TR2023003953T2 - METHOD FOR PREPARING INTERMEDIATE FOR THE SYNTHESIS OF SPHINGOSINE-1-PHOSPHATE RECEPTOR AGONIST - Google Patents
METHOD FOR PREPARING INTERMEDIATE FOR THE SYNTHESIS OF SPHINGOSINE-1-PHOSPHATE RECEPTOR AGONISTInfo
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- TR2023003953T2 TR2023003953T2 TR2023/003953 TR2023003953T2 TR 2023003953 T2 TR2023003953 T2 TR 2023003953T2 TR 2023/003953 TR2023/003953 TR 2023/003953 TR 2023003953 T2 TR2023003953 T2 TR 2023003953T2
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Abstract
Mevcut buluş, sfingozin-1-fostaf reseptör agonistinin sentezinde etkili bir şekilde kullanılabilen kimyasal formül 6 ile ifade edilen bir ara madde üretmeye yömelik yeni bir yöntem ile ilgilidir.The present invention relates to a new method for producing an intermediate expressed by chemical formula 6 that can be effectively used in the synthesis of sphingosine-1-phosphaph receptor agonist.
Description
TARIFNAME SFINGOZIN-l-FOSFAT RESEPTÖR AGONISTININ SENTEZI IÇIN ARA MADDE ILAZIRLAMAYA YÖNELIK YÖNTEM TEKNIK ALAN Mevcut bulus, sfigozin-l-fosfat reseptör agonistlerini sentezlenmeye yönelik bir ana ara madde hazirlama yöntemi ile ilgilidir. Daha spesifik olarak, mevcut bulus, asagidaki Formül 63in bir ara madde bilesiginin, hafif kosullar altinda basit bir proses ile yüksek bir verimde büyük ölçekli üretimini gerçeklestirebilen yeni bir hazirlama yöntemi ile ilgilidir: R2 Cl 0 X, C veya Nsdir; R1 ve R23nin her biri bagimsiz olarak hidrojen, alkil, halojen, haloalkil veya alkoksialkildir; R4 hidrojen veya alkildir ve R5 hidrojen, alkil, halojen, CN, CF3 veya COCF3Stür. ÖNCEKI TEKNIK 17464.38 Sfingozin-l-fosfat (SlP), seramidin baslangiç malzemesi oldugu bir hücre içi seramid yolagi araciligiyla üretilmektedir. Seramid, birincisi de n0v0 biyosentetik yolak olmak üzere iki yolak araciligiyla üretilmektedir. Seramid ayrica, bir hücre zari yapitasi olan sfingomiyelinin bir hücrede parçalanmasi yoluyla üretilmektedir. Her dokudaki SlP seviyesi, iki biyosentetik sfingozin kinaz (Sthsler) ve iki biyolojik olarak parçalanabilen SlP fosfat (SlP liyaz ve lizofosfolipid fosfatazlar) ile kontrol edilmektedir. Sfingozinin sfingozin kinaz ile fosforilasyonu araciligiyla üretilen SlPsin hücre proliferasyonu, hücre iskeleti organizasyonu ve göçü, yapisma ve siki baglanti mekanizmasi ve morfogenez gibi çesitli hücresel tepkilere aracilik ettigi bilinmektedir. S lP, dokularda düsük bir seviyede olmakla birlikte yüksek seviyede (100 - albumin ihtiva eden plazma proteini ile birlesik bir formda mevcut bulunmaktadir. SlP, çesitli biyolojik fonksiyonlar göstermek için bir G proteini kenetli reseptör olan SlP reseptörü ile baglanmaktadir. SlPl ila SlP5 simdiye dek SlP reseptörünün alt tipleri olarak bilinmektedir ve sirasiyla endotelyal farklilasma geni (EDG) reseptörleri 1, 5, 3, 6 ve 8 olarak adlandirilmaktadir. SlP reseptörlerinin lökosit devridaimi, nöral hücre proliferasyonu, morfolojik degisiklikler, göç, endotel fonksiyonu, vazoregülasyon ve kardiyovasküler gelisim gibi çesitli biyolojik fonksiyonlarda rol oynadigi bilinmektedir. Son yillarda, birçok çalisma, bu reseptörler araciligiyla SlP sinyalleme prosesinin, enflamasyon yaniti ve onarim prosesi dahil olmak üzere multipl skleroz ile iliskili bir dizi yanitta önemli bir rol oynadigini bulmustur ve seçici olmayan SlPl agonisti aslinda multipl skleroz için bir terapötik ajan olarak onaylanmistir. SlP reseptörleri, multipl sklerozun indüksiyonu ile iliskili birçok hücrede genis ölçüde ifade edilmektedir. Özellikle, SlPl reseptörü bagisiklik sisteminde büyük bir rol oynamaktadir. SlPl reseptörü esas olarak T hücresi ve B hücresi gibi lenfositlerin yüzeyi üzerinde ifade edilmektedir ve SlP,e yanit vererek lenfositlerin devridaiminde tutuluma yol açmaktadir. Normal durumda, SlP konsantrasyonu vücut sivisinda lenfoid dokusunda oldugundan daha yüksektir ve bu yüzden eferent 17464.38 lenf dolasim yaptiktan sonra lenfositler dolasim yapmak üzere S1P konsantrasyonu farkina göre lenfoid dokusundan ayrilmaktadir. Bununla birlikte, lenfositlerdeki SlPl reseptörü, S1P1 agonisti ile asagi regüle edilirse, lenfositlerin lenfoid dokusundan çikisi meydana gelmemekte, bu da merkezi sinir sisteminde (CNS) enIlamasyon ve doku hasarina yol açan otoagresif lenfositlerin infiltrasyonunun azalmasina yol açmaktadir. Sonuç olarak, multipl skleroz üzerinde terapötik bir etki elde edilmektedir. Seçici olmayan bir S1P1 agonisti olan Fingolimod, multipl skleroz tedaVisine yönelik bir oral ilaç olarak onaylanmistir. Aktive olmak için SlPl reseptörüne baglandiginda, reseptör ironik bir sekilde lenfositlerin yüzeyinden parçalanmis veya içsellesmis hale gelmekte ve böylece fonksiyonel bir S 1P1 antagonizmasi olarak etki etmektedir. Basvurusu Yayininda, bir S 1 P reseptörü agonisti olarak etkili olan asagidaki Formül lsin yeni bilesikleri açiklanmaktadir: X, C veya Nsyi temsil etmektedir, R1, H veya istege bagli olarak sübstitüe edilmis alkili temsil etmektedir, R2 H, istege bagli olarak sübstitüe edilmis alkil, halojen, CN, CF3 veya COCFfü temsil etmektedir, W C, N, C-alkoksi, C-halojen veya C-CNSyi temsil etmektedir, 17464.38 Q, CH20 veya O_N "i temsil etmektedir, S asagidaki kalintilardan seçilmektedir: m ve n bagimsiz olarak 0, 1, 2 veya 3,ü temsil etmektedir, R3~R10 bagimsiz olarak H, alkil, halojen, halojenoalkil veya alkoksialkili temsil etmektedir, 17464.38 H2N OH R11 H, ' , OH , 0 veya 4 "OH" . . veya 1 temsil etmektedir. Yukaridaki dokümanin spesiIik bir örneginde, asagidaki Reaksiyon Semasi lse göre ilmetil]-piperidin-4-karb0ksilik asidin hazirlanmasi açiklanmaktadir (Reaksiyon ifade etmektedir). 