PT85581B - A process for the preparation of N- (S-3-ALHYLPEPTANOYL) -D-GAMA-GLUTAMYL-GLYCYL-D-ALANINE - Google Patents

Description

PROCESS FOR THE PREPARATION OF N- (S-3-ALKILHEPTAN0IL) -D

-GAMMA-GLUTAMYL-GLYCYL-D-ALANINE process is characterized by understanding:

(a) the reaction of the racemic trans-4-hexen-3-ol or tran_s -4-hepten-3-oI with t-butyl hydroperoxide, in the presence of titanium te traisopropoxide and L - (+) - diisopropyl tartrate, in a sufficient amount to oxidize the S-enantiomer and contain the unreacted trans-R-4-hexen-3-ol or trans-R-4-hepten-3-ol;

(b) condensing said trans-R-4-hexen-3-ol or trans-R-4-hepten-3-ol with a tri / (C4 -Cg) alkyl_7-orthoacetate in the presence of an acid to obtain an ester (C4 -Cg) alkyl-R-3-methyl-4-heptenoate or R-3-ethyl-4-heptenoate ester; and (c) hydrolysis of said (C ₁ -Cg) ester to _1: 11 to form said R-3-methyl-4-heptenoic acid or R-3-ethyl-4-heptenoic acid.

I

the present invention is directed to an advantageous process of preparing an immunoregulatory agent of formula

(I)

CO ₂ R ⁵ ;

5 where R is methyl or ethyl; and R and R are each hydrogen, or one of R ⁴ and R ⁵ is hydrogen and the other is (CpCg) alkyl or (Cg-Cg) cycloalkyl 1-methyl; a process and intermediates for the manufacture of trans-R-3-a 1qui1-4-heptenoic acids (VIb, below), S-3-methyl-6-heptenoic acid (Xb, below) and S- 3-alkyl-heptanoic, the last of the absolute chemical stereo formula

(II) where R is defined above, having utility as intermediates in the synthesis of the compound of formula (I); and for immune regulatory agents (or precursors) of the absolute stereochemical formula

(III) co ₂ R ³ ;

where one or the other but not both the dashed lines represent a double bond, R is as defined above and R and R are both hydrogen (Illa) or a pharmaceutically salt thereof

3 acceptable and R and R are each independently (C ^-Cg) aJ-kilo, (Cg-Cg) cycloalkimethyl or benzyl (Illb), with the condition that when the double bond is in the 6,7 tejr mini position , R is methyl.

Optically pure S-3-methyl-1-heptanoic acid (II, R = CHg) was originally prepared from the corresponding racemate in unspecified yield by multiple crystallizations of the quinine salt at -15 ° C. / levene et al., J. Biol. Chem., 95, pp. 1-24, 1932, on page 18, there called 4-2-n-butyl-4-butyric acid7. The optically active 3-methylheptanoic acid was subsequently produced by a number of other methods (Soai et al., J. Chem. Soc., Chem. Commun. 1985, pp. 469-470; Oppolzer et al., Helv. Chim. Acta. 68, pp. 212-215 (1985); Ohno et al., US Patent 4,564,620 (1986); Mori et aj_., Synthesis 1982, pp. 752-753; Oppolzer et al., Helv Chim. Acta. 64, pp. 2808-2811 (1981); Mukaiyama et al., Chem. Lett. 1981, pp. 913-916; Posner et al., J. Am. Chem. Soc. 103, pp. 2886-2888 (1981); Mukaiyama et al ·., Bull. Chem. Soc. Japan, 51, pp. 3368-3372 (1978); Meyers et al., J. Am. Chem. Soc. 98, pp. 2290 -2294 (1976) 7 but these preparations generally suffer from one or more disadvantages (the maximum possible yield is 50%, with rejection of at least 50% of the necessary unwanted by-product;

at least 50% of the unwanted by-product is transported through the final stages of the process; the acid product is not optimally pure; the use of organometallic reagents, which is difficult to handle on a large scale, is nevertheless necessary; global yields are low; and / or the necessary reagents are not readily available).

The asymmetric epoxidation currently employed (the so-called Sharpless resolution) was previously noted (Katsuki and Sharpless, J. Am. Chem. Soc. 102, pp. 5974-5976, 1980; Sharpless et al., Pure Appl. Chem. 55, pp. 589-604, 1983); as Claisen has stereospecific condensation (Chan et al., U.S. Patent 4,045,475) relatively recent field of immunopharmacology, and particularly its segment or sector that deals with immunomodulation, continues to develop at a rapid pace. A variety of naturally occurring compounds have been investigated, including the tetrapeptide Tuftsina, chemically known as N - / “1- (N -L-treoni 1-L-lisi 1) -L-prol i 17-L-arginine. Most of the attention was directed to synthetic peptidoglycan derivatives, especially those known as muramyl dipeptides.

The immunoregulatory agents of formula (I), generally as amorphous lyophilates when R = R = H and their method of use were previously disclosed in the copending PCT Application Series No. PCT / US85 / 02351, of 25 November 1985. Once Since this application is not yet publicly available, the preparation of such compounds and their method of use have been incorporated into the present disclosure in support of utility.

carboxymethylamine from PE-11283, published in 1980;

Other immunostimulatory peptides have been described in a number of patent specifications:

L-alanyl-alpha-glutaric acid N-acyl-dipeptides in German Patent 3,024,355, published January 15, 1981;

tetra and penta-peptides containing D-alni1-L-glutamyl moieties or L-alani1-D-glutamyl moieties in British Patent 2,053,231, published February 4, 1981, in German Patent 3,024,281, published January 8 1981, respectively;

derivatives of the N-acyl-alanyl-gamma-D-glamy1-tripeptide in which the C-terminal amino acid is 1isanine or diaminopimelic acid in German Patent 3,024,369, published January 15, 1981;

lactoi1-tetrapeptides composed of components N-lactylalanyl, glutamyl, diaminopimelil and 23 May of formula (A) polypeptides having the

R ^a - (HNCHCO) l _b

R ^u (A)

b where R is hydrogen or acyl; R is inter alia, hydrogen, lower alkyl, hydroxymethyl, benzyl; R and R are each hydrogen, carboxy, -C ⁹ NR ⁹ R ^{h on} If R ⁹ is hydrogen, lower alkyl, optionally substituted with hydroxy; and R is mono- or dicarboxy-lower alkyl; R ^e is hydrogen or carboxy with the proviso that when one of R and R is hydrogen, the other is carboxy or -CONR ^to R, R is hydrogen; mé 1 a3ené0a2, and their derivatives in which the carbt) xi and amino groups are protected, are disclosed in US Patents 4,311,640 and 4,322,341; PE requests 25.482; 50,856; 51,812; 53,388; 55,846; and 57,419; and peptides analogous to those of formula (A) above, but in which R ⁴ forms a basic amino acid moiety (Ives et al., U.S. Patent 4,565,653; PE Application 157,572) or a heterocyclic amino acid (Ives, PE Application 178.845).

Kitaura et al., J. Med. Chem., 25, - 7 “-

335-337 (1982) points out N (gamma-D-glutami1) -mono-2 (L), 2 (D) -diamino-pyelic acid as the minimum structure capable of eliciting a biological response characteristic of the compound of formula (A ) where n is 1; R ^a is CH3CH (OH) -CO-; R * ³ is CH3; each of R ^c and R ^e is COOH; R ⁴ is -COH NH ₂ C00H; and R ^f is H. The said compound of formula (A) is known as FK-156.

We now find a more stable crystalline form of the immunoregulatory compound, N- (JS-3-methylhep tanoyl) -D-gamma-glutamyl-glycyl-D-alanine, of formula (I) ari 4 5 terior where R = CH ₃ and R = R = hydrogen.

We have now discovered efficient processes for the manufacture of intermediates of R-3-alkyl 1-4-hezoic acids (VIb, below) and _S-3-alkyl1-heptanoic acids

X (II, behind) of high optical purity, with excellent overall yield, avoiding organometallic reagents and harmful underproduction of the last R-enantiomer in the synthesis.

In one way, the initial step is a Sharpless resolution of a trans-4-alken-3-ol of formula

where R is as defined above. Specifically, this step involves reacting the racemate of formula (IV) with t-butyl hydroperoxide, in a solvent inert to the reaction in the presence of titanium tetraisopropoxide and L - (+) - diisopropyl tartrate in an amount sufficient to oxidize the S -enantiomer and retain the desired, R ^ -enantiomer of the unreacted absolute stereochemical formula (V).

In the second step, the compound of fornula V is stereospecifically condensed with a tri / (CC ^) orthoacetate at 1 ch 1 o 7 and, in isolation, the rearranged allyl enolic ether intermediate, in the presence of an acid in an inert solvent reaction, to obtain a (C _-C ^ J) alkyl-R-3-alkyl1-4-heptanoate of the absolute stereochemical formula (Via).

(Via)

X = OH (VIb) (VIc) X = Cl (VId) X = H

In an alternative, the ester is then hydrolyzed to a trans-R-3-alkyl1-4-heptenoic acid (VIb), and if desired, hydrogenated to an S-3-alkyl-heptanoic acid (II). In another alternative, the ester is first hydrogenated to obtain S-3-alkyl-heptanoate of (C C-Cgjalkyl) and then hydrolyzed to the acid of formula (II).

