DE2118286A1 - Process for the production of amines - Google Patents

Description

Dr.-lnQ. by Kreisler Dr.-lng. Sch8nwald «« - «,, / ,,

Dr-lng.Th. Meyer Dr. Fues Dipl.-Chem. Alek vonKreisler 987-FTG-l

Did.-Chem. Corola Keller Dr.-lng. Klöpsch Diploma lng. SeIHn ₉ March 15, 1971

Cologne, D "ichm * nnhau · ... IK-ba

Process for the production of amines

This invention relates to the preparation of amines by desulfonylation of sulfonamides and shows on a way to prepare pure, functionally substituted amines and especially arylhydroxyalkylamines.

The desulfonylation of Sulfonamlden for preparing amines may be desirable in a variety of cases. Amines are often converted into their sulfonamides in order to protect them from undesired reactions, such as oxidation, or to modify their reactivity in the run-up to one of the subsequent chemical syntheses. For example, if one wants to monoalkylate a primary amine, one can easily form the corresponding sulfonamide , react this with an alkylating agent and then split off the sulfonamide group. Sulfonamide derivatives are also useful as intermediates in the purification of amines, since they are generally easily crystallized. Sulphonamides can also be used for the storage of amines, in order to reduce undesired oxidation to a minimum. This pilot? Possibility is of particular interest in connection with aromatic polyamines.

987-FTG-2 March 15, 1971

18286

Methods for the desulfonylation of sulfonamides have been extensively studied. [Compare, for example, Searles et al. "Cleavage and Rearrangement of Sulfonamides", Chemical Reviews, Vol. 59, pages 1077-1103 (1959).] Although the conversion of a sulfonamide by hydrolysis into the corresponding amine is generally known, this reaction is well known lengthy, and oxidation of the amine frequently occurs during the reaction. Furthermore, if a catalyst, such as, for example, sulfuric acid, is used to accelerate the hydrolysis, rearrangements to form sulfones or other undesirable side reactions can take place.

The desulfonylation of sulfonamides with metal hydrides has been described as generally unsatisfactory. On page 1094 of the above referenced Searles et al. it is determined:

. "Sulphonamides are very resistant to reduction Lithium aluminum hydride as well as other anionic reducing agents. Same cause used to explain the Resistance to alkaline cleavage is used, can also be applied here: The shielding of the Sulfur atom from nucleophilic attack by negatively charged oxygen and nitrogen atoms. Here, too, can It is found that primary sulfonamides are so persistent

- 2 109844/1994

987-FTG-3 March 15, 1971

are that they have not been cleaved by lithium aluminum hydride, and secondary sulfonamides only, by using unusually severe conditions. "

In addition, even if the application of lithium aluminum hydride To be successful, it requires the use of essential solvents that are highly flammable and therefore undesirable from an industrial point of view.

The invention relates to the conversion of a sulfonamide into an amine under safe, mild conditions in high yield by using sodium bis (2-methoxyethoxy) aluminum hydride as a reducing agent in at least a stoichiometric amount. The reaction product thus obtained is decomposed with an aqueous solution and the amine is recovered.

The sodium bis (2-methoxyethoxy) aluminum hydride used in this invention is represented by the formula NaAlH ₂ (OCH ₂ CH ₂ OCH ₃ ) ₂ and can be prepared, for example, by the method described in French patent 1,515,582.

- 3 109844/1994

OmtHA INSPECTED

987-FTG-4 March 15, 1971 IK-bi

According to the stoichiometry of the reductive cleavage of these Invention requires one mole of sulfonamide group two Moles of sodium bis (2-methoxyethoxy) aluminum hydride. Contains as described below, the sulfonamide compound other reducible functional groups, the amount of said hydride must be increased accordingly be., In all cases a disturbing " chiometric excess of sodium bis (2-methoxyethoxy) aluminum hydride used, such as 1.5 to 3 times the amount, especially double the amount the amount required.

