SE408640B - PROCEDURE FOR THE PREPARATION OF NEW ECOPROSTAGLANDINS WITH PHARMACOLOGICAL PROPERTIES - Google Patents

Description

Wherein R 1 and A have the meanings given, and R represents lower alkyl of 1-5 carbon atoms, are reacted with about one equivalent of a strong base and then with approximately one equivalent of the compound 1 - in X 3 HX Chz Z ç fl C (R) 2CH2CH2R OR9 wherein X represents halogen, Z, R3 and Ru have the meanings given, and R9 represents lower alkanoyl having 1-U carbon atoms, that the intermediate thus formed is recovered and subjected to mild hydrolysis for removal of the blocking groups R and R9, and that the desired product is recovered or that b) a compound of the formula R1-NH-cH2 + z1-ca- (CH2) Bal? In oR1 ° * wherein R1, Z1 and R12 have the meanings indicated and R10 represents tetrahydropyranyl, react with one equivalent of a strong base and then with about one equivalent of the compound x- wherein X represents halogen and A and R8 have stated meanings, that the intermediate product thereby formed is recovered, and subjected to mild hydrolysis to remove the blocking groups R 1 and R 9, and that the desired product is recovered.

It can be pointed out that the carbon atom bearing the hydroxyl group in the structural formula of compounds prepared according to the invention is asymmetric. The present invention also relates to the preparation of stereoisomers in which this asymmetric center is present exclusively in one or the other of the two possible configurations, R and S.

BACKGROUND OF THE INVENTION: The present compounds are referred to as 8-aza-11,12-secoprostaglandins due to their structural relationship with naturally occurring prostaglandins.

The prostaglandins constitute a biologically significant class of naturally occurring, highly specialized fatty acids with 20 carbon atoms, which fatty acids are easily anabolized in a variety of mammalian tissues starting from three essential fatty acids, namely 8,111,14-eicosatrienoic acid, 5,8,11, 14-eicosatetraenoic acid and 5,8,11,14,10-eicosapentaenoic acid. Each known prostaglandin is a formal derivative of the parent compound, called "prostanoic acid", the latter acid being a fatty acid having 20 carbon atoms with a covalent bond between carbon atoms 8 and 12 to form a vicinally transsubstituted cyclopentane, wherein the the carboxy-supporting side chain is in the 'Ui' position or below the plane of the ring and the other side chain is in the "fi" "position or above the plane of the ring as indicated in formula III: 9 8 7 6 5 4 3 ÉOH 10 - ° '\ / \ / \? / 2 III 11 12 / f4 \ / f6 \\ / fš \ / åo 13 15 17 19 The six known primary prostaglandins, PGE1, PGE2, PGE3, PGF1', PGF2O¿ and PGFBCK, formed directly in the anabolism of the above essential fatty acids under the action of prostaglandin synthetase, as well as the three prostaglandins formed by the in vivo dehydration of PGE compounds, i.e. PGAI, PGA2 and PGA3, can be divided into three groups, namely the PGE, PGF and PGA series due to three distinct substitution patterns for the cyclopentane nucleus as shown in the following: 10. 71403982-7 4 OH I Ra 2 Ra J '// \\\, "'HO Rb Rb PGE-core PGEa_-core PGA-core PG Ra ab EFAOH 1' 1 '-1 AAA? 2 vvvv Eg, P2, A2.' \ = / \ / \ Co211. X 135, Fj, A3. \, _____ / \ / co2H co H EQ, Fo, Ao. ° '\ / \ / \ / 2 It should be noted that the Arabic indices refer to the number of carbon-carbon double bonds in the indicated compound and that the Greek the index used in the PGF series refers to the stereochemistry of the hydro group at the carbon atom in the 9-position.Although the prostaglandins were discovered in the mid-1950s by Goldblatt ¿_J.Chem. Soc. Chem. Ind. Lond., 52, 1056 (l933l7 in England and Von Euler ¿fArch. Exp. Path. Pharmark., 175, 78 (l934l7 in Sweden independently, these complex natural products received little scientific attention until the early 1960s, which coincides with the advent of modern instrument (e.g. the mass spectrometer), which in turn were necessary for a successful isolation and a structural clarification of Berg- 10 15 20 25 §O 55 40 7lrÛ3982-? 5 streams etc. [Tse Angew.Chem. Int. Ed., Ä, 410 (1965) and the references cited therein Over the past ten years, a massive international scientific effort has been made to develop both biosynthetic and chemical pathways for prostaglandins and later to investigate the biological effects of these compounds. During this period, prostaglandins have been shown to occur largely in low concentrations in a myriad of mammalian tissues, where they are rapidly both anabolized and catabolized and exhibit a wide range of pharmacological properties including significant roles 1 (a) functional hyperemia, (b) inflammatory response , (c) the central nervous system, (d) transport of water and electrolytes and (e) regulation of cyclic AMP. More details regarding prostaglandins can be found in later reviews regarding their chemistry (me.

Pike, Fortschr. Chem. Org. Naturst. 28, 313 (1970) and G.F.

Bundy, A. Rep. in Med. Chem., 7, 157 (l972) 7, Biochemistry ¿fU.W.Hinman, A. Rev. Bieehem., 41, 161 (197217, fyeielegiex meaning ¿fE.w.

Horton, Physiol. Rev., 49, 122 (l969j7 and general clinical use ¿fU.w.Hinmen, Peetgrea. Med. J., 46, 562 (197o¿7).

The potential use of natural prostaglandins as medically suitable therapeutic agents in various disease states in mammals is obvious but has three extremely major drawbacks, namely (a) prostaglandins are known to be rapidly metabolized in vivo in various mammalian tissues to a variety of metabolites , lacking the desired original biological activities, (b) the natural prostaglandins lack the biological specificity necessary for a good drug and (c) although limited amounts of prostaglandins are currently produced by both chemical and biochemical means; the production cost of the prostaglandins is extremely high and consequently the supply of them is very limited.

The object of the present invention has therefore been to synthesize new compounds which are structurally related to natural prostaglandins, but which have the following unique advantages: (a) a simple synthesis which gives a low production cost, (b) specific biological activity, which is either prostaglandin-like or prostaglandin antagonizing, (c) increased metabolic stability.

