CH642960A5 - Process for preparing a piperazine derivative having a therapeutic activity - Google Patents

Abstract

1-[2-Hydroxy-3-methoxy-3-phenylpropyl]-4-[2-methoxy-2-phenylethyl]- piperazine is prepared by reacting (a) piperazine with methyl chloroformate, (b) reacting the mono-N-carbomethoxypiperazine obtained with 3-phenyl-3-methoxy-1,2-propylene oxide and (c) hydrolysing the derivative 1-[2-hydroxy-3-methoxy-3-phenylpropyl]-4-carbomethoxypiperazine to give the compound of the formula <IMAGE> which is reacted (d) with 2-methoxy-2-phenylethyl halide to give the desired product. The product prepared has a therapeutic activity.

Description

The present invention relates to a new process for the preparation of a piperazine derivative having therapeutic activity.

More precisely, the present invention relates to a new process for the production on an industrial scale of the compound l- (2-hydroxy-3-methoxy-3-phenylpropyl) -4- (2-methoxy - 2-phenylethyl) -piperazine of formula

/ ~

H_ C, —CH-CH 5 "1 2

OCH.

N-CH -CH-CH-CJL

»I

OH OCH.

(THE)

which is endowed with remarkable antitussive activity.

It is known from U.S. Pat. A. 3,718 650 that the piperazine derivative (I) is prepared by reaction of 1- [2-phenyl, 2-methoxy ethyl] piperazine with 3 phenyl, 3-methoxy-1, 2-propylene-oxide, according to equation

10 Always according to the same patent, the starting compound l-[2-phenyl, 2-methoxy ethyl] piperazine is prepared from styrene and tert-butyl hypobromite in the presence of methanol; the obtained product is then reacted with piperazine according to the following scheme:

0 CgHj-CfcCHg + CHjOSfterz. C ^ H ^ -BiO ■

CGH ^ -GH-CHgBr

OCH.

l) CgHj — CB-CHgBr +: 1 I

H - H.EBT

Now.

OCH,

This process is described in BSM 7 304 M.

Also the method of preparing the other reagent employed according to U.S. Pat. 3 718 650, 3-phenyl, 3-methoxy-1, 2-propylene oxide, is described in the previous French patent 6 944 218 and essentially comprises the steps schematized below, in which the starting products are cinnamic alcohol and hypobromite of tert.butyl in pre-30 without methanol:

a) H C -— CH * CH — CU OH + CH OH ■ + "tcrs. C.H —CEB:

5 6

i »H_C, —CH - CE-CH OH

5 6

THE

THE

0CH3 Br

Tj) H_C, -CH - CE-CH OH + aOH

56 I I 2

3 OCH ^ Br

4 9

'H ^ Cv-Cn - CH - CH

56I \ / 2

OCH, 0

In reality, the preparation of the compound (I) according to U.S. Pat. 3 718 650 is extremely difficult to carry out on a large scale and in any case gives low yields. 45 Essentially the weak points of the known summary are:

- it is impossible to limit the reaction between piperazine and 2-methoxy, 2-phenyl-ethyl bromide to a nitrogen only even in the presence of a strong excess of piperazine, whereby a mixture of mono-substituted product and di-so- is always formed

50 established

- the di-substituted product is difficult to separate from the mono-substituted, so the yields in useful product are always low.

From the foregoing, it is immediately evident that the process-55 of the U.S. Pat. 3 718 650, being conditioned by the first phase is absolutely uneconomical.

The new process according to the present invention obviates the drawbacks of the prior art process and, as already said, allows the preparation of the compound (I) on a large m scale, with pharmaceutical purity and with high yields.

The new process essentially comprises the steps represented by the following reaction schemes

3

642960

SE + C3.-C-OCH

H

0

/ CH O-O- / V-C-OCH, J

1 II> 'The 3

0 (17) 0

B-G-OCH.

HH + CH - CH - CH - C, H_ -

</ i. "

0 OCHj B-CH2-CH - C3-CgHj OH OCH,

3 * CH.O — C—! T

The S

lf-CHg-CH - CH - Cg ^ + KOH • OH OCH.

HH

H - CH - CH - CH - C, H

2 . . 6 5

I |

OH OCH.

(H)

4. m ^ S = \ - Ca ~ CH - CH - C, B_ + H_C, - CH - CH-Br • \ / 2 j (65 5 6 2

OH OCH.

H ^ Cg-OH - CHg-ÎT OCH.