The desulfonylation of a sulfonamide according to the invention Process can conveniently be carried out in an inert solvent such as, for example in the relatively safe aromatic hydrocarbon solvents (e.g. benzene, toluene and the xylenes) and ethereal solvents (e.g. dibutyl ether, Dioxane tetrahydrofuran, dimethyl ether of Ethylene glycol and diethylene glycol dimethyl ether). The reaction is preferably carried out by adding a troublesome excess of sodium bis (2-methoxyeth © 3ey) aluminum hydride, dissolved in an organic hydrocarbon, the sulfonamide, that too

109844/199 4

987-FTG-5 March 15, 1971

is dissolved in an aromatic hydrocarbon, adds. The said hydride should be in an approximate 3-4: 1 molar ratio of hydride to sulfonamide may be used, if not simultaneously others functional groups are reduced. The hydride is preferably in the form of a solution of the same in one Organic solvents are used, the solution having a content of 10 to 90 percent by weight, preferably Contains 60 to 80 percent by weight of said hydride. Preferably then the mixture can be used for some Be refluxed for hours. The cooled complex is then decomposed. An aqueous alkaline Solution of a base, such as NaOH and KOH, is preferred for decomposition because of ease of work-up used. [An aqueous acidic solution can also be used for the decomposition, but the subsequent work-up is more laborious.) The organic layer is then separated and the aqueous layers can also be extracted to recover any amine residues. The amine can pass through very easily the addition of an acid which forms insoluble crystalline acid addition salts with amines, recovered in pure form will. Many such acids are known, picric acid being typical.

109844/1994

987-FTG-6 15o March 1971 IK-ba

The chemical nature of the sulfonamide is for feasibility of the process according to the invention is not critical. Thus, aliphatic, aromatic and heterocyclic sulfonamides can be prepared by the process according to the invention can be desulfonylated to the amines »Both primary and secondary sulfonamides can be desulfonylated be to under the mild conditions of the invention Process to generate the amines. The desulfonylation of the primary sulfonamides according to the invention The process is particularly surprising because lithium aluminum hydride, as described above, is useless, even under unusually severe conditions, The The sulfino group of the starting material can be replaced by an organic group such as aliphatic, cycloaliphatic or aromatic hydrocarbon groups (e.g. phenyl, tolyl, xylyl and benzyl). The two most commonly used sulfonamides for the above purpose are paratoluenesulfonamide (mostly simply referred to as mesylamine). In addition, the sulfino group can be replaced by a halogen such as Chlorine, may be substituted.

Of course, when carrying out the Desulfonylation should be considered whether the Amino component of the sulfonamide functional groups

- 6 109844/1994

987-FTG-7 March 15, 1971 IK-ba

contains, which can be reduced by sodium bis (2-methoxyethoxy) aluminum hydride under the mild conditions of the process according to the invention. For example, if the amino component of the sulfonamide in question contains an easily reducible carbonyl function which is to be obtained, this function can easily be protected by the formation of a ketal or acetal in the usual manner. On the other hand, it is possible that one simultaneously wishes to reduce a carbonyl or carboxy group to an alcohol. For example, an aminoalkylbenzyl alcohol can be prepared by subjecting the corresponding N-tosylaminoalkylbenzoic acid or the N-tosylaminoalkylbenzyl aldehyde to the process according to the invention. The latter reaction is particularly expedient if _f meta-Aminoalkylbenzylalkohole are desirable because the alkylation of Benzotsäure or benzaldehyde by Friedel-Crafts directly to the meta-orientation results.

A special. Embodiment of the invention Desulfonylation process advantageously uses the simultaneous reduction of keto groups in order to be relatively pure Form the pharmacologically important Arylhydroxytlkylamlne of the formula (I)

H txk Ά,

I I * I *

» K - // Vv- C — C— NH (I)

8286

March 15, 1971

to produce * where X and Y are independently hydrogen, hydroxy) methoxy or hydroxymethyl; R _{1 is} hydrogen or lower alkyl $ R _{2 is} hydrogen, lower alkyl or phenyl-lower alkyl. The term "lower alkyl" used herein includes even «mM veriswisigtköttige as well as cyclic carbon

• hydrogen groups ^ in particular those with up to six carbon atoms ₉ mostly with up to four carbon atoms.

- These compounds are useful as adrenergic

• Means ₉ SronehodlXatoren, nasal © decongestants, Vasodilatoroa _s Stimulantlan etc. * Examples of this are epinephrine iäkd! © ^ epinephrine and di © sympathomlmetischen amines like Sph @ ai »iß5 PßGßgßylephrine, isoproterenol and Nylbidoethnarinol, isoproterenol, isoproterenol.

