WO2016026827A1

WO2016026827A1 - Crystalline boc-s-hadgly and process for its preparation

Info

Publication number: WO2016026827A1
Application number: PCT/EP2015/068884
Authority: WO
Inventors: Roland Barth
Original assignee: Sandoz Ag
Priority date: 2014-08-20
Filing date: 2015-08-18
Publication date: 2016-02-25

Abstract

The present invention refers to crystalline (S)-N-Boc-3-hydroxyadamant-1-yl glycine (abbreviated Boc-S-HADGLY) and a process for its preparation. More particularly, the present invention relates to a process for the preparation of crystalline (5)-N-Boc-3-hydroxyadamant-1-yl glycine in enantiopure form.

Description

Crystalline Boc-S-HADGLY and Process for its Preparation

The present invention refers to crystalline (S)-N-Boc-3-hydroxyadamant-l-yl glycine (abbreviated Boc-S-HADGLY) and a process for its preparation. More particularly, the present invention relates to a process for the preparation of crystalline (5)-N-Boc-3- hydroxyadamant-l-yl glycine in enantiopure form.

Technical Background

(S)-N-Boc-3-hydroxyadamant-l-yl glycine is a key intermediate of therapeutic compounds which act as dipeptidyl peptidase IV inhibitors including Saxagliptin.

Saxagliptin (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxy-l-adamantyl)acetyl]-2-azabicyclo [3.1.0]hexane-3-carbonitrile or its hydrochloride salt is an orally active reversible dipeptidyl peptidase-4 (DPP4) inhibitor, which is a therapeutic agent for treatment of type-2 diabetes mellitus, obesity or related diseases, and is disclosed for example in US 6,395,767 B2, example 60. Saxagliptin can be produced by coupling (S)-N-Boc-3- hydroxyadamant-l-yl glycine and methanoprolineamide as shown in the following scheme:

BOC-S-HADGLY ABH-Amid.salt BOC-SAXA-Amid BOC-SAXA

acidic

conditions

SAXA SAXA-HH

The prolineamide moiety is subsequently dehydrated to give the cyanide. Removal of the Boc protecting group, followed by neutralization gives Saxagliptin. Boc-HADGLY comprises two enantiomers, i. e. ( ?)-N-Boc-3-hydroxyadamant-l-yl glycine and (S)-N- Boc-3-hydroxyadamant-l-yl glycine. For the synthesis of Saxagliptin (S)-N-Boc-3- hydroxyadamant-l-yl glycine is to be used.

A process for the preparation of amorphous (S)-N-Boc-3-hydroxyadamant-l-yl glycine is described in WO 2004/052850, which is performed by treating the racemic mixture (N-Boc-3-hydroxyadamant-l-yl glycine) with a chiral base, drying the resulting mixture to dryness, resuspending the dried mixture in a solvent and heating the suspension for several hours. The product is obtained upon cooling of the mixture to room temperature. However, the process suffers from poor yield and low enantiomeric excess (ee) of (S)-N-Boc-3-hydroxyadamant-l-yl glycine of only about 70-80%.

A process for the preparation of amorphous (S)-N-Boc-3-hydroxyadamant-l-yl glycine having improved yield and higher enantiomeric excess is described in WO 2011/117393. Therein, racemic N-Boc-3-hydroxyadamant-l-yl glycine is subjected to a separation into its enantiomers by reacting the racemic solution with a chiral base to obtain the salt of N-Boc-3-hydroxyadamant-l-yl glycine racemic mixture. The racemic mixture is then transferred into (S)-N-Boc-3-hydroxyadamant-l-yl glycine by adding an acid to set the solution to pH 3, subsequent purification by extracting the solution with ethyl acetate and isolating (S)-N-Boc-3-hydroxyadamant-l-yl glycine from the organic phase to obtain it with an enantiomeric excess of 96%. However, (S)-N-Boc-3- hydroxyadamant-l-yl glycine is obtained in amorphous form, which has the disadvantages typically associated with amorphous compounds, such as low purity, poor stability and poor processability.

It was an object of the present invention to provide a process for the preparation of (S)-N-Boc-3-hydroxyadamant-l-yl glycine in high yield and improved purity. In particular, it was an object to provide a process for the preparation of (S)-N-Boc-3- hydroxyadamant-l-yl glycine in enantiopure form. Moreover, it was an object of the present invention to provide (S)-N-Boc-3-hydroxyadamant-l-yl glycine in a form having improved stability and processability, and a process for its preparation.

