1-[2-(2,4-Dimethylphenylsulfanyl)-Phenyl]Piperazine As A Compound With Combined Serotonin Reuptake, 5-HT3 And 5-HT1a Activity For The Treatment Of Cognitive Impairment

• US 20140371453A1
• Filed: 08/29/2014
• Published: 12/18/2014
• Est. Priority Date: 06/16/2006
• Status: Active Grant

• Current Assignee: H. Lundbeck A/S (Lundbeck Foundation)
• Original Assignee: H. Lundbeck A/S (Lundbeck Foundation)
• Inventors: Faldt, Andre, Ringgaard, Lone Munch, Mealy, Michael J., Rock, Michael Harold, Brodersen, Jorgen, Jorgensen, Morten
• Granted Patent: US 9,095,588 B2
• Time in Patent Office: Days
• US Class Current: 544/395
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 9/14 Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles microspheres A61K9/16; microcapsules A61K9/50; nanocapsules, nanoparticles of the matrix type A61K9/51
• CPC Class Codes: A61K 9/2009 Inorganic compounds
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61K 9/2027 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/2059 Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/08 for nausea, cinetosis or vertigo; Antiemetics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/16 Central respiratory analeptics
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/06 Antigout agents, e.g. antihyperuricemic or uricosuric agents
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 : Antidepressants
• CPC Class Codes: A61P 25/28 : for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 25/30 : for treating abuse or dependence
• CPC Class Codes: A61P 25/32 : Alcohol-abuse
• CPC Class Codes: A61P 25/34 : Tobacco-abuse
• CPC Class Codes: A61P 25/36 : Opioid-abuse
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/04 : Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/10 : Antioedematous agents; Diuretics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 295/096 : with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: Y02P 20/55 : Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
• CPC Class Codes: Y10T 428/2982 : Particulate matter [e.g., sphere, flake, etc.]

Abstract

This disclosure relates to a process for the preparation of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a salt thereof.

Claims

1. A process for the preparation of

2. The process according to claim 1, wherein compound II and compound III are reacted in a first reaction, and wherein the reaction product

3. The process according to claim 1, wherein compound II, compound III and compound IV are mixed together at the start of the process.

4. The process according to claim 1, wherein X₁ and X₂ independently represent Br or I.

5. The process according to claim 4, wherein X₁ represents Br and X₂ represents I.

6. The process according to claim 1, wherein said solvent is an aprotic solvent.

7. The process according to claim 1, wherein the solvent in selected from toluene, xylene, triethyl amine, tributyl amine, dioxin or N-methylpyrrolidone.

8. The process according to claim 7, wherein the solvent is toluene.

9. The process according to claim 1, wherein the palladium source is selected from Pddba₂, Pd(OAc)₂ and Pd₂dba₃.

10. The process according to claim 9, wherein said palladium source is Pddba₂ or Pd₂dba₃.

11. The process according to claim 1, wherein said phosphine ligand is selected from

2,2′

-bis-diphenylphosphanyl-[1,1′

]binaphtalenyl (rac-BINAP),

1,1′

-bis(diphenylphosphino)ferrocene (DPPF),

bis-(2-diphenylphosphinophenyl)ether (DPEphos),

tri-t-butyl phosphine (Fu'"'"'s salt),

biphenyl-2-yl-di-t-butyl-phosphine,

biphenyl-2-yl-dicyclohexyl-phosphine,

(2′

-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethyl-amine

[2′

-(di-t-butyl-phosphanyl)-biphenyl-2-yl]-dimethyl-amine, and

dicyclohexyl-(2′

,4′

,6′

-tri-propyl-biphenyl-2-yl)-phosphane.

12. The process according to claim 11, wherein said phosphine ligand is rac-BINAP.

13. The process according to claim 1, wherein said base is selected from NaO(t-Bu), KO(t-Bu), Cs₂CO₃, DBU and DABCO.

14. The process according to claim 13, wherein said base is NaO(t-Bu).

15. The process according to claim 1, wherein R represents hydrogen

16. The process according to claim 1, wherein R represents a protecting group selected from Boc, Bn, Cbz, C(═

O)Oet and Me.