In another alternative, the trans-4-alken-3-ol transform of formula (V) is converted to alkyd vinyl ether (IX) by the action of ethyl vinyl ether in the presence of mercuric acetate / Hg catalyst (0Ac) 27- The allyl-vinyl ether is then rearranged by heating in an R-3-alpha-4-1-4-heptenal, of formula (VId), which in turn is ox. given, e.g. with dones reagent (chronic anhydride in diluted mineral acid) to form the previous R-3-alk1-1-4-heptenoic acid (V)

R

Δ CrO_

--- ► (VId) ------ (VIb) (IX)

We have also discovered efficient processes for the manufacture of intermediates of high optical purity S-3-methyl-6-heptenoic acid (Xd, below) and S-3-methyl-1-heptanoic acid (II, R = CHg, above) excellent overall performance, avoiding organometallic reagents and harmful underproduction of R-enantiomers, from easily available S-acitro nelol, from the absolute stereochemical formula

(xi)

The initial steps of this synthesis are conventional and involve the optional protection of the alcohol group with a conventional silyl protecting group (such as the t-butyldimethylsilyl group) followed by ozonolysis by treatment. with methyl sulfide, to obtain a new compound of absolute stereochemical formula

O (XII)

ο where R is hydrogen (X11a) or a hydroxy protecting silyl group (X11b). The methods used are specifically shown in the following Preparations and are analogous to those prior to R-citronellol in the preparation of the R-enantiomer compound of formula (V) above wherein R is t-butyldimethylsilyl. The latter, not useful here, was employed in the synthesis of proxifomine (Tapolczay et al., 0. Chem S0C., Chem Commun. 1985, pp. 143-145).

the present invention is specifically directed to intermediate compounds of formula (V) and formula

(X)

(Xa) R ⁹ = CH ^ OR, R ^ = a protecting silyl group (Xb) R ⁹ = CH ₂ OH (Xc) R ⁹ = CH0 (Xd) R ⁹ = C00H (Xe) R ⁹ = COC1 and a process for converting a compound of formula (XII) into the optically active acids of formula (Xd) and (II, R = CH ₃ ), will comprise the steps of:

(a) reaction of a compound of formula (XII) with methylenetriphenylphosphorane

CH ₂ = P (C ₅ H ₆ ) ₃ to form a compound of formula (Xa) or (Xb);

(b) hydrolysis of diluted mineral acid when the compound is of formula (Xa) to form the compound of formula (Xb) carried out as a separate step or concurrently with the next step; and (c) oxidizing the compound of formula (Xb) with chronic amhydride to a diluted mineral acid to form an S-3-methyl-6-heptenoic acid of formula (Xd); and if desired, (d) catalytic hydrogenation of the compound of formula (Xd) to form S-3-methyl-heptanoic acid of formula (II) where R is methyl.

Q

R as hydrogen has the advantage of

The smallest number of steps, but R as a silyl protection group has the advantage of easier purification when we isolate the intermediate product from step (a). Preferred hydroxy protecting groups are trimethylethyl, pt-butylphenethyldimethylsilyl and t-butyldimethylsilyl. The preferred diluted mineral acid is H ₂ SO ₄ . It is preferred to synthesize the compound of formula (X11a) by ozomolysis of S-cytomelol by treatment with transformed methyl sulphide; and the compound of

The formula (Xllb), when R is t-butyldimethylsilyl, for the following countries:

(e) reaction of S-cytomelol with t-butyldimethylsilyl chloride; and

(f) ozomolysis of the resulting hydroxy-protected cytomelol, by treatment with trans-formed methyl sulphide the present invention is also directed to an improved process for the preparation of an immunoregulatory agent of formula (I) which comprises the steps of (a) complement in an activated form of R-3-alkyl-4-heptenoic acid or S-3-methyl-6-heptenoic acid (eg, VIc or Xe acid chloride) with a compound of the formula

(VII) / - -7 £ 7 where R ° and R ^z are both benzyl (or one of R ° and R 'is benzyl and the other is (C ^ - C ^ Jalkyl or (Cg-Cg) cycloalkylomethyl in a solvent inert to the reaction to form a compound in the middle of the above formula (Illb) in which R and R correspond to the present R and R, and (b) hydrogenation of said intermediate compound in a reaction-inert solvent in the presence of a catalyst of hydrogenation, with simultaneous reduction of double bond and hydrogenolysis of the benzyl group or groups.

Finally, the present invention is directed to immunopregulatory agents and / or precursors of the composition. to (I) of formula (III) above in a compound of formula (Illa), i. e., R = R = hydrogen, is obtained by conventional hydrolysis of the ester of a diester compound of formula (Illb).

The term reaction-inert solvent as used herein refers to a solvent that does not interact with the starting materials, intermediates or products in a manner that adversely affects the yield of the desired product.

preferred value of R is ethyl. Preferred acid catalysts are Lewis acids (e.g., dry HCl, AlClg). Although the present invention is not limited thereto, the preferred source of racemic trans-4-hexene-3-ol or trans-4-hepten-3-ol is via reaction of an ethyl Grignard regent with crotonaldehyde or 2-pentenal respectively .

the present invention is easily carried out. R-trans-4-alken-3-ol (V) is obtained by the asymmetric epoxidation technique called Sharpless resolution (references cited above). According to this technique, the undesirable S-trans-2-hexen-4-ol in the racemate (IV) reacted selectively with t-butyl hydroperoxide (at least 0.5 mol, but definitely less than 1 mol per mol of racemic hexenol), in the presence of a molar excess of L - (+) - additionpropyl tartrate and substantially. That which is equivalent to titanium tetraisopropoxide. The reaction is carried out under amidras condition in a reaction-inert solvent such as methylene chloride at reduced temperatures generally in the range of -20 to -80 ^s C. The desired R-trans-2-alkene-4-oI (V) that is not reacted is isolated by standard methods such as distillation or chromatography. Because of the relatively high volatility of the desired product, low boiling solvents such as pentane and ether are preferred for such as chromatography.

The next step is the Claisen rearrangement condensation of the R-trans-4-alken-3-ol (V) and a (C1 -Cg) tria 1qui1o otocetate to obtain an (CpCg R-3-alkyl1-4-heptenoate ) (VI a) alkyl. The reaction may be performed in a reaction - inert solvent but it is preferable to simply carry out the reaction in excess of the orthoacetate ester generally at elevated temperature (eg, 120-160 ^and C). when the triethyl orthoacetate (eg 142 ^to C) is the reagent, the reflux temperature is conveniently employed.

The reaction is carried out in the presence of an acid catalyst. Acids such as proponic acid, acid. of priválico, 2,4-dimitrophenol, dry HCl and AlClg are effective. The preferred catalysts are Lewwis acids. The most preferred is AlClg.

In an alternative, the resulting ester of formula (Via) is hydrolyzed by conventional methods to obtain the corresponding unsaturated acid of formula (VIb).

The alternative of the present invention is also readily realized. ^ -citromelol (XI), which is commercially available, is first converted into one of the optically active starting materials of formula (XII) by conventional methods, as noted above and illustrated in the Preparation below.

compound (XII) is converted to S-3-methyl-6-heptenoic acid or ^ -3-methyl-heptenoic acid, of the previous formulas (Xd) and (II) respectively, is prepared in steps as detailed in the following paragraphs.

In the first step, the hydroxy or hydroxy-protected aldehyde (Xlla or Xllb) is simply subjected to the Wittig reaction with methylene triphenylphosphorane, usually just formed in situ from (methyl) triphenylphosphonic halide (preferably bromide ) butyl in an aprotic solvent inert to the reaction, eg, in a mixture of tetrahydrofuran and hexane, eg,

Although the temperature is not a critical feature of phosphorane formation, pre wounds temperatures are in the range of t 25 ^Q C, more preferably in the range of 10 ⁹ t C 0 aldehyde (XIIa) or hydroxy protected aldehyde (XIIb) was reacted then with the phosphate in an analogous solvent and in an analogous temperature range to form the hydroxy- or hydroxy-protected olefin (Xb) or (Xa), respectively.

In the second step, only necessary when the hydroxy protecting group is present, said protecting group is removed by hydrolysis, more conveniently by means of aqueous acidic conditions employed in the

in the third step, which is a Jones oxidation of primary alcohol (Xb) to acid (Xd).

The Jones oxidation employs the so-called Jones reaction, in an aqueous solution of H ₂ C 0 ^ formed from C _f 0 ₃ and a strong acid

Typically, Jones' reagent is prepared from an excess of concentrate and

C 0 _q with about 1: 1 by weight of water and then diluted to the desired concentration, eg, about 3M, with water. The alcohol (Xlla) protected alcohol (Xiib) generally in solution in an organic solvent inert to the water miscible reaction such as acetone, reacted with at least two molar reagents of Jones reagent. Under these conditions, there is a rapid hydrolysis of any silic ether group to form the alcohol (Xb) which is then oxidized to the acid (xd). The temperature is not critical, eg, 0-50 ^s C is normally satisfactory, with room temperature eg, 17-27 ^and C, the most convenient.

Jones oxidation occurs through the initial oxidation of alcohol in the aldehyde of formula (Xc) not normally isolated in the Jones oxidation. If the isolation of the intermediate aldehyde is desired, the alcohol is oxidized with a more selective oxidizing agent such as pyridimium chlorochromate, which will cleanly originate the aldehyde intermediate (Xc), which in turn is oxidized (with Jones reagent or other appropriate reagent) in acid (Xd).

If desired, unsaturated acid (VIb) or (Xd), in activated form (e.g., as the acid chloride of formula (VIC) or (Xe) as a conventional mixed amhydride activated by a dehydrating bonding agent

-18 conventional such as dicyclohexylcarbodiimide7 is linked in a conventional manner with the compound of formula

(VIII)

10 wherein R and R are each independently (C ₁ -Cg) to 1Cl (Cg-Cg) cycloalkylmethyl or benzyl, to form an immunoregulatory diester compound of formula (Illb). The latter is hydrolyzed by conventional methods to the diacid immunoregulatory compound of formula (Illa) or a pharmaceutically acceptable salt thereof.

Alternatively, the compound of formula (Illb) when R and / or R is benzyl, is hydrogenated to form an immunoregulatory compound of formula (I). In this hydrogenation both double bonds are saturated with hydrogen and the benzyl group (s) are hydrogenated. The hydrogenation is carried out in a reaction-inert solvent on a hydrogenation catalyst, e.g., nickel or a metal in the bre; supported (e.g. Raney nickel, Pd / C) or unsupported (e.g. Rh Clg). Solvent, temperature and pressure are not critical. Suitable solvents include, but are not restricted to, lower alcohols, ethers such as dioxane, tetrahydrofuran or dimethoxyethane, and esters such as ethyl acetate. It is preferably used at room temperature, without cooling even if the reaction is somewhat exothermic, avoiding the cost of heating or cooling. Pressure is not critical, but will preferably be less than 7 atmos £

in order to avoid expensive high pressure equipment. The hydrogenation over Pd / C at pressure which is 3-6 times atmospheric pressure is particularly suitable for the present transformations.

