WO2014118612A1 - Process for the preparation of intermediates of synthesis of saxagliptin and novel compounds - Google Patents
Process for the preparation of intermediates of synthesis of saxagliptin and novel compounds Download PDFInfo
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- WO2014118612A1 WO2014118612A1 PCT/IB2014/000072 IB2014000072W WO2014118612A1 WO 2014118612 A1 WO2014118612 A1 WO 2014118612A1 IB 2014000072 W IB2014000072 W IB 2014000072W WO 2014118612 A1 WO2014118612 A1 WO 2014118612A1
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- saxagliptin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
Definitions
- Saxagliptin is the common international designation (DCI) of the compound ( 1 S,3 S,5S)-2-[(2S)-2-amino-2-(3-hydroxytricyclo[3.3.1.13 ,7]dec- 1 -yl)acetyl]-2- azabicyclo[3.1.0]hexan-3-carbonitrile having the structural formula reported below
- the object of the invention is a process for the preparation of the compound of formula (I)
- Pr is a protective group, which comprises reacting a compound of formula ( ⁇ )
- Pr is defined as above, with an oxidant agent of the tertiary carbon, preferably in the presence of a solvent and optionally of one or more catalysts.
- Pr is any protective group of the amine function.
- Such groups are widely described in literature, for example in the know handbook: Greene, T. W.; Wuts, P. G. M. ProtectiveGroups in OrganicSynthesis, published by John Wiley.
- Pr is a protective group selected from tert- butoxycarbonyl group (BOC), carbobenzyloxy group (CBZ), allyloxy carbonyl group (Alloc) and fluorenylmethoxycarbonyl group (F-moc).
- BOC tert- butoxycarbonyl group
- CBZ carbobenzyloxy group
- Alloc allyloxy carbonyl group
- F-moc fluorenylmethoxycarbonyl group
- the protective group is BOC.
- oxidant agent of the tertiary carbon a reactant able to introduce a hydroxyl group on the tertiary carbon of the adamantane ring.
- reactants are, for example, Ru0 4 , (Ru0 4 is in situ generated in the presence of Ruthenium based catalysts and bromates, for example alkali metal bromates, periodates, hypochlorites, hypervalent iodine, hydrogen peroxide, oxone and other oxidizing species), alkali metal permanganates, for example potassium permanganate and sulfonitric mixtures.
- Ruthenium based compounds are used, in particular RuCl 3 , in the presence of bromates, so to form, in situ, the Ru0 4 reactant.
- other compounds can be used that aid the reaction, such as for example pyridine.
- the reaction is preferably carried out in the presence of a solvent, advantageously a solvent selected from water; acetonitrile; esters, such as ethyl acetate; chlorinated solvents, such as CC1 4 .
- a solvent advantageously a solvent selected from water; acetonitrile; esters, such as ethyl acetate; chlorinated solvents, such as CC1 4 .
- mixtures of the above mentioned solvents for example mixtures of water and acetonitrile, are usable as well, according to the present invention.
- the reaction of the invention is carried out at a temperature between room temperature and the boiling temperature of the reaction mixture.
- the reaction is carried out at a temperature between 25°C and 80°C, advantageously between 35°C and 70°C, for example at about 50-60°C.
- Different temperatures can be used, keeping in mind that temperatures close to room temperature extend the reaction times.
- the object of the invention is the preparation of a compound of formula (I), wherein Pr is a BOC group, which comprises reacting a compound of formula (II), wherein Pr is a BOC group, with an alkali metal bromate, advantageously potassium bromate, in the presence of ruthenium (III) chloride and pyridine, in a solvent selected from a mixture of water and acetonitrile or a mixture of water, acetonitrile and ethyl acetate.
- an alkali metal bromate advantageously potassium bromate
- the used solvent is a mixture about 1/1 (v/v) of water and acetonitrile.
- reaction of the invention is completed in a few hours.
- a person skilled in the art can naturally follow the progress by known techniques, for example by chromatography, such as TLC or LC-MS.
- the compounds of formula (I) can be transformed into saxagliptin by cleavage of the Pr group according to known techniques.
- Pr is BOC
- an inorganic acid for example hydrochloric acid
- the object of the invention is a process for the preparation of saxagliptin which comprises reacting a compound of formula (II), as defined above, with an oxidant agent of the tertiary carbon, preferably in the presence of a solvent and optionally of one or more catalysts and subsequently cleaving the Pr group to give saxagliptin.
