STEREOSELECTIVE PROCESS FOR PREPARING SUBSTITUTED POLYCYCLIC PYRIDONE DERIVATIVE COMPOUNDS AND INTERMEDIATES
Patent Information
- Application Number
- ARP20180102884
- Authority / Receiving Office
- AR · AR
- Patent Type
- Patents
- Current Assignee / Owner
- Priority Date
- 2017-10-06
- Filing Date
- 2018-10-05
- Publication Date
- 2026-08-26
- Estimated Expiration
- 2038-10-05
AI Technical Summary
Existing methods for synthesizing substituted polycyclic pyridone derivatives, such as 7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-6,8-dione, lack stereoselectivity and efficiency, and involve the use of toxic reagents like selenium dioxide, making them unsuitable for industrial production.
A stereoselective process involving the introduction of a removable substituent on the carbon adjacent to the amide in the polycyclic pyridone derivative, followed by selective removal, using optically active intermediates and intramolecular cyclization to achieve high optical purity.
The process enables efficient production of polycyclic pyridone derivatives with high optical purity and selectivity, overcoming the limitations of existing methods by providing a more industrially viable and environmentally safer synthesis route.
Abstract
Description
147446 STEREOSELECTIVE PROCESS TO PREPARE POLYCYCLIC PYRIDONE DERIVATIVES INTERMEDIATES PHARMACEUTICAL SUBSTITUTES AND INTERMEDIARIES TECHNICAL FIELD
[0001] The present invention relates to a process for preparing substituted polycyclic pyridone derivatives. Specifically, the present invention relates to a stereoselective process for preparing substituted polycyclic pyridone derivatives and their intermediates. PREVIOUS ART
[0002] A tricyclic pyridine derivative such as 7-hydroxy-3,4,12,12a-tetrahydro-1H[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-6,8dione is known to serve as a core skeleton for substituted polycyclic pyridone derivatives that have cap-dependent endonuclease inhibitory activity and also as a common skeleton for other compounds useful as a drug, such as those compounds that have HIV integrase inhibitory activity. Developments have been made to provide more industrially appropriate methods for the synthesis of a common skeleton for such compounds useful as a drug. Furthermore, developments have been made to provide effective methods for manufacturing a pyrone compound as a raw material for the production of such 2642577 of 117 common skeleton.
[0003] Patent documents 1 to 14 disclose a stereoselective process for preparing Doltegravir using (R)-aminoalcohol shown below. where RA1 is hydroxyl, alkyloxy, halogen or the like; RA2 is hydrogen, difluorobenzylcarbamoyl, alkyloxycarbonyl, carboxy, or the like; RA3 is aldehyde or aldehyde equivalent; RA4 is alkyl, or the like. Patent document 15 and non-patent document 1 disclose a stereoselective process for preparing Doltegravir and its derivatives using optically active amino alcohol or diamine shown below, where RA5 is difluorobenzylcarbamoyl; RA6 is a protecting group for a hydroxyl group; X1 is O or NRA7; RA7 is alkyl, or similar; the other symbols are the same as defined above. Patent document 16 and non-patent document 2 disclose a process for preparing racemic derivatives of Doltegravir using the amino alcohol or diamine shown below, 2642577 of 117 OBn O OBn O where RA8 is hydrogen or difluorobenzylcarbamoyl; RA9 is hydrogen or two RA9s can be taken together with an adjacent carbon atom to form a carbocycle or heterocycle; the other symbols are the same as defined above. However, the above documents do not describe a process for preparing (R)-7-hydroxy-3,4,12,12atetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2, 1f][1,2,4]triazin-6,8-dione.
[0004] Patent document 17 discloses a process for preparing the enantiomixture of 7-(benzyloxy)-3,4,12,12-atetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1f][1,2,4]triazin-6,8-dione shown below. The wavy line signifies enantiomixture (1:1). Patent document 18 discloses a process for preparing the enantiomixture shown below. 2642577 of 117 However, patent documents 17 and 18 do not describe a process for preparing the optically active compound 7-hydroxy-3,4,12,12atetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2, 1 f] [ 1,2,4]triazin-6,8-dione. Patent documents 19 to 20 disclose a process that is the enantiomixture of 7-(benzyloxy)-3,4,12,12-atetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1f][1,2,4]triazin-6,8-dione, followed by optical resolution to give an optically active substance shown below. However, this process is not efficient because the compound having a desired stereoconfiguration is obtained after synthesizing the (1:1) enantiomeric mixture. OBn O Furthermore, patent documents 19 to 20 disclose a process for preparing 7-hydroxy-3,4,12,12-atetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1f][1,2,4]triazin-6,8-dione, which is substituted by a methyl group on the adjacent carbon of the amide. 2642577 of 117 of the introduction of Boc, the optically active compound is isolated and then deprotected to obtain the desired product. However, there is neither a description nor a suggestion of a stereoselective synthesis of 7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4c]pyrido[2,1-f][1,2,4]triazin-6,8-dione by introducing a substituent on the carbon adjacent to the amide. Furthermore, there is neither a description nor a suggestion of any process in which a removable substituent is introduced and then removed to obtain optically active compounds of 7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4c]pyrido[2,1-f][1,2,4]triazin-6,8-dione. Patent document 2 1 also reveals a similar process, although it was not published at the time of the priority date of the present application.
[0005] Patent documents 3, 4, 22, 23 and the 2642577 of 117 non-patent documents 3 to 7 disclose a process as follows, for preparing a pyrone compound by direct oxidation of maltol. However, selenium dioxide is a toxic reagent and, therefore, is not suitable for industrial production. Patent documents 1 to 4 and 24 to 29 disclose a process, as follows, in which the oxidation of maltol is carried out by means of olefin; however, the process involves a low temperature reaction at -70 °C in the second stage and, therefore, requires special equipment for industrial production. OH Bno 1)L¡HMDS OBn Me__o MephCHOy2) DBU kJí The patent documents 6 process comprising a RUC'3 OBn Bn ,.Ph Naloi 0. Λ _^0 AAY Ί o— YY%h Αχ° ΑχΟ , 18 and 30 to 36 reveal a condensation reaction as follows. No documents reveal examples only of pyrone that has ester, amide the α position of the carbonyl group compound of pyrone that has α position of the carbonyl group. „ 0 ΠΑ) JL^OMe 0 <xJ ci jf Bn-0 o Meo. A ” °yV' J 1 MeO^O A \ 0 embar go, estos para un compuesto o heteroanillo en pero no revelan un hidrógeno en la OMe 6 2642577 of 117 Documents of previous art Patent documents
[0006] License document 1: WO2010 / 011812 License document 2: WO2010 / 011819 License document 3: WO2010 / 068253 License document 4: WO2010 / 068262 License document 5: WO2010 / 110409 License document 6: WO2012 / 018065 License document 7: WO2014 / 128545 License document 8: WO 2015 / 009927 License document 9: WO 2015 / 019310 License document 10: WO 2015 / 110897 License document 11: WO 2015 / 111080 Document de Driving licence 12: WO 2015 / 177537 Driving licence document 13: WO 2016 / 092527 Driving licence document 14: WO 2016 / 125192 Driving licence document 15: WO 2006 / 116764 Driving licence document 16: WO 2016 / 094198 Driving licence document 17: WO 2012 / 039414 Driving licence document 18: WO 2014 / 099586 Driving licence document 19: WO 2016 / 175224 Driving licence document 20: WO 2017 / 104691 Driving licence document 21: PCT / JP2017 / 28923 Driving licence document 22: WO 2006 / 116764 Patent document 23: WO 2007 / 002109 Patent document 24: WO 2010 / 011814 Patent document 25: WO 2010 / 011815 Patent documentPatent 26: WO 2010 / 011816 Patent document 27: WO 2010 / 011818 Patent document 28: WO 2010 / 067176 2642577 of 117 Patent document 29: WO 2015 / 039348 Patent document 30: WO 2011 / 105590 Patent document 31: WO 2010 / 110409 Patent document 32: WO 2010 / 147068 Patent document 33: WO 2014 / 104279 Patent document 34: WO 2015 / 095258 Patent document 35: WO 2015 / 089847 Patent document 36: WO 2015 / 199167 Non-patent documents
[0007] Non-patent document 1: Journal of Medicinal Chemistry, 2013, 56(14), 5901-5916 Non-patent document 2: Journal of Medicinal Chemistry, 2013, 56(3), 1124-1135 Non-patent document 3: Bioorganic & Medicinal Chemistry Letters, 2004, 14(12), 3257-3261 Non-patent document 4: Journal of Medicinal Chemistry, 2017, 60(8), 3498-3510 Non-patent document 5: Medicinal Chemistry Research, 2013, 22(5), 2351-2359 Non-patent document 6: ChemMedChem, 2008, 3(5), 812-820 Non-patent document 7: Medicinal Chemistry Research, 2013, 22(5), 2351-2359; 2013 SUMMARY
[0008] The present invention provides an efficient method for preparing important intermediates for the production of substituted polycyclic pyridone derivatives, which are specifically a compound of 2642577 of 117 the formula (VIII) or (IX) as revealed herein or one of its salts. Furthermore, the present invention provides an efficient and more industrially appropriate method for the production of a pyrone derivative, as a raw material for the production of substituted polycyclic pyridone derivatives.
[0009] The present inventors have found efficient processes for the production of a compound of formula (VII) that is an important intermediate for producing a compound of formula (VIII) or (IX). Specifically, it was found that an optically active tricyclic pyridone derivative of formula (VII) can be obtained in high yield with high enantioselectivity by intramolecular cyclization of a novel compound of formula (III) or (VI) with controlled stereochemistry to obtain a novel compound of formula (IV) having a removable functional group on an asymmetric carbon, followed by removal of the functional group. In addition, a process for the production of new compounds of formula (III) and (VI) has been found. In addition, a new process was found for the production of a compound of the formula (X3), (X8) or (V4).
[0010] In other words, the present invention provides the following. (1) A process for preparing a compound of the 2642577 of 117 formula (VII) or one of its salts: where R1 is hydrogen hydroxyl group; X is O or characterized by removing formula (IV): or a protective group for CH2; -RA of a compound of the o1 O RA1 where R1 is hydrogen or a hydroxyl group protecting group; RA1 is hydrogen or RA; RA2 is hydrogen or RA; RA3 is hydrogen or RA; X is O, CH2 or CHRA; RA is a removable functional group; and the carbon atom to which RA is bonded is optically active; provided that one of RA1, RA2 and RA3 is RA, the other two are hydrogen and X is O or CH2 or RA1, RA2 and RA3 are hydrogen and X is CHRA. (2) A process for preparing a compound of formula (IV) or one of its salts: where each symbol is as defined below; characterized by subjecting a compound of formula (III) to an intramolecular cyclization reaction: 2642577 of 117 r1 0 RA1 rA3 where R1 is hydrogen or a protecting group for a hydroxyl group; RA1 is hydrogen or RA; RA2 is hydrogen or RA; RA3 is hydrogen or RA; X is O, CH2 or CHRA; RA is a removable functional group and the carbon atom to which RA is attached is optically active; provided that one of RA1, RA2 and RA3 is RA, the other two are hydrogen and X is O or CH2 or RA1, RA2 and RA3 are hydrogen and X is CHRA; R7 is NH2 or NHR2; R2 is a protecting group for an amino group; R8 is -CHO or CH(OR4) (OR4); R4 each is independently hydrogen or an acid-deprotectable protecting group or two R4s can be taken together to form a ring. (3) The process for preparing the compound of formula (VII) or one of its salts according to (1), comprising the process according to (2). (4) The process according to (2) or (3), wherein the intramolecular cyclization reaction is carried out in the presence of an acid. (5) A process for preparing a compound of formula (III) or one of its salts: r1 O RA1 rA3en where each symbol is as defined below; 2642577 of 117 characterized by the reaction of a compound of the formula (la): R,0 or °Y^|OH(la) R7 where R1 is hydrogen or a protecting group for a hydroxyl group; R7 is NH2 or NHR2; R2 is a protecting group for an amino group; with a compound of formula (II): RA1 I rA2H2Ni R®(H)L. r\ rA3where RA1 is hydrogen or RA; RA2 is hydrogen or RA; RA3 is hydrogen or RA; X is O, CH2 or CHRA; RA is a removable functional group and the carbon atom to which RA is attached is optically active; provided that one of RA1, RA2 and RA3 is RA, the other two are hydrogen and X is O or CH2 or RA1, RA2 and RA3 are hydrogen and X is CHRA; R8 is -CHO or -CH(OR4)(OR4); R4 each is independently hydrogen or an acid-deprotectable protecting group or two R4s can be taken together to form a ring. (6) A process for preparing a compound of formula (IV) or one of its salts: r1 O RA1 I ? I (IV) rx H Η rA3 where each symbol is as defined below; 2642577 of 117 characterized by subjecting a compound of formula (VI) to an intramolecular cyclization reaction: where R1 is hydrogen or a protecting group for a hydroxyl group; RA1 is hydrogen or RA; RA2 is hydrogen or RA; RA3 is hydrogen or RA; X is O, CH2 or CHRA; RA is a removable functional group and the carbon atom to which RA is attached is optically active; provided that one of RA1, RA2 and RA3 is RA, the other two are hydrogen and X is O or CH2 or RA1, RA2 and RA3 are hydrogen and X is CHRA; R3 is a protecting group for a carboxyl group; R5 is hydrogen or a protecting group for an amino group. (7) The process for preparing the compound of formula (VII) or one of its salts according to (1), comprising the process according to (6). (8) The process according to (6) or (7), wherein the intramolecular cyclization reaction is carried out in the presence of a base. (9) A process for preparing a compound of formula (VI) or one of its salts: 2642577 of 117 where each symbol is as defined below; characterized by the reaction of a compound of the formula (Ib): where R1 is hydrogen or a protecting group for a hydroxyl group; R3 is a protecting group for a carboxyl group; with a compound of the formula (V): where R5 is a protecting group for an amino group; R6 is substituted or unsubstituted alkyl or substituted or unsubstituted aromatic carbocyclyl; RA1 is hydrogen or RA; RA2 is hydrogen or RA; RA3 is hydrogen or RA; X is O, CH2 or CHRA; RA is a removable functional group and the carbon atom to which RA is attached is optically active; provided that one of RA1, RA2 and RA3 is RA, the other two are hydrogen and X is O or CH2 or RA1, RA2 and RA3 are hydrogen and X is CHRA. 2642577 of 117 (10) The process in accordance with any of (1) to (9), wherein RA1 is RA and RA is optionally carboxy protected or silyl type functional group.
