• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    process for the preparation of 1- [2- (2,4-dimethyl phenylsulfanyl) -phenyl] -piperazine. there is disclosed a process for the preparation of 1- [2- (2,4-dimethyl-phenylsulfanyl) -phenyl] -piperazine and pharmaceutically acceptable salts which involves reacting compounds of formula ii, iii, iv, under catalysis with pd and na presence of phosphine binders to give compound i.
    公开号:BR112014016322B1
    申请号:R112014016322-7
    申请日:2012-12-20
    公开日:2020-09-15
    发明作者:Kim Lasse Christensen
    申请人:H. Lundbeck A/S；
    IPC主号:
    专利说明:

    Field of invention
    [0001] The present invention relates to a process for the preparation of the compound 1- [2- (2,4-dimethyl-phenylsulfanyl) -phenyl] -piperazine and its pharmaceutically acceptable salts.
    [0002] Background of the invention
    [0003] International patent applications WO 03/029232 and WO 2007/144005 disclose the compound 1 - [2- (2,4-dimethyl-phenylsulfanyl) -phenyl] -piperazine, including various manufacturing routes. In the remainder of this document, 1- [2- (2,4-dimethyl-phenylsulfanyl) -phenyl] -piperazine and its pharmaceutically acceptable salts are called Compound I or Compound I XX when it is desired to refer to the XX salt.
    [0004] Compound I is a 5-HT3, 5-HT7 and 5-HTID receptor antagonist, a 5-HT1A receptor agonist and a partial 5-HT1B receptor agonist and a serotonin transporter inhibitor. In addition, Compound I has been shown to increase the levels of the neurotransmitters serotonin, norepinephrine, dopamine, acetylcholine and histamine in specific areas of the brain. All of these activities are considered clinically relevant and are potentially involved in the mechanism of action of the compound [J. Med. Chem., 54, 3206-3221, 2011; Eur. Neuropsychopharmacol., 18 (supplement 4), S321, 2008; Eur. Neuropsychopharmacol., 21 (supplement 4), S407-408, 2011; J. Psychiatry Clin Pract. 5, 47, 2012],
    [0005] Compound I has been shown in clinical trials to be a safe and effective treatment for depression. An article reporting the results of a proof-of-concept study to assess the compound's efficacy and tolerability in patients with major depressive disorder (MDD), authored by Alvares et al, was made available online by Int. J. Neuropsychofarm . July 18, 2011. The results of this six-week, randomized, placebo-controlled study of approximately 100 patients in each arm show that Compound I is significantly different from placebo in the treatment of depressive and anxiety symptoms in patients with MDD . It is also reported that no clinically relevant changes were observed in clinical laboratory results, vital signs, weight, or ECG parameters. The results of a long-term study also show that Compound I is effective in preventing recurrence in patients suffering from MDD [Eur. Neuropsychopharmacol. 21 (supplement 3), S396- 397, 2011].
    [0006] WO 2007/144005 discloses a manufacturing process in which the compounds
    they are mixed in the presence of a base and a palladium catalyst, consisting of a palladium source and a phosphine binder. The palladium catalyst catalyzes the formation of the CN bond, as disclosed in US 5,573,460. In the above process, piperazine can be optionally protected in one of the nitrogenous substances. This process gives rise to the desired compound in high yield and relatively high purity. Still, impurities are formed, which subsequently have to be removed. It is particularly difficult to remove impurities which, like compound I, contain a secondary amine, i.e., a piperazine fraction. Such compounds tend to have similar solubility properties, for example, including pH-dependent solubility properties, and thus are difficult to separate from Compound I using methods that take advantage of differences in solubility, for example, crystallization. WO 2010/094285 discloses a purification process that effectively removes such impurities, for example 1- [2- (2,4-dimethyl-phenylsulfanyl) -phenyl] -4- (2-piperazin-1-yl-phenyl ) -piperazine, which is formed when both nitrogens of the piperazine group form a CN bond. The purification process comprises precipitating an isopropanol solvate from the HBr salt of Compound I.
    [0007] The present invention provides a new manufacturing route that eliminates or reduces the aforementioned difficult to remove impurities. Summary of the invention
    [0008] The inventor found that a reaction between 1-halogen-2,4-dimethyl-phenyl, 2-halogen-thiophenol and an optionally protected piperazine, in the presence of a base and a palladium catalyst, is a reaction with high yield and purity, and which impurities are reduced or eliminated. Accordingly, in one embodiment, the invention relates to a process for the preparation of
    or their pharmaceutically acceptable salts (Compound I), the process of which involves reacting a compound of formula II
    where X represents Br or I, with a compound of formula III
    III where Y represents Cl or Br and R 'represents hydrogen or a metal ion, and a compound of formula IV
    where R represents hydrogen or a protecting group, in the presence of a solvent, a base and a palladium catalyst, consisting of a source of palladium and a phosphine binder, at a temperature between 50 ° C and 130 ° C. Detailed description of the invention
    [0009] In one embodiment, the compound of formula II and the compound of formula III can react in a first step to prepare the intermediate

    [0010] This intermediate can then be isolated before another reaction with a compound of formula IV to give Compound I. Alternatively, this additional reaction can occur without isolation of the intermediate. One-pot synthesis pathways, ie, synthesis pathways in which all reagents are loaded into the reactor at the start of the reaction without isolation or purification of intermediates, are generally preferred pathways due to their inherent simplicity . On the other hand, the number of possible unwanted side reactions also increases in one-step synthesis, with the corresponding increase in side products and loss of yield. For the present process, it is noted that piperazine contains two identical secondary amines, both of which can potentially participate in the formation of a C-N bond. Still, it has been found that the present manufacturing pathway manages to prevent such side reactions in a highly effective manner. In particular, it has been found that the present manufacturing process effectively prevents or reduces the formation of impurities produced by the formation of a C-N bond involving the secondary amine of Compound I. Examples of such impurities include 1- (2,4-dimethyl-phenyl) -4- [2- (2,4-dimethyl-phenylsulfanyl) -phenyl] -piperazine.
