FI56673C - NYTT FOERFARANDE FOER FRAMSTAELLNING AV ALFA-TERT-BYTYLAMINOMETHYL-4-HYDROXY-M-XYLEN-ALFA1 ALFA3-DIOL - Google Patents

Description

@ FINLAND — FINLAND patent publication patent patent 5 6673 @ Kv.lli: /lnt.CI.2 C 0? C 91/28 ® (S) Patent application — Patentansökning 982 / 7Jt ® @ Filing date - Ansökningsdag 29.03.7 * 4 (§) Starting date - Glltighetsdag 29.03.7 * 4 (g) Publication - Blivit offenclig 30.09.75 @ .publish date—

Ansökan utlagd och utl.skrlften publicerad 30.11.79

National Board of Patents and Registration (g) Patents granted - Patent meddelat 0U .02.81

Patent- och registerstyrelsen (33) (33) (31) Privilege claimed - Begärd priority (73) Huhtamäki-Yhtymä Oy, Leiraksen Lääkeainetehdas, Turku, Finland-Finland (FI) - (72) Jarkko Ruohonen, Turku, Finland-Finland ( Fl) (71 *) Oy Heinänen Ab (5I1) New method for the preparation of ος, Ι-tert - butylaminomethyl- * 4-hydroxy-ro-xylene - flC ^ ^ - diol - Nytt förfarande för framställning av rt1-tert - butylaminomethyl- The present invention relates to a new process for the treatment of a therapeutically valuable 11,13-tert-butylaminomethyl-4-hydroxy-m-xylene-α, β-diol, which the formula is

H0CHo ._ OH

HO / CHCH2NHC (CH3) 3 I

as well as for the preparation of its acid addition salts.

The compound is known for its pharmacological properties and has gained widespread use in the treatment of status asthma and other forms of severe bronchospasm.

The preparation of ex.1-tert-Butylaminomethyl-4-hydroxy-m-xylene-c <1> c <4 - diol has been described previously e.g. in British Patents 1,200,886 and 1,247,370.

2 56673

U.S. Pat. No. 1,200,886 discloses a process in which the 5- (n-benzyl-n-tert-butyl-glycyl) -salicylic acid methyl ester hydrochloride -? Eto- and ester groups are reduced with lithium aluranium hydride in tetrahydrofuran. The desired end product is then obtained from the catalytic hydrate. The process is expensive and dangerous on a factory scale due to the risk of ignition of the solvent and reducing agent. Alternatively, 2- (benzyltert-butylamino) - 't * -hydroxy-3'-hydroxymethylacetophenone hydrochloride, the keto group of which is reduced with sodium borohydride in ethanol, can be used as a starting material. Both of these methods are part of processes with several isolating intermediates, which is laborious and results in significant product loss.

The process disclosed in patent 1,247,370 also has several isolable steps, some of which are generated in very poor yields. In this process, the compound formed by 5-glyoxyloylsalicylic acid methyl ester and tert-butylamine is first treated with sodium borohydride to reduce the carbon-nitrogen double bond and the keto group, then the ester group is reduced with lithium aluminum hydride and the final product is extracted from aqueous solution. However, α-β-tert-butylaminoethyl-4-hydroxy-m-xylene-α, β-diol is highly soluble in water but very sparingly soluble in organic solvents, with the result that extraction of the product from aqueous solution on a factory scale is almost impossible.

A process has now been found which is very well suited for industrial production, in which tert-butylaminomethyl-4-hydroxy-m-xylene-β-diol can be prepared easily and in good yield. The essential features of the method are set out in the claim. ~

The process according to the invention can be carried out as part of a continuous process in which the starting material is first converted into the imine derivative mentioned in the claim and then into the final product as claimed, without isolating the intermediates. This avoids isolation losses and also eliminates the need to remove the medium from the process.

3 S 6 6 7 3

Amid the reaction equations, the process is as follows:

rOOC

FhCH20 \ 0 / COCK5 (i l)

SE02

V

RCOC

PhCH2CM ^ 3 ^) - COCH0 C1J I) h2hc (ch3) 5 (IV) v

rOOC

V___

PhCH.O YOv-COCH = NC (CH ^)., (V) ^ \ v._yj "" Ιΐ3Αΐ (0ΌΗ2Ο.ιι2Ο0Η ^) 2Η2 (VI) or

NeAl (C2H5) 2H2 (VJ1)

HCCH2 \ OH

FhCH20 VqV CHCH2NHC (CH5) 3 (VJ.il)

H2, Fd / C V

HOCH,

*> OH

in the scheme shown by ho - ((^) Vchch2nhc (ch3) 5 (I) h, R denotes a lower straight-chain or branched alkyl group containing 1 to 6 carbon atoms.

