DE3145486A1 - Novel optically active alkyl 5-chloro- and 5-bromo-3-methylpentanoates, their use as intermediate for the synthesis of the side chain of (R,R,R)- alpha -tocopherol and their preparation - Google Patents

Abstract

Novel optically active alkyl 5-chloro- and 5-bromo-3-methylpentanoates of the general formula I <IMAGE> in which Y represents Cl or Br and R represents a lower alkyl radical, a process for their preparation which is characterised in that an optically active 3-methylpentane-1,5-dioic acid monoalkyl ester of the general formula II <IMAGE> in which R has the abovementioned meaning, is converted into an optically active 3-methylvalerolactone by selective reduction of the acid group or by selective reduction of the ester group and this lactone is treated at 0 to 50 DEG C with a solution of hydrogen chloride or hydrogen bromide in an alkanol ROH, and their use as optically active intermediates for the preparation of the C15-building blocks required for the synthesis of the side chain of (R,R,R)- alpha -tocopherol, and a process for the preparation of (3R,7R)-1-chloro- and (3R,7R)-1-bromo-3,7,11-trimethyldodecane starting from (R)-5-chloro- and (R)-5-bromo-3-methylpentanoic esters.

Description

New optically active 5-chloro and 5-bromo-3-methyl-pentane

acid alkyl esters, their use as intermediate for the synthesis of the side chain of (R, R, R) - «- tocopherol and their preparation ) -5-Bromo-3-methyl-pentanoic acid alkyl ester of the general formula I. in which Y is C1 or Br and R is a lower alkyl radical, a process for their preparation and their use as optically active intermediates for the preparation of the C15 required for the synthesis of the side chain of (R, R, R) -d-tocopherol Building blocks and processes for the production of (3R, 7R) -l-chloro- or (3R, 7R) -l-bromine-3,7,11-trimethyl-dodecane starting from (R) -5-chloro- or .

(R) -5-Bromo-3-methylpentanoic acid esters.

Natural optically active Vltamin E (2R, 4 'R, 8'Rd-To c opherol) has the formula The substituents of the optically active structural formula indicated and of the other optically active structural formula used in this application are identified by the symbol A 1, provided they lie in front of the plane of the molecule, provided that they are behind the plane of the molecule by the symbol. The substituents of the structural formulas which are not specifically characterized stereochemically can either be oriented R or S, or the compound can be present as a mixture of the R and S isomers.

Natural i-tocopherol contains a chroman ring system as structural elements and an aliphatic side chain linked to the chromium component in the 2-position, where the 3 chiral centers are assigned the (2R, 4'R, 8'R) -conriguration.

A major part of the total synthesis of (R, R, R) -Od-tocopherol is the synthesis of the side chain that contains two centers of asymmetry. From literature (cf. Helv. Chim.

Acta 62 (1979), pp. 464 ff. And 474 ff.) Are known processes with which C15 building blocks for the side chain of vitamin E are obtained, which are obtained by reacting with the corresponding formylchroman of the formula can be converted to (R, R, R) -4-tocopherol. The construction of the optically active C15 module is based on the concept C * + C * + = C15, ie by linking two optically active C5 modules with one inactive C5 module. The production of the optically active J C5 building blocks is based on 2- and 3-methyl-butyrolactone.

The disadvantage of this method is that the optically active C5 module so far only through complex and lossy microbiological conversion relatively poorly accessible starting materials can be produced and that the over management of these building blocks in the side chain of o (, - tocopherol a large number of complex Requires reaction stages and the use of expensive special reagents.

It was therefore the object of the invention, more easily accessible optically To find active building blocks, which are optically suitable in a simpler way active C15 block can be linked.

With the new optically active 5-chloro or 5-bromo-3-methyl-pentanoic acid alkyl esters, in particular the (R) - and the (S) -5-chloro-3-methyl-pentanoic acid methyl ester advantageous optically active intermediates for the synthesis of the side chain of (R, R, R) -i-tocopherol found, which are produced in a relatively simple manner can and a far less complex synthetic route to the desired optical enable active C15 building blocks for the tocopherol side chain.

In Can. J. Chem. 57 (1979) 5. 1025 to 1032, in particular pages 1031 to 1032), the preparation of (3R) -5 - bromopentanoic acid esters of the formula 'in the R for the ethyl, the n-propyl, the phenylethyl, the benzyl and the cyclohexyl group is described in the context of studies on the absolute configuration of the corresponding 3-substituted valerolactones, but the only ones for the synthesis of the side chain Compounds of interest from (R, R, R) -d - tocopherol, the (3R) -5-halo-pentanoic acid esters substituted in the 3-position by a methyl group, were not described there.

The invention accordingly relates to the new optically active 5-chloro or 5-bromo-3-methyl-pentanoic acid alkyl esters of the general formula I and their use as optically active intermediates for the synthesis of the side chain of (R, R, R) - <-Tocopherol a process for their preparation, which is characterized in that an optically active 3-methyl-pentane-1,5-diacid monoalkyl ester of the general formula II in which R has the meaning given above, by selective reduction of the acid group or by selective reduction of the ester group into an optically active 3-methyl - valerolactone III and this at temperatures of 0 to 50 ° C, preferably 20 to 250C with a solution treated by hydrogen chloride or hydrogen bromide in an alkanol ROH.

