EP1735272A1

EP1735272A1 - Method for producing azidoalkyl amines

Info

Publication number: EP1735272A1
Application number: EP05736801A
Authority: EP
Inventors: Jan Haller
Original assignee: Dynamit Nobel GmbH
Current assignee: Dynamit Nobel GmbH
Priority date: 2004-04-07
Filing date: 2005-04-07
Publication date: 2006-12-27
Also published as: DE102004045870A1; WO2005097736A1; JP2007532505A

Abstract

The invention relates to a method for producing azidoalkyl amines. According to said method, in a first step a bifunctional alkane comprising two different nucleofugic groups is reacted with an azide to form a monofunctional azidoalkane, during which process one nucleofugic group is cleaved and in a second step, the monofunctional azidoalkane is reacted with a primary or secondary amine to form azidoalkyl amine, during which process the second nucleofugic group is cleaved.

Description

Process for the preparation of azidoalkylamines

The invention relates to a process for the preparation of azidoalkylamines.

Azidoalkylamines play an important role as intermediates in organic synthesis.

The synthesis of alkyl azides by means of nucleophilic substitution is known. The corresponding starting compound reacts with an azide.

J. Org. Chem. 1957, 22, 238-240 describes the synthesis of alkyl azides starting from alkyl bromides and iodides in alcohols or 2-alkoxyethanols with the addition of water. The alkyl azides have no other functional groups.

In Tetrahedron Lett. 1991, 32, 183-186 describes the preparation of diazidoallenes from the corresponding dichloro or dibromo derivatives in dimethylformamide.

J. Org. Chem. 1957, 22, 995-996 describes the synthesis of 2-chloroethyl azide starting from 2-chloroethyl-p-toluenesulfonate in a mixture of methanol and water. The reaction mixture is refluxed for 24 hours and the product is then extracted and distilled.

J. Org. Chem. 1993, 58, 3736-3741 describes the synthesis of azidoalkylamines and N- (azidoalkyl) -diaminoalkanes, N- (haloalkyl) -amines or -diaminoalkanes serving as intermediates. These have the disadvantage that their synthesis is complicated and that they can cyclize through intramolecular substitution. In the synthesis of N- (4-azidobutyl 1,3-propanediamine in particular, the yield in the last stage is only 30%, since the ring-closing nucleophilic substitution to N- (3-aminopropyl) pyrrolidine comes to the fore The synthesis of azidobutylamines by aminolysis of 1-azido-4-iodobutane is also described, which in turn is described in two Stages prepared by the reaction of 1-bromo-4-chlorobutane with sodium azide to 1-azido-4-chlorobutane and the activation of the nucleofugic group chloride by replacing it with iodide.

The synthesis of azidoalkylamines is particularly problematic when additional positions on the amino group can be substituted. Either a poor yield or complex protection group technology has to be accepted.

JP 2002-332274 describes such a synthesis in which the amino groups are protected. This makes the synthesis very complex and the yield across all stages is below 40%.

The object of the invention is to overcome the disadvantages of the prior art and in particular to provide a process for the preparation of azidoalkylamines which delivers good yields with relatively little effort.

The object is achieved by a method with the characteristics of the main claim. In the first stage of the process, a bifunctional alkane with two different nucleofugic groups is reacted with an azide with elimination of a nucleofugic group to form a monofunctional azidoalkane. In the second stage, the monofunctional azidoalkane is reacted with a primary or secondary amine to split off the second nucleofugic group to give the azidoalkylamine.

A bifunctional alkane is understood here to mean a compound which contains two different nucleofugic groups, in which each of the two nucleofugic groups is bonded to a primary, secondary or tertiary alkyl group and the two alkyl groups are connected to one another directly or via one or more intermediate members Z. Intermediate links Z can be, for example: saturated or unsaturated hydrocarbon chains, aryl groups, saturated or unsaturated carbocycles, which furthermore link members such as -O-, -S-, -C (= O) -, -CO ₂ -, - SO2 and non-reacting substituents such as ester, amide or ether groups may contain.