[0011] (11) A process for preparing a compound of formula (X3) or one of its salts: where each symbol is as defined below, comprising (Step 1) reacting a compound of formula (X): wherein R1a is a protecting group for hydroxyl group except optionally substituted aromatic carbocyclylalkyl and optionally substituted aromatic heterocyclylalkyl, with a halogenating agent to obtain a compound of formula (X1): where Z1 is halogen and the other symbols are as previously defined; (Step 2) react the compound of formula (X1) with hydroxide ion to obtain a 2642577 of 117 compound of the formula (X2): where each symbol is as previously defined; and (Step 3) react the compound of formula (X2) with an oxidizing agent to obtain the compound of formula (X3). (12) The process according to (11), wherein the halogenating agent is NBS, NCS, NIS, Br2, Cl2, I2 or DBDMH and the solvent in Step 1 is methyl acetate, ethyl acetate, propyl acetate or acetonitrile. (13) The process according to (11) or (12), wherein the oxidizing agent is sodium hypochlorite. (14) A process for preparing a compound of formula (X8) or one of its salts: where each symbol is as defined below, comprising (Step 1) reacting a compound of formula (X4): where R1 is a protective group for group 2642577 of 117 hydroxyl, with a compound of the formula: rbIRo Rcrb{X5'J Rden where each RBes, independently, is optionally an alkyl substituted with a group selected from the substituent group E or an aromatic carbocycle optionally substituted with a group selected from the substituent group E or the two RBs can be taken together with an adjacent nitrogen atom to form a heterocycle optionally substituted with a group selected from the substituent group E; each RDes, independently, is an alkyloxy or dialkylamino; The substituent group E comprises halogen, hydroxy, sulfanyl, amino, alkyl, haloalkyl, alkyloxy, alkylsulfanyl, alkylsilyl, aromatic carbocyclylsilyl optionally substituted with a group selected from substituent group F, carbocyclyl optionally substituted with a group selected from substituent group F, heterocyclyl optionally substituted with a group selected from substituent group F, a carbocyclylalkyloxy optionally substituted with a group selected from substituent group F, heterocyclylalkyloxy optionally substituted with a group selected from substituent group F, carbocyclylalkylsulfanyl 2642577 of 117 optionally substituted with a group selected from the substituent group F, heterocyclylalkylsulfanyl optionally substituted with a group selected from the substituent group F, carbocyclylalkylamino optionally substituted with a group selected from the substituent group F, heterocyclylalkylamino optionally substituted with a group selected from the substituent group F, carbocyclyloxy optionally substituted with a group selected from the substituent group F, heterocyclyloxy optionally substituted with a group selected from the substituent group F, haloalkyloxy, alkyloxyalkyl, alkyloxyalkyloxy, alkyloxycarbonylamino, alkylamino, alkylcarbonylamino, alkylsulfoniol and alkylsulfonylamino; The substituent group F comprises halogen, hydroxy, amino, oxo, nitro, alkyl, haloalkyl, alkyloxy and a protecting group for the amino protecting group; to obtain a compound of the formula (X6): where each symbol is as previously defined; (Step 2) react the compound of formula (X6) with an oxidizing agent to obtain a compound of formula (X7): 2642577 of 117 where each symbol is as previously defined; and (Step 3) react the compound of formula (X7) with an oxidizing agent to obtain the compound of formula (X8). (15) The process in accordance with (14), wherein Stage 1 is carried out in the presence of a base. (16) The process according to (14) or (15), wherein the oxidizing agent is sodium periodate. (17) A process for preparing a compound of formula (V4) or one of its salts: where each symbol is as defined below, comprising (Step 1) reacting a compound of formula (X9): R1c (X9) where R1c is hydrogen or a protecting group for a hydroxyl group, with a compound of the formula: 2642577 of 117 RcI Rc >CIV1} ><= <v1> wherein each Rces, independently, is an alkyl optionally substituted with a group selected from the substituent group E or an aromatic carbocyclyl optionally substituted with a group selected from the substituent group E or the two Rcs are taken together with the nitrogen atom to form a heterocyclyl optionally substituted with a group selected from the substituent group E; each RDes, independently, is an alkyloxy or dialkylamino; the substituent group E is as defined above in (14) to obtain a compound of formula (V2): where the wavy line represents the E or Z shape or one of their mixtures and the other symbols are as previously defined; (Step 2) subject the compound of formula (V2) to an intramolecular cyclization reaction by reaction with a compound of formula (V3): O (V3) O where R3 is optionally substituted alkyl with a group selected from the substituent group E, 2642577 of 117 aromatic carbocyclylalkyl optionally substituted with a group selected from substituent group B; and Z2 is hydrogen, halogen or alkyloxy optionally substituted with a group selected from substituent group E, to obtain a compound of formula (V4). (18) The process according to (17), wherein Step 1 is carried out using DMSO as a solvent in the presence of an additive agent. (19) The process according to (17) or (18), wherein the intramolecular cyclization reaction is carried out in the presence of an acid in anhydrous condition. (20) A process for preparing a compound of formula (Villa) or formula (IXa) or one of its salts: that comprises the process according to any of (1) to (19). (21) A compound of formula (III) or one of its salts: o1 Ύ) O RA1 rA3 where each symbol is as defined in (2). 2642577 of 117 (22) A compound of formula (VI) or one of its salts: where each symbol is as defined in (6). (23) A compound of formula (IV) or one of its where each symbol is as defined in (1).
[0010] (24) A crystal of phosphate, methanesulfonate or p-chlorobenzoate salt of the compound of the formula: OMe H2N OMe (25) The crystal according to (24) which is a crystal of the phosphate salt. (26) The crystal according to (25) characterized by an X-ray powder diffraction spectrum comprising peaks at a diffraction angle (2θ) of 5.1° ± 0.2°, 15.3° ± 0.2°, 20.5° ± 0.2°, 25.7° ± 0.2° and 30.9° ± 0.2°. (27) The crystal according to (25) characterized 2642577 of 117 by an X-ray powder diffraction spectrum comprising peaks at diffraction angles (2θ) of 5.1° ± 0.2°, 10.2° ± 0.2°, 15.3° ± 0.2°, 20.5° ± 0.2°, 21.8° ± 0.2°, 25.7° ± 0.2°, 30.9° ± 0.2° and 36.3° ± 0.2°. (28) The crystal according to (25) characterized by an X-ray powder diffraction spectrum substantially in accordance with that shown in Figure 1.
[0011] The process of the present invention allows for the efficient production of a polycyclic pyridone derivative of formula (VIII) or (IX) with high optical purity. One of the features of the present invention is that a carbon atom is substituted with RA and then said RA is removed. A compound of formula (IV) can be selectively produced by intramolecular cyclization using an optically active compound of formula (III) or (VI). The selectivity is approximately 2 to 30 times. In particular, when RA1 is RA, which is a protected carboxy, the compound of formula (VI) can be prepared with a selectivity of approximately 10 to 20 times. Brief description of the drawings
[0012] Fig. 1 is a powder diffraction spectrum by 2642577 of 117 X-rays of the phosphate salt crystal of compound 26. Method for carrying out the invention
[0013] The meaning of each term used in this description is explained below. Unless otherwise specified, each term has the same meaning as when used alone or in combination with another term. The expression "which consists of" or "consists of" means that the elements mentioned are included exclusively. The expression "which includes", "to include", "which comprises" or "comprises" means to include, but without limitation, the elements mentioned, that is, other elements are not excluded.
[0014] The expression "optionally substituted with a group selected from the substituent group A" means that any position can be substituted with one, two or more equal or different groups selected from the substituent group A. The same applies to the expressions "optionally substituted with a group selected from substituent group B", "optionally substituted with a group selected from substituent group C", "optionally substituted with a group selected from substituent group D", "optionally substituted 2642577 of 117 with a group selected from the substituent group E” and optionally substituted with a group selected from the substituent group F”. substituent group A: halogen, amino, alkylamino, alkylsulfonyl, aromatic carbocyclylsulfonyl, alkylsulfinyl, aromatic carbocyclylsulfinyl, nitro, alkyloxy, alkyloxycarbonyl, alkylcarbamoyl and aromatic carbocyclyl. substituent group B: halogen, amino, alkylamino, alkylsulfonyl, aromatic carbocyclylsulfonyl, alkylsulfinyl, aromatic carbocyclylsulfinyl, nitro, alkyl, haloalkyl, alkyloxy, alkyloxycarbonyl, alkylcarbamoyl and aromatic carbocyclyl. substituent group C: halogen, amino, alkylamino, alkyloxy, aromatic carbocyclyl. substituent group D: halogen, amino, alkylamino, alkyl, alkyloxy and aromatic carbocycline group. the substituent group E: halogen, hydroxy, sulfanyl, amino, alkyl, haloalkyl, alkyloxy, alkylsulfanyl, alkylsilyl, aromatic carbocyclylsilyl optionally substituted with a group selected from substituent group F, carbocyclyl optionally substituted with a group selected from substituent group F, a heterocyclyl optionally substituted with a group selected from substituent group F, a carbocyclylalkyloxy optionally substituted with a group selected from substituent group F, heterocyclylalkyloxy optionally substituted with a group selected from substituent group F 2642577 of 117 of the substituent group F, carbocyclylalkylsulfanyl optionally substituted with a group selected from the substituent group F, heterocyclylalkylsulfanyl optionally substituted with a group selected from the substituent group F, carbocyclylalkylamino optionally substituted with a group selected from the substituent group F, heterocyclylalkylamino optionally substituted with a group selected from the substituent group F, carbocyclyloxy optionally substituted with a group selected from the substituent group F, heterocyclyloxy optionally substituted with a group selected from the substituent group F, haloalkyloxy, alkyloxyalkyl, alkyloxyalkyloxy, alkyloxycarbonylamino, alkylamino, alkylcarbonylamino, alkylsulfonyl and alkylsulfonylamino. substituent group F: halogen, hydroxy, amino, oxo, nitro, alkyl, haloalkyl, alkyloxy and a protecting group for amino protecting group.
[00157] The term "halogen" includes fluorine, chlorine, bromine, or iodine. Fluorine and chlorine are preferred, and fluorine is especially preferred.
[0016] The term "alkyl" means a linear or branched C1 to C6 alkyl group and includes C1 to C4 alkyl, C1 to C3 alkyl, and the like. Examples include 2642577 of 117 methyl ethyl n-propyl isopropyl n-butyl isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl, and the like. The expression "substituted or unsubstituted alkyl" in R6 is not limited as long as it allows Step 3 of Scheme 4 in the general procedure described below to proceed efficiently. Examples include, but are not limited to, alkyl optionally substituted with a group selected from substituent group A. The term "haloalkyl" means the above "alkyl" substituted with one or more of the previously described "halogens". Examples include trifluoromethyl, trifluoroethyl, and the like. The term "alkylcarbamoyl" means a carbamoyl group substituted with one or two identical or different alkyl groups, as previously described, on the nitrogen atom. Examples include methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, and the like. The term "alkylamino" means an amino group substituted with one or two identical or different alkyl groups, as previously described, on the nitrogen atom. Examples include methylamino, ethylamino, dimethylamino, diethylamino, and similar compounds. The term "alkylsilyl" means a group in which one, two, or three identical or different alkyl groups, as previously described, are substituted onto the silyl group. Examples include methylsilyl, 2642577 of 117 ethylsilyl, dimethylsilyl, diethylsilyl, methylethylsilyl, trimethylsilyl, and the like.
[0019] The expression "carbocyclyl" means "aromatic carbocyclyl" or "non-aromatic carbocyclyl".
[0020] The term "carbocycle" means a ring derived from the "carbocyclyl" described above.
[0021] The expression "heterocyclyl" means "aromatic heterocyclyl" or "non-aromatic heterocyclyl".
[0022] The term "heterocycle" means a ring derived from "heterocyclyl" as previously described. [001723] The term "aromatic carbocyclyl" means a monocyclic or polycyclic aromatic hydrocarbon group. Examples include phenyl, naphthyl, anthril, phenantril, and the like. A preferred embodiment of "aromatic carbocyclyl" is phenyl or naphthyl. The expression "substituted or unsubstituted aromatic carbocyclyl" in R6 is not limited as long as it allows Step 3 of Scheme 4 in the general procedure described below to proceed. Examples include, but are not limited to, aromatic carbocyclyl optionally substituted with a group selected from substituent group B. 2642577 of 117
[0018] The expression "aromatic carbocycle" means a ring derived from the previously described "aromatic carbocyclyl". [001925] The expression "non-aromatic carbocyclyl" means a saturated monocyclic or polycyclic hydrocarbon group or an unsaturated non-aromatic hydrocarbon group. The "non-aromatic carbocyclyl" that is polycyclic includes a fused ring group, wherein a non-aromatic carbocyclyl, which is monocyclic or polycyclic, is fused to a ring of the previous "aromatic carbocyclyl". In addition, examples of "non-aromatic carbocycline" also include a group having a bridge or group to form a spiro ring as follows: LLL The non-aromatic carbocyclyl that is monocyclic is preferably C3 to C16 carbocyclyl, more preferably C3 to C12, and more preferably C4 to C8. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclohexadienyl, and similar compounds. Examples of non-aromatic, polycyclic carbocyclyl compounds include indanyl, indenyl, and acenaphthyl. 2642577 of 117 tetrahydronaphthyl, fluorenyl, and the like.
[00206] The expression "non-aromatic carbocycle" means a ring derived from the previously described "non-aromatic carbocyclyl".
[00217] The expression "aromatic heterocyclyl" means an aromatic cycloyl that is monocyclic or polycyclic, containing one or more heteroatoms, identical or different, independently selected from O, S, and N. The "aromatic heterocyclyl," which is polycyclic, includes a fused ring group, where an aromatic heterocyclyl, which is monocyclic or polycyclic, is fused to a ring of the previous "aromatic carbocyclyl." The free valency of the "heterocyclyl" can be on any ring. Aromatic heterocyclines, which are monocyclic, are preferably 5 to 8 members, and more preferably 5 or 6 members. Examples of 5-membered heterocyclines include pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, and the like. Examples of 6-membered aromatic heterocyclines include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like. Aromatic heterocyclines, which are bicyclic, are preferably 8 to 10 members, and more preferably 9 or 10 members. Examples include indolyl, isoindolyl, and indazolyl. 2642577 of 117 indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, oxazolopyridyl, thiazolopyridyl, and the like. Aromatic heterocyclyls, which are tricyclic or more, are preferably 13 to 15 members. Examples include carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxatiynyl, phenoxazinyl, dibenzofuryl, and the like.
[00228] The expression "aromatic heterocycle" means a ring derived from the previously described "aromatic heterocyclyl".
[00239] The term "non-aromatic heterocyclyl" means a non-aromatic cyclyl that is monocyclic or polycyclic, containing one or more identical or different heteroatoms independently selected from O, S, and N. The "non-aromatic heterocyclyl" that is polycyclic includes a previously mentioned non-aromatic heterocyclyl that is monocyclic or polycyclic, fused to a ring of the above "aromatic carbocyclyl," "non-aromatic carbocyclyl," and / or "aromatic heterocyclyl," and also includes a previously mentioned non-aromatic heterocyclyl. 2642577 of 117 mentioned, which is monocyclic or polycyclic, fused with a ring of the above "aromatic heterocyclyl" and the free valency can be on any ring. Furthermore, examples of the "non-aromatic heterocycle" include a group that has a bridge or a group to form a spiro ring as follows: Non-aromatic heterocyclyls, which are monocyclic, are preferably 3 to 8 members, and more preferably 5 to 6 members. Examples of 3-membered non-aromatic heterocyclyls include thiiranyl, oxiranyl, and aziridinyl. Examples of 4-membered non-aromatic heterocyclyls include oxetanyl and azetidinyl. Examples of 5-membered non-aromatic heterocyclyls include oxathiolanyl, thiazolidinyl, pyrrolidinyl, pyrrolynyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, tetrahydrofuryl, dihydrothiazolyl, tetrahydroisothiazolyl, dioxolanyl, dioxolyl, thiolanyl, and the like. Examples of non-aromatic heterocyclyl, which is 6-membered, include dioxanyl, tianyl, piperidyl, piperazinyl, morpholinyl, morpholino, thiomorpholyl, thiomorpholino, dihydropyridyl, tetrahydropyridyl, tetrahydropyranyl, dihydrooxazinyl, tetrahydropyrandinyl, hexahydropyrimidinyl, 2642577 of 117 dioxazinyl, thiynyl, thiazinyl, and the like. Examples of non-aromatic heterocyclyl, which is 7-membered, include hexahydroazepinyl, tetrahydrodiazepinyl, and oxepanil. The non-aromatic heterocycle, which is polycyclic, is preferably 8 to 20 members and, more preferably, 8 to 10 members. Examples include indolinyl, isoindolinyl, chromanyl, isochromanyl, and the like.
[0024] The expression "non-aromatic heterocycle" means a ring derived from the previously described "non-aromatic heterocyclyl".