17464.38 . 5335 ç' :I 3 LAH ;i IJIAD ' x a Reaksiyon Semasi lsdeki 1-klor0-6-(3-klor0-1-izopropil-lH-indazol-5-ilmet0ksi)- 3,4-dihidr0-naftalen-2-karbaldehid hazirlama adimlari asagidaki sekilde ayrintili olarak açiklanabilmektedir: (1) (3-klor0- 1 -izopropil- 1 H-indazol-5-il)-metanol Sentezi lH-indazol-5-karb0ksilik asit metil ester, dimetilformamid içinde çözündürülmüstür ve bunun içine izopropil iyodür ve sodyum hidrit 0°C3de damlatilarak yavasça ilave edilmis, ardindan 8 saat boyunca 50°C3de karistirilmistir. lN hidroklorik asit çözeltisi ilave edilmis, ardindan etil asetat ile ekstraksiyon gerçeklestirilmistir. Tuzlu su ile yikama ve anhidröz magnezyum sülfat üzerinde kurutmadan sonra, filtrelenmis filtrat indirgenmis basinç altinda damitilmistir. Elde edilen ürün, kolon kromatografisi ile ayrilarak 1-iz0pr0pil-1H-indaz01-5- karboksilik asit metil ester elde edilmistir. Elde edilen 1-izopropil-lH-indazol-5-karb0ksilik asit metil ester, dimetilformamid içinde çözündürülmüstür ve bunun içine N-klorosüksinimid ilave edilmis, ardindan 17464.38 18 saat boyunca oda sicakliginda karistirilmistir. Su ilave edilmistir ve reaksiyon karisimi etil asetat ile ekstrakte edilmistir. Tuzlu su ile yikama ve anhidröz magnezyum sülfat üzerinde kurutmadan sonra, filtrelenmis filtrat indirgenmis basinç altinda damitilmistir. Kalinti kolon kromatografisi ile ayrilarak 3-kloro-1- izopropil-1H-indazole-5-karboksilik asit metil ester elde edilmistir. Elde edilen 3-kloro-1-izopropil-1H-indazol-5-karboksilik asit metil ester tetrahidrofuran içinde çözündürülmüstür ve bunun içine lityum alüminyum borohidrit damlatilarak ilave edilmistir. 1 saat boyunca oda sicakliginda karistirmadan sonra, su, 6N sulu sodyum hidroksit çözeltisi ve su sirayla ilave edilmistir. Selit damlatilarak ilave edilmistir ve filtrelenmis filtrat indirgenmis basinç altinda damitilmistir. Kalinti, kolon kromatografisi ile ayrilarak (3 -kloro- 1 -izopropil-1H-indazol-5-il)-metanol elde edilmistir. (2) 1-kloro-6-hidroksi-3,4-dihidro-naftalen-2-karbaldehid Sentezi Ilk olarak, 6-metoksi-3,4-dihidronaftalen-1(2H)-on,un toluen içinde çözündürüldügü bir çözeltiye, N,N-dimetilformamid (DMF) ve fosfor oksiklorür (POCl3) 0°C3de damlatilarak ilave edilmis, ardindan 70°C3de 6 saat boyunca karistirilmistir. Reaksiyon karisimi buz içine dökülmüs ve etil asetat ile ekstrakte edilmistir. Organik katman, tuzlu su ile yikanmis, kurutulmus ve konsantre edilmistir ve elde edilen kalinti, silika jel kolon kromatografisi (heksan:etil asetat = naftalenkarbaldehid elde edilmistir. Sonrasinda, alüminyum klorür (AlCl3), 0°C3de diklorometan içinde bir 1-kloro-6- metoksi-3,4-dihidro-2-naftalenkarbaldehid çözeltisine ilave edilmis ve ardindan 50°C3de 6 saat boyunca karistirilmistir. Reaksiyon karisimi buz içine dökülmüs ve etil asetat ile ekstrakte edilmistir. Organik katman, kurutulmus ve konsantre edilmistir ve elde edilen kalinti, silika jel kolon kromatografisi (heksan:tetrahidrofuran = 5:1 ila 3:1) ile saflastirilarak 1-kloro-6-hidroksi-3,4- 17464.38 dihidro-2-naftalenkarbaldehid elde edilmistir. (3) 1-kloro-6-(3-kloro-1-izopropil-1H-indazol-5 -ilmetoksi)-3 ,4-dihidro-naftalen- 2-karbaldehid Sentezi Elde edilen (3-kloro-1-izopropil-1H-indazol-5-il)-metanol ve 1-kloro-6-hidroksi- 3,4-dihidro-naftalen-2-karbaldehid, toluen içinde çözündürülmüstür ve bunun içine tribütilfosfin (PBu3) ve damlatilarak ilave edilmistir. 18 saat boyunca oda sicakliginda karistirmadan sonra, fazladan bir heksan ilave edilmistir. Filtrasyon ve indirgenmis basinç altinda damitmadan sonra, kalinti kolon kromatografisi ile saIlastirilarak 1-kloro-6-(3-kloro-1- izopropil- 1 H-indazol-5 -ilmetoksi)-3 ,4-dihidro-naftalen-2-karbaldehid elde edilmistir. Bununla birlikte, yukaridaki reaksiyon, klinik bir ilaç etken maddesinin (API) hazirlanmasi bakimindan asagidaki sorunlara sahip olabilmektedir. Ilk olarak, 3-kloro-1-izopropil-1H-indazol-5-karboksilik asit metil esterin sentezlenmesi prosesinde, N2 izomerinin üretim oranina göre bir sorun olabilmektedir ve (3-kloro-1-izopropil-1H-indazol-5-il)-metanol sentezi için kullanilan lityum alüminyum hidrit (LAH), büyük bir ölçekte kullanilmasi için stabilite bakimindan çok sinirlidir ve nem ile kolaylikla ayrismasi dezavantajina sahiptir. Ek olarak, 1-kloro-6-metoksi-3,4-dihidro-2-naftalenkarbaldehidin elde edilmesi için Vilsmeier-Haack reaksiyonu sirasinda, 70°Cslik yüksek bir sicaklikta reaksiyona girdigi için bir eksotermik sorun bulunabilmektedir ve 1-kloro-6- hidroksi-3,4-dihidro-2-naftalenkarbaldehidin elde edilmesi için reaksiyonda, AlCl3 kullanimindan dolayi bir reaktör kontaminasyon sorunu veya tehlikeli reaktiflerin kullanimindan dolayi güvenlik sorunu olabilmektedir. AlCl3 kullanimi sirasinda, reaksiyon durmasi veya yan reaksiyon ilerlemesine göre yigin basarisizliginin 17464.38 meydana gelmesinden dolayi bir stabilite problemi olabilmektedir ve toplam verim %70 