The combination of these benefits provides effective, orally and parenterally active therapeutic agents for the treatment of a variety of diseases in animals and humans. This includes use in the treatment of the renal, cardiovascular, gastrointestinal, respiratory system and in the control of lipid metabolism, inflammation, thrombosis, skin diseases and certain cancers.

More specifically, the prostaglandin agonists may act as agents for improving renal function (eg renal vasodilation), such as antihypertensive agents, such as agents for gastric ulcers, anti-thrombotic agents, anticoagulants, antilipolytic agents, antineoplastic agents and agents for treating certain diseases. domar.

Prostaglandin antagonists can act as anti-inflammatory drugs, anti-diarrhea drugs, antipyretic drugs, and headache remedies.

The compounds of the present invention are particularly useful for improving renal function, for treating hypertension and for preventing blood clot formation. It should be emphasized that not all of these compounds have all properties, but each of the compounds has been tested in a series of experiments and has been shown to have activity in at least one area of activity.

The compounds of the present invention may be administered either topically or systemically (ie, intravenously, subcutaneously, intramuscularly, orally, rectally, or by aerosolization), in the form of long-acting sterile implants.

Regardless of the route of administration, doses in the range of about 0.10 to 20 mg per kg of body weight per day were used. The exact dose depends on the age, weight and condition of the patient as well as the mode of administration and frequency. The low cost and the good availability of the compounds according to the invention make them particularly promising in terms of use in veterinary medicine, in which area their use is comparable to the use in human medicine.

PROCEDURES FOR PREPARING THE COMPOUNDS OF THE PRESENT INVENTION: The novel chemical compounds are prepared according to the invention according to two methods. The first process involves the reaction of a compound III with, for example, a compound IV R1-NH- (cH2) uA-coong * iii -___ 3 14 x cH2 z and c (fl) 2cH cH2R _Iv OCOCH3 2 a. ... andx- umuuunæn .... .- - w ».AV - snewuwåwuäß-ef 10 15 20 7 wherein A, R1, Z, R5 and Ru 7 # 03982-7 have previously given meanings and R 8 represents lower alkyl having 1-5 carbon atoms, preferably ethyl and X be- The reaction is carried out represents halogen, eg chlorine, bromine or iodine. by preparing the alkali metal salt of III by reacting III with sodium hydride in a solvent such as a mixture of benzene and dimethylformamide (1: 1), after which compound IV is added at room temperature and the reaction mixture is heated at 50-10000 for 1 to 20 hours. illustrated by formula V: H1-T- (cH2> uA-cooR8 one-z-en-c (H5) 2-cH2ca2R “OCOCH3 In this reaction, intermediate- Mild basic hydrolysis (NaOH in aqueous methanol or ethanol) is obtained of the functional ester groups in compound V give desirable compounds, for example, of formula VI: 1R -w- (CH2) uA-COOH I - _ _ 3 L! CH2 Z? HC (R) 2CH2CH2R OH VI According to the second process a compound, for example of formula VII, is reacted with a compound of formula VIII, wherein A, R and R 1 have previously given meanings, X represents halogen, eg chlorine, bromine or iodine, R 8 represents lower alkyl having 1-5 carbon atoms , preferably ethyl, and THP represents 2-tetrahydropyranyl groups.

The reaction is carried out by preparing the alkali metal salt of VII by reaction of VII with sodium hydride in a solvent such as a mixture of benzene and dimethylformamide (1). : 1), after which compound VIII is added at room temperature and the reaction mixture is heated at 50-10000 for 1-20 hours. tion gives intermediates which can be illustrated by formula IX: V n. krv-month .n-op-Wa ". <..--.» - - »qaue fi rše-äßstmuf-fk -« - - Denna reak-, ..- ... n-ßobiw ”. Abba» - .- 10 15 20 25 BO 7403982-7 1_ _ _ _ _ 5 v RT ( (co 72 (CH 72)); - ïH-C H 'IX 5 11 OTHP, Mild acid hydrolysis (aqueous HCl in methanol or ethanol) removes the tetrahydropyranyl protecting group, after which mild basic hydrolysis (NaOH in aqueous methanol or ethanol) of the funk From the therapeutic standpoint, it is often advantageous to prepare the compounds of the invention, in which compounds the asymmetric carbon atom, which contains the compounds of formula I, for example X: R 1 -N-HX (cH 2) 3-ou-c 11 5 OH carries OR2, is available exclusively in R or S configuration. ' It should be remembered that the corresponding center in the natural prostaglandins is the S-configuration, inverting this center may possibly result in a decrease in biological activity, but a marked increase in biological specificity is often achieved. 11,12-secoprostaglandin series, compounds present exclusively in the R or S configuration at this center can be prepared using pre-divided compounds IV or VII and by performing the steps of procedure 1 or 2. An example on the use of such a pre-divided compound IV is given in the section "Preparation of intermediates (Example J)".

DERIVATIVE PREPARATION: The compounds of the present invention can be converted to derivatives thereof. fl. In the preparation of carboxy salts, the acid products are dissolved in a solvent such as ethanol, methanol, glyme or the like and the solution is treated with a suitable hydroxide of alkali metal or alkaline earth metal or alkoxide to form the metal salt, or with an equivalent amount of ammonia, amine or quaternary when ammonium hydroxide to form the amine salt. In each individual case, either the salt is precipitated from the solution and separated by filtration or, when soluble, the salt can be recovered by evaporation of the solvent. Aqueous solutions of carboxylic acid salts can be prepared by treating an aqueous suspension of the carboxylic acid with an equivalent amount of a hydroxide or oxide of an alkaline earth metal, alkali metal hydroxide, carbonate or bicarbonate, ammonia, an amine or an amine. a quaternary ammonium hydroxide.

Carboxy esters are obtained by treating the compounds in ether with an ethereal solution of a suitable diazoalkane. For example, methyl esters are prepared by reacting the compounds with diazomethane. Carbamoyl derivatives or substituted carbamoyl derivatives are obtained by first transferring the compounds to an active Woodward ester. For example, the compound can be reacted with N-tert-butyl-5-methylisoxazolium perchlorate in acetonitrile in the presence of a base, such as triethylamine, to form an active ester, wherein -COOH is replaced by -C-3-C (CH 3 ) = CH-NH-C (CH5) 3. Active esters of this type can be reacted with ammonia to form compounds, wherein -COOH is replaced by carbamoyl; with primary or secondary amines or lower alkylaminoalkylamines to give products wherein -COOH is replaced by substituted carbamoyl, i.e. -CONH R 7. In compounds of formula X, reaction with formic acid, acet anhydride, propionic anhydride, butyric anhydride, isobutyric anhydride, valeric anhydride, pivalic anhydride or the like without solvent and at temperatures from 25 to 6000 gives the corresponding formyl, acetyl, propionyl, butyryl , isobutyryl, valeryl and pivaloyl derivatives, respectively.