Surprisingly, it was found that the monofunctional azidoalkane obtained in the first stage (e.g. an azidochloroalkane) reacts with a primary or secondary amine without a prior exchange reaction being necessary (e.g. the less nucleofugic group chlorine is exchanged for a more reactive group such as iodine). It is also surprising that when the monofunctional azidoalkane is reacted with an amine, it is not the double-azidoalkylated product but almost exclusively the desired single-azidoalkylated product.

The course of the reaction can be shown schematically as follows (bifunctional alkane contains only unbranched, saturated hydrocarbon chains as intermediate members Z, second stage alternatively with a primary or secondary amine):

- <CH ₂₎ (primary amine)

R

N ₃ \ NH ^N \ N ₃ CH ₂ ) ^ R '(CH2) _n R' ⁷ HG ¹

(secondary amine) With:

G ¹ = nucleofuge group 1 G ² = nucleofuge group 2

n = natural number from 1 to 20, preferably from 2 to 10, particularly preferably from 3 to 6.

M = metal, preferably monovalent metal such as Li, Na, K, Rb, Cs (in the case of a polyvalent metal, the formula MN _{3 must} be adapted accordingly, for example M (N ₃ ) ₂ in the case of a divalent metal such as Ba, Zn, or M (N ₃ ) ₃ in the case of a trivalent metal such as Al); Ammonium, optionally also with organic substituents, where up to four H atoms of the ammonium ion can be substituted by, optionally also different, organic radicals, for example methyl, ethyl, propyl, butyl, benzyl), for example (NMe ₃ H) ⁺ , ( NEt ₃ H) ⁺ , (NBu) ⁺ or (NMe ₃ CH ₂ Ph) ⁺ or with M = substituted metal or semimetal, e.g. MN ₃ = SiMe ₃ N ₃ , SnBu ₃ N ₃ , AIEt ₂ N ₃ .

R, R '= alkyl having 1 to 20, preferably 2 to 10, particularly preferably 3 to 6 C atoms or functionalized alkyl having 1 to 20, preferably 2 to 10, particularly preferably 3 to 6 C atoms, where R and R '' can also be connected to form a ring, for example with the following functional groups (non-restrictive list):

Amin,

-OR ¹ with {R ¹ = H, alkyl, alkenyl, alkynyl, aryl, heterocycle, -C (= O) R ² , -C (= S) R ² with [R ² = alkyl, alkenyl, alkynyl, aryl, Heterocycle, alkoxy, aryloxy, heterocyclyloxy, -NR ³ R ⁴ with (R ³ and R ⁴ independently of one another = H, alkyl, alkenyl, alkynyl, aryl, heterocycle, where R ³ and R ^{4 can} also be linked to form a ring ), -SR ⁵ with (R ⁵ = alkyl, alkenyl, alkynyl, aryl, heterocycle)]}, -NR ⁶ R ⁷ with R ⁶ and R ⁷ independently of one another = R ¹ as previously defined and additionally -SO ₂ R ⁵ , where R ⁶ and R ^{7 can} also be linked to form a ring; -N = CR ⁸ R ⁹ with R ⁸ and R ⁹ independently of one another = R ² as previously defined, where R ⁸ and R ^{9 can} also be linked to form a ring,

-SR ¹⁰ with R ¹⁰ = R ¹ as previously defined but without H;

-C (= O) R ¹¹ , -C (= O) C (= O) R ¹¹ , -C (= NOR ³ ) R ¹¹ , -SOR ¹¹ , -SO ₂ R ¹¹ , -P (= O) R ¹¹ R ¹² with R ¹¹ and R ¹² = R ² as previously defined and additionally -OH;

-BR ¹³ R ¹⁴ with R ¹³ and R ¹⁴ independently of one another = R ⁵ , OR ³ , NR ³ R ⁴ as previously defined;

-SiR ¹⁵ R ¹⁶ R ¹⁷ with R ¹⁵ , R ¹⁶ and R ¹⁷ independently of one another = R ⁵ , OR ³ ;

-SnR ¹⁸ ₃ with R ¹⁸ = alkyl;

-F; -CN; -N ₃ ; -NO ₂ ;

Alkenyl, alkynyl, aryl or heterocycle.