Alternatively, the unsaturated acid of formula (VIb) or (Xd) is hydrogenated under conditions identical to those detailed in the previous paragraph to obtain the S-3-alkyl-heptanoic acid (II), also obtained from a trans-R (C ₁ -C ₃ ) -3-alkyl1-4-heptenoate to (Chloride) via (CC4) S-3-alkyl-1-heptanoate to 1 ch by inversion of the hydrogenation / hydrolysis pathways. Finally, S-3-alkyl-heptanoic acid is activated in a manner as detailed above, coupled with a diester of formula (VII) above, and hydrated by methods detailed above to form an immunoregulatory compound of formula (I).

In yet another alternative of the present invention, R-trans-4-alkene-3-ol (V) is converted into the corresponding vinyl ether of formula (IX), by the action of ethyl vinyl ether in the presence of HgOAc ^ as a catalyst in a solvent inert to the reaction (preferably excess ethyl vinyl ether) at a temperature in the range 25-40 ° C, conveniently at the reflux temperature of ethyl vinyl ether (pp. 36 ° C). the resulting vinyl ether (IX) is heated to 140-200 ° C, usually in a high-boiling solvent, hypophilic, inert to the reaction such as xylenes or decalin, under pressure if necessary, to stereospecifically rearrange it in the unsaturated aldehyde of formula (VId). To obtain the unsaturated acid of formula (VIb), the aldehyde is readily oxidized, conveniently with the so-called jones reagent, an aqueous solution of F ^CrO ^ formed from CrO ₃ and a strong acid. Typically, Jones' reagent is prepared from an excess of concentrated F FSO ^ and Cr0 ₃ with about 1: 1

by weight of water, and then diluted to the desired concentration, e.g., about 3M, with water. To form the unsaturated acid (VIb), the unsaturated aldehyde (VId), usually in solution in a reaction-inert organic solvent, miscible with water such as acetone, reacted with at least 1 molar equivalent of Jones reagent. The temperature is not critical, e.g., 0-50 ° C is normally satisfactory, with room temperature, e.g. 17-27 ° C, the most convenient.

The crystalline form of the compound of form 4 · 5 mule (I) in which R is methyl and R = R = hydrogen is obtained by crystallization from an organic solvent or a combination of organic solvents. Suitable solvents are acetone, acetonitrile / ethanol or tetrahydrofuran / ether. The preferred solvent in terms of product recovery is acetonitrile / ethanol, but in terms of product purity, acetone is preferred. This new form has defined stability advantages over the previous amorphous lyophilate. It is much more easily handled, being more dense and much less electrostatic, allowing the preparation of more sophisticated dosage forms.

The pharmaceutically acceptable mono- and dibasic salts of the compound of formula (I) or (Illa) are generally obtained by treating a solution, preferably an aqueous solution of the acid with a base such as NaOH, KOH, Na ₂ CO ₃ or an amine in the appropriate stoichiometric proportions. The salts are isolated by evaporation or precipitation.

The products of this invention of formula (I) or (III) are useful as medicinal agents in mammals including humans, for the clinical and therapeutic treatment of diseases originated by various pathogenic microorganisms, especially gram-negative bacteria. They are also useful as immunostimulants in mammals, including humans having an increased risk of infection due to the existence of clinically induced immunosuppression.

The testing process employs normal or immune compromised C ^ H / HeN mice from the Charles River Breeding Laboratory. The mice are acclimatized for 5 days before use and then treated either subcutaneously (SC) or orally (PO) with various dilutions (100, 10, 1 and 0.1 mg / kg) of the test compound or placebo ( pyrogen-free saline) using a volume of 0.2 ml. The treatment regimen was dependent on the infectious organism used: 24 and 0 hours before challenge to Klebsiel1 pneumoniae in normal mice; and 3, 2 and 1 day (s) before the challenge to Escherichia coli or Staph. aureus in immune compromised mice. The challenge is administered intramuscularly (IM) in the hip in the case of K. pneumoniae or intraperitoneally (IP) in the case of £. coli and Staph. aureus. A volume of 0.2 ml was used in the challenge. Mortality was recorded after 7 days in the case of two other challenge microorganisms.

CULTURE OF PREPARATION:

J <. pneumoniae, E. coli, or Staph. aureus: the culture was tested for purity from a cold blood stock over brain-generation agar (BHI) infusion. Three colonies were removed from the culture in dishes after 18 hours and placed in 9 ml of BHI broth. The broth culture was grown for 2 hours at 37 ° C on a rotary shaker after which 0.2 ml was tested on the surface of several inclined planes BHI agar.

-22After 18 hours of incubation at 37 ° C, the inclined planes were washed with BHI broth, the culture density adjusted using a spectronic 20 and the appropriate dilution made to obtain an LD90 challenge level in normal rats.

When used as anti-infectious or immunostimulating agents in humans, the compounds (I) or (III) of this invention are conveniently administered orally, subcutaneously, intramuscularly, intravenously or intraperitoneally generally in forms of composition that are standard in pharmaceutical practice. For example, they can be administered in the form of tablets, pills, powders, or granules containing excipients such as starch, milk sugar, certain types of clay, etc. They can be administered in capsules, in mixtures with them or with equivalent excipients. They can also be administered in the form of oral suspensions, solutions, emulsions, syrups, elixirs which may contain flavoring and coloring agents. For oral administration of the therapeutic agents of this invention, components or capsules containing about 50 to about 500 mg of the active component are suitable for most applications.

The physician will determine the dosage that will be most appropriate for an individual patient and will vary with the age, weight and response of the particular patient and the route of administration. The favorite oral dosage range ranges from about 1.0 to about 300 mg / kg / day, in single or divided doses. The favorite parenteral dose ranges from about 1.0 to about 100 mg / kg / day; the most favorite range being from about 1.0 to about 20 mg / kg / day.

The following examples are presented for illustration and should not be understood as limitations of this invention, many variations of which are possible within its scope and spirit.

EXAMPLE 1

R-trans-4-Hexene-3-ol

In a 500 ml 3-neck round-bottom flask equipped with a magnetic stirrer, septum, thermometer and N ₂ inlet, 270 ml of CH ₂ C1 ₂ and 7.2 g of molecular sieves type 4A were placed. We added Ti / OCH (CH ₃ ) ₂ 7 ^ (10.7 ml; 0.036 mol) through a syringe the mixture was cooled to -66 ° C, at which time we added L - (+) - diisopropyl tartrate (10, 1 g, 0.043 mol), diluted with 10 ml of CH ₂ CL ₂ to reduce its viscosity, through a cannula and washed with an additional 5 ml of CH ₂ C _{1 2} «The temperature rose to -62 ° C, in which moment, racemic trans-2-hexen-4-ol (3.60 g, 0.036 mol) was added and washed with 5 ml of CH ₂ C _{1 2} . After stirring in an acetone / dry ice bath for 8 minutes, the temperature dropped to -68 ° C, at which point we added it via a syringe t-butyl hydroperoxide (7.18 ml of 3M toluene; 0.022 mol). The reaction mixture was heated to -35 ° C and maintained for 18 hours at that temperature in a freezer. The cold mixture was then filtered, using striated filter paper, in a stirred mixture of 450 ml of acetone and 11 ml of H ₂ O which was cooled to -20 ° C. The mixture was slowly warmed to room temperature and stirred for 20 hours. The mixture was filtered over diatomaceous earth with CH ₂ C1 ₂ washing. The filtrate and wash set was vaporized, without heat, to an oil (17.62g).

-24We avoid excess vaporization, since the desired product is very volatile. The oil was chromatographed on 176 g of silica gel, using 4: 1 hexane: isopropyl ether as the eluent, accompanied by TLC. The solvent was removed by distillation using a small filling column equipped with glass propellers with a variable starter head. Solvents, entering and boiling at a top temperature of 69.5 ° C (at which point the top temperature started to drop) were then removed to give the substantially pure title product as a container residue; TLC rf 0.25 (3: 1 hexane: ether). In a repeat of this experiment, we used 4: 1 pentane: more volatile ether as an element, in order to speed up the removal of the solvent and to minimize the loss of product by evaporation.

EXAMPLE 2

Ethyl R-3-Methi1-4-hexenoate product from the previous Example (0.4 g), triethyl orthoacetate (3 ml) and pivalic acid were heated under reflux for 2.5 hours, cooled and the total reaction mixture chromatographed two times on silica gel, initially with 6: 1 hexane: ether as eluent to obtain 0.45 g of product, and then with 7: 1 hexane: ether as eluant to obtain the purified title product, 0.35 g; iv (film) 2960, 1736, 1456, 1367, 1334, 1280, 1232, 1172, 1028, 962, 840 cm " ¹ .

Alternatively, the pentane / ether fractions containing the pure S-trans-2-hexen-4-ol were introduced directly in this step, with the pentane and ether initially removed by distillation of the reaction mixture.

propionic acid was replaced by pivalic acid with substantially the same result. Dry HCl and 2,4-dinitrophenol have also been used successfully as the acid catalyst but AlClg as used in the Example below is the preferred catalyst.

EXAMPLE 3

R-3-Methi1-4-heptenoic acid

Method A

In a 35 ml flask, equipped with a magnetic stirrer and a Soxhlet extractor containing type 4A molecular sieves, the product of the previous Example (1.5 g; 0.015 mol) was placed. We add triethyl orthoacetate (9 ml; 0.049 mol) and then AlClg (0.12 g;

0.009 mol), and the aforementioned mixture on the Soxhlet extractor for 2 hours, after which the CCF indicated that the conversion to ethyl _R-3-methyl-1-4-hexenoate was complete; TLC rf 0.75 (4: 1 hexane: ethyl acetate, rf 0.85 (15: 5: 2 hexane: ether: acetic acid).

