DESC:FIELD OF THE INVENTION
The present invention relates to novel pyridone derivatives and processes for their preparation.

BACKGROUND OF THE INVENTION
Polycyclic carbamoylpyridone derivatives having HIV integrase inhibitory activity are described in WO 2006/116764 assigned to Shionogi & Co. Ltd.

Dolutegravir and cabotegravir are polycyclic carbamoylpyridone derivatives. Dolutegravir is used against HIV infections as a single drug or fixed-dose combination with abacavir sulphate and lamivudine under the trade names Tivicay® and Triumeq® respectively. These commercial products contain dolutegravir as its sodium salt. It was first approved by the US FDA on Aug 12, 2013. It is chemically known as (4R,12aS)-9-{[(2,4-difluorophenyl)methyl]carbamoyl}-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazin-7-olate having chemical structure of formula I.

Cabotegravir is in phase II clinical trials and is chemically known as (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo-[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide having following chemical structure of formula II.

I II

Various pyridone derivatives are described in US 2013/0172551 and US 2014/0011995 as useful intermediates for the synthesis of carbamoylpyridone derivatives.
The present invention provides the novel pyridone derivatives and processes for their preparation. These novel pyridone derivatives are important intermediates for the synthesis of carbamoylpyridone derivatives such as dolutegravir and cabotegravir.

SUMMARY OF THE INVENTION
The present invention provides a compound of formula V or salt thereof

V
wherein,
R1 is hydrogen, halogen, lower alkyloxy optionally substituted by substituent E, carbocyclyl lower alkyloxy optionally substituted by substituent E, heterocyclyl lower alkyloxy optionally substituted by substituent E, or --OSi(R')3,
R' is each independently lower alkyl optionally substituted by substituent E, carbocyclyl optionally substituted by substituent E, heterocyclyl optionally substituted by substituent E, carbocyclyl lower alkyl optionally substituted by substituent E, or heterocyclyl lower alkyl optionally substituted by substituent E,
R2 is hydrogen, lower alkyl optionally substituted by substituent E, carbocyclyl lower alkyl optionally
substituted by substituent E, or heterocyclyl lower alkyl optionally substituted by substituent E,
Substituent E: halogen, cyano, hydroxyl, carboxy, formyl, amino, oxo, nitro, lower alkyl, halogen, lower alkyl, lower alkyloxy, carbocyclyl optionally substituted by substituent F, heterocyclyl optionally substituted by substituent F, carbocyclyl lower alkyloxy optionally substituted by substituent F, heterocyclyl lower alkyloxy optionally substituted by substituent F, carbocyclyl lower alkylthio optionally substituted by substituent F, heterocyclyl lower alkylthio substituted by substituent F, carbocyclyl lower alkylamino optionally substituted by substituent F, heterocyclyl lower alkylamino optionally substituted by substituent F, carbocyclyloxy optionally substituted by substituent F, heterocyclyloxy optionally substituted by substituent F, carbocyclylcarbonyl optionally substituted by substituent F, heterocyclylcarbonyl optionally substituted by substituent F, carbocyclylaminocarbonyl optionally substituted by substituent F, heterocyclylaminocarbonyl optionally substituted by substituent F, halogen, lower alkyloxy, lower alkyloxy lower alkyl, lower alkyloxy lower alkyloxy, lower alkylcarbonyl, lower alkyloxycarbonyl, lower alkyloxy carbonylamino, lower alkylamino, lower alkylcarbonylamino, lower alkylaminocarbonyl, lower alkylsulfonyl, and lower alkylsulformylamino;
Substituent F: halogen, hydroxyl, carboxy, amino, oxo, nitro, lower alkyl, halogen lower alkyl, lower alkyloxy, and amino protecting group.

The present invention further provides a compound of formula VII or salt thereof

VII
wherein,
R1 and R2 are as defined above,
R5 is lower alkyl optionally substituted by substituent E, or lower alkenyl optionally substituted by substituent E.

The present invention provides a process for the preparation of compound of formula V or salt thereof

V
wherein,
R1 and R2 are as defined above,
comprising a step of
(Step A)
reacting a compound of formula III

III
wherein,
R1 and R2 are as defined above,
R3 is hydrogen, lower alkyloxy optionally substituted by substituent E, -N(R'')2, or -OR'',
R'' is each independently lower alkyl optionally substituted by substituent E, or two R'' in -N(R'')2 together with the adjacent nitrogen atom may form a heterocycle,
and
a wavy line means E form and/or Z form or a mixture thereof;
with a compound of formula IV

IV
wherein,
R4 is lower alkyl optionally substituted by substituent E, carbocyclyl lower alkyl optionally substituted by substituent E, or heterocyclyl lower alkyl optionally substituted by substituent E.

