EP1358170A1 - Process for preparing higher primary alkanols - Google Patents
Process for preparing higher primary alkanolsInfo
- Publication number
- EP1358170A1 EP1358170A1 EP02718061A EP02718061A EP1358170A1 EP 1358170 A1 EP1358170 A1 EP 1358170A1 EP 02718061 A EP02718061 A EP 02718061A EP 02718061 A EP02718061 A EP 02718061A EP 1358170 A1 EP1358170 A1 EP 1358170A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- formula
- preparing
- acid
- vhi
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
- C07D295/033—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
- C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
- C07C29/147—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of carboxylic acids or derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/56—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/385—Saturated compounds containing a keto group being part of a ring
Definitions
- the present invention concerns a process for preparing higher primary alkanols and in particular for preparing 1-octacosanol.
- 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 «.C 28 H5 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.
- solvents examples include: 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.
- This invention relates to a process of preparing a compound of formula (I): n.C n H 2n+1 OH (I)
- n is an integer in the range from about 18 to about 34; comprising the steps of
- R 1 and R 2 independently are C ⁇ .. 6 alkyl, or R 1 and R 2 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):
- 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):
- R 3 is C ⁇ alkyl, preferably methyl
- the invention concerns a process for preparing an alcohol (I) comprising reaction steps (b), (c), (d) and (e) as outlined herein.
- this invention relates to a process of preparing 1- octacosanol of formula (I-a):
- R is Ci- ⁇ alkyl, preferably methyl
- the present invention concerns novel intermediates used in these processes.
- n can be as defined above but in particular is in the range of 24 to
- 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.
- Y is a halogen atom, most preferably chloro or bromo.
- 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- ⁇ alkanoyl encompasses alkylcarbonyl radicals having 1 to 6 carbon atoms such as formyl (HCO-), acetyl, ethanoyl, propanoyl and the like
- 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.
- a suitable deshydrating agent which preferably is titanium(IN)chloride.
- the amine H ⁇ R 2 R 3 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.
- 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.
- 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.
- cyclododecanone (II) and a secondary amine (IJJ), which preferably is morpholine are reacted in the presence of TiCl 4 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).
- 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.
- the latter is isolated from the reaction mixture and can be used in the further reaction steps with or without purification.
- cyclododecanone (U.) and morpholine (HI) are dissolved in an aromatic hydrocarbon, preferably toluene.
- TiCl 4 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.
- 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).
- a small excess of TiCl (1.05 mol-eq.) can also be used. In the latter instance, the excess of
- TiCl 4 reacts after filtration with air-humidity and the thus-formed TiO 2 precipitates and can be removed by filtration.
- the reaction can also be conducted without TiCl 4 by physically removing the water, e.g. by using a Dean-Stark separator.
- (II) is reacted with H ⁇ R 2 R 3 (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.
- 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.
- an acidic catalyst such as a Lewis acid, e.g. a boron trifluoride such as BF 3 .Et 2 O, or a sufficiently strong organic acid, in particular a sulfonic acid, e.g. tosyl sulfonic acid and the like.
- 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.
- morpholine (TH-a) is replaced by other secondary amines like dibutylamine or a cyclic amine such as 1- methylpiperazine, piperidine, and pyrrolidine.
- N-morpholino-1-cyclododecene (IN-a) is commercially available, but can also be prepared according to the procedure of step (a).
- N-sec.amino-1-cyclododecene (IN) is reacted with an activated acid of formula (N).
- 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.
- 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.
- 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
- a suitable base can be added, preferably an inorganic base such as an alkali metal hydroxide or an alkali metal alkoxide.
- suitable bases are sodium hydroxide, sodium methoxide, sodium ethoxide and the like.
- 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.
- 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.
- the mixture is allowed to stir for a time period of at least one hour. Then an aqueous ⁇ aOH-solution is added.
- the mixture 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 ⁇ aOH-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.
- 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 ⁇ aOH 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.
- the main intermediate in the mixture is the bicyclic compound (IV-b), which is stable at 0°C.
- 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 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.