The optically active 3-methyl-pentane-1,5-diacid monoalkyl ester II required as the starting compound is a well-known connection, which, however, has not yet been technically relevant plays has, since it could only be produced in an extremely laborious manner (cf. J. Chem. Soc 1955> p. 3851 f, especially p. 3854 below). With a new manufacturing method the easily and inexpensively available 3-methyl-pentane-1,5-diol became the half-ester II to an advantageous hard starting product for the side chain of cC-tocopherol.

In the new process, the 3-methyl-pentane-1,5-diol is oxidized with KMnO4 in very good yield to the 3-methyl-pentane-1,5-diacid, the latter being converted into its anhydride, this with a lower alkanol transferred into the Monoesterll, which according to the Canad. J. Chem. 57 (1979), p.1025 f, described method can be broken down into its optical antipodes with good yields. In the process according to the invention, it is now possible either to use both antipodes of the 3-methyl-pentane-1,5-diacid monomethyl ester II in the same synthesis, or to convert the diastereomer, which may not be desired in each case, back into the 3-methyl- To cleave pentane-1,5-diacid, which can be converted again into the Monoesterll. The usability of both enantiomers in one synthesis results from the bifunctional character of the pentanedioic acid monoester11: For example, by selective reduction processes known per se from one enantiomer, e.g. IIa, by selective reduction of the acid function or by selective reduction of the ester group, both antipodes of the intermediate 3-methylvalerolactone III (namely IIIa and IIIb) are accessible, or else one and the same enantiomer, for example IIIa, can be prepared from the two enantiomers IIa and IIb by appropriate selective reduction.

To (3R) -5-chloro- or (3R) -5-bromo-3-methyl-pentanoic acid alkyl esters is accordingly obtained by using (3R) -3-methyl-1,5-pentanedioic acid monoalkyl ester by selective reduction of the ester group or else (3S) -3 - methyl-1,5-pentanedioic acid monoalkyl ester converted into (3S) -3-methyl-valerolactone by selective reduction of the acid group and this with a solution of hydrogen chloride or hydrogen bromide in an alkanol ROH at temperatures of 0 to 500C, preferably 20 to 250C, treated.

For the production of (3S) -5-chloro- or (3S) -5-bromo-3-methyl-pentanoic acid alkyl esters one proceeds so that one (3R) -3-methyl-1,5-pentanedioic acid monoalkyl ester by selective Reduction of the acid group or (3S) -3-methyl-1,5-pentanedioic acid monoalkyl ester converted into (3R) -3-methyl-valerolactone by selective reduction of the ester group and this with a solution of hydrogen chloride or hydrogen bromide in an alkanol ROH treated at temperatures from 0 to 30 ° C.

The selective reduction of the ester group of the optically active 3-methyl-1,5-pentanedioic acid monoalkyl ester takes place in a manner known per se with the aid of those known for such ester cleavage Reducing agents. Lithium borohydride, a mixture of lithium chloride, is particularly suitable 'and Sodium borohydride, lithium triethyl borohydride or sodium in liquid ammonia. the selective reduction of the acid group of the optically active 3-methyl-1,5-pentanedioic acid monoalkyl ester succeeds with borohydride in suitable inert solvents such as ethers, halogenated hydrocarbons, Alkanes or aromatic hydrocarbons.

Refer to for more details on this process step we on J. Am. Chem. Soc. 97 (1975) p. 4144 and Aldrichimica Acta 12, No. 1 (1979) P. 3.

The conversion of the optically active 3-methyl-valerolactone into the optically active 5-chloro or 5-bromo-3-methyl-pentanoic acid alkyl ester takes place through Reacting the valerolactone with a solution of HC1 or HBr in the appropriate Alkanol at temperatures from 0 to 50001, preferably from 10 to 30 ° C., in particular 20 to 2500.

The hydrogen halide is generally used in excess from 2 to 20 moles, preferably 5 to 10 moles per mole of valerolactone.

The alkanol is generally used in amounts from 5 mol to 20 moles per mole of valerolactone. The reaction time depends on the reaction temperature and type of hydrogen halide generally 2 to 20 hours.

The reaction mixture is worked up in a known manner, for example by applying the reaction mixture to ice water, extraction with an inert water-insoluble solvent and distillation.

The new optically active 5-halo-3-methyl-pentanoic acid alkyl ester open up numerous advantageous ways of producing optically active Cl5 building blocks for the synthesis of. (R, R, R) -4-tocopherol.

For example, they can be obtained in very good yields by Grignard addition of methyl iodide into the corresponding optically active 6-chloro- or 6-bromo-2,4-dimethyl-hexan-2-ols convert which into the corresponding optically active ones by elimination of water 6-chloro- or 6-bromine - 2> 4-dimethyl-2-hexene can be converted. From the latter can by ozonolysis or ozonolysis and subsequent reduction with NaBH4 die optically active 4-chloro- or 4-bromo-2-methyl-butanals and -butanols will. The latter compounds are valuable optically active C5 building blocks that easily by organophosphorus or organomagnesium O-C linkage methods and, if necessary,

subsequent hydrogenation in that for the synthesis of the side chain of (R, R, R) -drTocopherol sought-after (3R, 7R) -1-chloro- or (3R, 7R) -l-bromo-3,7,11-trimethyl-dodecane can be transferred (see. Examples 5 and 6).