[0025] The expression "hydroxyl group protecting group" means a group that replaces a hydrogen atom of a hydroxyl group and a group that is deprotected by a general method, as described in Protective Groups in Organic Synthesis, Theodora W. Green (John Wiley & Sons), to generate a hydroxyl group. Examples include aromatic carbocyclylalkyl optionally substituted with a group selected from substituent group B (e.g., benzyl, p-methoxyphenylbenzyl), alkylcarbonyl optionally substituted with a group selected from substituent group A (e.g., acetyl, pivaloyl, chloroacetyl), formyl, and aromatic carbocyclylcarbonyl optionally substituted with a group selected from the group 2642577 of 117 substituent B (e.g., benzoyl), alkyloxycarbonyl optionally substituted with a group selected from substituent group A (e.g., methoxycarbonyl, isobutyloxycarbonyl, benzyloxycarbonyl, vinyloxycarbonyl), aromatic carbocyclyloxycarbonyl optionally substituted with a group selected from substituent group B (e.g., phenyloxycarbonyl), alkylsulfonyl optionally substituted with a group selected from substituent group A (e.g., mesyl), aromatic carbocyclylsulfonyl optionally substituted with a group selected from substituent group B (e.g., tosyl), trialkylsilyl (e.g., trimethylsilyl, triethylsilyl, t-butyldimethylsilyl), alkyloxyalkyl optionally substituted with a group selected from substituent group A (e.g., methoxymethyl, benzyloxymethyl, methoxyethoxymethyl), 2-(trimethylsilyl)ethoxymethyl, propenyl, phenacyl, tetrahydropyranyl, alkyl, and the like. Examples of "a protecting group for a hydroxyl group except optionally substituted aromatic carbocyclylalkyl and optionally substituted aromatic heterocyclylalkyl" in R1a include optionally substituted alkylcarbonyl with a group selected from substituent group A, formyl, optionally substituted aromatic carbocyclylcarbonyl with a group selected from substituent group B, optionally substituted alkyloxycarbonyl 2642577 of 117 substituted with a group selected from substituent group A, aromatic carbocyclyloxycarbonyl optionally substituted with a group selected from substituent group B, alkylsulfonyl optionally substituted with a group selected from substituent group A, aromatic carbocyclylsulfonyl optionally substituted with a group selected from substituent group B, trialkylsilyl, alkyloxyalkyl optionally substituted with a group selected from substituent group A, 2-(trimethylsilyl)ethoxymethyl, propenyl, phenacyl, tetrahydropyranyl, alkyl, and the like.
[0026] The expression "amino group protecting group" means a group that replaces a hydrogen atom of an amino group and a group that is deprotected by a general method, such as described in Protective Groups in Organic Synthesis, Theodora W. Green (John Wiley & Sons), to generate an amino group. Examples include trialalkylsilyl (e.g., tert-butyldimethylsilyl, 2,2,2-trichloroethoxycarbonyl), alkyloxycarbonyl optionally substituted with a group selected from substituent group A (e.g., tert-butoxycarbonyl), aromatic carbocycloxycarbonyl optionally substituted with a group selected from substituent group B (e.g., benzyloxycarbonyl), and carbocyclylalkyloxycarbonyl. 2642577 of 117 aromatic (for example, 9-fluorenylmethyloxycarbonyl), aromatic carbocyclyloxycarbonyl, and the like. As the "protecting group for amino group" at R2, t-butyldimethylsilyl, t-butoxycarbonyl or benzyloxycarbonyl are preferred. As the "protecting group for amino group" in R5, Alloc or Fmoc are preferable.
[0027] The expression "protecting group for a carboxy group" means a group that replaces a hydrogen atom of a carboxy group and a group that is deprotected by a general method, as described in Protective Groups in Organic Synthesis, Theodora W. Green (John Wiley & Sons), to generate a carboxy group. Examples include alkyl (e.g., methyl, ethyl, tert-butyl) or aromatic carbocyclylalkyl optionally substituted with a group selected from substituent group B (e.g., benzyl).
[0028] The expression "protecting group unprotectable by an acid" includes an optionally substituted alkyl group selected from substituent group A and a ring, where two R4s can be taken together to form the ring. For example, when R4 is alkyl, -CH(OR4)(OR4) is a dialkylacetal (preferably dimethylacetal), which is well known as an aldehyde protecting group. Furthermore, when two R4s are 2642577 of 117 can take together to form a ring, CH(OR4) (OR4) is a cyclic acetal, which is well known as a protecting group for aldehydes. These protecting groups can be deprotected by an acid and converted to -CHO.
[0029] The term "removable functional group" means a leaving group or a functional group that can be converted into a leaving group. Examples include optionally protected carboxyl, optionally protected amino, optionally protected hydroxyl, chlorine, bromine, iodine, or silyl-type functional groups. Optionally protected carboxyl is preferred, and more protected carboxyl is preferred. The expression "optionally protected carboxy" means a carboxy group that can be deprotected according to a general method, as described in Protective Groups in Organic Synthesis, Theodora W. Green (John Wiley & Sons), to generate a carboxy group. Optionally substituted alkyloxycarbonyl with a group selected from substituent group A (e.g., methyloxycarbonyl, ethyloxycarbonyl) is preferred. The "optionally protected carboxy" can be deprotected into carboxy, which is then removed, or it can be converted into "active ester," which is then removed. Examples of the "active ester" include those already reported, in particular, such as an ester that has 2642577 of 117 high desorption capacity, a group of the formula: -C (=0)-0-R9 where R9 is a group of the formula: independent, hydrogen or halogen; R10 is alkyl optionally substituted with a group selected from substituent group A or aromatic carbocyclyl optionally substituted with a group selected from substituent group B; R11 is alkyl optionally substituted with a group selected from substituent group A or optionally substituted with from substituent group B). A group of aromatic carbocyclyl a selected group the following formula: where each symbol is as previously defined.
[0030] A silyl functional group is any substance that can be used as long as it can be removed by fluoride ion reagent. Examples include a group of the formula: -Si(RA4)a where RA4 is independently an alkyl group. 2642577 of 117 optionally substituted with a group selected from substituent group A or aromatic carbocyclyl optionally substituted with a group selected from substituent group B.
[0031] An example of a compound with the formula (IV): where "RA1 is hydrogen or RA; RA2 is hydrogen or RA; RA3 is hydrogen or RA; X is O, CH2 or CHRA; RA is a removable functional group; and the carbon atom to which RA is attached is optically active; provided that one of RA1, RA2 and RA3 is RA, the other two are hydrogen and X is O or CH2 or RA1, RA2 and RA3 are hydrogen and X is CHRA” includes compounds of the formulas shown below. 2642577 of 117 In particular, it is preferable that RA1 be RA, also preferable is a compound of formula (IVa), a compound of formula (IVb), a compound of formula (IVg) or a compound of formula (IVh) and most preferred of all is a compound of formula (IVa).
[0032] In the next step to obtain a compound of formula (IV) from a compound of formula (III) or (VI), if the compound of formula (IV) has configuration (R) around the carbon atom bonded with a dashed wedge line with hydrogen, the compound of formula (III) or (VI) may have configuration (R) or (S) around the carbon atom to which RA is bonded, provided that the desired steric configuration around the atom of The 2642577 of 117 carbon to which RA is attached will depend on the type of RA group, the position of RA, or the condition of the intramolecular cyclization reaction. For example, a compound of formula (IV) having an (S) configuration around the carbon atom bonded with a dashed wedge line to hydrogen can be obtained by an intramolecular cyclization reaction using a compound of formula (III) or (VI) having an (R) configuration around the carbon atom to which RA is bonded. If so, a compound of formula (IV) having an (R) configuration around the carbon atom bonded with a dashed wedge line to hydrogen could be obtained by an intramolecular cyclization reaction using a compound of formula (III) or (VI) having an (S) configuration around the carbon atom to which RA is bonded. Alternatively, a compound of formula (IV) having an (S) configuration around the carbon atom bonded with a dashed wedge line to hydrogen can be obtained by an intramolecular cyclization reaction using a compound of formula (III) or (VI) having an (S) configuration around the carbon atom to which RA is bonded. If so, a compound of formula (IV) having an (R) configuration around the carbon atom 2642577 of 117 joined with a dotted wedge line with hydrogen could be obtained by intramolecular cyclization reaction using a compound of formula (III) or (VI) having configuration (R) around the carbon atom to which RA is attached. Examples of such a stage include, but are not limited to, the following: (III') (IV) (III) (IV) (Him) (IVm)
[0033] The preferred embodiments for each substituent and for the reaction conditions in each process are described below. The possible combinations of the following embodiments are preferred. A preferred embodiment for R1 is benzyl or alkyl, and alkyl is preferred. A preferred embodiment for R2 is t42 2642577 of 117 butyldimethylsilyl, t-butoxycarbonyl or benzyloxycarbonyl and t-butoxycarbonyl is preferred. A preferred embodiment for R3 is alkyl or haloalkyl. A preferred embodiment for R4 is hydrogen or alkyl. A preferred embodiment for R5 is hydrogen, Alloc, or Fmoc. A preferred embodiment for R6 is I rent. A preferred embodiment for R7 is NH2 or NHBoc. A preferred embodiment for R8 is -CHO or -CH(OR4)(OR4), where R4 is hydrogen or alkyl. A preferred embodiment for RA is optionally carboxy-protected, silyl-type functional group, and optionally carboxy-protected is preferred. A preferred embodiment for R1aes alkyl. A preferred embodiment for R1 is benzyl or alkyl. A preferred embodiment for R1ces benzyl or alkyl. A preferred embodiment for alkyl RBes. A preferred form of realization for alkyl RCs. A preferred embodiment for alkyloxy or dialkylamino RDes. 2642577 of 117 A preferred embodiment for Z1 is chlorine, bromine, or iodine. A preferred embodiment for Z2 is hydrogen, halogen, or alkyloxy.
[0034] The general procedures of the process of the present invention are represented by the following diagrams. As used herein, "solid wedge line" and "dashed wedge line" indicate an absolute configuration. In a reaction of one compound with another compound, as described herein, these compounds may be a salt or a solvate of each other. Furthermore, reactions as described below can be carried out "in continuous steps" without isolation. "Continuous step" implementation involves carrying out the next step without isolating a compound obtained by reaction in the preceding step. For example, two steps can be carried out in one vessel.
[0035] A compound of formula (VIII) or (IX) may be used as a drug in the form of a salt. Examples of such a pharmaceutically acceptable salt of the compound of formula (VIII) or (IX) include salts with alkali metals (e.g., lithium, sodium, potassium), alkaline earth metals (e.g., calcium, barium), magnesium, and transition metals (e.g., magnesium ... 2642577 of 117 example, zinc, iron), ammonia, organic bases (for example, trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, pyridine, picoline, quinoline) or amino acids or salts with inorganic acids (for example, hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid) or organic acids (for example, formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, acid (ptoluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid), in particular, salts with hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, methanesulfonic acid, and the like.These salts can be formed according to conventional methods.
[0036] The meaning of each term is as follows. ABCN: 1, 1'-azobis(cyclohexanecarbonitrile) acac: acetylacetonate AIBN: azobisisobutironitri lo Alloc: allyl oxycarbonyl or AZADO: 2-azaadamantan-N-oxyl Boc: tert-butoxycarbonyl 2642577 of 117 COD: 1,5-cyclooctadiene DABCO: 1,4-diazabicyclo[2,2,2]octane dba: dibenzylideneacetone DBDMH: 1,3-dibromo-5,5-dimethylhydantoin DBU: diazabicicloundecene DDDS: 4,4'-dichlorodiphenyl disulfide DMA: N, N - tell me tilacetamid a DME: dimethoxyethane DMF: N,N-dimethylformamide EDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Et2O: diethyl ether Fmoc: 9-fluorenylmethyloxycarbonyl HATU: O-(7-azabenzotriazol-1yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate HF: hydrogen fluoride HOBt: 1-hydroxybenzotriazole n-Hex: n-hexyl NaH: sodium hydride NBS: N-bromosuccinimide NCS: N-chlorosuccinimide NIS: N-iodosuccinimide TBABr: tetrabutylammonium bromide TBACl: tetrabutylammonium chloride TBAF: tetrabutylammonium fluoride TBAOAc: tet rabu thylammonium acetate TFA: trifluoroacetic acid TEMPO: 2,2,6,6-tetramethylpiperidin-1-oxyl TEMPOL: 4 -hydroxy- 2,2,6,6- tetrame tilpipe ridin- 1 oxyl THF: tetrahydrofuran 2642577 of 117 T3P: propylphosphonic anhydride (cyclic trimer) V-7 0: 2,2'-azobis(4-methoxy-2,4-dimethylvaleronitrile) WSCD HC1: l-Ethyl-3-(3 dimethylaminopropyl)carbodiimide hydrochloride
[0037] Scheme 1 (X) (xn where each symbol is as previously defined.
[0038] Stage 1 In this stage, a compound of formula (X) is reacted with a halogenating agent to give a compound of formula (XI). The compound of formula (XI) can be obtained by reacting the compound of formula (X) with a halogenating agent in the presence of a radical initiator. Examples of radical initiators include AIBN, ABCN, V-70, triethylborane, diethylzinc, and the like, preferably AIBN. Examples of halogenating agents include NCS, NBS, NIS, chlorine, bromine, iodine, DBDMH, and similar agents, preferably NBS. The reaction can be carried out in an amount of 1.0 to 3.0 molar equivalents, preferably 1.0 to 2.2. 2642577 of 117 molar equivalents, based on the compound of formula (X). The solvent is not limited as long as it allows this step to proceed efficiently. Examples include ethyl acetate, acetonitrile, carbon tetrachloride, dichloromethane, THF, DMF, DMA, and similar solvents. The reaction can be carried out in a single solvent, a mixed solvent, or without a solvent. Preferred solvents include ethyl acetate, acetonitrile, and carbon tetrachloride. The reaction temperature can be, but is not limited to, approximately 0 to 100 °C, preferably room temperature to 90 °C. The reaction time can be, but is not limited to, 0.5 to 24 hours, preferably 1 to 12 hours.
[0039] Stage 2 In this step, a compound of formula (X1) undergoes nucleophilic substitution with hydroxide ion to give a compound of formula (X2). The compound of formula (X2) can be obtained by reacting the compound of formula (X1) with hydrogen ion in the presence of a base. Examples of the base include sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide, potassium hydroxide, calcium hydroxide, and the like, preferably calcium carbonate. The reaction can be carried out in an amount of 1.0 to 10 molar equivalents, preferably 2.0 to 5.0 molar equivalents, based on the compound of the 2642577 of 117 formula (X1). The solvent is not limited as long as it allows this step to proceed efficiently. Examples include acetonitrile, dioxane, water, dichloromethane, THF, DMF, DMA, DME, and similar solvents. The reaction can be carried out in a single solvent, a mixed solvent, or without a solvent. Preferred solvents include a mixture of acetonitrile and water and a mixture of dioxane and water. The reaction temperature can be, but is not limited to, from room temperature to 150 °C, preferably room temperature to 100 °C. The reaction time can be, but is not limited to, 0.5 to 24 hours, preferably 1 to 12 hours.
[0040] Stage 3 In this stage, a compound of formula (X2) is oxidized to give a compound of formula (X3). The compound of formula (X3) can be obtained by reacting the compound of formula (X2) with a radical initiator and an oxidizing agent in the presence of a base. Examples of the base include sodium bicarbonate, sodium carbonate, sodium hydroxide, potassium carbonate, calcium carbonate, and the like, preferably sodium bicarbonate. The reaction can be carried out in an amount of 1.0 to 2.0 molar equivalents, preferably 1.0 to 1.2 molar equivalents, based on the compound of formula (X2). 2642577 of 117 Examples of the radical initiator include TEMPO, AZADO, TEMPOL, and similar ones, preferably TEMPO. Examples of the oxidizing agent include sodium chlorite, sodium hypochlorite, tert-butyl oxychloride, NCS, methchloroperbenzoic acid, and the like, preferably sodium hypochlorite. The reaction can be carried out in an amount of 2.0 to 5.0 molar equivalents, preferably 2.2 to 2.5 molar equivalents, based on the compound of formula (X2). The solvent is not limited as long as it allows this step to proceed efficiently. Examples include acetonitrile, water, dichloromethane, THF, DMF, DMA, and the like. The reaction can be carried out in a single solvent, a mixed solvent, or without a solvent. Preferred solvents include a mixture of dichloromethane and water and a mixture of acetonitrile and water. The reaction temperature can be, but is not limited to, approximately 0 to 100 °C, preferably from 0 °C to room temperature. The reaction time can be, but is not limited to, 0.5 to 24 hours, preferably 1 to 12 hours.