    [0011] WO 2010/094285 discloses a purification process that can be used to remove impurities generated when the second amine of the piperazine fraction also participates in the formation of a C-N bond. The purification process disclosed in WO 2010/094285 is applied to a process for the preparation of Compound I in which 2,4-dimethyl-thiophenol, 1,2-dihalobenzene and optionally substituted piperazine react in the presence of a palladium catalyst. This process was first disclosed in WO 2005/144005. The data provided in WO2010 / 094285 seems to indicate that impurities formed when the second amine also participates in the formation of a CN bond in this reaction, for example, 1- [2- (2,4-dimethyl-phenylsulfanyl) -phenyl] -4- (2-piperazin-1-yl-phenyl) - piperazine, are generated in an amount of 0.5% to 4.8%. This is consistent with the data presented in Example 4 in the present application, where 1% of that impurity is generated. As discussed below, the palladium catalyst also catalyzes the formation of C-S bonds. It is further noted that, in the manufacturing process of the present invention, impurities generated by the reaction of two (or more) thiol compounds (compound of formula III) are not generated in any significant amount.
    [0012] As shown in the examples, the present invention provides an alternative manufacturing process for Compound I in which few or no impurities are generated via formation of a C-N bond in the second piperazine nitrogen. At the same time, the level of total impurities is also reduced compared to the process disclosed in WO 2005/144005 and the overall yield is maintained at a high level. In addition, the manufacturing process of the present invention provides a simpler overall process, as purification steps can be avoided to remove impurities generated via the formation of a C-N bond in the second piperazine nitrogen, for example, as disclosed in WO 2010/094285. The data presented in examples 1-4 show that, for all practical purposes, no impurities generated when the second amine participates in the formation of a CN bond, for example, Impurities A and B. This compares favorably with the level of such impurities of about 1% with the WO 2005/144005 process, as demonstrated in example 4, and the even greater numbers reported in WO 2010/094285. It is also to be noted that the overall level of impurities is significantly lower, that is, about 50% lower, with the manufacturing process of the present invention, which, again, means that the purity of Compound I obtained in the process of manufacturing of the present invention is much higher.
    [0013] The compound of formula II is 1-halogen-2,4-dimethyl-phenyl, in which said halogen is selected from Br and I. In one embodiment, the compound of formula II is 1-iodo-2,4 -dimethyl-phenyl.
    [0014] The compound of formula III is 2-halogen-thiophenol, in which said halogen is selected from Cl and Br. In one embodiment, the compound of formula III is 2-bromo-thiophenol.
    [0015] The compound of formula III is a thiol or the corresponding thiolate. Due to basic reaction conditions, the reactive species is thiolate. From an occupational health perspective, it may be beneficial to use a thiolate, such as Li +, Na +, K + or Ca ++ thiolate, to avoid odor problems associated with thiols. Still, in one embodiment, R 'is hydrogen.
    [0016] The compounds of the formula II and III are typically added in equimolar amounts, and these compounds are also typically added in a limiting amount.
    [0017] The compound of the formula IV is a piperazine compound. Piperazine has two nitrogens, only one of which must participate in the formation of a C-N bond. In one embodiment, the formation of bonds with the second nitrogen is avoided using a monoprotected piperazine, that is, a modality in which R is a protecting group. Many protecting groups are known in the art, and useful examples include -C (= O) O-W, -C (= O) -W, boc, Bn and Cbz, and in particular boc. W represents alkyl or aryl; Bn is the abbreviation for benzyl; boc is the abbreviation for t-butyloxycarbonyl; and cbz is the abbreviation for benzyloxycarbonyl. If a protected piperazine is used in the reactions, the protecting group must be removed in a subsequent step, typically by adding an aqueous acid. It was found that the present process gives rise only to low levels of impurities generated via the formation of a C-N bond in the second amine of the piperazine. This allows you to use unprotected piperazine (that is, R is hydrogen). The use of unprotected piperazine allows an inherently simpler process, as the deprotection step can be avoided.
    [0018] The compound of formula IV is typically added in an amount of 1-100 equivalents, such as 1-10 equivalents, typically 1-3 equivalents. Alternatively, piperazine can be used as a solvent, that is, a modality in which piperazine acts as a reagent and solvent.
    [0019] The solvent used in the process of the present invention can be selected from aprotic organic solvents or mixtures of such solvents with a boiling temperature in the range of reaction temperatures, that is, 50-130 ° C. Typically, the solvent is selected from toluene, xylene, triethyl amine, tributyl amine, dioxane, N-methylpyrrolidone, pyridine or any mixture thereof. Toluene is particularly mentioned as a solvent.