In the present invention it has surprisingly be found that the above objects can be solved by the provision of a process as specified in the claims, by which (S)-N-Boc-3- hydroxyadamant-l-yl glycine is obtained in crystalline form.

Summary of the Invention

In one embodiment, the present invention refers to a process for the preparation of (S)-N-Boc-3-hydroxyadamant-l-yl glycine, comprising the steps of (a) providing a salt of (S)-N-Boc-3-hydroxyadamant-l-yl glycine,

(b) adding a mixture of methyl-te/t-butylether and water to provide a solution of the salt of (S)-N-Boc-3-hydroxyadamant-l-yl glycine,

(c) adding an acid to set the pH of the aqueous phase to 1-6, (d) extracting and optionally isolating (S)-N-Boc-3-hydroxyadamant-l-yl glycine from the organic phase.

In another embodiment the present invention refers to (5)-N-Boc-3-hydroxyadamant- 1-yl glycine in crystalline form, which can be obtained by the process described herein. Figure 1 shows an HPLC chromatogram of (S)-N-Boc-3-hydroxyadamant-l-yl glycine prepared by a conventional method in accordance with WO 2011/117393, having an enantiomeric ratio of (S)-N-Boc-3-hydroxyadamant-l-yl glycine to ( ?)-N-Boc-3- hydroxyadamant-l-yl glycine of 94:6 and in which (S)-N-Boc-3-hydroxyadamant-l-yl glycine is obtained in amorphous form. Figure 2 shows an HPLC chromatogram of enantiopure (S)-N-Boc-3-hydroxyadamant-l- yl glycine obtained in crystalline form by the process as described herein.

Figure 3 shows an XRD chromatogram of enantiopure (S)-N-Boc-3-hydroxyadamant-l- yl glycine obtained in crystalline form by the process as described herein.

Figure 4 shows an IR chromatogram of enantiopure (S)-N-Boc-3-hydroxyadamant-l-yl glycine obtained in crystalline form by the process as described herein.

Detailed Description of the Invention

According to the present invention, it is possible to obtain (S)-N-Boc-3- hydroxyadamant-l-yl glycine in crystalline form by a process as described herein.

Step (a) of the process of the present invention comprises providing a salt of (S)-N-Boc- 3-hydroxyadamant-l-yl glycine.

The salt of (S)-N-Boc-3-hydroxyadamant-l-yl glycine is typically a salt obtained from treating a mixture of (S)-N-Boc-3-hydroxyadamant-l-yl glycine and ( ?)-N-Boc-3- hydroxyadamant-l-yl glycine such as a racemic mixture of N-Boc-3-hydroxyadamant-l- yl glycine or an isolated or not isolated derivative thereof with a chiral base. The chiral base can be a chiral amine such as a chiral amino alcohol, e.g. a chiral 1,2- diphenylaminoalcohol. Preferably, the chiral amino alcohol is (l ?,2S)-l,2-diphenyl-2- hydroxyethyl amine (ADPE) or S-(-)-l-l (l-naphthyl)ethylamine, most preferably is (1 ?,2S)- l,2-diphenyl-2-hydroxyethyl amine. Preparation of the chiral amine salt can be performed as described in WO 2011/117393. Typically, preparation of the salt of (S)-N-Boc-3-hydroxyadamant-l-yl glycine is performed in an organic solution, preferably in the presence of an organic solvent such as a non-protic solvent. Suitable non-protic solvents include but are not limited to dimethylsulfoxide, acetonitrile, dimethylformamide, acetone, dimethylether, dioxane, ethyl acetate, isopropyl acetate and mixtures thereof, preferably ethyl acetate and isopropyl acetate, most preferably ethyl acetate. The salt of (5)-N-Boc-3- hydroxyadamant-l-yl glycine typically precipitates from the reaction mixture whereas the salt of ( ?)-N-Boc-3-hydroxyadamant-l-yl glycine stays in solution. The salt of (S)-N- Boc-3-hydroxyadamant-l-yl glycine can then be isolated by methods known in the art, for example by filtration or centrifugation, most preferably by filtration.

For example, a racemic mixture of (S)-N-Boc-3-hydroxyadamant-l-yl glycine and ( ?)-N- Boc-3-hydroxyadamant-l-yl glycine is solved in ethyl acetate and reacted with ADPE. After reaction is complete, ( ?)-N-Boc-3-hydroxyadamant-l-yl glycine amine salt stays in solution, whereas (S)-N-Boc-3-hydroxyadamant-l-yl glycine amine salt precipitates and can be isolated from the reaction mixture by filtration. Typical reaction conditions for racemisation are for example described in WO 2011/117393.

