WO2015067539A1 - Process and intermediates for the preparation of linagliptin - Google Patents

Process and intermediates for the preparation of linagliptin Download PDF

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Publication number
WO2015067539A1
WO2015067539A1 PCT/EP2014/073478 EP2014073478W WO2015067539A1 WO 2015067539 A1 WO2015067539 A1 WO 2015067539A1 EP 2014073478 W EP2014073478 W EP 2014073478W WO 2015067539 A1 WO2015067539 A1 WO 2015067539A1
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formula
group
compound
viii
potassium
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PCT/EP2014/073478
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French (fr)
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Mauro Gaboardi
Graziano Castaldi
Marta CASTALDI
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Chemelectiva S.R.L.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms

Definitions

  • the present invention relates to a process for the synthesis of Linagliptin and intermediates useful for its preparation.
  • Linagliptin is a reversible and competitive inhibitor of dipeptidyl-peptidases 4 (DPP- 4), enzymes that degrade the incretin hormones, which is used in adults suffering from diabetes mellitus type 2 (non-insulin dependent diabetes) to improve the control of blood glucose levels.
  • DPP- 4 dipeptidyl-peptidases 4
  • Incretins are hormones produced in the gastrointestinal region and they are mainly GLP-1 (Glucagon-Like Peptide 1 ) and GIP (Glucosedependent Insulinotropic Peptide). They are secreted after meals, particularly GLP-1 , and have the function of controlling glycemia in different ways: increase of insulin secretion by pancreatic beta cells, decrease of glucagon secretion (insulin antagonist) by pancreatic alpha cells, slowdown of motility and of gastric empty with the consequent decrease in appetite.
  • GLP-1 Glucagon-Like Peptide 1
  • GIP Glucosedependent Insulinotropic Peptide
  • GLP-1 is rapidly degraded into an inactive peptide by DDP-4, moreover its production decreases when glycemia decreases, its control over the latter is then calibrated and "when needed” thus avoiding hypersecretion of insulin and consequent dangerous hypoglycemia.
  • GLP-1 In diabetic patients, the natural action of GLP-1 is defective, it was therefore thought to restore such activity for exploiting it, particularly for the oral therapy of diabetes mellitus type 2, a disorder in which pancreas is not able to produce enough insulin to control blood glucose levels or in which the body is not able to effectively use insulin with the consequent advantage of decreasing the various and problematic side effects due to a prolonged oral therapy with the traditional drugs.
  • Linagliptin acting as DPP-4 inhibitor, inhibits the degradation of incretin hormones in the body, particularly GLP-1 , increasing their blood level and stimulating the pancreas to produce more insulin when there is a high glycemic level, thus decreasing the amount of glucose produced by the liver, it also decreases glucagone levels, allowing the control of diabetes mellitus type 2.
  • Linagliptin is a compound of formula (I)
  • Z represents a leaving group such as for example an halogen, an hydroxyl group, a mercapto group or other commonly known groups.
  • Z represents a leaving group such as for example an halogen, an hydroxyl group, a mercapto group or other commonly known groups.
  • EP 2 468 749 discloses processes for the synthesis of Linagliptin which comprise a Lossen or Curtius rearrangement of the following compounds into Linagliptin:
  • X represents an hydrogen or a hydroxyl Ci-C 8 alkyl, Ci-C 4 alkoxy, aryl, amine, N 3 group or an halogen.
  • R represents a COOR 1 group or a NHCOOR 1 group, wherein R-i represents a linear or branched Ci-C 6 alkyl group;
  • the catalyst is preferably selected among potassium iodide, tetrabutylammonium iodide, sodium iodide, copper iodide, potassium iodide being more preferably used, and the base is preferably selected among sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, potassium carbonate being more preferably used.
  • the aprotic polar solvent is preferably selected among dimethylsulphoxide, acetonitrile, dimethylformamide, dimethylacetamide or mixtures thereof. Dimethylsulphoxide is preferably used.
  • the step e) of the process object of the present invention is preferably carried out in the presence of diphenylphosphorylazide and a tertiary amine preferably selected among triethylamine, tributylamine, diisopropylethylamine, N,N- dimethylaminopyridine and a suitable linear or branched Ci-C 4 alcohol preferably selected among methanol, ethanol, isopropanol, ter-butanol.
  • diphenylphosphorylazide and a tertiary amine preferably selected among triethylamine, tributylamine, diisopropylethylamine, N,N- dimethylaminopyridine and a suitable linear or branched Ci-C 4 alcohol preferably selected among methanol, ethanol, isopropanol, ter-butanol.
  • the bases are preferably selected among sodium terbutoxide, potassium terbutoxide, sodium hydride, sodium amide. Potassium terbutoxide is preferably used.
  • the intermediate (VI) can be obtained through a process which comprises:
  • a further object of the present invention is a process for the synthesis of Linagliptin which comprises:
  • an organic or inorganic base is used preferably selected among triethylamine, tributylamine, diisopropylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate.
  • Triethylamine is preferably used.
  • the aprotic polar solvent is selected preferably among dimethylsulphoxide, acetonitrile, dimethylformamide, dimethylacetamide or mixtures thereof. Dimethylsulphoxide is preferably used.
  • the catalyst used is preferably selected among potassium iodide, tetrabutylammonium iodide, sodium iodide, copper iodide, potassium iodide being more preferred and the base is preferably selected among sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, potassium carbonate being more preferred and the aprotic polar solvent is preferably selected among dimethylsulphoxide, acetonitrile, dimethylformamide, dimethylacetamide or mixtures thereof. Dimethylsulphoxide is more preferably used.