PREPARATION OF STARTING MATERIAL: 1, Reagent III, having the general formula shown, wherein H 1 and R 6 have the meanings given above, are prepared as follows: 1 8 R -NH- (cnzhl-A-coon II: Corresponding amino acid is treated with the appropriate the anhydride R1COOCOR1 suitable alcohol, RSOH 2. The reagent IV A, which has the following general formula and the acylated compound formed is esterified in the (x) 3cH2th2R Iv A OCOCH3 wherein X represents halogen and RB and Ru has previously indicated meanings, is prepared as follows: A Grignard reagent, RuCH2CH2 (R3) 2C-Mgl or R5CH2CH2 (R3) 2C-MgBr is reacted with a nitrile X ( CH2) 3pN in ether The imine formed is hydrolyzed in aqueous acidic solution to give ketones of the formula X (CH2) á3 (= O) - C (R3) 2CH2CH2R4 The ketones are reduced to the corresponding alcohols x (cH2) 3cH (oH) -c (Rac fi gcfiznu with sodium or potassium boron arylide 1 a suitable solvent, such as methanol, ethanol or of the such alcohols, preferably with acetane hydride, IV A. gives the reagent. Reagent IV B, which has the following general formula I! X-CH2-Z -CH-C5H11 IV B OCOCHB wherein X represents halogen and Z "represents -CEEEC-, is prepared as follows. 1-octyn-5-ol is treated with acetane anhydride to give the acetylated alcohol HC55C-CH This compound is treated OCOCHB with paraformaldehyde and diethylamine to give the tertiary amine (C2H5) 2N-CHQCEEEC-CH-C5H11 which, when treated with bromocyanide, gives 00OCH3 reagent IV B. Analogous compounds with longer or shorter chains produced in the same way.

By using the divided R and S forms of 1-octyn--3-ol in the indicated scheme, the corresponding R and S forms of the reagent IV B can be obtained.

It should be noted that the use of the R or S enantiomers of the reagent IV B gives R and S enantiomers, respectively, of the compounds of formula VI A, wherein B1 has the meaning given in formula I and Z "denotes -C ä C- These optically active products VI A can be hydrogenated over a platinum catalyst to form R 1 and S enantiomers of the A 2 (CE) 6-c ooH __ CH 2 -Z "-ïH-C 5 H 11 VI A OH. compounds of formula VI A, wherein Z represents ethylene, -CH 2 -CH 2 -.

The reagent IV C, which has the following general formula X-CHQ-c fl a ". Hc HC SHM IV C OCOCH3 diglyme. Acetylation, e.g., wherein X represents halogen, is prepared as follows. A Grignard reagent, C5H11MgBr or C5H11MgI, is reacted with crotonaldehyde to give the alcohol CH3pH = CH-CH (OH) -C5H11 after hydrolysis. This alcohol is preferably acetylated with acetane hydride without solvent at 30-10 ° C for 2-12 hours, the intermediate CH5§H = CH-CH (COCOCH3) C5H11 This reaction is reacted with N-bromosuccinimide in chloroform at 50-7000 for 2.5 to 5 hours to give allylic bromination to give the reagent of formula IV C As previously stated, longer or shorter chain analogs are prepared with the corresponding Grignard reagent 3. Reagent VII of the following formula 1 nl-NH- (cH 2) 5 OH-c 5 H 11 VII OTHP is prepared by the following reactions: The alcohol prepared inevenitc 2 even with the formula x (cH2) ¿% å-c (R5) 2c H2cH2a ”(with R3 = H and R = CH2CH) is treated with dihydropyran and a catalytic amount of acid to give X (CH2) 3-CH-C5H11. Treatment of this halogen compound with the sodium salt of OTHP phthalimide in dimethylformamide gives the corresponding phthalimido compound. Digestion of this compound with hydrazine in ethanol gives the amine NH 2 - (CH 2) 3 - H-C 5 H 11, which upon acetylation with acetane hydride in pyridine gives the OTHP reagent VII. As previously stated, the length of the chain can be varied by selecting a suitable starting material. 4. The preparation of the reagents of formula VIII 8 X- (CH 2) ¿-A-COOR VIII has been described in the scientific literature and the patent literature for the cases where A represents ethylene, trimethylene, fx-methylethylene, ß-methylethylene, n, Α-dimethylethylene, 16β-dimethylethylene. To prepare reagents wherein A represents oxymethylene, an ester of glycolic acid, HOCHECOOR8, is treated with a strong base, preferably sodium hydride, in an aprotic solvent (dimethylformamide, glyme or the like) and the anion formed is reacted with 1,4 ~ dihalobutane, preferably 1,4-dibromobutane. The glycol ester and base were used in approximately equimolar amounts; an excess of 1.5 to 2 moles of dihalobutane can be used to advantage. Methods for obtaining optical antipodes of some compounds prepared according to the invention have been described above, in which one of the molecular components is divided before it is combined into the whole molecule. Other methods can also be used; for example, mixtures of the racemate can be separated by taking advantage of physicochemical differences between the components by chromatography and / or fractional crystallization. The racemic products and intermediates can be divided into the optically active components according to any of the methods of division, which are well described in the chemical literature.

The compounds consisting of carboxylic acids can be converted into diastereoisomeric salts by treatment with an optically active base, such as + or - amylbenzylamine, + or -6X- (1-naphthyl) -ethylamine, brucine, cinconin, cinconidine or quinine. These diastereoisomeric salts can be separated by fractional crystallization.

The carboxylic acids prepared according to the invention can also be converted into esters with an optically active alcohol, such as estradiol 5-acetate or d- or 1-menthol, and the diastereoisomeric esters are partitioned by crystallization or by chromatographic separation.