    [0020] In the present process it is central to use a palladium catalyst, without which Compound I is not formed. As discussed above, the palladium catalyst catalyzes the formation of the C-N bond, but also the formation of the C-S bond [Bull. Chem. Soc. Jpn., 53, 1385-1389, 1980]. The palladium catalyst consists of a palladium source and a phosphine binder. Useful palladium sources include palladium in different oxidation states, such as, for example, 0 and II. Examples of palladium sources that can be used in the process of the present invention are Pd2 (dba) 3, Pd (dba) 2 and Pd (OAc) 2. dba is the abbreviation for dibenzylidene acetone. In particular Pd (dba) 2 and Pd (OAc) 2 are mentioned. The palladium source is typically applied in an amount between 0.1 and 6 mol%, such as 0.5 and 2 mol%, typically about 1 mol%. Throughout that order, molar% and equivalents are calculated for the limiting reagent.
    [0021] Numerous phosphine, monodentate and bidentate ligands are known. Useful phosphine binders include 2,2'-bis-diphenylphosphanyl- [1,1 '] racemic binaphthalenyl (rac-BINAP), (S) -BINAP, (R) -BINAP, 1,1'-bis (diphenylphosphine) ferrocene ( DPPF), bis- (2-diphenylphosphinophenyl) ether (DPEphos), tri-t-butyl phosphine (Fu 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) -phosphan. In addition, carbene linkers, such as, for example, 1,3-bis- (2,6-diisopropyl-phenyl) -3H-imidazole-1-io chloride, can be used instead of phosphine linkers. In one embodiment, the phosphine ligand is rac-BINAP, DPPF or DPEphos, and in particular rac-BINAP. The phosphine binder is usually applied in an amount between 0.2 and 12 mol%, such as 0.5 and 4 mol%, typically about 2 mol%.
    [0022] The base is added to the reaction mixture to increase the pH. In particular, selected bases from NaOt-Bu, KOt-Bu, Na2CO3, K2CO3 and Cs2CO3 are useful. Organic bases, such as 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) and 1,4-diazabicyclo [2.2.2] octane (DABCO), can also be applied. Particular mention is made of NaO (t-Bu) and KO (t-Bu). Typically, the base is added in an amount of about 2-10 equivalents, like 2-5 equivalents, like 2.5-3.5 equivalents.
    [0023] In some situations it may be desirable to obtain an acid addition salt of 1 - [2- (2,4-dimethyl-phenylsulfanyl) -phenyl] -piperazine instead of the free base. Acid addition salts can be obtained at an additional step in the process, in which the obtained free base reacts with a relevant acid, such as, for example, lactic acid, hydrochloric acid or hydrobromic acid. The acid can be added directly to the reaction mixture or, alternatively, the free base can be initially purified to any suitable degree before such a step. If the free base has been isolated as a solid compound, it may be necessary to use a solvent to bring the free base into solution before reacting with the acid. In one embodiment, aqueous hydrobromic acid is added directly to the reaction mixture without any initial purification of the free base. Alternatively, HBr can be added in an alcoholic solution.
    [0024] In processes in which a protected piperazine is used, it is necessary to remove the protecting group, for example, by adding an aqueous acid, as explained above. In one embodiment, said aqueous acid can be selected to obtain two transformations, that is, the deprotection of the protected piperazine and the formation of an acid addition salt. In particular, aqueous hydrobromic acid can be used to unprotect the protected piperazine and to obtain the hydrobromic acid addition salt in one step of the process.
    [0025] In one embodiment, the process of the present invention is conducted at 75 ° -120 °, or 80 ° -120 °.
    [0026] For all the reactions and reaction mixtures mentioned here, it can be an advantage to purge them with an inert gas or process them under a blanket of inert gas. Nitrogen is an example of an economical and easily available inert gas.
    [0027] In one embodiment, Compound I is prepared in a process that comprises reacting

    [0028] in the presence of a solvent, a base and a palladium catalyst, consisting of a source of palladium and a phosphine binder, at a temperature between 50 ° C and 130 ° C. In a further embodiment, the compound obtained is reacted with an acid to obtain a desired pharmaceutically acceptable salt of 1- [2- (2,4-dimethyl-phenylsulfanyl) -phenyl] -piperazine.
    [0029] In one embodiment, the invention provides a process for the preparation of Compound I, the process of which comprises the following steps: a) Dissolve or disperse 0.1 mol% - 3 mol% of bis (dibenzylidenoacetone) palladium (0) and 0.5 mol% - 4 mol% of racemic 2,2'-bis-diphenylphosphanyl- [1,1 '] binaphthalenyl and 2-6 equivalents of toluene base to obtain Mixture A; b) adding 1 equivalent of 1-iodo-2,4-dimethylbenzene, 0.8-1.2 equivalents of 2-bromo thiophenol and 1-10 equivalents of piperazine to Mixture A to obtain Mixture B; and c) heat Mixture B to 80 ° C-120 ° C or 75 ° -120 ° to obtain
    d) optionally adding an appropriate acid to the product obtained in step c) to obtain the corresponding salt. The addition of aqueous HBr is particularly mentioned.
    [0030] In one embodiment, the invention relates to Compound I and, in particular, the HBr salt of Compound I obtained in a process comprising or consisting of steps a) to d) above.
