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Title:
PROCESS FOR THE MANUFACTURE OF 2,6,10-TRIMETHYLUNDEC-9-ENAL
Document Type and Number:
WIPO Patent Application WO/2018/069454
Kind Code:
A1
Abstract:
The present invention relates to an improved process for the manufacture of 2,6,10-trimethylundec-9-enal.

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Inventors:
BEUMER, Raphael (Patent Department Wurmisweg 576, 4303 Kaiseraugst, 4303, CH)
BONRATH, Werner (Patent Department Wurmisweg 576, 4303 Kaiseraugst, 4303, CH)
FISCHESSER, Jocelyn (Patent Department Wurmisweg 576, 4303 Kaiseraugst, 4303, CH)
Application Number:
EP2017/076085
Publication Date:
April 19, 2018
Filing Date:
October 12, 2017
Export Citation:
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Assignee:
DSM IP ASSETS B.V. (Het Overloon 1, 6411 TE HEERLEN, 6411, NL)
International Classes:
C07C45/54; C07C47/21
Other References:
GORA JOZEF ET AL: "Synthesis and odor characteristics of some analogs of acyclic sesquiterpenoids", PERFUMER & FLAVORIST,, vol. 5, no. 1, 1 January 1980 (1980-01-01), XP009502825, ISSN: 0361-8587
ASIAN, JOURNAL OF CHEMISTRY, vol. 26, no. 13, 2014, pages 3958 - 3962
Attorney, Agent or Firm:
STECK, Melanie (DSM Nutritional Products Ltd, Patent Department Wurmisweg 576, 4303 Kaiseraugst, 4303, CH)
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Claims:
Claims

1. A process for the manufacture of the compound of formula (I)

wherein in a first step i) a Darzens reaction is carried out with a compound formula (II)

(I")

and a compound of formula

wherein X is CI or Br,

in the presence of NaOR, wherein R is Ci-C4-alkyl, (step (ia))

followed by a saponification reaction (step (ib)) to form the compound of formula

(V)

(V)

and in a second step ii) the compound of formula (V) is undergoing a decarboxylation reaction to form the compound of formula (I).

2. Process according to claim 1 , wherein step (i) is carried out in at least one solvent.

3. Process according to claim 2, wherein the at least one solvent is at least one aliphatic hydrocarbon or at least one aromatic hydrocarbon or any mixture thereof.

4. Process according to claim 2, wherein step (i) is carried out in at least one solvent chosen from the group consisting of cyclohexane, n-hexane, n-heptane, benzene, o-xylene, m-xylene, p-xylene and toluene.

5. Process according to anyone of the preceding claims, wherein the reaction temperature of step (ia) is < -15° C, preferably in a range of from -45 °C to -15° C, more preferably in a range of from -30°C to -15°C.

6. Process according to anyone of the preceding claims, wherein step (ib) is carried out at a reaction temperature in the range of from 30° C to 60° C.

7. Process according to anyone of the preceding claims, wherein step (ii) is carried out at a reaction temperature of > 160°C.

8. Process according to anyone of the preceding claims, wherein step (ii) is carried out in the absence of a metal. 9. Process according to anyone of the preceding claims, wherein step (ii) is carried out in the absence of copper.

Description:
PROCESS FOR THE MANUFACTURE OF 2,6, 10-TRIMETHYLUNDEC-9-ENAL

The present invention relates to an improved process for the manufacture of 2,6, 10-trimethylundec-9-enal.

2,6,10-Trimethylundec-9-enal (compound of formula (I)) is a colorless to pale yellow clear liquid, which is also known as Farenal® as well as Adoxal®. The odor of Farenal® is described mainly as aldehydic-waxy slightly flowery odor.

Due to the importance of 2,6, 10-trimethylundec-9-enal the objective of the invention was to provide an improved process for the manufacture of 2,6, 10- trimethylundec-9-enal.