Typically, the salt of (S)-N-Boc-3-hydroxyadamant-l-yl glycine can be obtained by the above described process in an enantiomeric excess (ee) of above 80 %, and is then used in the process of the present invention as described herein.

Optionally, the salt of (S)-N-Boc-3-hydroxyadamant-l-yl glycine has been subjected to one or more purification steps. For example, the salt may be dissolved in a suitable solvent such as one of the non-protic solvents mentioned above, preferable in ethyl acetate, optionally by heating to a temperature of preferably between 60 to 80°C to obtain a clear solution and cooling down the clear solution to precipitate the product. The optionally purified salt of (S)-N-Boc-3-hydroxyadamant-l-yl glycine is then used in the process of the present invention as described herein.

Step (b) of the process of the present invention comprises adding a mixture of methyl- te/t-butylether (MTBE) and water to provide a solution of the salt of (S)-N-Boc-3- hydroxyadamant-l-yl glycine,

The ratio (vol. /vol.) watenMTBE is typically 4:1 to 1:4, preferably 2:1 to 1:2, most preferably about 1:1.

Step (c) of the process of the present invention comprises adding an acid to set the pH of the solution of step (b) to 1-5. Addition of an acid has the effect that the salt is transferred into the organic phase in its acid form (S)-N-Boc-3-hydroxyadamant-l-yl glycine.

Preferably, the pH is set to a range of 1.5 to 3.0, more preferably of 1.8 to 2.2, most preferably the pH is set to about 2.

The acid is typically selected from organic or inorganic acids including hydrochloric acid (HCI) or sulphuric acid (H₂S0₄), preferably is hydrochloric acid. Step (d) of the process of the present invention comprises extracting and optionally isolating (S)-N-Boc-3-hydroxyadamant-l-yl glycine from the organic phase.

Moreover, isolating in step (d) may comprise the steps of

(dl) separating the organic phase and the aqueous phase, and (d2) removing methyl-te/t-butylether from the organic phase to obtain (S)-N-

Boc-3-hydroxyadamant-l-yl glycine as crystalline solid.

Step (d2) may be performed by partially removing MTBE by distillation followed by addition of a seed crystal. Crystallisation of (S)-N-Boc-3-hydroxyadamant-l-yl glycine typically occurs within 24 hours, after which (S)-N-Boc-3-hydroxyadamant-l-yl glycine can be isolated by filtration or other methods known in the art.

As the product obtained from step (d) is preferably obtained in high purity with an enantiomeric excess of more than 90%, more preferably more than 95%, most preferably in enantiopure (>99% ee) form, it can be used without further purification steps in the preparation of saxagliptine or a derivative thereof. Moreover, the aqueous phase may be subjected to one or more additional purification steps such as additional extraction steps. Thus, MTBE and optionally water may be added to the aqueous phase obtained in step (d) after which steps (c) and (d) may be repeated once, twice, or possibly more than twice. (S)-N-Boc-3-hydroxyadamant-l-yl glycine is then isolated from the (combined) organic phases as described above. For illustrative purposes a possible reaction scheme of the process of the present invention using 1,2-aminodiphenyl alcohol (ADPE) as chiral base for the provision of the amine salt of (S)-N-Boc-3-hydroxyadamant-l-yl glycine is shown in the following:

crystaline solid

ee ~ 92% It was surprisingly found in the present invention that (5)-N-Boc-3-hydroxyadamant-l- yl glycine can be obtained by the above described process in crystalline form.

The crystalline form of (S)-N-Boc-3-hydroxyadamant-l-yl glycine has an X-ray powder diffraction patter (XRD) substantially as shown in Figure 3. In particular, the crystalline form of (S)-N-Boc-3-hydroxyadamant-l-yl glycine can be characterized by peaks at the following positions in the XRD chromatogram:

Further, characteristic reflexes in the XRD chromatogram are as follows:

Position °2Theta

8.4 +/- 0.2

10.9 +/- 0.2

14.0 +/- 0.2

15.2 +/- 0.2

16.5 +/- 0.2

Enantiopure (S)-N-Boc-3-hydroxyadamant-l-yl glycine obtained in crystalline form by the process as described herein can further be characterized by the HPLC chromatogram shown in Figure 2. Enantiopure (S)-N-Boc-3-hydroxyadamant-l-yl glycine obtained in crystalline form by the process as described herein can further be characterized by the IR chromatogram shown in Figure 4. The present invention has the surprising and advantageous effects of providing (S)-N- Boc-3-hydroxyadamant-l-yl glycine in its crystalline form, which can optionally be easily further purified, and having improved product properties such as improved chemical and physical stability and improved processability. In addition, the process of the present invention can easily be reproduced and can be performed in industrial scale.