    [0031] In one embodiment, the invention provides a process for the preparation of Compound I, the process of which comprises the following steps: a) Dissolve or disperse 0.1 mol% - 3 mol% of bis (dibenzylidenoacetone) palladium (0) and 0.5 mol% - 4 mol% of racemic 2,2'-bis-diphenylphosphanyl- [1,1 '] binaphthalenyl, 1-10 equivalents of piperazine and 2-6 equivalents of toluene base to obtain Mixture A; b) adding 1 equivalent of 1-iodo-2,4-dimethylbenzene and 0.8-1.2 equivalents of 2-bromo thiophenol to Mixture A to obtain Mixture B; and c) heat Mixture B to 80 ° C-120 ° C or 75 ° -120 ° to obtain
    d) optionally adding an appropriate acid to the product obtained in step c) to obtain the corresponding salt. The addition of aqueous HBr is particularly mentioned.
    [0032] In one embodiment, the invention relates to Compound I and, in particular, the HBr salt of Compound I obtained in a process comprising or consisting of steps a) to d) above.
    [0033] All references, including publications, patent applications, and patents, cited in this document are hereby incorporated in their entirety by reference and in the same way as if each reference were individually and specifically indicated to be incorporated by reference and were presented in its entirety in this document (to the maximum extent permitted by law), regardless of any incorporation provided separately from private documents elsewhere in this document.
    [0034] The use of the terms "one", "one", "o" and "a" and similar referents in the context of the description of the invention should be understood as including the singular and the plural, unless otherwise indicated in this document or explicitly contradicted by the context. For example, the phrase "the compound" is to be understood as referring to various compounds of the invention or the particular aspect described, unless otherwise indicated.
    [0035] The description of any aspect or aspect of the invention in this document using terms such as "comprising", "possessing", "including" or "containing" with reference to an element or elements is intended to provide a basis for a similar aspect or aspect of the similar invention which "consists of", "essentially consists of" or "substantially comprises" such particular element or particular elements, unless otherwise stated or explicitly contradicted by the context (for example, a composition described herein as comprising a particular element should be understood as the description also of a composition consisting of that element, unless otherwise indicated or explicitly contradicted by the context). Examples
    [0036] Example 1

    [0037] Bis (dibenzylidenoacetone) palladium (0) (0.610 g, 1.06 mmol), 2.2'-bis (diphenylphosphine) -1.1 '-racemic bisphine (1.34 g, 2.15 mmol), sodium tert-butoxide (31.0 g, 323 mmol) and toluene (150 ml, degassed) were mixed. The reaction mixture was stirred for 2 hours at room temperature (23 ° C) under an atmosphere of nitrogen.
    [0038] To this mixture were added piperazine (23.0 g, 267 mmol), 1-iodo-2,4-dimethylbenzene (25.0 g, 108 mmol) and 2-bromo thiophenol (20.5 g, 108 mmol). The reaction mixture was then heated to 100 ° C for 5 hours, after which it was cooled to room temperature. To the reaction mixture, water (80 ml) was added (IPC (Process Control) sampled here) and then Celite 545 (8.0 g). The reaction was stirred for 20 minutes before being filtered. The phases were separated and the toluene phase was washed 2 times with water (2 x 80 ml).
    [0039] The toluene phase was heated to 60 ° C. To the warm toluene phase, hydrobromic acid (8.9 M, 13.0 mL, 116 mmol) was added, crystallization cores ((HBr salt) of the title compound, 10 mg) were added and the solution was left cool to room temperature.
    [0040] The HBr salt of 1 - [2- (2,4-dimethyl-phenylsulfanyl) -phenyl] -piperazine was isolated by filtration and the filter cake was washed twice with toluene (2 x 30 ml).
    [0041] Yield 80.1% HBr salt of 1 - [2- (2,4-dimethyl-phenylsulfanyl) -phenyl] -piperazine (33.5 g, 88.3 mmol).
    [0042] Purity 97.9% (HPLC, UV detection at 254 nm)
    [0043] 1H NMR (DMSO-d6; 500 MHz): 8.83 (broad s, 2H), 7.34 (d, 1H), 7.26 (s, 1H), 7.15 (m, 3H) , 6.98 (dd, 1H), 6.43 (d, 1H), 3.26 (m wide, 4H), 3.21 (m wide, 4 H), 2.33 (s, 3H), 2 , 25 (s, 3H). Example 2

    [0044] Bis (dibenzylideneacetone) palladium (0) (665 mg, 1.15 mmol), 2,2'-bis (diphenylphosphine) -1,1'-racemic binaftyl (1.44 g, 2.30 mmol), sodium tert-butoxide (22.2 g, 231 mmol), piperazine (16.6 g, 193 mmol), and toluene (110 ml, degassed) were mixed. The reaction mixture was stirred for 1 hour at room temperature (23 ° C) under an atmosphere of nitrogen.
    [0045] To this mixture were added 1-iodo-2,4-dimethylbenzene (15.1 g, 65.0 mmol) and 2-bromo thiophenol (11.8 g, 62.4 mmol). The reaction mixture was then heated to 100 ° C for 4 hours, after which it was cooled to room temperature. To the reaction mixture, water (60 ml) was added (IPC sampled here) and then Celite 545 (9.5 g). The reaction was stirred for 20 minutes before being filtered. The phases were separated and the toluene phase was washed 2 times with water (2 x 60 ml).