The present invention also provides a process for the preparation of compound of formula VII or salt thereof

VII
wherein,
R1, R2 and R5 are as defined above,
comprising a step of
(Step B)
reacting a compound of formula V or salt thereof

V
with a compound of formula VI

VI
wherein,
R5 is as defined above.
The present invention also provides a process for the preparation of compound of formula VII or salt thereof

VII
wherein,
R1, R2 and R5 are as defined above,
comprising steps of
(Step A)
reacting a compound of formula III

III
wherein,
R1, R2 and R3 are as defined above,
with a compound of formula IV

IV
wherein,
R4 is as defined above,
to obtain a compound of formula V or salt thereof

V
R1 and R2 are as defined above,
and
(Step B)
reacting a compound of formula V or salt thereof

V
wherein,
R1 and R2 are as defined above,
with a compound of formula VI

VI
wherein,
R5 are as defined above.

The present invention further relates to the use of compounds of formula V and VII for the synthesis of carbamoylpyridone derivatives such as dolutegravir and cabotegravir.

DETAILED DESCRIPTION OF THE INVENTION
Hereinafter, the terms used in the present specification are described.

The term "halogen" encompasses fluorine, chlorine, bromine, and iodine atoms.

The term "lower alkyl" encompasses linear or branched alkyl having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, further preferably 1 to 4 carbon atoms, most preferably 1 or 2 carbon atoms. Examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl, and n-decyl. Examples of preferred embodiments of "lower alkyl" include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and n-pentyl. Examples of more preferred embodiments thereof include methyl, ethyl, n-propyl, isopropyl, and tert-butyl.

The term "lower alkenyl" encompasses linear or branched alkenyl having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, further preferably 2 to 4 carbon atoms and having one or more double bonds at an arbitrary position. Specifically, the "lower alkenyl" encompasses vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, and the like. Examples of preferred embodiments of "lower alkenyl" include vinyl, allyl, propenyl, isopropenyl, and butenyl. Examples of particularly preferred embodiments thereof include allyl.

The lower alkyl moieties of "lower alkyloxy", "lower alkylcarbonyl", "lower alkyloxycarbonyl", "carbocyclyl lower alkyl", "heterocyclyl lower alkyl", "halogeno lower alkyl", "carbocyclyl lower alkyloxy", "heterocyclyl lower alkyloxy", "halogeno lower alkyloxy", "lower alkyloxy lower alkyl", "lower alkyloxy lower alkyloxy", "lower alkylamino", "lower alkylcarbonylamino", "lower alkylaminocarbonyl", "lower alkylsulfonyl", "lower alkylsulfonylamino", "carbocyclyl lower alkylthio", "heterocyclyl lower alkylthio", "carbocyclyl lower alkylamino", and "heterocyclyl lower alkylamino" are also the same as the "lower alkyl" described above.

The halogen moieties of "halogeno lower alkyl" and "halogeno lower alkyloxy" are also the same as the "halogen" described above. In this context, the "lower alkyl" and the "lower alkyloxy" may be substituted by one halogen atom or more identical or different halogen atoms at their respective arbitrary positions on the alkyl groups.

The term "carbocyclyl" means carbocyclyl having 3 to 20 carbon atoms, preferably 3 to 16 carbon atoms, more preferably 4 to 12 carbon atoms and encompasses cycloalkyl, cycloalkenyl, aryl, non-aromatic condensed carbocyclyl, and the like.

The "cycloalkyl" means carbocyclyl having 3 to 16 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 4 to 8 carbon atoms and encompasses, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl.

The "cycloalkenyl" encompasses a group having one or more double bonds at an arbitrary position in the ring of the cycloalkyl. Examples thereof include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptynyl, cyclooctynyl, and cyclohexadienyl.

The "aryl" encompasses phenyl, naphthyl, anthryl, phenanthryl, and the like. Particularly, phenyl is preferred.

The "non-aromatic condensed carbocyclyl" encompasses a group in which two or more cyclic groups selected from the "cycloalkyl", "cycloalkenyl", and "aryl" described above are condensed. Examples thereof include indanyl, indenyl, tetrahydronaphthyl, fluorenyl, and adamantyl.

