CA1040658A - INDUSTRIAL METHOD FOR PRODUCING .alpha.1-TERT.-BUTYLAMINO-METHYL-4-HYDROXY-M-XYLENE-.alpha.1,.alpha.3-DIOLE - Google Patents

INDUSTRIAL METHOD FOR PRODUCING .alpha.1-TERT.-BUTYLAMINO-METHYL-4-HYDROXY-M-XYLENE-.alpha.1,.alpha.3-DIOLE

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Publication number
CA1040658A
CA1040658A CA223,245A CA223245A CA1040658A CA 1040658 A CA1040658 A CA 1040658A CA 223245 A CA223245 A CA 223245A CA 1040658 A CA1040658 A CA 1040658A
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Prior art keywords
alpha
tert
xylene
diole
formula
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Expired
Application number
CA223,245A
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French (fr)
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CA223245S (en
Inventor
Jarkko Ruohonen
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Huhtamaki Oyj
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Huhtamaki Yhtyma OY
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/56—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by hydroxy groups
    • C07C215/58—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by hydroxy groups with hydroxy groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
    • C07C215/60—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by hydroxy groups with hydroxy groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain the chain having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

ABSTRACT OF THE DISCLOSURE
The present invention relates to a method for producing therapeutically valuable .alpha.2-tert.-butylaminomethyl-4-hydroxy-m-xylene-.alpha.2 ,.alpha.3-diole, which has the formula and its acid addition salts, characterized in that an imine deri-vative having the formula where R stands for a lower straight-chain or branched hydrocarbon radical containing 1 to 6 carbon atoms, and Ar stands for an aryl group, is converted by simultaneous hydrogenation and reduction into a compound having the formula

Description

New industrial method for producing~ -tert-butyl-aminomethyl-4-hydroxy-m-xylene-~l, ~3-diole The present invention concerns a new method for producing therapeutically valuable ~l-tert-butylaminomethyl-4-hydroxy-m-xylene-~l, ~3-diole, which has the formula \ OH
; HO ~ C~CH~HC(CH3)3 and its acid addition salts.
The compound is known for its pharmacological properties and it has come into extensive use in treating status asthmaticus and other forms of severe bronchospasm.
The preparing of ~l-tert.-butylaminomethyl-4-, hydroxy-m-xylene-~l,~3-diole has been described e.g. in the ~ British Patents N. 1,200,~386 and 1,247,370. The method of the `! British Patent N. l, 200,886 involves several intermediate , . ~
, steps. In addition, the reduction of ester group is carried out with lithium aluminium hydride in diethyl ether or tetra-~ 20 hydrofurane, which is an expensive step and one that is I dangerous when performed on an industrial scale, owing to the risk of ignition of the solvents. The British Patent N
l,247,370 likewise comprises several steps, and part of the intermediates are produced with a very poor yield. In this method the generally known selenium dioxide oxidation is employed. The present invention also incorporates a similar oxidation, but the starting substance is another compound.
The method of the British Patent N 1,247,370 comprises as its last step a procedure which is unsuitable for industrial production runs: lithium aluminium hydride reduction and extraction of the product from an aqueous solution. However, knowing the solubility characteristics of ~ -tert.-butylamino-.' ~

., .

.. . .

~ 104~;S~

methy,l-4-hydroxy-m-xylene-al, ~3-diole, one may say that the method is realizable on a laboratory scale only.
A method appropriate for industrial production work has now been invented, wherein ~ -tert.-butylaminomethyl-4-hydroxy-m-xylene-a1,a3-diole can be easily produced with a good yield in a continuous process, without isolating the intermediate products. The invention is characterized by a continuous production process taking place in one substrate and starting from a benzoic acid derivative having the formula ROOC

ArCH20~ COCH3 II

wherein R = a lower straight-chain or branching hydrocarbon radical containing from 1 to 6 carbon atoms, and Ar = an aryl group, and which is oxidized with selenium dioxide in dioxane ,~
to give the corresponding glyoxal derivative, which has the formula .1 .
, ROOC
. '~ . ' ' :
; ArCH20 ~ COCHO III ~; -.`
~, and which is reacted with tert.-butylamine, which has the -`' formula ! H2NC(CH3)3 IV
:~ ~
to give an imine derivative having the formula ~rCH20 - ~ CCH=NC(CH3~3 and which latter is converted by simultaneous hydrogenation and reduction with an alkali metal aluminium hydride deriva-. , .

