EP1358170A1

EP1358170A1 - Process for preparing higher primary alkanols

Info

Publication number: EP1358170A1
Application number: EP02718061A
Authority: EP
Inventors: Arnold Braier; Martin Rettig; Max Rey
Original assignee: Cilag AG
Current assignee: Cilag AG
Priority date: 2001-01-26
Filing date: 2002-01-25
Publication date: 2003-11-05
Also published as: WO2002059101A1; CA2461450A1

Abstract

The present invention concerns a process for preparing higher primary alkanols and in particular for preparing 1-octacosanol comprising a multistep process involving reacting cyclodecanone with a secondary amine, reacting the resulting 1-amino-1-cyclodecene with an activated alkanoic acid, subjecting the thus obtained 2-n.alkyl-cyclotetradecan-1,3-dione to a ring opening reaction and a Wolff-Kishner conversion, eterifying the thus obtained alkanoic acid with an alkanol and subsequently reducing the thus obtained ester to the desired higher primary alcohol.

Description

Process for Preparing Higher Primary Alkanols

Brief description of the invention

The present invention concerns a process for preparing higher primary alkanols and in particular for preparing 1-octacosanol.

Background of the Invention

Higher primary alcohols are known to possess certain pharmacological properties and mixtures thereof have been described as cholesterol-lowering, antiplatelet, anti-thrombotic and / or anti-ischaemic agents as well as antagonists of drug-induced ulcers and as agents for improving male sexual activity. Another application is their use as plant growth regulators. They can also be used as food supplement. One particular example of these alcohols is 1-octacosanol, or «.C₂₈H5 OH. Mixtures of higher primary alcohols are normally obtained from natural sources like sugar cane wax, beeswax or birch bark, which mixtures contain said higher alcohols with a chain length ranging from 24 to 38 carbon atoms. Mixtures obtained from these sources contain between 60 to 70 % of 1-octacosanol. The latter compound in particular has the aforementioned pharmacological properties and uses.

A number of synthetic approaches for the preparation of 1-octacosanol and other higher primary aliphatic alcohols have been described in the prior-art. Methods for the preparation or isolation of mixtures of higher primary aliphatic alcohols from natural sources as well as their applications have been described in US-4367346 and US-4167641.

Additionally, A. Wanatabe in the Bulletin of the Chemical Society of Japan,

Nol. 33(4), pp. 531-534 (1960) describes the synthesis of normal higher alcohols in a multi-step process starting from an ethoxyalkyl bromide. S. Hϋnig in Chemische Berichte 100(12), pp. 3996-4009 describes an acylation reaction of 1-morpholino-

COΝFIRMATIOΝ COPY cyclododecen-(l) with ring expansion. Hϋnig and Buysch in Chemische Berichte 100912) pp 4010-4016 describe a chain expansion reaction of mono- and dicarbonic acids with 12 carbon atoms. Hunter and Light in Biochemistry 9(22), pp. 4283-4288 describe the acylation of cyclic enamines with subsequent ring-opening to oxo-acids. EP-A-64021 teaches the preaparation of long-chain carboxylic acids and alcohols from cyclkododecanone and acyl chlorides. SU-1,366,504 reported in CA. 109(23): 210514, describes the cleavage of 2-alkylcyclotetradecane-l,3-dione in ethanol in the presence of EtONa with subsequent reduction with NaBH_t to the corresponding ethyl 13- oxoalkanoate, which is dehydrated in the presence of askanite. The resulting ethyl alkenoate is reduced with hydrogen over a Cu-Cr catalyst.

However, none of these prior art approaches is suitable for the production of larger quantities thereof and in particular of 1-octacosanol. Moreover, none of these synthetic methods result in end products of food-grade quality, i.e. fulfilling the requirements that only solvents have been used that are generally recognized as safe and which are compatible with food ingredients.

Examples of these solvents are: acetone, isobutylmethyl ketone, 1- and 2- butanol, triethylene glycol, methanol, ethanol, 2-propanol, butyl acetate, ethyl acetate, dibutylether, cyclohexane, N,N-dimethylacetamide, glycol, diisopropylether, hydrocarbons, triethanolamine, acetonitrile.

It is an object of the present invention to provide a process in accordance with the given solvent-restrictions that can be scaled up for the production of multi-kilogram quantities of higher primary alkanols and in particular of 1-octacosanol. It is a further object to provide a process that is reproducible, is economical, and through which the end product is obtained in high yield and with a high degree of purity.

Summary of the Invention

This invention relates to a process of preparing a compound of formula (I): n.C_nH_2n+1OH (I)

wherein n is an integer in the range from about 18 to about 34; comprising the steps of

(a) reacting cyclotetradecanone of formula (II) with a secondary amine of formula (ID);

wherein R¹ and R² independently are Cι..₆alkyl, or R¹ and R² taken together with the NH moiety to which they are attached can form a cyclic secondary amine such as 4- morpholine, pyrrolidine, piperidine, piperazine or 4-substituted piperazine: thus preparing an enamine of formula (IN):

(π) (in) (IV)

(b) reacting an enamine of formula (IN) with an activated alkanoic acid of formula (N) thus preparing a 2-n.alkyl-cyclotetradecan-l,3-dione of formula (NI):

(IN) (V) (VI)

wherein Y is a suitable acid activating group: (c) subjecting a 2-n.alkyl-cyclotetradecan-l,3-dione (NI) to a ring-opening reaction with a suitable base and subsequently to a Wolff-Kishner conversion reaction, thus preparing an acid of formula (Nil):

(vi) (vπ)

(d) esterifying an acid (Nil) with a lower alkanol R³-OH, thus preparing an ester (NIH):

(vπ) (Nπi)

wherein R³ is C βalkyl, preferably methyl;

(e) reducing an ester (VUI) thus preparing an alkanol of formula (I)

(vm) (i)

In a further aspect, the invention concerns a process for preparing an alcohol (I) comprising reaction steps (b), (c), (d) and (e) as outlined herein.