  • the intermediate of formula (VI) can be obtained through a process of synthesis which comprises:
  • a further object of the present invention is a process for the synthesis of Linagliptin which comprises:
  • R represents a group COOR 1 or a group NHCOOR 1 wherein R-i represents a linear or branched CrC 6 alkyl group;
  • the catalyst is preferably selected among potassium iodide, tetrabutylammonium iodide, sodium iodide, copper iodide, potassium iodide being more preferably used.
  • the base is preferably selected among sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, potassium carbonate being more preferably used.
  • the aprotic polar solvent is preferably selected among dimethylsulfoxide, acetonitrile, dimethylformamide, dimethylacetamide or mixtures of thereof.
  • Dimethylsulfoxide is preferably used.
  • a preferred practical embodiment of the process object of the present invention is the following.
  • the compound (II) is reacted with the compound (III) in the presence of triethylamine in dimethylsulphoxide at about 50°C, to give the compound (IV) which is subsequently reacted with 2-(chloromethyl)-4-methylquinazoline in dimethylsulphoxide in the presence of potassium carbonate and potassium iodide at about 60°C to give the compound (IV).
  • polar solvent refers to a solvent which is a proton donor, such as water; an alcohol, for example methanol, ethanol, propanol, /so-propanol, butanol; or a polarized solvent, such as for example esters, for example, ethyl acetate, butyl acetate; nitriles, for example acetonitrile; ethers, for example, tetrahydrofuran, dioxane; ketones, for example acetone, methylbutylketone and the like.
  • esters for example, ethyl acetate, butyl acetate
  • nitriles for example acetonitrile
  • ethers for example, tetrahydrofuran, dioxane
  • ketones for example acetone, methylbutylketone and the like.
  • non polar or polar, protic or aprotic solvents can be found in organic chemistry books or in specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification, 4th ed., John A. Riddick, et al., Vol. II, in "Techniques of Chemistry Series", John Wiley & Sons, NY, 1986.
  • solvents are known to the person skilled in the art and it is moreover clear to the person skilled in the art that different solvents or mixtures thereof can be preferred.

Abstract

The present invention relates to a process for the synthesis of Linagliptin and intermediates useful for its preparation.

Description

PROCESS AND INTERMEDIATES FOR THE PREPARATION OF LINAGLIPTIN
The present invention relates to a process for the synthesis of Linagliptin and intermediates useful for its preparation.
Linagliptin is a reversible and competitive inhibitor of dipeptidyl-peptidases 4 (DPP- 4), enzymes that degrade the incretin hormones, which is used in adults suffering from diabetes mellitus type 2 (non-insulin dependent diabetes) to improve the control of blood glucose levels.
Incretins are hormones produced in the gastrointestinal region and they are mainly GLP-1 (Glucagon-Like Peptide 1 ) and GIP (Glucosedependent Insulinotropic Peptide). They are secreted after meals, particularly GLP-1 , and have the function of controlling glycemia in different ways: increase of insulin secretion by pancreatic beta cells, decrease of glucagon secretion (insulin antagonist) by pancreatic alpha cells, slowdown of motility and of gastric empty with the consequent decrease in appetite.
GLP-1 is rapidly degraded into an inactive peptide by DDP-4, moreover its production decreases when glycemia decreases, its control over the latter is then calibrated and "when needed" thus avoiding hypersecretion of insulin and consequent dangerous hypoglycemia.
In diabetic patients, the natural action of GLP-1 is defective, it was therefore thought to restore such activity for exploiting it, particularly for the oral therapy of diabetes mellitus type 2, a disorder in which pancreas is not able to produce enough insulin to control blood glucose levels or in which the body is not able to effectively use insulin with the consequent advantage of decreasing the various and problematic side effects due to a prolonged oral therapy with the traditional drugs.
Linagliptin, acting as DPP-4 inhibitor, inhibits the degradation of incretin hormones in the body, particularly GLP-1 , increasing their blood level and stimulating the pancreas to produce more insulin when there is a high glycemic level, thus decreasing the amount of glucose produced by the liver, it also decreases glucagone levels, allowing the control of diabetes mellitus type 2.
Linagliptin is a compound of formula (I)
Figure imgf000003_0001
chemically known as 8-[3(R)-aminopiperidin-1 -yl]-7-(2-butynyl)-3-methyl-1 -(4- methylquinazolin-2-ylmethyl)xantine, disclosed in US 7,407,955 and commercially available under the name Tradjenta®.
There are different methods for the synthesis of Linagliptin known in literature.
US 7,407,955 discloses the following processes for the synthesis of Linagliptin:
Figure imgf000003_0002
wherein Z represents a leaving group such as for example an halogen, an hydroxyl group, a mercapto group or other commonly known groups.
US 7,820,815 discloses the following process for the synthesis of Linagliptin
Figure imgf000004_0001
(I)
wherein Z represents a leaving group such as for example an halogen, an hydroxyl group, a mercapto group or other commonly known groups.
EP 2 468 749 discloses processes for the synthesis of Linagliptin which comprise a Lossen or Curtius rearrangement of the following compounds into Linagliptin:
Figure imgf000004_0002
wherein X represents an hydrogen or a hydroxyl Ci-C8 alkyl, Ci-C4 alkoxy, aryl, amine, N3 group or an halogen.
We have now found a process for the synthesis of Linagliptin that, by the introduction of the alkyl group in a masked form, allows a decrease of the secondary reactions and the obtainment of Linagliptin and its intermediates with high yields and high purities.