The reaction mixture was cooled, diluted with 15 ml of 2N NaOH and 12 ml of CH2 OH, and stirred for 27 hours at room temperature, after which TLC indicated that the hydrolysis was complete. The reaction mixture was sprayed with methanol, diluted with 12 ml of water and extracted 3 x 25 ml of 2N NaOH. We added the aqueous layer and washes, the pH was adjusted to 1 with concentrated HCl, and extracted with 3 x Ch ₂ Cl ₂ . We add the last organic layers, dry over MgSO4 and vaporize to obtain the title product in the form of oil, 1.28 g (60%); CCf rf 0.65 (15: 5: 2 hexane: ether: acetic acid); ¹ H-NMR (CDCl ₃ ) delta (ppm) 9.4 (s, 1H), (-C0 ₂ H), 5.5 (m, 2H, -CH = CH-), 3.0-1.6 (m, 5H), 1.3-0.8 (m, 6H); iv (film) 3400-2400, 2960, 2925, 2860, 1708, 1458, 1410, 1380, 1295, 1228, 1 190, 1 152, 1 100, 930 cml ·

Method B ester product of the previous Example (o, 24 g) was combined with 25 ml of CHgOH and 11.5 ml of 1N NaOH. The mixture was stirred 3.5 hours at room temperature, after which TLC indicated that the hydrolysis was complete. The mixture was extracted with 2 x 35 ml of ether, adjusted to pH 2 with concentrated HCl and extracted with 3 x 35 ml of ether. We juiced the acid extracts, dried and steamed to obtain the title product, 0.20 g, identical to the product of Method A.

EXAMPLE 4

Ethyl S-3-Methi1-heptanoate

The product of Example 2 (0.20 g) is hydrogenated in 40 ml of ethyl acetate over 0.20 g of 5% Pd / C (wetted with 50% water) under a hydrogen pressure of 4 atmospheres in a hydrogenation Paar for 3 hours. The catalyst is recovered by filtration over earth

diatoms. The title compound is collected by spraying the filtrate from the solvent.

EXAMPLE 5

S-3-Methylheptanoic acid

Method The product of Example 3 (0.20 g) in 40 ml of ethyl acetate was hydrogenated over 0.2 g of 5% Pd / C, wetted in 50% water, in a Paar hydrogenation apparatus under a hydrogen atmosphere. 4 atmospheres for 3 hours. The catalyst was collected by filtration over diatomaceous earth and the title product collected by spraying the filtrate to an oil, 0.2 g. If desired, the purified title product is obtained by distillation under high vacuum; pp. 77-79 ° C / 0.2 mm; ¹ H-NMR (CDClg) delta (ppm); 12.0 (s, -C00H), 1.0 (d, -CHg), 0.6-2.8 (m, remaining 13H); iv (film) 3400-2400, 2950, 2925, 2860, 1708, 1458, 1410, 1380, 1295, 1228, 1190, 1152, 1100, 930 cm ¹ ; / alfaj ²⁵ = -6.41 ° (= 1% in CHgOH); n ²² ' ⁵ = 1.427.

Method B product of the previous Example is hydrolyzed to the title product according to Method B of Example 3.

EXAMPLE 6

S-3-Methyl-heptanoyl chloride acid product from the previous Example or Example 27 (8.5 g; 0.062 mol) was dissolved in 18 ml of CH2 Cl2. The oxalyl chloride (5.36 ml; 7.80 g; 0.0614 mol) was mixed into the solution and the mixture left to stand for 4 hours, after which time the reaction was complete as evidenced by the lack of release of more gas. This acid chloride solution was immediately used directly in Example 8, Method C. Alternatively, the straight heat of the acid was isolated by vaporizing the solvent for use in Method A of Example 8 and, if desired , is further purified by distillation, pp. 45 ° / 1.5 mm.

EXAMPLE 7

R-3-Methi1-4-heptenoyl chloride acid product of Example 3 (0.747 g; 5 mmol) was converted to a CHgClg solution of the title product by the method of the previous Example and used directly in Example 9 below. Alternatively, the reaction mixture is vaporized to obtain the title product which, if desired, is distilled under reduced pressure.

EXAMPLE 8

Benzyl N- (S-3-Methyl-heptanoyl) -D-gamma-glutamyl ester (alpha benzyl ester) -glycyl-D-alanine

Method A

To a solution of 1.0 g (2.03 mol) of benzyl ester hydrochloride of D-gamma-glutami1 (alpha benzyl ester) -glyc1-D-alanine benzyl ester (Preparation 4) and 616 mg (6.09 mmol) of triethylamine in 50 ml of methylene chloride, 660 mg (4.06 mmol) of 1-3-methylheptanoyl chloride were added and the reaction mixture was stirred at room temperature for 80 hours. The methylene chloride was evaporated in vacuo and the residue dissolved in ethyl acetate. The resulting solution was washed sequentially with 2.5% hydrochloric acid, water, 10% potassium carbonate, water, and a saline solution. The organic phase was separated, dried over magnesium sulfate and concentrated in vacuo. The residue was digested with diethyl ether and filtered under nitrogen to obtain the title product, all of which was used. directly in Example 10, Method A.

Method B product of Preparation 4 (0.75 g;

1.53 mmol), 5 ml CH ₂ C ₁₉ and triethylamine (0.212 ml; 1.53 mmol) were mixed and stirred under N ₂ . S-3-Methyl-heptanoic acid (Example 5, 0.20 g; 1.39 mmol) is added in 4 ml of CH ₂ C _{1 2} and then dicyclohexylcarbodiimide (0.286 g;

1.37 mmol) and the mixture was stirred for 16 hours. The reagent mixture was filtered, the filtrate vaporized, and the residue

Duo processed in 10 ml of ethyl acetate, and the solution washed in sequence with 5 ml of 2.5% HCl, 5 ml of H ₂ 0, 5 ml of 10% K ₂ CO ₃ and 5 ml of water salted, dried over MgSO4 to obtain 71 mg (88%) of the title product.

Method C

In a 500 ml flask with four round necks equipped with a stirrer, thermometer, decanting funnel and N ₂ inlet, the product from Preparation 4 (32.8 g; 0.059 mol) was dissolved in 175 ml of CH ₂ C1 ₂ and cooled to 0-5 ° C. Keeping that temperature range, we added triethylamine (24.7 ml; 17.9 g; 0.177 mol; 3 equivalents) in the form of a slow flow for 15 minutes. The ice water bath was maintained and the total pool of S-3-methyl-heptanoyl chloride in CH ₂ C ₁₂ from Example 6 added over 15 minutes as the temperature rises to 21 ° C. Stirring in the ice water bath continued for 45 minutes, after which time the gelatinous mixture became too thin to stir. The gelatinous mass was broken and mixed with 125 ml of 10% HCl and 50 ml of CH ₉ C1 ₂ . The organic layer was separated, washed sequentially with 2 x 125 ml H ₉ 0, dried over MgSO₄ and stripped to yield 82.3 g of white solid, moist. These only readings were processed in 500 ml of hot ethyl acetate. Upon slow cooling to room temperature, the title product crystallized strongly, and the mixture was diluted with an additional 40 ml of ethyl acetate in order to maintain easy stirring. The purified title product was collected by filtration and dried in vacuo at 40 ° C, 31.1 g, (90.5%).

-31 ¹ H-NMR (CDCl ₃ ) delta (ppm): 8.4-8.1 (m, 3H), 7.15 (s, 10H), 5.1 (s, 4H), 4.4- 4.2 (m, 2H), 3.7 (d, 2 H), 2.2 (t, 2H), 2.1-1.7 (m, 6H), 1.4-1.1 (m , 10H),

0.92-0.8 (m, 6H).

EXAMPLE 9

Benzyl ester of N- (R-3-methyl-4-heptenoyl) -D-gamma-glutatanyl- (alpha benzyl ester) -glycol-D-alanine

By method C of the previous Example, the product of preparation 4 (2.77g, 5 mmol) is mixed with the total acid chloride pool in CH conjuntoCl do of Example 7. The product collected by spraying the dried and washed organic layer , and repeatedly dissolving the residue in ethyl acetate and spraying.

EXAMPLE 10

N- (S-3-Methylheptanoi1) -D-gamma-glutamyl-glycyl-D-alanine

METHOD A

The entire product of Method A of the Example was dissolved in 65 ml of methanol. Palladium hydroxide (250 mg) is added to the solution and the coarse mixture was stirred in a hydrogen atmosphere at a pressure of 4 atmospheres for 3 hours. The catalyst was filtered and the solvent removed in vacuo. The residue was dissolved in water and lyophilized to obtain the desired product.

X

NMR spectrum (DM 50-dg) showed absorption at 8.27-8.03 (m, 3H), 4.32-4.1 (m, 2H), 3.72 (d,

J-6 HZ, 2H), 2.22 (t, J = 8 HZ, 2H), 2.27-1.68 (m, 6H), 1.42-1.0 (m, 10H) and 0, 94-0.8 (m, 6H).

When carried out on a heavy quantity of the title product of Example 8 (0.50 g) using 90 mg of 20% Pd (0H) ₂ / C (wetted in 31% water) in 25 ml of CHgOH, this method gave rise to 0.24 g of the same title product, fluffy, electrostatic; IV (nujol paste) 3300, 2940, 1740, 1650, 1540, 1468, and 1380 cm ¹ ; all but if the last two peaks are wide and weakly resolved.

METHOD B The product of Method C of Example 8 (30.8 g) was soaked in 300 ml of absolute ethanol in a 2 liter autoclave. We added 5% Pd / C 1.54 g, wet in 50% water and the mixture was hydrogenated at 4x atmospheric pressure for 1 hour, after which time the hydrogen intake was complete. The catalyst was collected by filtration first on paper then on 0.45 micron nylon millipores, using 100-150 ml of ethanol for transfer and washing. The filtrate and washing liquids were evaporated to a moist white solid which was dissolved in a hot mixture, 1:10 of absolute ethanol and acetomitrile, clarified by boiling reduced by boiling to 35 ml, and slowly cooled to temperature environment, granulated and filtered to obtain the product in grapevine, crystalline, dense, non-electrostatic, 20.1 g (94%) characterized by its IV (nujol paste) which includes sharp, large peaks, well distributed at 3340 , 3300, 2900,2836, 1725, 1650, 1628, 1580, 1532, 1455, 1410, 1370, 1280,1240, 1216, and 1175 cm ¹

METHOD C

The crystalline product (9.4 g), prepared according to Method B, immediately above, was dissolved in 1000 ml of acetone by heating at reflux for 1 hour. The solution was cooled to room temperature and seeded with a trace of the product of Method B to induce crystallization. After stirring for 6 hours, further purified title product was recovered by filtration with minimal acetone wash, and dried in vacuo at 35 ⁹ C 7.25 g IR peaks having identical with those of crystals acetomitrilo / / ethanol Method B.

