METHOD FOR PREPARING 5-¬4-(2-HYDROXY-ETHYL)-3,5-DIOXO-4,5-DIHYDRO-3H-¬1,2,4|-TRIAZIN-2-YL|BENZAMIDE DERIVATIVES WITH P2X7 INHIBITING ACTIVITY BY REACTION OF THE DERIVATIVE UNSUBSTITUTED IN 4-POSITION OF THE TRIAZINE WITH AN OXIRAN IN THE PRESENCE OF A LEWIS ACIDThe present invention relates to methods of preparing compounds of formula (I), R7 is -CH2-C(R10R11)-OH, wherein R10 and R11 are independently selected from the group consisting of: hydrogen, phenyl, and (C1-C6)alkyl optionally substituted with one to three halos, hydroxy, -CN, (C1-C6)alkoxy-,((C1-C6)alkyl)n-N-,(C1-C6)alkyl-(C=O)-,(C3-C8)cycloalkyl-(C=O)-, 5 or 6-membered heterocycloalkyl-(C=O)-,phenyl-(C=O)-,naphthyl-(C=O)-,5- or 6-membered heteroaryl-(C=O)-,(C1-C6)alkyl-(C=O)O-,(C1-C6)alkyl-O(C=O)-,(C3-C8)cycloalkyl, phenyl, naphthyl, 5 or 6-membered heterocycloalkyl, and 5- or 6-membered heteroaryl; or a pharmaceutically acceptable salt thereof, wherein R1, R2 and R4 have any of the values as defined in the specification. Wherein said method comprises reacting a compound of formula (II) with a compound of formula (VIII) in the presence of at least one Lewis acid. The compounds are useful as agents in the treatment of diseases, including inflammatory diseases such as rheumatoid arthritis. Also provided are compositions of crystalline 2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2R-hydroxy-3-methoxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide comprising less than 2.5% residual organic solvent, and methods for preparing said compositions. Further provided are methods for crystallizing 2-Chloro-N-(1-hydroxy-cycloheptylmethyl)-5-[4-(2R-hydroxy-3-methoxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-benzamide.A method of preparing a compound of formula I or a pharmaceutically acceptable salt thereof, wherein R1 is optionally substituted by (C3-C8)cycloalkyl, phenyl, naphthyl, 5 or 6-membered heterocycloalkyl, or a 5- or 6- membered heteroaryl, wherein each of said (C1-C6)alkyl, (C3- C8)cycloalkyl, phenyl, naphthyl, 5 or 6-membered heterocycloalkyl, or 5- or 6-membered heteroaryl are optionally substituted by one to three moieties independently selected from the group consisting of hydroxy, halo, CN-, (Ci-C6)alkyl, HO(C1- C6)alkyl, (CrC6)alkyl-NH(C=O)-, NH2(C=O)-, (C1-C6)alkoxy, or (C3-C8)cycloalkyl;R2 is hydrogen, halo, -CN, or (Cϊ-C6)alkyl, wherein said (Ci-C6)alkyl is optionally substituted by one to three moieties, independently selected from the group consisting of halo, hydroxy, amino, -CN, (d-C6)alkyl, (d-C6)alkoxy, -CF3, CF3O-, (CrC6)alkyl-NH-, [(C1- C6)alkyl]2-N-, (C1-C6)alkyl-S-, (C1-C6)alkyl-(S=O)-, (C1-C6)^yI- (SO2)-, (C1-C6)alkyl-O-(C=O)-, formyl, (C!