oldugu için verimin iyilestirilmesi gerekmektedir. Ayrica, (3-kloro-1-izopropil-lH-indazol-5-il)-metanol ve 1-kloro-6-hidroksi-3,4- dihidro-naftalen-2-karbaldehidn kenetlenme reaksiyonunda kullanilan 1,1'- (azodikarbonil)dipiperidin (ADD) durumunda, düsük verim ve maliyet bakimindan dolayi tercih edilmemektedir. BULUSUN AÇIKLAMASI TEKNIK SORUN Buna uygun olarak, mevcut bulusun teknik sorunu, mükemmel bir sfingozin-l- fosfat reseptör agonisti sentezinde kilit bir ara madde olan Formül 63in bir bilesiginin daha basit bir proses araciligiyla yüksek bir verimde büyük ölçekli üretimine uygun bir yöntemin saglanmasidir. SORUNA YÖNELIK ÇÖZÜM Yukaridaki teknik sorunun çözülmesi için, mevcut bulus, asagidaki Formül 63in bir ara madde bilesigini hazirlamaya yönelik bir yöntem saglamakta olup, asagidaki adimlari içermektedir: i) Formül 23nin bir bilesiginin bir dealkilleme reaksiyonu yoluyla Formül 33ün bir bilesiginin hazirlanmasina yönelik bir adim, ii) Formül 33ün bilesiginin ve Formül 43ün bir bilesiginin bir kenetlenme reaksiyonu yoluyla Formül 53in bir bilesiginin hazirlanmasina yönelik bir adim ve iii) Formül 53in bilesiginin fosforil klorür (POCls) ve dimetilformamid ile reaksiyona sokulmasi yoluyla Formül 63nin bir bilesigini hazirlamaya yönelik bir adim: 17464.38 [Formül 6] 17464.38 R1 ve R23nin her biri bagimsiz olarak hidrojen, alkil, halojen, haloalkil veya alkoksialkildir; R3 alkildir; R4 hidrojen veya alkildir; R5 hidrojen, alkil, halojen, CN, CF3 veya COCF33tür; X, C veya Nsdir VE L bir ayrilan gruptur. Mevcut bulus bundan sonra ayrintili olarak açiklanmaktadir. Mevcut bulusun bir yönüne göre, yukaridaki Formüllerde, R1 ve R23nin her biri bagimsiz olarak hidrojen, C1-C6 alkil, halojen, halo-C 1-C6 alkil veya C1-C6 alkoksi- Cl-C6 alkildir; R3 Cl-C6 alkildir; R4 hidrojen veya Cl-C6 alkildir; R5 hidrojen, Ci- C6 alkil, halojen, CN, CF3 veya COCF33tür; X C veya Nsdir ve L bir ayrilan gruptur. Mevcut bulusun baska bir yönüne göre, yukaridaki formüllerde, R1 ve R23nin her biri bagimsiz olarak hidrojen veya C1-C4 alkildir; R3 C1-C4 alkildir; R4 C1-C4 alkildir; R5 halojendir; X Nsdir ve L klor (Cl), brom (Br), iyot (I), metansülfonat (OMs), p-toluensülfonat (OTs) ve triIlorometansülfonattan (OTI) seçilen bir ayrilan Mevcut bulusun hazirlama yönteminde, (i) adiminda, Formül 3 ,ün bilesigi, Formül 23nin bilesiginin bir dealkilleme reaksiyonu yoluyla hazirlanmaktadir. Mevcut bulusun hazirlama yönteminde, Formül 3 ,ün bilesigi, bilesigin dealkilleme reaksiyonu gerçeklestirilerek Formül 23nin stabil bilesiginden ayristirilmasinda bir sorun olmaksizin büyük ölçekli bir üretimde yüksek bir verimde hazirlanabilmektedir. Mevcut bulusa göre bir uygulamada, (i) adimindaki dealkilleme reaksiyonu, örnegin, hidrojen bromür (HBr), alüminyum klorür (AlCl3) ve demir (III) klorürden 17464.38 (FeCls) seçilen biri kullanilarak gerçeklestirilmektedir. Mevcut bulusun hazirlama yönteminde, (ii) adiminda, Formül 53in bilesigi, Formül 33ün bilesiginin ve Formül 43ün bilesiginin bir kenetlenme reaksiyonu yoluyla hazirlanmaktadir. Mevcut bulusa göre baska bir uygulamada, Formül 33ün bilesiginin ve Formül 43ün bilesiginin kenetlenme reaksiyonu, dimetilformamid (DMF) çözücüde K2CO3 kullanilarak kolaylikla gerçeklestirilebilmektedir. Mevcut bulusa göre baska bir uygulamada, yüksek safliga sahip Formül 53in bilesigi, Formül 33ün bilesiginin ve Formül 43ün bilesiginin kenetlenme reaksiyonundan sonra kristalizasyon araciligiyla elde edilebilmektedir. Mevcut bulusun hazirlama yönteminde, (iii) adiminda, Formül 63nin bilesigi, Formül 53in bilesiginin fosforil klorür (POCls) ve dimetil formamid ile reaksiyona sokulmasi yoluyla hazirlanmaktadir. Mevcut bulusun baska bir uygulamasinda, Formül 53in bilesiginin fosforil klorür (POCl3) ve dimetilformamid ile reaksiyonu 60°C veya altindaki, daha tercihen 55°C veya daha altindaki bir sicaklikta gerçeklestirilebilmektedir. Mevcut bulusun baska bir yönüne göre, Formül 43ün bilesigi asagidaki adimlar ile hazirlanmaktadir: 1) Formül 73nin bir bilesigine R4 ve R4 sübstitüentlerinin eklenmesi yoluyla Formül 83in bir bilesigini hazirlamaya yönelik bir adim, 2) Formül 83in bilesiginin bir indirgeme ajani ile reaksiyona sokulmasi yoluyla Formül 93un bir bilesigini hazirlamaya yönelik bir adim ve 3) Formül 93un bilesiginin alkol grubuna bir ayrilan grubun eklenmesi yoluyla Formül 43ün bilesigini hazirlamaya yönelik bir adim: 17464.38 burada, R4, R5, X ve L yukarida tanimlanan ile aynidir. Mevcut bulusun baska bir yönüne göre, yukaridaki formüllerde, R4 C1-C4 alkildir; R5 halojendir; X Nsdir ve L klor (Cl), brom (Br), iyot (I), metansülfonat (OMs), p- toluensülfonat (OTs) ve triIlorometansülfonattan (OTI) seçilen bir ayrilan gruptur. Mevcut bulusun hazirlama yönteminde, adim (1),de, Formül 83in bilesigi, Formül 73nin bilesigine R4 ve R5 sübstitüentlerinin eklenmesi yoluyla hazirlanmaktadir. Mevcut bulusun baska bir uygulamasinda, R5, R43ten önce Formül 73nin bilesigine eklenmektedir. R53in hacimce büyük bir grubunun Formül 73nin bilesigine 17464.38 eklenmesi durumunda, örnegin, X N oldugunda ve R53in hacimce büyük bir grubu indazolün 3 konumunda eklendiginde, N2 izomerinin üretimi baskilanabilmekte ve verim iyilestirilebilmektedir. Mevcut bulusun hazirlama yönteminde, adim (2),de, Formül 93un bilesigi, Formül 83in bilesiginin bir indirgeme ajani ile reaksiyona sokulmasi yoluyla hazirlanmaktadir. Mevcut bulusun baska bir uygulamasinda, adim (2),deki indirgeme ajani sodyum borohidrit (NaBH4), lityum borohidrit (LiBH4), boran (BH3) ve diizobütilalüminyum hidritten (DIBAH) seçilen biri veya daha fazlasi olabilmektedir. Mevcut bulusun hazirlama yönteminde, adim (3),te, Formül 43ün bilesigi, Formül 93un alkol grubuna bir ayrilan grubun eklenmesi yoluyla hazirlanmaktadir. Mevcut bulusun baska bir uygulamasinda, adim (3),te, örnegin, Br gibi bir ayrilan grubun eklenmesi yoluyla, Formül 33ün bilesiginin ve Formül 43ün bilesiginin kenetlenme reaksiyonundaki verim iyilestirilebilmektedir. BULUSUN ETKILERI Mevcut bulusun hazirlama yöntemi, güvenlik ve stabilite saglamakla birlikte reaksiyonlarin daha basit bir proses ile gerçeklestirilmesi yoluyla Formül 63nin ara maddesinin hafif kosullar altinda yüksek bir verimde büyük ölçekli üretimini saglayabilmektedir. BULUSA YÖNELIK MOD Bundan sonra, mevcut bulus, asagidaki örneklerle daha ayrintili olarak açiklanacaktir. Bununla birlikte, mevcut bulusun koruma kapsaminin örneklere 17464.38 Örnek 1-1: 3-kloro-1-izopropil-lH-indazol-S-karboksilik asit metil ester 1H-indazol-5-karboksilik asit metil ester (200 g, 1,14 mol), N-klorosüksinimid (NCS, bir reaktöre ilave edilmistir ve reaksiyon karisiminin iç sicakligi 70°C3ye yükseltilmis, ardindan 150 dakika boyunca karistirilmistir. Iyon-çifti kromatografisi (IPC), HPLC ile gerçeklestirilmistir ve reaksiyon tamamlanmistir (%1 1H-indazol-5-karboksilik asit metil ester). Dis sicaklik 0°C3ye ayarlanmistir ve 30 dakika boyunca sogutma gerçeklestirilmistir. Reaktörün iç sicakligi 50°C3de tutulurken K2CO3 edilmistir, ardindan 360 dakika boyunca 60°C3de alkilasyon reaksiyonu gerçeklestirilmistir. HPLC ile iyon-çifti kromatografisi (IPC) gerçeklestirilmesi sonucunda, geri kalan metil 3-kloro-1H-indazol-5-karboksilat ve dolayisiyla izopropil iyodür (31 g) reaksiyonun tamamlanmasi için ek olarak iki defa ilave edilmistir. Reaksiyon karisimi 0°C3ye sogutulmustur, su (1,6 L) yavasça ilave edilmistir ve elde edilen kristal filtrelenmistir. Filtrelenmis kristal, 800 mL su ve 400 mL su ile iki defa yikanmistir ve ardindan azot ile kurutularak baslik bilesigi (292 g, net verim: %79,3) elde edilmistir. 8,06 (dd, 1H), 8,44 (s, 1H) Örnek 1-2: (3-klor0-1-iz0pr0pil-1H-indazol-S-il)-metanol Sentezi Tetrahidrofuran (THF, 1,37 L) ve 3-kloro-1-izopropil-1H-indazol-5-karboksilik asit yükseltilmistir. NaBH4 (51,1 g, 1,35 mol) reaksiyon karisimina ilave edilmistir ve metanol (MeOH, 40 dakika boyunca damlatilarak yavasça ilave edilmis, ardindan 30 dakika boyunca reaksiyon gerçeklestirilmistir. IPC, HPLC 17464.38 kullanilarak gerçeklestirilmistir. Geri kalan yaklasik (3 -kloro-1-izopropil-1H- indazol-5-il)-metanolün yaklasik %70,i ve dolayisiyla NaBH4 ve MeOH, reaksiyon tamamlanana kadar 30 dakikalik araliklarda ek olarak ilave edilmistir (%1 3- kloro-1-izopropil-1H-indazol-5-karboksilik asit metil ester). Reaktörün iç sicakligi 0°C3ye sogutulmustur, 3N HCl, reaksiyon çözeltisinin pHSinin 2,0,da tutulmasi için 60 dakika boyunca yavasça ilave edilerek borun (3 -chloro-1-isopropyl-1H-indazol- -yl)-metanol) alkolü ve kalinti NaBH4,e konjüge edildigi B-kompleksi (N aBH4 ile üretilen kompleks) uzaklastirilmistir. Elde edilen ürün, diklorometan (DCM, 1 L) ile iki defa ekstrakte edilmistir ve indirgenmis basinç altinda damitilarak baslik bilesigi (173 g, net verim: %86) elde edilmistir. Örnek 1-3: 5-bromometil-3-klor0-1-iz0propil-lH-indazol Sentezi DCM ( ve (3-kloro-1-izopropil-1H- indazol-5-il)-metanol (173 g, 0,77 mol) bir reaktöre ilave edilmistir ve iç sicaklik karisimina yavasça ilave edilmistir ve reaksiyon karisimi 80 dakika boyunca gerçeklestirilmistir. IPC, HPLC kullanilarak gerçeklestirilmis ve reaksiyon tamamlanmistir (%3 (3-kloro-1-izopropil-1H-indazol-5-il)-metanol). 1,5 N NaOH (13,6 L) reaksiyonun sonlandirilmasi için 120 dakika boyunca yavasça ilave edilmistir. DCM ( reaksiyon karisimina ilave edilmis ve 30 dakika boyunca karistirilmistir ve sonrasinda katmanlar, sulu katmanin uzaklastirilmasi için ayrilmistir. Organik katman, su ( ile iki defa yikanmistir ve indirgenmis basinç altinda damitilarak baslik bilesigi (228,2 g, net verim: %90,8) elde edilmistir. lH NMR (, 7,51-7,6 (m, 2H), : 19,57 mts 17464.38 Su içinde çözündürülen HBr (HzO içinde HBr, 1,5 L) ve 6-metoksi-3,4-dihidro-2H- naftalen-1-on bir reaktöre ilave edilmis ve 52 saat boyunca 120°Cslik bir dis sicaklikta reflüks edilmistir. IPC, HPLC kullanilarak gerçeklestirilmis ve reaksiyon tamamlanmistir (%3 6-metoksi-3,4-dihidro-2H-naftalen-1-on). Iç sicakligin 10°C3ye sogutulmasindan sonra, elde edilen kati filtrelenmistir. Filtrelenmis kati su ( ile iki defa yikanmis ve azot ile kurutularak baslik bilesigi (123 g, net verim: %89,1) elde edilmistir. 