Alternatively, a compound belonging to the following general formula can also be used as the bifunctional alkane:

with R ¹¹ , R ¹ ", R ^IV and R ^v = independently of one another H, alkyl, aryl, also linked to one another to form a ring; Z = saturated or unsaturated hydrocarbon chains with 1 to 20 C atoms, preferably 1 to 4 C atoms, aryl groups, saturated or unsaturated carbocycles, which furthermore have bridging members such as -O-, -S-, -C (= 0) - , -CO ₂ -, -SO ₂ - and non-reacting substituents, such as ester, amide or ether groups. Z can also be omitted, in which case the two carbon atoms in the above formula are directly linked to one another.

Nucleofuge groups (substituents) can e.g. be: chloride, bromide, iodide or sulfonates (such as methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate). The nucleofugic group with the higher reactivity is substituted in the first reaction step (process step) by the azide group, while the nucleofugic group with the lower reactivity is only substituted in the second reaction step (process step) by the primary or secondary amine. Examples of bifunctional alkanes are 1-bromo-2-chloroethane, 1-bromo-3-chloropropane, 1-bromo-3-chloro-2-methylpropane, 1-bromo-4-chlorobutane, 1-bromo-5-chloropentane, 1 -Bromo-6-chlorohexane, 2-bromo-1-chloropropane, 1-bromo-3-chloro-2,2-dimethoxypropane, 1-chloro-3-iodopropane, 1-chloro-4-iodobutane, 1-chloro-5 -iodpentane, 1-chloro-6-iodohexane, p-toluenesulfonic acid 2-chloroethyl ester, methanesulfonic acid 2-chloroethyl ester, p-toluenesulfonic acid 3-chloropropyl ester. An example of a bifunctional alkane with an aryl intermediate is 2- (chloromethyl) benzyl bromide.

Preferably the first stage of the process is carried out in a polar solvent, e.g. Formamide, dimethylformarnide, dimethylacetamide, dimethyl sulfoxide, diethylene glycol, methanol, acetone or water. Mixtures of these solvents, in particular an organic solvent and water, can also be used. Such a mixture preferably contains at most 30% by weight of water. Those solvents are particularly preferred in which both the bifunctional alkane and the azide are at least 1% by weight soluble.

The azidoalkane, which still contains a nucleofugic group, can - but does not have to - be purified before it reacts with the primary or secondary amine to form the azidoalkylamine. The intermediate connection is preferred with a extracted non-polar solvent from the polar solvent of the first stage. It is particularly preferred to add water after the addition of the non-polar solvent.

The primary or secondary amine is preferably used in excess in the second process step. The excess is particularly preferably 1 to 5000 mol%, in the case of monoamines preferably 10 to 100 mol% and in the case of polyvalent amines, such as diamines, preferably 100 to 1000 mol%. In particular, if the primary amine is a diamine and only one amino group is to be azidoalkylated, an excess of the diamine is used or this is used simultaneously as a solvent. Water is preferably added before, during or after the reaction with the amine, or a water-containing amine is used. The amount of water present in the reaction is preferably 5 to 90% by weight of the total amount of amine and water, particularly preferably 15 to 50% by weight.

To isolate the azidoalkylamine, it can be separated from the excess amine using an apolar solvent and distilled. The azidoalkylamine can be precipitated as a salt by adding an acid and can be further purified by recrystallization. In particular, N- (azidoalkyl) diaminoalkanes can be worked up in this way. The azidoalkylamine is preferably fractionally precipitated by first precipitating the excess, unreacted amine with the required amount of acid and separating it before the azidoalkylamine is precipitated with acid.

The azidoalkylamine obtained can be purified by chromatography as a free base, as a salt of the acid which is released in the reaction in the second stage, or as a salt of precipitation with an acid.

