1) A method for 18F labelling synthesis comprising reacting a radiolabelling precursor of Formula X:
with 18Ffluoride to obtain an 18F-labelled synthon of Formula Y:
2) The method as defined in claim 1 wherein
said radiolabelling precursor of Formula X has the following chemical structure:
and said 18F-labelled synthon of Formula Y has the following chemical structure:
3) The method as defined in claim 1 wherein
said radiolabelling precursor of Formula X has the following chemical structure:
and said 18F-labelled synthon of Formula Y has the following chemical structure:
4) The method as defined in claim 1 which further comprises the step:
(ii) coupling the 18F-labelled synthon of Formula Y as defined herein with a cross-coupling partner in a transition metal-mediated coupling reaction to obtain an 18F-labelled product.
5) The method as defined in claim 4 wherein said transition metal is palladium.
6) The method as defined in claim 4 wherein said coupling step comprises reaction of said 18F-labelled synthon of Formula Y with a compound of Formula Ia:
wherein R1 is a monovalent aliphatic or aromatic hydrocarbon group;
to obtain an 18F-labelled product of Formula IIa:
7) The method as defined in claim 4 wherein said coupling step comprises reaction of the 18F-labelled synthon of Formula I with a compound of Formula Ib:
Bu3SnR2\u2003\u2003(Ib)
wherein R2 is a monovalent aliphatic or aromatic hydrocarbon group;
to obtain an 18F-labelled product of Formula IIb:
8) The method as defined in claim 4 wherein said coupling step comprises reaction of the 18F-labelled synthon of Formula I with a compound of Formula Ic:
wherein R3 is a monovalent aliphatic or aromatic hydrocarbon group;
to obtain an 18F-labelled product of Formula IIa:
9) The method as defined in claim 4 wherein said coupling step comprises reaction of the 18F-labelled synthon of Formula I with a compound of Formula Id:
wherein R4 is a monovalent aliphatic or aromatic hydrocarbon group;
to obtain an 18F-labelled product of Formula IId:
10) The method as defined in claim 4 wherein said coupling step comprises reaction of the 18F-labelled synthon of Formula I with a compound of Formula Ie:
wherein R5 and R6 are independently hydrogen or a monovalent aliphatic or aromatic hydrocarbon group, or together with the nitrogen to which they are attached form a nitrogen-containing aliphatic or aromatic ring;
to obtain an 18F-labelled product of Formula IIe:
11) The method as defined in claim 4 wherein said coupling step comprises reaction of the 18F-labelled synthon of Formula I with a compound of Formula Ie
wherein R5 and R6 are independently hydrogen or a monovalent aliphatic or aromatic hydrocarbon group, or together with the nitrogen to which they are attached form a nitrogen-containing aliphatic or aromatic ring;
in the presence of a source of carbon monoxide to obtain an 18F-labelled product of Formula IIf:
wherein R7 and R8 are as defined for R5 and R6, respectively.
12) The method as defined in claim 1 which is automated.
13) A cassette for carrying out the method as defined in claim 12 wherein said cassette comprises:
i) a vessel containing a precursor compound of Formula X
ii) means for eluting the vessel of step (i) with 18Ffluoride.
14) The cassette as defined in claim 13 which further comprises:
iii) a vessel comprising a compound of any one of Formula Ia-e
wherein R1 is a monovalent aliphatic or aromatic hydrocarbon group;
Bu3SnR2\u2003\u2003(Ib)
wherein R2 is a monovalent aliphatic or aromatic hydrocarbon group;
wherein R3 is a monovalent aliphatic or aromatic hydrocarbon group;
wherein R4 is a monovalent aliphatic or aromatic hydrocarbon group;
wherein R5 and R6 are independently hydrogen or a monovalent aliphatic or aromatic hydrocarbon group, or together with the nitrogen to which they are attached form a nitrogen-containing aliphatic or aromatic ring.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A compound (2R)-(3-amino-2-fluoropropyl)phosphinic acid in crystalline form.
2. The compound (2R)-(3-amino-2-fluoropropyl)phosphinic acid form B, characterized in providing an X-ray powder diffraction pattern exhibiting substantially the following peak with d-value: 2.87 \u212b.
3. The compound (2R)-(3-amino-2-fluoropropyl)phosphinic acid form B according to claim 2, characterized in providing an X-ray powder diffraction pattern exhibiting substantially the following peaks with d-values: 6.2 \u212b, 4.05 \u212b and 2.87 \u212b.
4. The compound (2R)-(3-amino-2-fluoropropyl)phosphinic acid form B according to claim 3, characterized in providing an X-ray powder diffraction pattern exhibiting is substantially the following peaks with d-values: 6.2 \u212b, 4.10 \u212b, 4.05 \u212b, 2.87 \u212b, 2.60 \u212b and 2.47 \u212b.
