CYCLOHEXEN-1 -YL)-NONA-2Z,7E-DIEN-4-YNE-1 ,6-DIOL

The present invention relates to an improved method for producing 3,7-dimethyl- 9-(2,6,6-trimethyl-1 -cyclohexen-1 -yl)-nona-2Z,7E-dien-4-yne-1 ,6-diol.

3,7-Dimethyl-9-(2,6,6-trimethyl-1 -cyclohexen-1 -yl)-nona-2Z,7E-dien-4-yne-1 ,6- diol, which trivial name is oxenine, has the following formula (I)

is an intermediate in a process to produce vitamin A (and its derivatives as i.e. vitamin A acetate).

Oxenine as an intermediate in the production of vitamin A is known for a long time. It is known i.e. from Isler et al., Helv. Chim. Acta 30, 191 1 (1947); from US 2451739 or from US 3046310.

Vitamin A

(fl//-£)-retinol (vitamin A) is an important ingredient for many applications. Vitamin A (and its derivatives) plays a role in a variety of functions throughout the (human and animal) body, such as e.g. vision process, gene transcription, immune function, bone metabolism, haematopoiesis, skin and cellular health and antioxidant function.

An important derivative of vitamin A is the vitamin A acetate, which is the compound of the following formula (ΙΓ):

Due to the importance of vitamin A (and its derivatives) and the complexity of the synthesis thereof, there is always a need for improved processes of its production.

Vitamin A (retinol or its derivatives) can be produced (when starting from oxenine, which is the compound of formula (I)) according to the following reaction schemes, which are known i.e. from US2451739: 

Oxenine is usually obtained by the condensation reaction of the following compound of formula (III) and (IV)

This condensation reaction is usually carried out as a Grignard reaction, wherein a compound of formula (III)

is reacted with the Grignard compound of formula (IV)

In the prior art, a yield of oxenine of about 50 % is achieved.

Surprisingly, a new process was found wherein the yield of oxenine is improved significantly.

The new process for the production of oxenine is characterized in that in step (a) the compound of formula (IV), which is (Z)-l -pentol (or (Z)-3-methylpent-2-en-4- yn-1 -ol):

is reacted with a compound of formula (X) wherein

Ri is a Ci-C alkyl group and

R ₂ is a C3-C-6 alkylene group, or

Ri and R2 form together a C5-C7 aliphatic ring, comprising at least one C=C bond, and

afterwards in step (b) the reaction product of step (a) is reacted with a compound of formula (XI)

wherein

X is CI, Br, or I (preferably Br), and

finally, in step (c), the reaction product of step (b) is reacted with a compound of formula (III)

to obtain oxenine (compound of formula (I))

An essential feature of this process is that in step (b) and in step (c) the reactions are carried out in 2-methyltetrahydrofuran (also known as 2-methyloxolane) as a solvent.

2-Methyltetrahydrofuran is the compound of formula (XII)

The fact that we found that for step (b) and (c) the same solvent (2- methyltetrahydrofuran) can be used it a surprising and huge advantage. In contrast to the prior art the new process is less work intensive and less material is consumed.

Furthermore, no alkali metals are needed for the process according to the present invention.

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

wherein a first step (a)

a compound of formula (IV

is reacted with a compound of formula (X)

wherein

Ri is a Ci-C alkyl group and

R2 is a C3-C-6 alkylene group, or

Ri and R ₂ form together a C5-C7 aliphatic ring, comprising at least one C=C bond, and

the reaction product of step (a) is reacted

in a second step (b) with a compound of formula (XI)

wherein

X is CI, Br, or I (preferably Br), and

in step (c) the reaction product of step (b) reacted with a compound of formula (III)

to form the compound of formula (I), and

wherein

the reactions of step (b) and of step (c) are carried out in 2-methyltetrahydrofuran as solvent.

Furthermore, the present invention relates to a process (Ρ'), which is process (P), wherein no alkali metal is used in any process steps of the process according to the invention.

In the following the 3 steps (a), (b) and (c) are discussed in more details.

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Step (a)

In a first step (step (a)) the compound of formula (IV),

which is (Z)-l -pentol,

is reacted with the compound of formula (X)

wherein

Ri is a Ci-C alkyl group and

R ₂ is a C3-C-6 alkylene group, or

Ri and R ₂ form together a C5-C7 aliphatic ring, comprising at least one C=C bond.

A preferred embodiment of the present invention is a process, wherein Ri is -CH ₃ or -CH ₂ CH ₃ and R ₂ is C ₃ -C ₅ alkylene group.

Another preferred embodiment of the present invention is a process, wherein Ri and R ₂ together form a C-6 aliphatic ring comprising at least one C=C bond.