It is therefore object of the present invention a process for the synthesis of Linagliptin which comprises:
d) the reaction of the intermediate of formula (VI)
Figure imgf000005_0001
with a compound of formula (VII)
Figure imgf000005_0002
wherein R represents a COOR1 group or a NHCOOR1 group, wherein R-i represents a linear or branched Ci-C6 alkyl group;
in the presence of a catalyst and a base, in an aprotic polar solvent, to give the intermediate of formula (VIII)
Figure imgf000005_0003
wherein R has the above reported meanings;
e) the optional conversion of the intermediate (VIII) wherein R represents a COOR1 group into the intermediate (VIII) wherein R represents a NHCOOR1 group;
f) the conversion into Linagliptin of the compound (VIII) wherein R represents a NHCOOR1 group, by treatment with bases;
In step d) of the process object of the present invention the catalyst is preferably selected among potassium iodide, tetrabutylammonium iodide, sodium iodide, copper iodide, potassium iodide being more preferably used, and the base is preferably selected among sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, potassium carbonate being more preferably used. ln step d) the aprotic polar solvent is preferably selected among dimethylsulphoxide, acetonitrile, dimethylformamide, dimethylacetamide or mixtures thereof. Dimethylsulphoxide is preferably used.
The step e) of the process object of the present invention is preferably carried out in the presence of diphenylphosphorylazide and a tertiary amine preferably selected among triethylamine, tributylamine, diisopropylethylamine, N,N- dimethylaminopyridine and a suitable linear or branched Ci-C4 alcohol preferably selected among methanol, ethanol, isopropanol, ter-butanol.
In step f) of the process object of the present invention the bases are preferably selected among sodium terbutoxide, potassium terbutoxide, sodium hydride, sodium amide. Potassium terbutoxide is preferably used.
The intermediate (VI) can be obtained through a process which comprises:
a) the reaction of the compound of formula (II)
Figure imgf000006_0001
with a compound of formula (III), in the presence of a base, in an aprotic polar solvent
Figure imgf000006_0002
to give the intermediate of formula (IV)
Figure imgf000006_0003
b) the reaction of the intermediate of formula (IV) with a compound of formula (V)
Figure imgf000007_0001
wherein X represents a halogen, preferably chlorine, in the presence of a catalyst and a base, in an aprotic polar solvent, to give the intermediate of formula (VI).
Then a further object of the present invention is a process for the synthesis of Linagliptin which comprises:
a) the reaction of the compound of formula (II)
Figure imgf000007_0002
with a compound of formula (III), in the presence of a base, in an aprotic polar solvent
W ON)
CH3
to give the intermediate of formula (IV)
Figure imgf000007_0003
b) the reaction of the intermediate of formula (IV) with a compound of formula (V)
Figure imgf000007_0004
CH3 wherein X represents an halogen, preferably chlorine, in the presence of a catalyst and a base, in an aprotic polar solvent, to give the intermediate of formula (VI)
Figure imgf000008_0001
d) the reaction of the intermediate of formula (VI) with a compound of formula (VII)
Figure imgf000008_0002
wherein R represents a COOR1 group or a NHCOOR1 group, wherein R-i represents a linear or branched Ci-C6 alkyl group,
in the presence of a catalyst and a base, in an aprotic polar solvent, to give the intermediate of formula (VIII)
Figure imgf000008_0003
wherein R has the above reported meanings;
e) the optional conversion of the intermediate (VIII) wherein R represents a
COOR1 group into the intermediate (VIII) wherein R represents a NHCOOR1 group;
f) the conversion into Linagliptin of the compound (VIII) wherein R represents a NHCOORi group, by treatment with bases.
In step a) of the process object of the present invention an organic or inorganic base is used preferably selected among triethylamine, tributylamine, diisopropylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate. Triethylamine is preferably used.
The aprotic polar solvent is selected preferably among dimethylsulphoxide, acetonitrile, dimethylformamide, dimethylacetamide or mixtures thereof. Dimethylsulphoxide is preferably used.
In step b) of the process object of the present invention the catalyst used is preferably selected among potassium iodide, tetrabutylammonium iodide, sodium iodide, copper iodide, potassium iodide being more preferred and the base is preferably selected among sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, potassium carbonate being more preferred and the aprotic polar solvent is preferably selected among dimethylsulphoxide, acetonitrile, dimethylformamide, dimethylacetamide or mixtures thereof. Dimethylsulphoxide is more preferably used.
Alternatively, the intermediate of formula (VI) can be obtained through a process of synthesis which comprises:
a) the reaction of the compound of formula (II)
Figure imgf000009_0001
with a compound of formula (III), in the presence of a base, in an aprotic polar solvent
Figure imgf000009_0002
to give the intermediate of formula (IV)
Figure imgf000010_0001
b') the reaction of the compound of formula (IV) with chloroacetonitrile, in the presence of a catalyst and a base in an aprotic polar solvent, to give the intermediate of formula (IX)
Figure imgf000010_0002
the reaction of the intermediate of formula (IX) with aminoacetophenone in the presence of anhydrous hydrochloric acid 1 ,4-dioxane, to give the intermediate of formula (VI).
Then a further object of the present invention is a process for the synthesis of Linagliptin which comprises:
a) the reaction of the compound of formula (II)
Figure imgf000010_0003
with a compound of formula (III), in the presence of a base, in an aprotic polar solvent
Figure imgf000011_0001
to give the intermediate of formula (IV)
Figure imgf000011_0002
b') the reaction of the compound of formula (IV) with chloroacetonitrile, in the presence of a catalyst and a base, in an aprotic polar solvent, to give the intermediate of formula (IX)
Figure imgf000011_0003
the reaction of the intermediate of formula (IX) with aminoacetophenone in the presence of anhydrous hydrochloric acid 1 .4-dioxane, to give the intermediate of formula (VI)
Figure imgf000011_0004
the reaction of the intermediate of formula (VI) with a compound of formula (VII)
Figure imgf000012_0001
wherein R represents a group COOR1 or a group NHCOOR1 wherein R-i represents a linear or branched CrC6 alkyl group;
in the presence of a catalyst and a base, in an aprotic polar solvent, to give the intermediate of formula (VIII)
Figure imgf000012_0002
wherein R has the above reported meanings;
e) the optional transformation of the intermediate (VIII) wherein R represents a COOR1 group into the intermediate (VIII) wherein R represents a NHCOOR1 group;
f) the conversion into Linagliptin of the compound of formula (VIII) wherein R represents a NHCOOR1 group by treatment with bases.