K Racemic carboxylic acids can also be separated by counterflow and absorption chromatography with optically active vehicle and absorbent.

The compounds prepared according to the invention contain a free hydroxy group which can be esterified with acid chlorides or anhydrides derived from optically active acids, such as (+) - 10-camphorsulfonic acid, (+) 1X-bromocamphor-sulfonic acid, or d- or 1-6,6'-dinitrodiphenic acid to form esters, which can be broken down by crystallization.

Another way of obtaining pure optical isomers is that the racemic mixture is inoculated with certain microorganisms, such as fungi, according to well-known methods, and that the product formed during the enzymatic conversion is recovered.

The methods described above are particularly effective if the method is applied to a compound in which an asymmetric center has been previously divided according to any method already described.

The invention is further described in the following * examples.

PREPARATION OF INTERMEDIATE PRODUCTS 5. Preparation of 1-chloro---acetoxynonane Step 1. Preparation of 1-chloro-H-nonanone A Grignard reagent, which is prepared from a mixture of amyl- and. .v-_u1-.fu- .www-. -fl- v .. __ _. m., .gps -._. 10. 15. 20. 25. ÉO. 55.

HO. Bromide (226.59 g, 1.5 mol) and magnesium (56, N8 g, 1.5 mol) in ether (1000 ml) are added dropwise over one hour with 4-chlorobutyronitrile (155.5 g) , 1.5 mol). Stirring is continued for another hour. The reaction mixture is poured into a mixture of finely crushed ice (1000 g) and concentrated hydrochloric acid (750 ml). The ether layer is quickly separated and discarded. The aqueous layer is heated on a steam bath for one hour to hydrolyze the intermediate imine and to effect separation of the ketone in the form of an oil. After cooling, the oil is extracted with ether and the combined extracts are washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent is removed in vacuo and the residual oil is distilled to give 69.0 g (26%) of a colorless oil, b.p. 115-170 / 1.9 kPa; pmr (CDCl 3) tfo, 90 (3H, t), 3.56 (2H, t, cH 2 Cl).

Step 2. Preparation of 1-chloro-4-nonanol 8 A suspension of sodium borohydride (6.62 g, 0.175 mol) and sodium hydroxide (1.5 g) in ethanol (310 ml) is treated dropwise over one hour with 1-chloro- 4-nonanone (61, 40 g, 0.349 mol), while maintaining the temperature at 55 - 50 ° C. Stirring is continued for another hour without external cooling. The reaction mixture is acidified with concentrated hydrochloric acid to the end point of Congo red and then the ethanol is removed under reduced pressure. The residue is treated with water (200 ml) and the oil obtained is extracted with ether. The combined extracts are washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent is removed in vacuo to give the title compound as a pale yellow residual oil, yield 58.85 g, IR (neat) 3400 cnil. Step 3. Preparation of 1-chloro-4-acetoxynonane A mixture of 1-chloro-4-nonanol (11.1, 99 g, 0.627 mol) and acetane hydride (228.0 g, 1.254 mol) is heated on a steam bath in 1-1 /2 hours.

Volatiles are removed under reduced pressure and the residual oil is distilled to give 88.6 g (6.1%) of a colorless oil, mp 130-133 ° / 1.9 kPa; pmr (cnclj) ff 0.89 (3H, t), 2.02 (5H, s oaScoo), 3.53 (2H, t 011201), 14.89 (1H, m).

Calculated for c11 fl glcloz: c 59.85; H 9.59 manet: c 59.87, - H 9.67.

Analysis: Q. Preparation of 1-chloro-4-acetoxy-8-methylnonane Step 1. Preparation of 1-chloro-8-methyl-4-nonanone The Grignard reagent, which is prepared from a mixture of 1-bromo- 4-Methyl pentane (200.00 g, 1.21 mol) and magnesium (29.45 g, 1.21 mol) in ether (800 ml) are added dropwise over one hour to red chloro- 10. 15. 20. 7lr03982 Butyronitrile (125.30 g, 1.21 mol) Stirring is continued for another hour - 6 'The reaction mixture is poured into a mixture of finely crushed ice (800 g) and concentrated hydrochloric acid (600 ml). The ether layer is separated rapidly The aqueous layer is heated on a steam bath for one hour to hydrolyze the intermediate laminate to effect separation of the ketone in the form of an oil. After cooling, the oil is extracted with ether and the combined extracts are washed with saturated sodium chloride solution and dried over anhydrous The solvent is removed in vacuo and the residual oil is distilled to give 23.3 g (10%) of sodium sulfate. a colorless oil, b.p. 121 DEG-222 DEG / 2.0 kPa, pmr (CDCl3) δ {0.89 (6H, d), 3.57 (2H, t CH2Cl).

Analysis: Calculated for C 10 H 19 ClO: C 62.98; H 10.0 Ä Found: C 62.86; H 10.20.

Step 2. Preparation of 1-chloro-8-methyl-Ä-nonanol A suspension of sodium borohydride (2.3 g, 0.061 mol) and sodium hydroxide (0.5 g) in ethanol (110 ml) is treated dropwise over one hour with 1 -chloro-8-methyl-4-nonanone (23.0 g, 0.121 mol), while the temperature is kept at 45 DEG-50 DEG. omr-aningen fereeattee in another tin- me without external cooling.

The reaction mixture is acidified with concentrated hydrochloric acid to the end point of Congo red and then the ethanol is removed under reduced pressure. The residue is treated with water (70 ml) and the resulting 25. 30.

RO. the oil is extracted with ether¿ The combined extracts are washed with saturated sodium chloride solution and dried over anhydrous sodium sulphate. The solvent is removed in vacuo to give the title compound as a pale yellow residual oil, yield 22.73 g, IR (neat) 30 cm 3.

Step 3. Preparation of 1-chloro-Ä-acetoxy-b-methylnonane A mixture of 1-lelen-S-methyl---nenanel (22.73 g, 0.118 mol) and acetane hydride (24.07 g, 0.236 mol) is heated on steam bath for ll / 2 hours. y The volatile constituents are removed under reduced pressure and the residual oil is distilled to give lÄ, 53 g (58 å) of a colorless oil, kekpunk: 158 - l59 ° / 2, o me; pmr (011013) e! o, 85 (6H, d), 2.02 (3H, s CH 3 §100), 3.53 (2H, t CH 2 Cl), 4.92 (1H, m).