Experimental Parameters X-ray powder diffraction: X-ray powder diffraction patterns (XRPD) were obtained with a PANalytical X'Pert PRO diffractometer equipped with a theta/theta coupled goniometer in transmission geometry, Cu-Kal,2 radiation (wavelength 0,15419 nm) with a focusing mirror and a solid state PIXcel detector. The patterns were recorded at a tube voltage of 45 kV and a tube current of 40 mA, applying a stepsize of 0.013° 2-Theta with 40s per step (255 channels) in the angular range of 2° to 40° 2-Theta at ambient conditions.

A typical precision of the 2-theta values is in the range of about ± 0.2° 2-Theta. Thus a diffraction peak that appears at 5.0° 2-Theta can appear between 4.8 and 5.2° 2-Theta on most X-ray diffractometers under standard conditions.

Experimental Parameters IR-Spectrometer:

Infrared spectra (IR) were recorded on an MKII Golden Gate™ Single Reflection Diamond ATR (attenuated total reflection) cell with a Bruker Tensor 27 FTIR spectrometer with 4 cm-1 resolution at ambient conditions. To record a spectrum a spatula tip of a sample was applied to the surface of the diamond in powder form. Then the sample was pressed onto the diamond with a sapphire anvil and the spectrum was recorded. A spectrum of the clean diamond was used as background spectrum.

A typical precision of the wavenumber values is in the range of about ± 2 cm -1. Thus, an infrared peak that appears at 1716 cm-1 can appear between 1714 and 1718 cm-1 on most infrared spectrometers under standard conditions.

Claims

1. Process for the preparation of crystalline (S)-N-Boc-3-hydroxyadamant-l-yl glycine, comprising the steps of

(a) providing a salt of (S)-N-Boc-3-hydroxyadamant-l-yl glycine,

(b) adding a mixture of methyl-te/t-butylether and water to provide a

solution of the salt of (S)-N-Boc-3-hydroxyadamant-l-yl glycine,

(c) adding an acid to set the pH of the aqueous phase to 1-5,

(d) extracting and optionally isolating (S)-N-Boc-3-hydroxyadamant-l-yl glycine from the organic phase.

2. Process according to claim 1, wherein the salt of step (a) is an amine salt.

3. Process according to claim 1 or 2, wherein the salt is obtained by reacting (S)-N- Boc-3-hydroxyadamant-l-yl glycine with a chiral base, preferably an amino alcohol, more preferably (1R,2S)- l,2-diphenyl-2-hydroxyethyl amine or S-(-)-l-l (1- naphthyl)ethylamine, most preferably (1R,2S)- l,2-diphenyl-2-hydroxyethyl amine.

4. Process according to any one of the previous claims, wherein the salt of (S)-N- Boc-3-hydroxyadamant-l-yl glycine is provided in form of the racemic mixture of (S)-N- Boc-3-hydroxyadamant-l-yl glycine and ( ?)-N-Boc-3-hydroxyadamant-l-yl glycine.

5. Process according to any one of the previous claims, wherein the acid in step (c) is HCI or H₂S0₄, preferably is HCI.

6. Process according to any one of the previous claims, wherein the pH in step (c) is between 1.5 and 3.0, preferably between 1.8 and 2.2.

7. Process according to any one of the previous claims, wherein isolating in step (d) comprises the steps of

(dl) separating the organic phase and the aqueous phase, and

(d2) removing methyl-te/t-butylether from the organic phase to obtain (S)-N- Boc-3-hydroxyadamant-l-yl glycine as crystalline solid.

8. Crystalline (S)-N-Boc-3-hydroxyadamant-l-yl glycine, characterized by peaks in the XRD chromatogram at positions 8.4 +/- 0.2, 10.9 +/- 0.2, 14.0 +/- 0.2, 15.2 +/- 0.2, 16.5 +/- 0.2 °2Theta

9. Crystalline (S)-N-Boc-3-hydroxyadamant-l-yl glycine, obtainable by the process according to any one of claims 1 to 7, wherein the enantiomeric excess is more than 90%.

10. Use of crystalline (S)-N-Boc-3-hydroxyadamant-l-yl glycine in the preparation of saxagliptine or a derivative thereof.