNB = -CH2- ^ ^ _NO2

A solution of 1.69 g (4.85 mmol) of p-nitro-2-benzyl-60O- [1 '(R) -hydroxyethyl] -3,7-dioxo-1-azabicyclo (3.2 .0) hept-2-ene-2-carboxylate (1) in 20 ml of acetonitrile, cooled to 0 ° C under a nitrogen atmosphere. A solution of 726 mg (7.18 mmol) of diisopropylethylamine in 2 mL of acetonitrile was added and then 1.51 g (5.60 mmol) of diphenyl chlorophosphate in 12 mL of acetonitrile was added dropwise over 3 minutes. The resulting solution was stirred at 0 ° C for 20 minutes to give p-nitrobenzyl-3- (diphenylphosphoryloxy) -6c6-ZX_ (R) -hydroxyethyl./30 7-oxo-1-azabicyclo [2.2.1] hept. -2-ene-2-carboxylate. To this solution was added a solution of 726 mg (7.18 mmol) of diisopropylethylamine in 2 mL of acetonitrile followed by a solution of 439 mg (5.63 mmol) of 2-mercaptoethanol in 2 mL of acetonitrile. Reaction solution 8 76302 was stirred at 0 ° C for 3 hours and then diluted with 200 mL of ethyl acetate and washed with 200 mL of water, 100 mL of 20% aqueous H 2 PO 4, and brine. Evaporation of the dried (MgSO 4) solution to dryness gave a semi-solid which was triturated with methylene chloride and filtered to give 1.2 g (61% yield) of the title product 2 as a white amorphous solid. NMR (DMSO-d 6) δ: 1.20 (3H, d, J = 6.0 Hz), 2.9-3.2 (9H, m), 5.22 (1H, d, J = 8.5) Hz) and 8.23 (2H, d, 10 J = 8.5 Hz); IR (KBr) ν max: 3500, 1770 and 1700 cm -1.

Analysis calculated for c 18 H 20 N 2 O 7 S: C, 52.93; H, 4.94; N, 6.86; S, 7.85; Found: C, 52.83; H, 4.90; N, 6.42; S, 8.31.

B. p-Nitrophenyl-3- (2-methanesulfonyloxyethyl-15-thio) -60C-ZJ- (R) -hydroxyethyl] -7-7-oxo-1-azabicyclo [2.2.2] hept-2-ene-2 carboxylate

OH

I &

20 y - ^ SCH_CH.OH

* Γ ~ | T 2 -

0 ^ CO2pNB

2 25

OH

'L-χ. ^ ^ Ch2ch2oso2ch

IXX

CO 2 pNB 3 35 To a solution of 4.2 g (10.3 mmol) of compound

II

9 76802 in 2,200 ml of tetrahydrofuran, 1/3 g (11.3 mmol) of methanesulfonyl chloride were added at -40 [deg.] C. and then 12.6 g (12.4 mmol) of triethylamine in 5 ml of tetrahydrofuran were added dropwise. The reaction mixture was stirred for 5 hours at -40 ° C, then stirred for 2 hours at -30 ° C under a nitrogen atmosphere and then poured into a mixture of ethyl acetate (700 ml) and 5% aqueous phosphoric acid (1000 ml). . The organic layer was washed with brine, dried over MgSO 4, filtered and condensed into a syrup. This material was purified by silica gel column chromatography eluting with methylene chloride-ethyl acetate (3:10 v / v) to give 3.55 g (75% yield) of the title compound as a white amorphous solid. NMR 15 (CDCl 3) δ: 1.25 (3H, d, J = 6.0 Hz), 3.03 (3H, s), 3.06-3.40 (5H, m), 4.05-4.40 (4H, m), 5.25 (1H, d , J = 14.0 Hz), 5.50 (1H, d, J = 14.0 Hz), 7.70 (2H, d, J = 8.5 Hz) and 8.23 (2H, d, J = 8.5 Hz); IR (KBr)) fmax: 3400, 1770 and 1600 cm-1. Analysis calculated for c 19 H 22 N 2 O 9 S: 20 C, 46.90; H, 4.56; N, 5.76; Found: C, 46.52; H, 4.32; OF; 5.91.