Q. Preparation of 1-chloro-4-acetoxyundecane Step 1. Preparation of 1-chloro---undecanone This compound is prepared in substantially the same manner as described for 1-chloro-4-nonanone (Example A, step 1) with the following reagents: 10. 15. ' 20. 25. 50: 35. ÄO. 7403982-7 / 15 l-bromoheptane ... ............ 2lü, 9ä g (1.2 mol) Magnesium ................ ........... 29.18 g (1.2 mol) Ether ............................ 80 80 ml of 4-chlorobutyronitrile ............. ... 124.27 g (1.2 mol) The title compound is obtained as a colorless oil, yield 60, 4 g (15 56), boiling point 135 - 140 ° / 2, o kPa; pmr (cbclš) J 0.93. (3H, fi), 3.57 (2H, fi CH2Cl) - Step 2. Preparation of 1-chloro-un-undecanol This compound is prepared in essentially the same manner as described for 1-chloro---nonanol (Example A, step 2) with the following reagents:: oceanen- Sodium borohydride ... . . . ...... . . . ...... 5.56 g (0.147 mol) Sodium hydroxide ...................... 1.2 g Ethanol ...... ......................... 265 ml 1-chloro-4-undecanone ................ ... 60.00 g (0.294 mol) The title compound is obtained in the form of a yellow residual oil, yield 60.02 g.

Step 3. Preparation of 1-chloro-β-acetoxyundecane This compound is prepared in essentially the same manner as described for 1-chloro-4-acetoxynonane (Example A, step 3) with the following reagents: 1-chloro-4-undecanol ................... 60.02 g (0.29 mol) Acetanhydride .................. .. ... 59, 16 g (0.58 mol) The title compound is obtained in the form of a colorless oil, yield 44.6 g (62%), b.p. 155-1580 / 2.0 kPa; pmr (cDc13) 0 / o, 88 (3H, u), 2.02 (3155 cflcoo), 3.53 (2H, 1; cnaci), 4.92 (1H, m).

Analysis: Calculated for C 13 H 25 ClO 2: C 62.76; H 10, 11} Found: c 63.03; H 10.40. Preparation of 1-chloro-β-acetoxy-8,8-dimethylnonane Following the procedure described for 1-chloro-4-acetoxynonane (Example A) but replacing the amyl bromide with 1-bromo-4,4-dimethylnonane dimethylpentane is obtained sequentially: 1-chloro-8,8-dimethyl-H-nonanone, 1-chloro-8,8-dimethyl-4-nonanol and 1-chloro-4-acetoxy-8,8-dimethylnonane.

§. Preparation of 1-chloro-4-acetoxy-9,0,9-trifluorononane Following the procedure described for 1-chloro-4-acetoxynonane (Example A) but replacing the amyl bromide with 1-bromo-5.5, 5-Trifluoropentane is obtained in sequence: 1-chloro-9,9,9-trifluoro-nonenonone, 1-chloro-9,9,9-trifluoro-4-nonanol and 1-chloro-β-acetoxy-9,9,9 -trifluoro- nOfland.

E. Preparation of 1-chloro-4-acetoxy-8-nonene By following the procedure described for 1-chloro-α-α a _ _...- 10. 15. 20. 25: 35- 40. jvaosssz of acetoxinonane (Example A) but replacing the amyl bromide with 1-bromo-4-pentene, are obtained as follows: 1-chloro-8-nonen-4-one, 1-chloro-8-nonen-4-ol and 1 Chloro-4-acetoxy-8-nonene.

Q. Preparation of 1-chloro-4-acetoxy-5,5-dimethylnonane Step 1. Preparation of 1-chloro-5,5-dimethyl-4-nonanone 400 ml of a solution in ether of 1,1-dimethylpentylmagnesium chloride, which prepared from magnesium (24.3 g, 1.0 mol) and 1-chloro-1,1-dimethylpentane (155.5 g, 1.0 mol) according to the Whitmore and Badertscher methods [J.Am. Chem. soc. 55, 1559 (195517) is added alternately with stirring to 4-chlorobutyryl chloride (197 g, 1.4 mol) in ether (400 ml) for 6 hours and the reaction mixture is stirred for a further 12 hours.

It is then poured into a mixture of ice and dilute hydrochloric acid. The ether layer is separated, washed with water and brine and dried over sodium sulfate. The ether is evaporated and the residue is distilled in vacuo (water suction) through a Vigreaux column to give the product as a colorless oil.

Step 2. Preparation of 1-chloro-5,5-dimethyl-4-nonanol By following the procedure described for 1-chloro--4-nonanol (Example A, step B) but replacing 1-chloro-4-nonanone against 1-chloro-5,5-dimethyl-4-nonanone and continuing stirring and heating at 50 ° for 6 hours, 1-chloro-5,5-dimethyl-4-nonanol is obtained.

Step 5. Preparation of 1-chloro-4-acetoxy-5,5-dimethylnonane Following the procedure described for the chloro-4-acetoxynonane (Example A, step 3) but replacing 1-chloro-4-nonanol with 1 chloro-5,5-dimethyl-phenonanol and continuing to heat on a steam bath for 4 hours, 1-chloro-4-acetoxy-5,5-dimethylnonane is obtained. 5 pg. Preparation of 1-bromo-U-acetoxy-2-nonene A mixture of U-acetoxy-2-nonene (73.5 g, 0.4 mol), N-bromo-succinimide (80.0 g, 0.45 mol) and carbon tetrachloride (500 ml) are refluxed for 3 hours. The mixture is then cooled and the suspended succinimide is removed by filtration. The carbon tetrachloride solution is washed with dilute sodium bicarbonate solution and water and dried over sodium sulfate. The carbon tetrachloride is evaporated in vacuo and the residual oil is distilled to give 62 g (59 ß) of 1-bromo-4-acetoxy-2-nonene as a pale yellow oil, b.p. 10 - 1120/13 Pa.