In a preferred embodiment, this invention relates to a process of preparing 1- octacosanol of formula (I-a):

n.C₂₈H₅₇OH (I-a) comprising the steps of

(a) reacting cyclotetradecanone of formula (H) with 4-morpholine (Ill-a), thus preparing the enamine of formula (IN-a):

(π) (JH-a) (IV-a)

(b) reacting the enamine of formula (IN-a) with an acid chloride of formula (N-a) thus preparing 2-n.tetradecyl-cyclotetradecan-l,3-dione ofiormula (Vl-a):

(IN-a) (V-a) (Nl-a) (c) reacting 2-n.tetradecyl-cyclotetradecan-l,3-dione (Nl-a) with a base and subsequently with hydrazine, thus preparing the acid of formula (NlJ-a):

(Vl-a) (Nπ-a)

(d) esterifying the acid (VH-a) with an alcohol R³-OH thus preparing the ester (VUl-a):

n.C₂₇H₅₅-COOH -^ n.C₂₇H₅₅-COOR³ (Vπ-a) (VTπ-a)

wherein R is Ci-βalkyl, preferably methyl;

(e) reducing the ester (VHI-a) thus preparing octacosanol (I-a)

n.C₂₇H₅₅-COOR³ ^ n.C₂₇H₅₅-CH₂-OH

In a further aspect, the present invention concerns novel intermediates used in these processes.

Detailed Description of the Invention

The integer n can be as defined above but in particular is in the range of 24 to

32. As mentioned herein, the secondary amine (UJ) amongst others can be a 4- substituted piperazine. Particular 4-substituents in the latter are, for example, ^alkyl, benzyl, C^alkanoyl, e.g. acetyl.

Y is an acid activating group. Preferably Y is a halogen atom, most preferably chloro or bromo.

As used herein .₆ alkyl refers to straight and branched saturated hydrocarbon radicals such as for example methyl, ethyl, n.propyl, i.propyl, n.butyl, 2-methylpropyl, n.pentyl, n.hexyl, and the like. Halogen or halo refers to fluoro, chloro, bromo or iodo. Ci-βalkanoyl encompasses alkylcarbonyl radicals having 1 to 6 carbon atoms such as formyl (HCO-), acetyl, ethanoyl, propanoyl and the like

The various process steps of the process of this invention are outlined hereafter in more detail.

Step (a): synthesis of 1-sec.amino-l-cyclododecene

(π) (m) (TV)

This step comprises the condensation reaction of (H) with (HI) with water removal, either physically or chemically with a suitable deshydrating agent which preferably is titanium(IN)chloride. The amine HΝR²R³ is as specified above, and preferably is a cyclic amine such as morpholine. This process is conducted in a suitable solvent such as for example a hydrocarbon, more particularly an aliphatic or aromatic hydrocarbon. Examples of aromatic hydrocarbon solvents are toluene and xylene. Preferably the reaction is conducted in an acyclic or cyclic hydrocarbon, for example in pentane, hexane, heptane, octane, cyclopentane, cyclohexane, cycloheptane, including alkyl substituted derivatives thereof, their isomers and mixtures thereof.

In a particular execution of this step, cyclododecanone (II) and a secondary amine (IJJ), which preferably is morpholine, are reacted in the presence of TiCl₄ in a suitable solvent, which preferably is a acyclic or cyclic hydrocarbon, e.g. pentane, hexane, cyclohexane and the like, or which can also be an aromatic hydrocarbon such as, for example, toluene, xylene and the like, to yield the desired product (IN). The latter is isolated from the reaction mixture and can be used in the further reaction steps with or without purification.

In a preferred execution of this process step, cyclododecanone (U.) and morpholine (HI) are dissolved in an aromatic hydrocarbon, preferably toluene. TiCl₄ is added to the reaction mixture within a time period of several hours, preferably 4 h, at lower temperature, preferably at 0°C. The reaction mixture is allowed to stand over a sustained period of time, for example it is allowed to stand over night at room- temperature. Afterwards, the mixture is filtered to remove the formed TiO and morpholine hydrochloride. The solvent is distilled off under reduced pressure and the thus obtained N-morpholino-1-cyclodecene (IN) can be used without further purification.

Molar equivalents of the reagents can be used, although good results are obtained with excess quantities of (HJ). Preferably about 2 molar equivalents of (H) and about 6 molar equivalents of (HI) are reacted with one equivalent of TiCl₄. A small excess of TiCl (1.05 mol-eq.) can also be used. In the latter instance, the excess of

TiCl₄ reacts after filtration with air-humidity and the thus-formed TiO₂ precipitates and can be removed by filtration.