[0041] Scheme 2 2642577 of 117 rbI rd N. 1bA'pB pibD D1bD1b "O 0 (X4) (X6) (X7) where each symbol is as before.
[0042] Stage 1 In this step, a compound of the {X8} defined with formula (X4) is converted into an enamine by reaction with a compound of formula (X5) or (X5') to give a compound of formula (X6). The compound of formula (X6) can be obtained by reacting the compound of formula (X4) with the compound of formula (X5) or (X5') in the presence of an additive agent. Examples of compounds of formula (X5) or (X5') include DMF-dimethylacetal, DMF-diethylacetal, Brederick's reagent, DMF-dimethyl sulfate adduct, and the like, preferably DMF-dimethylacetal. The reaction can be carried out in amounts from 1.0 to 10 molar equivalents, preferably 4.0 to 6.0 molar equivalents, based on the compound of formula (X4). Examples of additive agents include TBAOAc, TBAC1, TBABr, DBU, diazabicyclononene, trimethylglycine, potassium acetate, and similar agents, preferably TBAOAc. The reaction can be carried out in an amount of 0.5 to 3.0 molar equivalents, preferably 1.0 to 1.5 equivalents. 2642577 of 117 molars, based on the compound of formula (X4). The solvent is not limited as long as it allows this step to proceed efficiently. Examples include DMSO, dichloromethane, THF, DMF, DMA, and similar solvents. The reaction can be carried out in a single solvent, a mixed solvent, or without a solvent. The preferred solvents are DMSO and solvent-free. The reaction temperature can be, but is not limited to, approximately room temperature to 200 °C, preferably from 80 °C to 150 °C. The reaction time can be, but is not limited to, 0.5 to 24 hours, preferably 1 to 12 hours.
[00439] Stage 2 In this stage, a compound of formula (X6) is oxidatively cleaved to give a compound of formula (X7). The compound of formula (X7) can be obtained by reacting the compound of formula (X6) with an oxidizing agent in the presence or absence of an acid. Examples of the oxidizing agent include sodium periodate, hydrogen peroxide, m-chloroperoxybenzoic acid, potassium permanganate, and the like, preferably sodium periodate. The reaction can be carried out in an amount of 1.0 to 3.0 molar equivalents, preferably 1.5 to 2.0 molar equivalents, based on the compound of formula (X6). Examples of the acid include copper(I) chloride, and similar compounds. 2642577 of 117 The solvent is not limited as long as it allows this step to proceed efficiently. Examples include acetonitrile, water, dichloromethane, THE, DMF, DMA, and similar solvents. The reaction can be carried out in a single solvent, a mixed solvent, or without a solvent. The preferred solvent is a mixture of acetonitrile and water. The reaction temperature can be, but is not limited to, approximately 0 to 100 °C, preferably from 0 °C to room temperature. The reaction time can be, but is not limited to, 0.5 to 24 hours, preferably 1 to 12 hours. [004450] Stage 3 In this stage, a compound of formula (X7) is oxidized to give a compound of formula (X8). The compound of formula (X8) can be obtained by reacting the compound of formula (X7) in the same way as in Step 3 of Scheme 1. [ 00451] Scheme 3 Rc uD N R1c OY Rc K'O J- CR3 □ 1c I Λ I Z2 tT R'f Ό Rd (V1) o (V3) 9 9 °vJ — ] Eaaa 1 Λ Elsm 2 LQ <x9>{V2} where each symbol is as s O'r3 and was defined with 53 2642577 53 of 117 previously. [004652] Stage 1 In this stage, a compound of formula (X9) is reacted with a compound of formula (V1) or (V1') to give a compound of formula (V2). The compound of formula (V2) can be obtained by reacting the compound of formula (X9) with the compound of formula (V1) or (V1') in the presence of an additive agent. Examples of compounds of formula (V1) or (V1') include DMF-dimethylacetal, DMF-diethylacetal, Brederick's reagent, DMF-dimethylsulfate adduct, and the like, preferably DMF-dimethylacetal. The reaction can be carried out in amounts of 1.0 to 3.0 molar equivalents, preferably 1.5 to 2.5 molar equivalents, based on the compound of formula (X9). Examples of the additive agent include formic acid, acetic acid, oxalic acid, citric acid, trifluoroacetic acid, and similar, preferably acetic acid. The solvent is not limited as long as it allows this step to proceed efficiently. Examples include toluene, DMSO, dichloromethane, THF, DMF, DMA, cyclopentyl methyl ether, and similar solvents. The reaction can be carried out in a single solvent, a mixed solvent, or without a solvent. The preferred solvents include DMSO and DMA. The reaction temperature may be, but without 2642577 of 117 limitation, from approximately 0 to 100 °C, preferably from room temperature to 80 °C. The reaction time can be, but is not limited to, 0.5 to 48 hours, preferably 12 to 24 hours. [004753] Stage 2 In this stage, a compound of formula (V2) is reacted with a compound of formula (V3) to give a compound of formula (V4). The compound of formula (V4) can be obtained by reacting the compound of formula (V2) with the compound of formula (V3) in the presence of a base and then subjecting the resulting compound to intramolecular cyclization in the presence of an acid. Examples of the compound of formula (V3) include dimethyl oxalate, diethyl oxalate, oxalyl chloride, monomethyl oxalate chloride, monoethyl oxalate chloride, preferably diethyl oxalate. The reaction can be carried out in an amount of 1.0 to 4.0 molar equivalents, preferably 2.0 to 3.0 molar equivalents, based on the compound of formula (V2). Examples of the base include sodium methoxide, sodium ethoxide, sodium t-butoxide, lithium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, DBU, DBN, and similar compounds, and preferably sodium ethoxide. The solvent for the reaction with the compound of formula (V3) is not limited as long as it allows this step to proceed efficiently. Examples 2642577 of 117 include toluene, dichloromethane, THF, DMF, DMA, and similar substances. The reaction can be carried out in a single solvent, in a mixed solvent, or without a solvent. The preferred solvent includes toluene. The reaction temperature for the reaction with the compound of formula (V3) can be, but is not limited to, approximately 0 to 100 °C, preferably from 0 °C to room temperature. The reaction time for the reaction with the compound of formula (V3) can be, but is not limited to, 0.5 to 24 hours, preferably 1 to 12 hours. Examples of the acid include p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, pyridinium p-toluenesulfonate, and the like, preferably pyridinium p-toluenesulfonate. The solvent for the intramolecular cyclization reaction is not limited as long as it allows this step to proceed efficiently. Examples include dichloromethane, THF, DMF, DMA, 1,3-dimethyl-2-imidazolidinone, N-methyl-2-pyrrolidone, and similar solvents. The reaction can be carried out in a single solvent, in a mixed solvent, or without a solvent. Preferred solvents include DMA, DMF, 1,3-dimethyl-2-imidazolidinone, and N-methyl-2-pyrrolidone. The reaction temperature for the intramolecular cyclization reaction can be, but is not limited to, approximately 0 to 100 °C, preferably from room temperature to 70 °C. 2642577 of 117 The reaction time for the intramolecular deletion reaction can be, but is not limited to, 0.5 to 24 hours, preferably 0.5 to 4 hours. [004854] Scheme 4 (VIII) (IX) where each symbol is as previously defined. [004955] Stage 1 In this stage, a compound of formula (la) is reacted with a compound of formula (II) to give a compound of formula (III). The protecting group for the carboxy group of the compound of formula (I) can be removed to give the compound of formula (a). The reaction of 2642577 of 117 Deprotection can be carried out by a conventional method as described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons). After this, the compound obtained from formula (a) is reacted with an amine of formula (II) using a condensing agent in the presence or absence of a base to give a compound of formula (III). Examples of the base include triethylamine and diisopropylethylamine. The solvent is not limited as long as it allows this step to proceed efficiently. Examples include dichloromethane, THE, DMF, and DMA. The reaction can be carried out in a single solvent, a mixed solvent, or without a solvent. Dichloromethane is the preferred solvent. Examples of the condensing agent include dicyclohexylcarbodiimide, carbonyldiimidazole, dicyclohexylcarbodiimide-N-hydroxybenzotriazole, EDC, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, HATU, and WSCD»HC1. The condensing agent can be used in an amount of 1 to 5 molar equivalents, preferably 1 to 2 molar equivalents, based on the compound of formula (la). The reaction temperature can be, but is not limited to, approximately 0 to 100 °C, preferably from 0 °C to room temperature. The reaction time can be, but is not limited to, 0.5 to 24 hours, preferably 1 to 12 hours. 2642577 of 117 The previous step is carried out under conditions that are appropriately selected so that RA does not need to be removed and does not react with another functional group.
[00506] Stage 2 In this stage, a compound of formula (III) undergoes intramolecular cyclization to give a compound of formula (IV). For example, the compound of formula (I II) undergoes intramolecular cyclization in the presence of an acid to give a compound of formula (IV). The solvent is not limited as long as it allows this step to proceed effectively. Examples include acetonitrile, toluene, and THF, which can be used alone or in combination. The preferred solvent is acetonitrile. Examples of the acid include methanesulfonic acid, p-toluensulfonic acid, camphorsulfonic acid, acetic acid, and trifluoroacetic acid, which can be used alone or in combination. The preferred acid is methanesulfonic acid. The acid can be used in an amount of 1 to 5 molar equivalents, preferably 1 to 3 molar equivalents, based on the compound of formula (III). The reaction temperature can be, but is not limited to, approximately 0 to 100 °C, preferably from room temperature to 80 °C. The reaction time can be, but is not limited to, 1 to 24 hours, preferably 1 to 12 hours. 2642577 of 117 The previous step is carried out under conditions that are appropriately selected so that RA does not need to be removed and does not react with another functional group.
[00517] Stage 3 In this stage, a compound of formula (Ib) is reacted with a compound of formula (V) to give a compound of formula (VI). The protecting group for the amino group of the compound of formula (I) can be removed to give the compound of formula (Ib). The deprotection reaction can be carried out by a conventional method as described in Protective Groups in Organic Synthesis, Theodora W. Green (John Wiley & Sons). Afterward, the compound obtained from formula (Ib) is reacted with a compound of formula (V) in the presence of an acid to give a compound of formula (VI). Examples of acids include Lewis acids such as boron trifluoride, tin tetrachloride, and zinc chloride, and Brønsted acids such as methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, acetic acid, and trifluoroacetic acid. Preferred acids include boron trifluoride and tin tetrachloride. The solvent is not limited as long as it allows this step to proceed effectively. Examples include acetonitrile, toluene, and THF, which can be used alone or in combination. The preferred solvent 2642577 of 117 includes acetonitrile. The reaction temperature can be, but is not limited to, approximately -80 °C to room temperature, preferably -40 to 0 °C. The reaction time can be, but is not limited to, 0.1 to 24 hours, preferably 0.25 to 2 hours. The previous step is carried out under appropriately selected conditions so that RA does not need to be removed and does not react with another functional group.
[00528] Step 4 In this stage, a compound of formula (VI) undergoes intramolecular cyclization to give a compound of formula (IV). The compound of formula (VI) can be subjected to intramolecular cyclization in the presence of a base, using a Pd catalyst if necessary, to give the compound represented by formula (IV). The solvent is not limited as long as it allows this step to proceed effectively. Examples include acetonitrile, toluene, and THF, which can be used alone or in combination. The preferred solvent is THF. Examples of the base include morpholine, piperidine, and dimedone, which can be used alone or in combination. The preferred base includes morpholine. Examples of Pd catalysts include tetrakistriphenylphosphine palladium. The reaction temperature may be, but without 2642577 of 117 limitation, from approximately 0 to 100 °C, preferably from 20 to 50 °C. The reaction time can be, but is not limited to, 0.1 to 24 hours, preferably 1 to 4 hours. The previous step is carried out under conditions that are appropriately selected so that RA does not need to be removed and does not react with another functional group.