This continuous process is made possible by the invention that the hydrogenation of the double bond between the carbon and nitrogen in the imine derivative (v) and the reduction of the keto and ester groups can be carried out simultaneously with a suitable alkali metal alkali metal hydride derivative. The reaction first forms a complex between the irine derivative and the alkali metal alalainium hydride derivative, which is then decomposed by conventional means by the addition of either an acidic or alkaline aqueous solution into compound VIII, from which the benzyl group is then catalytically removed by hydrogenation.

In addition to the above, the protection of the phenolic hydroxyl group in the benzoic acid derivative (II) with a benzyl group has altered the solubility properties so that the compound VIII remains in the organic phase in the process. In addition, the protection of the benzyl group advantageously affects the whole process, so that the proportion of side reactions is considerably reduced.

the process begins with the oxidation of the ester derivative (II), to the corresponding glyoxal derivative (lii) with selenium dioxide in dioxane at the boiling point of the solvent. The selenium released in Eeuktic is filtered off. Then, tert-butylamine is added to the reaction mixture, whereby the imine derivative (V) is formed at room temperature within a few hours, a.

Surprisingly, the process involves the hydrogenation of the carbon-thyroid double bond in the isine derivative (V) with the simultaneous reduction of the keto and ester groups. No such reaction has been reported in the literature before. . Sodium bis (2-methoxy) aluminum aluminum hydride (VI) or sodium aluminum diethyl dihydride (VII) are best suited for this. When these two reducing agents are used, the solvent is usually bonzene or toluene, which can also be used in this case. However, a better result is obtained when the reaction is carried out in dioxane, i.e. the reaction mixture used in the preparation of the imine derivative can be used as it is.

5 56673 YRCC'R Siret tert-butylamine is evaporated off under reduced pressure to save the reducing agent. heoction can be performed ^., gs 1it iumalumin iumhydride, but this reducing agents) is noticeable + more expensive to use so much more dangerous that v - here there is no reason to use. In this simultaneous hydraulic and reduction process, a complex is first formed between the imine compound and the hydride reducing agent used, which is then decomposed into a compound (VIT.l) by conventional means using either an acidic or alkene-aqueous solution. .

the benzyl group in compound (Vili) causes this product "to remain in the organic phase during the process, in the absence of the benzyl / l group, the compound formed at this stage would already be the finished product. However, the final product is so water soluble that it enters the aqueous phase from the isolation is almost impossible because it practically does not disappear. it is not soluble at all in suitable organic extraction solvents.

Removal of the benzyl group in compound (VIII) is carried out by catalytic hydrogenation, with a suitable catalyst being, for example, palladium on carbon and a suitable solvent, for example an alcohol.

6

The invention is illustrated below by means of examples. 56673

Example 1 4-tert-Butylaminomethyl-4-benzyloxy-m-xylene-4-diol

The preparation of the title substance is described below as a continuous process in which an imine derivative is initially prepared, which forms the starting material for the process according to the invention.

a) Preparation of the imine derivative 0.35 kg of water are added to 59 kg of dioxane and the mixture is heated to 70-30 ° C. Add 4 * 39 kg of selenium dioxide. After dissolving the selenium dioxide, 11.8 kg of 5-aceto-2-benzyloxy-benzoic acid ethyl ester dissolved in 35.5 kg of dioxane are added. During the addition, the reaction mixture is further heated until the reaction mixture boils (100 ° C). Return cooking is continued for six hours. During cooking, the color of the reaction mixture turns black due to precipitated selenium. After cooking, the mixture is allowed to cool to room temperature. Filter off the selenium. (If it is desired to isolate the glyoxal derivative, this is done by evaporating the dioxane to give the glyoxal derivative prepared in this way as a viscous oil.)

To the filtrate at room temperature is added 5.9 kg of tert-butylamine and stirred at room temperature for four hours. Evaporate the excess tert-butylamine under reduced pressure.

b) The method according to the invention

The reaction mixture is poured under a nitrogen atmosphere into 40 kg of a benzene solution of sodium bis (2-methoxyethoxy) aluminum hydride. The addition takes place at about 60 ° C. After the addition of a return soup for an hour. The complex formed between the reducing agent and the product is normally decomposed with water and hydrochloric acid. The oily product layer is separated, dissolved in chloroform, liberated from its hydrochloride salt with a basic solution, dried over sodium sulfate and treated with activated carbon. Evaporate the chloroform under reduced pressure. Ife, the product can be reused from the etarx list if necessary.