- the compounds of formula (II) are novel compounds and represent a further object of the present invention.
- the compounds of formula ( ⁇ ) are the object of the invention
- Pr is a protective group, provided that Pr is not BOC.
- Pr is selected from carbobenzyloxy group (CBZ), allyloxycarbonyl group (Alloc) and fiuorenylmethoxycarbonyl group (F-moc).
- the compounds of formula (II) and (IV) can be prepared by condensation between the compounds of formula III) and (IV) according to the following reaction
- reaction above can be carried out according to methods well known to the person skilled in the art for the preparation of amides starting from carboxylic acids and amines.
- the compound of formula (IV) is known in the art, see for example WO01/68603.
- Different compounds of formula (III) are known in the art, see for example WOO 1/68603.
- the preparation of said compounds, starting from the non-protected compound of formula (III), is however available to a person skilled in the art.
- the process of the mvention represents an innovative and original synthesis pathway for the preparation of saxagliptin, alternative to known synthesis pathways and non- derivable therefrom.
- oxidations of the tertiary carbons of the adamantane ring to give the corresponding alcohol are known, such oxidations have never been made on the adamantane ring already condensed with the cyclopropyl-pyrrolidine ring.
- a solution containing ruthenium trichloride in water is prepared at room temperature. Potassium bromate, pyridine and the substrate solution in acetonitrile (H 2 0/CH 3 CN in 1 :1 ratio) are added in the mentioned order. The mixture is heated at 60°C and it is left under stirring following the progress of the reaction by LC-MS. After 1-2 hours the reaction is interrupted by quenching with a Na 2 S03 1M solution, diluted with water and the product is extracted with ethyl acetate (2x). The organic phase is anhydrified over Na 2 S0 4 , filtered and the solvent evaporated. Thus the compound ( ⁇ ) is obtained with a conversion of 74%.
- an amine solution in anhydrous DMF is prepared.
- 3 equivalents (1.48 mL) of anhydrous DIPEA are added and left under stirring for 30 minutes.
- a solution is added to the just prepared one and cooled with an ice bath containing the acid, the condensing agent and the remainder of anhydrous DIPEA (2 eq, 992 ⁇ ).
- the reaction is interrupted and the solvent evaporated.
- the residue is collected with dichloromethane and washed with a solution of 5% citric acid, with a saturated sodium bicarbonate solution and finally with brine.
- a solution of the compound of formula ( ⁇ ) obtained from the reaction of example 1 is prepared at room temperature, in iPrOH/H 2 0. 0,2 eq. of hydrochloric acid are added at room temperature hence heated at 65°C. When this temperature is reached, the remainder of the acid is added and is left under stirring following the progress of the reaction by LC-MS. After 3 hours the deprotection is complete.
- the reaction is interrupted and isopropanol evaporated. It is basified with a 24% by weight K 2 C0 3 solution (pH 9), diluted with water and extracted with toluene. Saxagliptin is isolated from the aqueous phase by counter-extracting it twice with dichloromethane.
- dichloromethane solution is concentrated at reduced pressure, each time replacing the evaporated volume with as much ethyl acetate.
- dichloromethane is not distilling anymore, 1 equivalent of water is added to induce the precipitation of Saxagliptin monohydrate, which is recovered for subsequent filtration.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The object of the present invention is the preparation of saxagliptin and novel intermediate compounds.
Description
ft Process for the preparation of intermediates of synthesis of saxagliptin and novel compounds"
* * * *
Technical Background
Saxagliptin is the common international designation (DCI) of the compound ( 1 S,3 S,5S)-2-[(2S)-2-amino-2-(3-hydroxytricyclo[3.3.1.13 ,7]dec- 1 -yl)acetyl]-2- azabicyclo[3.1.0]hexan-3-carbonitrile having the structural formula reported below
and commercialized with the trade mark "onglyza®" for the treatment of non-insulin dependent diabetes.
Different syntheses for the preparation of saxagliptin are known. In general, two key synthons are prepared, one containing the cyclopropyl-pyrrolidine ring and the other containing the adamantane ring, which are then condensed to give the structure of saxagliptin. The synthon containing the adamantane ring already always has the hydroxyl group in the desired position. In fact syntheses of saxagliptin, wherein the last reaction step is the introduction of the hydroxyl group for oxidation of saxagliptin, are not known.