The azidoalkylamine obtained can also be separated off and / or purified by distillation. The invention is illustrated by the following examples, without restricting it:

Example 1: Preparation of N- (4-azidobutyl) -1,3-diaminopropane with addition of water and fractional precipitation as N- (4-azidobutyl) -1,3-propanediammonium bismethanesulfonate

Level 2)

65 g of 1-bromo-4-chlorobutane were metered into 27.1 g of sodium azide in 455 ml of dimethyl sulfoxide at room temperature. After stirring overnight at room temperature, a suspension was formed, ie 250 ml of hexane and 455 ml of water were added. After phase separation, the aqueous phase was extracted with a further 125 ml of hexane. The combined organic phases were washed with 250 ml of water and treated with 140.5 g of 1,3-diaminopropane. After 40 ml of water had been metered in, the hexane was distilled off in vacuo at 35 ° C. and the mixture was stirred at 35 ° C. for a further 5 hours. The cooled reaction mixture was extracted successively with 390 ml and 130 ml of toluene. 515.5 g of toluene extract were obtained. The main part of the 1,3-diaminopropane was fractionally precipitated from 250 g of the toluene phase in accordance with the analytically determined content by adding 16.9 g of methanesulfonic acid as 1,3-propanediammonium bismethanesulfonate. The solid was filtered off and washed with 30 ml of toluene and dried. 24.2 g of a colorless solid were obtained which contained 0.9% by weight of N- (4-azidobutyl) -1, 3-propanediammonium bismethanesulfonate. The main product was precipitated from the combined filtrates by metering in 22.3 g of methanesulfonic acid, filtered off and washed with 30 ml of toluene and twice with 30 ml of isopropanol each. After drying the solid, 39.6 g of N- (4-azidobutyl) -1, 3-propanediammonium bismethanesulfonate were obtained as a colorless solid with a purity of 98.2% by weight (58% yield). From the filtrate were able to acidify to pH 3 with a further 7.7 g of methanesulfonic acid, filter, wash the solid with toluene and isopropanol and dry a further 11.5 g of product with a content of 80.6% by weight (14% yield) N- ( 4-azidobutyl) -1, 3-propanediammonium bismethanesulfonate can be obtained.

300 MHz ¹ H NMR (CD ₃ OD): δ = 1.65-1.74 (m, 2H); 1.76-1.86 (m, 2H); 2.05-2.16 (m, 2H); 2.73 (s, 6H); 3.05-3.17 (m, 6H); 3.41 (t, 2H).

IR (KBr): v (cm ^"1 ) = 3425, 2947, 2781, 2098, 1504, 1196, 1161, 1057, 783, 563,

536th

Melting point (DSC): 115 ° C; Decomposition (DSC): 217 ° C (onset).

Warning: The 1-azido-4-chlorobutane isolated from the hexane extract by distilling off the solvent has an extremely high decomposition energy of 4000 J / g and is sensitive to impact!

Example 2: Preparation of N- (4-azidobutyl) -1,3-propanediamine with addition of water and precipitation as N- (4-azidobutyl) -1,3-propanediammonium bis-methanesulfonate

65 g of 1-bromo-4-chlorobutane were metered into 27.1 g of sodium azide in 260 ml of dimethyl sulfoxide at room temperature. After stirring for two hours at room temperature, a suspension was formed to which 260 ml of hexane and 260 ml of water were added. After phase separation, the aqueous phase was extracted with a further 130 ml of hexane. The combined organic phases were washed with 260 ml of water and treated with 140.4 g of 1,3-diaminopropane. After 40 ml of water had been metered in, the hexane was distilled off at 35 ° C. in vacuo and the mixture was stirred at 35 ° C. for a further 4 hours. The cooled reaction mixture was extracted successively with 390 ml and 130 ml of toluene and the product was precipitated from the toluene phase by adding 120 g of methanesulfonic acid. The solid was washed with 130 ml of isopropanol and extracted with 730 ml of hot isopropanol. From the cooled extract, 69.4 g (56% yield) of N- (4-azidobutyl) -1,3-propanediammonium bismethanes-ionfonate crystallized as a colorless solid with a purity of 95%. The product could be further purified by recrystallization from isopropanol / water.