104065~3 tive,selected from the group consisting of sodium bis(2-methoxyethoxy)aluminium hydride of the formula NaAl(OCH2CH2OCH3)2H2 VI
and sodium aluminium diethylhydride of the formula ~aA~C2H5)2 2 VII
to give a compound having the formula ~2 \f~ OH
ArCH2O ~ _ CHcH2NHc(cH3)3 VIII

-'' and from which latter the arylmethyl protective group may~ -be removed by catalytic hydration.
An essential feature of the invention is the continui-ty of the method, which has been achieved by protecting the phenolic hydroxyl group in the benzoic acid derivative with the aid of a suitable arylmethyl group. In this manner the losses in the isolation and purification of intermediates are avoided and the final product is obtained in a highly pure and easily isolated form. The intermediates (III, V

and VIII) formed in our method all are also new compounds, the preparation and properties of which have not been described in the literature heretofore.
In our method the ester derivative (II) is first oxidized with selenium dioxide in dioxane, preferably at the 1, boiling point of the solvent, to give the corresponding glyoxal s derivative (III). In the continuation the reaction mixture may be used as such, after the selenium precipitated in the reaction has been filtered off.
When to the filtrate tert.- butylamine is added, standing at room temperature for a few hours already suffices for the formation of the desired imine derivative (V). Thus, by means of a suitable choice of solvent and of temperature, ~ .

. ~, .

1()406S8 the reaction of the tert.-butylamine with the second reactive keto group in the glyoxal derivative (III) has been prevented.
An unexpected feature of the invention is further-more the simultaneous hydrogenation and reduction of the carbon-nitrogen double bond in the imine derivative (V) and of the keto and ester group by the aid of a suitable alkali metal aluminium hydride derivative. No reaction of this type has been presented in the literature heretofore. When the reducing ~ -agent used is sodium bis(2-methoxyethoxy)-aluminium hydride or sodium aluminium diethylhydride, the solvent is most usually benzene or toluene, which both may also be used in the present instance. However, it has unexpectedly been found that a better result is achieved if the reaction is carried out in dioxane that is, the reaction mixture used in the preparation of the imine derivative may be used as such. It is indicated to evaporate the excess amount of tert.-butylamine at reduced pressure, in order to save reducing agent. This simultaneous -hydrogenation and reduction of the imine derivative (V) is only possible provided that the phenolic hydroxyl group in the benzene ring is protected. If no protection has been applied, one has to extract the product from an aqueous solu-tion, considering the known solubility characteristics of ~1_ ' tert.-butylaminonethyl-4-hydroxy-m-xylene-~1, ~3-diole, thisis an impossible undertaking on an industrial scale, and in ; addition considerable amounts of undesired secondary products are formed.
The arylmethyl protective group in the compound (VIII) may be removed by catalytic hydration, for which ' palladium carbon, for instance, is a suitable catalyst and '~ 30 alcohol, for instance, is a suitable solvent.
The invention is illustrated with the ald of examples in the following.

.
- . - . ~. , ., ~ . , : : , Example 1 1040~58 -tert.-butylaminomethvl-4-benzyloxy-m-xylene-~1, a3-diole To 59 kg of dioxane, 0.35 kg water are added and the mixture is heated to 70-80C. Addition of 4.39 kg selenium dioxide. After the selenium dioxide has dissolved, 11.8 kg ethylester of 5-aceto-2-benzyloxybenzoic acid, dissolved in 35.5 kg dioxane, are added. The reaction mixture is further heated during this addition until the reaction mixture boils (appr. 100 C). Reflux boiling is continued for 6 hrs. During the boiling the colour bf the reaction mixture turns black, owing to the selenium precipitated.
After the boiling the mixture is allowed to cool to room temperature. The selenium is filtered off. (If it is desired --to isolate the glyoxal derivative, this is done by evaporating the dioxane, whereby the glyoxal derivative, prepared in this manner, is obtained as a viscous oil.) Addition to the filtrate at room temperature, of 5.9 kg tert.-butylamine and agitation for 4 hrs at room temperature. Evaporation of the excess of tert.-butylamine at reduced pressure.
The reaction mixture is poured, in a nitrogen atmosphere, into 40 kg of a 70% benzene solution of sodium bis(2-methoxyethoxy~aluminium hydride. The addition is made at about 60C. After the addition, reflux boiling for one hour. The complex compound of reducing agent and product is decomposed in normal manner with the aid of water and hydrochloric acid. The oily product layer is separated, ~ dissolved in chloroform, dried with sodium sulphate and treated ; with active carbon. Evaporation of the chloroform at reduced pressure. From the evaporation residue the product may be recrystallized from ethanol if necessary. Yield: 8.8-9~0 kg (65-70% of theoretical), melting point: appr.l35C.