6,80 (d, 1H), 7,90 (d, 1H) naftalen-l-on Sentezi ( reaktöre ilave edilmistir ve reaksiyon 3 saat boyunca 25°Cslik iç sicaklikta gerçeklestirilmistir. IPC, HPLC kullanilarak gerçeklestirilmistir. Geri kalan %5 6-hidroksi-3,4-dihidro-2H-naftalen-1-on ve dolayisiyla 5-bromometil-3- kloro-1-izopropll-lH-indazol (13 g) reaksiyonun (%1 6-hidroksi-3,4-dihidro-2H- naftalen-1-on) tamamlanmasi için ek olarak ilave edilmistir. Su ( reaktöre ilave edilmistir, iç sicaklik 0°C3ye sogutulmustur ve elde edilen kati filtrelenmistir. Filtrelenmis kati su ( ile 2 defa yikanmis ve ardindan azot ile kurutularak baslik bilesigi (178 g, net verim: %79,9) elde edilmistir. Örnek 1-6: 1-klor0-6-(3-kloro-l-izopropil-lH-indazol-S-ilmetoksi)-3,4- dihidro-naftalen-Z-karbaldehid Sentezi 17464.38 Fosforil klorür (POC13, 411,5 g, 2,68 mol) bir reaktöre ilave edilmistir ve iç sicaklik 0°C3ye sogutulmustur. DMF (327 g, 4,47 mol) damlatilarak yavasça ilave edilmis ve 2 saat boyunca 50°Cslik iç sicaklikta karistirilmistir. Bunun içine 6-(3-Kloro- mol) ilave edilmistir ve reaksiyon 3 saat boyunca 50°Cslik iç sicaklikta gerçeklestirilmistir. Reaksiyon sirasinda fazla HCl gazi üretildigi için bir NaOH tuzagi kurulmustur ve nötralizasyon için bir havalandirma hatti baglanmistir. IPC, HPLC kullanilarak gerçeklestirilmistir ve reaksiyon tamamlanmistir ve iç sicaklik 0°C3ye sogutulmustur. Soguk su ( ve MTBE ( baska bir reaktöre ilave edilmistir ve bunun içine yukaridaki reaksiyon karisimi, kristallerin olusturulmasi için 90 dakika boyunca damlatilarak ilave edilmistir. TR TR TR DESCRIPTION METHOD FOR PREPARING INTERMEDIATE FOR THE SYNTHESIS OF SPHIGOSINE-1-PHOSPHATE RECEPTOR AGONIST TECHNICAL FIELD The present invention relates to a method for preparing a key intermediate for synthesizing sphingosine-1-phosphate receptor agonists. More specifically, the present invention relates to a new preparation method capable of achieving the large-scale production of an intermediate compound of Formula 63 in a high yield by a simple process under mild conditions: R 2 Cl 0 X is C or Ns; R1 and R23 are each independently hydrogen, alkyl, halogen, haloalkyl or alkoxyalkyl; R4 is hydrogen or alkyl and R5 is hydrogen, alkyl, halogen, CN, CF3 or COCF3S. BACKGROUND ART 17464.38 Sphingosine-1-phosphate (SlP) is produced via an intracellular ceramide pathway in which ceramide is the starting material. Ceramide is produced through two pathways, the first of which is the n0v0 biosynthetic pathway. Ceramide is also produced by the breakdown of sphingomyelin, a cell membrane structure, in a cell. The level of SlP in each tissue is controlled by two biosynthetic sphingosine kinases (Sthsler) and two biodegradable SlP phosphates (SlP lyase and lysophospholipid phosphatases). It is known that SlPs, produced through phosphorylation of sphingosine by sphingosine kinase, mediates various cellular responses such as cell proliferation, cytoskeletal organization and migration, adhesion and tight junction mechanism and morphogenesis. SlP is present in tissues at a low level but at a high level (100 - in a form associated with albumin-containing plasma protein. SlP binds with the SlP receptor, a G protein-coupled receptor, to exert various biological functions. SlP1 to SlP5 so far SlP They are known as subtypes of the receptor and are called endothelial differentiation gene (EDG) receptors 1, 5, 3, 6 and 8, respectively. In recent years, many studies have found that the SlP signaling process through these receptors plays an important role in a number of responses associated with multiple sclerosis, including the inflammatory response and the repair process, and the non-selective SlP1 agonist is actually a therapeutic agent for multiple sclerosis. It has been approved as. SlP receptors are widely expressed in many cells associated with the induction of multiple sclerosis. In particular, the SlP1 receptor plays a major role in the immune system. The SlP1 receptor is mainly expressed on the surface of lymphocytes such as T cells and B cells and responds to SlP, causing involvement in the circulation of lymphocytes. In the normal situation, the SlP concentration is higher in the body fluid than in the lymphoid tissue, and therefore, after the efferent 17464.38 lymph circulation, the lymphocytes leave the lymphoid tissue for circulation according to the difference in S1P concentration. However, if the SlP1 receptor on lymphocytes is downregulated by the S1P1 agonist, the egress of lymphocytes from the lymphoid tissue does not occur, leading to reduced infiltration of autoaggressive lymphocytes leading to inflammation and tissue damage in the central nervous system (CNS). As a result, a therapeutic effect on multiple sclerosis is achieved. Fingolimod, a non-selective S1P1 agonist, is approved as an oral medication for the treatment of multiple sclerosis. When it binds to the S1P1 receptor to become activated, the receptor ironically becomes cleaved or internalized from the surface of lymphocytes, thus acting as a functional S1P1 antagonist. The Reference Publication discloses novel compounds of the following Formula I that are effective as an S1P receptor agonist: X represents C or Ns, R1 represents H or optionally substituted alkyl, R2 represents H, optionally substituted alkyl, halogen represents CN, CF3 or COCF, W represents C, N, C-alkoxy, C-halogen or C-CNS, 17464.38 Q represents CH2O or O_N, S is selected from the following residues: m and n independently 0 represents 1, 2 or 3, R3~R10 independently represents H, alkyl, halogen, halogenoalkyl or alkoxyalkyl, 17464.38 H2N OH R11 represents H, ', OH, 0 or 4"OH" In a specific example of the above document, the following Reaction Scheme describes the preparation of ylmethyl]-piperidine-4-carboxylic acid (referring to Reaction 17464.38 5335 ç' :I 3 LAH ;i IJIAD ' x a Reaction Scheme 1-chloro-). The preparation steps of 6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthalene-2-carbaldehyde can be explained in detail as follows: (1) (3-chloro-1-isopropyl - Synthesis of 1H-indazole-5-yl)-methanol 1H-indazole-5-carboxylic acid methyl ester was dissolved in dimethylformamide and isopropyl iodide and sodium hydride were added dropwise slowly at 0°C, then at 50°C for 8 hours. mixed. 