OCH.

E-CHg-CH - CH - C ^ 5 OH OCH.

EBr

(THE)

We now describe in detail the individual stages of the process, indicating the operating procedures for each of them.

1. As mentioned in the introductory part of this description, one of the biggest drawbacks in the process of the prior art is given by the fact that the hydrogens linked to the two piperazine nitrogen are equally reactive, the reaction of piperazine with 2-methoxy, 2-phenyl -ethyl gromide proceeds only in part towards the mono-replacement. That is, a mixture of mono-substituted and substituted piperazine derivatives is formed (also by working with an excess of piperazine equal to 5-10 times the stoichiometric) in which the mono-substituted compound is difficult to separate from the analogue di- replaced.

However, it has been ascertained that radiation of piperazine if carried out in critical conditions, i.e. with methylchlo-ro-formed, in aqueous solution and in a well-determined pH range, leads with a strong prevalence to the mono-substituted derivative. Furthermore, the small quantities of substituted compound that are formed are eliminated very easily since it is a diamide which, unlike the monosubstituted derivative, is not absolutely basic.

The reaction between piperazine and methylchloroformate occurs in an aqueous solution, at a pH critically between 3.5 and 4, mixing the two reagents in a stoichiometric ratio or using a slight excess of methylchloroformate. Outside the indicated pH limits the reaction either does not proceed or gives derivatives to the two nitrogen.

The dicaromethoxylation product is eliminated by extracting the aqueous solution repeatedly with ethyl ether.

The mono-carbomethoxylation product is separated from the aqueous solution as an oily residue after neutralization and evaporation of the water.

2. The N-carbomethoxy piperazine is reacted with 3-phenyl, 3-methoxy-1, 2-propylene oxide in solution in an inert organic solvent, heating under reflux. In this case, being one of the piperazine functions blocked, the reaction runs only on the other function and the derivative l [2-hydroxy-3-methoxy, 3-phenyl propyl] piperazin is formed with practically quantitative yields.

5 3. The so obtained piperazine derivative is subjected to alkaline hydrolysis, in order to detach the metho-carboxylic radical and restore the free piperazine hydrogen.

The hydrolysis is preferably carried out with alcoholic potash on the solution coming from the previous phase, without separation of the product to be hydrolyzed. The compound 1 [2-hydroxy-3-methoxy, 3-phenylpropyl] -piperazine is extracted from the aqueous solution with an organic solvent which cannot be mixed with water, preferably with ethyl ether and purified by crystallization from a suitable solvent. i5 The hydrolysis yields are greater than 90%, while in the purification phase there is a loss of 10% of the product. Phases 2 and 3 'can be carried out in succession, without separation of intermediates. The product (II) is a new product.

20 4. The l [(2-hydroxy-3-methoxy) 3-phenyl propylj-piperazine is reacted with a 2-methoxy, 2-phenylethyl halide by melting the mixture at temperatures around 100 ° C and for times of approximately 30 hours.

Also in this case the operating methods are critical -25 that, outside the given limits, there are not useful results.

The preferred halide is bromide as it is more reactive than chloride and less expensive than iodide.

The obtained semi-solid mass is taken up with water and the disubstituted piperazine derivative of formula (I) is separated after neutralization of the hydrogen halide, by extraction with organic solvent, not miscible with water, preferably with ethyl ether.

In conclusion, the new process according to the present invention allows to produce the compound of formula

35

/

H_C -— CH - CII - CiL - K

5 6

: * - CH - CH - C-H,

THE

THE

0CH3 OH

1

cai.

6 5

0)

with overall yields of between 80 and 90%, through a number of industrially realizable phases without the use of complex equipment, nor of expensive or difficult to handle reagents.

As for the raw materials used in the new process, they are essentially:

50

a) piperazine b) 3-methoxy-3-phenyl-1,2-propylene oxide c) 2-methoxy-2-phenyl-ethyl bromide

55 a) Piperazine is obviously a product widely available on the market at a low price, so there is no problem whatsoever.

b) As regards the compound 3-methoxy-3'-phenene-1, 2 - propylene oxide, it is prepared according to a process which essentially consists in reacting the cinnamic alcohol with methyl alcohol and bromine in the presence of a strongly basic resin. Alternatively, mercury acetate can be used instead of the resin. Both the resin and the Hg (OAc) 2 must be used in a pro-65 portion at least stoichiometric with respect to the starting cinnamic alcohol.