- 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).
- VTfl-a 1-methyloctacosanoate
- VH-a 1-octacosanoic acid
- VHI methyloctacosanoate
- 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.
- 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.
- 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.
- step (c) is conducted with excess quantities of KOH, EtOH, and
- N H .H 2 O 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.
- the reaction mixture is heated for another few hours, e.g. for 2 hours.
- 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.
- reaction step (d) the starting acid (VH) is reacted in the alcohol of which the ester (VHI) is derived.
- the alcohol of which the ester (VHI) is derived Typically a C ⁇ .. 6 alkanol is used, preferably methanol, thus yielding the corresponding C ⁇ _ 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.
- a strong acid preferably a hydrohalic acid such as 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.
- the reaction-mixture is slowly cooled to room-temperature whereupon the product precipitates and subsequently is filtered off.
- 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.
- 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.
- reaction-mixture of the Wolff-Kishner-reduction is directly alcoholized with MeOH (or another C 2 - 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.
- the ester (VTA) is reduced to the corresponding alcohol (I) by a suitable reduction agent.
- a suitable reduction agent may be a metal hydride or a complex metal hydride such as lithium aluminium hydride or derivatives thereof.
- silane agents such as trialkylsilanes, dialkylsilanes, trialkoxysilanes and preferably poly methylhydrogensiloxane ('PMHS') in the presence of a suitable catalyst.
- a suitable catalyst 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.
- 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.
- suitable solvents comprise diethyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, diglyme.
- ERS A is a solution of NaBBU in tetraglyme
- ERS B is a solution of Zn(carboxylate) 2 *H 2 O, in particular of Zn(2-ethylhexanoate) *H 2 O, 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.
- 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.
- 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 ⁇ aOH solution.
- 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.
- 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.
- immediatly ERS C is added within one hour.
- 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.
- 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 excess of ERS C can be destroyed with a suitable ester, in particular with ethyl acetate.
- a suitable ester in particular with ethyl acetate.
- 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.
- 'industrial ethanol' refers to ethanol containing 5% water and 5% isopropanol.
- 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.
- the reaction mixture is quenched by addition of ⁇ aOH-solution (10%, 1.3 mol-eq) at 1 - 6 °C.
- HCl (16%, 3.25 mol-eq) is added at 45 - 50 °C.
- 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.
- 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).
- 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 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.
- VenPureTMERS-A (9.2 g) and VenPureTMERS-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.
- VenPureTMERS-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%)
- reaction mixture is refluxed for approx. 2 h (80-95° C).
- the reaction mixture is cloudy because of zinc-metal.
- the refluxing should be continued until the di-n-butylether phase is clear.
- 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).
- 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.
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EP02718061A EP1358170A1 (en) | 2001-01-26 | 2002-01-25 | Process for preparing higher primary alkanols |
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PCT/EP2002/000953 WO2002059101A1 (en) | 2001-01-26 | 2002-01-25 | Process for preparing higher primary alkanols |
EP02718061A EP1358170A1 (en) | 2001-01-26 | 2002-01-25 | Process for preparing higher primary alkanols |
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US4367346A (en) * | 1981-04-23 | 1983-01-04 | The Goodyear Tire & Rubber Company | Method for synthesis of long-chain alcohols |
SU1366504A1 (en) * | 1986-02-11 | 1988-01-15 | Институт элементоорганических соединений им.А.Н.Несмеянова | Method of obtaining higher c26,c28 or c30 1-alkanol |
-
2002
- 2002-01-25 EP EP02718061A patent/EP1358170A1/en not_active Withdrawn
- 2002-01-25 WO PCT/EP2002/000953 patent/WO2002059101A1/en not_active Application Discontinuation
- 2002-01-25 CA CA002461450A patent/CA2461450A1/en not_active Abandoned
Non-Patent Citations (1)
Title |
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See references of WO02059101A1 * |
Also Published As
Publication number | Publication date |
---|---|
WO2002059101A1 (en) | 2002-08-01 |
CA2461450A1 (en) | 2002-08-01 |
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