:' :
., ,,,, , . . ,. ., . ~ : . .
,: ,. .:... : . ' ., .' , , :

Example 2 104~6S8 Start as in Example 1, but after preparation of the imine derivative the solvents are evaporated. By this procedure the imine derivative is obtained as a viscous oil, which is dissolved in 80 kg benzene. The benzene solution is poured, in a nitrogen atmosphere, into 40 kg of a 70% benzene solution of sodium bis(2-methoxyethoxy) aluminium hydride. Continue as in Example 1. Yield: 7.5-8.0 kg (58-62% of theoretical), melting point: appr. 135C. -Example 3 As Examples 1 and 2, but using instead of the ethyl ester of 5-aceto-2-benzyloxybenzoic acid, the equivalent amount of methylester. ~ ~
Example 4 ~ -To 66 kg of dioxane, 0.4 kg water are added and the mixture is heated to 70-80C. Addition of 4.92 kg selenium -~
dioxide. After the selenium dioxide has dissolved, addition of 13.2 kg ethylester of 5-aceto-2-benzyloxybenzoic acid, dissolved in 40 kg of dioxane. Heating continued until the '~ 20 reaction mixture boils (appr. 100C), followed by reflux boiling for 6 hrs. During the boiling the reaction mixture turns black - from the selenium precipitated. The reaction mixture is allowed to cool to room temperature and the precipitated selenium is filtered off. Addition to the filtrate at room temperature, of 6.6 kg tert.- butylamine and agitation at room temperature for 4 hrs. Evaporation of the excess of tert.-butylamine at reduced pressure.
; Dioxane solution at room temperature is added, in a nitrogen atmosphere, to 85.5 kg of 25% toluene solution of sodium aluminium diethyldihydride at a rate such that the temperature in the reaction mixture does not surpass 25C.
After this addition, continue agitating at 25C for one hour.

,, . : . . . , . . : ~ ,.
.: , : . . .
.

The complex compound o~ product and reducing agent thus formed is decomposed in normal manner by additing water and alkali solution. The additions have to be made slowly, owing to the effervescence caused by the liberated ethane.
The organic phase is separated and inspissated. From the evaporation residue the product may be recrystallized from ethanol if required. Yield: 9.5-10.3 kg (65-70% of theore-tical), melting point: appr. 135C.
Example 5 As Example 4, but after preparation of the imine derivative the solvents are evaporated. The imine derivative is then obtained as a viscous oil, which is dissol~ed in 90 kg of toluene, and this toluene solution is used in the continua-tion. Continue as in Example 4. Yield: 8.5-9.1 kg (58-62%
of theoretical), melting point: appr. 135C.
Example 6 As Examples 4 and 5, but instead of the ethylester of 5-aceto-2-benzyloxybenzoic acid, use the equivalent amount of methylester.

Example 7 a1-tert -butylaminomethyl-4-hydroxy-m-xylene-al, a3-diole 10 kg of al-tert. -butylaminomethyl-4-benzyloxy-~ m-xylene-al, a3 diole are added to 135 kg of 95% ethanol.
-' Addition of 0.3 kg palladium carbon and hydrogenation at normal pressure, until the hydrogen consumption ceases. After , removal of the catalyst, evaporate the solvents. From the , evaporation residue the product is crystallized with the aid of a methanol-ethanol mixture. Yield: 6.5 kg (90% of theoretical?, melting point: 157-158C.
Example 8 a1=tert.-butylaminomethyl-4-hvdroxY-m-xylene-al,~3-diol To 66 kg of dioxane, 0.4 kg water are added and the mixture is heated to 70-80C. 4.92 kg of selenium dioxide are ~ 7 ~

: , :
., ., . , ., .. . , ,, .