The synthesis of 2,6, 10-trimethylundec-9-enal is carried out according to the following reaction scheme:

(I) (V) It was found that it is very advantageous to use NaOR, wherein R is Ci-C 4 -alkyl, preferably wherein R is methyl or ethyl, as a base and methyl chloroacetate or methyl bromoacetate (compound (III) with X being CI or Br) as a-haloester at a low temperature, preferably at a temperature < -15 °C, in the first step.

Furthermore, the decarboxylation can be carried out also in a continuous manner. Additionally, the decarboxylation is carried without any metal powder.

Therefore, the present invention relates to a process (P) for the manufacture of the compound of formula (I)

(I) wherein in a first step i) a Darzens reaction is carried out with a compound formula (II)

and a compound of f

wherein X is CI or Br, preferably wherein X is CI,

in the presence of NaOR, wherein R is Ci-C 4 -alkyl, preferably wherein R is methyl or ethyl, (step (ia)) followed by

a saponification reaction (step (ib)) to form the compound of formula (V)

(V)

and wherein in a second step ii) the compound of formula (V) is undergoing a decarboxylation reaction to form the compound of formula (I ). In the following the process steps are discussed in more detail.

Step (i)

Step i) is in fact two steps (step (ia) and step (ib)) which are done in sequence without isolating the reaction product of the first reaction step, i.e. the compound of formula (IV).

Step (ia) is a glycidic ester condensation, whereby an α, β-epoxy ester (= glycidic ester) is formed. Then (= step (ib)) this glycidic ester (compound of formula (IV)) is saponified into the corresponding acid, the compound of formula (V).

It was found that it is very advantageous to use NaOR, wherein R is Ci -C 4 -alkyl, preferably wherein R is methyl or ethyl, more preferably wherein R is methyl, as a base and methyl chloroacetate or methyl bromoaceate, preferably methyl chloroacetate, as a-haloester at a low temperature, preferably at a temperature < -15 ° C, in step (ia). After the glycidic ester condensation took place, remaining base can be neutralized with an acid. Step iib) is the saponification of the glycidic ester, i.e. the α,β-epoxy ester of formula (IV), into the corresponding acid, the compound of formula (V). It is preferably carried out in the presence of a strong base. Example of such a base is NaOH. Excess of the base is neutralized after the reaction with an acid. Examples of such an acid are HCl or H2SC .

Due to these reaction conditions the conversion of the starting material is increased significantly.

It is also possible to isolate the reaction product of step (iia) if needed and desired.

The reaction of step (i) (step (ia) and step (ib)) is usually carried out in a solvent (or a mixture of solvents). Suitable solvents are aliphatic hydrocarbons or aromatic hydrocarbons or any mixture thereof. Examples of aliphatic hydrocarbons are straight and branched C 6 -io-alkanes and C 6 -io-cylcoalkanes such as cyclohexane, n-hexane and n-heptane. Examples of aromatic hydrocarbons are benzene, toluene, o-xylene, m-xylene and p-xylene. Especially suitable are cyclohexane, n-hexane, n-heptane, benzene, o-xylene, m-xylene, p-xylene or toluene. Preferred are n-hexane, n-heptane and toluene. The most preferred solvent is n-heptane.

Therefore, the present invention relates to a process (P1 ), which is process (P), wherein step (i) is carried out in at least one solvent.

Therefore, the present invention relates to a process (Ρ1 ' ), which is process (P1 ), wherein step (i) is carried out in at least one aliphatic hydrocarbon or in at least one aromatic hydrocarbon. Therefore, the present invention relates to a process (P1 "), which is process (P1 ), wherein step (i) is carried out in at least one solvent chosen from the group consisting of cyclohexane, n-hexane, n-heptane, benzene, o-xylene, m-xylene, p- xylene and toluene.

The reaction temperature of step (ia) is < -15°C, preferably in a range of from - 45°C to -15°C, more preferably in a range of from -30°C to -15°C. Therefore, the present invention relates to a process (P2), which is process (P), (P1 ), (Ρ1 ') or (P1 "), wherein step (ia) is carried out at a reaction temperature of < -15°C.