[00539] Stage 5 In this step, the RA group is removed from a compound of formula (IV) to give a compound of formula (VII). [005460] Stage 5-1 (RA = optionally protected carboxy) When RA is optionally carboxy-protected, a protecting group for the carboxy is removed from the compound of formula (IV) under conventional deprotection conditions to give a corresponding carboxylic acid. If RA is carboxy, carboxylic acid of formula (IV) can be used as such. The deprotection reaction can be carried out according to a conventional method as described in Protective Groups in Organic Synthesis, Theodora W. Green (John Wiley & Sons). The carboxylic acid is reacted using a photocatalyst and disulfide under light irradiation in the presence of a base to give a compound of formula (VII). 2642577 of 117 The solvent is not limited as long as it allows this step to proceed effectively. Examples include methanol, ethanol, water, dichloromethane, and dichloroethane, which can be used alone or in combination. The preferred solvent is a mixture of methanol and water. Examples of the base include 2,6-lutidine, pyridine, DBU, diisopropylethylamine, triethylamine, N-methylimidazole, imidazole, and DABCO. The preferred base includes 2,6-lutidine. Examples of photocatalysts include acridinium salts. Acridinium salts are not limited as long as they allow the reaction to proceed efficiently under light irradiation. Preferred examples include 9-mestyl-10alkylacridinium salt and aromatic 9-mestyl-10carbocyclylacridinium salt. Preferred examples also include 9-mestyl-2,7-dimethyl-10methylacridinium salt and 9-mestyl-10-methylacridinium salt. A disulfide is a compound that has a disulfide group as a functional group. Examples include di(aromatic carbocyclyl)disulfide. Preferred disulfides include diphenyl disulfide and 4,4'-dichlorodiphenyl disulfide. Examples of the light include blue LEDs. The reaction temperature can be, but is not limited to, approximately 0 to 50 °C, preferably room temperature. The reaction time can be, but is not limited to, 0.5 to 48 hours, preferably 1 to 24 hours. 2642577 of 117 [ 005561] Stage 5-2 (RA = optionally carboxy protected) Carboxylic acid can be obtained in the same way as in Step 5-1. Carboxylic acid can be reacted with an N-hydroxy compound, etc., using a condensing agent in the presence or absence of a base to give an active ester. Examples of the base include triethylamine, diisopropylethylamine, and DABCO. The solvent is not limited as long as it allows the step to proceed efficiently. Examples include dichloromethane, THE, DMF, and DMA. The reaction can be carried out in a single solvent, a mixed solvent, or without a solvent. The preferred solvent is dichloromethane. Examples of the condensing agent include dicyclohexylcarbodiimide, carbonyldiimidazole, dicyclohexylcarbodiimide-N-hydroxybenzotriazole, EDC, WSCD»HC1, 4-(4,6-dimethoxy-1,3,5-triazin2-yl)-4-methylmorpholinium chloride, HATU and T3P, which can be used in an amount of 1 to 5 molar equivalents, preferably 1 to 2 molar equivalents, on a compound (IV) basis. The reaction temperature can be, but is not limited to, approximately 0 to 100 °C, preferably from 0 °C to room temperature. The reaction time can be, but is not limited to, 0.5 to 24 hours, preferably 1 to 12 hours. 2642577 of 117 [ 00562] The active ester obtained is decarboxylated using a metal catalyst, a ligand, and a reducing agent to give a compound of formula (VII). Examples of metallic catalysts include nickel catalysts, palladium catalysts, copper catalysts, cobalt catalysts, and iron catalysts such as N1Cl2, NiBr2, N1I2, Ni(COD)2, Ni(acac)2, Pd2(dba)3, PdCl2, Pd(OAc)2, CuCl, CuBr, CuCl2, CuBr2, CuCl2, Cu(OAc), Cu(OAc)2, Co(acac)2, Co(acac)3, CoCl2, CoBr3, CoI2, Fe(OAc)3, Fe(acac)3, FeCl3, FeBr3, Fel3, and similar. The preferred metallic catalyst includes NiCl2*5H2O. Examples of the ligand include PPh3, Xantphos, and 2,2'-bipyridine derivatives. The 2,2'-bipyridine derivative is not restricted as long as it functions as a bipyridine ligand. Examples include 4,4'-dimethyl-[2,2']bipyridine, 4,4'-diethyl[2,2']bipyridine, and 4,4-dinonyl-[2,2']bipyridine. 4,4'-dicyano-2,2'-bipyridine, 2,2'-bipyridine4,4'-dicarboxylic acid, dimethyl 2,2'-bipyridine-4,4'-dicarboxylate, 2,2'-bipyridine-4,4'-dicarboxamide, 4,4'bis(hydroxymethyl)-2,2'-bipyridine, Tetraethyl 4,4'bis(bromomethyl)-2,2'-bipyridine, 2,2'-bipyridin-4,4'diylbis(methylene)diphosphonate, (E / Z)4,4'-distyryl-2,2'-bipyridine, 4,4'-dimethoxy-2,2'bipyridine, 2,2'-bipyridine-4,4'-dicarboxylate diisobutyl, 4,4'-di-tert-butyl-2,2'-bipyridine, and the like. The preferred ligand includes 4,4'-di-tert-butyl-2,2'-bipyridine. The solvent is not limited as long as it allows that 2642577 of 117, the step proceeds efficiently. Examples include DMF, DMA, THF, isopropyl alcohol, and dichloromethane. The reaction can be carried out in a simple solvent, in a mixed solvent, or without a solvent. The preferred solvent includes a mixture of DMF, THF, and isopropyl alcohol. Examples of reducing agents include zinc, manganese, phenylsilane, triethylsilane, chlorosilane, and mixtures thereof. The preferred reducing agent is a mixture of zinc and phenylsilane. The reaction temperature can be, but is not limited to, approximately 0 to 100 °C, preferably from room temperature to 80 °C. The reaction time can be, but is not limited to, 0.5 to 24 hours, preferably 1 to 12 hours. [005763] The active ester obtained is decarboxylated using thiol or another reducing agent in the presence or absence of a radical initiator to give a compound of formula (VII). A thiol is a compound that has a hydrogenated sulfur atom at its terminal end. Examples include alkylthiols optionally substituted with a group selected from substituent group C and aromatic carbocyclylthiols optionally substituted with a group selected from substituent group D. The preferred thiol is t-nonanethiol. Examples of the other reducing agent include tin hydride and tris-(trimethylsilyl)silane. 2642577 of 117 Examples of radical initiators include AIBN, ABCN, V-70, triethylborane, and diethylzinc. The preferred radical initiator is AIBN. The solvent is not limited as long as it allows the step to proceed efficiently. Examples include DMF, DMA, THF, isopropyl alcohol, and dichloromethane. The reaction can be carried out in a single solvent, a mixed solvent, or without a solvent. The preferred solvent is DMA. The reaction temperature can be, but is not limited to, approximately 0 to 100 °C, preferably from room temperature to 80 °C. The reaction time can be, but is not limited to, 0.5 to 24 hours, preferably 1 to 12 hours. [005864] Stage 5-3 (RA = silyl type functional group) The compound of formula (IV) is reacted with a fluoride ion reagent to give the compound of formula (VII). Examples of fluoride ion reagents include TBAF, HF*pyridine, and HF·triethylamine. The preferred fluoride ion reagent is TBAF. The solvent is not limited as long as it allows the step to proceed efficiently. Examples include DMF, DMA, THF, dichloromethane, and ethyl acetate. The reaction can be carried out in a single solvent, a mixed solvent, or without a solvent. Preferred solvents include THF and dichloromethane. 2642577 of 117 The reaction temperature can be, but is not limited to, approximately 0 to 100 °C, preferably from 0 °C to room temperature. The reaction time can be, but is not limited to, 0.5 to 24 hours, preferably 1 to 12 hours.
[0065] Stage 5-4(1) (RA = optionally protected amino acid) The protecting group for the amino group is removed from a compound of formula (IV) under a conventional deprotection condition. The resulting amine is diazotized and then reduced to give a compound of formula (VII). The deprotection reaction can be carried out by a conventional method as described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons). Examples of reducing agents include hypophosphorous acid. The solvent is not limited as long as it allows the step to proceed efficiently. Examples include DMF, DMA, THF, dichloromethane, and ethyl acetate. The reaction can be carried out in a single solvent, a mixed solvent, or without a solvent. Preferred solvents include THF and dichloromethane. The reaction temperature can be, but is not limited to, approximately 0 to 100 °C, preferably from room temperature to 80 °C. Reaction time can be, but is not limited to, 2642577 of 117 from 0.5 to 24 hours, preferably from 1 to 12 hours.
[0059] Stage 5-4(2) (RA = optionally protected amino acid) The protecting group for the amino group is removed from a compound of formula (IV) under a conventional deprotection condition. The resulting primary amine is converted to isonitrile and then reduced using a reducing agent in the presence or absence of a radical initiator to give a compound of formula (VII). The deprotection reaction can be carried out by a conventional method as described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons). Examples of reducing agents include tin hydride, tris(trimethylsilyl)silane, and thiol. Examples of radical initiators include AIBN, ABCN, V-70, triethylborane, and diethylzinc. The preferred radical initiator is AIBN. The solvent is not limited as long as it allows the step to proceed efficiently. Examples include DMF, DMA, THF, dichloromethane, and ethyl acetate. The reaction can be carried out in a single solvent, a mixed solvent, or without a solvent. Preferred solvents include THF and dichloromethane. The reaction temperature can be, but is not limited to, approximately 0 to 100 °C, preferably room temperature to 80 °C. 2642577 of 117 The reaction time can be, but is not limited to, 0.5 to 24 hours, preferably 1 to 12 hours.
[0060] Stage 5-5 (RA = chlorine, bromine or iodine) The compound of formula (IV) is reduced to remove the RA group to give a compound of formula (VII). Examples of the reducing condition include Pd—C / H2, NaBH4, LiBH4, and LAH. The preferred reducing condition includes Pd-C / H2. The solvent is not limited as long as it allows the step to proceed efficiently. Examples include DMF, DMA, THF, dichloromethane, and ethyl acetate. The reaction can be carried out in a single solvent, a mixed solvent, or without a solvent. Preferred solvents include THF and dichloromethane. The reaction temperature can be, but is not limited to, approximately 0 to 100 °C, preferably from 0 °C to room temperature. The reaction time can be, but is not limited to, 0.5 to 24 hours, preferably 1 to 12 hours.
[0061] Stage 5-6 (RA = optionally hydroxy protected) The protecting group for the hydroxyl group is removed from a compound of formula (IV) under conventional conditions. The hydroxyl group of the resulting compound is converted into a pseudohalide and then... 2642577 of 117 reduces by reduction to give a compound of formula (VII). The deprotection reaction can be carried out by a conventional method as described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons), and similar works. Examples of pseudohalides include mesylate, tosylate, and triflate. The preferred pseudohalide is triflate. The solvent is not limited as long as it allows the step to proceed efficiently. Examples include DMF, DMA, THF, dichloromethane, and ethyl acetate. The reaction can be carried out in a single solvent, a mixed solvent, or without a solvent. Preferred solvents include THF and dichloromethane. The reaction temperature can be, but is not limited to, approximately 0 to 100 °C, preferably from 0 °C to room temperature. The reaction time can be, but is not limited to, 0.5 to 24 hours, preferably 1 to 12 hours.
[0062] Stage 6 The compound of formula (VIII) or (IX) can be obtained according to the method described in any of patent documents 19 to 21.
[0063] As used herein, "diastereomeric ratio" refers to the ratio of the area of 2642577 of 117 HPLC in percentage or NMR peak intensity between the two stereoisomers as shown below where each symbol is as previously defined.
[0064] The present invention will be explained in more detail below by means of the Examples, but the present invention is not limited to them.
[0065] NMR analysis was performed at 400 MHz, using DMSO-de or CDCl3. RT represents a retention time to LC / MS: liquid chromatography / mass spectrometry and was measured under the following conditions. (Measurement condition) [1] Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm id 2.1x50mm) (Waters) Flow rate: 0.8 mL / min UV detection wavelength: 254 nm Mobile phase: [A]: 0.1% formic acid in water, [B]: 0.1% formic acid in acetonitrile Gradient: a linear gradient from 5% to 100% solvent [B] for 3.5 minutes and then 100% of 2642577 of 117 solvent [B] held for 0.5 minutes.
[0066] Measurement of the powder diffraction pattern by beams X The X-ray powder diffraction measurement of the crystal obtained in each example was carried out according to the general test method described in the Japanese Pharmacopoeia. The measurement conditions are as follows.
[0067] Apparatus: MinFlex 600 RINT-TTRIIII (Rigaku Corporation) Detector: High-speed one-dimensional detector (D / TecUltra 2) with variable blade edge Detection mode: reflection Light source: copper bulb Operating wavelength: CuKa rays Tube current: 10 mA or 15 mA Tube voltage: 30 Kv or 40 Kv Sample plate: aluminum or glass X-ray incidence angle (θ): 3-40°, sample width: 0.01°, or X-ray incidence angle (θ): 4-40°, sample width: 0.02° In general, diffraction angles (2θ) in X-ray powder diffraction can contain errors within the range of ±0.2°, and thus, diffraction angle values should be understood to include values within the range of ±0.2°. Accordingly, the present invention comprises crystals having peak diffraction angles that coincide within an error of ±0.2°, thus 2642577 of 117 as crystals that have peak diffraction angles that completely match in powder X-ray diffraction. Furthermore, the data, especially the X-ray intensity, can vary significantly depending on the X-ray diffraction measurement conditions, such as the method of loading the crystals in the X-ray diffraction apparatus and the particle size of the crystals. Thus, the identity of the compound's crystalline form is not negated even if the data do not agree on the relative peak intensity.
[0068] Example 1 CQ2H CO;H CO2MeR°CsN'A> OMe ----► OMe Η I Esas 1Hη 1E'a:B2 AI 1 UM OMe Bn„, n-Hex^ n-Hex 0 0 0 0 o A ---- 0::> A>_. JÍ ..--· Y-Au ] ] ° Eaaa 3 ] ] O Those 4 ] Y...0 A--° AJ 4 5 n uHex, 0 CO2Me ° e”6 V ñ ¿A' E"7 - NHBoc ' Step 1 To a suspension of NaH (3.96 g, r'o'c \°γγ·'·οι 1 E-apa 5 1 NHBqc NHBoc 6 7 O CQoMe υά H 9 3 A^.-O 4 1 11 99 mmol) in DMF (36 74 A solution of Boc-Lserine (9.27 g, 45 mmol) was added dropwise to DMF (45 mL) in 117 mL of 2642577 for 30 minutes with ice cooling under a nitrogen atmosphere, and then bromoacetate dimethylacetal (10.6 mL, 90 mmol) was added dropwise for 10 minutes. The mixture was heated to room temperature for 3 hours and stirred for 5 hours. The mixture was poured into water (90 g) and concentrated. The aqueous layer was washed with Et2O and the pH was adjusted. 3.3 by addition of hydrochloric acid. The aqueous layer was extracted with ethyl acetate (100 mL). The aqueous layer was extracted again with ethyl acetate (100 mL). The organic layers were combined and dried over sodium sulfate and concentrated under reduced pressure to obtain crude compound 2 (9.52 g). 1H-NMR (CDCl3)5: 5.54-5.52 (br m, 1H), 4.50 (t, J = 5.1 Hz, 1H), 4 .44-4.42 (br m, 1H), 4.0 1-3.99 (br m, 1H), 3.74 (dd, J = 9.7, 4.1 Hz, 1H), 3.55 (d, J = 5.1 Hz, 2H), 3.39 (s, 6H), 1.47 (s, 9H). Stage 2 To a solution of crude compound 2 (9.52 g) in methanol (33 mL) methanesulfonic acid (6.32 mL, 97 mmol) was added at 0 °C under a nitrogen atmosphere, and the mixture was stirred at room temperature for 18 hours. The solvent was removed from the mixture under reduced pressure, and the resulting residue was added to an aqueous solution of potassium carbonate at 0 °C. The mixture was extracted five times with chloroform (50 mL). The organic layers were combined and washed with 2642577 of 117 brine (20 mL), were dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to obtain compound 3 (3.76 g, 40% in 2 stages). 1H-NMR (CDCl3) δ: 4.48 (t, J = 5.2 Hz, 1H), 3.80-3.70 (m, 5H), 3.65 (t, J = 4.7 Hz, 1H), 3.52 (d, J = 5.1 Hz, 2H), 3.39 (s, 6H). Stage 3 To a solution of compound 4 (3.00 g, 11.5 mmol) in dichloromethane (12 mL) TFA (8.88 mL, 13.1 mmol) was added under a nitrogen atmosphere and the mixture was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure and the resulting solid was treated with a mixed solution of diisopropyl ether and hexane (1:1) and filtered to obtain an unprotected product (1.98 g). To a solution of the obtained compound (1.98 g, 11.6 mmol) in DMA (40 mL), 1-iodohexane (5.15 mL, 35.0 mmol) and DBU (5.26 mL, 35.0 mmol) were added, and the mixture was stirred at room temperature for 18 hours. Aqueous hydrochloric acid (1 M) was added to the mixture, and the mixture was extracted three times with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 5 (2.42 g, 82%). LC / MS (ESI): m / z = 255 [M+H]+, RT = 1.97 min 2642577 of 117 Stage 4 Compound 6 was obtained in the same manner as described in document WO 2016 / 175224. Stage 5 A solution of compound 6 (3.00 g, 8.14 mmol) in ethanol (7.86 mL) was mixed with 2 M aqueous sodium hydroxide (17.8 mL, 35.6 mmol) under a nitrogen atmosphere, and the mixture was stirred at 60 °C for 6 hours. 2 M aqueous hydrochloric acid (18 mL) was then added to the mixture, followed by water. The precipitated solid was filtered and washed with water to obtain compound 7 (2.75 g, 95%). LC / MS (ESI): m / z = 354 [M+H]+, RT = 1.24 min Stage 6 To a solution of compound 3 (494 mg, 2.03 mmol) and compound 7 (532 mg, 1.50 mmol) in DMF (11 mL), HOBt (263 mg, 1.95 mmol) and WSCD·HCl (374 mg, 1.95 mmol) were added at 0 °C under a nitrogen atmosphere, and the mixture was stirred at 0 °C for 2 hours and then stirred at room temperature for 1 hour. Water (20 mL) was added to the mixture, and the mixture was extracted twice with ethyl acetate (30 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (20 mL) and brine (20 mL). The organic layers were combined and dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by 2642577 of 117 silica gel column chromatography (chloroform-methanol) to obtain compound 8 (777.0 mg, 95%). 1H-NMR (CDCl3)5: 8.54 (s, 1H), 8.09 (s, 1H), 7.34(d, J = 7.9 Hz, 1H), 6.38 (d, J = 7.8 Hz, 1H), 4.77-4.74 (m, 1H), 4.44 (t, J = 5.1 Hz, 1H), 4.31-4.18 (m,2H), 4.04 (dd, J = 9.7, 3.5 Hz, 1H), 3.81-3.74 (m,4H), 3.51 (d, J = 5.1 Hz, 2H), 3.36 (d, J = 2.1 Hz, 6H), 1.75-1.60 (m, 2H), 1.48 (s, 9H), 1.42-1.25 (m,6H), 0.88 (t, J = 6.8 Hz, 3H). Stage 7 To a solution of compound 8 (114 mg, 0.21 mmol) in acetonitrile (2.3 mL), water (0.46 mL) and methanesulfonic acid (0.041 mL, 0.63 mmol) were added under a nitrogen atmosphere, and the mixture was stirred at 60 °C for 3 hours. Saturated aqueous sodium bicarbonate (5 mL) was added to the mixture, and the mixture was extracted three times with chloroform (10 mL). The organic layers were combined and washed with brine (5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain compound 9 (58.5 mg, 75%). 1H-RMN (CDCl3) δ : 7,36 (d, J = 7,7 Hz, 1H), 6,25(d, J = 7,7 Hz, 1H), 5,55 (d, J = 13,4 Hz, 1H), 5,00-4,95 (m, 2H), 4,50 (d, J = 11,9 Hz, 1H), 4,28-4,23(m, 1H), 4,14 (dd, J = 11,4, 4,7 Hz, 1H), 3,99-3,84(m, 2H), 3,78 (s, 3H), 3,25 (t, J = 10,8 Hz, 1H), 1,781,70 (m, 2H), 1,60 (s, 9H), 1,40-1,25 (m, 6H),0,87 2642577 de 117 (t, J 6,9 Hz, 3H). Etapa 8 A solution of compound 9 (100 mg, 0.26 mmol) in methanol (1.0 mL) and THF (0.5 mL) was mixed with 2 M aqueous sodium hydroxide (0.26 mL, 0.53 mmol) at 0 °C under a nitrogen atmosphere, and the mixture was heated to room temperature for 4 hours with stirring. 1 N aqueous hydrochloric acid (0.55 mL) was added to the mixture, and the mixture was extracted three times with chloroform (10 mL). The organic layers were combined and washed with brine (10 mL), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain compound 10 (85.3 mg, 89%). 1H-NMR (DMSO — De) δ: 7.71 (d, J = 7.7 Hz, 1H), 7.35(d, J = 12.8 Hz, 1H), 6.21 (d, J = 7.7 Hz, 1H), 4.90-4.83 (m, 2H), 4.34 (d, J = 11.9 Hz, 1H), 4.07 (dd, J = 11.3, 4.6 Hz, 1H), 3.95 (dt, J = 21.9, 7.8 Hz, 2H), 3.71 (dd, J = 12.0, 3.8 Hz, 1H), 3.17 (t, J =10.9 Hz, 1H), 1.69-1.58 (m, 2H), 1.39-1.23 (m, 6H), 0.86 (t, J = 6.8 Hz, 3H). Stage 9 A mixture of compound 10 (37 mg, 0.10 mmol), DDDS (2.87 mg, 10 pmol) and 9-mesethyl-2,7-dimethyl-10-methylacridinium salt (0.88 mg, 2.0 pmol) were added to methanol (1.8 mL) and water (45 pL, 2.5 mmol) under a nitrogen atmosphere. After degassing with nitrogen bubbling for 15 minutes, 2,6-lutidine (2.3 pL, 20 pmol) was added. The mixture was 2642577 of 117 was stirred at room temperature under blue LED lighting for 14 hours. The mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain compound 11 (29.4 mg, 92%).
