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• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
  • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
  • C07C49/607—Unsaturated compounds containing a keto groups being part of a ring of a seven-to twelve-membered ring
• • 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
  • C07C29/36—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal
  • C07C29/38—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones
  • C07C29/40—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones with compounds containing carbon-to-metal bonds
• • 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
  • C07C29/36—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal
  • C07C29/38—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones
  • C07C29/42—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones with compounds containing triple carbon-to-carbon bonds, e.g. with metal-alkynes
• • 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
  • C07C45/51—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition
  • C07C45/511—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups
• • 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
  • C07C45/51—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition
  • C07C45/511—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups
  • C07C45/512—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups the singly bound functional group being a free hydroxyl group
• • 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
• • 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
  • C07C49/413—Saturated compounds containing a keto group being part of a ring of a seven- to twelve-membered ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
  • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/09—Geometrical isomers
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
  • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/18—Systems containing only non-condensed rings with a ring being at least seven-membered
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/18—Systems containing only non-condensed rings with a ring being at least seven-membered
  • C07C2601/20—Systems containing only non-condensed rings with a ring being at least seven-membered the ring being twelve-membered

Definitions

• the present invention relates to a new thermal isomerization process for the rapid and simple production of macrocyclic ketones.
• Macrocyclic ketones are of great importance in perfumery due to their musky odor properties. So far, cyclopentadecanone (exalton "), 3-methylcyclopentadecanone (muscon), cycloheptadec-9-en-l-one (cibeton) and ⁇ E / Z) -cyclohexadec-5-en-l-one ( Ambretones *, Musk TM II * ) As is known from the specialist literature, such macrocyclic ketones can be prepared by multi-stage syntheses which are essentially based on two basic methods:
• Macrocyclization reactions such as the so-called acyloin condensation of ⁇ , ⁇ -diesters with subsequent reduction or intramolecular olefin metathesis (ring closure metathesis, RCM) etc.
• RCM ring closure metathesis
• Ring expansion reactions which are either based on a multistage sequence of annealing and fragmentation reactions, or on sigmatropic [3.3] rearrangement reactions (eg oxy-Cope reaction of 1 / 2-divinylcycloalkan-1-ols) or also [1.3] - Shift reactions in l-vinylcycloalk-3-en-l-ols are based (W. Thi es, P. Daruwala, J. Org. Chem. 1987, 52, 3798 - 3806).
• Vinylcyclopropanols already irreversibly rearrange into 2-substituted cyclobutanones when heated to only 100 ° C under a [1.2] migration. However, will instead of the vinylcyclopropanols whose trimethylsilyl ether derivatives (1-trimethylsilyloxy-l-vinylcyclopropane) are heated, these can in turn be converted into cyclopentanones with a [1.3] migration (J. Am. Chem. Soc. 1973, 95, 5311-5321; and J. Org. Chem. 1981, 46, 506-509).
• the object of the present invention is a simple and inexpensive process for the preparation of macrocyclic ketones.
• R 1 , R 2 , R 3 independently of one another are hydrogen or a Cj . to C 6 alkyl group
• R 4 represents hydrogen, a linear or branched C 1 -C 4 -alkyl group, where n is an integer, and
• n 7 to 14
• R 1 and R 2 or R 2 and R 3 can form a ring independently of one another.
• ketones of the formula la or Ib which have been expanded by two carbon atoms are converted by converting a macrocyclic tertiary allyl or propargyl alcohol of the formula Ila or Ilb
• R 1 , R 2 , R 3 , R 4 and n have the same meaning as above and R s is either hydrogen or trialkylsilyl or an alkali metal cation,
• n 1, 8-membered cyclic alcohols become 10-membered cyclic ketones.
• r 14, 17-membered cyclic ketones can accordingly be obtained from 15-membered cyclic alcohols.
• C x -C ⁇ -alkyl is, for example, methyl, ethyl, propyl, isopropyl, butyl, sec- or tert-butyl, pentyl or hexyl, with methyl being particularly preferred.
• the process described enables, depending on the nature of the substituents on the vinyl group of the tertiary cyclic alcohol of the formula Ila used as the starting material, if the substituents differ from hydrogen, the production of ring-expanded and additionally regioselectively substituted macrocyclic ketones at the same time.