C. p-Nitrobenzyl-3- (2-iodoethylthio) -6c (-ΖΊ- (R) -

hydroxyethyl 7-7-oxo-1-azabicyclo (3,2,0) hept-2-ene-2-carboxylate: 25H

I H ^ K sch2ch2oso2ch3

SSJS _ = N-J-CO ^ NB

30 1 PH H

▼ 'N -s = / \ ^ 6CH CH I

Π Γ

O 2 -N-1-CO 2 pNB

35 1 10 76302

A solution of 350 mg (0.72 mmol) of intermediate 3 and 216 mg (1.4 mmol) of sodium iodide in 20 ml of acetone was heated at reflux for 4 hours. Evaporation of the acetone gave a white amorphous solid which was suspended in a mixture of ether (10 ml) and water (10 ml). Filtration of the white solid and drying in vacuo gave 300 mg (80% yield) of the title compound 4 as a white amorphous powder. NMR (DMSO-d 6) δ: 1.18 (3H, d, J = 6.0 Hz) 3.20-3.60 (7H, m), 3.80-4.25 δ (2H, m), 5.10 (1H, d, J = 5.5 Hz), 5.25 (1H, d, J = 12.0 Hz), 5.45 (1H, d, J = 12.0 Hz); 7.70 (2H, d, J = 8.5 Hz), and 8.27 (2H, d, J = 8.5 Hz), IR (KBr): 3500, 1768 and 1700 cm-1.

Analysis calculated for c 18 H 19 N 2 O 6 J: C, 41.71; H, 3.70; N, 5.41; J, 24.48; Found: C, 42.10; H, 3.75; N, 5.97; J, 23.20.

D. 3- [2- (1-Pyridinium) ethyl] -6,6- (R) -hydroxyethyl-4-oxo-1-azabicyclo [2.0.1] hept-2-ene-2-carboxylate

OH H

20 ^^ vns ^ SCH2CH2I ^

f, X

t-X02pNB

4 OH tv 25 I H A n \\ SCH.CHÄ 7 n ^ -N-ly

0 CO2pNB

5 30

OH

^ 2 '—- ^ - »CO ® 35 2 6 il n 76302

To a solution of 327 mg (0.63 mmol) of intermediate 4 in 20 ml of tetrahydrofuran at 0 ° C was added 100 mg (1.26 mmol) of pyridine, followed by a solution of 139 mg (0.67 mmol) of pyridine. mmol) of silver-5 perchlorate in 1 ml of tetrahydrofuran. The mixture was stirred for 1 hour at 0 ° C and then for 2 hours at room temperature. The solvent was evaporated in vacuo to give compound 5 as a slightly yellowish resin which was digested with 300 mg of Celite to give an amorphous solid. IR (KBr) ν max: 3400, 1770, 1700 and 1100 cm -1. Compound 5 was hydrogenated without further purification.

A solution of 125 mg (1.26 mmol) of potassium hydrogen carbonate and 110 mg (0.63 mmol) of dibasic potassium phosphate in 50 ml was then added to a suspended mixture of compound 5 in 50 ml of ether and 50 ml of tetrahydrofuran. 350 mg of 10% palladium-on-charcoal was then added and the mixture was hydrogenated at 40 psi on a Parr shaker 60 for 20 minutes, then the mixture was filtered and the catalyst was washed with water (2 x 10 mL). ether (2 x 100 mL) and then freeze-dried to give a yellow powder The crude yellow powder was purified on a Cgg BONDPAK reverse phase column (8 g) (Waters Associates) eluting with water at 8 psi. Each 15 ml fraction was analyzed - using high pressure liquid chromatography, and the fractions with ultraviolet absorption Amaks 300 nm / were combined and lyophilized to give 40 mg (yield from compound 4, 19%) of the title product 6 as a white amorphous solid.