[0069] Example 2 Stage 1 To a solution of compound 10 (183 mg, 0.50 mmol) and N-hydroxyphthalimide (163 mg, 1.00 mmol) in dichloromethane (1.8 mL), WSCD·HC1 (288 mg, 1.50 mmol) was added at 0 °C under a nitrogen atmosphere, and the mixture was stirred at room temperature for 1 hour. Water (10 mL) was added to the mixture, and the mixture was extracted twice with ethyl acetate (20 mL). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate) to obtain compound 12 (203 mg, 80%). 1H-MRI (CDC13)5: 7.90-7.79 (m, 4H), 7.35 (d, J = 7.7 Hz, 1H), 6.20 (d, J = 7.7 Hz, 1H), 5.81 (d, J = 13.3 2642577 of 117 Hz, 1H), 5.41 (d, J = 3.5 Hz, 1H), 5.07-5.01 (m, 1H), 4.74 (d, J = 12.2 Hz, 1H), 4.28-4.17 (m, 3H), 3.90 (dd, J = 16.1, 7.1 Hz, 1H), 3.40 (t, J = 10.8 Hz, 1H), 1.80-1.68 (m, 2H), 1.40-1.24 (m, 6H), 0.83 (t, J = 6.9 Hz, 3H). Stage 2 To a mixture of compound 12 (51 mg, 0.10 mmol) and zinc powder (3.27 mg, 50 μmol), THF (0.5 mL) and 2-propanol (51 pL) were added under a nitrogen atmosphere. After degassing with nitrogen bubbling for 15 minutes, a solution of nickel chloride hexahydrate (2.4 mg, 10 pmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (5.37 mg, 20 pmol) in DMF (0.1 mL) was added. Phenylsilane (37 pL, 0.3 mmol) was added to the mixture, and the mixture was stirred at 60 °C for 2 hours. The mixture was then concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (chloroform-methanol) to obtain compound 11 (15 mg, 48%).
[0070] Example 3 2642577 of 117 To a solution of compound 13 (37.1 mg, 1.00 mmol), which was synthesized in the same manner as described in Steps 1 to Step 8 of Example 1 and 3-hydroxy-4-methylthiazol-2(3H)-thione (22.1 mg, 1.50 mmol) in N-methylpyrrolidone (0.9 mL), DABCO (44.9 mg, 4.00 mmol) and T3P (255 mg, 4.00 mmol) were added at room temperature under a nitrogen atmosphere, and the mixture was stirred at room temperature for 2 hours to obtain a solution of compound 14. t-Nonanethiol (0.9 mL, 74 mmol) was added to the mixture under a nitrogen atmosphere, and the mixture was stirred at 55 °C for 2 hours. The mixture was then concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (chloroform-methanol) to obtain compound 15 (27 mg, 83%). 1H-NMR (DMSO)5: 2.80-3.00 (m, 1H), 3.10-3.18 (m, 1H), 3.38-3.50 (m, 1H), 3.98-4.08 (m, 2H), 4.10-4.20 (m, 1H), 4.76-4.84 (m, 1H), 5.04-5.14 (m, 2H), 6.22 (m, J = 7.6Hz, 1H), 7.27-7.40 (m, 4H), 7.56-7.60 (m, 2H), 7.70 (d, J = 7.6Hz, 1H).
[0071] Example 4 E-jpa 2 2642577 of 117 Stage 1 Compound 15 (1100 g, 3360 mmol) and 7,8-difluoro6,11-dihydrodibenzothiephin-11-ol (977 g, 3697 mmol) were suspended in 50% wt% T3P in ethyl acetate (3208 g, 5041 mmol) and ethyl acetate (1.1 L). Methanesulfonic acid (436 mL, 6721 mmol) was added to the mixture at room temperature, and the mixture was stirred at 70 °C for 5.5 hours. Water was added to the mixture with ice cooling, and the mixture was stirred at room temperature for 1 hour. THF was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and 8% aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was dissolved in THF (5.5 L), and potassium carbonate (790 g, 5713 mmol) was added. The mixture was heated to 50 °C, and benzyl bromide (240 mL, 2016 mmol) was added dropwise. The mixture was stirred at 60 °C for 8.5 hours. 2 mol / L of aqueous hydrochloric acid was added dropwise to the mixture with ice cooling, and the mixture was stirred at room temperature for 10 minutes and extracted with ethyl acetate.The organic layer was washed with water and 8% aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate. Activated carbon (Norit SX-2, 240 g) was added, and the mixture was filtered through Celite. The filtrate was then concentrated under reduced pressure. Ethyl acetate was added to the resulting residue. 2642577 of 117 hexane and the precipitated solid was filtered to obtain compound 16 (1019 g, 1776 mmol, 53%). 1H-NMR (CDCl3) δ: 2.88 (1H, t, J = 11.2 Hz), 3.283.39 (2H, m), 3.72 (1H, d, J = 12.6 Hz), 3.86 (1H, d, J = 9.6 Hz), 4.03 (1H, d, J = 13.9 Hz), 4.45 (1H, d, J = 8.6 Hz), 4.67 (1H, d, J = 13.1 Hz), 5.19-5.26 (2H, m), 5.45 (1H, d, J = 10.9 Hz), 5.63 (1H, d, J = 10.9 Hz), 5.77 (1H, d, J = 7.6 Hz), 6.40 (1H, d, J = 7.8 Hz), 6.68 (1H, t, J = 6.9 Hz), 6.94-7.01 (2H, m), 7.03-7.12 (3H, m), 7.29-7.38 (3H, m), 7.61 (2H, d, J = 7.1 Hz). Stage 2 Lithium chloride (443 g, 10.5 mol) was added to a solution of compound 16 (1200 g, 2092 mmol) in DMA (3.6 L) at room temperature, and the mixture was stirred at 80 °C for 3 hours. Acetone (1.2 L), 0.5 mol / L aqueous hydrochloric acid (6.0 L), and water (2.4 L) were added to the mixture with ice cooling, and the mixture was stirred for 1 hour. The precipitated solid was filtered. The resulting solid was dissolved in chloroform, and isopropyl ether was added to the precipitated solid, which was then filtered to obtain compound (Villa) (950 g, 1965 mmol, 94%). 1H-NMR (CDCls)ó: 2.99 (1H, dt, J = 17.5, 6.8 Hz), 3.47 (1H, td, J = 11.9, 2.5 Hz), 3.60 (1H, t, J = 10.6 Hz), 3.81 (1H, dd, J = 11.9, 3.3 Hz), 3.96 (1H, dd, J = 11.0, 2.9 Hz), 4.07 (1H, d, J = 13.8 Hz), 4.58 (1H, dd, J = 10.0, 2.9 Hz), 4.67 (1H, dd, J = 13.5, 1.9 Hz), 5.26-5.30 (2H, m), 5.75 (1H, d, J = 2642577 of 117 7.8 Hz), 6.69 (1H, d, J = 7.7 Hz), 6.83-6.87 (1H, m) 6.99-7.04 (2H, m), 7.07-7.15 (3H, m).
[0072] Example 5 H Stage 1 Compound 11 (12.0 g, 24.3 mmol) was added 7,8-Difluoro-6,11-dihydrodibenzothiepin-11-ol (8.0 g, 30.3 mmol), ethyl acetate (48.7 g), and cyclohexane (14.1 g) were added and the mixture was stirred at 25°C. 50 (w / w)% T3P in ethyl acetate (20.91 g, 32.9 mmol) was added, followed by the addition of methanesulfonic acid (3.5 g, 36.4 mmol). The mixture was heated to 60°C and stirred for 24 hours. After cooling to 25°C, THE (32.0 g) and water (24.0 g) were added, and then 24% aqueous sodium hydroxide (30.8 g) was added slowly. The mixture was allowed to stand, and the organic and aqueous layers separated. The organic layer was washed twice with 7% aqueous sodium chloride (60.0 g). A mixture of cyclohexane (9.3 g), ethyl acetate (32.1 g), and methanesulfonic acid (2.80 g, 29.1 mmol) was added to the resulting solution. The mixture was stirred at 25 °C for 2 2642577 for 117 hours and the resulting white precipitate was filtered. The solid obtained was washed with ethyl acetate (43.3 g) and dried to obtain mesylate of compound 17 (13.65 g, 84.6%). 1H-NMR (DMSO-de) δ: 0.90 (3H, t, J = 6.0 Hz), 1.291.36 (4H, m), 1. 39-1. 49 (2H, m), 1. 67-1. 79 (2H, m), 2.38 (3H, s), 2.94 (1H, br s), 3.30 (1H, td, J = 11.6, 2.4 Hz), 3.51 (1H, t, J = 10.4 Hz), 3.66(1H, dd, J = 11.2, 2.8 Hz), 3.92-4.01 (2H, m), 4.07(1H, d, J = 14.3 Hz), 4.20 (1H, s), 4.42-4.52 (1H,m), 5.43 (1H, dd, J = 14.4, 2.1 Hz), 5.79-5.83 (2H,m), 6.81 (1H, td, J = 7.6, 1.2 Hz), 6.96 (1H, dd, J = 7.8, 1.0 Hz), 7.09 (1H, J = 8.0, 1.6 Hz), 7.12-7.18 (1H, m), 7.32 (1H, d, J = 7.7 Hz), 7.37-7.49 (2H, m) Stage 2 To compound 17 (15.0 g, 22.6 mmol), N-methylpyrrolidone (52.4 g) was added, and the mixture was stirred. Lithium chloride (8.6 g, 203.3 mmol) was added, and the mixture was heated to 75 °C. The mixture was stirred at 75 °C for 20 hours and then cooled to 40 °C. Acetonitrile (20.0 g) was added, followed by the addition of water (11.6 g). After cooling the mixture to 30 °C and stirring for 30 minutes, water (142.5 g) was added slowly. After stirring at 30 °C for 1.5 hours, the resulting white precipitate was filtered. The resulting solid was washed with 2-propanol (60.1 g) and dried to obtain the compound (Villa) (9.91 g, 90.7%).
[0073] 2642577 of 117 Example 6 To a suspension of compound (Villa) (1.00 g, 2.07 mmol) in DMA (5 mL), chloromethylmethyl carbonate (0.483 g, 3.10 mmol), potassium carbonate (0.572 g, 4.14 mmol), and potassium iodide (0.343 g, 2.07 mmol) were added, and the mixture was stirred at 50 °C for 6 hours. DMA (1 mL) was then added, and the mixture was stirred for another 6 hours. The mixture was cooled to room temperature, DMA (6 mL) was added, and the mixture was stirred at 50 °C for 5 minutes. The mixture was filtered. To the filtrate, 1 mol / L aqueous hydrochloric acid (10 mL) and water (4 mL) were added dropwise with ice cooling, and the mixture was stirred for 1 hour. The precipitated solid was filtered and dried under reduced pressure at 60 °C for 3 hours to obtain compound (IXa) (1.10 g, 1.93 mmol, 93%). 1H-NMR (DMSO—D6) δ: 2.91-2.98 (1H, m), 3.24-3.31(1H, m), 3.44 (1H, t, J = 10.4 Hz), 3.69 (1H, dd, J = 11.5, 2.8 Hz), 3.73 (3H, s), 4.00 (1H, dd, J =10.8, 2,9 Hz), 4,06 (1H, d, J = 14,3 Hz), 4,40 (1H, d, J = 11,8 Hz), 4,45 (1H, dd, J = 9,9, 2,9 Hz), 5,42(1H, dd, J = 14,4, 1,8 Hz), 5,67 (1H, d, J = 6,5 Hz), 2642577 de 117 5, 72-5, 75 (3H, m) , 6, 83-6, 87 (1H, m) , 7,01 (1H, d, J = 6,9 Hz), 7,09 (1H, dd, J = 8,0, 1,1 Hz), 7,14-7,18 (1H, m) , 7,23 (1H, d, J = 7,8 Hz), 7,37-7,44 (2H, m) .