• the positions of these substituents in the macrocyclic ketones are, as shown in formula la, on the two successive carbon atoms adjacent to the carbon atom of the carbonyl group (viewed as C (D)) and are distributed as follows: R 1 is located on
• R 4 is an additional substituent on the ring system of the cyclic alcohol, so that R 4 differs from hydrogen, regioisomeric ring-extended macroeyclic ketones can also be obtained, depending on which half of the cyclic system the two carbon atoms of the original vinyl group of the starting material according to that previously described Way to be incorporated. This also applies mutatis mutandis when R 'represents several substituents.
• the described thermal isomerization process can be used to produce macroeyclic ketones from tertiary cyclic allyl or propargyl alcohols, which in turn can be efficiently and easily converted again into cyclic tertiary allyl or propargyl alcohols by the known methods, which in turn can then be used can again be used as a starting material in the thermal isomerization process described, the described process additionally offers, by repetitive use, the possibility of iterating to produce the macrocyclic ketones ringed by four, six, eight, etc. carbon atoms, only two synthesis steps per repetitive cycle required are.
• the described method can also be applied in the same way to the analog etherified derivatives of the underlying macrocyclic tertiary alcohols, for example to trialkylsilyl ether, in particular to trimethylsilyl ether (if R 5 in formula Ila or Ilb represents a trimethylsilyl group), but then initially in an analogous manner in each case mixtures of the corresponding ring-expanded cyclic trimethylsilylenol ethers are obtained.
• the hydrolysis of these trimethylsilylenol ether mixtures then also leads again to the same ketones which can be obtained from the corresponding underlying alcohols in a direct manner, that is to say without prior derivatization by a suitable silyl group and without the hydrolysis stage additionally required.
• the process according to the invention can be carried out without the use of solvents and thus with due regard for environmental protection, provided that the starting material is evaporated directly into the gas phase and transferred to the reactor unit.
• An appropriate design of the apparatus also allows the described thermal isomerization process to be carried out continuously and thus potentially also enables process automation.
• the process according to the invention for the production of macrocyclic ketones is based on the thermal isomerization of tertiary macrocyclic allyl alcohols or propargyl alcohols in the gas phase at temperatures from 500 to 700 ° C.
• the alcohol used as the starting material is either introduced into an evaporation unit or else is added continuously, either undiluted or else dissolved in a suitable inert solvent (such as xylene), using a metering device, such as a metering or syringe pump, from a storage vessel and heated under reduced pressure depending on the boiling point of the starting material used to temperatures in the range of approximately 100-300 ° C., preferably in the range of 120-250 ° C., and thereby converted into the gas phase.
• the alcohol preheated in the evaporation unit is now in the gas phase, optionally also using a controllable inert gas stream, the inert gas being, for example, nitrogen, argon or helium, and at reduced
• the reactor unit expediently has a generally tubular shape, advantageously consists of a thermostable inert material which does not interfere with the course of the isomerization reaction, such as, for example, certain high-melting glass types, and can be arranged horizontally or vertically or at any angle, and independently of the evaporation unit generally known manner, for example, to be heated with an electric heating jacket.
• the temperature range required for the thermal isomerization process described depends simultaneously on several factors, such as, for example, the prevailing pressure in the reactor, the shape and dimensions of the reactor vessel, the size of the inert gas stream (flow) and the rate of addition or evaporation rate of the starting material or from its solutions and from the solvent and is preferably in the range from 500 to 700 ° C.
• the thermal isomerization process becomes so slow that mainly unchanged starting material and possibly dehydration products are found, while at temperatures above 700 ° C decomposition products and disturbing side reactions are increasingly observed.
• the preferred temperature range for the most complete possible conversion of the starting materials used in the thermal isomerization process described is, depending on the individual reactor parameters mentioned, frequently above 550 ° C., particularly optimally in the range from 570-670 ° C., especially if without solvent with a weak one Inert gas stream or in a high vacuum without an inert gas stream and without a packing.
• the thermal isomerization process described is preferably carried out under reduced pressure, particularly advantageously under a vacuum in the range from about 1 to 10 mbar (1-10 hPa), in any case expediently below the saturation vapor pressure of the alcohol used as starting material, but can also be carried out in the inert gas stream observe the desired product formation even under less strongly reduced pressure, such as on a water jet vacuum or with laboratory membrane vacuum pumps.