The process which is carried out according to the present invention is represented in each case by the following reaction

642960

4

CH OH

Cgiy-CH * CH-CHgOH ^> C6H5-CH - CH - CHgOH

OCHj Br

C, Hc-CH - CH - CM OH ^> C-He - CH - CH - CH 65 | , 2 6 5, N / 2

OCH ^ Br OCH ^ O

In the case where the basic resin is used, the brominated compound is obtained directly; on the other hand, if mercury acetate is used, a compound of formula is formed as intermediate

C / B * CH • CH • CH OH

i i 2

OCH ^ HgOAo which is only later decomposed by bromine, which replaces the group -HgOAc.

Compared to the best process of prior art (French patent 6 944 218), the new process gives much higher yields and has the advantage of avoiding the use of tertiary butyl hypo-myth, the preparation of which is very delicate and easily leads to heavy product losses. The reaction between cinnamic alcohol, methyl alcohol and bromine is carried out by cooling to temperatures between 10 ° and - 10 ° C. Sometimes, however, it is advisable (especially when carrying out the reaction with mercury acetate) to heat slightly at the end of the reaction to facilitate its completion.

The formation of the epoxide from the Br-derivative is carried out by using a strong alkaline base (soda or potash) in alcohol or ether, carefully heating to reflux, c) The compound 2-methoxy-2-phenyl-ethylbromide:

C6H5-CH-OH2Br

THE

OCH3

it is preferably prepared by reaction of styrene with methyl alcohol and bromine in the presence of a strongly basic resin or of mercury acetate according to the equation

CH OH

C ^ Hj-CH - CH2 * ■ CgHy-CH - CH ^ Br och3

The reaction is carried out in the presence of an at least stoichiometrically equivalent quantity of resin or mercury acetate, at temperatures between -10 ° and 10 ° C. When using acetate it is preferable to heat slightly. This process is preferred because it avoids the use of tert-butyl-hypobromite and gives high yields in the final product.

In order to facilitate the reproduction of the new process and to provide all the operational details, an example of implementation is shown below.

Example 1

17.2 grams of piperazine (0.2 moles) are placed in a 1 liter four-necked flask, equipped with a mechanical stirrer, two drip funnels and a pH meter. The piperazine is brought into solution with 100 ml of water and the pH is brought to about 4 by means of 2N HCl.

28 g of methyl chloroformate (about 0.3 moles) are placed in a dropping funnel and in the other a saturated solution of sodium acetate.

Under strong stirring, the contents of the two funnels are slowly and simultaneously dripped, so as to maintain the pH strictly between 3.5 and 4. The flask is cooled by an ice bath.

The reaction mixture is extracted three times with ethyl ether to remove all the dicarboxyloxylation product.

The aqueous phase is saturated with potassium carbonate, filtered on a porous septum and extracted several times with ethyl ether.

The extract is anhydrified with potassium carbonate and the solvent is evaporated under vacuum.

The yellow, oily residue thus obtained is distilled at 1 torr. At 94-96 ° C they distil 21.6 g of N-carbomethoxy piperazine (yield 75%).

The IR, NMR and elementary analysis spectra are in agreement with the structure (III).

8.2 g of N-carboxymetypiperazine (0.056 moles), 8.65 g of 3-methoxy, 3-fe-nyl-1, 2 are placed in a 500 ml flask equipped with a mechanical stirrer and a reflux refrigerant. propylene oxide (0.053 mol) and 100 ml of methanol.

The mixture is heated under reflux for 3 hours and then a solution of g5 of KOH in 50 ml of methanol is added. The mixture is heated under stirring for 20 h and then the solvent is evaporated under vacuum.

Water is added to dissolve the precipitated solid and extracted with ethyl ether.

The extracts are washed with water, dried on potassium carbonate and evaporated under vacuum.

16.1 g of 1 [2-hydroxy-3-methoxy, 3-phenylpro-pil] piperazine are obtained in the form of a viscous oil (yield 93%).

The IR, NMR and elementary analysis spectra are in agreement with the structure (II).

25 grams of l [2-hydroxy-3-methoxy, 3-phenylpropyl] piperazine eg 21.5 of 2-methoxy, 2-phenyl-ethyl bromide are melted at 100 ° C in a 250 ml balloon and kept at this temperature for 30 hours.

The semisolid mixture obtained is taken up with water and a little ethyl ether.

The aqueous phase is saturated with potassium carbonate and extracted 4 times with ethyl ether.