The invention accordingly also provides a process for the preparation of (3R, 7R) -l-chloro- or (3R, 7R) -1-bromo-3,7,11-trimethyl-dodecane, which is characterized in that one (R) -5-chloro- or (R) -5-bromo-3-methyl-pentanoic acid ester of the general formula Ia according to claim 2 converted by Grignard addition of methyl iodide into the corresponding 6-chloro- or 6-bromo-2,4-dimethyl-hexan-2-ols of the general formula IV, splitting off water from these in a manner known per se; the (S) -6-chloro- or (S) -6-bromo-2,4-dimethyl-2-hexenes of the formula V obtained by ozonolysis into the corresponding (S) -4-chlorine resp.

(S) -4-Bromo-2-methyl-butanals of the formula VI transferred.

this in a Wittig reaction with a triphenylphosphonium bromide of the formula VII in which the dashed lines can in each case mean a further bond, reacted and then hydrogenated 'and a process for the preparation of (3R, 7R) -l-chloro- or. (3R, 7R) -1-bromo-3,7, ll-trimethyldodecane, which is characterized in that (R) -5-chloro- or (R) -5-bromo-3-methyl pentanoic acid ester of the general formula Ia according to claim 2 converted by Grignard addition of methyl iodide into the corresponding 6-chloro or 6-bromo-2,4-dimethyl-hexan-2-ols of the general formula IV, from these, water is split off in a manner known per se, the (S) -6-chloro- or (S) -6-bromo-2,4-dimethyl-2-hexenes of the formula V obtained converted into the corresponding (S) -4-chloro- or (S) -4-bromo-2-methyl-butanols of the general formula VIII by ozonolysis and subsequent reduction with NaBH4 these are converted into compounds of the general formula IX by substitution of the OH group by a suitable exchange group in a manner known per se in the Z for -OS02R; Br or J when Y is Cl and Z is —OSO2R or J when Y is Br, where R is phenyl or p-tolyl, the compound of the general formula IX in the presence of copper ions, preferably in the presence of Li2CuC14 with an organomagnesium compound of the general formula X in which the dashed lines can in each case denote a further bond, reacted and, if appropriate, then hydrogenated.

Since the individual reaction steps of the process are known per se Be carried out in a manner superfluous detailed information about it at this point. For further details regarding the Grignard coupling of the compounds of the formula IX with organomagnesium compounds of the formula X in the presence of copper ions we refer, for example, to the work of G. Fouquet and M. Schlosser in Angew. Chem. 86 (1974) p. 50 f and by Tamura in Synthesis 1971, pp. 303 f).

The optically active compounds required for the processes described of the formulas VII and X are relatively easy to obtain from the same optically active starting compounds accessible. For example, they can be obtained by (3S) -3-methyl-valerolactone in hexane with diisobutylaluminum hydride to form (S) -2-hydroxy-4-methyl-tetrahydropyran reduced, this in a -Wittig reaction with (2-methyl-prop-l-yl) -triphenylphosphonium bromide to (R) -3,7-dimethyl-oct-5-en-l-ol, which - if necessary after hydrogenation - in an known manner into a suitable triphenylphosphonium halide of the formula VII or can be converted into a suitable magnesium halide of the formula X.-Above The (R) -5-halo-3-methyl-pentanoic acid alkyl esters according to the invention can also be used in good yield to the corresponding optically active 5-chloro or

5-bromo-3-methyl-pentanals reduce which, for example, by Reaction with (R) -E2,6-dimethyl-hept-l-yl] -triphenylphosphonium bromide in a Wittig reaction converted into the desired (3R, 7R) -l-chloro- or (3R, 7R) -1-bromo-3,7,1l-trimethyl-dodecane can be (see. Example 8).

Furthermore, they can be obtained in good yields in a manner known per se reduce to the corresponding optically active 5-chloro- or 5-bromo-3-methyl-pentanols, which after conversion into tosylate - with 5-chloro-penta- 9 'noles even after conversion into bromide or iodide - through a Grignard coupling with (R) -l-bromo-2,6-dimethyl-heptane can be converted into the desired (3R, 7R) -l-chloro-3,7,11-trimethyldodecane (see example 7). The second required for the described implementations is also optical active compound, the (R) -l-bromo-2,6-dXmethyl-heptane, can from the invention Connections are obtained. For this purpose, for example, (S) -5 bromo-3-methyl-pentanoic acid ethyl ester is used in a Grignard reaction with 3-bromo-2-methyl-propane in tetrahydrofuran (THF) (R) -3,7-Dimethyl-octanoic acid ethyl ester, from which after saponification to (3R) -3,7-dimethyl-octanoic acid obtained by the so-called Hunsdiecker degradation (R) -l-bromo-2,6-dimethyl-heptane can be.

The compounds and methods of the invention open up numerous advantageous ways of producing optically active C15 building blocks for synthesis on (R, R, R) -i - toxopherol.