With this ©? Embodiment is a sulfonamide Formula CIl)

0 Rn

V - ^^ - C - C - K - SO ₂ R ₃ (II)

®in _s % / oi ⁴ ifi I ₁ tmd Bg are as defined above , VX or a © to S reckoned group ^ % 1 or a group to Y redu

844/188 *

987-FTG-9 March 15, 1971 IK-ba

edible group and R _{3 is} an organic group or a Ha] Pgen (for example chlorine). This compound is reacted with sodium bis (2-methoxyethoxy) aluminum hydride and the resulting complex is worked up in the usual way. The nature of the organic group R ^ is not critical to the operability of the process, but obviously for reasons of convenience and convenience (e.g., when storing the hydride) one would choose a hydrocarbon group such as methyl, phenyl or tolyl.

In cases where reduction occurs at the same time, roan of course the relative molar amount of sodium bis (2-methoxyethoxy) aluminum hydride increase up to at least the stoichiometrically necessary amount "

The following examples illustrate the inventive desulfonylation of sulfonamides.

example 1 Desulfonylation of N-Tosyläthylamln

120 g of a 70 # solution of sodium bis (2-methoxyethoxy) aluminum hydride in benzene (0.4 mol) are added to 19.7 g of N-tosylethylamine (0.1 mol). Man removed the benzene under vacuum and replaced it with 350 ml

987-FTG-lO March 15, 1971

dry toluene. The mixture is heated under reflux for 36 hours, cooled to tree temperature and decomposed with 75 ml of a 25% sodium hydroxide solution. The emerging gaseous ethylamine is collected in salt form by passing it through an ethereal picric acid solution. 15.6 g (51% yield) of ethylammonium picrate, melting point 170-

Example 2

pesulfonylation ^ on N-Tosyldeoxyephedrln

12.9 g of DN-tosyldeoxyephedrine (0.0425 mol) are dissolved in 100 μl of dry benzene and 49.5 g of a 70% solution of sodium bis (2-methoxyethoxy) aluminum hydride in benzene (0.169 mol) are added with stirring. The mixture is refluxed for 10 hours, cooled and then 50 ml of a 10% sodium hydroxide solution are slowly added. The layers are separated and the aqueous layer is extracted 3 times with 100 ml portions of ether. The organic extract is dried over sodium sulfate and filtered. An ethereal solution of picric acid is added to and thus gains 10.3 g (82 # yield) D-Desoxyephedrinpikrat, melting point 145-145.5 ⁰ C.

103844/19 9

ORlGiNAL JNSPECTED

987-FTG-U March 15, 1971 ma IK-ba

Example 3 Desulfonylation of N-Meayldesoxyephedrln -

The procedure of Example 2 is repeated, 9.66 g of D-N-methyldeoxyephedrine (0.0425 mol) being used instead of the Toayl compound. The heating under reverse

flow is reduced to four hours. After adding the picric acid, QTί yield of D-deoxyephedrine plkrat, melting point 145-145.5 ⁰ C _{0, is isolated}

Example 4 Desulfonylation of 3- carboxy-4-hydroxy-qC- (M-t-butyl-

tosylamln) acetophenone

10.1 g of the above-mentioned compound (0.025 mol) are dissolved in 100 ml of benzene. (This starting compound can be obtained by alkylating salicylic acid according to Friedel-Crafts with N-tosyl ^ -t-butylaminoacetic acid chloride are prepared. 68 g of a 70% solution of sodium bis (2-methoxyethoxy) aluminum hydride in benzene (0.25 mol) are added at such a rate that gentle reflux is obtained remain. As soon as the addition is complete, the mixture is refluxed for 12 hours and cooled, slowly add water and filter the mixture. The organic layer is separated off and the aqueous layer is washed

109844/1994

- 11 -

987-FTQ-12 March 15, 1971

^IK - ^ba

Phase once with 100 ml of ether, brings the pH value of the aqueous phase using hydrochloric acid to 10-10.5. The solution is filtered, the water is removed and the mixture is extracted the residue continuously with ether. The ether is removed and the product N-t-butyl-jSM-dihydroxy-S-hydroxymethylphenethylamine is crystallized (Salbutamo'l) from isopropanol to, melting point 153.5-154.5 ° C.