Examples of preferred embodiments of "carbocyclyl" include cycloalkyl, aryl, and non-aromatic condensed carbocyclyl. Specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and phenyl.

The carbocyclyl moieties of "carbocyclyl lower alkyl", "carbocyclyl lower alkyloxy", "carbocyclyl lower alkylthio", "carbocyclyl lower alkylamino", "carbocyclyloxy", "carbocyclylcarbonyl", and "carbocyclylaminocarbonyl" are also the same as the `carbocyclyl` described above. In this context, the "carbocyclyl lower alkyl" in particularly preferred embodiments is benzyl.

Examples of preferred embodiments of "carbocyclyl lower alkyloxy" include benzyloxy.

Examples of preferred embodiments of "carbocyclyl lower alkylthio" include benzylthio.

Examples of preferred embodiments of "carbocyclyl lower alkylamino" include benzylamino.

Examples of preferred embodiments of "carbocyclyloxy" include phenyloxy.

Examples of preferred embodiments of "carbocyclylcarbonyl" include phenylcarbonyl.

Examples of preferred embodiments of "carbocyclylaminocarbonyl" include phenylaminocarbonyl.

The term "heterocyclyl" encompasses heterocyclyl having, in the ring, one or more identical or different heteroatoms arbitrarily selected from O, S, and N, such as heteroaryl, non-aromatic heterocyclyl, bicyclic condensed heterocyclyl, and tricyclic condensed heterocyclyl.

Examples of the "heteroaryl" include 5- to 6-membered aromatic cyclyl such as pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, and thiadiazolyl.

Examples of the "non-aromatic heterocyclyl" include dioxanyl, thiiranyl, oxiranyl, oxetanyl, oxathiolanyl, azetidinyl, thianyl, thiazolidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, dihydropyridyl, tetrahydropyridyl, tetrahydrofuryl, tetrahydropyranyl, dihydrothiazolyl, tetrahydrothiazolyl, tetrahydroisothiazolyl, dihydrooxazinyl, hexahydroazepinyl, tetrahydrodiazepinyl, tetrahydropyridazinyl, hexahydropyrimidinyl, and dioxolanyl.

Examples of the "bicyclic condensed heterocyclyl" include indolyl, isoindolyl, indazolyl, indolizinyl, indolinyl, isoindolinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzopyranyl, benzimidazolyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, thienopyridyl, thienopyrrolyl, thienopyrazolyl, thienopyrazinyl, furopyrrolyl, thienothienyl, imidazopyridyl, pyrazolopyridyl, thiazolopyridyl, pyrazolopyrimidinyl, pyrazolotriazinyl, pyridazolopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, quinazolinyl, quinolyl, isoquinolyl, naphthyridinyl, dihydrothiazolopyrimidinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, dihydrobenzofuryl, dihydrobenzoxazinyl, dihydrobenzimidazolyl, tetrahydrobenzothienyl, tetrahydrobenzofuryl, benzodioxolyl, benzodioxonyl, chromanyl, chromenyl, octahydrochromenyl, dihydrobenzodioxynyl, dihydrobenzooxedinyl, dihydrobenzodioxepinyl, and dihydrothienodioxynyl.

Examples of the "tricyclic condensed heterocyclyl" include carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, dibenzofuryl, imidazoquinolyl, and tetrahydrocarbazolyl.

Examples of preferred embodiments of "heterocyclyl" include 5- to 6-membered heteroaryl or non-aromatic heterocyclyl, and tricyclic condensed heterocyclyl.

The heterocyclyl moieties of "heterocyclyl lower alkyl", "heterocyclyl lower alkyloxy", "heterocyclyl lower alkylthio", "heterocyclyl lower alkylamino", "heterocyclyloxy", "heterocyclylcarbonyl", and "heterocyclylaminocarbonyl" are also the same as the "heterocyclyl" described above. In this context, the "heterocyclyl lower alkyl" in particularly preferred embodiments is pyridylmethyl.

Examples of preferred embodiments of "heterocyclyl lower alkyloxy" include pyridylmethyloxy.

Examples of preferred embodiments of "heterocyclyl lower alkylthio" include pyridylmethylthio.

Examples of preferred embodiments of "heterocyclyl lower alkylamino" include pyridylmethylamino.