In step b') the catalyst is preferably selected among potassium iodide, tetrabutylammonium iodide, sodium iodide, copper iodide, potassium iodide being more preferably used.
The base is preferably selected among sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, potassium carbonate being more preferably used.
The aprotic polar solvent is preferably selected among dimethylsulfoxide, acetonitrile, dimethylformamide, dimethylacetamide or mixtures of thereof. Dimethylsulfoxide is preferably used.
A preferred practical embodiment of the process object of the present invention is the following. The compound (II) is reacted with the compound (III) in the presence of triethylamine in dimethylsulphoxide at about 50°C, to give the compound (IV) which is subsequently reacted with 2-(chloromethyl)-4-methylquinazoline in dimethylsulphoxide in the presence of potassium carbonate and potassium iodide at about 60°C to give the compound (IV). (R)-isopropyl-piperidine-3-yl carbamate in dimethylsulfoxide is reacted with the compound (VI) in the presence of potassium carbonate and potassium iodide to give (R)-isopropyl 1 -(7-(3-chlorobut-2-enyl)-3-methyl-1 -((4-methylquinazolin-2-yl)methyl-2,6- dioxo-2,3,6,7-tetrahydro-1 /-/-purin-8-yl)pyperidin-3-yl carbamate that is subsequently reacted in the presence of dimethylacetamide and potassium tert-butoxide to give (R)-isopropyl 1 -(7-(but-2-inyl)-3-methyl-1 -((4- methylquinazolin-2-yl)methyl -2,6 - dioxo - 2,3,6,7 - tetrahydro-1 H-purin-8- yl)piperidine-3-yl- carbamate which is converted into Linagliptin through hydrolysis in the presence of water, dimethylacetamide and potassium hydroxide.
The compounds of formula (IV), (VI), (VIII) and (IX) are new intermediates useful for the synthesis of Linagliptin and represent a further object of the present invention.
All the terms used in the present application, unless otherwise indicated, are to be understood in their common meaning as known in the art. Other more specific definitions for certain terms, as indicated in this patent application, are underlined later and are constantly applied for the whole description and the claims unless a different definition provides specifically a wider meaning. The term "polar solvent" refers to a solvent which is a proton donor, such as water; an alcohol, for example methanol, ethanol, propanol, /so-propanol, butanol; or a polarized solvent, such as for example esters, for example, ethyl acetate, butyl acetate; nitriles, for example acetonitrile; ethers, for example, tetrahydrofuran, dioxane; ketones, for example acetone, methylbutylketone and the like.
Further information about non polar or polar, protic or aprotic solvents can be found in organic chemistry books or in specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification, 4th ed., John A. Riddick, et al., Vol. II, in "Techniques of Chemistry Series", John Wiley & Sons, NY, 1986. Such solvents are known to the person skilled in the art and it is moreover clear to the person skilled in the art that different solvents or mixtures thereof can be preferred.
Although the present invention has been described in its characterizing features, the equivalents and modifications obvious to the skilled in the art are included in the following invention.
The present invention will be now illustrated through some examples without limiting the scope of the invention.
EXAMPLES
EXAMPLE 1
Synthesis of 8-bromo-7-(3-chlorobut-2-enyl)-3-methyl-1 H-purin- 2,6(3H,7H)-dione.
8-bromo-3-methyl-1 H-purin-2,6-(3H,7Hj-dione (10.00 g, 41.00 mmol), dimethylsulphoxide (30 ml), triethylamine (6.25 ml_, 45.10 mmol) were charged into a reaction flask, the temperature was brought to about 50°C and 1 ,3-dichlorobutene (4.40 ml, 41.00 mmol) was charged. The reaction mixture was kept under such conditions for about one hour. At the end of the reaction, the resultant solid was filtered and dried in oven under vacuum at 50°C to give 12.10 g of 8-bromo-7-(3-chlorobut-2-enyl)-3-methyl-1 H-purin- 2,6(3H,7Hj-dione.
1H-NMR (DMSO, 300 MHz): δ 1 1 .32 (s, 1 H), δ 5.84 (t, 1 H), δ 4.98 (d, 2H), δ 3.33 (m, 3H), 6 2.50 (s, 1 H), 5 2.13 (s, 2H).
13C-NMR (DMSO, 300MHz): δ 154.54 (C), δ 151.1 1 (C), δ 149.87 (C), δ 133.77 (C), δ 128.16 (C), δ 121 .09 (CH), δ 109.18 (C), δ 46.00 (CH2), δ 29.10 (CH3), 6 26.16 (CH3).
EXAMPLE 2
Synthesis of 8-bromo-7-(3-chlorobut-2-enyl)-3-methyl-1 -((4-methyl quinazolin-2-yl)-methyl)-1 H-purin-2,6(3H,7H)-dione.