Objects of the invention
It is an object of the invention to provide a novel process, alternative compared to known processes, for the preparation of a key intermediate compound in the synthesis of saxagliptin and for the preparation of saxagliptin itself.
It is also an object of the invention to provide novel compounds for the preparation of a key intermediate compound in the synthesis of saxagliptin.
Description of the invention
According to one of its aspects, the object of the invention is a process for the preparation of the compound of formula (I)
wherein Pr is a protective group, which comprises reacting a compound of formula (Π)
wherein Pr is defined as above, with an oxidant agent of the tertiary carbon, preferably in the presence of a solvent and optionally of one or more catalysts.
According to the present invention, Pr is any protective group of the amine function. Such groups are widely described in literature, for example in the know handbook: Greene, T. W.; Wuts, P. G. M. ProtectiveGroups in OrganicSynthesis, published by John Wiley.
According to a preferred embodiment, Pr is a protective group selected from tert- butoxycarbonyl group (BOC), carbobenzyloxy group (CBZ), allyloxy carbonyl group (Alloc) and fluorenylmethoxycarbonyl group (F-moc).
According to a preferred embodiment, the protective group is BOC.
By "oxidant agent of the tertiary carbon", it is herein meant a reactant able to introduce a hydroxyl group on the tertiary carbon of the adamantane ring. Such reactants are, for example, Ru04, (Ru04 is in situ generated in the presence of Ruthenium based catalysts and bromates, for example alkali metal bromates, periodates, hypochlorites, hypervalent iodine, hydrogen peroxide, oxone and other oxidizing species), alkali metal permanganates, for example potassium permanganate and sulfonitric mixtures.
According to an advantageous embodiment, Ruthenium based compounds are used, in particular RuCl3, in the presence of bromates, so to form, in situ, the Ru04 reactant. In addition, other compounds can be used that aid the reaction, such as for example pyridine.
The reaction is preferably carried out in the presence of a solvent, advantageously a solvent selected from water; acetonitrile; esters, such as ethyl acetate; chlorinated solvents, such as CC14. When possible, mixtures of the above mentioned solvents, for example mixtures of water and acetonitrile, are usable as well, according to the present invention.
The reaction of the invention is carried out at a temperature between room temperature and the boiling temperature of the reaction mixture. According to a preferred embodiment, the reaction is carried out at a temperature between 25°C and 80°C, advantageously between 35°C and 70°C, for example at about 50-60°C. Different temperatures can be used, keeping in mind that temperatures close to room temperature extend the reaction times.
According to a particularly preferred embodiment, the object of the invention is the preparation of a compound of formula (I), wherein Pr is a BOC group, which comprises reacting a compound of formula (II), wherein Pr is a BOC group, with an alkali metal bromate, advantageously potassium bromate, in the presence of ruthenium (III) chloride and pyridine, in a solvent selected from a mixture of water and acetonitrile or a mixture of water, acetonitrile and ethyl acetate.
According to a preferred embodiment, the used solvent is a mixture about 1/1 (v/v) of water and acetonitrile.
The reaction of the invention is completed in a few hours. A person skilled in the art can naturally follow the progress by known techniques, for example by chromatography, such as TLC or LC-MS.
If desired, the compounds of formula (I) can be transformed into saxagliptin by cleavage of the Pr group according to known techniques. By way of example, when Pr is BOC, it is possible to obtain saxagliptin by hydrolysis with an inorganic acid, for example hydrochloric acid, in an appropriate solvent, for example in an alcohol. According to another of its aspects, the object of the invention is a process for the preparation of saxagliptin which comprises reacting a compound of formula (II), as defined above, with an oxidant agent of the tertiary carbon, preferably in the presence of a solvent and optionally of one or more catalysts and subsequently cleaving the Pr group to give saxagliptin.
With the exception of the compound wherein Pr is BOC, the compounds of formula (II) are novel compounds and represent a further object of the present invention. Thus, according to another of its aspects, the compounds of formula (ΙΓ) are the object of the invention
wherein Pr is a protective group, provided that Pr is not BOC.
According to a preferred embodiment of this aspect of the invention, in the formula (ΙΓ) Pr is selected from carbobenzyloxy group (CBZ), allyloxycarbonyl group (Alloc) and fiuorenylmethoxycarbonyl group (F-moc).