Example 1 Preparation of the starting compounds a) 3-methyl-1,5-pentanedioic acid To a solution of 256 g (1.5 mol) KMnO4 and 15 g (approx. 0.25 mol) 85 pointer aqueous KOH in 1.5 liters of H 2 O is converted into 50 g (0.42 mol) of 3-methylpentane-1,5-diol within 60 minutes at 25 to 320C added dropwise in 500 ml H20. The reaction mixture is 4 h at room temperature (RT) Stirred, treated with 200 ml of methanol while cooling with ice, stirred for a further 45 minutes, filtered, adjusted to pH 1 with hydrochloric acid, then saturated with NaCl and 8 times with acetic acid ethyl ester extracted. After drying and concentration of the extract gives 57.6 g of 3-methyl-1,5-pentanedioic acid as a white Solid with a melting point of m.p. = 70 to 790C. This corresponds to a yield of 93% of theory.

b) 3-methylpentane-1,5-diacid anhydride 88.9 g (0.61 mol) of one according to a) 3-methyl-1,5-pentanedioic acid obtained are mixed with 300 ml of acetic anhydride for 7 h Reflux heated to boiling. It is then concentrated and the residue is distilled. 67 g of 3-methylpentane-1,5-diacid anhydride are obtained as a colorless bl with the boiling point Bp = 122 to 12500 at 1 mbar, which crystallizes quickly at RT. The yield is 86% of theory.

c) 3-methylpentane-1,5-diacid monomethyl ester 3160 kg (28.2 mol) 3-Methyl-pentane-1,5-diacid anhydride are heated to 70 ° C. with 1.15 1 (28.2 mol) of methanol warmed up. After the exothermic reaction has started, ice is used for cooling. Afterward the reaction mixture is left to stand at RT for 20 h. 4.51 kg of 3-methylpentane-1,5-diacid monomethyl ester are obtained corresponding to 97% of theory, the purity according to GC is 98%. The racemate was according to the Canad. J.

Chem. 57 (1979), p. 1025 f, described processes into the enantiomers split.

d) Possible recycling of an enantiomer 16 g (0.1 mol) of 3-methylpentane-1,5-diacid monomethyl ester (D25 = -0.34 / neat) are dissolved in 20 ml of methanol and mixed with 20 ml of 50% sodium hydroxide solution under lighter Cooling offset. Then the reaction Stirred mixed for 1 h at RT, adjusted to a pH value of 4 with dilute HCl and then extracted continuously with ethyl acetate. The extract is dried and narrowed. 14.0 g of 3-methyl-1,5-pentanedioic acid are obtained back, correspondingly a yield of 96% of theory.

Example 2 Preparation of (3R) -5-chloro-3-methyl-pentanoic acid ethyl ester a) Preparation of (S) -3-methyl-valerolactone 1) with BH3-THF To a solution of 16 g (0.10 mol) of (S) -3-methyl-pentanedioic acid monomethyl ester in 80 ml of tetrahydrofuran (THF) 150 ml of a 1 M solution of BH3 in THF are added dropwise at 20 to 25 ° C. After standing at room temperature (RT) for 4.5 h, the reaction mixture is mixed with 100 ml of methanol added and left to stand overnight. It is then concentrated, again with Added methanol and concentrated. The same operation is repeated twice more, then the crude product is distilled in a bulb tube. 9.7 g of a colorless one are obtained Oil with a boiling point of 120 to 130 ° C at 0.1 mbar. That corresponds to a yield of 85% of theory.

3F = -23.69 (C = 2.06 / CH2C12) The NMR spectrum shows the addition of Eu (hfbc) 3 only one enantiomer.

2) with BH3-dimethyl sulfide To a solution of 25.0 g (0.158 mol) (S) -3-methyl-pentanedioic acid monomethyl ester In 125 ml of CH2Cl2, 18.8 ml (0.188 mol) of BH3-dimethyl sulfide are dissolved in 30 ml at 0 ° C CH2C12 added dropwise. After 19 hours of standing at RT, the process is carried out as under a). Man receives 23.2 g of an oil with a content of 76% of (S) -3-methyl-valerolactone, corresponding to a yield of 98% of theory. A sample is placed in a spherical tube distilled.

(cLJJ25 = 2.6 / CH2Cl2) D -23> 4 (C = 3) with LiEt3BH to a solution of 1.00 g (6.25 mmol) of (R) -3-methyl-pentanedioic acid monomethyl-ster in 15 ml of THF a solution of 25 mmol LiEt3BH in 25 ml THF was added at RT. After 1.5 hours Standing at RT, the reaction mixture is cooled to 0 ° C. and at the same time with 8.5 ml of a 30% aqueous H2O2 solution and 3.5 ml of a 50% aqueous NaOH solution offset. The mixture is then stirred at RT for 1 h, acidified with HCl and with diethyl ether extracted continuously. The crude product obtained is distilled in a bulb tube.

This gives 0.55 g with a content of 90% of 3-methyl-valerolactone, corresponding to a yield of 70% of theory. The NMR spectrum shows when added of Eu (hfbc) (S) -3-methyl - valerolactone with 98% enantiomeric purity.