    [0046] The toluene phase was heated to 60 SC. To the warm toluene phase, hydrobromic acid (8.9 M, 9.3 ml, 82.8 mmol) was added, crystallization cores were added (HBr salt of the title compound, 10 mg) and the solution was left cool to room temperature.
    [0047] The HBr salt of 1- [2- (2,4-dimethyl-phenylsulfanyl) -phenyl] -piperazine was isolated by filtration and the filter cake was washed 3 times with toluene (3 x 25 ml).
    [0048] Yield 77.1% HBr salt of 1 - [2- (2,4-dimethyl-phenylsulfanyl) -phenyl] -piperazine (18.6 g, 49.0 mmol).
    [0049] Purity 98.2% (HPLC, UV detection at 254 nm)
    [0050] 1H NMR (DMSO-de): 8.83 (broad s, 2H), 7.34 (d, 1 H), 7.26 (s, 1 H), 7.14 (m, 3H), 6.97 (dd, 1H), 6.42 (d, 1H), 3.26 (m wide, 4H), 3.21 (m wide, 4 H), 2.33 (s, 3H), 2, 25 (s, 3H). Example 3

    [0051] Palladium (ll) acetate (580 mg, 2.58 mmol), 2,2'-bis (diphenylphosphine) -1, racemic T-binaftyl (3.20 g, 5.16 mmol), tert-butoxide sodium (49.5 g, 516 mmol), piperazine (37.0 g, 430 mmol), and toluene (250 ml, degassed) were mixed. The reaction mixture was stirred for 2 hours at room temperature (23 ° C) under an atmosphere of nitrogen.
    [0052] To this mixture were added 1-iodo-2,4-dimethylbenzene (40.0 g, 172 mmol) and 2-bromo thiophenol (32.6 g, 172 mmol). The reaction mixture was then heated to 100 ° C for 1 hour, after which it was cooled to room temperature. To the reaction mixture, water (80 ml) was added (IPC sampled here) and then Celite 545 (12 g). The reaction was stirred for 20 minutes before being filtered. The phases were separated and the toluene phase was washed 2 times with water (2 x 80 ml).
    [0053] The toluene phase was heated to 60 ° C. To the warm toluene phase, hydrobromic acid (8.9 M, 20.8 ml, 185 mmol) was added, crystallization cores (HBr salt of the title compound, 10 mg) were added and the solution was allowed to cool to at room temperature.
    [0054] The HBr salt of 1- [2- (2,4-dimethyl-phenylsulfanyl) -phenyl] -piperazine was isolated by filtration and the filter cake was washed 3 times with toluene (3 x 40 ml).
    [0055] Yield 84.3% of HBr salt of 1 - [2- (2,4-dimethyl-phenylsulfanyl) -phenyl] -piperazine containing 0.60 eq of tert-butanol (62.1 g, 147 mmol) .
    [0056] Purity 98.6% (HPLC, UV detection at 254 nm).
    [0057] 1H NMR (DMSO-d6): 8.82 (broad s, 2H), 7.34 (d, 1H), 7.26 (s, 1H), 7.15 (mp, 3H), 6, 98 (dd, 1H), 6.43 (d, 1H), 3.27 (m wide, 4H), 3.21 (m wide, 4 H), 2.34 (s, 3H), 2.25 ( s, 3H), 1.12 (s, 5.4H). Example 4

    [0058] Bis (dibenzylidenoacetone) palladium (0) (307 mg, 0.530 mmol), 2,2'-bis (diphenylphosphine) -1,1'-racemic binaftyl (0.66 g, 1.06 mmol), terti- sodium butoxide (44.7 g, 466 mmol), piperazine (40.3 g, 469 mmol) and toluene (200 mL, degassed) were mixed. The reaction mixture was stirred for 35 minutes at room temperature (23 ° C) under an atmosphere of nitrogen.
    [0059] To this mixture were added 1-bromo-2-iodo-benzene (39.2 g, 135 mmol) and 2,4-dimethyl-benzenethiol (18.3 g, 133 mmol). The reaction mixture was then heated to reflux for 6 hours, after which it was cooled to room temperature. To the reaction mixture, water (60 ml) was added (IPC sampled here) and then Celite 545 (9.0 g). The reaction was stirred for 20 minutes before being filtered. The phases were separated and the toluene phase was washed 2 times with water (2 x 60 ml).
    [0060] The toluene phase was heated to 60 ° C. To the warm toluene phase, hydrobromic acid (8.9 M, 16.8 mL, 150 mmol) was added, crystallization cores (HBr salt of the title compound, 10 mg) were added and the solution was allowed to cool to at room temperature.
    [0061] The HBr salt of 1 - [2- (2,4-Dimethyl-phenylsulfanyl) -phenyl] -piperazine was isolated by filtration and the filter cake was washed 3 times with toluene (3 x 25 ml).
    [0062] Yield 81.5% 1 - [2- (2,4-dimethyl-phenylsulfanyl) -phenyl] -piperazine HBr salt containing 0.70 eq of tert-butanol (51.2 g, 118 mmol) .
    [0063] Purity 96.0% (HPLC, UV detection at 254 nm).