1N hydrochloric acid solution was added, followed by extraction with ethyl acetate. After washing with brine and drying over anhydrous magnesium sulfate, the filtered filtrate was distilled under reduced pressure. The obtained product was separated by column chromatography to obtain 1-is0pr0pyl-1H-indaz01-5-carboxylic acid methyl ester. The obtained 1-isopropyl-1H-indazole-5-carboxylic acid methyl ester was dissolved in dimethylformamide and N-chlorosuccinimide was added into it, then 17464.38 was stirred at room temperature for 18 hours. Water was added and the reaction mixture was extracted with ethyl acetate. After washing with brine and drying over anhydrous magnesium sulfate, the filtered filtrate was distilled under reduced pressure. The residue was separated by column chromatography to obtain 3-chloro-1-isopropyl-1H-indazole-5-carboxylic acid methyl ester. The obtained 3-chloro-1-isopropyl-1H-indazole-5-carboxylic acid methyl ester was dissolved in tetrahydrofuran and lithium aluminum borohydride was added dropwise. After stirring at room temperature for 1 hour, water, 6N aqueous sodium hydroxide solution and water were added sequentially. Celite was added dropwise and the filtered filtrate was distilled under reduced pressure. The residue was separated by column chromatography to obtain (3-chloro-1-isopropyl-1H-indazol-5-yl)-methanol. (2) Synthesis of 1-chloro-6-hydroxy-3,4-dihydro-naphthalene-2-carbaldehyde First, 6-methoxy-3,4-dihydronaphthalen-1(2H)-one was dissolved in toluene into a solution, N,N-dimethylformamide (DMF) and phosphorus oxychloride (POCl3) were added dropwise at 0°C, then stirred at 70°C for 6 hours. The reaction mixture was poured into ice and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = naphthalenecarbaldehyde). Subsequently, aluminum chloride (AlCl3) was dissolved in dichloromethane at 0°C as a solution of 1-chloro-6. - methoxy-3,4-dihydro-2-naphthalenecarbaldehyde solution and then stirred at 50°C for 6 hours. The reaction mixture was poured into ice and extracted with ethyl acetate. The organic layer was dried and concentrated and the resulting residue was silica. Purification by gel column chromatography (hexane:tetrahydrofuran = 5:1 to 3:1) yielded 1-chloro-6-hydroxy-3,4- 17464.38 dihydro-2-naphthalenecarbaldehyde (3) 1-chloro-6-(3). Synthesis of -chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthalene-2-carbaldehyde Obtained (3-chloro-1-isopropyl-1H-indazol-5-yl)-methanol and 1-chloro-6-hydroxy-3,4-dihydro-naphthalene-2-carbaldehyde was dissolved in toluene and tributylphosphine (PBu3) was added dropwise. After stirring at room temperature for 18 hours, an additional hexane was added. After filtration and distillation under reduced pressure, the residue was purified by column chromatography to yield 1-chloro-6-(3-chloro-1-isopropyl-1H-indazole-5-ylmethoxy)-3,4-dihydro-naphthalene-2-carbaldehyde. has been done. However, the above reaction may have the following problems in terms of the preparation of a clinical active ingredient (API). Firstly, in the process of synthesizing 3-chloro-1-isopropyl-1H-indazole-5-carboxylic acid methyl ester, there may be a problem depending on the production rate of the N2 isomer and (3-chloro-1-isopropyl-1H-indazole-5-yl) Lithium aluminum hydride (LAH), used for methanol synthesis, is too limited in stability to be used on a large scale and has the disadvantage of being easily decomposed by moisture. Additionally, during the Vilsmeier-Haack reaction to obtain 1-chloro-6-methoxy-3,4-dihydro-2-naphthalenecarbaldehyde, an exothermic problem may exist as it reacts at a high temperature of 70°C and 1-chloro-6-hydroxy In the reaction to obtain -3,4-dihydro-2-naphthalenecarbaldehyde, there may be a reactor contamination problem due to the use of AlCl3 or a safety problem due to the use of hazardous reagents. During the use of AlCl3, there may be a stability problem due to reaction stoppage or batch failure due to side reaction progress, and the efficiency needs to be improved since the total efficiency is 70%. Additionally, 1,1'- (1,1'-((1)) used in the coupling reaction of (3-chloro-1-isopropyl-1H-indazol-5-yl)-methanol and 1-chloro-6-hydroxy-3,4-dihydro-naphthalene-2-carbaldehyde In the case of azodicarbonyl)dipiperidine (ADD), it is not preferred due to low efficiency and cost. DESCRIPTION OF THE INVENTION TECHNICAL PROBLEM Accordingly, the technical problem of the present invention is to provide a method suitable for the large-scale production of a compound of Formula 63, a key intermediate in the synthesis of an excellent sphingosine-1-phosphate receptor agonist, in a high yield by means of a simpler