5. The compound (2R)-(3-amino-2-fluoropropyl)phosphinic acid form B according to claim 4, characterized in providing an X-ray powder diffraction pattern exhibiting substantially the following peaks with d-values: 6.2 \u212b, 4.10 \u212b, 4.05 \u212b, 3.88 \u212b, 3.36 \u212b, 3.28 \u212b, 2.87 \u212b, 2.60 \u212b, 2.47 \u212b and 2.25 \u212b.
6. The compound (2R)-(3-amino-2-fluoropropyl)phosphinic acid form B according to claim 1, characterized in providing an X-ray powder diffraction pattern essentially as shown in FIG. 1.
7. A compound as defined in any one of claims 1 to 6 for use in therapy.
8. A pharmaceutical formulation comprising a compound according to any one of claims 1-6 in admixture with at least one pharmaceutically acceptable excipient.
9. Use of a compound according to any one of claims 1 to 6 as active ingredient in the manufacture of a medicament for the prevention or treatment of asthma, such as reflux-related asthma, pulmonary diseases, cough, laryngitis, chronic laryngitis, pain, failure to thrive, gastric emptying disorders, irritable bowel syndrome (IBS), functional gastrointestinal disorder (FGD), inhibition of transient lower esophageal sphincter relaxations (TLESR), emesis, gastric motility disorders, prevention of regurgitation, belching, hiccups, functional dyspepsia, gastro-esophageal reflux disease (GERD), pharyngitis, sinusitis, otitis media, dental erosions, aspiration prophylaxis, Barett’s esophageus or non-erosive reflux disease (NERD).
10. A method of treatment or prevention of asthma, such as reflux-related asthma, pulmonary diseases, cough, laryngitis, chronic laryngitis, pain, failure to thrive, gastric emptying disorders, irritable bowel syndrome (IBS), functional gastrointestinal is disorder (FGD), inhibition of transient lower esophageal sphincter relaxations (TLESR), emesis, gastric motility disorders, prevention of regurgitation, belching, hiccups, functional dyspepsia, gastro-esophageal reflux disease (GERD), pharyngitis, sinusitis, otitis media, dental erosions, aspiration prophylaxis, Barett’s esophageus or non-erosive reflux disease (NERD) which comprises administration of a therapeutically effective amount of a compound according to any one of claims 1 to 6, to a patient in need thereof.
11. A process for preparing (2R)-(3-amino-2-fluoropropyl)phosphinic acid form B as defined in any of claims 2 to 6, comprising the sequential steps of:
a. dissolving (2R)-(3-amino-2-fluoropropyl)phosphinic acid form A in a polar solvent;
b. adding an anti-solvent or a mixture thereof over a period of time and optionally cooling and optionally isolating the product; and
c. stirring at an elevated temperature for a period of time.
12. The process according to claim 11, wherein said polar solvent is methanol or water, or a mixture thereof.
13. The process according to any one of claims 11 or 12, wherein said anti-solvent is acetonitrile, acetone, ethanol, isopropanol or ethyl acetate.
14. The process according to any one of claims 11 to 13, wherein said period of time in step b is 10 hours.
15. The process according to any one of claims 11 to 14, wherein said temperature in step c is 40\xb0 C.
16. The process according to any one of claims 10 to 15, wherein said period of time in is step c is 33 hours.
17. A process for preparing (2R)-(3-amino-2-fluoropropyl)phosphinic acid form B as defined in any of claims 2 to 6, comprising the step of treating (2R)-(3-amino-2-fluoropropyl)phosphinic acid form A in a water-containing vapor phase optionally including vapor of other solvents a period of time, wherein the relative humidity is equal to or less than 55%.
18. The process according to claim 17, wherein (2R)-(3-amino-2-fluoropropyl)phosphinic acid form B is kept at saturated NaBr salt solution in water.
19. The process according to any one of claims 17 or 18, wherein the relative humidity is 51%.
20. The process according to any one of claims 17 to 19, wherein the temperature is 60\xb0 C.
21. The process according to any one of claims 17 to 20, wherein the period of time is 12 hours.
22. A process for preparing (2R)-(3-amino-2-fluoropropyl)phosphinic acid form B as defined in any of claims 2 to 6, comprising the step of keeping (2R)-(3-amino-2-fluoropropyl)phosphinic acid form A as a suspension in a solvent or a mixture of solvents with a water activity equal to or less than 25%; and then isolating the product from the suspension.
23. The process according to claim 22, wherein said solvent is a mixture of ethanol (90%, vol.vol.) and water (10%, vol.vol.).
24. The process according to claim 22, wherein said solvent is a mixture of acetone (50%, vol.vol.), methanol (40%, vol.vol.) and water (10%, vol.vol.).
25. The process according to any one of claims 22 to 24, wherein the temperature is kept at between 5\xb0 C. and 70\xb0 C.
26. The process according to claim 25, wherein the temperature is kept at between 20\xb0 C. and 50\xb0 C.