-C6)alkyl-(C=O)-, and (C3-C6)cycloalkyl; wherein R4 is independently selected from the group consisting of hydrogen, halo, hydroxy, -CN, HO-(Ci-C6)alkyl, (C1-C6)alkyl optionally substituted with one to three fluoro, (Q-C^alkoxy optionally substituted with one to three fluoro, HO2C-, (d-C6)alkyl-O-(C=O)-, R5R6N(O2S)-, (C1-C6)alkyl-(O2S)-NH-, (C1-C6)alkyl-O2S-[(Ci-C6)alkyl-N]-, R5R6N(C=O)-, R5R6N(CH2V , phenyl, naphthyl, (C3-C8)cycloalkyl, 5- or 6-membered heteroaryl, 5 or 6-membered heterocycloalkyl, phenyl-O-, naphthyl-O-, (C3-C8)cycloalkyl-O-, 5- or 6-membered heteroaryloxy and 5 or 6-membered heterocycloalkyl-O-; and R7 is -CH2-C(R10Rπ)-OH, wherein R10 and R11 are independently selected from the group consisting of: hydrogen, phenyl, and (C1-C6)alkyl optionally substituted with one to three halos, hydroxy, -CN, ((C1- C6)alkyl)n-N-, (C1-C6)alkyl-(C=O)-, (C3-C8)cycloalkyl-(C=O)-, 5 or 6-membered heterocycloalkyl-(C=0)-, phenyl-(C=O)-, naphthyl-(C=O)-, 5- or 6-membered heteroaryl-(C=O)-, (C1- C6)alkyl-(C=O)O-, (Cj-C6)alkyl-O(C=O)-, (C3-C8)cycloalkyl, phenyl, naphthyl, 5 or 6-membered heterocycloalkyl, and 5- or 6-membered heteroaryl; R5 and R6 are each independently selected from the group consisting of hydrogen, (Ci-C6)alkyl, HO-(C2-C6)alkyl and (C3-C8)cycloalkyl, or R5 and R6 may optionally be taken together with the nitrogen atom to which they are attached to form a 5 or 6-membered heterocycloalkyl; n is one or two; and m is one or two; wherein said method comprises reacting a compound of formula II with a compound of Formula VJH in the presence of at least one Lewis acid.The method of claim 1 wherein said Lewis acid is selected from(a) boron trifluoride diethyl etherate;(b) Al2O3, T-(O-Po4, LiClO4, or Zn(OAc)2;(c) Eu(OTf)3, Dy(OTf)3, Ho(OTf)3, Er(OTf)3, Lu(OTf)3, Yb(OTf)3,Nd(OTf)3, Gd(OTf)3, Lu(OTf)3, La(OTf)3, Pr(OTf)3, Tm(OTf)3, Sc(OTf)3, Sm(OTf)3, AgOTf, or Y(OTf)3;(d) AlCl3, AlI3, AlF3, AlBr3, AsCl3, AsI3, AsF3, AsBr3, BCl3, BBr3, BI3,BF3, FeCl3, FeBr3, FeI3, FeF3, FeCl2, FeBr2, FeI2, FeF2, GaCl3, GaI3, GaF3, GaBr3, MgCl2, MgI2, MgF2, MgBr2, NbCl5, SbCl3, SbI3, SbF3, SbBr3, SbCl5, SbI5, SbF5, SbBr5, SnCl2, SnI2, SnF2, SnBr2, SnCl4, SnI4, SnF4, SnBr4, TiBr4, TiCl2, TiCl3, TiCl4, TiF3,TiF4, TiI4, ZnCl2, ZnI2, ZnF2, or ZnBr2.(e) BF3BCl3-SMe2, BI3-SMe2, BF3-SMe2, BBr3-SMe2, BF3-OEt2, Et2AlCl,EtAlCl2, MgCl2-OEt2, MgI2-OEt2, MgF2-OEt2, MgBr2-OEt2, Et2AlCl, EtAlCl2, or Zn(OAc)2; and (f) (CH3CO2)2Co, CoBr2, CoCl2, CoF2, CoI2, Co(NO3)2, cobalt (D) triflate, cobalt (E) tosylate, (CH3CO2)2Cu, CuBr2, CuCl2, CuF2, CuI2, Cu(NO3)2, copper (π) triflate, copper (II) tosylate, (CH3CO2)2Ni, NiBr2, NiCl2, NiF2, NiI2, Ni(NO3)2, nickel (EQ triflate, or nickel (II) tosylate.