METHOD D The product of the previous Example (0.50 g) was added with 0.026 g of 5% Pd / C (spotted in 50% water) in 125 ml of absolute ethanol in a Paar hydrogenation bottle. The mixture was hydrogenated under 4χ at atmospheric pressure of hydrogen for 2.5 hours. The catalyst was collected by filtration and the filtrate vaporized to obtain the title product in the form of sticky solids which crystallize according to the Immediately previous Methods.

EXAMPLE 11

N- (R-3-MethiΙ-4-heptenoi1) -D-gamma-glutami1-glycine-D-alanine product of Example 9 (1 g) is dissolved in 5 ml of CH ^OH. 1N NaOH (2.50 ml) is added and the mixture is stirred for 3 hours at room temperature.

CH ^OH is vaporized and the aqueous residue diluted with 7.5 ml of H ^O, extracted 2x7.5 ml of ethyl acetate and acidified to pH 3.0 with 1N HCl. The acidified aqueous part is extracted.

from continuously with fresh ethyl acetate, and the extract vaporized to obtain the title product which is converted into a lyophilate according to Method A of Example 10.

EXAMPLE 12

R-trans-4-Heptene-3-ol

By the Method of Example 1, but used at a reaction temperature of -20 ^s C at all stages during the combination of the reagents the title product of Preparation 5 (10 g; 0.088 mol) was converted to the present title product. After all the reagents were combined, the mixture was stirred for 1.5 h ^and at -20 C and then warmed to room temperature, quenched by dropwise addition of 25 ml of I O and then 6 ml of NaOH 30% (saturated with NaCl). The cooled mixture was stirred for 20 minutes diluted with 20 ml of CF4 Cl2, and the aqueous layer separated and washed 2x50 ml of fresh CH2 Cl2. We combined the organic layers, dried over MgSO4, distilled to a residual volume of 50 ml, which was chromatographed on silica gel using pentane and then 4: 1 pentane: ether as eluent.

The initial fractions containing an improper less polar impurity were discarded. The fractions of the pure product, having Rf 0.3 (4: 1 pentane: ether) were combined evaporated to obtain the title product as a clear, colorless liquid, 5.7 g.

-35EXAMPLE 13

R-3-Eti1-4-heptenoic acid

By Method A of Example 3, except for using ether instead of CH ₂ C1 ₂ in isolation, the product of the previous Example (5.7 g; 0.05 mol) was condensed with ethyl orthoacetate, rearranged and saponified to obtain the title product in the form of oil, 1.4 g; TLC Rf 0.4 (2: 1 hexane: ether).

ethyl ester intermediate presented Rf 0.25 in the same tlc system.

EXAMPLE 14

S-3-Eti1-heptanoic acid product from the previous Example (1.4 g) was hydrogenated in 10 + 10 ml of CH2 OH over 0.1 g 5% Pd (0M) ₂ / C at 4x atmospheric pressure for 1 hour . The catalyst was collected by filtration. The filtrate was vaporized from the solvent and the residue distilled to obtain the title product, 1.0 g: bp 76- = 77 ^s C / 0.4 torr; / alphaj ⁵ -1.6 ^S (C = 2% in CHgOH).

EXAMPLE 15

S-3-Eti1-heptanoyl chloride

Under dry Ng, the product of the previous Example (1.0 g; 0.00633 mol) was dissolved in 10 ml of CHgClg. We added oxalyl chloride (0.547 ml; 0.00627 mol) and the mixture was stirred for 1 hour, after which the gas evolution was over. The resulting solution of the title product was evaporated under a flow rate of Ng to 7 ml and used directly in the next step.

By the same method, the unsaturated acid of Example 13, is converted to a solution of R-3-ethyl 1-4-heptenoyl chloride.

EXAMPLE 16

Benzyl ester of N- (S-3-Eti1-heptanoi1) -D-gamma-glutami1 (alpha benzyl ester) -g1icí1-Da 1anine The title product of Preparation 4 (1.1 g; 0.00222 mol) was dissolved in 30 ml of CH2 Clg and triethylamine (0.935 ml; 0.00666 mol). The CHgClg solution of S-3-ethyl-1-heptanoyl chloride (2.4 ml; 0.00211 mol) from the previous example, was added and the mixture stirred under Ng for 0.75 hours, washed sequentially with a 20 ml portion. HCl 10%, HgO, 10% KgCOg and saturated brine, dried over MgSO4, evaporated to a solid residue, digested with ether and collected by filtration, 0.8 g. The latter was processed in ethyl acetate, washed again as before and evaporated to a second solid, 0.7 g,

which was chromatographed on silica gel using 97: 3 CHCl ^:

: CHgOH as eluent to obtain the purified title product, 467 mg.

By the same method, 3-ethyl-4-heptenoyl chloride is coupled with the title product of Preparation 4 to obtain the benzyl ester of N- (R-3-ethyl-4-heptenoyl) -D-gamma-glutami1 (alpha benzyl ester) -glycyl-D-alanine.

EXAMPLE 17

N- (S-3-Ethyl-heptanoyl) -D-gamma-glutami1-g1ici1-D-alanine title product of the previous Example (467 mg) was hydrogenated by the method of Example 14. After recovery of the catalyst, the filtrate was vaporized to a foam, processed in L ^ O, filtered and lyophilized to obtain the title product, 238 mg.

¹ H-NMR (DMSO-dg) delta (ppm): 8.20-8.00 (m, 3H), 4.24-4.16 (m, 2H), 3.74-3.60 (m, 2H), 2.18 (t, J = 7, 2H), 2.02 (d, J = 7, 2H), 2.02-1.60 (m, 3H), 1.26 (d, 0 = 6, 3H), 1.26-1.08 (m, 8H), 0.92-0.74 (m, 6H).

By the same method, the unsaturated product of the previous Example is converted to the same product.

EXAMPLE 18

N- (R-3-Et1-1-4-heptenoyl) -D-gamma-glutamiI -glycyl-D-alanine unsaturated product of Example 16 is hydrolyzed to the present title product by the method of Example 11.

EXAMPLE 19

Benzyl ester of N- (S-3-Ethylheptanoi1-D-gamma-glutami1 (alpha benzyl ester) -glycyl-D-alanine

By the methods of Example 17, _S-3-ethylheptanoi chloride of Example 16 and benzyl ester of D-gamma-glutami1 (alpha benzyl ester) -glycyl-D-alanine (1.0g 0.00222 mol) were coupled to produce the present title product, isolated and purified in a similar manner. The yield was 0.7 g.

^ N-NMR (DMSO-dg) delta (ppm): 8.22 (d, J = 7, 1H), 8.12-8.00 (m, 2H), 4.40-4.16 (m, 2H), 4.08-3.95 (m, 2H), 3.75-3.62 (m, 2H), 2.18 (t, J = 6, 2H), 2.02 (d, J = 6, 2H), 2.04-1.62 (m, 3H), 1.60-1.46 (m, 2H), 1.38-1.10 (m, 15H), 0.90-0, 75 (m, 9H).

By the same method, the R-3-ethyl-4-heptenoyl chloride is converted to the N- (R-3-ethyl-4-heptenoyl) -D-gamma-g1utartri1 (alpha benzyl) -glycyl-D- butyl ester alanine.

EXAMPLE 20

N- (S-3-Ethyl-heptanoyl) -D-gamma-gIutami 1-glycyl-D-alanine butyl ester

By the same method as in Example 14, the title product of the previous Example was hydrogenated to produce the present title product. After recovery of the catalyst, the filtrate was vaporized from the solids which were recovered by digestion with ether and filtration, 256 mg, mp 130-131 ° C.

By the same method the unsaturated product of the previous Example is converted to the same product.

EXAMPLE 21

R-3-Eti1-4-heptenol

A solution of R-trans-4-hepten-3-ol dc Example 12 (3.0 g) in 300 ml of dry ethyl vinyl ether is heated under reflux while adding HOCOAC ^ (2 g each, after another 18 hours under reflux, a series of cin is made with two interval sandpapers). the clear solution is cooled to room temperature, treated with 0.5 ml of glacial acetic acid, and stirred for 3 hours. The resulting solution is diluted with ether, poured into 200 ml of 5% KOH solution and extracted three times with ether. The set of ethereal extracts is then dried over KgCOg and vaporized to obtain the al-1-vinyl ether, R-trans-O-vinyl-4-heptene-3-ol.

A solution of the said allyl vinyl ether (2.3 g) in 20 ml of decaline is refluxed for

10.5 hours. The resulting solution is then cooled to room temperature and placed directly on a silica gel column. After washing with hexane to remove the decalin, the title product is collected by eluting the column with ether and spraying.

EXAMPLE 22

S-3-Ethi1-4-heptenoic acid product from the previous Example (100 mg) is dissolved in 4 ml of acetone and cooled to 0-5 ° C. In a separate flask, we mix Cr0 _q (72.1 g, 0.72 mol) with 50 ml of H ^ O and stir at 0-5 ° C and slowly add 62.1 ml of concentrated H ^ SO ^, and the mixture it was diluted to 250 ml with water to obtain a 2.88M HgCrO ^ solution (Jones reagent). The last solution (1 ml) is added in portions to the previous acetone solution over 1 hour. The temperature rises and is maintained at 17-25 ° C while the reagent is added. The mixture is cooled to 6 ° C again, 70 ml of 2-propanol are added for 10 minutes (during which the temperature is allowed to rise to 20 ° C), and then concentrated in vacuo to an oil, to which we add with stirring 8 ml of 2.5N NaOH for 50 minutes, maintaining the temperature at 22 ± 5 ° C. The mixture is heated and filtered over diatomaceous earth with washing with hot 2.5N NaOH. The filtrate and wash assembly is extracted 3 x 300 ml with isopropyl ether. The combined organic layers are again extracted with 200 ml of 2N NaOH. The set of organic layers is acidified to pH 1.0 by the slow addition of 0; 5 ml of concentrated HCl and the product extracted in 3 x 300 ml of ether

recent isopropyl. We add the organic extracts and vacuum to obtain the title product in the form of an oil.

