Login| Sign Up| Help| Contact|

Patent Searching and Data


Title:
PROCESS FOR THE MANUFACTURE OF 2,6,10-TRIMETHYLUNDECA-5,9-DIENAL
Document Type and Number:
WIPO Patent Application WO/2018/069457
Kind Code:
A1
Abstract:
The present invention relates to an improved process for the manufacture of 2,6,10-trimethylundeca-5,9-dienal (Darzens reaction, saponification, decarboxylation).

Inventors:
BEUMER, Raphael (Patent Department Wurmisweg 576, 4303 Kaiseraugst, 4303, CH)
BONRATH, Werner (Patent Department Wurmisweg 576, 4303 Kaiseraugst, 4303, CH)
EGGERTSWYLER, Christophe (Patent Department Wurmisweg 576, 4303 Kaiseraugst, 4303, CH)
FISCHESSER, Jocelyn (Patent Department Wurmisweg 576, 4303 Kaiseraugst, 4303, CH)
Application Number:
EP2017/076088
Publication Date:
April 19, 2018
Filing Date:
October 12, 2017
Export Citation:
Click for automatic bibliography generation   Help
Assignee:
DSM IP ASSETS B.V. (Het Overloon 1, 6411 TE HEERLEN, 6411, NL)
International Classes:
C07C45/58; C07C47/21; C07D303/48
Foreign References:
US3939202A1976-02-17
Other References:
None
Attorney, Agent or Firm:
STECK, Melanie (DSM Nutritional Products Ltd, Patent DepartmentWurmisweg 576, 4303 Kaiseraugst, 4303, CH)
Download PDF:
Claims:
Claims

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

(I) comprising the following steps:

i) a Darzens reaction of a compound of formula (II) and a compound of formula (III),

(I")

wherein X is CI or Br,

in the presence of NaOR, wherein R is Ci-C4-alkyl, followed by ii) a saponification reaction to form the compound of formula (V)

(V) and iii) a decarboxylation reaction of the compound of formula (V) to form the compound of formula (I).

2. The process according to claim 1 , wherein steps i) and ii) are carried out in at least one solvent.

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

4. The process according to claim 2, wherein the at least one solvent is chosen from the group consisting of benzene, toluene, o-xylene, m-xylene, p-xylene, cyclohexane, n-hexane and n-heptane. 5. The process according to anyone of the preceding claims, wherein the reaction temperature of step i) is < -15°C, preferably in the range of from -45°C to -15°C, more preferably in the range of from -30°C to -15°C.

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

7. The process according to anyone of the preceding claims, wherein step iii) is carried out at a reaction temperature of > 160°C. 8. The process according to anyone of the preceding claims, wherein the decarboxylation (step iii) is carried out in the absence of a metal catalyst.

9. The process according to claim 8, wherein the metal catalyst is a copper catalyst.

Description:
PROCESS FOR THE MANUFACTURE OF 2,6, 10-TRIMETHYLUNDECA-5,9-DIENAL

The present invention relates to an improved process for the manufacture of 2,6, 10-trimethylundeca-5,9-dienal.

2,6,10-Trimethylundeca-5,9-dienal (compound of formula (I))

is a colorless to pale yellow clear liquid, which is also known as Profarnesal® as well as Oncidal®. Profarnesal® cannot be found in nature and therefore needs to be synthesized.

The odor of Profarnesal® is described mainly as aldehydic-floral odor reminiscent of nerolidol.

Due to the importance of 2,6,10-trimethylundeca-5,9-dienal the objective of the invention was to provide an improved process for the manufacture of 2,6, 10- trimethylundeca-5,9-dienal.

It was found that it is very advantageous to use NaOR in step i), wherein R is Ci- C 4 -alkyl (preferably 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.

Furthermore, the decarboxylation (step iii)) can be carried out also in a continuous manner; additionally, the decarboxylation is carried out without any metal powder. Therefore, the present invention relates to a process (P) for the manufacture of the compound of formula (I ) comprising the following steps

i) a Darzens reaction of a compound of formula (II ) and a compound of formula

(I")

wherein X is CI or Br, preferably CI,

in the presence of NaOR with R being Ci-C 4 -alkyl,

followed by

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

iii) a decarboxylation reaction of the compound of formula (V) to form the compound of formula (I ), whereby preferably no metal catalyst such as a copper catalyst is used.

In the following the process steps are discussed in more detail.

Step (i)

This step is a glycidic ester condensation, whereby an α, β-epoxy ester (=glycidic ester) is formed.