In an alternative realization of step (a), the reaction can also be conducted without TiCl₄ by physically removing the water, e.g. by using a Dean-Stark separator.

In this procedure, (II) is reacted with HΝR²R³ (HJ), the latter being as defined above and preferably being morpholine (IH-a), in a suitable solvent such as, for example, a saturated hydrocarbon such as cyclohexane and the like, an aromatic hydrocarbon such as xylene, e.g. p.xylene and the like, or preferably in toluene. Preferably, the reaction is conducted in the presence of an acidic catalyst such as a Lewis acid, e.g. a boron trifluoride such as BF₃.Et₂O, or a sufficiently strong organic acid, in particular a sulfonic acid, e.g. tosyl sulfonic acid and the like.

In a preferred execution of this process variant an excess of (HI) or of (HT-a) is used, e.g. more than 1.5 equivalents, in particular 2.0 molar equivalents of (HI) or of morpholine (Tfl-a) are used, with toluene as solvent andjc-toluenesulfonic acid as acidic catalyst. The catalyst is usually added in sub-equivalent quantities, for example in an amount lower than 0.1 molar equivalents, preferably in an amount of 0.01 molar equivalents.

In alternative executions of this process step, morpholine (TH-a) is replaced by other secondary amines like dibutylamine or a cyclic amine such as 1- methylpiperazine, piperidine, and pyrrolidine.

Step (b): Synthesis of 2-n.tetradecyl-cyclotetradecan-l,3-dione (VI)

(IV) (V) (VI)

The starting compound N-morpholino-1-cyclododecene (IN-a) is commercially available, but can also be prepared according to the procedure of step (a). In the second step N-sec.amino-1-cyclododecene (IN) is reacted with an activated acid of formula (N). In a preferred execution the secondary amino group (sec.amino) is morpholino. The activated acid of formula (N) in particular is an alkanoyl halide, preferably an alkanoyl chloride. This reaction is conducted in a suitable solvent, for example in a ketone, such as methyl ethylketone methyl isobutylketone or preferably acetone, or also preferably in a polar aprotic solvent such as acetonitrile, in the presence of an appropriate base, e.g. a tertiary amine such as triethylamine. The reaction is conducted at lower temperatures, in particular below 15 °C, preferably below 10°C. Most preferably the temperature is kept in the range from 0-10°C.

Subsequently a suitable base can be added, preferably an inorganic base such as an alkali metal hydroxide or an alkali metal alkoxide. Examples of suitable bases are sodium hydroxide, sodium methoxide, sodium ethoxide and the like.

In a preferred execution of this process step N-morpholino-1-cyclododecene (IN-a) and triethylamine are dissolved in acetonitrile. The reaction mixture is cooled, preferably to 1-6°C, and palmitoyl chloride is added over a time period of several hours, in particular from 5-10 hours, preferably about 6 hours. During the addition of the palmitoyl chloride, the whole is stirred and kept at lower temperature, preferably between 1-6°C. Good stirring is recommendable for reproducible results, because the reaction is heterogeneous. After the addition is complete, the mixture is allowed to stir for a time period of at least one hour. Then an aqueous ΝaOH-solution is added. After a period of more than about 5 minutes, preferably after ten minutes, the mixture is heated to 45-50°C and kept at least for one hour at this temperature. Alternatively, the reaction-mixture can be stirred overnight at room temperature after the addition of the aqueous ΝaOH-solution.

Hydrochloric acid is added, preferably in excess quantity (e.g. 3.25 mol-eq., 16%) and the mixture is refluxed for a time period of more than 5 minutes, preferably ten minutes. After the two-layer-system is cooled to room-temperature, the desired product precipitates and is recrystallized from ethanol to obtain 2-n.tetradecyl- cyclotetradecan-l,3-dione (Nl-a) as a white solid. Ethanol is preferably used as solvent for recrystallisation.

The amount of tertiary amine and in particular of triethylamine used in the reaction is in the range of 1.1 to 2.5 molar equivalents. Preferably about 1.16 mole equivalents of triethylamine are used. The amount of enamine (IN) that is used preferably is in the range from 1.0 to 2.0 molar equivalents, more preferably between 1.0 to 1.5 molar equivalents, and most preferably is about 1.125 molar equivalents. The amount of (N) is in the range of 1 to 1.5 molar equivalents, preferably it is about 1 molar equivalent.

The amount of solvent preferably is kept as low as possible and is such that stirring of the reaction mixture is not hindered. The quantity of ΝaOH solution that is added may vary between 0.3 to 1.6 molar equivalents and preferably is about 1.3 molar equivalent. The said solution is in a concentration of 5 to 20% (w/w), preferably about 10% (w w). The quantity of hydrochloric that is added is in the range of 2-5 molar equivalent, preferably it is about 3,25. The concentration of said acid is from 10-30%, and preferably is about 16% molar equivalents.

The product (NI) can be dried at higher temperatures, preferably at a temperature of 50° or higher but below the melting point of (VI), or preferably at about 60°C in a vacuum below 30 mbar for 16 hours. In order to shorten the drying time, the temperature can be increased to e.g. 60°C. The solvent for recrystallisation preferably is ethanol. In case ethanol is used as solvent in the next step, drying is not necessary.