8-bromo-7-(3-chlorobut-2-enyl)-3-methyl-1 H-purin-2,6(3H, H)-dione (5.00 g, 14.98 mmol), dimethylsulphoxide (50 ml), potassium carbonate (2.07 g, 14.98 mmol), potassium iodide (0.25 g, 1.50 mmol) and 2-(chloromethyl)-4- methylquinazoline (2.89 g, 14.98 mmol) were charged into a reaction flask. The temperature was brought to about 60°C and the reaction mixture was kept under such conditions for about 3 hours. At the end of the reaction, demineralized water (40 ml) was added and the resultant solid was filtered under vacuum and washed with demineralized water (1 x 20 ml) and dried in oven under vacuum at 50°C to give 6.43 g of 8-bromo-7-(3-chlorobut-2-enyl)-
3-methyl-1 -((4-methylquinazolin-2-yl)methyi -iH-pur/'n-2,6(3H H -c//'one. 1H-NMR (DMSO, 300 MHz): δ 8.04 (d, 1 H), δ 7.84 (d, 1 H), δ 7.78 (t, 1 H), δ 7.54 (t, 1 H), δ 5.70 (t, 1 H), δ 5.55 (s, 2H), δ 5.12 (d, 2H), δ 3.59 (s, 3H), δ
2.89 (s, 3H) 6 2.12 (s, 3H).
13C-NMR (DMSO, 300MHz): δ 168.74 (C), δ 160.54 (C), δ 154.26 (C), δ
151 .44 (C), δ 149.95 (C), δ 148.85 (CH), δ 134.88 (C), δ 133.44 (CH), δ 128.89 (CH), δ 127.64 (C), δ 126.92 (CH), δ 124.96 (CH), δ 123.22 (C), δ 1 19.63 (CH), δ 109.06 (C), δ 77.19 (CH2), δ 45.92 (CH2), δ 29.99 (CH3), δ 26.20 (CH3), δ 21 .87 (CH3).
EXAMPLE 3
Synthesis of (R)-isopropyl 1 -(7-(3-chlorobut-2-enyl)-3-methyl-1 -((4- methylquinazolin-2-yl)-methyl)-2,6-dioxo-2,3,6,7-tetrahydro- H-purin-8- yl)piperidin-3-yl carbamate
(R)-isopropyl-piperidin-3-ylcarbamate (0.92 g, 4.90 mmol), dimethylsulphoxide (10 ml) were charged into a reaction flask and keeping the reaction mixture under stirring, 8-bromo-7-(3-chlorobut-2-enyl) -3-methyl - 1 - ((4-methylquinazolin-2-yl)methyl) -1 H-purin-2,6(3H-7H)-dione (2.42 g,
4.90 mmol) and potassium carbonate (0.74 g, 5.39 mmol) were charged. The temperature was brought to about 80°C and potassium iodide in catalytic amounts was charged and the reaction mixture was kept under such conditions for 40 hours. At the end of the reaction, the temperature was brought to room temperature, demineralized water (15ml) was added and the resultant solid was filtered and washed with demineralized water (1 x 15 ml) and dried in oven under vacuum at 50°C to give 2.30 g of (R) -isopropyl 1 - (7-(3-chlorobut-2-enyl)-3-methyl-1 -((4-methylquinazolin-2-yl)-methyl)-2,6- dioxo-2,3,6,7-tetrahydro-7H-purin-8-yl)piperidin-3-yl carbamate.
1H-NMR (DMSO, 300 MHz): δ 7.99 (d, 1 H), δ 7.85 (d, 1 H), δ 7.75 (t, 1 H), δ 7.51 (t, 1 H), δ 5.84 (t, 1 H), δ 5.54 (s, 2H), δ 5.28 (s, 1 H), δ 4.88 (t, 1 H), δ 4.83 (d, 1 H) δ 3.89 (m, 1 H), δ 3.58 (m, 3H), δ 3.19 (m, 3 H), δ 2.88 (m, 3H), δ 2.14 (s, 2H), 6 2.10 (s, 3H), δ 1 .83 (m, 2H), δ 1 .73 (m, 2H), δ 1 .21 (d, 6H). 13C-NMR (DMSO, 300MHz): δ 168.63 (C), δ 161 .13 (C), δ 156.47 (C), δ 155.63 (C), δ 153.00 (C), δ 151 .92 (C), δ 150.03 (C), δ 149.00 (C), δ 133.33 (CH), δ 128.97 (CH), δ 126.81 (CH), δ 124.93 (CH), δ 123.25 (C), δ 121.45
(CH), δ 105.00 (C), δ 68.04 (CH), δ 54.69 (CH2), δ 51 .84 (CH2), δ 46.45 (CH), δ 46.34 (CH2), δ 44.58 (CH2), δ 44.46 (CH2), δ 29.85 (CH3), δ 29.80 (CH2), 6 26.17 (CH3), 6 22.17 (2 CH3), 6 21.85 (CH3).
EXAMPLE 4
Synthesis of (R)-ethyl 1 -i7-i3-clorobut-2-enyl)-3-methyl-1 -ii4-methyl quinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1 H-purin-8- yl)piperidin-3-carboxylate.
(R)-ethyl-piperidin-3-carbossylate (0.29 g, 1.02 mmol), dimethylsulfoxide (5 ml) were charged into a reaction flask and, keeping the reaction mixture under stirring, potassium iodide in catalytic amounts, potassium carbonate
(0.14 g, 1 .02 mmol) and 8-bromo-7-(3-chlorobut-2-enyl)- 3 -methyl-1 -((4- methylquinazolin-2-yl)methyl)--/H-purin-2,6(3H, 7H)-dione (0.50 g, 1.02 mmol). The temperature was brought to about 60°C and maintaining under such conditions for about 15 hours. At the end of the reaction, the temperature was brought to room temperature and demineralized water
(5ml) was added. The resultant solid was filtered and washed with demineralized water (1 x 5 ml) and dried in oven under vacuum at 50°C to give 0.48 g of (R) -ethyl 1 -(7-(3-chlorobut-2-enyl)-3-methyl-1 -((4-methyl quinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1 /-/-purin-8-yl)piperidin- 3-carboxylate.