4) with Na / NH3 to 25.6 g (0.16 mol) (R) -3-methyl-pentanedioic acid monomethyl ester in 80 ml of ethanol and 800 ml of liquid NH3 are at -70 ° C within 25 min 36.8 g (1.6 mol) Na metal were added in pieces. Then the reaction mixture Stirred for 30 min at -78 ° C, mixed with 160 ml of ethanol at -70 to -40 ° C, 1 h at Stirred RT and concentrated. The white residue is mixed with H 2 O and acidified to pH 1 and extracted continuously for 3 h with diethyl ether and the extract is distilled. 12.0 g (corresponding to 66% of theory) of (S) -3-methylvalerolactone are obtained an S rotation value 1D - -23.4 (C = 2.6 / CH2C12).

b) (3R) -5-chloro-3-methyl-pentanoic acid ethyl ester To a solution of 142 g (3.95 mol) of hydrogen chloride in 225 ml of absol. Ethanol are at 0 to 5 0C 71.3 g (0.625 mol) of (S) -3-methylvalerolactone were added dropwise within 5 minutes. To Standing at RT for 18 hours, the reaction mixture is poured onto approx. 2 l of ice water, the mixture extracted 3 times with CH2Cl2, the extract washed with NaCl solution, dried and concentrated.

The crude product is distilled. 100.9 g of (3R) -5-chloro-3-methyl-pentanoic acid ethyl ester are obtained (98% content according to GC) from boiling point 83 to 840C at 14 mbar. That corresponds to a Yield of 91% of theory.

[α] D25 = -8.6 (C = 2.0 / CH2C12) The NMR spectrum shows in the presence of Eu (hfbc) 3 only 1 enantiomer.

L J Example 3 Preparation of (3R) -5-bromo-3-methyl-pentanoic acid ethyl ester To a solution of 745 g (9.2 mol of HBr in 1.1 l of absolute ethanol) are added at RT 114 g (1 mol) of a (3S) -3-methylvalerolactone prepared according to Example 2A admitted. The reaction mixture is then stirred for 2.5 h, then on ice water poured and extracted with chloroform.

The organic phase is saturated with NaHCO3 solution and water washed, dried and concentrated. The crude product is distilled. You get 198 g of (3R) -5-bromo-3-methyl-pentanoic acid ethyl ester with a boiling point of 900C at 15 mbar.-Das corresponds to a yield of 89% of theory.

[α] D25 = -12.3 (C = 4, O / CHCl3).

In game 4 a) Production of (3R) -3-methyl-valerolactone to a Solution of 16 g (0.10 mol) (R) -3-methyl-1,5-pentadienoic acid monomethyl ester in 80 150 ml of a 1M solution of BH3 in THF are added dropwise at 20 ° to 250 ° C. ml of THF. After standing at RT for 4.5 h, 100 ml of methanol are added to the reaction mixture and left to stand overnight. It is then concentrated again with methanol offset and narrowed.

The same operation is repeated two more times, then the crude product distilled in a bulb tube. 9.7 g of a colorless oil with a boiling point of bp are obtained = 120 to 130C- at 0.1 mbar. This corresponds to a yield of 85% of theory.

[α] D25 = + 23.8 ° (0 = 2.0 / CH2Cl2) The NMR spectrum shows only one enantiomer when Eu (hfbc) 3 is added.

b) Preparation of (3S) -5-bromo-3-methyl-pentanoic acid ethyl ester analog Example 3 is by reacting (3R) -3-methyl-valerolactone with HBr in absolute Ethanol (3S) -5 - ethyl bromo-3-methyl-pentanoate prepared.

[α] 25 D = +12.2 (C = 4.1 / CHCl3).

Example 5 a) Preparation of (4R) -6-chloro-2,4-dimethyl-hexan-2-ol To a Grignard solution, prepared from 1.35 g (56 mmol) Mg and 7.90 g (56 mmol) Methyl iodide in 25 ml of diethyl ether is 1.50 g (25 mmol) of (3R) -5 - chloro-3-methylpentanoic acid ethyl ester added dropwise in 5 ml of diethyl ether without cooling. The reaction mixture is then Heated to boiling for 1 h with stirring and reflux cooling, then with saturated NH4 Cl solution is added, the mixture is extracted with diethyl ether, and the extract is dried and concentrated. 3.55 g of (4R) -6-chloro-2,4-dimethylhexan-2-ol are obtained, corresponding to a yield of approx. 90% of theory.

t325 = -5.5 (C = 30 / CH2C12) b) Production of (3S) -l-chloro-3,5-dimethyl-4-hexene 0.50 g of (4R) -6-chloro-2,4-dimethyl-hexan-2-ol become p-toluenesulfonic acid with a spatula tip distilled at 100 ° C / 16 mbar in a spherical tube. 0.34 g of a colorless oil is obtained, which has a content of 85% of (3R) -l-chloro-3,5-dimethyl-4-hexene and up to 9 contains 5% of the double bond isomer (3R) -l-chloro-3,5-dimethyl-5-hexene.-The Yield is about 70% of theory.