NMR (D 2 O) δ: 1.20 (3H, d, J = 6.0 Hz), 2.90-3.70 (7H, m), 3.75-4.20 (2H, m), and δ Δ 70-8.80 (5H, m); IR (KBr) fmax: 3400, 1760 and 1590 cm-3 Analysis calculated for c 16 H 18 N 2 O 4 S. 2H 2 O: C, 51.89; H, 5.40; N, 7.56; Found: C, 49.91; H, 5.08; N, 7.11.

12 76802 OV λmax (CH3CH2OH) 296 nm (ε = 7696).

Example 2 Preparation of 3-Z 5 '(1'-Pyridinium) propylthio-7-ol-ZJ- (R) -hydroxyethyl-7--oxo-1-azabicyclo (3,2,0) hept-5 2-ene-2-carboxylate_

OH

! A.- p-Nitrobenzyl-3- (2-hydroxypropylthio) -6 * -N- (1-hydroxy) -6- (1-hydroxy) R) -hydroxyethyl 7-7-oxo-1-azabicyclo (3,2,0) -4-hept-2-ene-2-carboxylate__

OH H O

J * 11 20 1) pStp), PC1 x

1 2) HSCH-CH-CH-OH

> —N - \

O 'CO2pNB

2

25 OH

”/ \ ^ Sch2ch2ch2oh

π T

i — n --K

o CO 2 pNB

30 3

II

13 76302

A solution of 926 mg (2.66 mmol) of p-nitrobenzyl-6H- (R) -hydroxyethyl--3,7-dioxo-1-azabicyclo (3.2.0) hept-2 -ene-2-carboxylate (2) in 15 ml of acetonitrile was cooled to 5-10 ° under a nitrogen atmosphere. A solution of 349 mg (2.7 mmol) of diisopropylethylamine in 1 ml of acetonitrile was added, followed by dropwise addition of 725 mg (2.0 mmol) of diphenyl chlorophosphate in 0.7 ml of acetonitrile over 2 minutes. The resulting solution was stirred at -10 ° for 15 minutes to give p-nitrobenzyl-3- (diphenylphosphoryloxy) -6H-1- (R) -hydroxyethyl-7-oxo-1-azabicyclo. ^ 5.2.0 / hept-2-ene-2-carboxylic azodicarboxylate. To this solution was added a solution of 326 mg (2.8 mmol) of diisopropylethylamine in 1 mL of acetonitrile followed by a solution of 273 mg (3.0 mmol) of 3-mercaptopropanol in 0.5 mL. acetonitrile. The reaction mixture was stirred for 5 hours at room temperature and then overnight at 5 °. The reaction mixture was diluted with 100 mL of ethyl acetate and washed with 100 mL of water and then brine. Condensation of the dried (MgSO 4) solution to a volume of about 5 ml gave white crystals which were washed with ether to give 830 mg (74%) of the title compound (3) as white crystals; mp. 142-144 ° C.

NMR (DMSO-d 6) δ: 1.20 (3H, d, J = 6.0 Hz), 1.5-2.0 (2H, m), 2.8-3.6 (7H, m) , 4.60 (1H, 5, J = 5.0 and 5.0 Hz), 5.1 / (1H, d, J = 5.0 Hz), 5.25 (1H, d, J = 14, 0 Hz), 5.50 (1H, ^ d, J = 14.0 Hz), 7.70 (2H, d, J = 8.5 Hz) and 8.23: (2H, d, J = 8, 5 Hz); IR (KBr) fmax: 3400, 1770, and 1600 cm-1.

Analysis calculated for C 22 H 22 O 2 () 78.1 / 2H 2 O: C, 52.90; H, 5.33; N, 6.49; S, 7.42; Found: C, 53.10; H, 5.08; N, 6.61; S, 7.65.

