CA3006537A1 - Process for preparation of lisdexamphetamine - Google Patents
Process for preparation of lisdexamphetamine Download PDFInfo
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- CA3006537A1 CA3006537A1 CA3006537A CA3006537A CA3006537A1 CA 3006537 A1 CA3006537 A1 CA 3006537A1 CA 3006537 A CA3006537 A CA 3006537A CA 3006537 A CA3006537 A CA 3006537A CA 3006537 A1 CA3006537 A1 CA 3006537A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/14—Preparation of carboxylic acid amides by formation of carboxamide groups together with reactions not involving the carboxamide groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D203/00—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom
- C07D203/04—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D203/06—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D203/16—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with acylated ring nitrogen atoms
- C07D203/18—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with acylated ring nitrogen atoms by carboxylic acids, or by sulfur or nitrogen analogues thereof
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- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The present invention relates to a process for preparation of lisdexamphetamine and its pharmaceutically acceptable salts via a novel aziridine intermediate of Formula IV.
Description
PROCESS FOR PREPARATION OF LISDEXAMPHETAMINE
RELATED APPLICATIONS
This application claims the benefit of Indian Patent Application no.
4670/MUM/2015 filed on December 11, 2015 which is hereby incorporated by reference.
FIELD OF THE INVENTION
The present invention relates to a process for preparation of lisdexamphetamine and its pharmaceutically acceptable salts via a novel aziridine intermediate.
BACKGROUND OF THE INVENTION
Lisdexamphetamine, a compound of Formula I
0 oH3 1110 Formula I
is a conjugate of D-amphetamine and L-lysine and is chemically named as (2S)-
RELATED APPLICATIONS
This application claims the benefit of Indian Patent Application no.
4670/MUM/2015 filed on December 11, 2015 which is hereby incorporated by reference.
FIELD OF THE INVENTION
The present invention relates to a process for preparation of lisdexamphetamine and its pharmaceutically acceptable salts via a novel aziridine intermediate.
BACKGROUND OF THE INVENTION
Lisdexamphetamine, a compound of Formula I
0 oH3 1110 Formula I
is a conjugate of D-amphetamine and L-lysine and is chemically named as (2S)-
2,6-diamino-N-R2S)-methy1-2-phenylethyl]hexanamide. It is used for treatment of attention deficit hyperactivity disorder (ADHD).
Lisdexamphetamine and its pharmaceutically acceptable salts were first disclosed in US patent 7662787 wherein it is exemplified as hydrochloride salt. Process for preparation of lisdexamphetamine as disclosed comprises reaction of Boc-Lys-(Boc)-hydroxysuccinimido ester with D-amphetamine in 1,4-dioxane using N,N-diisopropylethylamine (DIPEA) as a base to obtain Boc-protected lisdexamphetamine which is then purified using flash chromatography and further reacted with a mixture of 4M hydrochloric acid/dioxane to yield L-lysine-D-amphetamine hydrochloride. The process is as shown in following scheme:
Lisdexamphetamine and its pharmaceutically acceptable salts were first disclosed in US patent 7662787 wherein it is exemplified as hydrochloride salt. Process for preparation of lisdexamphetamine as disclosed comprises reaction of Boc-Lys-(Boc)-hydroxysuccinimido ester with D-amphetamine in 1,4-dioxane using N,N-diisopropylethylamine (DIPEA) as a base to obtain Boc-protected lisdexamphetamine which is then purified using flash chromatography and further reacted with a mixture of 4M hydrochloric acid/dioxane to yield L-lysine-D-amphetamine hydrochloride. The process is as shown in following scheme:
3 "H
H C I
...--"( >4-----N-----N,..--ro H2N 3 õ..s. " 4 NH
N-0 HI'l H3 110 1,4 dioxane 1101 DIPEA
o c iy..,..
H 4Mdioxane 2HCI :
US 7659253 provide process for preparation of mesylate salt as shown below.
o o Na2 0 HO
HCI NH.-1-'0"----IC--1. H20, -35 C 0 NH2 2. Na0H, Boc anhydride HO
30 - 50 C, 2 hours $
1-1' NHS, DCC
H N3-0 Isopropyl acetate -50 hours 0_ /.._ o H
NH
,,,...0 \ ,,, I
D-amphetamine N-methyl momholine Isopropyl acetate, ¨25 C, 1 hour ---T
____________________________________________ A. NH
0 0 --*-0 telphcial Meth neralCid, HP
NH i The process includes preparation of Boc-Lys-(Boc)-hydroxysuccinimido ester wherein use of reagents like N-hydroxy-succinimide (NHS) and N,N-dicyclohexyl-carbodimiide(DCC) is carried out. The above processes involve use of flash column chromatography to purify crude Boc-protected L¨lysine-D¨amphetamine intermediate. Use of column chromatography is very cumbersome, tedious and time consuming, therefore not advisable at commercial scale.
International patent publication W02010042120A1 discloses a process for preparing lisdexamphetamine or its salts by reacting D-amphetamine with protected lysine or its salt by using an alkylphosphonic acid anhydride (For E.g. T3P) as coupling agent in presence of a base and solvent.
The process is as shown in following scheme:
_________________________________________________________________ 0 Ty aH3 H 0 DIPEA, Et0Ac H C NH I;
NH
\O
declOtse0;011, to H. 0 NH, NH NH, .s The application discloses use of alkylphosphonic acid anhydrides, which are expensive and need additional testing to show absence of phosphoric impurities in intermediate or final compound to meet regulatory requirements. So it is not appealing to use alkylphosphonic anhydrides for scale up operations.
International patent publication W02010/148305 discloses a process for preparation of lisdexamphetamine by removal of chlorine from N,N'-bis-trifluoroacetylchloro-lisdexamphetamine by hydrogenation in presence of a catalyst like Palladium on charcoal (Pd/C), to form N,N'-bis-trifluoroacetyl-lisdexamphetamine which on deprotection forms lisdexamphetamine. The process involves additional steps of inserting chloro group and thereafter removing the chloro group in subsequent step.