• the pressure in the apparatus and thus at the same time the contact time in the reactor unit can additionally be influenced by the regulation of the inert gas flow or, in the case of injection of liquid starting materials, by the rate of addition or, in the case of initially solid starting materials, by the evaporation rate become .
• the gaseous reaction products obtained by the thermal isomerization process are cooled to room temperature or below using a suitable medium by known methods and liquefied again (or in some cases resublimated) and finally collected in a collecting container.
• the reduced pressure in the apparatus is generated by a vacuum pump unit with a suitable suction capacity, with particular advantage by means of a high vacuum pump, it being possible for further cooling traps with a suitable cooling medium to be connected between the vacuum pump and the apparatus for collecting volatile by-product components.
• the tertiary macrocyclic allyl alcohols required as starting materials for the thermal isomerization process of the formula Ila can easily be prepared by known methods, for example preferably by adding suitable organometallic alkenyl compounds such as magnesium or lithium 1-alkenylene to the corresponding macrocyclic ketones.
• suitable organometallic alkenyl compounds such as magnesium or lithium 1-alkenylene
• the temperature is then kept under stirring for a further 10 to 120 minutes at 35 to 40 ° C., and after checking the course of the reaction, for example by gas chromatography of the reaction mixture, if appropriate again 0.1 to 0.2 mol equivalents of the alkenyl or alkynyl compound are added until the ketone used is as complete as possible.
• the tertiary macroeyclic allyl or propargyl alcohol obtained after hydrolysis of the reaction mixture is either purified by distillation under high vacuum or by recrystallization or chromatography, or is used directly as a raw product for the subsequent thermal iso erization as starting material.
• reaction mixture is allowed to cool to room temperature and poured onto 1 l of ice water, covered with an extractant (toluene or TBME) and slowly mixed with an approx. 5 - 10% aqueous hydrochloric acid solution until the mucilaginous or gel-like consistency of the Mixture has disappeared (approx. PH 3 or below) and a clear phase boundary can finally be seen when a yellow to brownish color occurs.
• extractant toluene or TBME
• aqueous hydrochloric acid solution an approx. 5 - 10% aqueous hydrochloric acid solution until the mucilaginous or gel-like consistency of the Mixture has disappeared (approx. PH 3 or below) and a clear phase boundary can finally be seen when a yellow to brownish color occurs.
• the aqueous phase is removed and the organic phase is first washed several times with water, then with sodium hydrogen carbonate solution or also approx.
• EI-MS (GC / MS) from A: 266 (2, ⁇ f.), 248 (28, M - H 2 0), 233 (7), 219 (11), 121 (40), 107 (55), 94 (58), 67 (83), 55 (100); from B: 266 (4, Af.), 248 (100, M - H 2 0), 233 (12), 219 (16), 121 (30), 107 (42), 67 (55), 55 (100).
• EI-MS 208 (1, M + .), 190 (15), 175 (4), 161 (10), 147 (20), 133 (25), 119 (30), 105 (50), 93 ( 60), 91 (100), 79 (75), 67 (35), 55 (32).
• the tertiary cyclic alcohol was placed in a spherical tube flask (50 or 100 ml, with two grinding necks opposite) together with a small magnetic stirrer. After attaching an inert gas feed line (stainless steel capillary melted into a standard ground section) to the rear of the neck, the flask was ground to the slightly inclined reactor vessel (quartz glass reactor, inner diameter 25 or 40 mm, length 40 cm, heated with a Thermolyne tube Furnace, 35 cm) connected. At the opposite end of the reactor vessel there is a cold trap (cooling medium liquid nitrogen or dry ice / acetone), which is connected to a high-vacuum pump unit.
• a spherical tube flask 50 or 100 ml, with two grinding necks opposite
• an inert gas feed line stainless steel capillary melted into a standard ground section
• the flask was ground to the slightly inclined reactor vessel (quartz glass reactor, inner diameter 25 or 40 mm
• the second component (29%) was identified as 2-methyl-2-pentadecen-4-one.
• the isolated crystalline fraction shows two signals in the GC in a ratio of approx. 9: 1 (trans / cis isomers).
• ⁇ -NMR 75 MHz, CDC1 3 ): 201.8 (s), 158.4 (s), 125.0 (d), 41.8 (t), 31.6, 29.3, 27.0, 26.9, 26.8, 26.7, 26.5, 26.3, 26.1, 25.3 , (10 t) 25.1 (g). 23.8 (t).

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