1H-NMR (DMSO, 300 MHz): 6 7.98 (d, 1 H), 6 7.84 (d, 1 H), 6 7.74 (t, 1 H), 6 7.50 (t, 1 H), 6 5.87 (m, 1 H), 6 5.54 (s, 2H), 6 4.81 (d, 2H), 6 4.17 (m, 2H), 6 3.69 (m, 1 H) 6 3.55 (s, 3H), 6 3.43 (m, 1 H), 6 3.17 (m, 1 H), 6 3.00 (m, 1 H), 6 2.87 (s, 3H), 6 2.76 (m, 1 H), 6 2.09 (m, 4H), 6 1 .84 (m, 3H), 6 1.26 (t, 3H).
EXAMPLE 5
Synthesis of (R)-isopropyl 1 -(7-(but-2-inyl)-3-methyl-1 -((4- methylquinazolvn-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1 H-purin-8- yl)piperidin-3-yl carbamate (R)-isopropyl 1 -(7-(3-chlorobutyl-2-enyl)-3-methyl-1 -((4-methylquinazoline-2- yl)methyl-2,6-dioxo-2,3,6,7-tetrahydro-1 /-/-purin-8-yl)piperidin-3-yl carbamate (0.50 g, 0.84 mmol), dimethylacetamide (5 ml) were charged into a reaction flask under inert atmosphere, the temperature was brought to a temperature from 0°C to 5°C and, keeping the reaction mixture under stirring, potassium ie f-butoxide (0.16 g, 1 .70 mmol) was charged and the reaction mixture was kept under such conditions for about 13 hours. At the end of the reaction, demineralized water (5 ml) and toluene (5 ml) were added; the organic phase was reduced to residue by distillation under vacuum to give 0.32 g of (R)- isopropyl 1 -(7-(but-2-inyl)-3-methyl-1 -((4-methylquinazolin-2-yl)methyl)-2,6- dioxo-2,3,6,7-tetrahydro-1 H-purin-8-yl)piperidin-3-yl carbamate.
1H-NMR (DMSO, 300 MHz): δ 8.20 (d, 1 H), δ 7.86 (t, 1 H), δ 7.75 (d, 1 H), δ 7.65 (t, 1 H), δ 7.19 (d, 1 H), δ 5.30 (s, 2H), δ 4.86 (s, 2H), δ 4.75 (m, 2H), δ 3.65 (m, 3H) δ 3.38 (d, 2H), δ 3.00 (t, 1 H), δ 2.95 (s, 4H), δ 1.84 (m, 2H), δ 1 .80 (m, 3H), δ 1 .77 (m, 1 H), δ 1 .45 (m, 1 H), δ 1.15 (d, 6H).
13C-NMR (DMSO, 300MHz): δ 170.00 (C), δ 163.89 (C), δ 157 (C), δ 156.30 (C), δ 155.75 (C), δ 153.49 (C), δ 150 (C), δ 147.90 (C), δ 133.89 (CH), δ 129 (CH), δ 127.71 (CH), δ 126.29 (CH), δ 123.06 (C), δ 103.93 (CH), δ 81.65 (C), δ 75.00 (CH), δ 68.30 (CH), δ 53.00 (CH2), δ 50.00 (CH2), δ 47.25 (CH3), δ 45.00 (CH2), δ 33.70 (CH2), δ 32.17 (CH2), δ 30.00 (CH3), δ 23.69 (CH2), δ 22.61 (CH3), δ 22.61 (CH3), δ 3.63 (CH3).
EXAMPLE 6
Synthesis of Linagliptin
(R)-isopropyl 1 -(7-(but-2-inyl)-3-methyl-1 -((4-methylquinazolin-2-yl)methyl)- 2,6-dioxo-2,3,6,7-tetrahydro-1 /-/-purin-8-yl)piperidin-3-il carbamate (0.30 g, 0.55 mmol), dimethylacetamide (5ml) were charged into a reaction flask under inert atmosphere, the reaction mixture was brought to a temperature from 0°C to 5°C and under stirring, potassium hydroxide (0.032 g, 0.57 mmol) and water (3 ml) were charged. The temperature was brought to about 50°C and the reaction mixture was kept under such conditions for about 5 hours. At the end of the reaction demineralized water (5 ml) was added, the resultant solid was filtered and washed with demineralized water (1 x 5 ml) and dried in oven under vacuum at about 50°C to give 0.23 g of Linagliptin.
EXAMPLE 7
Synthesis of 2-(8-bromo-7-(3-chlorobut-2-enyl)-3-methyl-2.6-dioxo- 2,3,6J-tetrahydro-7H-purin-1 -yl)acetonitrile
8-bromo-7-(chlorobut-2-enyl)-3-methyl-1 H-purin-2,6(3H, 7H -dione (1 .00 g,
3.00 mmol), dimethylsulfoxide (10 ml), potassium carbonate (0.46 g, 3.30 mmol), potassium iodide in catalytic amounts and 2-chloroacetonitrile (0.19 ml_, 3.00 mmol) were charged into a reaction flask. The temperature was brought to about 70°C and the reaction mixture was kept under such conditions for about three hours. At the end of the reaction, demineralized water (10 ml) and toluene (10 ml) were added; the aqueous phase was extracted with toluene (4 x 10 ml) and the collected organic phases were concentrated to residue through distillation under vacuum to give 1 .05 g of 2- (8-bromo-7-(3-chlorobut-2-enyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1 H- purin-1 -yl)acetonitrile.