EXAMPLE 23

S-7- (t-Buti1dimethylsi1yloxy) -5-meti1-1-heptene

In a 500 ml flask, of 4 round-bottom tubules equipped with a stirrer, thermometer, N ₂ inlet and addition funnel, (methyl) triphenylphosphonium bromide (25.7 g; 0.072 mol, 1.25 equiv.) made into a paste in 77 ml of THG (tetrahydrofuran) and cooled in a wet acetone / ice bath. We place n-butU lithium (43.2 ml of 1.6N hexane, 0.069 mol, 1.20 equiv.) In the addition funnel. With the slurry initially at -8 ° C, butyllithium was added over 1 hour while the temperature rose and was maintained at ± 1 ° C. The mixture was stirred an additional 0.5 hours at 0-2 ° C to ensure complete formation of the daily methylene-triphenylphosphorane intermediate in a thin LiBr suspension. The aldehyde product of Preparation 2 (14.1 g; 0.0576 mol), in 14 ml of THF was added dropwise over 40 minutes, maintaining the temperature at 3-7 ° C. After stirring for a further 15 minutes, no aldehyde was detected by TLC using 3: 1 hexane: ether as eluent (rf starting aldehyde 0.6; mp product 0.95). The reaction mixture was warmed to room temperature and diluted with 150 ml of ethyl acetate and 90 ml of H ₂ 0. The organic layer was separated and washed 2 x 100 ml of H ₂ 0. We dye the three aqueous layers and rinse with 40 ml of ethyl acetate. We combine the organic layers, dry over MgSO4 and vaporize to an oil, 25 g, which was digested with 10 ml of hexane, filtered through a concrete glass funnel, the solids retransformed.

pulp no. place with 4 x 10 ml of hexane, and the set of the hexane filtrate and evaporated wash to obtain the title product in the form of oil, 13.5 g (96.6%); H-NMR (CDClg) delta (ppm) includes 5.4-6.2 (m, = CH), 4.8-5.3 (m, = CH ₂ ), 3.7 (t, J = 6, 5Hz, -0CH ₂ -), 0.08 (s, C (CHg) ₃ ) and 0.0 (s, Si (CH ₃ ) ₂ ), contaminated with 8 mol% (0θΗ ₅ ) ₃ Ρ0 (7.6 , s, 1.25H).

EXAMPLE 24

S-3-Methyl-hept-6-en-1-ol

Method A

By the method of the previous Example, except the use of 2.2 equivalents of each of reneth 1 bromide (triphenylphosphonium) and n-butyl lithium, the aldehyde product of Preparation 6 (26.3 g; 0.20 mol; corrected for purity) reacted with methylenetriphenylphosphorane. Although it is. formation of gummy solid was noted during the addition of the aldehyde solution, the reaction became a thin paste once heated to room temperature for processing. The reaction mixture was diluted with 500 ml H ₉ 0 and 300 ml ethyl ac £ touch. The layers were separated and washed 3 x 250 ml of HgO. The combined aqueous layers were again washed 2 x 300 ml of ethyl acetate. We combined the three organic layers, dried over MgSO4 and vaporized to obtain 65.7 g of oil containing 25.6 g (100%) of the title product and about 40 g of triphenylphosphine oxide, suitable for further processing in Example 25 Next.

Method puro pure title product is most readily obtained by conventional hydrolysis of the product of Example 23, e.g., in diluted sulfuric acid of Example 26 below. The title product is isolated by extraction in ethyl acetate, drying over MgSO4 and spraying.

EXAMPLE 25

S-3-Methi1-6-heptenal title product of the previous Example (1.14 g; 0.01 mol) is dissolved in 20 ml of CH2 Cl2 and cooled to 0 ° C. We add pyridinium chlorochromate (4.30 g?) 0.02 mol) in portions, maintaining the temperature at 0-5 ° C. The mixture is warmed to room temperature, stirred for 2 hours, filtered through a pad of silica gel, and the filtrate vaporized to obtain the title product in the form of an oil, which if desired is further purified afterwards. styling.

EXAMPLE 26

S-3-Meti1-6-heptenoic acid

Method A

In a 2000 ml 3-neck round-bottom flask equipped with a stirrer, thermometer and addition funnel, the title product of Example 23 (81 g; correct for purity; 0.033 mol) was dissolved in

400 ml of acetone and cooled to 0-5 ° C. In a separate flask, we mix CrOg (72.1 g; 0.72 mol) with 50 ml of H ₂ 0 and stir at 0-5 ° C and slowly add 62.1 ml of concentrated H ₂ SO ₄ and the mixture was diluted to 250 ml with H ₂ 0 to obtain a 2.88M solution of 1- CrO ^ (Jones reagent). The last solution (240 ml; 0.67 mol) was added portionwise to the previous acetone solution over 1.2 hours. The temperature rose rapidly to 17 ° C, and was maintained at 17-25 ° C as we added the reagent. At the end of the addition, there was no exotherm. The mixture was cooled again to 6 ° C, and 70 ml of 2-propanol were added for 10 minutes (during which the temperature rose to 20%), and then concentrated in vacuo to obtain an oil which was added with stirring. 400 ml of 5N NaOH for 50 minutes, maintaining the temperature at 22 ± 5 ° C. The thick reagent mixture was diluted with 400 ml of water and filtered over diatomaceous earth. The wet pole was again repulped with 400 ml of H ₂ O and 50 ml of 5N NaOH, heated in a steam bath and refiltered. The filtrate pool was washed 3 x 300 ml isopropyl ether. The combined organic layers were extracted again with 200 ml of 2N NaOH. The set of aqueous layers was acidified to pH 1.0 by adding 50 ml of concentrated HCl and the product extracted in 3 x 300 ml of fresh isopropyl ether. We add the organic extracts and vaporize to obtain the title product in the form of oil, 29.1 g (61%). We obtained an additional 7.7 g (16%) by a second basic extraction of the filtered paste of tomatia earth followed by similar insulation. H-NMR of the combined product (CDCl4) delta (ppm) includes 11.9 (s, -C00H), 5.8 (m, = CH), 5.0 (m, = CH ₂ ) and 1.0 ( d, -CH ^) and peaks of iso propyl ether at 3.7 and 1.1 showing contamination with 8.6 mol% (6.3% by weight) of isopropyl ether, which does not interfere with the use of this product in further processing.

Method B

The product of Method A of Example 24 (65.7 g, containing 26.3 g; 0.20 mol of S-3-methylhept-6-en-1-ol) was oxidized according to method A of the present Example. After cooling with isopropanol and stirring for 1 hour at 0-5 ° C, after which time the reaction mixture turned completely green, we vaporized the organic solvents, and diluted the aqueous residue with 250 ml of and extracted with 3 x 250 ml of isopropyl ether. We add the organic extracts and treat with 160 ml of 2N NaOH, causing a great precipitation of (CgH ^ gPO (contaminant in the starting material) which was collected by filtration with a good wash of 1N NaOH.

We added the filtrate and the wash, the layers were separated and the organic layer washed with 80 ml of more 1N NaOH. We combine all the aqueous layers, wash with 3 x 250 ml of isopropyl ether, acidify with 50 ml of concentrated HCl to pH 1.0, and extract the desired product in 3 x 250 ml of fresh isopropyl ether. The set of the acidic organic extracts was dried over MgSO4 and evaporated to obtain the title product, 14.0 g, which, if desired, is further purified by distillation.

EXAMPLE 27

S-3-Meti1-heptanoic acid

In a Paar hydrogenation bottle it was loaded with 10% Pd / C (Γ, '64 g wetted in 50% water, 150 ml of ethyl acetate, and the unsaturated acid from Example ante-46-

(3.28 g; corrected for purity), and the paste is hydrogenated at 4 x atmospheric pressure for 1.5 hours after which time the consumption of H? it was complete. The catalyst was collected by filtration over diatomaceous earth and the filtrate vaporized to obtain the title product in the form of oil, 3.20 (96%).

Alternatively, 5% Pd / C (2 g wet in 50% water) and then the title compound from the previous Example (33.3 g; corrected for purity) in 150 ml of ethyl acetate, was loaded into an autoclave of 1 1 and hydrogenated at 4 w atmospheric pressure for 2 hours at 30-31 ° C, after which the consumption of H ₂ was complete. The catalyst was collected by filtration over diatomaceous earth and the filtrate vaporized until an oil was obtained, 35.4 g which was distilled under high vacuum to obtain the purified title product, 29.6 g (87.6%); p and 77 ~ 79 ° C / 0.2 mm; ¹ H-NMR (CDCl ₃ ) delta (ppm): 12.0 (s, -COOH), 1.0 (d, -CH ₃ ), 0.6-2.8 (m, remaining 13H), IV ( film) 3400-2400, 2960, 2925, 2860, 2708, 1458, 1410, 1380, 1295, 1228, 1190, 1,152, 1,100, 930 cm ^-1 ; / alpha7n ⁵ = -6.4P (C =. 1% in CFLOH);

5 - - u ύ ηθ ’= 1.427.

EXAMPLE 28

S-3-Methi1-6-heptenoyl chloride acid product of Example 4 (0.747 g;

mmol) was converted to a CH ₂ C _{1 2} solution of the title product by the method of Example 27 and used directly in Example 29 below. Alternatively, the reaction mixture is vaporized to obtain the title product, which, if desired, is distilled under reduced pressure.

-47EXAMPLE 29

Benzyl ester of N- (S-3-methyl-6-heptenoyl) -D-gamma-glutamyl (alpha-benzyl ester) -glyc1-D-alanine

By Method C of Example 8, the product of Preparation 4 (2.77 g; 5 mmol) was mixed with the totality of the acid chloride in CH2 Clg of Example 28. The product initially obtained, 2.77 g, collected by vaporization of the washed dry organic layer, it was processed in 20 ml of hot ethyl acetate, the solution diluted with 20 ml of hexane, cooled and the purified product collected by filtration, 2.24 g (77%) mp 137.5-139.5.