I. Preparation of 1-bromo-α-acetoxy-2-nonyne Step 1. Preparation of 3-acetoxy-1-octyl-1-octyn-3-ol (100 g, 0.794 mol) is dissolved in pyridine (79 g, * 1.0 mol) and acetane hydride (81.6 g, 0.80 mol) are added dropwise with stirring for 1 hour. The temperature rises to H50. The solution is heated at 50 10. 15. 20. 25. 30. 55. 40. 17 7403982-7 55 ° for one hour and then cooled and poured into 200 ml of ice-cold 5% hydrochloric acid. The oily product is taken up in ether, washed with water and brine and dried over sodium sulfate. The ether is evaporated and the residual oil is distilled to give 106.4 g (80%) of 3-acetoxy-1-octyne, m.p. 91 DEG-92 DEG / 2, 0 kPa. Step 7 Preparation of 1-diethylamino-4-acetoxy-2-nonyne A mixture of 3-acetoxy-1-octyne (58.8 g, 0.35 mol), diethylamine (28.5 g, 0.39 mol), paraformaldehyde (13.8 g, 0.46 mol) and p-dioxane (60 ml) are heated on a steam bath with reflux condenser for 17 hours.

The resulting solution is cooled and diluted with 250 ml of ether. The solution is extracted with 300 ml of 5% hydrochloric acid. The acidic aqueous extract is made basic with 10% sodium hydroxide solution. The liberated amine is taken up in ether, washed with water and brine and dried over sodium sulfate. The ether is evaporated and the residual oil is distilled to give 73.1 g (89%) of 1-diethylamino-4-acetoxy-2-nonyne, b.p. 103 DEG-110 DEG / 110 DEG.

Analysis: Calculated for C 15 H 27 NO 2: C 71.10; H 10.74; N 5.33 Found: C 70.75; H 11.03; N 5.55 Step, 3. Preparation of 1-bromo-4-acetoxy-2-nonyne A solution of i-diethiamino-IL-acetoxy-α-nonyne (50, 6 g, 0.20 mol) and bromocyanide (2.1, 2 g, 0.20 mol ) in ether (250 ml) is allowed to stand at 25 - 27 ° for 18 hours. The ether solution is washed with 5% hydrochloric acid solution, water and brine and dried over sodium sulfate. The ether is evaporated and the residual oil is distilled. After a pre-distillate of diethyl cyanamide, 34.1 g (65,76) of 1-bromo-IL-acetoxy-α-nonyne, boiling point 97-150 ° / 27 Pa, are collected.

Analysis: Calculated for C 11 H 17 BrO 2: C 50.59; H 6.56 Found: C 50.54; H 6.49 Q. Preparation of 1-bromo-4 (R) -acetoxy-2-nonyne Following the procedure described in Example H, substituting the racemic 1-octyn-3-ol compound for ( R) -1-octyn-3- 01 [α] 25 D + 6.1 ° [c 3.1, 0110137, is obtained in the following; 3 (R) -a @ eto »x ~; -1- 01mm, [BJ šó; 70 ° [c 3,1,1010137, i-ethylamino-u (Hyacetoxy-e-nonyn, ¿¶ ¥ _7 šó + 740 ¿f0 3,2, CHCl3_7 and l-bromo-4 (R) -acetoxy-2- nonyn, [jaa] ff + 75 [c 3,2, cncljj. ß. Preparation of 1-bromo-455) -acetoxy-2-nonyn - By following the procedure described in Example H but replacing racemic 1-octyn -3-ol with (S) ~ 1-octyn-3-ol, Å7ï; 7 go f -6.11 ° [c 3.3, cnci fl, arr-miles in föijd; 3 (s) -acetoxy.-1-ol-79 -f733.0, CHCl3; 7,1-diethylamino-4 (S) -acetoxy-2-nonyn, ÅQY Du-300 10. 15. 20. 25. 50 35. 40. '7403982 / -7 I [c 3,3, cnciz] and i-bromo-lus) -a <= eu0x1-2-ncnyn, [å] â ° -83 ° [3 _,?, C fl ci fl .

Q. Preparation of methyl 7-bromo-2-methylhentanoate Step 1. Preparation of 5-acetoxynethyl chloride Acetane hydride (102 g, 1 mol) is added dropwise with stirring to pentamethylene chlorohydrin (90 g, 0.74 mol). The solution formed is heated on a steam bath for one hour and allowed to stand overnight at room temperature. The reaction mixture is distilled to give 83.6 g (69%) of 5-acetoxypentyl chloride, b.p. 101-1040 / 270 Pa.

Step 2. Preparation of diethyl (5-acetoxypentyl) methylmalonate Sodium hydride (4.8 g, 0.2 mol) in the form of a 50% suspension in mineral oil is washed with petroleum ether in a nitrogen atmosphere to remove the mineral oil, suspended in dry benzene (150 ml) and the suspension is cooled in an ice bath. Diethyl methyl malonate (34.8 g, 0.2 mol) dissolved in dried DNF (150 ml) is added dropwise to the sodium hydride suspension. The mixture is allowed to stand overnight at room temperature. Potassium iodide (0.4 g) and 5-acetoxypentyl chloride (} 2.9 g, 0.2 mol) are then added, and the mixture is heated for 24 hours at 1250 l in an oil bath. The reaction mixture is concentrated in vacuo, diluted with ether (200 ml) and filtered to remove sodium chloride.

The filtrate is washed with brine, dried over anhydrous magnesium sulfate and concentrated to give 39.6 g (66%) of oily diethyl (5-acetoxypentyl) methyl malonate. .

Step 2. Preparation of 7-bromo-2-methylheptanoic acid A mixture of the crude diethyl (5-acetoxypentyl) methylmalonate (68 g, 0.23 mol) and 48% aqueous hydrobromic acid (100 ml) is refluxed for 20 hours. . The mixture is then concentrated by distillation, until the internal temperature rises to 120 °; Collect 96 ml of distillate (2 layers). The residual liquid is cooled, dissolved in ether, washed with brine, dried over magnesium sulphate, and the solution concentrated in vacuo gives 54 g of crude 7-bromo-2-methylheptanoic acid as a dark viscous liquid.

Step Ä._Preparation of methyl 7-bromo-2-methylheotenoate A solution of crude 7-bromo-2-methylheptanoic acid (SA g, 0.24 mol) and concentrated sulfuric acid (2 drops) in absolute methanol (500 ml) is refluxed in 5 hours. When the solution has stood overnight at room temperature, it is concentrated in vacuo and diluted with water.