    [0064] 1H NMR (DMSO-d6): 8.78 (broad s, 2H), 7.34 (d, 1H), 7.26 (s, 1H), 7.15 (m, 3H), 6, 98 (dd, 1H), 6.43 (d, 1H), 3.27 (m wide, 4H), 3.20 (m wide, 4 H), 2.34 (s, 3H), 2.26 ( s, 3H), 1.12 (s, 6.3H).
    [0065] The table below shows analytical data of impurities (% Area per hplc) for IPC and final product for examples 1-4. HPLC method • Column type: UPLO Acquity BEH C18 1.7pm; 2.1x150 mm • Column temperature: 60 ° C • Detection at 254 nm • Flow: 0.6 mL / minute • Solvents: A: Water containing 0.05% TFA (trifluoroacetic acid) B: Acetonitrile containing 5% Water and 0.035% TFA

    [0066] Impurity A is 1,2-bis (1'-piperazinyl) benzene.
    [0067] Impurity B is 1-phenyl-piperazine.
    [0068] Impurity C is 1- (2-bromo-phenyl) piperazine.
    [0069] Impurity D is 1- (2,4-dimethyl-phenyl) -piperazine.
    [0070] Impurity E is 1 - [2- (2,4-dimethyl-phenylsulfanyl) -phenyl] -4- (2-piperazin-1-yl-phenyl) -piperazine.
    [0071] Impurity F is 1- (2,4-dimethyl-phenyl) -4- [2- (2,4-dimethyl-phenylsulfanyl) -phenyl] piperazine.
    [0072] Impurity G is 2,4-dimethyl-1-phenylsulfanylbenzene.
    权利要求:
    Claims (18)
    [0001]
    1. Process for preparing
    [0002]
    2. Process according to claim 1, characterized by the fact that X represents I.
    [0003]
    3. Process according to claim 1 or 2, characterized by the fact that Y represents Br and R 'represents H.
    [0004]
    Process according to any one of claims 1 to 3, characterized by the fact that R represents H.
    [0005]
    Process according to any one of claims 1 to 3, characterized by the fact that R represents a protecting group selected from -C (= 0) 0-W, -C (= 0) -W, boc, Bn and Cbz , where W represents alkyl or aryl.
    [0006]
    Process according to any one of claims 1 to 5, characterized in that said solvent is an aprotic solvent.
    [0007]
    7. Process according to claim 6, characterized by the fact that said solvent is toluene.
    [0008]
    Process according to any one of claims 1 to 7, characterized in that said source of palladium is selected from Pd (dba) 2, Pd (OAc) 2 and Pd2dba3.
    [0009]
    9. Process according to claim 8, characterized by the fact that the referred source of palladium is Pd (dbah or Pd (OAc) 2.
    [0010]
    Process according to any one of claims 1 to 9, characterized by the fact that said phosphine ligand is selected from racemic 2,2'-Bis-diphenylphosphanyl- [l, l '] binaphthalenyl (rac-BINAP), l , l'-bis (diphenylphosphino) ferrocene (DPPF), bis- (2-diphenylphosphinophenyl) ether (DPEphos), tri-t-butyl phosphine (Fu 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.
    [0011]
    11. Process according to claim 10, characterized by the fact that the aforementioned phosphine ligand is 2,2'-bis-diphenylphosphanyl- [l, l '] binaphthalenyl (rac-BINAP).
    [0012]
    Process according to any one of claims 1 to 11, characterized in that said base is selected from NaO (t-Bu), KO (t-Bu), K2CO3, Na2CO3, Cs2CO3, DBU and DABCO.
    [0013]
    13. Process according to claim 12, characterized by the fact that said base is NaO (t-Bu).
    [0014]
    Process according to any one of claims 1 to 13, characterized in that it further comprises reacting the product obtained in said claims with an appropriate acid to remove the protecting group (when R is a protecting group) and / or to obtain the desired pharmaceutically acceptable salt.
    [0015]
    15. Process according to claim 1, characterized by the fact that it comprises reacting
    [0016]
    16. Process according to claim 15, characterized in that it further comprises reacting the compound obtained in said claim with an acid to obtain a desired pharmaceutically acceptable salt of said compound.
    [0017]
    17. Process according to claim 1, characterized by the fact that it comprises the following steps: a) dissolve or disperse 0.1 mol% - 3 mol% of bis (dibenzylidenoacetone) palladium (0) and 0.5 mol% - 4 mol% of racemic 2,2'-bis-diphenylphosphanyl- [1,1 '] binaphthalenyl and 2-6 equivalents of toluene base to obtain Mixture A; b) adding 1 equivalent of 1-iodo-2,4-dimethylbenzene, 0.8-1.2 equivalents of 2-bromo thiophenol and 1-10 equivalents of piperazine to Mixture A to obtain Mixture B; and c) heat Mixture B to 80 ° C-120 ° C to obtain
    [0018]
    18. Process according to claim 1, characterized by the fact that it comprises the steps of: a) dissolving or dispersing 0.1 mol% - 3 mol% of bis (dibenzylidenoacetone) palladium (0) and 0.5 mol% - 4 mol% of racemic 2,2'-bis-diphenylphosphanyl- [1,1 '] binaphthalenyl, 1-10 equivalents of piperazine and 2-6 equivalents of toluene base to obtain Mixture A; b) adding 1 equivalent of 1-iodo-2,4-dimethylbenzene and 0.8-1.2 equivalents of 2-bromo thiophenol to Mixture A to obtain Mixture B; and c) heat Mixture B to 80 ° C-120 ° C to obtain d) optionally adding an appropriate acid to the product obtained in step c) to obtain the corresponding salt.