1H-NMR (DMSO, 300 MHz): δ 5.66 (t, 1 H), δ 5.07 (d, 2H), δ 4.88 (s, 2H), δ 3.58 (s, 3H), 6 2.18 (s, 3H).
EXAMPLE 8
Synthesis of (R)-isopropyl 1 -(7-(3-chlorobut-2-enyl)-1 -(cianomethyl)-3- (methyl-2.6-dioxo-2,4,6,7-tetrahydro- H-purin-8-yl)piperidin-3-yl carbamate.
2-(8-bromo-7-(3-chlorobut-2-enyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1 H- purin-1 -yl)acetonitrile (1 g, 2.70 mmol), dimethylsulfoxide (10 ml), potassium carbonate (0.41 g, 3.00 mmol), (R)-isopropyl-piperidin-3-yl carbamate (0.50 g, 2.70 mmol) were charged into a reaction flask. The temperature was brought to about 70°C and the reaction mixture was kept under such conditions for about 5 hours. At the end of the reaction, demineralized water (5 ml) and toluene (5 ml) were added; the aqueous phase was extracted with toluene (3 x 5 ml) and the collected organic phases were concentrated to residue through distillation under vacuum to give 1 .37 g of (R)-isopropyl 1 - (7-(3-chlorobut-2-enyl)-1 -(cianomethyl)-3-(methyl-2,6-dioxo-2,4,6,7- tetrahydro-7/-/-purin-8-yl)piperidin-3-yl carbamate.
1H-NMR (DMSO, 300 MHz): δ 5.78 (t, 1 H), δ 5.56 (m, 1 H), δ 4.90 (s, 2H), δ 4.80 (d, 2H), δ 3.87 (s, 1 H), δ 3.48 (m, 4H), δ 3.18 (m, 3H), δ 2.20 (m, 3H), δ 1 .87 (m, 2H), δ 1.73 (m, 3H), δ 1 .23 (m, 6H).
13C-NMR (DMSO, 300MHz): δ 157.14 (C), δ 155.55 (C), δ 152.67 (C), δ 150.55 (C), δ 148.55 (C), δ 134.22 (C), δ 121.84 (CH), δ 1 15.18 (C), δ 104.32 (C), δ 68.14 (CH), δ 54.59 (CH2), δ 51.20 (CH2), δ 46.36 (CH), δ
44.68 (CH2), δ 43.81 (CH2), δ 41.08 (CH), δ 30.00 (CH3), δ 29.61 (CH2), δ 28.44 (CH2), δ 26.24 (CH3), δ 22.27 (2 CH3).
EXAMPLE 9
Synthesis of (R)-isopropyl 1 -(7-(3-chlorobut-2-enyl)-3-methyl-1 -((4- methylquinazolvn-2-yl)methyl-2,6-dioxo-2,3,6,7-tetrahydro- H-purin-8- yl)piperidin-3-yl carbamate.
2-aminoacetophenone (0.17 g, 1 .26 mmol), 1 ,4-dioxane (1 ml) were charged into a reaction flask, the temperature was brought to about 10°C and gaseous hydrochloric acid (0.29 g, 7.56 mmol), (R)-isopropyl 1 -(7-(3- chlorobut-2-enyl)-1 -(cianomethyl)-3-(methyl-2,6-dioxo-2, 4,6, 7-tetrahydro- 1H- purin-8-yl)piperidin-3-yl carbamate (0.5 g, 1.05 mmol) and the reaction mixture was kept under such conditions for about three hours. At the end of the reaction, the temperature was brought to about 5°C and sodium hydroxide solution 50% (0.60 g, 7.56 mmol) were added and the resultant solid was filtered and washed with demineralized water (1 x 0.5 ml) and 1 ,4- dioxane (1 x 0.5 ml) and dried in oven under vacuum at 50°C to give 0.47 g of (R)-isopropyl 1 -(7-(3-chlorobut-2-enyl)-3-methyl-1 -((4-methylquinazolyn-2- yl)methyl-2, 6-dioxo-2, 3, 6, 7-tetrahydro-•//-/-purin-8-yl)piperidin-3-yl carbamate.
EXAMPLE 10
Synthesis of 8-bromo-7-(3-chlorobut-2-enyl)-3-methyl-1 -((4- methylquinazolin-2-yl)methyl)- H-purin-2,6(3H,7H)-dione
2-aminoacetophenone (0.43 g, 3.20 mmol), 1 ,4-dioxane (2.5 ml) were charged into a reaction flask, the temperature was brought to about 10°C and gaseous hydrochloric acid (0.70 g, 19.2 mmol), 2-(8-bromo-7-(3-chloro- 2-enyl)-3-methyl-2,6-dioxo-2, 3, 6, 7-tetrahydro- 7H-purin-1 -yl)acetonitrile (1.0 g, 2.70 mmol) were charged and the reaction mixture was kept under such conditions for about three hours. At the end of the reaction, the temperature was brought to about 5°C and sodium hydroxide solution 50% (1 .54 g, 19.2 mmol) were added and the resultant solid was filtered and washed with demineralized water (1 x 1 ml) and 1 ,4-dioxane (1 x 1 ml) and dried in oven under vacuum at 50°C to give 1 .1 g of 8-bromo-7-(3-chlorobut-2-enyl)-3- methyl-1 -((4-methylqunazolin-2-yl)methyl)-'//-/-purin-2,6(3/-/, 7/-/ -dione.