EXAMPLE 30

N- (S-3-Methyl1-6-heptenoyl) -D-gamma-glutamino-glycol-D-alanine product of Example 29 (1 g.) Is dissolved in 5 ml of CH2 OH. 1N NaOH (2.50 ml) is added and the mixture is stirred for 3 hours at room temperature. The CHgOH is vaporized and the aqueous residue diluted with 7.5 ml of H ₂ O, extracted with 2 x 7.5 ml of ethyl acetate, and made to pH 3.0 with 1N HCl. The aqueous acidified is continuously extracted with fresh ethyl acetate, and the extract vaporized to obtain the title product which is converted into a lyophilate according to Method A of Example 10.

EXAMPLE 31

Butyl ester N- (S-3-Methi1-6-heptenoyl) -D-gamma-glutamyl (alpha benzyl ester) -glicy1-D-alanine

D-gamma-glutami1- (alpha benzyl ester) -glycyl-D-alanine butyl ester (Preparation 4) is mixed with S-3-methyl-6-heptenoyl chloride (Example 28) by Method A of Example 8 to obtain the title product.

EXAMPLE 32

N- (S-3-Methyl-heptanoyl) -D-gamma-glutami 1-glyc 1-D-alani.na butyl ester

By the hydrogenation methods of Example 10, the product of the previous Example is converted to the present title product.

PREPARATION 1 racemic trans-4-Hexen-3-ol

In a 3 liter flask with 4 trays equipped with a stirrer, addition funnel, thermometer and nitrogen inlet, we put 400 ml of THC. $ THF was cooled to -70 C and ² joined ethylmagnesium bromide (600 mL of 2M in THF, 1.2 mol). Maintaining the temperature of -70 ^s C to -60 ⁹ C. We add crotonaldehyde (78 ml; 0.94 mol) for 7 minutes After stirring for 20 minutes at -70 ⁵ C, and then for 1 hour while the mixture was gradually heated to -20 ^and C the mixture was cooled again to -70 ^s C and carefully cooled only with 200 ml of saturated NH4 Cl (foam, initial), warmed to room temperature and diluted with 200 ml of CH ₃ COOH and 100 ml of H ₂ 0. The two-layer system was saturated with NaCl. The aqueous layer was separated and extracted with 2x χ500 ml of ether.

The original organic layer and the ether extracts were combined, washed with 4x250 ml of saturated NaHCOp, dried over MgSO4, evaporated and the residue was distilled at atmospheric pressure, 69 g; eg 133-137 ^S C; ¹ H-NMR (CDCl ₃ ) delta (ppm); 5.53 (m complex, 2H); 3.935 (m, 1H); 2.26 (s, 1H); 1.71 (d, 3H); 1.43 (m, 2H); 6.84 (t, 3H).

-50PREPARATION 2

Benzyl glycyl ester hydrochloride - D - alanine

To a cold solution (0 ^s C) of 100 ml of methylene chloride containing 10 g (57 mmol) of Nt-butyloxycarbonylglycine, 20 g (57 mmol) of salt of the D-alanine-benzoic ester p-toluene- sulfonic acid and 5.77 g (57 mmol) of triethylamine, 12.3 g (60 mmol) of dicyclo-luxylcarbodiimide are added and the resulting reaction mixture is allowed to warm to room temperature. After 18 hours the mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in 200 ml of ethyl acetate and the organic layer washed with 2.5% hydrochloric acid, water in a saturated sodium bicarbonate solution and a saline solution. The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure. To the resulting oil we add 200 ml of dioxane saturated with hydrochloric acid. After 30 minutes, 400 ml of diethyl ether were added and the product was filtered under nitrogen, 10.9 g (yield 70%).

PREPARATION 3

Ester N-t-butoxycarboni1-D-gamma-glutami1 (benzyl ester) hydro-succinamide

..To 1500 ml of methylene chloride containing 50 g (143 mmol) of Nt * butoxycarbonyl-D-gamma-glutamic acid alpha-benzyl ester is 17.3 g (150 mmol) of N-hydroxysuccinamide, we add 30.9 g (15 mmol) of dicyclohexyl carbodiimide and the resulting reaction mixture was stirred at room temperature for 18 hours. The solids were filtered and the filtrate in vacuo concentrated the residue was digested with diethyl ether and the solids fixed.

nitrogen under 43.7 g (68% yield).

PREPARATION 4

D-gamma-glutamyl- (alpha Benzyl ester) -glycyl-D-alanine benzyl ester hydrochloride

In a solution containing 4.3 g (9.45 mmol) of Nt-butoxycarbonyl1-D-gamma-glutami 1 (benzyl ester) -hydroxy succinamide ester, 2.71 g (9.92 mmol) of ester chloride benzyl glycine-D-alanine and 1.0 g (9.92 mmol) of triethylamine in 100 ml of methylene chloride was allowed to stir at room temperature for 18 hours, and was then concentrated in vacuo. The residue was dissolved in 200 ml of ethyl acetate and the solution washed with 2.5x hydrochloric acid, water, 10% potassium carbonate and a saline solution. The organic phase was separated, dried over magnesium sulfate and evaporated under reduced pressure. The residue was treated with 200 ml of dioxane saturated with hydrochloric acid and left to stir for 2 hours. The solution was concentrated to dryness in vacuo and the residue digested with diethyl ether. The solids were filtered under nitrogen, 3.41 g (73% yield).

By the same method, the product of the previous Preparation and glycyl-D-alamine butyl ester were converted to the D-gamma-glutami1 (alpha benzyl ester) -glycyl 1-D-alanine butyl ester.

PREPARATION 5

Racemic Trans ~ 4-Hepten-3-ol

By the method of Preparation 1, except for the use of ordinary ether as a solvent, 2-pentenol (25 g 0.30 mol) was converted into the distilled title product 25.6 g; p.r. 145-15QSC

PREPARATION 6

0- (t-Butildimethylsi1i1) -S-cytomelol

In a 500 ml 4-neck round-bottom flask equipped with a stirrer, thermometer, N ₂ inlet and addition funnel, we dissolve S-citromelol (547g; 3.5 mol) in 547 ml of DMF (dimethylfornamic) at room temperature (21 ^and C). We added imizadazole (262.1 g; 3.85 mol; 1.1 equiv). The temperature dropped to 13 C ^S, was further reduced to -6.5 ^W C with an ice / acetone bath. We add t-butyldim tylchlorosilane (580.3 g; 3.85 mol; 1.1 equiv), previously dissolved by vigorous stirring in 1160 ml of DMF, for 1.25 hours, allowing the temperature to rise slowly at 11 ^S C during the same period of time. After a further 0.25 hours TLC (3: 1 hexane: ester) indicated complete conversion of the desired product (Rf of starting material 0.2: Rf of product 0.9).

To 500 ml of hexane and 1000 ml of ice and water. The layers were separated and the organic layer washed with 2000 ml of ice cold 0.25 N HCl. We join the two aqueous layers and rinse with 500 ml of he-53xane, the kilos of are combined with the original organic layer, washed with 500 ml of saturated NaHC0 ₃ , dried over MgSO4 and vaporized to produce quantitative yield of the product in epigraph, 986.7g, 104% of theory due to minor solvent retention; H-NMR (CDC1 ₃ ) delta (ppm) includes 5.2 (t, J = 7 Hz, = cH), 3.65 (t, J = 6.5 Hz, -0-CH ₂ -) 1.7 and , 65 (25.2 = C (CH ₃ )), 0.8 (s, - si C (CJd ₃ ) ₃ ), and 0.0 (s, -Si (CH ₃ ) ₂ ).

PREPARATION 7

S-6- (t-Butyldimethylsilyloxy) -4-methyl-hexanol. In a flask of 500 ml 4 - necked round bottom, equipped with a mechanical stirrer, a narrow entrance glass at a flow rate _{3 0/2} 0, a thermometer and an outlet connected to a device. The saturated product of the previous preparation (81.2 g corrected for 0.30 mol solvent content) was dissolved in 120 ml of CH ₂ C _{1 2} and 81 ml of CH ₃ OH. We combined NaHC0 ₃ (6.3 g, 0.075 mol) and 0.25 equiv and the mixture was cooled to -10 ^Q C in an acetone / dry ice bath. The temperature was further reduced and held at -72 to -75 0 C when ^the _3/2 0 borbolhava the reaction for 6 hours. After a little less than an hour, not all of the 0 ₃ had been absorbed by the reaction mixture, as evidenced by the yellow color formed on the device or Kl, CCF, with hexane as eluent indicated that the reaction was complete (Rf of the starting material , 0.3 Rf of intermediate material 0.0).

The reaction mixture was purged from excess of 0 ₃ with N _2, adding dimethyl sulfide (26.4 ml 22.4 g; 0.36 mol; 1.2 equivalents), the bath was reduced

allowed to warm to room temperature and stirred under N ₂ for 16 hours, after which the TLC (6: 1 hexane: ether) indicated no remaining intermediate material (Rf of the intermediate material, 0.8; Rf of the product , 0.05). The mixture was then vaporized and the residue was distributed between 150 ml of ethyl acetate and 300 ml of F2O. The organic layer was washed with 300 ml of fresh H2 O. The combined F0O layers were again washed with 150 ml of fresh ethyl acetate. We join the organic layers, dry over

MgSO4 and vaporized until an oil was obtained, after 16 hours under high vacuum for quantitative measurement of the product in theory due to less contamination than ultimately producing a yield of 74.7 g, 101.9% of the solvent; ¹ H-NMR (CDC1 ₃ ) delta (ppm) includes 9.75 (t, -CHO), 3.6 (t, J = 6Hz, -0-CH ₂ -), 0.9 (s, -SiC ( CH ₃ ) ₃ ), 0.0 (s, -Si (CH ₃ ) ₂ ).