Thus there is a need for an efficient process for preparation of lisdexamphetamine and its pharmaceutically acceptable salts using easily available, less expensive and easy to handle raw materials.
SUMMARY OF THE INVENTION
The present invention provides a process for preparation of lisdexamphetamine, a compound of Formula I or pharmaceutically acceptable salts thereof;
f 0 bH 3 Oil Formula I
comprising:
a) reducing the compound of Formula IV
H\N H 410 X
Formula IV
wherein X and Y are independently selected from amino protecting groups or hydrogen, to obtain a compound of Formula I' NH
x/N
k 0 CH 110 wherein X and Y in compound of Formula I' are independently selected from amino protecting groups or hydrogen;
b) when X and/or Y in compound of Formula I' are amino protecting group, deprotecting the compound of Formula I' to obtain the compound of Formula I.
Thus, the present invention provides a process for preparation of lisdexamphetamine which involves the use of intermediates which are easily available, less expensive and easy to handle.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for preparation of lisdexamphetamine or pharmaceutically acceptable salts thereof.
According to the present invention there is provided a process for preparation of lisdexamphetamine, a compound of Formula I or pharmaceutically acceptable salts thereof;
H C I
...--"( >4-----N-----N,..--ro H2N 3 õ..s. " 4 NH
N-0 HI'l H3 110 1,4 dioxane 1101 DIPEA
o c iy..,..
H 4Mdioxane 2HCI :
US 7659253 provide process for preparation of mesylate salt as shown below.
o o Na2 0 HO
HCI NH.-1-'0"----IC--1. H20, -35 C 0 NH2 2. Na0H, Boc anhydride HO
30 - 50 C, 2 hours $
1-1' NHS, DCC
H N3-0 Isopropyl acetate -50 hours 0_ /.._ o H
NH
,,,...0 \ ,,, I
D-amphetamine N-methyl momholine Isopropyl acetate, ¨25 C, 1 hour ---T
____________________________________________ A. NH
0 0 --*-0 telphcial Meth neralCid, HP
NH i The process includes preparation of Boc-Lys-(Boc)-hydroxysuccinimido ester wherein use of reagents like N-hydroxy-succinimide (NHS) and N,N-dicyclohexyl-carbodimiide(DCC) is carried out. The above processes involve use of flash column chromatography to purify crude Boc-protected L¨lysine-D¨amphetamine intermediate. Use of column chromatography is very cumbersome, tedious and time consuming, therefore not advisable at commercial scale.
International patent publication W02010042120A1 discloses a process for preparing lisdexamphetamine or its salts by reacting D-amphetamine with protected lysine or its salt by using an alkylphosphonic acid anhydride (For E.g. T3P) as coupling agent in presence of a base and solvent.
The process is as shown in following scheme:
_________________________________________________________________ 0 Ty aH3 H 0 DIPEA, Et0Ac H C NH I;
NH
\O
declOtse0;011, to H. 0 NH, NH NH, .s The application discloses use of alkylphosphonic acid anhydrides, which are expensive and need additional testing to show absence of phosphoric impurities in intermediate or final compound to meet regulatory requirements. So it is not appealing to use alkylphosphonic anhydrides for scale up operations.
International patent publication W02010/148305 discloses a process for preparation of lisdexamphetamine by removal of chlorine from N,N'-bis-trifluoroacetylchloro-lisdexamphetamine by hydrogenation in presence of a catalyst like Palladium on charcoal (Pd/C), to form N,N'-bis-trifluoroacetyl-lisdexamphetamine which on deprotection forms lisdexamphetamine. The process involves additional steps of inserting chloro group and thereafter removing the chloro group in subsequent step.
Thus there is a need for an efficient process for preparation of lisdexamphetamine and its pharmaceutically acceptable salts using easily available, less expensive and easy to handle raw materials.
SUMMARY OF THE INVENTION
The present invention provides a process for preparation of lisdexamphetamine, a compound of Formula I or pharmaceutically acceptable salts thereof;
f 0 bH 3 Oil Formula I
comprising:
a) reducing the compound of Formula IV
H\N H 410 X
Formula IV
wherein X and Y are independently selected from amino protecting groups or hydrogen, to obtain a compound of Formula I' NH
x/N
k 0 CH 110 wherein X and Y in compound of Formula I' are independently selected from amino protecting groups or hydrogen;
b) when X and/or Y in compound of Formula I' are amino protecting group, deprotecting the compound of Formula I' to obtain the compound of Formula I.
Thus, the present invention provides a process for preparation of lisdexamphetamine which involves the use of intermediates which are easily available, less expensive and easy to handle.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for preparation of lisdexamphetamine or pharmaceutically acceptable salts thereof.
According to the present invention there is provided a process for preparation of lisdexamphetamine, a compound of Formula I or pharmaceutically acceptable salts thereof;
4 Formula I
comprising:
a) reducing the compound of Formula IV
X
Formula IV
wherein X and Y are independently selected from amino protecting groups or hydrogen, to obtain a compound of Formula I' H-N
wherein X and Y in compound of Formula I' are independently selected from amino protecting groups or hydrogen;
b) when X and/or Y in compound of Formula I' are amino protecting group, deprotecting the compound of Formula I' to obtain the compound of Formula I.
Protecting group, X and Y are defined as any group which is suitable to protect amino group for example t-butyloxycarbonyl (Boc), benzyloxycarbonyl (CBz), trifluoroacetyl (TBA), trimethylsilylethyloxycarbonyl (Teoc), allyloxycarbonyl (Alloc), fluorenylmethyloxycarbonyl (Fmoc) etc. The preferred amino protecting groups are t-butyloxycarbonyl (Boc) or CBz.
In step a, the compound of Formula IV is subjected to reduction to form compound of Formula I'. The compound of Formula I' represents a protected compound of Formula I
wherein the two amino groups in the compound of Formula I are protected by amino protecting groups X and Y.