1A 76302 14 B. p-Nitrobenzyl-3- (2-iodopropylthio) -6α- [1- (R) -hydroxyethyl] -7-oxo-1-azabicyclo (3,2,0) -hept-2-ene- 2-carboxylate-5 J ^ _X ^ / \ - SCH2CH2CH2SO2 "\ /" CH3

TsCl v '| \ \ = /

-N - "* - cO-pNB

0 1 10 i

f H

Säi-> □ I

15 g N 2 O 3 P113 5

To a solution of 810 mg (1.91 mmol) of compound 3 in 20 mL of dry tetrahydrofuran was added 400 mg (2.10 mmol) of p-toluenesulfonyl chloride followed by 268 mg (2.20 mmol) of dimethylaminopyridine. and the mixture was stirred for two hours at room temperature under a nitrogen atmosphere. The reaction mixture was then poured into ethyl acetate-ice water. The organic layer was washed with 40% H 2 PO 4 and then dried over MgSO 4. Evaporation of the dried solvents gave the tosylate 4 as a yellow oil which was converted to the iodine compound 5 without further purification. The crude compound 4 was dissolved in 30 ml of acetone, 1.5 g (10 mmol) of sodium iodide was added, and the mixture was stirred for 16 hours at room temperature. The reaction mixture was poured into ethyl acetate-water. Evaporation of the dried (MgSO 4) solvent gave a yellow syrup which was purified on a silica gel column by chromatography eluting with methylene chloride-ethyl acetate (9: 1 v / v) to give 142 mg.

II

is 76802 (yield 18.5%) of the title compound as a white amorphous powder.

NMR (acetone-d 6) δ: 1.25 (3H, d, J = 6.0 Hz), 2.7-3.5 (7H, m), 4.0-4.4 (2H, m), 5.30 (1H, d, J = 14.0 Hz), δ 5.65 (1H, d, J = 14.0 Hz), 7.80 (2H, d, J = 8.5 Hz); 8.30 (2H, d, J = 8.5 Hz); IR (KBr) ν max: 3500, 1770 and 1600 cm C. 3 - [* 2- (1-pyridinium) propylthio] -6- [1- (R) -hydroxyethyl] -7-oxo-1-azabicyclo (3 , 2.0) hept-2-ene-2-carboxylate__.

15 θ C104® r \ 20% = / * - ^ 002? ^

AgClO. 6 - ° H H e f / \ 25 H2 Π ί. W.

To a solution of 140 mg (0.3 mmol) of iodine in 5 mL of dry tetrahydrofuran was added 50 mg (0.6 mmol) of pyridine followed by a solution of 100 mg (0.5 mmol) of pyridine. silver perchlorate in 1 ml of tetrahydrofuran. The mixture was stirred for two hours at room temperature and then the solvent was evaporated off in vacuo to give compound 6 as a slightly yellow resin.

IR (KBr) ν max: 3400, 1770, 1600 and 110 cm -1. Compound 6 was hydrogenated without further purification.

A solution of 30 mg (0.3 mmol) of potassium bicarbonate and 52 mg (0.3 mmol) of dibasic potassium phosphate in 20 ml was then added to a suspended mixture of compound 6 in 20 ml of ether and 20 ml of tetrahydrofuran. of water. 100 mg of 10% palladium on charcoal was then added and the mixture was hydrogenated at 40 psi on a Parr shaker for sixty minutes. The mixture was then filtered and the catalyst was washed with water (2 x 5 mL). The combined filtrate and washings were extracted with ether (2 x 5 mL) and then lyophilized to give a yellow solid. The crude material was purified on a C 8 8 BONCAPAK reverse phase column (8 g) (Waters Associates), eluting with water at 8 psi. Each 10 ml fraction was analyzed by high pressure liquid chromatography, and fractions with ultraviolet absorbance at 20 ° C were combined and lyophilized to give 8 mg of the title compound as a slightly yellow glassy powder.

NMR (D 2 O) δ: 1.25 (3H, d, J = 6.5 Hz), 1.5-1.8 (2H, ra), 2.2-3.70 (7H, m); 4.0-4.3 (2 H, m), 7.9-8.9 (m, 5 H); IR (KBr) max: 3400, 1760, and 1590 cm -1.