Without being bound by theory, it is believed that the reaction occurs via an intermediate (TV-b), as represented in the following scheme.

(IV) (V) (IV-b)

(NI-a) (Vl-b)

It is assumed that after addition of the palmitoyl chloride, the main intermediate in the mixture is the bicyclic compound (IV-b), which is stable at 0°C. Under basic conditions, this intermediate (IN-b) is converted to a product-mixture of (NI-a) and (Nl-b) with a very high excess of the desired product (NI-a). The same applies to the reactions where activated acids other than palmitoyl chloride are used for preparing the various compounds of formula (VI). The compounds of formula (VI) and in particular the compound of formula (Vl-a) are deemed to be novel compounds which comprises an additional feature of the present invention.

Step (c): Preparation of 1 -alkanoic acids (VII)

(VI) (VH)

The conversion of (VI) to (NH) is a multi-step process, after which the acid (VH) is isolated and recrystallized, before it is converted to the corresponding ester (VH!). Preferred is the conversion of (Vl-a) to octacosanoic acid (VH-a).

In a particular execution, it is also possible to synthesize 1-methyloctacosanoate (VTfl-a) in a one-step procedure, without isolation of 1-octacosanoic acid (VH-a) or with direct conversion of the crude, undried octacosanoic acid (VH) to methyloctacosanoate (VHI).

Step (c) comprises three sub-steps. First the cleavage of 2-n.alkyl- cyclotetradecane-l,3-dione (VI) under basic conditions, secondly a Wolff-Kishner reduction and thirdly acidic work-up.

The reaction of step (c) is conducted in a suitable solvent such as a glycol, a polyethylene glycol, or a glycol ether or polyethylene glycol ether, e.g. glycol, triethylene glycol and, preferably, diethylene glycol. Basic conditions, as referred above, are obtained by using a suitable inorganic base such as an alkali metal hydroxide, e.g. sodium or potassium hydroxide. A small amount of alcohol is preferably added, e.g. a lower alkanol such as methanol or ethanol.

The reaction of step (c) is conducted with excess quantities of KOH, EtOH, and

N H .H₂O in particular with 2-6 equivalents, or with 3-5 equivalents of said reagents, and preferably with 4 equivalents of said reagents.

The basic cleavage of (VI) typically takes a few hours, e.g. 1-3 hours. The standard reaction-time of the basic cleavage however is 2 hours. After the addition of the hydrazine monohydrate the reaction mixture is heated for another few hours, e.g. for 2 hours. Subsequently, the excess of hydrazine monohydrate and ethanol are distilled off, and the reaction-mixture is heated for a period of 12 to 20 hours preferably for a period of at least 16 hours, at a temperature in the range of 190 to 220°C.

The acid (VH) and in particular octacosanoic acid (VH-a) are isolated by acidic work-up. After the 12 to 20 hours heating of the reaction mixture between 190 and 220°C, H O, and an aqueous hydrochloric acid solution, e.g. 6 N HC1 is added, until the reaction-mixture reaches a pH- value between 0 and 2. Upon allowing the reaction- mixture to slowly cool down to room temperature, the product (VH) precipitates as a white to off-white solid which can optionally be dried. Drying can be done for example at 60°C for 16 hours at a vacuum of below 30 mbar but product (VH) usually is used without drying in the subsequent recrystallisation step. The acid (VH) can be recrystallized from a ketone such as methylisobutylketone.

Step (d): Preparation of lower alkyl 1-n.alkanoate (VIII)

C_n._jHs_n-i-COOH - C^H^_.j-COOR³

(VH) (vm)

According to reaction step (d) the starting acid (VH) is reacted in the alcohol of which the ester (VHI) is derived. Typically a Cι..₆ alkanol is used, preferably methanol, thus yielding the corresponding C ι_₆ alkyl esters or preferably the methyl ester of (VHJ).

The reaction is conducted with an excess of a strong acid, preferably a hydrohalic acid such as HCl, in particular with 2-5 molar equivalents, preferably with 3.0 molar equivalents of concentrated HCl. The reaction also works with a catalytic amount of sulfuric acid.

The reaction preferably is conducted at higher temperatures, more specifically at the reflux temperature of the reaction mixture. The reaction time is several hours, e.g. 2-6 hours, preferably 4 hours.

In a particular execution of this process step, the reaction-mixture is slowly cooled to room-temperature whereupon the product precipitates and subsequently is filtered off. The thus obtained ester of formula (VTfl), or in particular 1 -methyl octacosanoate (VHI-a), normally do not need drying before recrystallisation.

The crude, undried ester of formula (VTA), or in particular 1 -methyl octacosanoate (VHI-a), can be recrystallized from methanol. Other solvents that can be used in the recrystallization are acetone, methyl isobutylketone, 1-butanol, ethanol, ethyl acetate, acetonitrile or water, or mixtures thereof.

After recrystallisation, the product may be dried, at increased temperature and at reduced pressure, e.g. at 60°C for 16 hours in a vacuum of below 30 mbar.