When X and Y are hydrogen, the compound of Formula I' is same as the compound of Formula
comprising:
a) reducing the compound of Formula IV
X
Formula IV
wherein X and Y are independently selected from amino protecting groups or hydrogen, to obtain a compound of Formula I' H-N
wherein X and Y in compound of Formula I' are independently selected from amino protecting groups or hydrogen;
b) when X and/or Y in compound of Formula I' are amino protecting group, deprotecting the compound of Formula I' to obtain the compound of Formula I.
Protecting group, X and Y are defined as any group which is suitable to protect amino group for example t-butyloxycarbonyl (Boc), benzyloxycarbonyl (CBz), trifluoroacetyl (TBA), trimethylsilylethyloxycarbonyl (Teoc), allyloxycarbonyl (Alloc), fluorenylmethyloxycarbonyl (Fmoc) etc. The preferred amino protecting groups are t-butyloxycarbonyl (Boc) or CBz.
In step a, the compound of Formula IV is subjected to reduction to form compound of Formula I'. The compound of Formula I' represents a protected compound of Formula I
wherein the two amino groups in the compound of Formula I are protected by amino protecting groups X and Y.
When X and Y are hydrogen, the compound of Formula I' is same as the compound of Formula
5 I. Reduction can be performed by hydrogenating a solution of compound of Formula IV in a suitable solvent in presence of a catalyst. Catalyst can be selected from transition metal catalyst (usually Pd, Pt, Ni, or Rh). Preferably, the hydrogenating catalyst used is Pd/C. Reaction can carried out in presence of a solvent selected from methanol, ethanol, n-propyl alcohol, isopropyl alcohol, tetrahydrofuran, N,N-dimethylformamide, dimethylsulfoxide, acetonitrile etc.
Preferably, the solvent used is isopropyl alcohol. The reaction can be performed at room temperature for 7-8 hours. The completion of reaction can be monitored by thin layer chromatography (TLC). The compound of Formula I' can be isolated by any standard method known in the art typically the product is isolated by filtering off the catalyst and concentrating the filtrate.
When X or Y or both are protecting group, the product obtained in step a is subjected to deprotection to afford a compound of Formula I. Deprotection can be carried by any method known in the prior art for example by using a suitable acid in presence of solvent or by hydrogenation depending upon the nature of the protecting group. Suitable acid can be selected from the group consisting of methanesulphonic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, orthophosphoric acid etc. Preferably, acid used is methanesulfonic acid. Solvent can be selected from the group consisting aromatic hydrocarbon such as toluene, xylene, cyclohexane; ethers like tetrahydrofuran, 2-methyltetrahydrofuran and 1,4-dioxane etc.
Preferably, the solvent used is 1,4-dioxane. The reaction can be performed at temperature below C for 4-5 hours. The completion of reaction can be monitored by thin layer chromatography (TLC). The product can be isolated by any method known in the art; typically the product is isolated by filtration.
25 Lisdexamphetamine obtained by step a or step b can optionally be converted to its pharmaceutically acceptable salts. Pharmaceutically acceptable salt may be obtained by any of the methods known in the prior art, for instance, by treating it with a suitable acid in presence of solvent. Solvent can be selected from the group consisting hydrocarbon such as toluene, xylene, cyclohexane; ethers like tetrahydrofuran, 2-methyltetrahydrofuran and 1,4-dioxane etc.
Preferably, the solvent used is 1,4-dioxane. The completion of reaction can be monitored by thin
Preferably, the solvent used is isopropyl alcohol. The reaction can be performed at room temperature for 7-8 hours. The completion of reaction can be monitored by thin layer chromatography (TLC). The compound of Formula I' can be isolated by any standard method known in the art typically the product is isolated by filtering off the catalyst and concentrating the filtrate.
When X or Y or both are protecting group, the product obtained in step a is subjected to deprotection to afford a compound of Formula I. Deprotection can be carried by any method known in the prior art for example by using a suitable acid in presence of solvent or by hydrogenation depending upon the nature of the protecting group. Suitable acid can be selected from the group consisting of methanesulphonic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, orthophosphoric acid etc. Preferably, acid used is methanesulfonic acid. Solvent can be selected from the group consisting aromatic hydrocarbon such as toluene, xylene, cyclohexane; ethers like tetrahydrofuran, 2-methyltetrahydrofuran and 1,4-dioxane etc.
Preferably, the solvent used is 1,4-dioxane. The reaction can be performed at temperature below C for 4-5 hours. The completion of reaction can be monitored by thin layer chromatography (TLC). The product can be isolated by any method known in the art; typically the product is isolated by filtration.
25 Lisdexamphetamine obtained by step a or step b can optionally be converted to its pharmaceutically acceptable salts. Pharmaceutically acceptable salt may be obtained by any of the methods known in the prior art, for instance, by treating it with a suitable acid in presence of solvent. Solvent can be selected from the group consisting hydrocarbon such as toluene, xylene, cyclohexane; ethers like tetrahydrofuran, 2-methyltetrahydrofuran and 1,4-dioxane etc.
Preferably, the solvent used is 1,4-dioxane. The completion of reaction can be monitored by thin
6 layer chromatography (TLC). The product can be isolated by any standard method known in the art, typically the product is isolated by filtration.
The compounds of Formula IV have favorable physical properties which facilitate ease of handling, storage, transportation etc. For instance a compound of Formula IV
where X and Y are Boc, is a crystalline free flowing solid hence, is easy to handle, store and transport.
The compound of Formula IV may be prepared by a process comprising coupling a compound of Formula II
H Y
HZ
xI
Formula ll wherein, X and Y are same or different amino protecting groups or are hydrogen and Z is a leaving group, with a compound of Formula III
H3c Formula III
and optionally deprotecting a compound of Formula IV when X and Y are amino protecting groups.