process. SOLUTION TO THE PROBLEM To solve the above technical problem, the present invention provides a method for preparing an intermediate compound of Formula 63, comprising the following steps: i) a step of preparing a compound of Formula 33 by a dealkylation reaction of a compound of Formula 23, ii) ) a step to prepare a compound of Formula 53 by a coupling reaction of the compound of Formula 33 and a compound of Formula 43; and iii) a step to prepare a compound of Formula 63 by reacting the compound of Formula 53 with phosphoryl chloride (POCl 5 ) and dimethylformamide: 17464.38 [Formula 6] 17464.38 R1 and R23 are each independently hydrogen, alkyl, halogen, haloalkyl or alkoxyalkyl; R3 is alkyl; R4 is hydrogen or alkyl; R5 is hydrogen, alkyl, halogen, CN, CF3 or COCF33; X is C or N5 AND L is a leaving group. The present invention is described in detail hereinafter. According to one aspect of the present invention, in the above Formulas, R1 and R23 are each independently hydrogen, C1-C6 alkyl, halogen, halo-C1-C6 alkyl or C1-C6 alkoxy-C1-C6 alkyl; R3 is Cl-C6 alkyl; R4 is hydrogen or Cl-C6 alkyl; R5 is hydrogen, C1-C6 alkyl, halogen, CN, CF3 or COCF33; X is C or N5 and L is a leaving group. According to another aspect of the present invention, in the above formulas, R1 and R23 are each independently hydrogen or C1-C4 alkyl; R3 is C1-C4 alkyl; R4 is C1-C4 alkyl; R5 is halogen; where The compound of is prepared via a dealkylation reaction of the compound of Formula 23. In the preparation method of the present invention, the compound of Formula 3 can be prepared in a high yield in a large-scale production without any problem in separating the compound from the stable compound of Formula 23 by performing the dealkylation reaction of the compound. In an embodiment according to the present invention, the dealkylation reaction in step (i) is carried out using one selected from, for example, hydrogen bromide (HBr), aluminum chloride (AlCl3) and iron (III) chloride 17464.38 (FeCls). In the preparation method of the present invention, in step (ii), the compound of Formula 53 is prepared via a coupling reaction of the compound of Formula 33 and the compound of Formula 43. In another embodiment according to the present invention, the coupling reaction of the compound of Formula 33 and the compound of Formula 43 can be easily carried out by using K2CO3 in dimethylformamide (DMF) solvent. In another embodiment according to the present invention, the compound of Formula 53 with high purity can be obtained through crystallization after the coupling reaction of the compound of Formula 33 and the compound of Formula 43. In the preparation method of the present invention, in step (iii), the compound of Formula 63 is prepared by reacting the compound of Formula 53 with phosphoryl chloride (POCl 5 ) and dimethyl formamide. In another embodiment of the present invention, the reaction of the compound of Formula 53 with phosphoryl chloride (POCl3) and dimethylformamide can be carried out at a temperature of 60°C or below, more preferably at 55°C or below. According to another aspect of the present invention, the compound of Formula 43 is prepared by the following steps: 1) a step to prepare a compound of Formula 83 by adding substituents R4 and R4 to a compound of Formula 73, 2) a step to prepare a compound of Formula 93 by reacting the compound of Formula 83 with a reducing agent. and 3) a step for preparing the compound of Formula 43 by adding a leaving group to the alcohol group of the compound of Formula 93: 17464.38 wherein R 4 , R 5 , X and L are the same as defined above. According to another aspect of the present invention, in the above formulas, R4 is C1-C4 alkyl; R5 is halogen; where In the preparation method of the present invention, in step (1), the compound of Formula 83 is prepared by adding substituents R4 and R5 to the compound of Formula 73. In another embodiment of the present invention, R5 is added to the compound of Formula 73 before R43. If a large group of R53 is added to the compound of Formula 73 17464.38, for example, when X is N and a large group of R53 is added at the 3 position of indazole, the production of the N2 isomer can be suppressed and the yield can be improved. In the preparation method of the present invention, in step (2), the compound of Formula 93 is prepared by reacting the compound of Formula 83 with a reducing agent. In another embodiment of the present invention, the reducing agent in step (2) may be one or more selected from sodium borohydride (NaBH4), lithium borohydride (LiBH4), borane (BH3) and diisobutylaluminum hydride (DIBAH). In the preparation method of the present invention, in step (3), the compound of Formula 43 is prepared by adding a leaving group to the alcohol group of Formula 93. In another embodiment of the present invention, in step (3), by adding a leaving group, such as Br, the efficiency of the coupling reaction of the compound of Formula 33 and the compound of Formula 43 can be improved. EFFECTS OF THE INVENTION The preparation method of the present invention, while providing safety and stability, can enable large-scale production of the intermediate of Formula 63 in high yield under mild conditions by carrying out the reactions in a