(25 = +61.5 (C = 2.6 / CH2C12) D c) Preparation of (2S) -4-chloro-2-methyl-butanal In a solution of 1.85 g (14.2 mmol) (3S) -l-chloro-3,5-dimethyl-4-hexene in 100 ml of ethyl acetate is passed in at -78 ° C. for 10 minutes. Ozone is passed in until it turns blue occurs. The excess ozone is expelled with N2. Then 1.6 ml (22 mmol) of dimethyl sulfide are added and the mixture is left to warm to RT. After concentration, 1.8 g of a colorless oil are obtained which, according to GC, is 80% (2S) -4-chloro-2-methyl-butanal contains. This corresponds to a yield of about 85% of theory.

[α] D25 = -32.8 ° (C = 3.0 / CHCl3).

d) Preparation of (3R, 7R) -1-chloro-3,7,11-trimethyl-4 - dodecene a suspension of 4.83 g (10 mmol) (3R) -E3,7-dimethyl-oct-1-yl] -triphenylphosphonium bromine id in 20 ml of absolute THF at -78 ° C to -60 ° C 8.7 ml of a 1.3 M solution of Butyllithium was added dropwise to hexane (10 mmol) and the reaction mixture was then 1 stirred at RT for h. For this purpose, 0.46 g (3.8 mmol) (S) -4-chloro-2-methyl-butanal is added at RT added to 2 ml of THF, the mixture was stirred at RT for 4 h, then poured onto ice water, extracted with diethyl ether, the extract washed neutral with saturated NaCl solution, dried and concentrated. The crude product obtained is poured onto 300 g of Al2O3 with diethyl ether / heptane (50/50) chromatographed. 0.42 g (39% of theory) of l-chlorine are obtained r -3,7911-trimethyl-4-dodecene isolated as E / Z isomer mixture 9 (content according to GC: 80%).

e) Preparation of (3R, 7R) -l-chloro-3,7,11-trimethyl-dodecane 0.25 g (1.03 mmol) (3R, 7R) -l-chloro-3,7,11-trimethyl-4-dodecene are added to 0.1 g Pd / C in 20 ml of ethyl acetate are hydrogenated at RT and normal pressure. Then it is filtered, concentrated and distilled in a bulb tube at 1600C at 0.01 mbar. 0.19 is obtained g of a colorless Cl, corresponding to a yield of 76% of theory.

Example 6 a) Preparation of (2S) -4-chloro-2-methyl-butanol In a Solution of 0.70 g of a (3S) -l-chloro-3,5-dimethyl-hex-4-ene prepared according to Examples 5A and 5B ozone is introduced into 30 ml of ethyl acetate at -780C until a blue coloration occurs. The reaction mixture is then mixed with a solution of 1 g of NaHBH4 in 20 ml Ethanol is added and the mixture is stirred at RT overnight. Then it is acidified with acetic acid, extracted with diethyl ether, the extract dried, concentrated and in a bulb tube distilled.

E &] D5 = -22.00 (C = 3.0 / CH2Cl2).

b) Preparation of (2S) -4-chloro-1-bromo-2-methyl-butane 1.23 g (10 mmol) (2S) -4-chloro-2-methyl-butanol are mixed with 2.90 g (11 mmol) triphenylphosphine in 15 ml of CH2C12 dissolved. At a temperature of less than 15 to 20 ° C, a solution is added to this solution Solution of 0.56 ml (11 mmol) bromine in 3 ml CH2Cl2 added dropwise, the reaction mixture is stirred for 30 min. at RT, diluted with hexane, washed with water, dried and concentrated. The crude product is on 50 g of silica gel with a diethyl ether-hexane (1/9) mixture chromatographed. 1.6 g of an oil are obtained which distills in a bulb tube will. This gives 1.43 g of a colorless oil.

[α] D25 = -4.62 ° (C = 1.925 / CB, C13).

D 4> 62O (C = 1> 925 / CH2Cl2).

c) Preparation of (3R, 7R) -l-chloro-3,7,11-trimethyl-dodecane A Grignard solution, prepared from 2.21 g (10 mmol) (R) -l-bromo-3,7-dimethyl-octane and 0.24 g (10 mmol) of Mp turnings in 12 ml of absolute THF with heating to reflux cooled to -400C and then with 0.93 g (5 mmol) (2S) -4-chloro-1-bromo-2-methyl-butane dropwise and 1 ml of a 0.5 M solution of CuLi2C14 in THF is added. Then the Reaction mixture for a further 30 minutes at -400 ° C., then for 2.5 hours at -5 to 0 ° C. and finally Stirred overnight at RT, then mixed with 50 ml of saturated NH4-Cl solution and extracted 4x with hexane, the extract dried, concentrated and in a bulb tube distilled.

1.73 g of crude product are obtained which, according to GC, consists of 42% (3R, 7R) -1-chloro-3,7,11-trimethyl-dodecane exists (corresponding to a crude yield of 59% of theory). Another distillation yields 0.58 g of an oil which, according to GC, is 91% of (3R, 7R) -1-chloro-3,7,11 - trimethyldodecane exists, corresponding to a yield of 42% of theory.