The compound of Formula III, (2S,3R)-2-methyl-3-phenylaziridine, can be prepared as described in "Synthesis of 15N-labeled vicinal diamines through N-activated chiral aziridines:
Tools for the NMR study of platinum-based anticancer compounds, Tetrahedron Letters, 2013, Volume 54, Pages 545-548."
Z is a leaving group formed by reacting the corresponding free carboxylic acid of the compound of Formula II with either a suitable acid activating agents like carbonyldiimidazole (CDI), 1-(3-
The compounds of Formula IV have favorable physical properties which facilitate ease of handling, storage, transportation etc. For instance a compound of Formula IV
where X and Y are Boc, is a crystalline free flowing solid hence, is easy to handle, store and transport.
The compound of Formula IV may be prepared by a process comprising coupling a compound of Formula II
H Y
HZ
xI
Formula ll wherein, X and Y are same or different amino protecting groups or are hydrogen and Z is a leaving group, with a compound of Formula III
H3c Formula III
and optionally deprotecting a compound of Formula IV when X and Y are amino protecting groups.
The compound of Formula III, (2S,3R)-2-methyl-3-phenylaziridine, can be prepared as described in "Synthesis of 15N-labeled vicinal diamines through N-activated chiral aziridines:
Tools for the NMR study of platinum-based anticancer compounds, Tetrahedron Letters, 2013, Volume 54, Pages 545-548."
Z is a leaving group formed by reacting the corresponding free carboxylic acid of the compound of Formula II with either a suitable acid activating agents like carbonyldiimidazole (CDI), 1-(3-
7 dimethylaminopropy1)-3-ethylcarbodiimide (EDCI), benzotriazol-1 -ylox ytris(pyrrolidino)phosphonium hex afluoropho sphate (PyB OP), 0-( 1H-benzotriazol-1 -y1)-N,N,N,AP-tetramethyluronium hexafluorophosphate (HBTU) , N-hydroxybenzotriazole, N,N-dicyclohexyl-carbodimiide (DCC), N-hydroxysuccinimide (HOSu); or by reacting with a suitable halogenating agent. Preferably, the leaving group is chloro, bromo, iodo or hydroxysuccinimido ester (0Su). The structure of 0Su is as shown below:
0-....,,, o) OSii The most preferred leaving group is hydroxysuccinimido ester (0Su).
Coupling of the compound of Formula II with the compound of Formula III can be conveniently carried out in presence of a solvent and a base. Solvent can be selected from the group consisting of aromatic hydrocarbon such as toluene, xylene, cyclohexane; ethers like tetrahydrofuran, 2-methyltetrahydrofuran and 1,4-dioxane etc. Preferably, the solvent used is 1,4-dioxane. A
suitable base for the purpose can be selected from N-methylmorpholine, diisopropylethyl amine (DIPEA), triethylamine, tri-n-propylamine, tri-n-butylamine, pyridine and alkaline metal hydroxide & carbonates. Preferably, the base used is N-methylmorpholine. The reaction can be performed at temperature range of 20-35 C for 1-2 hours. The completion of reaction can be monitored by thin layer chromatography (TLC). After completion of reaction, the reaction product can be isolated as per any process under the purview of a person skilled in the art for example reaction mass is concentrated under vacuum and the residue obtained is dissolved in isopropyl acetate followed by washing with acid, a base followed by water, and concentrating the organic layer. The product of the coupling step having X or Y or both as protecting groups, can optionally be subjected for deprotection by method described earlier in the specification.
In another aspect, the present invention provides a compound of Formula IV
0-....,,, o) OSii The most preferred leaving group is hydroxysuccinimido ester (0Su).
Coupling of the compound of Formula II with the compound of Formula III can be conveniently carried out in presence of a solvent and a base. Solvent can be selected from the group consisting of aromatic hydrocarbon such as toluene, xylene, cyclohexane; ethers like tetrahydrofuran, 2-methyltetrahydrofuran and 1,4-dioxane etc. Preferably, the solvent used is 1,4-dioxane. A
suitable base for the purpose can be selected from N-methylmorpholine, diisopropylethyl amine (DIPEA), triethylamine, tri-n-propylamine, tri-n-butylamine, pyridine and alkaline metal hydroxide & carbonates. Preferably, the base used is N-methylmorpholine. The reaction can be performed at temperature range of 20-35 C for 1-2 hours. The completion of reaction can be monitored by thin layer chromatography (TLC). After completion of reaction, the reaction product can be isolated as per any process under the purview of a person skilled in the art for example reaction mass is concentrated under vacuum and the residue obtained is dissolved in isopropyl acetate followed by washing with acid, a base followed by water, and concentrating the organic layer. The product of the coupling step having X or Y or both as protecting groups, can optionally be subjected for deprotection by method described earlier in the specification.
In another aspect, the present invention provides a compound of Formula IV
8 Y
X H
Formula IV
or acid addition salt thereof;
wherein X and Y are independently selected from amino protecting groups or hydrogen.
Protecting group, X and Y are defined as any group which is suitable to protect amino group as described earlier in the specification. The preferred amino protecting groups are t-butyloxycarbonyl (Boc) or CBz.
The present invention is further illustrated in detail with reference to the following examples. It is desired that the examples be considered in all respect as illustrative and are not intended to limit the scope of the claimed invention.
EXAMPLES:
Example 1:
0.......,õ0.x., ,t1 HN y ao...., X
HN
p ,..õ... 0,.......0 () 0 .1_, 0-( s .......NH
0 0 1,4 choxane, N-methyl morphohne NH¨\ 1-1 H
- r Boc-L-Lys(Boc)-0Su (compound of Formula II wherein X and Y both are, Boc & Z
is 0Su; 4.0 g) was dissolved in 1,4-dioxane (24.0 mL) under inert atmosphere and was stirred for 10-15 mm.