1~40658 added. On dissolution of the selenium dioxide, 13.2 kg of 5-aceto-2-benzyloxybenzoic acid ethyl ester, solved in 40 kg of dioxane, are added. Heating is continued until the reaction mixture boils (appr. 100C), followed by reflux boiling for six hours. During the boiling the reaction mixture turns black from precipitated selenium. The reaction mixture is ~ -allowed to cool to room temperature and the precipitated selenium is filtered off. Addition to the filtrate at room temperature of 6.6 kg tert. butylamine and agitation at room ~-temperature during four hours. The excess tert. butylamine -~
is evaporated at reduced pressure.
Dioxane solution at room temperature is added in a nitrogen atmosphere to 85.5 kg of a 25% toluene solution of sodium aIuminium diethyldihydride at a rate such that the temperature in the reaction mixture does not exceed 25C.
Following the addition, agitation is continued at 25C for one hour. The complex compound of product and reducing agent that has formed is decomposed in normal manner by adding water and alkali solution. The additions have to be made slowly owing to the effervescence caused by released ethane.
The organic phase is separated and insipissated. 135 kg of 95% ethanol are added to the inspissation residue. Further, addition of 0.3 kg of 10% palladium carbon and hydrogenation at normal pressure, until the hydrogen consumption ceases. On removal of the catalyst, the solvents are evaporated. The product is crystallized from the evaporation residue with the aid of a methanol/ethyl acetate mixture.
The yield is 6.2-6.7 kg (59-63% of theoretical), -melting point 157-158C.
Example 9 ~ ;
-tert.-butylaminomethy1-4-hydroxv-m-xylene-~1, ~3-diol To 59 kg of dioxane, 0,35 kg water are added and k ~ .
`' ... , . : : .
,: ~ , . . , ; :

lQ4~658 the mixture is heated to 70-80C. 4.39 kg of selenium dioxide are added. On dissolution of the selenium dioxide, 11.8 kg of 5-aceto-2-benzyloxybenzoic acid ethyl ester, solved in 35.5 kg of dioxane, are added. The reaction mixture is further heated during the addition until the reaction mixture boils (appr. 100C). Reflux boiling is continued for six hours.
I During the boiling the colour of the reaction mixture turns j black, owing to precipitated.

, .
A

,~ ' ' . . .

104al~S~
selenium. ~fter boiling, the mixture i9 allowed to cool to room temperature. The selenium is filtered off (If it is de 9i-red to isolate the glyoxal derivative, this is done by evapora-ting the dioxane, whereby the glyoxal derivative, prepared in this manner~ is obtained as a viscous oil.) To the filtrate at room temperature, 5.9 kg of tert.butyla-mine are added, with agitation at room temperature during four hours. Evaporation of the exce~s tert.butylamine at reduced pressure.
The reaction mixture is made to run, in a nitrogen atmosph~-re, into 40 kg of 70% benzene solution of sodium bis(2-methoxy) aluminiumhydride. The addition is made at appr. 60C. After ; this addition, reflu~ boiling for one hour. The complez com-pound which is formed between the reducing agent and the pro-i duct i9 decomposed in normal manner with the aid of water and hydrochloric acid. The oily product layer is separated, solved 1 in chloroform, set free from it~ hydrochloride salt with a basic I ~olution, dried with sodium sulphate and treated with active carbon. ~he chloroform is evaporated at reduced pressure. To the evaporation residue 120kg of 95% ethanol are added. Addi-tion of 0.26 kg of 10~ palladium carbon and hydrogenation at normal pressure, until the hydrogen consump-tion ceases. After , removal o~ the catalyst, the solvents are evaporated. ~he pro-. .
duct is crystallized from the evaporation residue with the aid of a methanol/ethyl aoetate mixture.
The yield is 5.5-5.9 kg (58-62% of theoretical), melting ~ -point 157-158C.
.

~; ~ . . - , .

.''i.................................................... . .

:, .
_ ~ _ :~
.~. . . . . ..

. .