    类似技术:
    公开号 | 公开日 | 专利标题
    BR112014016322B1|2020-09-15|PROCESS FOR THE PREPARATION OF 1- [2- | -FENYL] -PIPERAZINE
    TWI267381B|2006-12-01|Stilbene derivatives and their use for binding and imaging amyloid plaques
    AU2014220735B2|2017-06-22|Vortioxetine manufacturing process
    BRPI1006975A2|2020-08-18|processes for making a compound, and to remove or lessen an impurity of a solid compound and a solution, liquid solution, and compound
    WO2016007966A2|2016-01-14|2-imidazolyl-pyrimidine scaffolds as potent and selective inhibitors of neuronal nitric oxide synthase
    MX2012013083A|2013-01-22|Compositions, methods and systems for the synthesis and use of imaging agents.
    Zhang et al.2018|Preparation of Tetradentate Copper Chelators as Potential Anti‐Alzheimer Agents
    BR112015022849B1|2020-02-18|NITROXOLIN BASE ADDITION SALES, USES AND PROCESS FOR THE PREPARATION OF THE SAME, AS WELL AS ITS CRYSTAL, PHARMACEUTICAL COMPOSITION AND PROCESS FOR THE PREPARATION OF THE SAME
    JP2021535103A|2021-12-16|Succinic acid-added salt and fumaric acid-added salt of piperazine derivatives useful as glycosidase inhibitors
    Mastalir et al.2015|A practical synthesis of substituted 2, 6-diaminopyridines via microwave-assisted copper-catalyzed amination of halopyridines
    ES2726573T3|2019-10-07|Process for the manufacture of 1- [2- | -phenyl] -piperazine
    Acosta Quintero et al.2016|Similar molecular constitutions but different conformations and different supramolecular assemblies in two related fused tetracyclic benzo [b] pyrimido [5, 4-f] azepine derivatives
    WO2016174496A1|2016-11-03|P-gp radiotracers for imaging as biomarker involved in onset of neurodegenerative diseases
    BRPI0712153A2|2012-01-24|processes for the synthesis of pyrerazine-piperidine compounds
    US20130338361A1|2013-12-19|Radiofluorination method
    Sebti et al.2015|Rock inhibitors and uses thereof
    CN114195800A|2022-03-18|USP7 inhibitor
    AU2019258078A1|2020-11-19|10H-phenothiazine ferroptosis inhibitor and preparation method therefor and application thereof
    JPH1171362A|1999-03-16|Radioactive labeled compound
    Cortes-Salva2011|Guanidines, Amidines and Carbamides as Novel Sigma Receptor Ligands for Post-Stroke Therapeutics
    OA17454A|2016-12-22|Vortioxetine manufacturing process.
    NZ710779A|2020-09-25|Vortioxetine manufacturing process
    同族专利:
    公开号 | 公开日
    JP6018644B2|2016-11-02|
    AU2012364402B2|2016-10-06|
    EP2800746B1|2019-04-17|
    SI2800746T1|2019-06-28|
    CA2860103A1|2013-07-11|
    CO7000771A2|2014-07-21|
    US20140343287A1|2014-11-20|
    EP2800746A1|2014-11-12|
    BR112014016322B8|2020-12-01|
    BR112014016322A8|2017-07-04|
    HRP20190769T1|2019-06-28|
    MX344144B|2016-12-07|
    HK1200827A1|2015-08-14|
    AU2012364402A1|2014-07-03|
    WO2013102573A1|2013-07-11|
    US9133144B2|2015-09-15|
    CL2014001765A1|2014-10-03|
    SG11201403835UA|2014-10-30|
    BR112014016322A2|2017-06-13|
    IL233093A|2017-04-30|
    CN104011034B|2016-08-17|
    KR20140107357A|2014-09-04|
    KR102008039B1|2019-08-06|
    ZA201404881B|2015-12-23|
    RU2014131943A|2016-02-27|
    LT2800746T|2019-06-10|
    MX2014008052A|2014-09-26|
    JP2015504062A|2015-02-05|
    RU2608307C2|2017-01-17|
    RS58683B1|2019-06-28|
    CA2860103C|2020-07-07|
    IL233093D0|2014-08-03|
    CN104011034A|2014-08-27|
    DK2800746T3|2019-05-20|
    PL2800746T3|2019-07-31|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    JPH07110050A|1993-10-13|1995-04-25|Daikin Mfg Co Ltd|Torsional vibration damping device|
    AR036659A1|2001-10-04|2004-09-22|Lundbeck & Co As H|COMPOUNDS DERIVED FROM PHENYL-PIPERAZINE, PHENYL-PIPERIDINE AND PHENYL-TETRAHIDROPIRIDINE AS INHIBITORS OF THE REABSORTION OF SEROTONINE, A PHARMACEUTICAL COMPOSITION AND USE OF THE SAME FOR THE PREPARATION OF MEDICINES|
    CA2467118A1|2001-12-20|2003-07-03|H. Lundbeck A/S|Aryloxyphenyl and arylsulfanylphenyl derivatives|
    AR061481A1|2006-06-16|2008-08-27|Lundbeck & Co As H|COMPOUNDS WITH COMBINED ACTIVITY ON SERT, 5-HT3 AND 5-HT1A|