Therefore, the present invention relates to a process (Ρ2'), which is process (P), (P1 ), (P1 ') or (P1 "), wherein step (ia) is carried out at a reaction temperature in the range of from -45 °C to - 15°C.

Therefore, the present invention relates to a process (P2"), which is process (P), (P1 ), (P1 ') or (P1 "), wherein step (ia) is carried out at a reaction temperature in the range of from -30° C to -15° C.

The starting material (compound (II) and compound (III) can be added in equimolar amounts with respect to each other. Preferably compound of formula (III) is added in excess, i.e. the molar ratio of the compound of the formula (III) to the compound of formula (II) is in the range of from 1.1 :1 to 5: 1 , preferably in the range of from 1.5: 1 to 3:1.

Step (ib) is usually carried out at slightly elevated temperature; usually up to Therefore, the present invention relates to a process (P3), which is process (P), (P1 ), (PT), (P1 "), (P2), (Ρ2') or (P2"), wherein step (ib) is carried out at elevated temperature. Therefore, the present invention relates to a process (Ρ3'), which is process (P), (P1 ), (Ρ1 '), (P1 "), (P2), (Ρ2') or (P2"), wherein step (ib) is carried out at a reaction temperature in the range of from 30°C to 60°C.

The reaction product of step (i), which is the compound of formula (V) is extracted from the reaction mixture by an aliphatic or aromatic hydrocarbon (with the preferences as given above) and it can be washed with an aqueous phase.

Usually the reaction product is not isolated completely but left solved in the solvent (the aliphatic hydrocarbon or the aromatic hydrocarbon).

Step (ii) The reaction product of step (i), which is the compound of formula (V) in at least one aliphatic or aromatic hydrocarbon, is heated up (preferably to a temperature > 160°C; more preferably to a temperature in the range of from 160 to 300° C) in step (ii), which is a decarboxylation step. After the decarboxylation, the side products are removed by distillation, preferably at reduced pressure, i.e. a pressure in the range of from 10 to 300 mbar.

These reaction conditions are very mild and no need of any metal powder is needed. In the prior art copper powder is essential for this step (see Asian Journal of Chemistry 2014, 26(13), 3958-3962). Because the process of the present invention does not need any heavy metals such as copper, it is an ecological process. The invention is illustrated by the following Example. All percentages are related to the weight and the temperature is given in °C.

Example

Step (i)

In a 1000-ml glass reactor 100 g (347.9 mmol) of citronellyl acetone, 255 ml of n- heptane and 69.91 ml (789.5 mmol) of methyl chloroacetate (2) are charged. The mixture is cooled to -20°C (internal temperature) under stirring. 44.89 g (789.5 mmol) of sodium methoxide is added in a powder dropping funnel. The base is added to the reaction mixture within 2 hours.

Afterwards the reaction mixture is held at -20°C for 2 hours, then at 0°C for 10 hours. After heating to ambient temperature (ca. 20°C), 250 ml of n-heptane are added and the reaction mixture is stirred for 1 hour at 20 °C.

Afterwards 137.9 ml of sodium hydroxide (4 M; 551.7 mmol) are added and the reaction mixture is stirred at 45 °C for 8 hours.

Afterwards sulfuric acid (2 M) is added until the pH of the aqueous layer reached pH = 2. The reaction mixture is stirred for 30 minutes at 20° C. The n-heptane layer is separated and dried over 20 g of anhydrous sodium sulfate.

The solvent is evaporated under reduced pressure (20 mbar, 50°C). A yellowish slightly viscous liquid (163.0 g) is obtained.

Step (ii)

In a 500-ml glass bottle 100 g of the obtained glycidic acid (compound of formula (V)) is dissolved in 150 g of n-heptane. This solution is fed through a tube reactor heated at 280 °C. The solvent is evaporated under reduced pressure (20 mbar, 50° C).

The overall yield of the compound of formula (I) is 51.1 % yield.