N-methylmorpholine (1.08 mL) was added to the mixture and was stirred for 10 min. A solution of (2S,3R)-2-methyl-3-phenylaziridine (compound of Formula III, 1.80 g) in 1,4-dioxane (8 mL) was slowly added maintaining temperature below 25 C during addition.
Resulting reaction
X H
Formula IV
or acid addition salt thereof;
wherein X and Y are independently selected from amino protecting groups or hydrogen.
Protecting group, X and Y are defined as any group which is suitable to protect amino group as described earlier in the specification. The preferred amino protecting groups are t-butyloxycarbonyl (Boc) or CBz.
The present invention is further illustrated in detail with reference to the following examples. It is desired that the examples be considered in all respect as illustrative and are not intended to limit the scope of the claimed invention.
EXAMPLES:
Example 1:
0.......,õ0.x., ,t1 HN y ao...., X
HN
p ,..õ... 0,.......0 () 0 .1_, 0-( s .......NH
0 0 1,4 choxane, N-methyl morphohne NH¨\ 1-1 H
- r Boc-L-Lys(Boc)-0Su (compound of Formula II wherein X and Y both are, Boc & Z
is 0Su; 4.0 g) was dissolved in 1,4-dioxane (24.0 mL) under inert atmosphere and was stirred for 10-15 mm.
N-methylmorpholine (1.08 mL) was added to the mixture and was stirred for 10 min. A solution of (2S,3R)-2-methyl-3-phenylaziridine (compound of Formula III, 1.80 g) in 1,4-dioxane (8 mL) was slowly added maintaining temperature below 25 C during addition.
Resulting reaction
9 mixture was stirred for an hour. After completion of reaction (monitored by TLC), water was added to quench the reaction. The reaction mass was concentrated under reduced pressure below 80 C to get solid residue. The solid residue was treated with isopropylacetate (152 mL) and washed with acetic acid (8.0 g)/NaC1 (60.0 g)/water mixture (240 mL). The organic layer was further washed with aq. sodium bicarbonate solution (12.0 g in 240 mL water).
Then silica gel was added into organic layer and organic layer was stirred for an hour. Silica gel was filtered and washed with isopropyl acetate (8.0 mL). The combined organic layer was then concentrated under reduced pressure below 80 C and was dried under reduced pressure to get solid product.
Yield: 99.67 %.
Melting point: 108.0-109.5 C.
ltINMR (CDC13):6 7.21-7.26 (m, 5H), 5.12-5.14 (s, -NH), 4.57(s, -NH), 4.27-4.28 (m, 1H), 3.69-3.7(m,1H) 3.07-3.09 (m, 2H), 2.92-2.95 ( m, 1H), 1.89-1.95 (m, 1H), 1.70-1.75 (m, 1H), 1.41-1.48( m, 4H) , 1.38 (s, 9H), 1.31 (s, 9H), 0.99 (d, 3H).
13CNMR (CDC13): 6 185.88 (1C), 156.04 (1C), 155.48 (1C), 134.54 (1C), 128.10 (2C), 127.51 (2C), 127.42 (1C), 79.68 (1C), 79.519 (1C), 55.02 (1C), 43.15 (1C), 40.08 (1C), 39.34 (1C), 33.18 (1C), 29.63 (1C), 28.38 (3C), 28.20 (3C), 22.54(1C), 12.66(1C).
IR : 3359 cm-1 , 3313 cm-1, 2926 cm-1, 2865 cm-1, 1698 cm-1, 1678 cm-1 MS: m/z 480.7 (M+H30) .
Example 2:
0 ____ CZ-- XH X
_______________________ H Pd/C, H2(40 psi) C¨(---- o o ______________________ ( E
N S
H 0 401 _____________________ NH
Diboc-Lysdex-aziridine (compound of Formula IV where X and Y both are, Boc;
3.0 g) was dissolved in isopropyl alcohol (IPA) (20.0 mL) and resulting solution was stirred for 15 minutes 25 to obtain clear solution. Pd/C (0.15 g) was added to the reaction mixture and was kept under hydrogen pressure for 5-6 hours at 40 psi. Then Pd/C was filtered and again fresh Pd/C (0.1 g) was added to the reaction mixture and was kept under 40 psi hydrogen pressure for 2 hour.
Completion of reaction was checked by TLC. Pd/C was filtered and washed with IPA (6.0 ml).
The reaction mixture was then concentrated under reduced pressure below 80 C.
Yield: 3.20 g, Purity by HPLC: 96.66 %.
Example 3:
0 ________________ (C)i& X ]0 NH
HI
NH¨\ CD IH z Methane sulfome acid ____________ \ 2 in a NH
H
Diboc-lisdexamphetamine (1.5 g) was dissolved in 1,4-dioxane (12.75 mL) and was kept under stiffing for 15 mm under inert atmosphere. Methanesulfonic acid (1.554 g) was slowly added to the reaction mixture with maintaining temperature below 25 C. Reaction mixture was maintained under stiffing for 4-5 hours. Completion of reaction was checked by TLC. Reaction mass was filtered and washed with dioxane (3.0 mL) to obtain white solid. End solid product was dried under vacuum overnight at 55- 60 C.
Yield: 73.50 %;
Purity by HPLC: 99.24 %.
Example 4:
(),.......,0x.
HN H
, C)y HN 401 0 __ (....... X
() 0 .......KNH H
NH C) S
H ____________________________________ 31.
()\ 1,4 &mane , N-methyl morpholine NH NH
N N
- r H
Boc-L-Lys(Boc)-0Su (compound of Formula II where X and Y both are Boc & Z is 0Su; 25.0 g) was dissolved in 1,4-dioxane (150.0 mL) under inert atmosphere and was stirred for 10-15 min. N-methylmorpholine (6.75 mL) was added to the mixture and was stirred for
Then silica gel was added into organic layer and organic layer was stirred for an hour. Silica gel was filtered and washed with isopropyl acetate (8.0 mL). The combined organic layer was then concentrated under reduced pressure below 80 C and was dried under reduced pressure to get solid product.