A more preferred embodiment of the present invention is a process, wherein the compound of formula (X) is a compound of formula (Χ'), (X") or (X'")

or

The two starting materials can be added in equimolar ratios.

Usually the compound of formula (X) is added in excess.

Usually the molar ratio of compound (IV) to compound (X) is 1 : 1 up to 1 :4.

The reaction of step (a) is usually (and preferably) catalyzed by at least one acid. The acid can be any commonly used acid.

Very preferred acids are i.e. sulfuric acid, p-toluene sulfonic acid hydrate (pTsOH) or benzoic acid.

The acid is used in a catalytic amount. Usually in an amount which is about 0.001 - 0.0000 1 mol equivalent (in regard to compound of formula (IV)).

Instead of using at least one acid, it is also possible to use an ion exchanger to catalyse the reaction. Strongly acidic cation exchange resins are usually used. Such acidic cation exchangers are available commercially.

Suitable ion exchangers are i.e. Amberlyst 15 ^® , Amberlyst 36 ^® , Amberlyst 70 ^® and Dowex 50 WX12 ^® .

A base is added at the end of the reaction to stop. Any commonly known base (or a mixture of bases) can be used.

The reaction of step (a) is exothermic. Therefore, the reaction mixture is usually cooled. This is done by any usually used external cooling systems.

The reaction of step (a) can be carried out without any solvent. Alternatively, the reaction of step (a) can be carried out with at least one solvent. Suitable solvents are polar aprotic solvents such as ethers.

Step (b)

In a second step (step (b)) the reaction product of step (a) is reacted with a compound of formula compound of formula (XI)

wherein X is CI, Br, or I (preferably Br).

The compound of formula (XI) is a classical Grignard compound. This compound is usually produced in situ by the addition of magnesium and bromoethane. This is the common way of preparing this compound. The reaction condition for preparing the compound of formula (XI) are the commonly used ones.

The reaction product of step (a) is added slowly to the reaction solution in which the compound of formula (XI) was produced.

2-Methyltetrahydrofuran is used in step (b) as a solvent.

The reaction of step (b) is usually carried out at elevated temperature. Usually at a temperature which is between 30 - 50°C.

The following compounds are the reaction products for the process when the compounds of formula (Χ'), (X") or (X'") have been used. Dimer compounds are formed when compounds of formula (Χ') or (X") are used:

ĨXVII) Step (c)

In a third step (step (c)) the compound of formula (III),

is added to the reaction mixture of step (b).

The reaction of step (c) is usually carried out at elevated temperature. Usually above 30°C up to about 40°C.

An essential feature of the new and improved process of the present invention is that the reactions of steps (b and c) is carried out in 2-methyltetrahydrofuran as solvent.

Some of the so obtained (non hydrolysed) reaction products are not known yet. The following compound of formula (XV) is new

(XV)

At the end of the reaction, the reaction mixture is poured into an ice/water solution and then this solution is acidified.

An extraction process is applied to isolate the reaction product. The yield of the new process is significantly higher as the yield from the reaction from the prior art. The following examples serve to illustrate the invention. If not otherwise stated the temperature is given in degree Celsius and all parts are related to the weight.

Examples

Example 1 :

6.17 g of (Z)-I -Pentol (96.6 w%; 62.0 mMol) and 1.35 mg of p-TsOH hydrate (99 %, 7.00μΜοΙ, were charged into a vessel and cooled to -3°C.

Afterwards 10.79 g of isopropenylmethyl ether (14.2 ml, 97 %, 145 mMol) were added dropwise while the temperature of the reaction mixture was kept at 0°C and the reaction mixture is stirred for additional 30 minutes.

9.72 mg Triethylamine (99.8 %, 0.096 mMol) were added and the reaction mixture was heated to about 20°C.

The non-reacted starting material was removed under reduced pressure (about 27 °C and up to 30 mbar).

The so obtained reaction product ((Z)-1 -pentol/isopropenylmethyl ether -product) was dissolved into 8 ml of 2-methyltetrahydrofuran (water-free).

1.36 g of magnesium (99.95 %, 56.0 mMol), in the form of flakes were charged in another vessel under argon.

2.7 ml of 2-methyltetrahydrofuran (water-free) was added to the magnesium.

6.79 g of ethyl bromide (99.7 %, 62.1 mMol) were dissolved in 3.4 ml of 2- methyltetrahydrofuran (water-free) and a bit of this mixture was added to the magnesium to start the reaction and afterwards another 8 ml of 2- methyltetrahydrofuran (water-free) was added. The rest of the ethyl bromide (in 2- methyltetrahydrofuran) was added slowly. The reaction mixture was always kept at a temperature of between 35 - 37°C.