N- Toaylplperidln

Dissolve il _s 97 g N-Tösyl & iperldin (0.05 mol) in 120 ml of dry benzene, add 57.1 g of a solution of 70 # Natrltäsbis- (2-methoxyethoxy) alUffliniumhydrid in benzene (0.2 IM) with stirring The mixture is heated under flow for 20 hours, cooled to room temperature, and the product is replaced by adding 75 ml of the above sodium hydroxide solution. Maa adds 100 ml of ether and separates the layers. The wisserig® layer is saturated with KatritUBhydroxyd and continuously extracted in a liquid-liquid extract ©? for two days. The organic feteakt® combined aan _9, dried over sodium sulfate and filtered. MkrineStif ¹ © is added to the ethereal solution and 11.8 g (75 µl yield ©)

987-FTG-13 March 15, 1971 ** IK-ba

point 148-150OC.

Example 6 Desulfonylation of Gls-3-methoxymethoxy »2-methyl-3 ~

phenyl-1-tosylazetidine

120 g of cls- 3-methoxymethoxy-2-methyl-3-phenyl-1-tosylazetidine (0.332 mol) are dissolved in 700 ml of benzene, and 390 g of a 70% solution of sodium (2-methoxyethoxy) aluminum hydride in benzene are added (1.33 mol) with stirring and the mixture is heated under reflux for 9 hours. The mixture is decomposed with 300 ml of the above aqueous alkali solution, the aqueous layer is drawn off and extracted twice with ether. The combined organic extracts are washed once with 150 ml of a 10% aqueous alkali solution and then twice with 200 ml of cold water each time. A slurry of 60 g (0.66 mol) of oxalic acid in 300 ml is added and the organic layer is extracted three times with 150 ml of water each time. The combined aqueous extracts are washed once with 250 ml of ether, cooled in an ice bath and saturated with sodium chloride. Then 60 g of sodium hydroxide are added and then 300 ml of ether. This mixture is filtered and the aqueous phase is extracted three times with 250 ml of ether each time. The essential solution is dried over sodium

108844/1894

_ 13 _

987-FTG-14

. March 15, 1971

ff- IK-ba

sulfate and filtered. The solvent is distilled off and the residue distilled at-76-78 ⁰ C (0.01 mm Hg) to yield cis-3-methoxymethoxy-2-methyl-3-phenylazetidin (59j £ yield). The steric configuration of the sulfonamide starting material is retained »

Example 7 Desulfonylation of N-mesylaniline

The benzene is removed under vacuum from 14.7 g of a 70% solution of sodium bis (2-methoxyethoxy) aluminum hydride in benzene (0.05 mol) and 100 ml of dry toluene are added. A solution of 1.71 is added with stirring g of N-mesylaniline (0.01 mol), removed 170 ml of toluene by distillation and continued heating under reflux for 18 hours. The reaction product is cooled, it is decomposed with 50 ml of a 10% aqueous sodium hydroxide solution, 50 ml of ether are added and the layers are separated o The aqueous layer is extracted with ether and the combined organic phases are washed with water, the organic extract is dried over sodium sulphate and filtered , add 5 ml of 4N ethereal hydrochloric acid to aniline and obtained in the form of the hydrochloric acid salt, melting point 197-19.8 ⁰ C (yield

109844/1994

_ 14 "

987-FTO-15 Mar 15, 1971 IK-ba

Example 8 Desulfonylation of N-methyl-H-tosyl - ^ - phanyl-l.S-

dloxolan-2-yl-methylaain

The benaol is removed in vacuo from 160 g of a solution of sodium bis (2-methoxyethoxy) aluminum hydride in benzene (0.55 mol), 300 ml of dry toluene and 48.8 g of N-methyl-N-tosyl 2-phenyX-1,3-dioxolan-2-ylmethylamine (0.137 mol) and heated under reflux for 22 hours. The reaction product is cooled, it is decomposed with 200 ml of a 10% aqueous sodium hydroxide solution and the layers are separated . The aqueous layer is extracted with ether, the organic phases are combined and washed with 10% aqueous sodium hydroxide, then with water. Then 25 g of oxalic acid and 150 ml of water are added, the layers are mixed and separated. The organic phase is extracted with water and the combined acidic aqueous extract is washed with ether. The aqueous layer is made alkaline with sodium hydroxide, the precipitated salts are filtered off and extracted with ether. After drying over sodium sulfate the ether is removed and the desired product is distilled N-methyl-2-pheny1-1,3-dioxolan-2-yl-methylamine at 73-75 ⁰ C at 0 "05 mm Hfe / 56Jf yield. The free ketone N-methylamine acetophenone can be used with

109844/1994

- 15 -

A>

987-FTG-16 March 15, 1971 IK-ba

Help to prepare water from hydrochloric acid. Example 9 Production of hexamethylenediamine