7 5667¾

Yield 8.5 to 9.0 kg (65-70 ° C theoretical), melting point approx. 135 °.

The product can be further converted to -tert-butylaminomethyl-4-hydroxy-m-xylene-β, β-diol catalytically by hydration according to Example 7.

Example 2

Start as in Example 1, but after preparation of the imine derivative, the solvents are evaporated off. In this way, the imine derivative is obtained as a viscous oil which is dissolved in 80 kg of Bent fungus. The benzene solution is drained under a nitrogen atmosphere into 40 kg of a 70% solution of sodium bis (2-methoxyethoxy) c. Aluminum hydride in benzene. Continuation as in the example, 1 · Sstanto 7 * 5 ™ 8 ^ 0 (58 62 ^ theoretically) ^ sul3m i s - point approx. 135 ° C.

Example 3

As Examples 1 and 2, but with an equivalent amount of methyl ester instead of 5-aceto-2-benzyloxybenzoic acid ethyl ester.

Example 4 s <11-tert-Butyl] aminomethyl-4-benzyloxy-m-xylene-4-diol

The preparation of the title substance is described below as a continuous process in which an imine derivative is initially prepared which forms the starting material of the process according to the invention.

a) Preparation of the imine derivative 0.4 kg of water are added to 66 kg of dioxane and the mixture is heated to 70-80 ° C. 4.92 kg of selenium dioxide are added. After dissolving the selenium dioxide, 13.2 kg of ethyl 5-aceto-2-benzyloxybenzoic acid dissolved in 40 kg of dioxane are added. Continue heating until the reaction mixture boils (-> 100 ° C), followed by refluxing for 6 hours. During cooking, the reaction mixture turns black from precipitating selenium. Allow the reaction mixture to cool to room temperature and filter off the precipitated selenium. To the filtrate at room temperature is added 8 56673 6.6 kg of tert-butylamine and stirred at room temperature for four hours. Evaporate the excess tert-butylamine under reduced pressure.

b) The method according to the invention

The dioxane solution at room temperature is added to 85.5 kg of a toluene solution of sodium aluminum diethyl dihydride under a nitrogen atmosphere at such a rate that the temperature in the reaction mixture does not rise above 25 ° C. After the addition, stirring is continued at 25 ° C for one hour. The complex formed between the product and the reducing agent is normally decomposed by adding water and an alkaline solution. The organic phase is separated and evaporated to dryness. Evaporation of the residue from the product, if necessary, can be reused from ethanol.

Yield 9.5-10.3 kg (65-70 io of theory), melting point approx. 135 ° C.

The product can be further converted to the? C-tert-butylanemetomethyl-4-hydroxy-m-xylene-? 2-diol by catalytic hydrogenation according to Example 7.

Example 5

As in Example 4, but after preparation of the imine derivative, the solvents are evaporated off. In this case, the imine derivative is obtained as a viscous oil which is dissolved in 90 kg of toluene, this toluene solution being used in the future. Continued as in Example 4.

Yield 8.5-9.1 kg (58-62 fo theoretical), melting point approx. 135 ° C.

Example 6

As Examples 4 and 5, but instead of 5-aceto-2-benzyloxy-benzoic acid ethyl ester, an equivalent amount of methyl ester.

Example 7 g <L1-tert-Butylaminomethyl-4-hydroxy-m-xylene- <?] - C 1-4 diol 10 kg N, O-tert-butylaminomethyl-4-benzyloxy-m-xylene-c, diol 135 kg are added to 95% ethanol. Add 0.3 kg of 10 l of palladium-carbon and hydrogenation at normal pressure until hydrogen consumption ceases. Cat- 9. 56673 After removal of the lysator, the solvents are evaporated off. From the evaporation residue, the product is crystallized from a methanol-ethyl acetate mixture. Yield 6.5 kg ($ 90 theoretical), melting point 157-158 ° C.