[0074] Ejemplo 7 Etapa 1 Tert-amyl alcohol (1195 pL, 10.99 mmol) was added to compound 18 (99.6 mg, 0.392 mmol), N-hydroxysuccinimidine (54.3 mg, 0.472 mmol), 1-hydroxybenzotriazole monohydrate (6.3 mg, 0.041 mmol) and l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (99.8 mg, 0.521 mmol) and the mixture was stirred at 35 °C. The reaction mixture was cooled to room temperature and acetic acid (7.1 mg, 0.12 mmol), compound 19 (99.2 mg, 0.513 mmol) and diazabicycloundecene (155.9 mg, 1.024 mmol) were added. The mixture was stirred at room temperature for 3 hours and 40 minutes. Water (1100 mL) and toluene (500 mL) were added to isolate the aqueous layer. Water (200 mL) and 25% aqueous sodium hydroxide solution (20 mL) were added to the layer. 2642577 of 117 organic. The layers were separated and the aqueous layer was isolated. The resulting aqueous layers were combined and toluene (500 μg) was added. The aqueous layer was isolated and concentrated under reduced pressure to obtain an aqueous solution of compound 20. Stage 2 Acetonitrile (1000 µL) and concentrated hydrochloric acid (200 µL) were added to the aqueous solution of compound 20, and the mixture was stirred at 45 °C and then allowed to stand overnight at room temperature. The mixture was concentrated under reduced pressure, and water (500 µL), formic acid (10 µL), 25% aqueous sodium hydroxide solution (180 µL), acetonitrile (300 µL), and methanol (3000 µL) were added. The mixture was concentrated to half volume under reduced pressure. Seed crystals were added to the precipitate, and the mixture was then concentrated under reduced pressure and allowed to stand overnight at room temperature. The resulting solid was collected by filtration and washed with water to obtain compound 10 (23.0 mg, 16.1%). [007582] The diastereomeric ratio of a:b = 20:1 was obtained in the intramolecular cyclization reaction of the step to prepare compound 9 in Example 1. The diastereomeric ratio of a:b = 67:3 was obtained in the intramolecular cyclization reaction of the step to prepare compound 10 in Example 7. [007683] 2642577 of 117 In this way, the intramolecular delamination reaction as described herein proceeds with high diastereoselectivity, so that an optically active compound of formula (VII) can be synthesized efficiently. [ 00774 ] Example 8 Stage 1 to Stage 3 Benzaldehyde (4.16 g, 38.43 mmol) was dissolved in 1,2-dimethoxyethane (10 mL) and compound 21 (2.35 g, 38.42 mmol) was added dropwise for approximately 30 minutes with stirring at approximately 25 °C. The reaction mixture was stirred for 20 minutes. The resulting reaction mixture was cooled with ice, and sodium tert-pentoxide (8.46 g, 76.82 mmol) and 1,2-dimethoxyethane (10 mL) were added to the reaction mixture. Compound 23 (8.45 g, 49.94 mmol) was then added, and the mixture was stirred at 50 °C for 13 hours. 2642577 of 117 Sodium borohydride (2.91 g, 76.92 mmol) was added to the resulting reaction mixture, followed by methanol (19.69 g, 614.45 mmol) dropwise. The mixture was stirred at the same temperature for 30 minutes. Deionized water (20 mL) was slowly added to the mixture, followed by 20% aqueous hydrochloric acid until the pH reached 2. Subsequently, isopropyl acetate (50 mL) was added, and the pH was adjusted to 10 with 20% aqueous sodium hydroxide. The mixture was then extracted with isopropyl acetate (50 mL). The resulting organic layer was washed with 20% aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated. Toluene (50 mL) was added to the concentrated solution and the mixture was concentrated again to obtain compound 2 5 (4.07 g, 44%). 1H-NMR (CDC13) δ: 2.82 (2H, t, J = 5.28Hz), 3.38 (6H, s), 3.50 (2H, d, J = 5.16Hz), 3.63 (2H, t, J = 5.28Hz), 3.81 (2H, s), 4.50 (1H, t, J = 5.24Hz), 7.29-7.34 (5H, m) Stage 4 The mixture of 53.5% water-5% wet Pd / C (3.01 g), compound 25 (7.00 g, 29.25 mmol), THF (70 mL), and acetic acid (1.76 g, 29.25 mmol) was degassed under reduced pressure and then subjected to hydrogen replacement twice. The mixture was stirred at 45 °C for 4 hours under hydrogen pressure of 0.3 to 0.2 MPa. The mixture was filtered, washed four times with THF (30 mL), and concentrated to obtain compound 26. Stage 5 THF was added to the obtained compound 26 and then, a 2642577 of 117 acid was added dropwise at approximately 25 °C to assess whether the compound crystallized. The results of the crystallization assessment and the properties of the resulting crystals are shown in Table 1 below. Table 1 Acid Crystallization Phosphoric acid Yes No Deliquescence MsOH Yes Deliquescent 4-Cl-PhCOOH Yes Deliquescent TsOH No AcOH No PhCOOH No PhSOaH No 4-MeOPhCOOH No Hydrochloric acid No Colored Sulfuric acid No Colored Crystallization of phosphate salt To a solution of compound 26 in THF (13.6 mL) phosphoric acid 85% (3.37 g, 29.25 mmol) at approximately 25 °C to precipitate the phosphate salt of compound 26. The resulting suspension was cooled to approximately 5 °C and then filtered. The solid obtained was washed three times with THF (15 mL) and dried under reduced pressure at approximately 40 °C to obtain crystals of phosphate salt of compound 26 (6.57 g, 91%). 2642577 of 117 1H-NMR (DMSO-D6) δ: 2.86 (2H, t, J = 5.62Hz), 3.29 (6H, s), 3.43 (2H, d, J = 5.14Hz), 3.59 (2H, t, J = 5.62Hz), 4.48 (1H, t, J = 5.14Hz) The results of powder diffraction by X-rays are shown below in terms of the 2θ(°) angle of diffraction peaks. Table 2 2Θ Relative intensity 5.10 100 10.16 1 15.32 9 20.46 28 21.82 1 25.66 11 30.92 5 36.26 1 As previously shown, the crystallization of compound 26 was evaluated, and its phosphate salt, methanesulfonate salt, and p-chlorobenzoate salt were crystallized. In particular, the phosphate salt crystals are excellent because they were non-deliquescent. Furthermore, the phosphate salt crystals of compound 26 allow for the elimination of dichloromethane extraction of the compound, thus making it easier to handle. Stage 6 A solution containing compound 27 (50.00 g, 133.55 mmol) and 20% sodium hydroxide (80.13 g, 2642577 of 117 400.65 mmol) in THF (100 mL) was stirred at 55 °C for 5 hours. The reaction mixture was concentrated. Water (34.6 g) and THF (50 mL) were added to the resulting residue. The mixture was heated to 50 °C and the organic and aqueous layers separated. The aqueous layer was concentrated (132.54 g). The resulting concentrate (79.52 g, 80.13 mmol) was then further concentrated to 69.11 g. The concentrate was added to a suspension of the phosphate salt of compound 26 (23.77 g, 96.16 mmol) in acetonitrile (300 mL) at 0 °C. Then, 1-hydroxybenzotriazole monohydrate (2.45 g, 16.00 mmol), WSCD*HCl (18.43 g, 96.14 mmol), and acetonitrile (540 mL) were added, and the mixture was stirred at 50 °C for 8 hours. The reaction mixture was concentrated to 144.71 g, and isopropyl acetate (300 mL) and water (60 mL) were added. The mixture was then extracted. The organic layer was washed three times with 20% aqueous sodium chloride and concentrated. The insoluble matter was removed by filtration and the filtrate obtained was concentrated to 60.46 g. Isopropyl acetate was added to the concentrate and the mixture was stirred at 22 °C for 30 minutes to obtain a suspension of compound 28. To the resulting suspension, 90 mL of heptane was added, followed by filtration and the filtrate was washed three times with 30 mL of a mixed solution (heptane: isopropyl acetate = 2: 1 (v / v)).The resulting solid was dried to obtain compound 28 (33.61 g, 85%). Stage 7 The compounds of formula (Villa) and formula (IXa) were obtained according to methods such as 2642577 of 117 is described in documents WO 2012 / 039414 and WO 2016 / 175224. [007885] Example 9 rt-Hex.. n-Hex._._ OOO oo Stage 1 Under a nitrogen atmosphere, compound 29 (105 mg, 0.5 mmol) was dissolved in ethyl acetate (5 mL), and N-bromosuccinimide (196 mg, 1.1 mmol) and AIBN (33 mg, 0.2 mmol) were added. The mixture was heated under reflux for 7 hours with stirring. After cooling to room temperature, ethyl acetate (10 mL) and saturated aqueous sodium bicarbonate (5 mL) were added. The organic layer was separated, washed with saturated brine (5 mL), and dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 75:25 to 70:30) to obtain compound 30 (126 mg, 87%). 1H-NMR (CDC13) δ: 0.90 (t, J = 7.0 Hz, 3H), 1.25-1.51 (m, 6H), 1.71-1.79 (m, 2H), 4.21 (t, J = 6.8 Hz, 2H), 4.41 (s, 2H), 6.38 (d, J = 5.8 Hz, 1H), 7.68 (d, J = 5, 6 Hz, 1H). Stage 2 Compound 30 (58 mg, 0.2 mmol) was dissolved in a mixed solution of acetonitrile (1.2 mL) and water (1.2 2642577 of 117 mL) under a nitrogen atmosphere, and then calcium carbonate (40 mg, 0.4 mmol) was added. The mixture was stirred at 85 °C for 24 hours. After cooling the mixture to room temperature, water (5 mL) and ethyl acetate (10 mL) were added. The organic layer was separated and washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 50:50) to obtain compound 31 (37 mg, 83%). 1H-NMR (CDC13) δ: 0.79-0.86 (m, 3H), 1.19-1.34 (m, 6H), 1.61-1.68 (m, 2H), 4.04 (t, J = 6.8 Hz, 2H), 4.56 (d, J = 6.1 Hz, 2H), 6.31 (d, J = 5.6 Hz, 1H), 7.66 (d, J = 5.6 Hz, 1H). Stage 3 Under a nitrogen atmosphere, compound 31 (45 mg, 0.2 mmol) was dissolved in a mixed solution of acetonitrile (0.9 mL) and water (0.45 mL), and then TEMPO (1.6 mg, 0.01 mmol), sodium bicarbonate (17 mg, 0.2 mmol), KBr (24 mg, 0.2 mmol), and NaClO₂·5H₂O (72 mg, 0.44 mmol) were added. After stirring for 2 hours at room temperature, 15% aqueous Na₂S₂O₃ (2 mL) and ethyl acetate (10 mL) were added. The organic layer was separated, washed with water (5 mL) and saturated brine (5 mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 100:0 to 80:20) to give compound 32 (48 mg, 99%). 1H-NMR (CDC13) δ: 0.90 (t, J = 7.1 Hz, 3H), 1.26-1.42 (m, 6H), 1.78-1.85 (m, 2H), 4.59 (t, J = 7.0 Hz, 2H), 2642577 of 117 6.51 (d, J 5, 6 Hz, 1H) , 7.84 (d, J 5.8 Hz, 1H)
[0079] Example 10 Stage 1 Dimethylformamide dimethylacetal (0.133 mL, 1.0 mmol) and acetic acid (9 mg, 0.15 mmol) were added to a solution of compound 33 (91 mg, 0.5 mmol) in DMSO (0.5 mL) under a nitrogen atmosphere. The mixture was stirred at 85 °C for 24 hours. After cooling the mixture to room temperature, ethyl acetate (10 mL) and water (5 mL) were added. The organic layer was separated and washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 70:30 to 10:90) to obtain compound 34 (79 mg, 72%). 1H-NMR (CDC13) δ: 2.84 (s, 3H), 3.10 (s, 3H), 4.04 (s, 2H), 4.60 (s, 2H), 5.40 (d, J = 12.7 Hz, 1H), 7.26-7.39 (m, 5H), 7.71 (d, J = 12.7Hz, 1H). Stage 2 To a solution of compound 34 (110 mg, 0.5 mmol) in toluene (2.2 mL) were added diethyl oxalate (219 mg, 1.5 mmol) and 20% by weight sodium ethoxide 2642577 of 117 in ethanol (0.29 mL, 0.75 mmol). The mixture was stirred at room temperature for 1 hour. Aqueous ammonium chloride 10% (5 mL) and ethyl acetate (10 mL) were added to the mixture. The organic layer was separated, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 70:30 to 50:50) to obtain compound 35 (154 mg, 96%). 1H-NMR (CDC13) δ: 1.34 (t, J = 7.2 Hz, 3H), 2.81(s, 3H), 3.17 (s, 3H), 4.33 (q, J = 7.2 Hz, 2H), 4.83(s, 2H), 5.43 (d, J = 12.4 Hz, 1H), 7, 32-7, 39 (m,3H), 7.45 (d, J = 7.0 Hz, 2H), 7.78 (d, J = 12.4 Hz, 1H). Stage 3 A solution of compound 35 (32 mg, 0.1 mmol) in N,N-Dimethylacetamide (1 mL) was added to pyridinium ptoluenesulfonate (75 mg, 0.3 mmol) under a nitrogen atmosphere. The mixture was stirred at 60 °C for 1 hour. Water (5 mL) and ethyl acetate (10 mL) were added to the reaction mixture. The organic layer was separated and washed with water (5 mL) and saturated brine (5 mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 80:20 a 70:30) to obtain compound 36 (26 mg, 97%).
[0080] Example 11 2642577 of 117 32 Stage 1 Under a nitrogen atmosphere, a suspension of potassium carbonate (8.22 g, 59.5 mmol) in DMA (25 mL) was heated to 78 °C with stirring. A solution of maltol (5.00 g, 39.6 mmol) and 1-bromohexane (6.68 mL, 47.6 mmol) in DMA (50 mL) was added dropwise to the suspension over 1 hour. The mixture was heated to 78 °C for 3 hours with stirring. After cooling the mixture to 40 °C, 1-ethylpiperazine (1.52 mL, 11.9 mmol) was added. The reaction mixture was heated to 70 °C and stirred with heating for 1 hour, then cooled to 40 °C. Ethyl acetate (50 mL) and water (100 mL) were added to the reaction mixture and the mixture was extracted with ethyl acetate (20 mL). The organic layer was separated, washed twice with 0.4 mol / L hydrochloric acid (20 mL) and once with 5% aqueous sodium bicarbonate (20 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure to give compound 38 (8.15 g, 98%). 1H-NMR (CDC13) δ: 0.84-0.93 (m, 3H), 1.29-1.45 (m, 6H), 1, 67-1, 74 (m, 2H), 2.32 (s, 3H), 4.04 (t, J = 6.8 Hz, 2H), 6.34 (d, J = 5.6 Hz, 1H), 7.60 (d, J = 5, 6 Hz, 1H). Stage 2 Under a nitrogen atmosphere, in a solution of Crude product 38 (1.00 g, 4.76 mmol) was added to DMSO (5.00 mL), along with dimethylformamide dimethylacetal (3.41 mL, 25.5 mmol), propionic acid (0.076 mL, 1.02 mmol), and triethylamine (0.424 mL, 3.06 mmol). The mixture was heated to 100 °C for 19 hours with stirring. After cooling the reaction mixture to room temperature, toluene (10 mL) and 10% aqueous NaCl solution (20 mL) were added, and the mixture was extracted with toluene (10 mL). The organic layer was washed twice with water (10 mL), and anhydrous sodium sulfate (1.00 g) and activated carbon (200 mg) were added. The mixture was stirred at room temperature for 1 hour, filtered through KCflock, and washed with toluene (30 mL). The filtrate was concentrated under reduced pressure to give compound 39 (1.30 g, 100%). 1H-NMR (CDCl3) δ: 0.89 (t, J = 7.2 Hz, 3H), 1.29-1.35 (m, 4H), 1.41 -1.48 (m, 2H), 1.68-1.76 (m, 2H), 2.94 (s, 6H), 4.03 (t, J = 6.8 Hz, 2H), 5.22 (d, J =13.3 Hz, 1H), 6.19 (d, J = 5.6 Hz, 1H), 7.12 (d, J =13.3 Hz, 1H), 7.42 (d, J = 5.6 Hz, 1H). Stage 3 Under a nitrogen atmosphere, sodium periodate (32.8 g, 154 mmol) was dissolved in water (122 mL) and acetonitrile (82 mL), and the mixture was heated to 45 °C with stirring. Crude product of compound 39 (8.15 g, 30.7 mmol) in acetonitrile (82 mL) was added dropwise to the reaction mixture for 2 hours and 40 minutes. The mixture was heated to 45 °C for 1 hour with stirring, filtered through KC-flock, and washed with ethyl acetate (200 mL). The filtrate was washed with 7.7% aqueous sodium chloride (106 mL). 100 2642577 100 of 117 aqueous sodium thiosulfate 10% (250 mL) and aqueous sodium hydrogen carbonate 5% (82 mL). Each aqueous layer was extracted with ethyl acetate (82 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 40 (6.26 g, 91%). 1H-NMR (CDCl3) δ: 0.90 (t, J = 7.0 Hz, 3H), 1.28-1.44 (m, 6H), 1.72-1.80 (m, 2H), 4.46 (t, J = 6.7 Hz, 2H), 6.47 (d, J = 5.8 Hz, 1H), 7.76 (d, J = 5.8 Hz, 1H), 10,19 (s, 1H). Stage 4 To a solution of the crude product of compound 40 (6.88 g, 30.7 mmol) in acetonitrile (7.3 mL), acetic acid (2.63 mL, 4.61 mmol) and 30% aqueous hydrogen peroxide (7.84 mL, 76.8 mmol) were added under ice cooling or a nitrogen atmosphere. An aqueous solution (73 mL) containing 80% sodium chlorite (7.64 g, 67.5 mmol) was added dropwise for 2–3 minutes, and the mixture was stirred at room temperature for 2 hours. Diisopropyl ether (73 mL) and 5% aqueous sodium bicarbonate (73 mL) were added to the reaction solution, and the mixture was extracted with 5% aqueous sodium bicarbonate (73 mL). Aqueous sodium bisulfite (73 mL) and diisopropyl ether (73 mL) were added to the aqueous layer, and the mixture was extracted with aqueous sodium bicarbonate (73 mL). Ethyl acetate (73 mL) and 2 mol / L hydrochloric acid (146 mL) were added to the resulting aqueous layer, and the mixture was extracted with ethyl acetate (73 mL).The organic layer was dried on anhydrous sodium sulfate and concentrated to 101 2642577 101 of 117 reduced pressure. Diisopropyl ether (37 mL) was added and the mixture was stirred at room temperature for 1 hour. The precipitated solid was filtered and washed with diisopropyl ether (36 mL) to obtain compound 32 (4.45 g, 60%). 1H-NMR (CDC13) δ: 0.89 (t, J = 6.9 Hz, 3H), 1.31-1.41 (m, 7H), 1.78-1.85 (m, 2H), 4.58 (t, J = 6.9 Hz, 2H), 6.51 (d, J = 5.6 Hz, 1H), 7.84 (d, J = 5.6 Hz, 1H).