In an alternative procedure, the reaction-mixture of the Wolff-Kishner-reduction is directly alcoholized with MeOH (or another C₂-₆ alkanol) and an excess of hydrohalic acid, for example 6.0 molar equivalents of HCl, is added. The mixture is refluxed for a period of 4 to 12 hours, preferably for 4 hours. In this way ester (VTfl) is directly obtained.

Recrystallisation of the ester (VHI) in the latter process variant is from the solvents mentioned above or in particular from the solvents mentioned above or in particular from methanol, methyl isobutyl ketone/water 1:1, or methyl isobutyl ketone/water 1:1 /methanol mixtures.

Step (e): Preparation of higher 1-n.alkanols

n.C₂₇H₅₅-COOR³ -> n.C₂₇H₅₅-CH₂-OH

(VHJ) (I)

According to this process step, the ester (VTA) is reduced to the corresponding alcohol (I) by a suitable reduction agent. The latter may be a metal hydride or a complex metal hydride such as lithium aluminium hydride or derivatives thereof.

Particular reduction agents for this reaction are silane agents such as trialkylsilanes, dialkylsilanes, trialkoxysilanes and preferably poly methylhydrogensiloxane ('PMHS') in the presence of a suitable catalyst. In particular the latter is a transition metal halogenide or carboxylate, and preferably the latter is a zinc carboxylate, such as zinc hexanoate or a derivative thereof, more preferably zinc 2-ethylhexanoate, in the presence of a metal hydride such as an alkali metal or earth alkaline metal hydride, or aluminium hydride, e.g. lithium, sodium, potasium, calcium hydride, or a complex hydride such as a borohydride or aluminium hydride, in particular an alkali metal borohydride or aluminiumhydride, e.g. lithium, sodium or potassium borohydride or aluminium hydride. A combination of zinc 2-ethylhexanoate and sodium borohydride is most preferably used as the catalyst mixture. These and similar reduction agents are described in Patent Application WO 96/12694 (1995) and in J. Ulman, The Alembic, 1999, 59, 1 ff.

The reaction of this process step is conducted in a suitable solvent, in particular a solvent that is generally accepted as safe, e.g. an ether or polyether. Specific examples of suitable solvents comprise diethyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, diglyme. The reduction agent can be formed by stirring a mixture of the agents ERS A and ERS B in a separate reaction vessel (ERS = Ester Reduction System), commercially available from Rhom & Haas). ERS A is a solution of NaBBU in tetraglyme, whereas ERS B is a solution of Zn(carboxylate)₂*H₂O, in particular of Zn(2-ethylhexanoate) *H₂O, in tetraglyme. ERS A and ERS B are preferably mixed at higher temperature, e.g. at. a temperature in the rage of 50 to 90°C, in particular at 70°C for a period of several minutes, e.g. for 30 min. Subsequently the ERS A and ERS B mixture is added to the ester (H) and ERS C is added. ERS C is poly methylhydrogensiloxane.

In a preferred execution, methyl octacosanoate (VHI-a) is dissolved at increased temperature, e.g. at 70°C, in a suitable ether, e.g. in di-n-butylether. The reducing agent, prepared as described above, is added in one portion to the solution, followed by the addition of ERS C within one hour. The reaction mixture optionally can be heated to 90°C prior to addition of ERS C. Then the temperature is increased to 90°C and kept at that temperature until an in-process-control shows a conversion of at least 99%. The reaction time is depending on the purity of the starting-material (NTH) and is in the range of 2 to 8 hours. After complete reduction the mixture is cooled to 45 °C and hydrolyzed carefully with aqueous alkali metal hydroxide solution, which preferably is a KOH solution in slight excess (e.g. 1.3 mol-eq., using a 33% solution), preferably containing a small amount of methanol. Somewhat poorer results are obtained when using a ΝaOH solution. Subsequently, the mixture is refluxed for 2 hours and the layers are separated at increased temperature, e.g. at 80°C. The organic layer is washed with acid, e.g. hydrochloric acid (16%), and aqueous basic solution, e.g. KOH-solution (33%). The organic layer is cooled to room temperature and the desired 1-alkanol (e.g. 1-octacosanol) precipitates. It is recrystallized from a mixture of n-dibutylether and ethanol.

The reducing agent can be generated in situ in the reaction vessel, which is particularly attractive. To this purpose, 1-methyloctacosanoate (VHI) is dissolved in n- dibutylether at a temperature of 90°C. ERS B is added first in one portion, followed by the addition of ERS A also in one portion. Then immediatly ERS C is added within one hour. Alternatively, the catalyst can also be generated by the reaction of NaBIL and Zn(acetate)₂*H O in diglyme.

The reaction preferably is conducted in a suitable solvent such as an ether, for example diisopropyl ether, and peferably in a di-n.butyl ether. The latter solvent has the additional advantage of avoiding the formation of peroxides. The quantity of ERS C is in the range of 2 to 4, in particular in the range of 2.2 to 3 molar equivalents, preferably 2.5 molar equivalents of ERS C are used.

The reaction is complete after 4 hours when the starting material 1 -methyl octacosanoate (VHI) has a purity of at least 98%. In case 1-methyloctacosanoate is of lower purity, it can not be reduced under standard conditions and an excess of reducing agent is needed. For example for product of 93% purity four times as much reducing agent as under standard-conditions needs to be used.