9 Further examples of the use of the compounds according to the invention for the C15 building blocks required for the synthesis of the side chain of (R, R, R) -α-tocopherol Example 7 Preparation of (3R, 7R) -l-chloro-3,7, ll-trimethyl-dodecane by Grignard coupling a) Preparation of (3R) -5-chloro-3-methyl-1-pentanol To a suspension of 40.9 175 g (0.92 mol) of (R) -5-chloro-3-methyl-pentanoic acid ethyl ester become g (1.08 mol) LiAlH4 in 1.2 l absolute diethyl ether (Content 94%) was added dropwise at +8 to + 120C. After standing for 4 h at RT, the mixture is cooled 400 ml of water are added, the reaction mixture is stirred at RT for 1 h, filtered, washed with diethyl ether, the extract dried and concentrated. You get 134.2 g of (R) -5-chloro - 3-methyl-pentanol as a colorless oil (content according to GC 93%) with the rotation value [α] D25 = -11.5 (C = 3.0 / CH2C12).

b) Preparation of (3R) -5-chloro-3-methyl-1-p-toluenesulfonyl oxy-pentane To a solution of 20.0 g (149 mmol) (3R) -5-chloro-3-methylpentanol and 32.9 g (N160 mmol) 95% p-toluenesulfonyl chloride in 130 ml absolute methylene chloride becomes a solution of 1.59 g (13 mmol) 4-N ', N'-dimethylaminopyridine at 0 to 200C dropped into 30 ml of methylene chloride and 55 ml of triethylamine. It is stirred for 18 h at RT, Poured onto ice water, extracted 5 times with methylene chloride. The extract will with Washed 10% hydrochloric acid and saturated NaHCO3 solution, dried and concentrated. 41.0 g of (3R) -5-chloro-3-methyl-1-p-toluenesulfonyloxypentane are obtained as brown Oil (96% of theory).

[α] D25 = -4.057 ° (C = 2.095 / CX2C12) c) Preparation of (3R, 7R) -l-chloro-3,7,11-trimethyl-dodecane by Grignard coupling A Grignard solution prepared from 2.97 g (13.8 mmol) (R) -l-bromo-2,6-dimethyl-heptane (96%) and 0.33 g (13.8 mmol) of Mg in 28 ml of THF is at -780C to a solution of 2.00 g (7 mmol) (R) -5-chloro-3-methyl-1-p-toluenesulfonyloxypentane in 12 ml THF given. The reaction mixture is then mixed with 1.4 ml of a 0.1 M solution of Li2CuC14 (0.14 mmol) in T11F and left to stand at 0 ° C. for 16 h. Then will saturated NH4Cl solution is added to the reaction mixture and the mixture is extracted with diethyl ether, the extract dried and concentrated. 2.19 g of a colorless oil are obtained is distilled in a spherical tube. 1.85 g of an oil with a boiling point of 150 ° C. are obtained at 10-2 mbar, which, according to GC, consists of 67% (3R, 7R) -1-chloro-3,7,11-trimethyldodecane.

Yield 72% of theory. A sample is purified by preparative GC.

[α] D25 = -1.2 ° (C = 4.08 / CH2C12) Example 8 a) Preparation of (3R) -5-chloro-3-methyl-1-pentanal 45.1 g (0.25 mol) of a 98% strength (R) -5-chloro-3-methyl-pentanoic acid ethyl ester are dissolved in 450 ml of hexane and the solution at -780C with 315 ml of a 1 M solution from Diisobutylaluminum hydride in hexane is added. After 5 h the reaction mixture becomes mixed with 14 ml of methanol. 400 ml of a 10% HCl are added, then is extracted twice with diethyl ether, washed neutral with saturated NaCl solution, the extract is dried, concentrated and distilled. 24.5 g of a colorless one are obtained Oil with a boiling point of 680C / 16 mbar which, according to GC, has a content of 95% of (3R) -5-chloro-3-methyl-pentanal having. This corresponds to a yield of 71% of theory.

-2 D 2.34 (C = 2> 730 / CH2Cl2) is obtained analogously from (3R) -5-bromo-3-methyl-pentanoic acid methyl ester (3R) -5-Bromo-3-methyl-1-pentanal in 83% yield.

b) Preparation of (3R, 7R) -l-chloro-3,7,11-trimethyl-dodecane To a Suspension of 4.70 g (10 mmol) (R) -E2,6-dimethyl-hept-1-yl) -triphenylphosphonium bromide in 20 ml of absolute THF at -780C to -600C 8.7 ml of a 1.3 M solution of Butyllithium was added dropwise in hexane (10 mmol) and the reaction mixture was stirred at RT for 1 h.

For this purpose, 0.67 g (3.8 mmol) (3R) -5-chloro-3-methyl-1-pentanal is added at RT (Content 75% according to NMR) was added in 2 ml of THF, the mixture was stirred at RT for 4 h, then Poured onto ice water, extracted with ether, the extract with saturated NaCl solution washed neutral, dried and concentrated. 3.1 g of crude product are obtained, which is chromatographed on 300 g of Al203 with ether / heptane (50/50). It will be 0.45 g (40% of theory) (3R, 7R) -l-chloro-3,7,11-trimethyl-dodec-5-en as E / Z isomer mixture (Salary according to GC: 80%) isolated, b.p. 130 to 150 ° / 10-3 mbar (bulb tube).

By reducing the dodecene obtained at RT and normal pressure in Ethyl acetate in the presence of Pd / C gives the desired (3R, 7R) -l-chloro-3,7,11-trimethyl-dodecane.