Yield: 99.67 %.
Melting point: 108.0-109.5 C.
ltINMR (CDC13):6 7.21-7.26 (m, 5H), 5.12-5.14 (s, -NH), 4.57(s, -NH), 4.27-4.28 (m, 1H), 3.69-3.7(m,1H) 3.07-3.09 (m, 2H), 2.92-2.95 ( m, 1H), 1.89-1.95 (m, 1H), 1.70-1.75 (m, 1H), 1.41-1.48( m, 4H) , 1.38 (s, 9H), 1.31 (s, 9H), 0.99 (d, 3H).
13CNMR (CDC13): 6 185.88 (1C), 156.04 (1C), 155.48 (1C), 134.54 (1C), 128.10 (2C), 127.51 (2C), 127.42 (1C), 79.68 (1C), 79.519 (1C), 55.02 (1C), 43.15 (1C), 40.08 (1C), 39.34 (1C), 33.18 (1C), 29.63 (1C), 28.38 (3C), 28.20 (3C), 22.54(1C), 12.66(1C).
IR : 3359 cm-1 , 3313 cm-1, 2926 cm-1, 2865 cm-1, 1698 cm-1, 1678 cm-1 MS: m/z 480.7 (M+H30) .
Example 2:
0 ____ CZ-- XH X
_______________________ H Pd/C, H2(40 psi) C¨(---- o o ______________________ ( E
N S
H 0 401 _____________________ NH
Diboc-Lysdex-aziridine (compound of Formula IV where X and Y both are, Boc;
3.0 g) was dissolved in isopropyl alcohol (IPA) (20.0 mL) and resulting solution was stirred for 15 minutes 25 to obtain clear solution. Pd/C (0.15 g) was added to the reaction mixture and was kept under hydrogen pressure for 5-6 hours at 40 psi. Then Pd/C was filtered and again fresh Pd/C (0.1 g) was added to the reaction mixture and was kept under 40 psi hydrogen pressure for 2 hour.
Completion of reaction was checked by TLC. Pd/C was filtered and washed with IPA (6.0 ml).
The reaction mixture was then concentrated under reduced pressure below 80 C.
Yield: 3.20 g, Purity by HPLC: 96.66 %.
Example 3:
0 ________________ (C)i& X ]0 NH
HI
NH¨\ CD IH z Methane sulfome acid ____________ \ 2 in a NH
H
Diboc-lisdexamphetamine (1.5 g) was dissolved in 1,4-dioxane (12.75 mL) and was kept under stiffing for 15 mm under inert atmosphere. Methanesulfonic acid (1.554 g) was slowly added to the reaction mixture with maintaining temperature below 25 C. Reaction mixture was maintained under stiffing for 4-5 hours. Completion of reaction was checked by TLC. Reaction mass was filtered and washed with dioxane (3.0 mL) to obtain white solid. End solid product was dried under vacuum overnight at 55- 60 C.
Yield: 73.50 %;
Purity by HPLC: 99.24 %.
Example 4:
(),.......,0x.
HN H
, C)y HN 401 0 __ (....... X
() 0 .......KNH H
NH C) S
H ____________________________________ 31.
()\ 1,4 &mane , N-methyl morpholine NH NH
N N
- r H
Boc-L-Lys(Boc)-0Su (compound of Formula II where X and Y both are Boc & Z is 0Su; 25.0 g) was dissolved in 1,4-dioxane (150.0 mL) under inert atmosphere and was stirred for 10-15 min. N-methylmorpholine (6.75 mL) was added to the mixture and was stirred for
10 min. A
11 solution of (2S,3R)-2-methyl-3-phenylaziridine (compound of Formula III, 11.30 g) in 1,4-dioxane (50 mL) was slowly added maintaining temperature below 25 C during addition.
Resulting reaction mixture was stirred for an hour. After completion of reaction (monitored by TLC), water was added to quench the reaction .The reaction mass was concentrated under reduced pressure below 80 C to get solid residue. The solid residue was treated with isopropylacetate (750 mL) and washed with acetic acid (50.0 g)/NaC1 (100.0 g)/water mixture (750 mL). The organic layer was further washed with aq. sodium bicarbonate solution (75.0 g in 750 mL water). Then silica gel was added into organic layer and organic layer was stirred for an hour. Silica gel was filtered and washed with isopropyl acetate (50.0 mL). The combined organic layer was then concentrated under reduced pressure below 80 C and was dried under reduced pressure to get solid product.
Example 5:
Pd/C, H2 (40 psi) ¨( /NHH IPA NH -\ 0 __ ( NH
N
Diboc-Lysdex-aziridine (compound of Formula IV where X and Y both are Boc;
25.0 g) was dissolved in isopropyl alcohol (150.0 mL) and resulting solution was stirred for 15 minutes to obtain clear solution. Pd/C (0.15 g) was added to the reaction mixture and was kept under hydrogen pressure for 3 hours at 40 psi. Completion of reaction was checked by TLC. Pd/C was filtered and washed with IPA (50.0 mL). The reaction mixture was then concentrated under reduced pressure below 80 C.
Yield: 26.53 g, HPLC purity: 97.83%.
Resulting reaction mixture was stirred for an hour. After completion of reaction (monitored by TLC), water was added to quench the reaction .The reaction mass was concentrated under reduced pressure below 80 C to get solid residue. The solid residue was treated with isopropylacetate (750 mL) and washed with acetic acid (50.0 g)/NaC1 (100.0 g)/water mixture (750 mL). The organic layer was further washed with aq. sodium bicarbonate solution (75.0 g in 750 mL water). Then silica gel was added into organic layer and organic layer was stirred for an hour. Silica gel was filtered and washed with isopropyl acetate (50.0 mL). The combined organic layer was then concentrated under reduced pressure below 80 C and was dried under reduced pressure to get solid product.