Afterwards the reaction mixture was kept at temperature of 36 - 38°C under stirring for additional 60 minutes. Then all the magnesium was dissolved and the reaction mixture is slightly greyish and clear (Grignard solution). In a next step (step (b)) the (Z)-1 -pentol/isopropenylmethyl ether-product, which was obtained in the first step was added dropwise to the Grignard solution. The temperature of the reaction mixture was kept at a temperature range between 35 - 40 °C.

The reaction mixture was stirred at that temperature for about an hour.

Ci ₄ -aldehyde, 10.53 g of the (compound of formula (III)) (98 w%, 50 mMol,) was dissolved in 5.4 ml of 2-methyltetrahydrofuran (water-free) and afterwards added to the solution of step (b) dropwise. The reaction temperature was kept at a temperature of between 35 - 40 °C.

The reaction mixture was stirred at a temperature of between 35 - 40 °C for about an hour, cooled to room temperature (20 - 25°C), and added to 67g of a water/ice mixture under stirring.

To this mixture about 21 g of a 15 w% H ₂ S0 _4aq were added and the pH was adjusted to pH 1 .25 - 1 .3 (measured by 780 pH meter of Metrohm (using an electrode 6.99104.02).

The mixture was stirred for about 2 hours at room temperature.

Afterwards ether was added to the reaction mixture and washed with a saturated NaHC0 _3aq solution.

The organic phase was dried and the solvent was removed under reduced pressure (0.1 mbar at 40 °C).

The yield of the final and pure product (oxenine) was 92.2 %. In comparison, the prior art the yield was improved significantly. Example 2:

6.17 g of (Z)-I -Pentol (96.6 w%; 62.0 mMol) and 0.25 g of Amberlyst 36 dry (5 eq H ⁺ / 1 kg Amberlyst), were put into a vessel and cooled to -3°C under stirring. Afterwards 12.9 g of butenylmethyl ether (96.9 %, 145 mMol) were added dropwise while the temperature of the reaction mixture is kept at 0°C and then the reaction mixture was stirred for another 30 minutes.

Afterwards 9.72 mg of triethylamine (13 μΙ_, 99.8 %, 0.096 mMol) were added and the reaction mixture was heated to about 20°C. The Amberlyst was separated over a 5 m Teflon filter and the reaction mixture was transferred to a larger vessel and the non-reacted starting material was removed by reduced pressure (about 27 °C and up to 30 mbar).

The so obtained reaction product ((Z)-1 -pentol/butenylmethyl ether-product) was solved into 8 ml of 2-methyltetrahydrofuran (water-free).

1.36 g of magnesium (99.95 %, 56.0 mMol), in the form of flakes were charged in another vessel under argon.

2.7 ml of 2-methyltetrahydrofuran (water-free) was added to the magnesium. 6.79 g of ethyl bromide (99.7 %, 62.1 mMol) were dissolved in 3.4 ml of 2- methyltetrahydrofuran (water free) and a bit of this mixture was added to the magnesium to start the reaction and afterwards another 8 ml of 2- methyltetrahydrofuran (water-free) was added. Now the rest of the ethyl bromide (in 2-methyltetrahydrofuran) was added slowly. The reaction mixture was always kept at a temperature of between 35 - 37°C.

Afterwards the reaction mixture was kept at temperature of 36 - 38°C under stirring for about 90 minutes. Then, all the magnesium was solved and the reaction mixture is slightly greyish and clear (Grignard solution). In a second step (step (b)), the (Z)-1 -pentol/butenylmethyl ether-product, was added dropwise to the Grignard solution. The temperature of the reaction mixture was kept at a temperature of between 35 - 40 °C.

The reaction mixture was stirred at that temperature for about an hour.

10.53 g of the Ci ₄ -aldehyde (compound of formula (III)) (98 w%, 50 mMol,) were dissolved in 5.4 ml of 2-methyltetrahydrofuran (water-free) and afterwards were added to the solution of the second step dropwise. The reaction temperature was kept at a temperature between 35 - 40 °C.

The reaction mixture was stirred at a temperature of between 35 - 40 °C for about an hour, cooled to room temperature (20 - 25°C), and the reaction mixture was added to 67 g of a water/ice.

To this mixture about 21 g of a 15 w% H ₂ S0 _4aq were added to adjust the pH to 1.25 - 1.3 (measured by 780 pH meter of Metrohm (using an electrode 6.99104.02).

The mixture was stirred for about 2 hours at room temperature.

Afterwards ether was added to the reaction mixture and washed with a saturated NaHC03aq solution.

The organic phase was dried and the solvent was removed by a rotary evaporator (0.1 mbar at 40 °C.)

The yield of the final and oure product (oxenine) was 85.1 %.