The compounds of formula (II) and (IV) can be prepared by condensation between the compounds of formula III) and (IV) according to the following reaction
The reaction above can be carried out according to methods well known to the person skilled in the art for the preparation of amides starting from carboxylic acids and amines.
The compound of formula (IV) is known in the art, see for example WO01/68603. Different compounds of formula (III) are known in the art, see for example WOO 1/68603. The preparation of said compounds, starting from the non-protected compound of formula (III), is however available to a person skilled in the art.
Detailed examples of reactions of the invention process are reported in the experimental section of the present invention.
The process of the mvention represents an innovative and original synthesis pathway for the preparation of saxagliptin, alternative to known synthesis pathways and non- derivable therefrom.
In fact, although in the processes for the preparation of saxagliptin, oxidations of the tertiary carbons of the adamantane ring to give the corresponding alcohol (see for example WO01/686803, example 60, Step 1, page 88) are known, such oxidations have never been made on the adamantane ring already condensed with the cyclopropyl-pyrrolidine ring. This is because the presence of several tertiary carbons leads a person skilled in the art to the conclusion that the introduction of the hydroxyl could indistinctly occur on any tertiary carbon (indicated with * in the formula reported below)
Conversely and surprisingly the introduction of the hydroxyl, by the reaction object of the invention, occurs almost exclusively on only one of the tertiary carbons of the adamantane, leading to optimal yields and thus providing an alternative and far from obvious synthesis pathway, for the preparation of saxagliptin.
The following examples illustrate the preferred aspects of the invention but they are absolutely not to be considered as limiting the protection scope of the invention. Experimental Section
Example 1
Compound (IV) 399.53 g/mol 100 mg 0.25 1
RuCl3.xH20 207.42 g mL 2.6 mg 0.0250 0.1
KBr03 167.00 g mol 125.4 mg 0.75 3 pyridine 79.10 g/mol 2 mg 0.98 g/mL 0.025 0.1
H20/CH3CN 1 :1 4 mL
A solution containing ruthenium trichloride in water is prepared at room temperature. Potassium bromate, pyridine and the substrate solution in acetonitrile (H20/CH3CN in 1 :1 ratio) are added in the mentioned order. The mixture is heated at 60°C and it is left under stirring following the progress of the reaction by LC-MS. After 1-2 hours the reaction is interrupted by quenching with a Na2S03 1M solution, diluted with water and the product is extracted with ethyl acetate (2x). The organic phase is anhydrified over Na2S04, filtered and the solvent evaporated. Thus the compound (Γ) is obtained with a conversion of 74%.
Example 2
The reaction of example 1 is repeated using a 2: 1 :1 H20/CH3CN/AcOEt mixture as solvent and reacting the mixture for 1 hour. Thus the compound of formula (Γ) is obtained with a conversion of 62%.
Example 3
At room temperature and under argon, an amine solution in anhydrous DMF is prepared. 3 equivalents (1.48 mL) of anhydrous DIPEA are added and left under stirring for 30 minutes. Hence such a solution is added to the just prepared one and cooled with an ice bath containing the acid, the condensing agent and the remainder of anhydrous DIPEA (2 eq, 992 μί). Hence it is left under stirring at 0°C following the progress of the reaction by LC-MS. After 20 hours (complete conversion, disappearance of the acid) the reaction is interrupted and the solvent evaporated. The residue is collected with dichloromethane and washed with a solution of 5% citric acid, with a saturated sodium bicarbonate solution and finally with brine. The organic phase is anhydrified over Na2S04, filtered and the solvent evaporated. The crude is purified by flash chromatography using 7:3 Petroleum ether/AcOEt as eluent. Thus the compound of formula (ΙΓ) is obtained with a yield of 70%.
Example 4
Preparation of saxagliptin
saxagliptin
P.M. Weight Density Volume mmoles Eq
Compound (Γ) 415.53 g/mol - 0.25 1
37% HC1 (11.6M) 2.6 mg 43.1 μΐ 0.5 2
iPrOH 975 μΐ.
H20 1.5 mL
A solution of the compound of formula (Γ) obtained from the reaction of example 1 is prepared at room temperature, in iPrOH/H20. 0,2 eq. of hydrochloric acid are added at room temperature hence heated at 65°C. When this temperature is reached, the remainder of the acid is added and is left under stirring following the progress of the reaction by LC-MS. After 3 hours the deprotection is complete. The reaction is interrupted and isopropanol evaporated. It is basified with a 24% by weight K2C03 solution (pH 9), diluted with water and extracted with toluene. Saxagliptin is isolated from the aqueous phase by counter-extracting it twice with dichloromethane.