After completion of the reduction reaction, the excess of ERS C can be destroyed with a suitable ester, in particular with ethyl acetate. After addition of the said ester, the mixture is stirred for one hour and hydrolized at 90°C by addition of aqueous base solution, preferably a KOH-solution (33%) and further preferably without the use of methanol. Further work-up comprises the separation of the organic layer and washing with aqueous basic solution (e.g. KOH-solution of 33%) and with water. The crude octacosanol can be recrystallized from ethanol.

The product of the recrystallisation can be dried at increased temperature and at reduced pressure, for a prolonged period of time, e.g. at 50°C for 16 h at a vacuum of below 30 mbar. The drying time can be shortened by increasing the drying temperature, e.g. to 60°C. The drying temperature cannot be increased too much because of the melting point of the 1-alkanols which, for example, in the case of 1-octacosanol is 84°C. Examples

As used herein the term 'industrial ethanol' refers to ethanol containing 5% water and 5% isopropanol.

Example 1: N-morpholinocyclododecene

8300 g (45.5 mol) of cyclododecanone and 11959 g (137.3 mol) of morpholine are dissolved in 33.8 kg of toluene resulting in a clear solution that is cooled to -5 to 0° C. A solution of 4341 g (22.9 mol) of titanium chloride in 10.6 kg of toluene is added to this precooled mixture keeping the temperature between 0 and 5° C (at this size of the reaction it takes 4 h at a mantel-temperature of -10 to - 20° C). After the complete addition of the TiCl₄-solution the reaction mixture is stirred at 15 to 25° C for at least 14 h.

Then the precipitated TiO₂ and mo holine-hydrochloride are filtered off during 6 h using four 10-1-buchner funnels and paper-filters (In case the filtrate is not clear or becomes cloudy upon standing, it should be filtered again.). The residue is washed with 18.0 kg of toluene and the combined organic layers are evaporated at 60° C until a pressure to 7 mbar was reached, to obtain the crude N; morpholinocyclododecene as a brown oil. At the end of the evaporation the temp, of the water bath is 60 - 70° C and the pressure into the flask brought to less than 40 mbar to remove the excess of morpholine as much as possible.

Yield: 10389 g crude N-morpholinocyclododecene as a yellow to brown oil. Purity assayed by 1H-ΝMR: 85 % = 8831 g of the pure substance = 77.1 % Example 2 : 2-rc.tetradec yl-cyclotetradecan- 1 ,3-dione

Palmitoyl acid-chloride (1.00 mol-eq) is slowly added (6 h) to a solution of N- morpholino-cyclododecene (1.14 mol-eq) and triethylamine (1.22 mol-eq) in acetonitrile at 1 - 6°C. After stirring for another 1 h, the reaction mixture is quenched by addition of ΝaOH-solution (10%, 1.3 mol-eq) at 1 - 6 °C. Then HCl (16%, 3.25 mol-eq) is added at 45 - 50 °C. After addition of HCl the reaction mixture is stirred at 73 - 78 °C for 10 min and then cooled to 10 - 25 °C. The desired product precipitates as a white solid and is filtered off and washed with industrial ethanol.

For recrystallisation the crude, wet 2-n-tetradecylcyclotetradecan-l,3-dione is dissolved in industrial ethanol under reflux, cooled to 20° C and filtered off. Drying under vacuum at 60° C (10 - 20 mbar, 12 h) yields the desired product as a white lumpy powder. Yield: 70 - 82 %, typically 80%

6962 g (25.3 mol) of palmitoyl-chloride is added to a solution 8553 g (28.9 mol)of N; morpholinocyclododecene and 3112 g(30.8 mol) of triethylamine in 30942 g of acetonitrile at 1 - 6° C (preferably 4° C) during a time period of at least 6 h in a constant flow. During the addition the reaction mixture becomes milky. After complete addition of the palmitinicacid-chloride the reaction mixture is stirred at 1 - 6 °C for at. least 1 h. Then a solution of 1476 g of sodiumhydroxide in 13284 g of water is added during 10 min. The temperature during the addition is allowed to rise at 25° C. Then the reaction mixture is stirred for another 10 min. at 15 - 25° C and for 1 h at 40 - 45° C. At this point the reaction-mixture can be stored at 20-25° C for at least 16 h. Then a solution of 9274 g of hydrochloric acid (32 - 34 %) in 9274 g of water was added at 20 - 50 °C during at least 10 min (slightly exothermic).

After addition of the hydrochloric acid the pH- value should be between pH 1 and pH 3. Otherwise 16% hydrochloric acid is added until the pH is lower than pH 3. Then the reaction mixture is stirred at 70 - 80 °C for 5 to 15 min., cooled down to 10 - 25 °C and stirred for at least 1 h at this temperature.

The suspension is filtrated and the residue washed with 7248 g of industrial ethanol. Yield: 20976 g wet raw-product.

Recrystallisation

20970 g of the wet raw-product were added with 56161 g of industrial-ethanol and stirred for 15 min. at reflux (jacket-temperature approx. 90 °C). The brown solution is cooled down to 15 - 25 °C and stirred at this temp, for at least 1 h.

Then the white precipitate is filtered off, washed with 14082 g of industrial-ethanol and dried for at least 12 h at 60 °C and 10 - 20 mbar.