Example 5:
Pd/C, H2 (40 psi) ¨( /NHH IPA NH -\ 0 __ ( NH
N
Diboc-Lysdex-aziridine (compound of Formula IV where X and Y both are Boc;
25.0 g) was dissolved in isopropyl alcohol (150.0 mL) and resulting solution was stirred for 15 minutes to obtain clear solution. Pd/C (0.15 g) was added to the reaction mixture and was kept under hydrogen pressure for 3 hours at 40 psi. Completion of reaction was checked by TLC. Pd/C was filtered and washed with IPA (50.0 mL). The reaction mixture was then concentrated under reduced pressure below 80 C.
Yield: 26.53 g, HPLC purity: 97.83%.
12 Example 6:
__________ 0 NH- \ ____ ( /NH
Methane sulfonte acid ¨
_____________ \
NH
¨ 2 Diboc-lisdexamphetamine (25.0 g) was dissolved in 1,4-dioxane (175.0 mL) and was kept under stiffing for 15 mm under inert atmosphere. Methanesulfonic acid (15.56 g) was slowly added to the reaction mixture with maintaining temperature below 25 C. Reaction mixture was maintained under stiffing for overnight. Completion of reaction was checked by TLC. Reaction mass was filtered and washed with dioxane (50.0 mL) to obtain white solid. End solid product was dried under reduced pressure overnight at 55- 60 C.
Yield: 19.96 g, HPLC Purity: 98.92 %.
Example 7:
Hµ N
HN H
HN H
0 ___________________ 0 410 \e 1,4 choxane , N-methyl morpholine CH3 ,LNH
0 ___________________________________________________________ 0 N 411 CBz-lys-cbz¨OSu (compound of Formula II where X and Y both are Cbz & Z is 0Su;
4.0 g) was dissolved in 1,4-dioxane (24.0 mL) under inert atmosphere and was stirred for 10-15 min. N-methylmorpholine (0.93 mL) was added to the reaction mixture and was stirred for 10 mm. A
solution of (2S,3R)-2-methyl-3-phenylaziridine (1.57 g) in 1,4-dioxane (8 mL) was slowly added. Resulting reaction mixture was stirred for three hour. After completion of reaction (monitored by TLC), water was added to quench the reaction. The reaction mass was concentrated under reduced pressure below 80 C to get solid residue. The solid residue was treated with isopropylacetate (152 mL) and washed twice with acetic acid (8.0 g)/NaC1(60.0
__________ 0 NH- \ ____ ( /NH
Methane sulfonte acid ¨
_____________ \
NH
¨ 2 Diboc-lisdexamphetamine (25.0 g) was dissolved in 1,4-dioxane (175.0 mL) and was kept under stiffing for 15 mm under inert atmosphere. Methanesulfonic acid (15.56 g) was slowly added to the reaction mixture with maintaining temperature below 25 C. Reaction mixture was maintained under stiffing for overnight. Completion of reaction was checked by TLC. Reaction mass was filtered and washed with dioxane (50.0 mL) to obtain white solid. End solid product was dried under reduced pressure overnight at 55- 60 C.
Yield: 19.96 g, HPLC Purity: 98.92 %.
Example 7:
Hµ N
HN H
HN H
0 ___________________ 0 410 \e 1,4 choxane , N-methyl morpholine CH3 ,LNH
0 ___________________________________________________________ 0 N 411 CBz-lys-cbz¨OSu (compound of Formula II where X and Y both are Cbz & Z is 0Su;
4.0 g) was dissolved in 1,4-dioxane (24.0 mL) under inert atmosphere and was stirred for 10-15 min. N-methylmorpholine (0.93 mL) was added to the reaction mixture and was stirred for 10 mm. A
solution of (2S,3R)-2-methyl-3-phenylaziridine (1.57 g) in 1,4-dioxane (8 mL) was slowly added. Resulting reaction mixture was stirred for three hour. After completion of reaction (monitored by TLC), water was added to quench the reaction. The reaction mass was concentrated under reduced pressure below 80 C to get solid residue. The solid residue was treated with isopropylacetate (152 mL) and washed twice with acetic acid (8.0 g)/NaC1(60.0
13 g)/water mixture (240 mL). The organic layer was further washed with aq.
sodium bicarbonate solution (12.0 g in 240 mL water). Both layer were separated, the organic layer was then concentrated under reduced pressure below 65 C and was dried under reduced pressure to get solid reaction product.
Yield: 4.35 g, Melting point: 96.4 C
Mass: 548.3 (M+H30)+, molecular weight 529.63(C311-135N305) IR: 3306 cm-1, 2934 cm-1, 1683 cm-1.
Examples 8:
Pd/C, H2 H2N f NH
IPA/Methanol jrn H2N
H Hs H CH, N H, Cbz protected lysdex-aziridine (compound of Formula IV where X and Y both are Cbz; 1.0 g) was dissolved in IPA/methanol (1:1, 40.0 mL) and resulting solution was heated to 70 C
temperature to obtain clear solution. Then reaction mixture was transferred in an autoclave. Pd/C
(0.1 g) was added to the reaction mixture and was kept under hydrogen pressure for 4-5 hours at 40 psi at room temperature. Completion of reaction was checked by TLC. Then the reaction mixture was heated to 70-80 C. Pd/C was hot filtered and washed with hot methanol (10.0 mL).
The reaction mixture was then concentrated under reduced pressure below 80 C.
Crude residue of lisdexamphetamine base (0.8 g) was purified by column chromatography using methanol as the starting mobile phase and then increasing the gradient to MeOH:aq.NH3 (100:5).
Yield: 0.30 g, HPLC purity: 97.04 %.
sodium bicarbonate solution (12.0 g in 240 mL water). Both layer were separated, the organic layer was then concentrated under reduced pressure below 65 C and was dried under reduced pressure to get solid reaction product.
Yield: 4.35 g, Melting point: 96.4 C
Mass: 548.3 (M+H30)+, molecular weight 529.63(C311-135N305) IR: 3306 cm-1, 2934 cm-1, 1683 cm-1.