17. The process according to claim 1, wherein R′

is hydrogen.

18. The process according to claim 1, wherein the temperature is between approximately 80°

C. and approximately 120°

C.

19. The process according to claim 3, comprising the steps of

a. Dissolving or dispersing 1-1.5 equivalents of compounds II, III, and IV in toluene to obtain mixture A;

b. Adding 1-2 mole-% of Pddba₂ and 1-2 mole-% of rac-BINAP together with 2-3 equivalents of NaO(t-Bu) to mixture A to obtain mixture B, which is heated to around 100°

C. until compound II and III are fully converted;

c. Increasing the temperature of the mixture obtained in step b to around 120°

C. until compound IV is fully converted; and

d. Optionally removing the protecting group by the addition of aqueous acid if compound IV is a protected piperazine.

20. The process according to claim 3, wherein 1-1.5 equivalents of 2,4-dimethyl-thiol, 1-bromo-1-iodo-benzene (or 1,2-dibromo-benzene), and piperazine are dispersed in toluene followed by the addition of 2-5 equivalents NaO(t-Bu) and 1-2 mole-% Pd₂dba₃ and rac-BINAP dispersed in toluene to obtain a mixture which is heated to 100-130°

C. for 2-10 hours to obtain the product 1-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine.

21. The process according to claim 3, wherein 2-5 equivalents of NaO(t-Bu), 2-5 equivalents piperazine, 0.2-0.6 mole-% Pddba2, and 0.6-1 mole-% rac-BINAP are dispersed in toluene to obtain mixture A′

, to which mixture approximately 1 equivalent 2-bromo-iodobenzene is added to obtain mixture B′

, to which mixture 1 equivalent 2,4-dimethylthiophenol is added and the resulting mixture is heated to reflux for 3-7 hours to obtain 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine.

22. The process according to claim 1, further comprising an additional step of reacting aqueous HBr with the product

23. The process of claim 22, further comprises precipitating the hydrobromic acid salt after 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine is reacted with the aqueous HBr,

wherein the hydrobromic acid salt is crystalline.

24. Compound 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt in a crystalline form prepared by the process of claim 23.

25. A process for the manufacturing of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromic acid addition salt in which process 1-1.5 equivalents of 2,4-dimethyl-thiol, 1-bromo-1-iodo-benzene or 1,2-dibromo-benzene, and piperazine are dispersed in toluene followed by the addition of 2-5 equivalents NaO(t-Bu) and 1-2 mole-% Pd₂dba₃ and rac-BINAP dispersed in toluene to obtain a mixture which is heated to reflux 3-5 hours to obtain the product 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine, which is further reacted with aqueous hydrobromic acid.

26. The process of claim 25, wherein the 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromic acid addition salt is crystalline and the process further comprises precipitating the 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromic acid addition salt after 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine is reacted with aqueous hydrobromic acid.

27. Compound 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt in a crystalline form prepared by the process of claim 26.

28. A process for the manufacturing of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromic acid addition salt in which process 2-5 equivalents of NaO(t-Bu), 2-5 equivalents piperazine, 0.2-0.6 mole-% Pddba₂, and 0.6-1 mole-% rac-BINAP are dispersed in toluene to obtain mixture A′

, to which mixture approximately 1 equivalent 2-bromo-iodobenzene is added to obtain mixture B′

, to which mixture 1 equivalent 2,4-dimethylthiophenol is added and the resulting mixture is heated to reflux for 4-6 hours to obtain 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine, which is further reacted with aqueous hydrobromic acid.

29. The process of claim 28, wherein the 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromic acid addition salt is crystalline and the process further comprises precipitating the 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromic acid addition salt after 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine is reacted with aqueous hydrobromic acid.

30. Compound 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt in a crystalline form prepared by the process of claim 29.