Yield: 8765 g 2-«-Tetradecylcyclotetradecan-l,3-dione as a white solid (82 %).

Example 3: Octacosanoic acid n.C₂₇H₅₅COOH

Wolff-Kishner reaction

1200 g (2.85 mol) of 2-rc-tetradecyl-cyclotetradecan-l,3-dione and 640 g (11,4 mol) of potassium hydroxide and 525 g of ethanol and 6055 g of diethylene glycol are stirred at 120-130° C. After 2 h at this temperature 571 g. (11.4 mol) of hydrazine-monohydrate is added to the solution in approx. 15 min. Then the excess of ethanol and hydrazine- monohydrate is destilled off by slowly heating of the reaction mixture to 195-205° C. After 16 h at 195-205° C the reaction-mixture is cooled to 100-110° C and poured into 8400 g of purified water.

To the aqueous suspension of the Wolff-Kishner reaction mixture a solution of 5700 g of hydrochloric acid, 32/34% in 4700 g of water is added and stirred for at least 30 min. (the pH after the addition of HCl should be under 2, otherwise more hydrochloric-acid should be added until the pH is below 2). Then the product is filtered off and recrystallised without drying as described hereafter.

Recrystallisation

The crude wet Octacosanoic acid (10165 g) is dissolved in 35000 g of isopropyl methylketone at reflux (jacket temperature 150° C) and stirred at this temperature for 30-45 min. The thus obtained solution is cooled to 15-25° C, and filtered. The white residue is dried at 50° C under vacuum. Yield: 4418 g Octacosanoic-acid as a white solid = 95 %

Analysis

1H-NMR (300 MHz, pyridine-d₅, D in ppm): 0.87 (t, J= 6.4 Hz, 3 H), 1.27-1.42 (m, 48 H), 1.81 (m, 2 H), 2.53 (t, J = 7.4 Hz, 2H).

¹³C-NMR (75 MHz, pyridine-d₅, D in ppm): 14.61 (CH₃), 23.27 (CH₂), 26.01 (CH₂), 29.96 (CH₂), 30.07 (CH₂), 30.17 (CH₂), 30.34 (CH₂), 32.47 (CH₂), 35,25 (CH₂), 176.30 (CO). Example 4: 1-Octacosanoic-acid-methylester n.C₂₇H₅5COOCH3

CH₃OH, HCl

4 h, rf H₃C(CH₂)₂₆COOH ^■ H₃C(CH₂)₂₆COOCH₃

4618 g (10.9 mol) of octacosaoic acid and 32705 g of methanol and 4334g of hydrochloric acid 32/34% are heated at reflux (68°C, jacket-temperature: 120°C) for at least 4 h. After cooling down to 15-25° C the formed precipitate is filtered off. Yield: 4215 g wet crude 1 -octacosanoic-acid-methylester

4215 g of the wet crude 1-octacosanoic-acid-methylester and 32710 g of methanol are refluxed for at least 1 h (68°C, mantel-temp.: 120°C). After cooling to 15-25° C the formed precipitate is filtered off (very fast filtering).and washed with 1600 g of methanol.

The resulting white crystals are dried at 50° C under vacuum. Yield: 3640 g 1^ octacosanoic-acid-methylester as white crystals = 76 %

Example 5: 1-octacosanol n.C₂₈H₅₇OH (I-a)

1 -Octacosanoic-acid-methylester is reduced by the VenPure™-ERS-System to 1- Octacosanol.

VenPure™ERS-A (9.2 g) and VenPure™ERS-B (9.2 g) are mixed and heated to 70° C to prepare the active ZnH-species. This solution is added to a solution of octacosanoic- acid-methylester (200g, 1 mol-eq) in di-n-butylether and heated at 70° C. To this solution VenPure™ERS-C (68.7 g) is slowly added so that the temperature does not exceed about 90° C. Work up is done by slowly hydrolysis with potassium hydroxide solution (33%) followed by two washing steps with hydrochloric acid (5%) and potassium hydroxide solution (33%). The crude product is isolated by cooling the solution to 20° C and filtration. Recrystallisation of the wet crude product in di-n-butylether and then in industrial ethanol affords the pure 1-octacosanol in a yield of typically 90% (Purity: 99.2%, assay: 100%)

Preparation of the Catalyst

161 g of ERS-A-Reagent and 161 g of ERS-B Reagent were added and heated to 70° C for 30 min. (during heating the mixture foams, so that the reaction vessel should be ten times larger than the volume of the reaction mixture). Then 351 g of di-rc-butylether are added to the mixture without further heating. The resulting warm solution (20-60° C, hereafter called "Reagent AB") has to be used as quickly as possible in the following reaction step (storage time should not be longer than 1 h).