Examples 8:
Pd/C, H2 H2N f NH
IPA/Methanol jrn H2N
H Hs H CH, N H, Cbz protected lysdex-aziridine (compound of Formula IV where X and Y both are Cbz; 1.0 g) was dissolved in IPA/methanol (1:1, 40.0 mL) and resulting solution was heated to 70 C
temperature to obtain clear solution. Then reaction mixture was transferred in an autoclave. Pd/C
(0.1 g) was added to the reaction mixture and was kept under hydrogen pressure for 4-5 hours at 40 psi at room temperature. Completion of reaction was checked by TLC. Then the reaction mixture was heated to 70-80 C. Pd/C was hot filtered and washed with hot methanol (10.0 mL).
The reaction mixture was then concentrated under reduced pressure below 80 C.
Crude residue of lisdexamphetamine base (0.8 g) was purified by column chromatography using methanol as the starting mobile phase and then increasing the gradient to MeOH:aq.NH3 (100:5).
Yield: 0.30 g, HPLC purity: 97.04 %.
14
Claims (5)
1. A process for preparation of lisdexamphetamine, a compound of Formula I or pharmaceutically acceptable salts thereof;
comprising:
(a) reducing the compound of Formula IV
wherein X and Y are independently selected from amino protecting groups or hydrogen, to obtain a compound of Formula I' wherein X and Y in compound of Formula I' are independently selected from amino protecting groups or hydrogen;
(b) when X and/or Y in compound of Formula I' are amino protecting group, deprotecting the compound of Formula I' to obtain the compound of Formula I.
comprising:
(a) reducing the compound of Formula IV
wherein X and Y are independently selected from amino protecting groups or hydrogen, to obtain a compound of Formula I' wherein X and Y in compound of Formula I' are independently selected from amino protecting groups or hydrogen;
(b) when X and/or Y in compound of Formula I' are amino protecting group, deprotecting the compound of Formula I' to obtain the compound of Formula I.
2. The process as in claim 1, wherein the compound of Formula IV is prepared by a process comprising coupling a compound of Formula II
wherein, X and Y are independently selected from amino protecting groups or hydrogen and Z is a leaving group, with a compound of Formula III
and optionally deprotecting a compound of Formula IV when X and Y are amino protecting groups.
wherein, X and Y are independently selected from amino protecting groups or hydrogen and Z is a leaving group, with a compound of Formula III
and optionally deprotecting a compound of Formula IV when X and Y are amino protecting groups.
3. The process as in claim I wherein X or Y or both are tert-butyl-carbamate (Boc).
4. The process as in claim I, wherein Z is C1, Br, I or hydroxysuccinimido ester (OSu)
5. A compound of Formula IV
or acid addition salt thereof;
wherein X and Y are independently selected from amino protecting groups or hydrogen.
or acid addition salt thereof;
wherein X and Y are independently selected from amino protecting groups or hydrogen.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN4670/MUM/2015 | 2015-12-11 | ||
| IN4670MU2015 | 2015-12-11 | ||
| PCT/IN2016/050441 WO2017098533A2 (en) | 2015-12-11 | 2016-12-12 | Process for preparation of lisdexamphetamine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA3006537A1 true CA3006537A1 (en) | 2017-06-15 |
Family
ID=59012856
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA3006537A Abandoned CA3006537A1 (en) | 2015-12-11 | 2016-12-12 | Process for preparation of lisdexamphetamine |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP3386944A4 (en) |
| BR (1) | BR112018011437A2 (en) |
| CA (1) | CA3006537A1 (en) |
| WO (1) | WO2017098533A2 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA3199184A1 (en) | 2020-11-18 | 2022-05-27 | Felix Lustenberger | Mdma prodrugs to assist psychotherapy |
| US11608312B1 (en) | 2021-07-22 | 2023-03-21 | Sci Pharmtech Inc. | Compound and method for preparation of lisdexamfetamine |
| EP4122914B1 (en) | 2021-07-22 | 2023-08-16 | SCI Pharmtech Inc | Compound and method for preparation of lisdexamfetamine |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2540678C (en) * | 2003-09-30 | 2011-02-22 | New River Pharmaceuticals Inc. | Pharmaceutical compositions for prevention of overdose or abuse |
| WO2010042120A1 (en) * | 2008-10-09 | 2010-04-15 | Archimica, Inc. | Process for the synthesis of amphetamine derivatives |
| US8614346B2 (en) * | 2009-06-19 | 2013-12-24 | Cambrex Charles City, Inc. | Methods and compositions for preparation of amphetamine conjugates and salts thereof |
| US8779191B2 (en) * | 2010-12-20 | 2014-07-15 | Cambrex Charles City, Inc. | Methods and compositions for preparing lisdexamfetamine and salts thereof |
| WO2013011526A1 (en) * | 2011-07-20 | 2013-01-24 | Ind-Swift Laboratories Limited | Process for preparation of lisdexamphetamine and salts thereof |
| WO2015130660A1 (en) * | 2014-02-25 | 2015-09-03 | Chemapotheca, Llc | Synthesis of racemic amphetamine derivatives by cuprate addition reaction with aziridine phosphoramidate compounds |
-
2016
- 2016-12-12 WO PCT/IN2016/050441 patent/WO2017098533A2/en active Application Filing
- 2016-12-12 EP EP16872573.7A patent/EP3386944A4/en not_active Withdrawn
- 2016-12-12 CA CA3006537A patent/CA3006537A1/en not_active Abandoned
- 2016-12-12 BR BR112018011437A patent/BR112018011437A2/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| EP3386944A4 (en) | 2019-08-28 |
| BR112018011437A2 (en) | 2018-11-27 |
| WO2017098533A3 (en) | 2017-08-10 |
| WO2017098533A2 (en) | 2017-06-15 |
| EP3386944A2 (en) | 2018-10-17 |
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| FZDE | Discontinued |
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