PREPARATION 8

S-6-Hydroxy-4-methyl-hexanal

METHOD A

In a 250 ml 3-neck round-bottom flask, equipped with a magnetic stirrer, thermometer, gas inlet tube and gas outlet tube leading to the gas washing bottle containing saturated Kl. The flask was charged with S-citronelol (31.25 g; 0.20 mol) in 81 ml CHgCl ₂ and 54 ml CH ₃ 0H and cooled to -8 ° C. Maintaining ^the temperature between -2 and -10 ° C borbolhamos 0 _2/3 0 through the reaction for 4.5 hours, after which time trapping of excess 0 ₃ was the KI solution and the reaction iii dicado complete was indicated by a positive test on starch / Kl paper on the reaction mixture. The mixture was maintained at -5 ° C, purged with N ₂ , methyl sulfide (17.7 ml; 15.0 g; 0.24 mol) was added. The area mixture. People were allowed to warm to room temperature, and then stirred for 16 hours, after which the TLC using isopropyl ether as eluent indicated that the reaction was complete (Rf of S-citronelol, 0.7; Rf of product, 0, 4), and finally vaporization of the solvent to obtain 50.8 g of oil. The oil was diluted with 30 ml of ethyl acetate and 25 ml of H ₂ 0 resulting in a single phase. A further addition of 150 ml of ether gave 2 phases. The layers were separated and the organic phase washed with 2 x 25 ml of H ₂ O, dried over MgSO4 and evaporated to obtain a colorless oil, 23.9 g. The combined aqueous layers were extracted with 2 x 50 ml of ethyl acetate, and the combined extracts were dried and sprayed to obtain an additional 7.8 g of colorless oil. We add the colorless oils and re-spray to produce the title product, 28.3 g (108.7% of theory) clean by TLC (as noted above) except for solvent contamination, suitable for use in later reactions as described above.

METHOD B The product of Preparation 2 is hydrolyzed by conventional methods, such as the diluted sulfuric acid of Example 4 above. The title compound is isolated by extraction in ethyl acetate and spraying as in Method A immediately above.

Claims (15)

1 ^â . - Process for the preparation of R-3-methyl-4-heptenoic acid or R-3-ethyl-4-heptenoic acid characterized by comprising the following steps: (a) reaction of racemic trans-4-hexen-3-ol or trans-4-hepten -3-01 with t-butyl hydroperoxide, in the presence of titanium tetraisoproxide and L - (+) - diisopropyl tartrate, in an amount sufficient to oxidize the S-enantiomer and retain the unreacted trans-R-4-hexen-3-ol or trans-R-4-hepten-3-ol; (b) condensation of said trans-R-4-hexen-3-ol or trans-R-4-hepten-2-ol with a tri-C ^ CgJalkylJortoacetate in the presence of an acid to obtain an ester (G ^ -Cg ) R-3-methyl-4-heptenoate alkyl or R-3-ethyl-4-heptenoate ester; and (c) hydrolysis of said alkyl (C4 -Cg) alkyl to form said R-3-methyl-4-heptenoic acid or R-3-ethyl-4-heptenoic acid. 2 ^ã . - Process for the preparation of S-3-methyl-heptanoic acid characterized by comprising the following steps: (a) reactions of racemic trans-4-hexen-3-ol or trans-4-hepten-3-ol or trans-4-hepten-3-ol with t-butyl hydroperoxide in the presence of titanium tetraisopropoxide and L- (+) - diisopropyl tartrates in an amount sufficient to oxidize the S-enantiomer and retain the unreacted trans-R-4-hexen-3-ol or trans-R-4-hepten-3 * ol; (b) condensation of said trans-R-4-hexen-3-ol or trans-R-4-hepten-3-ol with a tri ^ CpC ^ alkyljortoacetate in the presence of an acid to obtain a (C ₁ -C ₃ ) to 1-R1-3-methyl-4-heptenoate or R-3-ethyl-4-heptenoate; and want: (c) hydrolysis of said (C ₁ -C ₃ ) ester to 11quot to form R-3-methyl-4-heptenoic acid or R-ethyl 1-4-heptenoic acid; and (d) catalytic hydrogenation of said 4-heptenoic acid to produce said S-3-methylheptanoic acid or S-3-ethyl-heptanoic acid; or (e) catalytic hydrogenation of said ester (CC ₃ ) to 1 to 1 to produce (CC ₃ ) to 1 to 1 S-3-methylheptenoate or S-3-ethn heptanoate; and (f) hydrolysis ester of said S-3-methylheptanoate or S-3-ethylheptanoate ester to produce said S-3-me acid. tilheptanoic or S-3-ethylheptanoic acid. 3 ^â . Process according to claim 1 or 2, characterized in that the (C 1 -C ₃ ) alkyl groups are each ethyl and the acid is Al Cl _3> 4 ^â . - Process for the preparation of R-3-methyl-4-heptanoic acid or R-3-ethyl-4-heptenoic acid characterized by comprising the following steps: (a) reaction of the racemic trans-4-hexen-3-ol or trans-4-hepten-3-ol with t-butyl hydroperoxide, in the presence of titanium tetraisopropyloxide and L - (+) - diisopropyl tartrate, in a sufficient amount to oxidize the S-enantiomer and retain trans. -R-4-hexen-3-ol or unreacted trans-R-4-hepten-3-ol; (b) reaction of said trans-R-4-hexen-3-ol or trans-R-4-hepten-3-ol with ethyl vinyl ether in the presence of Hg (CH ₃ CO ₂ ) ₂ to produce a 0- corresponding vinyl; (c) rearrangement of said 0-vinyl ether by heating in a reaction-inert solvent to produce R-3-methyl 1-4-hej) tenol or R-3-ethyl1-4-heptenol; and (d) oxidizing said 4-heptenol with chromic anhydride to diluted mineral acid to form said R-3-methyl-4-heptenoic acid or R-3-ethyl-4-heptenoic acid. 5 ^â . - Process according to claim 4, characterized in that the mineral acid is sulfuric acid. 6 ^â . - Process for the preparation of S-3-methyl-6-heptenoic acid characterized by comprising the following steps: (a) reaction of S-6-hydroxy-4-methylhexanol or S-6- (protected silyl) hydroxy-4-methylhexanol with methylene phosphoran in a reaction inert solvent to form S-7-hydroxy-5-methyl -1-heptene or S-7- (protected silyl) hydroxy-5-methyl- -1-heptene; (b) when the product of step (a) contains a silyl protection group, the hydrolysis of said protection group in -59 diluted mineral acid to form said S-7-hydroxy-5-methyl-1-heptene, carried out as a separate step, or co-current with the next step; and (c) oxidizing said S-7-hydroxy-5-methyl-1-heptene with chromic anhydride in diluted mineral acid to form the S-3-methyl-6-heptenoic acid. 7 ^§ . - Process according to claim 6, characterized in that S-6-hydroxy-4-methylhexanol is the reagent in step (a), and the mineral acid is sulfuric acid. 8 ^â . - Process according to claim 6, characterized in that S-6- (protected silyl) hydroxy-4-hexanol is the reagent in step (a), steps (b) and (c) are carried out concurrently, the silyl protecting group is t-butyldimethylsilyl, and the mineral acid is sulfuric acid. 9 ^â . - Process for the preparation of S-3-methylheptanoic acid characterized by comprising the following steps: (a) reaction of S-6-hydroxy-4-methylhexanol or S-6- (protected silyl) hydroxy-4-methyl-hexanol with triphenylphosphoran methyl in a solvent inert to the reaction to form S-7-hydroxy-5 -methyl-1-heptene or S-7- (protected silyl) hydroxy-5-methyl-11-heptene; (b) when the product of step (a) contains a silyl protecting group, hydrolysis of said protecting group in a diluted mineral acid to form said S-7-hydroxy-5-methyl-1-heptene, is carried out in a separate step, or concurrently with the next step; (c) oxidizing said S-7-hydroxy-5-methyl-1-heptene with chromic anhydride in diluted mineral acid to form S-3-methyl-6-heptenoic acid; and (d) catalytic hydrogenation of the double bond in said 6-heptenoic acid to form said S-3-methylheptanoic acid. 10 ^â . - Process according to claim 9, characterized in that S-6-hydroxy-4-methylhexanol is the reagent in step (a), and the mineral acid is sulfuric acid. 11 ^â . - Process according to claim 9, characterized in that S-6- (protected silyl) hydroxy-4-hexanol is the reagent in step (a), and steps (b) and (c) are carried out concurrently, the silyl protecting group is t-butyl dimethyl and the mineral acid is sulfuric acid. 12 ^â . - Process for the preparation of a compound of absolute stereochemical formula 45 where R is methyl or ethyl, and R and R are each hydrogen, or one of R and R is hydrogen and the other is (C4 -Cg) alkyl or (Cg-Cg) cycloalkylmethyl characterized by comprising the steps (a) linking an activated form of R-trans-3-methyl 1-4-heptenoic acid, R-trans-3-ethyl-4-heptenoic acid or S-3-methyl-6-heptenoic acid with a compound of the absolute stereochemical formula 7 in which R and R are each benzyl, or one of R and R is benzyl and the other is (CC _g ) to 1q or o (Οθ-C _g ) cyc to 1 to methylmethyl to form a compound of stereochemical formula fight -62 in which one or the other, but not both dashed lines represents a double bond, with the proviso that when the double bond is at the 6,7 terminal position, R is methyl; and (b) hydrogenation of a compound of formula (IIIc) to form the compound of formula (I) with concurrent reduction of the double bond and hydrogenolysis of the benzyl ester group (s). 13 ^â . - Process according to claim 12, characterized in that the activated form of cy acid is hydrochloric acid, R and R are both benzyl, 45 and R and R are both hydrogen. 14 ^â . - Process for the preparation of a compound of absolute stereochemical formula (Illa) CO ₂ H; where one or the other, but not both of the strikethrough lines represents a double bond, R is methyl or ethyl, with the proviso that when the double bond is in the 6,7 ter position. minai, R is methyl, characterized by comprising the following steps: (a) linking an activated form of R-trans-3-methyl-4-heptenoic acid, R-trans-3-ethyl-4-heptenoic acid or S-3-methyl-6-heptenoic with a compound of absolute stereochemical formula fi 7 where R and R are each independently benzyl, (C C-Cg) alkyl or (Cg-Cg) cycloalkylmethyl to form a compound of stereochemical formula absolute (b) hydrolysis of the ester groups in the compound of formula (Illb) to form the compound of formula (I). 15 ^â . Process according to claim 14, characterized in that the activated form of the acid is hydrochloric acid and R ^q and R are both benzyl. -6416 ^â . - Process for the preparation of a crystalline compound of absolute stereochemical formula characterized by comprising the crystallization of said compound from an organic solvent or combination of organic solvents.