Example 3: Preparation of N- (4-azidobutyl) -1,3-propanediamine using water-containing 1,3-diaminopropane and precipitation as N- (4-azidobutyl) -1,3-propanediammonium bismethanesulfonate

5 g of 1-bromo-4-chlorobutane were metered into 1.9 g of sodium azide in 20 ml of dimethyl sulfoxide at room temperature. After stirring at room temperature overnight, a suspension was formed, to which 20 ml of hexane and 20 ml of water were added. After phase separation, the aqueous phase was extracted with a further 20 ml hexane. The combined organic phases were washed with 20 ml of water and added to 9.7 g of 1,3-diaminopropane, which contained about 20% by weight of water. The mixture was stirred at room temperature for 1 hour, warmed to 35 ° C., the hexane was distilled off in vacuo and the mixture was stirred at 35 ° C. for a further 4 hours. The cooled, cloudy solution was extracted twice with 10 ml of toluene and the product was fractionally precipitated from the toluene phase by adding 5.4 g of methanesulfonic acid. The solid was washed with acetonitrile and recrystallized from 50 ml of isopropanol. 6.0 g (56% yield) of N- (4-azidobutyl) -1, 3-propanediammonium bismethanesulfonate were obtained as a colorless solid with a purity of 98.4 ° / o.

Example 4: Preparation of N- (4-A_zidobutyl) -1,3-propanediamine and precipitation as N- (4-azidobutyl) -1,3-propanediarrimonium bismethanesulfonate

20 g of 1-bromo-4-chlorobutane were metered into 8 g of sodium azide in 80 ml of dimethyl sulfoxide at 35 ° C. After stirring for two hours at 35 ° C., a suspension was formed which, after cooling to room temperature, was admixed with 77 ml of hexane and with 77 ml of water. After phase separation, the aqueous phase was extracted with a further 40 ml of hexane. The combined organic phases were washed with 80 ml of water and 43.2 g of 1,3-diaminopropane were added. The mixture was heated to 35 ° C., the hexane was distilled off in vacuo and the mixture was stirred at 35 ° C. for a further 4 hours. Here, a colorless crystallized Solid. The cooled mixture was treated twice with 40 ml of toluene and the solid consisting mainly of 1,3-propanediamine hydrochloride was separated off. The product was precipitated from the toluene phase by adding 21.5 g of methanesulfonic acid. The solid was washed successively with 25 ml of toluene and 50 ml of isopropanol and taken up in 450 ml of hot isopropanol. The insoluble matter was filtered off. After the filtrate had cooled, 19.8 g (56% yield) of N- (4-azidobutyl) -1,3-propanediammonium bismethanesulfonate were obtained therefrom as a colorless solid with a purity of 90.8% and further purified by recrystallization from isopropanol.

Example 5: Preparation of 4-azidodibutylamine hydrochloride

Level 2)

25 g of 1-bromo-4-chlorobutane were metered into 10 g of sodium azide in 175 ml of dimethyl sulfoxide at 25 to 28 ° C. After stirring overnight at room temperature, the mixture was mixed with 100 ml of hexane and 175 ml of water, the separated aqueous phase was extracted with 50 ml of hexane and the combined organic phases were washed with 100 ml of water. 113.4 g of a solution of 1-azido-4-chlorobutane in hexane were obtained. 17.5 g of this solution were mixed with 3.3 g of butylamine and 10 ml of ethanol and the hexane was distilled off at 30 ° C. in vacuo. After stirring for four hours at 30 ° C., the reaction mixture was concentrated in vacuo and 4-azidodibutylammonium hydrochloride was purified by column chromatography on silica gel with dichloromethane / methanol. 1.3 g (28% yield) of 4-azidodibutylammonium hydrochloride were obtained as a colorless solid. 300 MHz ¹ H NMR (CD ₃ OD): δ = 1.00 (t, 3H); 1.37-1.48 (m, 2H); 1.62-1.76 (m,

6H); 2.90-2.98 (m, 4H); 3.39 (t, 2H).

IR (KBr): v (cm ^"1 ) = 2932, 2870, 2797, 2453, 2091, 1593, 1462, 1261.

Claims

claims

1. Process for the preparation of azidoalkylamines, characterized in that in the first process step a bifunctional alkane with two different nucleofugic groups with an azide with elimination of a nucleofugic group to form a monofunctional azidoalkane and in a second process step the monofunctional azidoalkane with an amine with elimination the second nucleofugic group is converted to azidoalkylamine.