Example 8 o 1-tert-Butylaminomethyl-4-hydroxy-m-xylene-oc1. g k ^ diol

The preparation of the title substance is described below as a continuous process in which an imine derivative is initially prepared, which forms the starting material for the process according to the invention.

a) Preparation of the imine derivative 0.4 kg of water are added to 6666 kg of dioxane and the mixture is heated to 70-80 ° C. 4.92 kg of selenium dioxide are added. After dissolving the selenium dioxide, 13.2 kg of 5-aceto-2-benzyloxy-benzoic acid ethyl ester dissolved in 40 kg of dioxane are added. Continue heating until the reaction mixture boils (^ 100 ° 0), followed by reflux for 6 hours. During cooking, the reaction mixture turns black from precipitating selenium. Allow the reaction mixture to cool to room temperature and filter off the precipitated selenium. To the filtrate at room temperature is added 6.6 kg of tert-butylamine and stirred at room temperature for four hours. Evaporate the excess tert-butylamine under reduced pressure.

___ b) The method according to the invention

The dioxane solution at room temperature is added under nitrogen to 85.5 kg of a toluene solution of sodium trainium diethyl dihydride of $ 25 at such a rate that the temperature in the reaction mixture does not rise above 25 ° C. After the addition, stirring is continued at 25 ° C for one hour. The complex formed between the product and the reducing agent is normally decomposed by adding water and an alkaline solution. The organic phase is separated and evaporated to dryness. To 135 kg of ethanol are added to the evaporation residue. Add 0.3 kg of 10 l »palladium on carbon and hydrogenation at normal pressure until hydrogen consumption ceases.

After removal of the catalyst, the solvents are evaporated off. Evaporation from the residue The product is crystallized from a methanol-ethyl acetate mixture.

10 & 6 6 7 3

Yield 6.2-6.7 kg (59-63 ° C theoretical), melting point 157-158 ° C.

Example 9 - <1-tert-Butylaminomethyl-4-hydroxy-m-xylene - <1'-diol

The preparation of the title substance is described below as a continuous process in which an imine derivative is initially prepared, which forms the starting material of the process according to the invention.

a) Preparation of the imine derivative 0.35 kg of water are added to 59 kg of dioxane and the mixture is heated to 70-80 ° C. 4.39 kg of selenium dioxide are added. After dissolving the selenium dioxide, 11.8 kg of ethyl 5-aceto-2-benzyloxybenzoic acid dissolved in 35.5 kg of dioxane are added.

During the addition, the reaction mixture is further heated until the reaction mixture boils (-100 ° C). The recovery soup is continued for six hours. During cooking, the color of the reaction mixture turns black due to precipitated selenium. After cooking, the mixture is allowed to cool to room temperature. Filter off the selenium. To the filtrate at room temperature is added 5.9 kg of tert-butylamine and stirred at room temperature for four hours. Evaporate the excess tert-butylamine under reduced pressure.

b) The method according to the invention

The reaction mixture is drained under a nitrogen atmosphere into 40 kg of a benzene solution of 70% sodium bis (2-methoxyethoxy) aluminum hydride. The addition takes place at about 60 ° C. After the addition of a return soup for an hour. The complex formed between the reducing agent and the product is normally decomposed with water and hydrochloric acid. The oily product layer is separated, dissolved in chloroform, liberated from its hydrochloride salt with a basic solution, dried over sodium sulfate and treated with activated carbon. Evaporate the chloroform under reduced weight. Evaporation to the residue add 120 kg of ethanol. Add 0.26 kg of 10 i »palladium · carbon and hydrogens, y3 at normal pressure, until hydrogen consumption ceases. After removal of the catalyst, the solvents are evaporated off. From the evaporation residue, the product is crystallized from a methanol-ethyl acetate mixture. Yield 5.5-5.9 kg (58-62% of theory), melting point 157-158 ° C.

Claims (1)

A process for the preparation of a therapeutically valuable -tert-butylaminomethyl 4-hydroxy-m-xylene-oC »diol of the formula HOCH2 ^ ___ OH" TT "" '1 and its acid addition salts, characterized in that the imine derivative of the formula ROOC ““ ““ '“Λ IT where R represents a lower straight-chain or branched alkyl group containing 1 to 6 carbon atoms is reacted with sodium urabis (2-methoxyethoxy) aluminum hydride of the formula NaAl (OCH2CH2OCH3 JgHg or sodium aluminum diethyl ) 2H2 in benzene, toluene or dioxane and the resulting complex between the imine derivative and the reducing agent by acidic or basic aqueous treatment is converted to the compound of formula hoch2 PhCH2OCHCH2NHC (CH3) 3 and the benzyl protecting group is removed by catalytic removal.