38 g of l- (2-hydroxy-3-methoxy-3-phenylpropyl) - 4- (2-methoxy-2-phenylethyl) piperazine are obtained with pure theoretical yields.

Mp 115-121 ° C.

The IR, NMR and elemental analysis spectra are in agreement with the structure (I).

Thin layer chromatography gives a unique stain.

Example 2

Preparation of the intermediate 2-methoxy, 2-phenyl-ethyl bromide.

52 g (0.5 moles) of styrene, 1000 ml of absolute methanol and 0.55 equivalents of Amberlite IRA 900 resin in basic form are placed in a 3-liter flask equipped with mechanical stirrer, reflux coolant and dripping funnel. The flask is cooled to keep the internal temperature at around - 10 ° C. 25.5 ml (0.5 mol) of bromine are slowly added under vigorous stirring.

The mixture is left to react for 30 'at - 10 ° C, then it is brought to room temperature and the resin is filtered.

5

10

15

20

25

30

35

40

45

50

55

60

6S

5

642960

The vacuum evaporated filtrate provides 100 g of pure 2-methoxy, 2-phenyl-ethyl bromide with a yield of 95%.

The same reaction was carried out by using mercury acetate as a catalyst instead of the basic resin.

In this case, after the addition of bromine was over, the mixture was heated for 30 minutes under reflux.

Yields of approximately 90%.

Example 3

Preparation of the intermediate 3-methoxy, 3-phenyl-1, 2-propi-lenoxide.

67 g (0.5 mol) of cinnamic alcohol, 1000 ml of absolute methanol and 0.55 equivalents of Amberlite IRA 900 resin are introduced into a 3 liter flask as used in Example 2.

Proceed as in example 2 obtaining 115 g of 3-methoxy, 3-phenyl-2-bromine propyl alcohol with a yield of 95%. 216 g of 3-methoxy, 3-phenyl-2-bromopropyl alcohol dissolved in 1000 ml of ethyl ether are introduced into a 2-liter three-necked flask equipped with a mechanical stirrer and a reflux condenser. This is cooled in ice and 100 g of finely pulverized KOH are added to portions. The mixture is kept under stirring for 1 hour.

It is filtered on a porous septum and the solvent is evaporated under vacuum.

The product is distilled at 2 torr and collected at 80-85 ° C. io 113 g of pure product are obtained with a yield equal to about 80%.

The same preparation was repeated, but preparing the 3-methoxy, 3-phenyl-2-bromine propyl alcohol with mercury acetate 15 as a catalyst instead of the basic resin. After the addition of bromine, the reaction mixture was refluxed for 30 minutes.

92% alcohol yield.

v

Claims (4)

642960 2. Process according to claim 1, characterized in that the N-carbomethoxy piperazine is reacted with 3-phenyl, 3-methoxy-1, 2-propylene oxide in solution in inert organic solvent, by heating under reflux. 2 i i ^ CH OCH, n_C "-0H-CH -K 56 the OCH, 5 H, C, -CH-CH-H 5 O 1 2 OCH. ^ N-H + CHg - CB-CH-CgHj OCH, / K-CH2-CH - ÇH-CgHj (THE) OH OCH, ff) characterized by the fate that prepares the mono N-carbome-. toxo piperazine by reaction of piperazine with methylchlo-roformate, the product obtained is reacted with 3-fe-nil, 3-methoxy-1, 2-propylene oxide and the derivative l [2-hydroxy - 3-methoxy, 3- phenylpropyl] -4'-carbomethoxy piperazine is hydrolyzed to give the compound of formula / ~ ^ \ "_ ER ÏI - CH - CH - CH - CgH_ \ / I I OH OCH. of) which is reacted with 2-methoxy, 2-phenyl ethyl halide. 2 CLAIMS 1. Process for the preparation of l- [2-hydroxy-3-methoxy, 3-phenyl-propyl] -4- [2-methoxy-2-phenylethyl] -piperazine of formula OCH. 17 »CH * • CÏÏ - CH * OJE 3. Process according to claim 1, characterized in that Pl [2-hydroxy-3-methoxy, 3-phenyl propyl] -4-carbo-methoxy piperazine is hydrolyzed with alcoholic potash. 4. Process according to claim 1, characterized in that ri [2-hydroxy-3-methoxy, 3-phenylpropyl] -piper-zine is reacted with 2-methoxy, 2-phenylethyl bromide by melting at temperatures around 100 ° C for about 30 hours.