2. The method according to claim 1, characterized in that the amine is a primary amine.

3. The method according to claim 1 or 2, characterized in that the azide is a metal azide with a monovalent metal from the group Li, Na, K, Rb, Cs.

4. The method according to claim 1 or 2, characterized in that the azide is a metal azide with a polyvalent metal from the group Ba, Zn, AI.

5. The method according to claim 1 or 2, characterized in that the azide is an ammonium azide, wherein up to four H atoms of the ammonium nitrogen can be substituted by organic radicals.

6. The method according to claim 1 or 2, characterized in that the azide is a metal or semi-metal azide in which the metal or the semi-metal carries organic substituents.

7. The method according to one or more of claims 1 to 6, characterized in that the nucleofugic groups are selected from: chloride, bromide, iodide or sulfonates.

8. The method according to one or more of claims 1 to 7, characterized in that 1-bromo-2-chloroethane, 1-bromo- as the bifunctional alkane 3-chloropropane, 1-bromo-3-chloro-2-methylpropane, 1-bromo-4-chlorobutane, 1-bromo-5-chloropentane, 1-bromo-6-chlorohexane, 2-bromo-1-chloropropane, 1- Bromine-3-chloro-2,2-dimethoxypropane, 1-chloro-3-iodopropane, 1-chloro-4-iodobutane, 1-chloro-5-iodopentane, 1-chloro-6-iodohexane, p-toluenesulfonic acid-2- chloroethyl ester, 2-chloroethyl methanesulfonate, 3-chloropropyl p-toluenesulfonate or 2- (chloromethyl) benzyl bromide is used.

9. The method according to one or more of claims 1 to 8, characterized in that the first stage of the method is carried out in a polar solvent.

10. The method according to one or more of claims 1 to 8, characterized in that the first stage of the method is carried out in a solvent in which both the bifunctional alkane and the azide are at least 1% by weight soluble.

11. The method according to one or more of claims 9 or 10, characterized in that formamide, dimethylformamide, dimethylacetamide, dimethyl sulfoxide or diethylene glycol is used as solvent.

12. The method according to one or more of claims 9 to 11, characterized in that the monofunctional azidoalkane is extracted with a non-polar solvent from the polar solvent of the first stage.

13. The method according to claim 12, characterized in that in the extraction of the monofunctional azidoalkane after the addition of the non-polar solvent, water is additionally added.

14. The method according to one or more of claims 1 to 13, characterized in that the monofunctional azidoalkane is reacted without isolation as a pure substance with the amine.

15. The method according to one or more of claims 1 to 14, characterized in that in the second stage of the process, the amine is used in an excess of 1 to 5000 mol%.

16. The method according to claim 15, characterized in that we use the amine in an excess of 10 to 100 mol% in the second stage of the process.

17. The method according to one or more of claims 1 to 16, characterized in that the amine contains one or more further functional groups.

18. The method according to one or more of claims 1 to 17, characterized in that the amine is a diamine.

19. The method according to claim 18, characterized in that the diamine is used in an excess of 100 to 1000 mol%.

20. The method according to one or more of claims 1 to 19, characterized in that water is added before, during or after the reaction with the amine, or a water-containing amine is used.

21. The method according to claim 20, characterized in that the amount of water present in the reaction is 5 to 90 wt .-% based on the total amount of amine and water.

22. The method according to claim 20, characterized in that the amount of water present in the reaction is 15 to 50 wt .-% based on the total amount of amine and water.

23. The method according to one or more of claims 1 to 22, characterized in that the azidoalkylamine is an N- (azidoalkyl) diaminoalkane and is extracted from the excess amine by extraction with a non-polar solvent.

24. The method according to one or more of claims 1 to 23, characterized in that the azidoalkylamine is precipitated by adding an acid.

25. The method according to claim 24, characterized in that the azidoalkylamine is fractionally precipitated by adding an acid.

26. The method according to one or more of claims 1 to 25, characterized in that the azidoalkylamine obtained as a free base, as a salt with the acid which is released in the reaction in the second stage, or as a salt of precipitation with an acid Chromatography is cleaned.

27. The method according to one or more of claims 1 to 23, characterized in that the azidoalkylamine obtained is separated off and / or purified by distillation.