Claims

A process for the synthesis of Linagliptin, comprising:
d) the reaction of the intermediate of formula (VI)
Figure imgf000021_0001
with a compound of formula (VII)
Figure imgf000021_0002
wherein R represents a COOR1 group or a NHCOOR1 group, wherein represents a linear or branched Ci-C6 alkyl group,
in the presence of a catalyst and a base, in an aprotic polar solvent, to give an intermediate of formula (VIII)
Figure imgf000021_0003
wherein R has the above reported meanings;
e) the optional conversion of the intermediate of formula (VIII) wherein R represents a COOR1 group into the intermediate of formula (VIII) wherein R represents a NHCOOR1 group; f) the conversion into Linagliptina of the compound of formula (VIII) wherein R represents a NHCOORi group, by treatment with bases.
2. A process for the synthesis of Linagliptin, comprising:
a) the reaction of the compound of formula (II)
Figure imgf000022_0001
with a compound of formula (III), in the presence of a base, in an aprotic polar solvent
Figure imgf000022_0002
to give the intermediate of formula (IV)
Figure imgf000022_0003
b) the reaction of the intermediate of formula (IV) with a compound of formula (V)
Figure imgf000022_0004
wherein X represents a halogen atom, preferably chlorine, in the presence of a catalyst and a base, in an aprotic polar solvent, to give the intermediate of formula (VI);
Figure imgf000023_0001
d) the reaction of the intermediate of formula (VI) with a compound of formula (VII)
Figure imgf000023_0002
wherein R represents a group COOR1 or a group NHCOOR1, wherein R-i represents a linear or branched Ci-C6 alkyl group,
in the presence of a catalyst and a base, in an aprotic polar solvent, to give the intermediate of formula (VIII)
Figure imgf000023_0003
wherein R has the above reported meanings;
e) the optional conversion of the intermediate of formula (VIII) wherein R represents a COOR1 group into the compound of formula (VIII) wherein R represents a NHCOOR1 group;
f) the conversion into Linagliptin of the compound of formula (VIII) wherein R represents a NHCOOR1 group, by treatment with bases.
3. A process for the synthesis of Linagliptin, comprising
a) the reaction of the compound of formula (II)
Figure imgf000024_0001
with a compound of formula (III), in the presence of a base, in an aprotic polar solvent
Figure imgf000024_0002
to give the intermediate of formula (IV)
Figure imgf000024_0003
b') the reaction of the compound formula (IV) with chloroacetonitrile, in the presence of a catalyst and a base, in an aprotic polar solvent,
to give the intermediate of formula (IX)
Figure imgf000024_0004
c) the reaction of the intermediate of formula (IX) with 2-aminoacetophenone in the presence of anhydrous hydrochloric acid, in 1 ,4-dioxane to give the intermediate of formula (VI);
Figure imgf000025_0001
the reaction of the intermediate of formula (VI) with a compound of formula (VII)
Figure imgf000025_0002
wherein R represents a group COOR1 or a group NHCOOR1, wherein represents a linear or branched Ci-C6 alkyl group,
in the presence of a catalyst and a base, in an aprotic polar solvent, to give a comp
wherein R has
Figure imgf000025_0003
e) the optional conversion of the intermediate of formula (VIII) wherein R represents a COOR1 group into the compound of formula (VIII) wherein R represents a NHCOOR1 group;
f) the conversion into Linagliptin of the intermediate of formula (VIII) wherein R represents a NHCOOR1 group, by treatment with bases.
Process according to anyone of the preceding claims, wherein in step d) the catalyst is preferably selected among potassium iodide tetrabutylammonium iodide, sodium iodide, copper iodide, more preferably potassium iodide and the base is preferably selected among sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, more preferably potassium carbonate; the aprotic polar solvent is preferably selected among dimethylsulphoxide, acetonitrile, dimethylformamide, dimethylacetamide or mixtures thereof, more preferably dimethylsulphoxide; step e) is carried out in the presence of diphenylphosphorilazide, and a tertiary amine preferably selected among triethylamine, tributylamine, diisopropylethylamine, N,N-dimethylaminopyridine and a suitable linear or branched C1-C4 alcohol preferably selected among methanol, ethanol, isopropanol, ter-butanol; in step f) the bases are selected among sodium terbutoxide, potassium terbutoxide, sodium hydride, metallic sodium, sodium amide, more preferably potassium terbutoxide.
Process according to claim 2, wherein in step a) an organic or inorganic base is used preferably selected among triethylamine, tributylamine, diisopropylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, more preferably triethylamine and the aprotic polar solvent is preferably selected among dimethylsulphoxide, acetonitrile, dimethylformamide, dimethylacetamide or mixtures thereof, more preferably dimethylsulphoxide; in step b) the catalyst is preferably selected among potassium iodide, tetrabutylammonium iodide, sodium iodide, copper iodide, more preferably potassium iodide and the base is preferably selected among sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, more preferably potassium carbonate and the aprotic polar solvent is preferably selected among dimethylsulphoxide, acetonitrile, dimethylformamide, dimethylacetamide or mixtures thereof, more preferably dimethylsulphoxide.
Process according to claim 3, wherein in step b') the catalyst is preferably selected among potassium iodide, tetrabutylammonium iodide, sodium iodide, copper iodide, more preferably potassium iodide and the base is preferably selected among sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, more preferably potassium carbonate and the aprotic polar solvent is preferably selected among dimethylsulphoxide, acetonitrile, dimethylformamide, dimethylacetamide or mixtures thereof, more preferably dimethylsulphoxide.
7. Compounds of formula (IV), (VI), (VIII) and (IX)
Figure imgf000027_0001
CH3
8. Use of the compounds according to claim 7 for the synthesis of Linagliptin.
PCT/EP2014/073478 2013-11-06 2014-10-31 Process and intermediates for the preparation of linagliptin WO2015067539A1 (en)

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