simpler process. MODE FOR THE INVENTION Hereinafter, the present invention will be explained in more detail with the following examples. However, the scope of protection of the present invention is limited to examples 17464.38 Example 1-1: 3-chloro-1-isopropyl-1H-indazole-S-carboxylic acid methyl ester 1H-indazole-5-carboxylic acid methyl ester (200 g, 1.14 mol ), N-chlorosuccinimide (NCS) was added to a reactor and the internal temperature of the reaction mixture was increased to 70°C, then stirred for 150 minutes. Ion-pair chromatography (IPC) was performed by HPLC and the reaction was completed (1% 1H-indazole-5 -carboxylic acid methyl ester) The external temperature was set to 0°C and cooling was carried out for 30 minutes while the internal temperature of the reactor was kept at 50°C, followed by the alkylation reaction by HPLC at 60°C. As a result of this, the remaining methyl 3-chloro-1H-indazole-5-carboxylate and therefore isopropyl iodide (31 g) were added additionally twice to complete the reaction. The reaction mixture was cooled to 0 °C, water (1.6 L) slowly. was added and the resulting crystal was filtered. The filtered crystal was washed twice with 800 mL of water and 400 mL of water and then dried with nitrogen to obtain the title compound (292 g, net yield: 79.3%). 8.06 (dd, 1H), 8.44 (s, 1H) Example 1-2: Synthesis of (3-chloro-1-is0pr0pil-1H-indazol-S-yl)-methanol Tetrahydrofuran (THF, 1.37 L ) and 3-chloro-1-isopropyl-1H-indazole-5-carboxylic acid were increased. NaBH4 (51.1 g, 1.35 mol) was added to the reaction mixture and methanol (MeOH) was slowly added dropwise over 40 min, followed by the reaction for 30 min. IPC was performed using HPLC 17464.38. The remainder was approximately (3-chloro Approximately 70% of -1-isopropyl-1H-indazole-5-yl)-methanol and therefore NaBH4 and MeOH were additionally added at 30 minute intervals until the reaction was complete (1% 3-chloro-1-isopropyl-1H-indazole -5-carboxylic acid methyl ester), the internal temperature of the reactor was cooled to 0°C, 3N HCl was added slowly over 60 minutes to keep the pH of the reaction solution at 2.0, and boron (3-chloro-1-isopropyl-1H-indazole- -yl)-methanol) alcohol and the B-complex (complex produced with N aBH4) in which it was conjugated to residual NaBH4 were removed. The resulting product was extracted twice with dichloromethane (DCM, 1 L) and distilled under reduced pressure to obtain the title compound (173 g, net yield: 86%). Example 1-3: Synthesis of 5-bromomethyl-3-chloro-1-isopropyl-1H-indazole DCM ( and (3-chloro-1-isopropyl-1H-indazole-5-yl)-methanol (173 g, 0.77 mol) was added to a reactor and slowly added to the internal temperature mixture and the reaction mixture was carried out using IPC, HPLC and the reaction was completed (3-chloro-1-isopropyl-1H-indazol-5-yl)-. methanol) 1.5 N NaOH (13.6 L) was added slowly over 120 min to terminate the reaction. DCM ( was added to the reaction mixture and stirred for 30 min, and then the layers were separated to remove the aqueous layer. The organic layer was mixed with water ( and was distilled under reduced pressure to obtain the title compound (228.2 g, net yield: 90.8%), 1H NMR (, 7.51-7.6 (m, 2H), : 19.57 mts). 17464.38 HBr dissolved in water (HBr in H2O, 1.5 L) and 6-methoxy-3,4-dihydro-2H-naphthalen-1-one were added to a reactor and refluxed at an external temperature of 120°C for 52 hours. IPC was performed using HPLC and the reaction was completed (3% 6-methoxy-3,4-dihydro-2H-naphthalen-1-one). After cooling the internal temperature to 10°C, the resulting solid was filtered. The filtered solid was washed twice with water and dried with nitrogen to obtain the title compound (123 g, net yield: 89.1%). 6.80 (d, 1H), 7.90 (d, 1H) naphthalene-1- synthesis ( was added to the reactor and the reaction was carried out for 3 hours at an internal temperature of 25°C. IPC was carried out using HPLC. The remaining 5% was 6-hydroxy-3,4-dihydro-2H-naphthalen-1-one and therefore 5-bromomethyl -3-chloro-1-isopropyl-1H-indazole (13 g) was additionally added to complete the reaction (1% 6-hydroxy-3,4-dihydro-2H-naphthalen-1-one). , the internal temperature was cooled to 0°C and the resulting solid was filtered. The filtered solid was washed 2 times with water and then dried with nitrogen to obtain the title compound (178 g, net yield: 79.9%). Example 1-6: 1- Synthesis of chloro-6-(3-chloro-1-isopropyl-1H-indazole-S-ylmethoxy)-3,4-dihydro-naphthalene-Z-carbaldehyde 17464.38 Phosphoryl chloride (POC13, 411.5 g, 2.68 mol) was added to a reactor and the internal temperature was cooled to 0°C. DMF (327 g, 4.47 mol) was added slowly dropwise and stirred at an internal temperature of 50°C for 2 hours. 6-(3-Chloro-mole) was added into it and the reaction was carried out for 3 hours at an internal temperature of 50°C. Since excess HCl gas was produced during the reaction, a NaOH trap was installed and a vent line was connected for neutralization. IPC was performed using HPLC and the reaction was completed and the internal temperature was cooled to 0°C. Cold water (and MTBE () were added to another reactor and the above reaction mixture was added dropwise for 90 minutes to form crystals.TR TR TR
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