. . ... . . , . . :: . . , :

Claims (2)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:
1. A method for preparing .alpha.1-tert.-butylaminomethyl-4-hydroxy-m-xylene-.alpha.1,.alpha.3-diole having the formula:

and its pharmaceutically acceptable acid addition salts, which comprises converting an imine derivative having the formula:

where R represents a lower straight-chain or branched hydrocarbon radical containing 1 to 6 carbon atoms, and Ar is an aryl group, into an intermediate compound having the formula:

by simultaneous hydrogenation and reduction in the presence of a catalyst selected from the group consisting of sodium bis-(2-methoxyethoxy) aluminum hydride and sodium aluminum diethyl dihydride, removing the arylmethyl protective group from the intermediate compound by catalytic hydrogenation and, where a pharmaceutically acceptable acid addition salt is required, reacting the resulting .alpha.1-tert.-butylaminomethyl-4-hydroxy-m-xylene-.alpha.1, .alpha.3-diole with a pharmaceutically acceptable organic or inorganic acid to provide the corresponding acid addition salt.
2. A method according to claim 1, wherein the simultaneous hydrogenation and reduction of the imine derivative is carried out in dioxane, benzene or toluene.
CA223,245A 1974-03-29 1975-03-27 INDUSTRIAL METHOD FOR PRODUCING .alpha.1-TERT.-BUTYLAMINO-METHYL-4-HYDROXY-M-XYLENE-.alpha.1,.alpha.3-DIOLE Expired CA1040658A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
FI982/74A FI56673C (en) 1974-03-29 1974-03-29 NYTT FOERFARANDE FOER FRAMSTAELLNING AV ALFA-TERT-BYTYLAMINOMETHYL-4-HYDROXY-M-XYLEN-ALFA1 ALFA3-DIOL

Publications (1)

Publication Number Publication Date
CA1040658A true CA1040658A (en) 1978-10-17

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CA223,245A Expired CA1040658A (en) 1974-03-29 1975-03-27 INDUSTRIAL METHOD FOR PRODUCING .alpha.1-TERT.-BUTYLAMINO-METHYL-4-HYDROXY-M-XYLENE-.alpha.1,.alpha.3-DIOLE

Country Status (7)

Country Link
JP (1) JPS5953256B2 (en)
CA (1) CA1040658A (en)
DK (1) DK135500C (en)
FI (1) FI56673C (en)
NO (1) NO140297C (en)
SE (1) SE433608B (en)
SU (1) SU538660A3 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7465831B2 (en) 2004-05-20 2008-12-16 Teva Pharmaceutical Fine Chemicals S.R.L. Levalbuterol hydrochloride Polymorph A
CN110963929A (en) * 2019-11-26 2020-04-07 安徽恒星制药有限公司 Preparation method of salbutamol hydrochloride suitable for industrial production

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0043807B1 (en) 1980-07-09 1984-05-30 Aktiebolaget Draco 1-(dihydroxyphenyl)-2-amino-ethanol derivatives; preparation, compositions and intermediates
FI118418B (en) 2003-04-17 2007-11-15 Ecocat Oy Aluminum-rounded catalytic converter for cleaning of gas leaks

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7465831B2 (en) 2004-05-20 2008-12-16 Teva Pharmaceutical Fine Chemicals S.R.L. Levalbuterol hydrochloride Polymorph A
US7488758B2 (en) 2004-05-20 2009-02-10 Teva Pharmaceutical Fine Chemicals, S.R.L. Levalbuterol hydrochloride polymorph B
CN110963929A (en) * 2019-11-26 2020-04-07 安徽恒星制药有限公司 Preparation method of salbutamol hydrochloride suitable for industrial production
CN110963929B (en) * 2019-11-26 2022-10-21 安徽恒星制药有限公司 Preparation method of salbutamol hydrochloride suitable for industrial production

Also Published As

Publication number Publication date
SU538660A3 (en) 1976-12-05
FI98274A (en) 1975-09-30
SE433608B (en) 1984-06-04
DK135500B (en) 1977-05-09
NO751034L (en) 1975-09-30
NO140297B (en) 1979-04-30
JPS5953256B2 (en) 1984-12-24
JPS50130732A (en) 1975-10-16
SE7503657L (en) 1975-09-30
DK135500C (en) 1977-10-24
NO140297C (en) 1979-08-08
DK133975A (en) 1975-09-30
FI56673B (en) 1979-11-30
FI56673C (en) 1981-02-04

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