13.6 g (0.05 mol) of bis-N, N »-dimethylsulfonylhexamethylenediamine and 51.3 g (0.25 mol) of sodium bis (2-

* Methoxyethoxy) aluminum hydride in 500 ml of diglyme (diethylene glycol dimethyl ether) and heated under reflux at 150 ° C. for 48 hours. The mixture is decomposed with 125 ml of a 10% sodium hydroxide solution, 250 ml of ether are added and the layers are separated. The aqueous layer is saturated with sodium hydroxide and extracted continuously in a liquid-liquid extractor for 3 days. The organic extracts are combined, dried over sodium sulfate and filtered. The solvent is removed and distilled

the desired product under vacuum.

Many variations of the method described above will be apparent to the average person.

109844/1994 Γ

- 16 -

Claims (20)

987-FTG-17 15th March 1971 ff Expectations Process for the preparation of amines by desulfonylation of sulfonamides, characterized in that that a sulfonamide with at least a stoichiometric amount of sodium bis (2-methoxyethoxy) aluminum hydride converts and decomposes the complex formed in this way. 2. The method according to claim 1, characterized in that 1.5 to 3 times the stoichiometric amount of sodium bis (2-methoxyethoxy) aluminum hydride is used. 3. The method according to claim 1, characterized in that twice the stoichiometric amount of sodium bis (2-methoxyethoxy) aluminum hydride begins. 4. The method according to any one of claims 1 to 3, characterized in that one dl «implementation of the sulfonamide with sodium bis (2-methoxyethoxy) aluminum hydride in an inert organic solvent. 5. The method according to claim 4, characterized in that the solvent is an aromatic hydrocarbon used. 987-FTG-18 March 15, 1971 6. The method according to claim 5, characterized in that the solvent benzene, toluene or one of the Xylenes used. 7. The method according to claim 4, characterized in that the solvent used is an ethereal solvent used. 8. The method according to claim 7, characterized in that the solvent used is dibutyl ether, dioxane, tetrahydrofuran, Dimethyl ether of ethylene glycol or diethylene glycol dimethyl ether used. 9. The method according to any one of claims 1 to 8, characterized characterized in that the reaction of the sulfonamide with sodium bis (2-methoxyethoxy) aluminum hydride with heating performs. 10. The method according to any one of claims 1 to 9, characterized in that the sulfino group of the starting material is substituted by an organic group or halogen. 11. The method according to claim 10, characterized in that the organic group is an aliphatic, cycloaliphatic 109844/1994 _ 1 O 987-FTG-19 March 15, 1971 is a table or aromatic hydrocarbon group. 12. The method according to claim 10 or 11, characterized in that the sulfino group by methyl, tolyl or chlorine is substituted. 13. The method according to any one of claims 1 to 12, characterized characterized in that the sulfonamide is a primary sulfonamide. 14. The method according to any one of claims 1 to 12, characterized in that said sulfonamide is a secondary sulfonamide is. 15. The method according to any one of claims 1 to 14, characterized characterized in that said sulfonamide additionally contains at least one reducible group, which is reduced during implementation. 16. The method according to claim 15, characterized in that 'the sulfonamide at least one carbonyl or carboxyl group contains. 109844/1994 - 19 - 987-FTG-20 March 15, 1971 IK-ba 17. The method according to any one of claims 1 to 16, characterized characterized in that the starting material is a sulfonamide of the general formula _r l
Z O R I Τ ι? ί C— c— N ^SO 2 ^R 3 ^(II) | l "is used, in which R _{1 is} hydrogen or lower alkyl, R« is hydrogen, lower alkyl or phenyl-lower-alkyl, V and Z are independently hydrogen, hydroxy, methoxy or hydroxymethyl or groups which can be reduced thereto, and R ^ is a organic group or halogen means _o 18. The method according to claim 17, characterized in that a sulfonamide of the formula (II) as the starting material is used, in which V is hydroxy or a reducing agent bare group, Z is hydroxymethyl or a group which can be reducible thereto, R-, hydrogen and R «is tert-butyl. 19. An amine prepared by the process according to any one of claims 1 to 18. - 20 109844/1994 987-FTG-21 15th March 1971 IK-ba 20. A compound of the general formula C-C-N-H where X and Y independently of one another are hydrogen,
Are hydroxy, methoxy or hydroxymethyl, R-. and R _{2 are} as defined above, produced by a method according to one of claims 17 and 18 « 109844/1994