    TW201033181A|2009-02-17|2010-09-16|Lundbeck & Co As H|Purification of 1-[2-phenyl]piperazine|IN2013MU03121A|2013-09-30|2015-07-17|Cadila Healthcare Ltd|
    EP2878596A1|2013-11-29|2015-06-03|LEK Pharmaceuticals d.d.|Synthesis of vortioxetine via phenyl)lithium intermediates|
    EP2894154A1|2014-01-14|2015-07-15|LEK Pharmaceuticals d.d.|Synthesis of vortioxetine via phenyl)aniline intermediates|
    CN103788019B|2014-01-22|2015-10-07|苏州明锐医药科技有限公司|The fertile preparation method for Xi Ting|
    CN103788020B|2014-01-22|2015-11-04|苏州明锐医药科技有限公司|The fertile preparation method for Xi Ting|
    US9822086B2|2014-01-31|2017-11-21|Egis Gyogyszergyar Zrt.|Process for the preparation of vortioxetine salts|
    EP2930171A1|2014-04-07|2015-10-14|LEK Pharmaceuticals d.d.|Synthesis of vortioxetine via sulfane intermediate|
    CN104974110A|2014-04-10|2015-10-14|江苏豪森药业股份有限公司|New crystal form of 1-[2-phenyl]piperazine hydrobromide, preparation method and application thereof|
    CN105254590B|2014-05-09|2019-09-03|江苏豪森药业集团有限公司|Vortioxetine hydrobromate crystal form and its preparation method and application|
    CN106170480B|2014-05-09|2019-09-20|上海科胜药物研发有限公司|New Vortioxetine intermediate and its synthetic method|
    CN104059030B|2014-05-30|2016-05-04|镇江圣安医药有限公司|Derivative and pharmaceutical composition and the purposes of [-phenyl] piperazine|
    CN104292183B|2014-09-29|2016-01-06|杨献美|A kind of antidepressant drug irrigates the preparation method for Xi Ting|
    WO2016079751A2|2014-11-17|2016-05-26|Megafine PharmaLtd.|A process for preparation of vortioxetine and polymorphs thereof|
    ES2634496T3|2014-11-21|2017-09-28|Dipharma Francis S.R.L.|Process for the preparation of an antidepressant and its intermediates|
    CN104356092B|2014-11-27|2017-03-22|合肥创新医药技术有限公司|Preparation method for vortioxetine|
    WO2016125191A2|2015-02-04|2016-08-11|Mylan Laboratories Limited|Processes for the preparation of vortioxetine hydrobromide|
    WO2016135636A1|2015-02-25|2016-09-01|Lupin Limited|Process for the preparation of vortioxetine|
    CN104650004B|2015-03-06|2017-06-06|中山万汉制药有限公司|A kind of preparation method of hydrobromic acid Vortioxetine|
    CN105061364A|2015-08-17|2015-11-18|河北国龙制药有限公司|Vortioxetine hydrobromide preparation method|
    EP3337789A1|2015-08-19|2018-06-27|Amneal Pharmaceuticals Company GmbH|Process for preparation of vortioxetine hydrobromide|
    CN106556663B|2015-09-30|2018-05-29|成都弘达药业有限公司|A kind of detection method of 1- [2-phenyl] piperazines or its salt|
    AU2017288456A1|2016-07-01|2018-12-13|H. Lundbeck A/S|Vortioxetine dosing regimes for fast onset of antidepressant effect|
    US10519121B2|2016-12-30|2019-12-31|Apicore Us Llc|Process and novel polymorphic form of vortioxetine and its pharmaceutically acceptable salts|
    CN106831652B|2017-01-23|2019-01-11|齐鲁天和惠世制药有限公司|A kind of preparation method of Wo Saiting|
    CN108017595A|2017-12-20|2018-05-11|安徽源久源科技有限公司|A kind of preparation method of 1- [2-phenyl] piperazine|
    JP2021527705A|2018-06-20|2021-10-14|バイオ アーゲー ファーマシューティカルズ エス．エー．|One-pot organic pseudocatalyst CH activation method for preparing vortioxetine and vortioxetine intermediates|
    CN109438390A|2018-11-26|2019-03-08|合肥创新医药技术有限公司|A kind of synthetic method of hydrobromic acid Vortioxetine impurity|
    法律状态:
    2018-10-16| B07D| Technical examination (opinion) related to article 229 of industrial property law|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |
    2019-11-19| B07E| Notice of approval relating to section 229 industrial property law|
    2020-04-07| B06U| Preliminary requirement: requests with searches performed by other patent offices: suspension of the patent application procedure|
    2020-08-18| B09A| Decision: intention to grant|
    2020-09-15| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 20/12/2012, OBSERVADAS AS CONDICOES LEGAIS. |
    2020-12-01| B16C| Correction of notification of the grant|Free format text: REF. RPI 2593 DE 15/09/2020 QUANTO A QUALIFICACAO. |
    优先权:
    申请号 | 申请日 | 专利标题
    DKPA201200006|2012-01-03|
    DKPA201200006|2012-01-03|
    PCT/EP2012/076377|WO2013102573A1|2012-01-03|2012-12-20|Process for the manufacture of 1-[2--phenyl]-piperazine|
    [返回顶部]