Reaction

3500 g; (8.0 mol) of octacosanoic-acid-methylester is solved in 13998 g of di-n- butylether at 65-75° C. To this solution 675 g of Reagent AB is added (no exothermic reaction is observed). Then 1205 g of ERS-C-Reagent is added at 65-90° C (moderate exothermic reaction). Then the reaction mixture is stirred at 85-90° C for approx. 4 h. Then the reaction mixture is cooled to 40-50° C and at this temperature a solution of 1800 g of potassium hydroxide in 3610 g of purified water and 638 g of methanol is added (moderate exothermic reaction). Then the reaction mixture is refluxed for approx. 2 h (80-95° C). At the beginning the reaction mixture is cloudy because of zinc-metal. The refluxing should be continued until the di-n-butylether phase is clear. Then the aqueous layer is separated at 75-85° C(disposal) and a solution of 259 g of hydrochloric-acid, 32/34% in 1458 g of water, 320 g of methanol is added and refluxed for 2 h (80-95° C). Now the (lower) aqueous layer is separated at 75-85° C (disposal). The resulting organic layer is cooled down to 10-20° C, stirred at this temp, for at least 15 min. and filtered. The resulting precipitate is washed with 1754 g of industrial ethanol and stored for recrystallization.

Recrystallisation

9907 g of the wet crude 1-octacosanol and 24308 g of di-n-butylether and 5000 g of purified water is stirred for at least 10 min. at 75-85° C. At this temp, the aqueous layer is separated (disposal). After cooling down to 10-20° C the formed precipitate is filtered off (fast filtrating) and washed with 3690 g of industrial ethanol. The resulting wet product (11292 g) is recrystallized once more. Yield: 6062 g 1-Octacosanol = 93 %.

Claims

1. A process of preparing a compound of formula (I):

n.C„H_2n+ιOH (I)

(a) reacting cyclotetradecanone of formula (H) with a secondary amine of formula (HI); wherein R¹ and R² independently are C^ancyl, or R¹ and R² taken together with the NH moiety to which they are attached can form a cyclic secondary amine; thus preparing an enamine of formula (TV):

(π) (HI) (IN)

(b) reacting an enamine of formula (IV) with an activated alkanoic acid of formula (V) thus preparing a 2-n.alkyl-cyclotetradecan-l,3-dione of formula (VI):

(IV) (V) (VI) wherein Y is a suitable acid activating group,

(c) subjecting a 2-n.alkyl-cyclotetradecan-l,3-dione (VI) to a ring-opening reaction with a suitable base and subsequently to a Wolff-Kishner conversion reaction, thus preparing an acid of formula (VH):

(VI) (VH)

(d) esterifying an acid (VH) with a lower alkanol R³-OH, thus preparing an ester (VHI):

Ca-iHan-i-COOH -» d-iHai-i-COOR³

(VH) (VHI)

wherein R³ is C_halky!;

(e) reducing an ester (VHI) thus preparing an alkanol of formula (I)

(VHI) (I)

2. A process according to claim 1 wherein in HNR^R² is dibutylamine, 4- morpholine, pyrrolidine, piperidine, piperazine or 4-substituted piperazine; R³ is methyl; Y is halogen.

3. A process according to claims 1 or 2 wherein n is the integer 28.

4. A process according to claim 1 wherein n is 28 and the end product is 1- octacosanol of formula (I-a):

n.C₂₈H₅₇OH (I-a)

comprising the steps of

(a) reacting cyclotetradecanone of formula (H) with 4-morpholine (HI-a), thus preparing an enamine of formula (TV):

cπ) (m-a) (TV-a)

(b) reacting the enamine of formula (IV-a) with an acid chloride of formula (V-a) thus preparing 2-n.tetradecyl-cyclotetradecan-l,3-dione of formula (Vl-a):

(IV-a) (V-a) (Vl-a)

(c) reacting 2-n.tetradecyl-cyclotetradecan-l,3-dione (Vl-a) with a base and subsequently with hydrazine, thus preparing the acid of formula (VH-a):

(VT-a) (VH-a)

(d) esterifying the acid (VH-a) with an alcohol R³-OH thus preparing the ester (VHI-a):

n.C₂₇H₅₅-COOH ^ n.C₂₇H₅₅-COOR³

(VH-a) (VHI-a)

wherein R³ is d^alkyl, preferably methyl;

(e) reducing the ester (VHI-a) thus preparing octacosanol (I-a)

n.C₂₇H₅₅-COOR³ ^ n.C₂₇H₅₅-CH₂-OH

(VHI-a) (I-a)

5. A process according to any of the preceding claims wherein process step (a) is conducted in a hydrocarbon, step (b) in a ketone or a polar aprotic solvent, step (c) in a glycol or glycol ether, step (d) in a -β alkanol, step (e) in an ether or polyether.

6. A process according to claim 5, wherein process step (a) is conducted in a saturated acyclic or cyclic hydrocarbon; step (b) in acetone, methyl ethylketone or methyl isopropylketone; step (c) in glycol, diethylene glycol or triethylene glycol; step (d) in methanol and step (e) in diglyme, or dibutylether.

7. A process according to any of the preceding claims wherein: in step (a) titanium (IV) chloride is used as dehydrating agent; in step (b) triethylamine is added as a base in step (c) the base is sodium or potassium hydroxide in step (d) hydrochoric acid is added in step (e) the reducing agent is polymethyl hydroxysilane

(polymethylhydrosiloxane PMHS) in the presence of a mixture of sodium borohydride and zinc 2-methylhexanoate.

8. A process according to any of the preceeding claims comprising process steps (b), (c), (d) and (e).

9. A chemical compound of formula (VI)

wherein n is an integer in the range of 18 to 34.

10. A compound according to claim 8 wherein n is 28.