Λ max (H 2 O) 294 nm (E = 6.082), 265 nm (E = 6.317).

Other antibiotic compounds of formula I may be prepared by the method of Example 1 or 2 by administering a suitable intermediate of formula 3 ° OH h

ryx__S-A-I

O-1J-CO2-p-nitrobenzyl 35

II

17 7 6 8 0 2 to react with a suitable heteroaromatic nucleophilic compound

O

and then deprotecting the p-nitrobenzylcarboxyl group by catalytic hydrogenation.

Claims (9)

A process for the preparation of a compound of formula II OH H CH 3 CH --- SAI I, di) 20 -N-COOR 2 wherein A is -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CHCH 2 - or - CH 3 - 21 o 25 and R is a common easily removable protecting group such as p-nitrobenzyl, characterized in that (1) a compound of formula III? OH H? ch3ch - (III) J 1 -i-1-COOR 2 'O 2 II 35 19 7 630 2 2 1 wherein R is as defined above is reacted in an inert organic solvent with diphenyl chlorophosphate in the presence of a base to give a compound of formula IV 5 OH H H 0 ch3ch_ (oc6h5) 2 I 2 '(IV) -N-1-COOR 10 2 1 wherein R is as defined above; (2) reacting a compound of formula IV in an inert organic solvent and in the presence of a base with a mercaptan compound of formula HS-A-OH wherein A is as defined above to give a compound of formula V OH HH CH-.CH fx ^ s SA-OH JF 2 '<V' O-ssst-N -'-COOR 25 2 'wherein R is as defined above; (3) reacting a compound of formula V with an methane or p-toluenesulfonyl chloride or an equivalent functional acylating agent in an inert organic solvent and in the presence of a base to give a compound of formula VI 20 7 6 3 0 2 OH HH, CH3 'H + t ^-A "OS ° 2R - (VI) -N'-COOR2' 5 21 3 wherein R is as defined above and R is methyl or p-tolyl; and (4) reacting a compound of formula VI 10 in an inert organic solvent with a source of iodide ion such that the methane or p-toluenesulfonyloxy group is replaced by iodine to give the desired compound of formula II II 2i 76302 · 2- [7hept-2-en-2-carboxylic acid 5 Raed formIn II H OH CH, CH - SAI 3 I 2 '(II> JNI — COOR io cr color A är -CH2CH2 ~, -CH2CH2CH2-, -CHCH2 eller- / \ CH., 3-f 2' J och R är en sedvanlig lätt avlägsbar skyddsgrupp säsom 15 p- nitrobensyl. 2. For the purposes of this Regulation, see Annex II OH H CH3CH --— S-A-I (II) N J_COOR2 'color A? -CH2CH2-, -CH2CH2CH2-, -CHCH2 eller- / \ 25 CH, -Λ- / 2 'J och R är en sedvanlig lätt avlägsbar skyddsgrupp säsom p-nitrobenyl, kännetecknat därav, att (1) en förening med formeIn III 30. H OH - CH, CH - Ϊf (III) _ -J- COOR2 's? No O 2 2 '22 76802 is defined as, in the case of inert organic solvents with diphenylchlorophosphate in the nervous system, the colors of which are derived from form IV 5 OH? 2 CH, CH-- ° P (OC6H5) 2 I 2 * (IV) X-N-1-COOR cr 10 2 1 color R är som ovan definierats; (2) For the purposes of formula IV, the inert and organic fractions of formula IV and the nervous system of the mercaptan formulation of formula 15 HS-A-OH color A are somewhat defined, the colors are different from the formulation of formula V 20. H OH H “• r S-A-OH ch3ch - J | T, <V> __N I - COOR2 'O ^ 25 2' color R är som ovan definierats; (3) for the preparation of formulas V in the form of inert organic solvents and for the use of methane or p-toluenesulphonyl chlorides or for their equivalents with functionally acylation rings, colors for the preparation of formulas VI