Claims (13)

Claims Optically active compounds of the general formula I in which Y is C1 or Br and R is a lower alkyl radical such as -CH3, C2H5, -C3H7 or -C4H9. 2. (R) -5-chloro- or (R) -5-bromo-3-methyl-pentanoic acid ester of the general formula Ia in which Y is C1 or Br and R is a lower alkyl radical such as -CH3, -C2H5, -C3H7 or -C4H9. 3. (R) -5-chloro-3-methyl-pentanoic acid methyl ester. 4. (S) -5-chloro-3-methyl-pentanoic acid methyl ester. 5. Process for the preparation of optically active 5-chloro- or 5-bromo-3-methyl-pentanoic acid alkyl esters of the general formula I. in which Y is C1 or Br and R is a Ci to C4-alkyl radical, characterized in that an optically active 3-methyl-pentane, 5-diacid monoalkyl ester of the general formula II in which R has the meaning given above, converted into an optically active 3-methylvalerolactone by selective reduction of the acid group or by selective reduction of the ester group and this at temperatures from 0 to 50 ° C. with a solution of hydrogen chloride or hydrogen bromide in an alkanol ROH treated. 6. Process for the production of (3R) -5-chlorine or (3R) -5-Bromo-3-methyl-pentanoic acid alkyl esters according to Claim 5, characterized in that characterized in that one (R) -3-methyl-pentanedioic acid monoalkyl ester by selective Reduction of the ester group converted into (S) -3-methyl-valerolactone and this with treated with the solution of hydrogen chloride or hydrogen bromide 7. Procedure for Production of (3R) -5-chlorine resp. (3R) -5-Bromo-3-methyl-pentanoic acid alkyl esters according to Claim 5, characterized in that characterized in that one (S) -3-methyl-pentanedioic acid monomethyl ester by selective Reduction of the acid group in (S) -3-methyl-valerolactone and this with treated with the solution of hydrogen chloride or hydrogen bromide. 8. Process for the production of (3S) -5-chlorine or (3S) -5-Bromo-3-methyl-pentanoic acid alkyl esters according to claim 51 characterized in that one (3R) -3-methyl-1 15-pentanedioic acid monoalkyl ester converted into (R) -3-methyl-valerolactone by selective reduction of the acid function and this treated with the solution of hydrogen chloride or hydrogen bromide. 9. Process for the production of (3S) -5-chlorine or (3S) -5-Bromo-3-methyl-pentanoic acid alkyl esters according to Claim 51 characterized in that one (3S) -3-methyl-1,5-pentanedioic acid monoalkyl ester by selective Reduction of the ester group converted into (R) -3-methyl-valerolactone and this with treated with the solution of hydrogen chloride or hydrogen bromide. 10. The method according to claims 5, 6 and 9, characterized in that that the selective reduction of the ester group with the aid of lithium borohydride; a mixture of lithium chloride and sodium borohydride; Lithium triethyl borohydride or with sodium in liquid ammonia. 11. The method according to claims 5, 7 and 8, characterized in that that the selective reduction of the acid group with borohydride in suitable inert Solvents such as ethers, halogenated hydrocarbons, alkanes or aromatic Carries out hydrocarbons. 12. Process for the preparation of (3R, 7R) -l-chloro- or (3R, 7R) -l-bromo-3,7,11-trimethyl-dodecane, characterized in that (R) -5-chloro- or (R) -5-bromo-3-methyl-pentanoic acid ester of general formula Ia according to claim 2 converted by Grignard addition of methyl iodide into the corresponding (4R) -6-chloro- or (4R) -6-bromo-2,4-dimethylhexan-2-ols of the general formula IV, the (3S) -l-chloro- or (3S) -l-bromine-3,5-dimethyl-4-hexenes of the formula V are spåltet from these in a manner known per se by ozonolysis into the corresponding (S) -4-chlorine or. (S) -4-Bromo-2-methyl-butanals of the formula VI transferred this in a Wittig reaction with a triphenylphosphonium bromide of the formula VII in which the dashed lines can in each case mean a further bond, reacted and then hydrogenated. 13. Process for the preparation of (3R, 7R) -l-chloro- or (3R, 7R) -1-bromo-3,7,1l-trimethyl-dodecane, characterized in that (R) -5-chloro- or. (R) -5-bromo-3-methyl-pentanoic acid ester of the general formula Ia according to claim 2 converted by Grignard addition of methyl iodide into the corresponding (R) -6-chloro- or (R) -6-bromo-2,4-dimethyl-hexan-2-ols of the general formula IV from these, water is split off in a manner known per se, the (3S) -l-chloro- or (3S) -l-bromine-3,5-dimethyl-4-hexenes of the formula V obtained by ozonolysis and subsequent reduction with NaBH4 into the corresponding (S) -4-chlorine or (S) -4-Bromo-2-methyl-butanols of the general formula VIII transferred these are converted into compounds of the general formula IX by substitution of the OH group by a suitable exchange group in a manner known per se in the Z for -OSO2R; Br or J when Y is C1 and Z is -OSO2R or J when Y is Br where R is phenyl or p-tolyl; the compound of the general formula IX in the presence of copper ions with an organomagnesium compound of the general formula X. in which the dashed lines can in each case denote a further bond, reacted and, if appropriate, then hydrogenated.