The mixture is made basic by the addition of saturated sodium carbonate solution and the product is taken up in ether. The ether extract is washed with water, dried over anhydrous magnesium sulfate and distilled to give 10. 15. 20. 25. 30. 35. ho. 11.8 g (16%) of methyl 7-bromo-2-methylheptanoate, b.p. 67-7077 Pa; pmr (CEC1) d 1.13 (§H, d 2-CH3), 2, U2 (1H, m CEQOOCHB), 5.58 (2H, t CHQBP), 5.65 (} H, s CHBO).

M. Preparation of ethyl 4-bromobutoxyacetate Sodium nyafide (9.0 g, 0.375 ml) is suspended in 1,2-dimecoxyl-ethane. The mixture is stirred and cooled in an ice bath while ethyl glycolate (39.0 g, 0.375 mol) is added dropwise over one hour. 1,4-Dibromobutane (108 g, -0.5 mol) is immediately added to the thick suspension formed. The mixture is heated slowly to initiate a strong exothermic reaction; then the mixture is heated for 5 hours in a steam bath. The mixture is poured into cold water. The heavy oil layer is taken up in ether, washed with three portions of water and dried over sodium sulfate. Evaporation of the ether and distillation of the residual oil gives 21.5 g (24%) of ethyl 4-bromobutoxyacetate, a colorless oil, b.p. 99 - 1050/27 Pa. Preparation of N- [4- (2-tetrahydropyranyloxy) nonyl] acetamide Step 1. Preparation of 1-chloro-4- (2-tetrahydropyranyloxy) nonane A stirred solution of 1-chloro-4-hydroxynonane (Example A, step 2) (11.0 g, 0.062 mol) and dihydropyran (5.2 g, 0.062 mol), cooled in an ice bath, are added with 5 drops of hydrochloric acid (conc.). A slight exotherm is observed and, when the reaction is complete, the mixture is allowed to cool to room temperature and then stand at this temperature for 2 hours. At the end of this period, several beads of sodium hydroxide are added, and the reaction mixture is distilled under vacuum.

The yield of 1-chloro-4- (2-tetrahydropyranylloxy) nonane is 12.5 g (77%), which boils at 96 DEG-10,200 .mu.l, 5 Pa. Upon redistillation, a boiling point of 90 - 92 ° c / 13.3 Pa is obtained.

Step 2. Preparation of N - (- (2-tetrahydropyranyloxy) nonyl] phthalimide Sodium hydride (55%) (1.5 g excess) is washed with benzene three times by decantation, after which dimethylformamide (100 ml) is added. This stirred suspension is added to a solution of phthalimide (4.5 g, 0.03 mol) in dimethylformamide (50 ml) at such a rate that the temperature is kept below 5500. A clear solution is obtained and this is added with 1-chloro-4- (2- tetrahydropyranyloxy) nonane (7.8 g, 0.03 mol) and the resulting clear solution is stirred and heated at 95 ° C for 20 hours, then the reaction mixture is concentrated to half its volume under vacuum, poured into ice water (200 ml) and extracted with ether (2 x 150 ml) The ether is washed with 5% sodium hydroxide (2 x 50 ml), saturated sodium chloride solution (2 x 50 ml) and dried over sodium sulphate.

Evaporation of the ether gives 4.5 g (45 S yield) of N- [ft- (2-tetrahydro-pyranyloxy) nonyl] phthalimide, melting at 59-6100. After recrystallization. 15. 20. 251. 30. 55. 40. 7403982-7 20 lysation from cyclohexane melts the product at 62 - 6300.

Analysis: Calculated for C 22 H 51 NO 2: C 70.75; H 8.36; N 3.75 Found: C 71.03; H 8.28; N 3.81.

Step_3. Preparation of H- (2-tetrahydronyranyloxy) nonylamine A solution of N- [2- (2-tetrahydropyranyloxy) nonyl] phthalimide (33.0 g, 0.88 mol) in absolute ethanol (300 ml) is added with hydrazine (64%) (10 ml excess) and the reaction mixture is heated at reflux temperature for 1.5 hours. An additional 5 ml of hydrazine (64%) is added and refluxing is continued for 1.5 hours.

The reaction mixture is cooled to room temperature and the white solid present is removed by filtration. The filtrate is concentrated in vacuo to 75 ml and then poured into 1 water (200 ml).

The solution is basified with 5% sodium hydroxide and then extracted with ether (3 x 100 ml). The ether layer is washed with saturated sodium chloride solution and then dried over sodium sulfate. The ether is removed in vacuo and the oil formed is distilled. The yield of 4- (2-tetrahydropyranyloxy) nonylamine is 16.0 g (75%), b.p. 102 DEG-104 DEG / 1.5 Pa. - Analysis: Calculated for clenegrloz: c 69.08, - H 12.01; N 5.75 Found: C 68.58; H 12.42; N 5.66.

Step 4: Preparation of N- [1H- (2-tetrahydronyranyloxy) nonyl] acetamide A stirred, ice-cold solution of 4- (2-tetrahydropyranyloxy) nonylamine (7.29 g, 0.03 mol) in pyridine (40 ml) is added with acetane hydride (3.06 g, 0.03 mol) at such a rate that the reaction temperature is maintained at 5-10 ° C. The reaction mixture is then allowed to stand at room temperature for 6 hours, after which it is poured into ice water (200 ml) and extracted with ether (2 x 100 ml). The ether is extracted with ice-cold 5% hydrochloric acid (2 x 20 ml), washed with brine (2 x 25 ml) and then dried over sodium sulphate. Evaporation in vacuo gives the title compound as a pale yellow oil. EXAMPLE 1 Preparation of 7-N- (4-hydroxynonyl) acetamide 97heptanoic acid.

Step A: Preparation of ethyl 7 - {- N- [4- (2-tetrahydropyranyloxy): onyl] 7L acetamido} -hentanoate.

A stirred suspension of sodium hydride (57%) in mineral oil (8.84 g, 0.21 mol) in the solvent mixture of benzene (75 ml) and dimethylformamide (75 mol) is treated for 30 minutes: ed N-¿TW- (2-Tetrahyopyranyloxy) ninnyl] Acetamide (Example H, stei 4) (7.2 g, 0.20 mol). Stirring is continued for 30 minutes. Then ethyl 7-bromoheptanoate (49.8, 0.21 mol) is added dropwise and the reaction mixture is heated at 100 DEG C. for 4.5 hours.