루이스 산의 존재하에 트리아진의 4-위치에서 치환되지않은5-[4-(2-하이드록시-에틸)-3,5-다이옥소-4,5-다이하이드로-3Ｈ-[1,2,4]트리아진-2-일]-벤즈아마이드 유도체와옥시란과의 반응에 의해 Ｐ2Ｘ7 억제 활성을 갖는 상기유도체의 제조방법본 발명은 하기 화학식 I의 화합물 또는 그의 약학적으로 허용가능한 염의 제조방법에 관한 것이다: 화학식 I  상기 식에서, R7는 -CH2-C(R10R11)-OH이고, 여기서, R10과 R11은 수소, 페닐, 및 1 내지 3개의 할로, 하이드록시, -CN, (C1-C6)알콕시-, ((C1-C6)알킬)n-N-, (C1-C6)알킬-(C=O)-, (C3-C8)시클로알킬-(C=O)-, 5- 또는 6-원 헤테로시클로알킬-(C=O)-, 페닐-(C=O)-, 나프틸-(C=O)-, 5- 또는 6-원 헤테로아릴-(C=O)-, (C1-C6)알킬-(C=O)O-, (C1-C6)알킬-O(C=O)-, (C3-C8)시클로알킬, 페닐, 나프틸, 5- 또는 6-원 헤테로시클로알킬 및 5- 또는 6-원 헤테로아릴로 임의로 치환된 (C1-C6)알킬로 이루어진 군으로부터 독립적으로 선택되며; R1, R2 및 R4는 명세서에서 정의된 임의의 값을 갖는다. 이 경우, 상기 방법은 하나 이상의 루이스 산 존재하에 하기 화학식 II의 화합물과 하기 화학식 VIII의 화합물을 반응시키는 것을 포함한다: 화학식 II  화학식 VIII  상기 화합물은 류마티스 관절염과 같은 염증 질환을 비롯한 질환 치료에서의 약물로서 유용하다. 또한, 잔류 유기 용매 2.5% 미만을 포함하는 결정질의 2-클로로-N-(1-하이드록시-시클로헵틸메틸)-5-[4-(2R-하이드록시-3-메톡시-프로필)-3,5-다이옥소-4,5-다이하이드로-3H-[1,2,4]트리아진-2-일]-벤즈아마이드의 조성물, 및 상기 조성물의 제조방법이 제공된다. 또한, 2-클로로-N-(1-하이드록시-시클로헵틸메틸)-5-[4-(2R-하이드록시-3-메톡시-프로필)-3,5-다이옥소-4,5-다이하이드로-3H-[1,2,4]트리아진-2-일]-벤즈아마이드를 결정화하는 방법이 제공된다.하나 이상의 루이스 산의 존재하에 하기 화학식 II의 화합물과 하기 화학식 VIII의 화합물을 반응시키는 것을 포함하는, 하기 화학식 I의 화합물 또는 그의 약학적으로 허용가능한 염의 제조방법: 화학식 I  화학식 II  화학식 VIII  상기 식에서, R1은 (C3-C8) 시클로알킬, 페닐, 나프틸, 5- 또는 6-원 헤테로시클로알킬 또는 5- 또는 6원-헤테로아릴로 임의로 치환된 (C1-C6) 알킬이고, 상기 (C1-C6) 알킬, (C3-C8) 시클로알킬, 페닐, 나프틸, 5- 또는 6-원 헤테로시클로알킬 또는 5-또는 6-원 헤테로아릴 각각은 임의로 하이드록시, 할로, CN-, (C1-C6)알킬, HO(C1-C6)알킬, (C1-C6)알킬-NH(C=O)-, NH2(C=O)-, (C1-C6)알콕시 또는 (C3-C8)시클로알킬로 이루어진 군으로부터 독립적으로 선택된 1 내지 3개의 잔기로 임의로 치환되고; R2은 수소, 할로, -CN 또는 (C1-C6)알킬이고, 상기 (C1-C6)알킬은 할로, 하이드록시, 아미노, -CN, (C1-C6)알킬, (C1-C6)알콕시, -CF3, CF3O-, (C1-C6)알킬-NH-,［(C1-C6)알킬]2-N-, (C1-C6)알킬-S-, (C1-C6)알킬-(S=O)-, (C1-C6)알킬-(SO2)-, (C1-C6)알킬-O-(C=O)-, 포르밀, (C1-C6)알킬-(C=O)- 및 (C3-C6)시클로알킬로 이루어진 군으로부터 독립적으로 선택된 1 내지 3개의 잔기로 임의로 치환되며; R4은 수소, 할로, 하이드록시, -CN, HO-(C1-C6)알킬, 1 내지 3개의 플루오로로 임의로 치환된 (C1-C6)알킬, 1 내지 3개의 플루오로로 임의로 치환된 (C1-C6)알콕시, HO2C-, (C1-C6)알킬-O-(C=O)-, R5R6N(O2S)-, (C1-C6)알킬-(O2S)-NH-, (C1-C6)알킬-O2S-[(C1-C6)알킬-N]-, R5R6N(C=O)-, R5R6N(CH2)m-, 페닐, 나프틸, (C3-C8)시클로알킬, 5- 또는 6-원 헤테로아릴, 5- 또는 6-원 헤테로시클로알킬, 페닐-O-, 나프틸-O-, (C3-C8)시클로알킬-O-, 5- 또는 6-원 헤테로아릴옥시 및 5- 또는 6-원 헤테로시클로알킬-O-로 이루어진 군으로부터 독립적으로 선택되고; R7는 -CH2-C(R10R11)-OH이고, 여기서, R10과 R11은 수소, 페닐, 및 1 내지 3개의 할로, 하이드록시, -CN, (C1-C6)알콕시-, ((C1-C6)알킬)n-N-, (C1-C6)알킬-(C=O)-, (C3-C8)시클로알킬-(C=O)-, 5- 또는 6-원 헤테로시클로알킬-(C=O)-, 페닐-(C=O)-, 나프틸-(C=O)-, 5- 또는 6-원 헤테로아릴-(C=O)-, (C1-C6)알킬-(C=O)O-, (C1-C6)알킬-O(C=O)-, (C3-C8)시클로알킬, 페닐, 나프틸, 5- 또는 6-원 헤테로시클로알킬 및 5- 또는 6-원 헤테로아릴로 임의로 치환된 (C1-C6)알킬로 이루어진 군으로부터 독립적으로 선택되며; R5와 R6은 각각 수소, (C1-C6)알킬, HO-(C2-C6)알킬 및 (C3-C8)시클로알킬로 이루어진 군으로부터 독립적으로 선택되거나, R5와 R6은 이들이 결합된 질소 원자와 함께 임의로 5- 또는 6-원 헤테로시클로알킬을 형성할 수 있고; n은 1 또는 2이며; m은 1 또는 2이다.