Example 5
Purification of saxagliptin
The dichloromethane solution is concentrated at reduced pressure, each time replacing the evaporated volume with as much ethyl acetate. When dichloromethane is not distilling anymore, 1 equivalent of water is added to induce the precipitation of Saxagliptin monohydrate, which is recovered for subsequent filtration.
Claims
1. A process for the reparation of a compound of formula (I)
wherein Pr is a protective group, which comprises reacting a compound of formula (II)
wherein Pr is defined as above, with an oxidant agent of the tertiary carbon, preferably in the presence of a solvent and optionally of one or more catalysts.
2. The process according to claim 1, which is carried out in the presence of one or more solvents.
3. The process according to claim 1 or 2, wherein Pr is a protective group selected from tert-butoxycarbonyl group (BOC), carbobenzyloxy group (CBZ), allyloxycarbonyl group (Alloc) and fluorenylmethoxycarbonyl group (F- moc).
4. The process according to any one of claims 1 to 3, wherein Pr is BOC.
5. The process according to any one of claims 1 to 4, wherein the oxidant agent of the tertiary carbon is selected from Ru04, alkali metal permanganates and sulfonitric mixtures.
6. The process according to claim 5 wherein the oxidant agent is Ru04 which is in situ generated in the presence of Ruthenium based catalysts and in the presence of at least a compound selected from bromates, periodates, hypochlorites, hypervalent iodine, hydrogen peroxide and oxone.
7. The process according to claim 6 wherein the oxidant agent is Ru0 which is in situ generated in the presence of Ruthenium based catalysts and bromates.
8. The process according to claim 1 wherein Pr is a BOC group, which comprises reacting a compound of formula (II), wherein Pr is a BOC group, with an alkali metal bromate, in the presence of ruthenium (III) chloride and pyridine, in a solvent selected from a mixture of water and acetonitrile or a mixture of water, acetonitrile and ethyl acetate.
9. The process according to claim 8 characterized in that it is carried out at a temperature between 50 and 70 °C.
10. The process according to any one of claims 1 to 9, which further comprises the cleavage of the Pr group to give saxagliptin or a salt thereof or a solvate thereof.
11. A compound of formula IF)
or a salt thereof, wherein Pr is a protective group, provided that Pr is not
BOC.
12. The compound of claim 11 wherein Pr is a protective group selected from carbobenzyloxy group (CBZ), allyloxy carbonyl group (Alloc) and fluorenylmethoxycarbonyl group (F-moc).
13. The use of a compound of formula (II) wherein Pr is defined according to any one of claims 1, 3 and 4, or of a compound of formula (IF) according to any one of claims 11 and 12, as an intermediate compound in the synthesis of saxagliptin.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT000132A ITMI20130132A1 (en) | 2013-01-30 | 2013-01-30 | PROCEDURE FOR THE PREPARATION OF INTERMEDIATES OF SAXAGLIPTINA SYNTHESIS AND NEW COMPOUNDS |
| ITMI2013A000132 | 2013-01-30 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2014118612A1 true WO2014118612A1 (en) | 2014-08-07 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IB2014/000072 WO2014118612A1 (en) | 2013-01-30 | 2014-01-27 | Process for the preparation of intermediates of synthesis of saxagliptin and novel compounds |
Country Status (2)
| Country | Link |
|---|---|
| IT (1) | ITMI20130132A1 (en) |
| WO (1) | WO2014118612A1 (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001068603A2 (en) | 2000-03-10 | 2001-09-20 | Bristol-Myers Squibb Co. | Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl iv, processes for their preparation, and their use |
-
2013
- 2013-01-30 IT IT000132A patent/ITMI20130132A1/en unknown
-
2014
- 2014-01-27 WO PCT/IB2014/000072 patent/WO2014118612A1/en active Application Filing
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001068603A2 (en) | 2000-03-10 | 2001-09-20 | Bristol-Myers Squibb Co. | Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl iv, processes for their preparation, and their use |
Non-Patent Citations (1)
| Title |
|---|
| GREENE, T. W.; WUTS, P. G. M.: "OrganicSynthesis", JOHN WILEY, article "Protective Groups" |
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| Publication number | Publication date |
|---|---|
| ITMI20130132A1 (en) | 2014-07-31 |
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