[0081] Example 12 BrK0 Stage 1 Dimethylformamide dimethylacetal (3.10 mL, 23.1 mmol) and N,N,N-trimethylglycine (108 mg, 0.925 mmol) were added to a solution of compound 41 (1.00 g, 4.62 mmol) in DMSO (5 mL) under a nitrogen atmosphere. The mixture was heated at 100 °C for 8 hours with stirring. After cooling the reaction mixture to room temperature, toluene (10 mL) and 10% aqueous NaCl solution (20 mL) were added. The mixture was extracted with toluene (10 mL). The organic layer was washed twice with water (10 mL) and concentrated under reduced pressure to 1.53 g. Toluene (1.5 mL) was added to the residue, and the mixture was stirred at 0 °C for 15 minutes. Diisopropyl ether (30 mL) was added to the solution and the mixture was stirred at 0 °C for 30 minutes. The precipitated solid was filtered and 102 2642577 102 of 117 was washed with a mixed solvent (21 mL) of toluene / diisopropyl ether (1:20) to obtain compound 42 (987 mg, yield 79%). 1H-NMR (CDCl3) δ : 2.83 (s, 6H), 5.01 (d, J = 13.4 Hz, 1H), 5.11 (s, 2H), 6.22 (d, J = 5.8 Hz, 1H), 7.03(d, J = 13.4 Hz, 1H), 7.29-7.35 (m, 3H), 7.42 (d, J =5.8 Hz, 1H), 7, 44-7, 47 (m,2H) . Stage 2 A solution of compound 42 (2.00 g, 7.37 mmol) in acetonitrile (30 mL) was added dropwise to an aqueous solution (30 mL) of sodium periodate (3.47 g, 16.2 mmol) over 16 minutes with ice cooling under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 5 hours, filtered through KC-flock, and washed with ethyl acetate (40 mL). Water (20 mL) was added to the filtrate. The organic layer was separated and washed with 10% aqueous sodium thiosulfate (20 mL) and 5% aqueous sodium bicarbonate (20 mL). Each aqueous layer was extracted with ethyl acetate (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 80:20 to 50:50) to obtain compound 43 (1.62 g, 95%). 1H-NMR (CDCl3) δ : 5.52 (s, 2H), 6.50 (d, J = 5.8 Hz, 1H), 7.33-7.40 (m, 5H), 7.75 (d, J = 5.8 Hz, 1H), 9.88 (s, 1H). Stage 3 To a solution of compound 43 (1.78 g, 7.74 mmol) 103 2642577 To 103 of 117 in acetonitrile (18 mL), TEMPO (121 mg, 0.774 mmol) and 5% aqueous sodium bicarbonate (10.7 mL) were added under a nitrogen atmosphere. The reaction mixture was cooled with ice, and 5% aqueous sodium hypochlorite (12.4 mL) was added dropwise for 8 minutes. The mixture was stirred at room temperature for 2.5 hours. Diisopropyl ether (36 mL) and 5% aqueous sodium bicarbonate (18 mL) were added to the reaction mixture, and the mixture was extracted with 5% aqueous sodium bicarbonate (18 mL). Aqueous sodium bisulfite (5%) (18 mL) and diisopropyl ether (36 mL) were added to the aqueous layer, and the mixture was extracted with aqueous sodium bicarbonate (18 mL). Hydrochloric acid (36 mL) was added to the aqueous layer, and the mixture was stirred for 30 minutes under ice cooling. The precipitated solid was filtered and washed with water (72 mL) to obtain compound 4 (1.08 g, 57%). 1H-NMR (CDCl3) δ : 5.65 (s, 2H), 6.53 (d, J = 5.8 Hz, 1H), 7.39-7.41 (m, 5H), 7.82 (d, J = 5.8 Hz, 1H).
[0082] In this way, the process for preparing a pyrone derivative according to the present invention can produce the pyrone derivative in a more industrially appropriate and efficient manner by avoiding the use of a toxic reagent or a cryogenic reaction and, therefore, allows the production of a compound having a common skeleton in a more industrially appropriate and efficient manner. 104 2642577 104 of 117 Industrial applicability
[0083] The present invention is useful as a process for preparing substituted polycyclic pyridone derivatives having closure-dependent endonuclease inhibitory activity and their intermediates. 105 2642577 105 of 117 CLAIMS 1. A process for preparing a compound intermediate of pharmaceutical substituted polycyclic pyridone derivatives, of formula (VII), or one of its salts: where R1 is hydrogen hydroxyl group; X is O or characterized by removing formula (IV): or a protective group for CH2; -RA of a compound of the where R1 is hydrogen or a hydroxyl group protecting group; RA1 is hydrogen or RA; RA2 is hydrogen or RA; RA3 is hydrogen or RA; X is O, CH2 or CHRA; RA is an optionally protected carboxy group; and the carbon atom to which RA is bonded is optically active; provided that one of RA1, RA2 and RA3 is RA, the other two are hydrogen and X is O or CH2 or RA1, RA2 and RA3 are hydrogen and X is CHRA.2 2. A process for preparing an intermediate compound of polycyclic pyridone derivatives 2642577 106 of 117 substituted pharmaceuticals, of formula (IV) or one of its salts, used in the process of claim 1: where each symbol is as defined below; characterized in that it comprises one of the following stages (a) or (b): (a) subjecting a compound of formula (III) to an intramolecular cyclization reaction: □ 1 O RA1 rA3 where R1 is hydrogen or a hydroxyl group protecting group; RA1 is hydrogen or RA; RA2 is hydrogen or RA; RA3 is hydrogen or RA; X is O, CH2 or CHRA; RA is an optionally protected carboxy group and the carbon atom to which RA is bonded is optically active; provided that one of RA1, RA2 and RA3 is RA, the other two are hydrogen and X is O or CH2 or RA1, RA2 and RA3 are hydrogen and X is CHRA; R7 is NH2 or NHR2; R2 is a protecting group for an amino group; R8 is -CHO or —CH(OR4) (OR4) ; R4 each is, independently, hydrogen or a protecting group unprotected by one or two acids; R4 can be taken 2642577 107 out of 117 together to form a ring; wherein the intramolecular cyclization reaction is optionally carried out in the presence of an acid; or (b) subjecting a compound of formula (VI) to an intramolecular cyclization reaction: where R1 is hydrogen or a protecting group for a hydroxyl group; RA1 is hydrogen or RA; RA2 is hydrogen or RA; RA3 is hydrogen or RA; X is O, CH2 or CHRA; RA is an optionally protected carboxy group and the carbon atom to which RA is bonded is optically active; provided that one of RA1, RA2 and RA3 is RA, the other two are hydrogen and X is O or CH2 or RA1, RA2 and RA3 are hydrogen and X is CHRA; R3 is a protecting group for a carboxyl group; R5 is hydrogen or a protecting group for an amino group; where the intramolecular cyclization reaction is optionally carried out in the presence of a base. 3. The process for preparing an intermediate compound of pharmaceutical substituted polycyclic pyridone derivatives, of formula (VII), or one of its salts, according to claim 1, 2642577 108 of 117 characterized in that it comprises the process according to claim 2. 4. A process for preparing an intermediate compound of pharmaceutical substituted polycyclic pyridone derivatives, of formula (III), or one of its salts, used in the process of claim 2: r1 Ύ) O RA1 rA3 where each symbol is as defined below; characterized in that it comprises reacting a compound of the formula (I a): where R1 is hydrogen or a protecting group for a hydroxyl group; R7 is NH2 or NHR2; R2 is a protecting group for an amino group: with a compound of formula (II): RA1 rA3 where RA1 is hydrogen or RA; RA2 is hydrogen or RA; RA3 is hydrogen or RA; X is O, CH2 or CHRA; RA is an optionally protected carboxy group and the carbon atom to which RA is attached is optically active; 2642577 109 of 117 provided that one of RA1, RA2 and RA3 is RA, the other two are hydrogen and X is O or CH2 or RA1, RA2 and RA3 are hydrogen and X is CHRA; R8 is -CHO or -CH(OR4) (OR4); R4 each is independently hydrogen or an acid-deprotectable protecting group or two R4s can be taken together to form a ring. 5. A process for preparing an intermediate compound of pharmaceutical substituted polycyclic pyridone derivatives, of formula (VI), or one of its salts, obtained in the process of claim 2: where each symbol is as defined below; characterized by reacting a compound of the formula (Ib): where R1 is hydrogen or a protecting group for a hydroxyl group; R3 is a protecting group for a carboxyl group; 2642577 110 of 117 with a compound of formula (V): (V) where R5 is a protecting group for an amino group; R6 is substituted or unsubstituted alkyl or substituted or unsubstituted aromatic carbocyclyl; RA1 is hydrogen or RA; RA2 is hydrogen or RA; RA3 is hydrogen or RA; X is O, CH2 or CHRA; RA is an optionally protected carboxy group and the carbon atom to which RA is attached is optically active; provided that one of RA1, RA2 and RA3 is RA, the other two are hydrogen and X is O or CH2 or RA1, RA2 and RA3 are hydrogen and X is CHRA. 6. A process for preparing a compound intermediate of pharmaceutical substituted polycyclic pyridone derivatives of formula (Villa) or formula (IXa): {Villa} or either (IXa} characterized in that it comprises the process according to any of claims 1 to 5. 2642577 111 of 117 7. An intermediate compound of pharmaceutical substituted polycyclic pyridone derivatives, of formula (III), or one of its salts, used in the process a) of claim 2: r1 or RA1 rA3 where R1 is hydrogen or a hydroxyl group protecting group; RA1 is hydrogen or RA; RA2 is hydrogen or RA; RA3 is hydrogen or RA; X is O, CH2 or CHRA; RA is an optionally protected carboxy group and the carbon atom to which RA is bonded is optically active; provided that one of RA1, RA2 and RA3 is RA, the other two are hydrogen and X is O or CH2 or RA1, RA2 and RA3 are hydrogen and X is CHRA; R7 is NH2 or NHR2; R2 is a protecting group for an amino group; R8 is -CHO or —CH(OR4) (OR4) ; R4 each is independently hydrogen or an acid-deprotectable protecting group or two R4s can be taken together to form an anyl . 8. An intermediate compound of pharmaceutical substituted polycyclic pyridone derivatives, of formula (VI), or one of its salts, used in the process b) of claim 2: 2642577 112 of 117 JC.r3 Y o ^n'nh (VI) >A3 I p5 RA1ra2 characterized in that R1 is hydrogen or a hydroxyl group protecting group; RA1 is hydrogen or RA; RA2 is hydrogen or RA; RA3 is hydrogen or RA; X is O, CH2 or CHRA; RA is an optionally protected carboxy and the carbon atom to which RA is bonded is optically active; provided that one of RA1, RA2 and RA3 is RA, the other two are hydrogen and X is O or CH2 or RA1, RA2 and RA3s are hydrogen and X is CHRA; R3 is a protecting group for a carboxyl group; R5 is hydrogen or a protecting group for an amino group. 9. An intermediate compound of pharmaceutical substituted polycyclic pyridone derivatives, of formula (IV), or one of its salts, used in the process of claim 1: o1 RA1 characterized in that R1 is hydrogen or a protecting group for a hydroxyl group; RA1 is hydrogen or RA; RA2 is hydrogen or RA; RA3 is hydrogen or RA; X is O, CH2 or CHRA; RA is an optionally protected carboxyl group; and the carbon atom to which RA is bonded 2642577 113 of 117 is optically active; provided that one of RA1, RA2 and RA3 is RA, the other two are hydrogen and X is 0 or CH2 or RA1, RA2 and RA3 are hydrogen and X is CHRA. Buenos Aires, February 2024 pp SHIONOGI & CO., LTD. O D.' HICHÉ-LÉ! 2642577 114 of 117 SUMMARY The present provides industrially appropriate processes for preparing intermediates in the production of substituted polycyclic pyridone derivatives that have a closure-dependent endonuclease inhibitory activity. An optically active tricyclic pyridone derivative of formula (VII) is obtained in high yield with high enantioselectivity by intramolecular cyclization of a compound of formula (III) or (VI) with controlled stereochemistry to obtain a compound of formula (IV) having a removable functional group on an asymmetric carbon and then removal of the functional group. 2642577 115 of 117 [Fig. i] Yo 2642577 116 of 117 RICARDO DANIEL RICHELET - 20042804046 Digitally signed by PORTALTRAMITES - INPI Date: 2024.02.26 09:09:01 -03:00 Reason: Digitally Signed by the INPI Location: Buenos Aires, Argentina 2642577 117 of 117
Claims
1. A process for preparing a substituted polycyclic pyridone derivative of formula (VII), or one of its salts: (FORMULA VII) wherein R1 is benzyl or n-hexyl; X is O; characterized by removing -RA from a compound of formula (IV): (FORMULA IV) wherein R1 is benzyl or n-hexyl; RA1 is RA; RA2 is hydrogen; RA3 is hydrogen; X is O; RA is a carboxy group or an active ester formed between said carboxy group and N-hydroxyphthalimide or 3-hydroxy-4-methylthiazol-2(3H)-thione; and the carbon atom to which RA is bonded is optically active. Six claims follow.