The cooled reaction mixture is poured into water (350 ml), and the organic layer is separated. The aqueous layer is extracted with ether (200 ml). The combined organic solutions are washed with saturated sodium chloride solution and then dried over sodium sulfate. The solvents are removed in vacuo to give ethyl - {- {N-β- (2-tetrahydropyranyloxy) nonyl] acetamido} heptanoate as a residual oil, yield 66.7 g.

Step B. Preparation of 7- [TN- (4-hydroxynonyl) acetamide] gentanoic acid A solution is prepared from ethyl 7- {N--fÄ- (2-tetrahydropyranyloxy) nonyl7acetamido} heptanoate (4.5 g, 0.01 mol ), ethanol (50 ml) and 4 drops of concentrated hydrochloric acid, and kept at room temperature for ,.5 hours. Then the reaction mixture is added with a solution of sodium hydroxide (0.72 g, 0.018 mol) in water (8 ml) and the mixture is kept at room temperature for another 20 hours. Most of the ethanol is removed by evaporation in vacuo and the resulting solution is diluted with water (100 ml). This solution is extracted once with ether and then acidified with hydrochloric acid. The oil which separates is extracted with ether, after which the ether extract is dried over sodium sulphate and the solvent is removed in vacuo to give 7-NfN- (4-hydroxynonyl) acetamide97heptanoic acid as a yellow oil; pmr (CDCl 3) J 0.93 (3H, m CH 3), 2.10 (3H, s CH 3 PO), 5.58 (4H, m NCH), 7.05 (2H, s coon, oH).

Analysis: Calculated for C 18 H 55 NO 4: C 65.61; H 10.71; N 4.25 Found: c 65.91, - H 10.87, - N 4.71 EXAMPLE 2 Preparation of 7-Å_N- (4-hydroxynonyl) acetamide27heptanoic acid Step A. Preparation of ethyl 7-acetamidohentanoate 0 7-aminoheptanoic acid (24 g, 0.165 mol), acetane hydride (00.8 g, 0.40 mol) and water (60 ml) are stirred at room temperature for 3 hours.

Volatiles are removed by distillation in vacuo. The liquid residue is dissolved in a mixture of benzene (100 ml), ethanol (40 ml) and concentrated sulfuric acid (1 ml). The solution is refluxed for EÄ hours while the water formed is continuously removed from the reaction mixture with a Dean-Stark apparatus.

The reaction mixture is cooled, poured into water (400 ml) and the pH is adjusted to 10 by the addition of aqueous sodium carbonate.

The mixture is extracted with ether and the organic layer is dried over anhydrous magnesium sulfate. Distillation gives ethyl 7-acetamidoheptanoate, Lcok point 131 .- 136% at 7 Pa. Analysis: Calculated for C 11 H 21 NO 3: C 61.36; H 9.83; N 6.51 Found: C 60.93; H 9.89; N 6.31.

Step B. Preparation of ethyl 7-NfN- (4-acetoxynonyl) acetamide 97heptanoate This compound is prepared in substantially the same manner as described in Example 1, Step A, but the N-f4- (2-tetrahydropyranyloxycinnyl) acetamide of Example 1, step A, is replaced by an equimolar amount of ethyl 7-acetamidoheptanoate and the ethyl 7-bromoheptanoate is replaced by an equimolar amount of 1-chloro-4-acetoxynonane (Example A, step 4) Purification of the product by column chromatography on silica gel gives ethyl 7-N- (4-acetoxynonyl) acetamide g7heptanoate.

Analysis: Calculated for C 22 H 11 NO 5: C 66.14; H 10, 3Ä; N 3.51 Found: C 66.27; H 10.52; N 3.14.

Steglg. Preparation of 7-β-N- (4-hydroxynonyl) acetamideg7heptanoic acid This compound is prepared in essentially the same manner as described in Example 1, step B, but ethyl 7- [N- [4- (2-tetrahydropyranyloxy) The nonyloacetamido} heptanoate of Example 1, step B, is replaced with an equimolar amount of ethyl 7-β- (4-acetoxynonyl) acetamide geptanoate, and the acid treatment is omitted to give the title compound.

Claims (2)

23 7 # 03982-7 Patent claims A process for the preparation of compounds of the formula nl-N- (ena), - A-coon Ü cnz-z-on-c (n3) 2cH2cH2R "or 1 on R1-N- (CH) uA-coon '. 1 ca, -z -on- (c fl2) 5 R on 2 wherein A represents ethylene, trimethylene, M-methylethylene, Dimethylethylene, M, Dimethylethylene or ß, g; dimethylethylene, R1 represents formyl, acem fl, propionyl or acryloyl, Z represents , vinylene or ethynylene, Z 1 represents ethylene, R 3 represents hydrogen or methyl, and R represents hydrogen or lower alkyl, and H 12 represents hydrogen or lower alkyl, characterized in that a) a compound of the formula R1-NH- (cH2) hA-coons in which B1 and A have the meanings indicated, and RB represents lower alkyl having 1 to 5 carbon atoms, are reacted with about one equivalent of a strong base and then with approximately one equivalent of the compound b _ _ _ _ 3 i '4 X CH2 Z CH C (R) 2Qh2CH2R ÖR9 '-.; _, Ü wherein X represents halogen, Z, H3 and Ru have the meanings given, and R9 represents lower alkanoyl_ with 1 - N carbon atoms, that the intermediate formed thereby mild hydrolysis to remove the blocking groups R8 and R9, and that the desired product is recovered or that b) a compound of the formula nl-NH-c fl -zl-on- (on) H12 2, 10 2 3 OR. 1 1 12. Wherein R, Z and R have the meanings indicated and R represents tetrahydropyranyl, are reacted with one equivalent of a strong base and then with approximately one equivalent of the compound x- (eng), - A-coonß wherein X represents halogen and A and H8 have the meanings indicated that the intermediate thus formed is recovered and subjected to mild hydrolysis to remove the blocking groups R8 and R9 and that the desired product is recovered. A '7403982-7. 24 A process according to claim 1, wherein R 8 represents ethyl and R 9 represents acetyl. -----_ - _ ------ _--- REQUIRED PUBLICATIONS:, av.