It was found that it is very advantageous to use NaOR, wherein R is Ci -C 4 -alkyl (preferably methyl or ethyl, more preferably 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.

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

It is also possible to isolate the reaction product, i.e. the compound of formula (IV), if needed and desired.

After the glycidic ester condensation took place, remaining base can be neutralized with an acid.

Step ii) This step is the saponification of the glycidic ester (the α,β-epoxy ester of formula (IV)) into the corresponding acid (compound of formula (V)). It is preferably carried out in the presence of a base. Example of such a base is NaOH. Excess of the base is neutralized after the reaction with an acid. Examples of such a base

In a preferred embodiment of the present invention step i) and step ii) are done in sequence without isolating the reaction product of the first reaction step, i.e. without isolating the compound of formula (IV).

The steps i) and ii) are usually carried out in a solvent (preferred) or a mixture of solvents (less preferred). 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 n-hexane, n-heptane, benzene, o-xylene, m-xylene, p-xylene and toluene. Preferred are n-hexane, n- heptane and toluene. Most preferred are n-heptane and toluene. Therefore, the present invention relates to a process (P1 ), which is process (P), wherein steps i) and ii) are carried out in at least one solvent.

Furthermore, the present invention relates to a process (Ρ1 ' ), which is process (P1 ), wherein steps i) and ii) are 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 steps i) and ii) are carried out in at least one solvent chosen from the consisting of n-hexane, n-heptane, benzene, o-xylene, m-xylene, p-xylene and toluene. The reaction temperature of step i) is preferably < -15°C. More preferably the reaction temperature is in a range of from -45 °C to -15°C, most preferably the reaction temperature is in a range of from -30°C to -15°C. Thus, the present invention relates to a process (P2), which is either process (P) or (P1 ) or(P1 ') or (P1 "), wherein step i) is carried out at a reaction temperature < -15°C.

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

Thus, the present invention relates to a process (P2"), which is either process (P) or (P1 ) or (P1 ') or (P1 "), wherein step i) 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 the 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 2: 1.

Step ii) is usually carried out at slightly elevated temperature, usually up to 60°C.

Therefore, the present invention relates to a process (P3), which is either process (P) or (P1 ) or (PT) or (P1 ") or (P2) or (Ρ2') or (P2"), wherein step ii) is carried out at elevated temperature.

Therefore, the present invention relates to a process (Ρ3'), which is either process (P) or (P1 ) or (PT) or (P1 ") or (P2) or (Ρ2') or (P2"), wherein step ii) is carried out at a reaction temperature in the range of from 30°C to 60°C. The reaction product of step ii), which is the compound of formula (V) is extracted from the reaction mixture with an aliphatic hydrocarbon or with an aromatic hydrocarbon (such as the ones 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 iii)

The reaction product of step ii), which is the compound of formula (V) in at least one organic solvent as given above, is decarboxylated in step iii) to the compound of formula (I).

This is done by heating up the reaction mixture to a temperature of at least 160°C (preferably to a temperature in the range of from 160-300° C) and removing the side-products by distillation. These reaction conditions are very mild and no metal powder is needed. In the prior art copper powder is essential for this step. Because the process of the present invention does not need any heavy metals such as copper, waste is avoided. Thus, it is an ecological process. The invention is now illustrated by the following example. All percentages given are related to the weight. Example

Steps i) and ii) In a 250-ml glass reactor 19.5 g (100 mmol) of geranyl acetone, 50 ml of toluene, 12.4 ml (140 mmol) of methyl chloroacetate are charged. The mixture is stirred and cooled to -20°C (internal temperature). 7.85 g (140 mmol) of sodium methoxide are added in a powder dropping funnel. The base is added to the reaction mixture within 2 hours. The mixture is held at -20° C for 1 hour. After heating to ambient temperature (ca. 20°C), 20 ml of 5 % w/w sulfuric acid are added drop-wise to the reaction mixture.

Afterwards 37.6 ml (150 mmol) of sodium hydroxide (4 M) are added. The mixture is stirred at ambient temperature (22 °C) for 2 hours. A slightly viscous liquid is obtained.

Step iii)

To the slightly viscous liquid of step ii) 120 g of n-heptane are added and this solution is fed through the tube reactor heated at 240° C.

The crude product is distilled over a short distillation column (Vigreux 10 cm, bath temperature = 147°C, head temperature = 90°C - 96°C, pressure = 0.3 mbar) to give Profarnesal® in an overall yield of 55.8%.