Examples of preferred embodiments of "heterocyclyloxy" include pyridyloxy.

Examples of preferred embodiments of "heterocyclylcarbonyl" include pyridylcarbonyl.

Examples of preferred embodiments of "heterocyclylaminocarbonyl" include pyridylaminocarbonyl.

The term "lower alkyl optionally substituted by substituent E" means that "lower alkyl" is unsubstituted or is bonded to one or more chemically acceptable substituents selected from substituent E. When the lower alkyl is bonded to a plurality of substituents, these substituents may be the same as or different from each other. Examples thereof include methyl, fluoromethyl, trifluoromethyl, chlorodifluoromethyl, and

The term "carbocyclyl optionally substituted by substituent E" means that "carbocyclyl" is unsubstituted or is bonded to one or more chemically acceptable substituents selected from substituent E. When the carbocyclyl is bonded to a plurality of substituents, these substituents may be the same as or different from each other. The "carbocyclyl optionally substituted by substituent E" encompasses, for example, fluorophenyl, difluorophenyl, and methoxyfluorophenyl.

The term "carbocyclyl lower alkyl optionally substituted by substituent E" means that "carbocyclyl" and/or "lower alkyl" is unsubstituted or is bonded to one or more chemically acceptable substituents selected from substituent E. When the carbocyclyl and/or the lower alkyl is bonded to a plurality of substituents, these substituents may be the same as or different from each other. The "carbocyclyl lower alkyl optionally substituted by substituent E" encompasses, for example, 4-fluorobenzyl, 2,4-difluorobenzyl, 4-methoxy-2-fluorobenzyl, and 4-methoxyphenyldifluoromethyl.

The terms "lower alkyloxy optionally substituted by substituent E", "carbocyclyl lower alkyloxy optionally substituted by substituent E", "heterocyclyl lower alkyloxy optionally substituted by substituent E", and "lower alkenyl optionally substituted by substituent E" are also defined similarly.

The term "carbocyclyl optionally substituted by substituent F" means that `carbocyclyl` is unsubstituted or is bonded to one or more chemically acceptable substituents selected from substituent F. When the carbocyclyl is bonded to a plurality of substituents, these substituents may be the same as or different from each other. The "carbocyclyl optionally substituted by substituent F" encompasses, for example, fluorophenyl, difluorophenyl, and methoxyfluorophenyl.

The term "carbocyclyl lower alkyloxy optionally substituted by substituent F" means that the `carbocyclyl` moiety is unsubstituted or is bonded to one or more chemically acceptable substituents selected from substituent F. When the carbocyclyl moiety is bonded to a plurality of substituents, these substituents may be the same as or different from each other. The "carbocyclyl lower alkyloxy optionally substituted by substituent F" encompasses, for example, fluorobenzyloxy, difluorobenzyloxy, and methoxyfluorobenzyloxy.

The terms "heterocyclyl optionally substituted by substituent F", "heterocyclyl lower alkyloxy optionally substituted by substituent F", "carbocyclyl lower alkylthio optionally substituted by substituent F", "heterocyclyl lower alkylthio optionally substituted by substituent F", "carbocyclyl lower alkylamino optionally substituted by substituent F", "heterocyclyl lower alkylamino optionally substituted by substituent F", "carbocyclyloxy optionally substituted by substituent F", "heterocyclyloxy optionally substituted by substituent F", "carbocyclylcarbonyl optionally substituted by substituent F", "heterocyclylcarbonyl optionally substituted by substituent F", "carbocyclylaminocarbonyl optionally substituted by substituent F", and "heterocyclylaminocarbonyl optionally substituted by substituent F" are also defined similarly.

The phrase “two R'' in -N(R'')2 together with the adjacent nitrogen atom may form a heterocycle” encompasses, for example, formulas shown below:

The "amino protective group" can be any general protective group for the amino group and exemplified by amino protective groups described in, for example, Protective Groups in Organic Synthesis, Theodora W Greene (John Wiley & Sons). The "amino protective group" is preferably a tert-butyloxycarbonyl or benzyloxycarbonyl group.

The "leaving group" refers to a substituent that is eliminated through nucleophilic reaction. Examples thereof include halogen, -O-SO2-CH3, -O-SO2-CF3, -O-SO2-Ph, and -O-SO2-Ph-CH3. The "leaving group" is preferably halogen.

Examples of the salt include basic salts or acidic salts.

Examples of the basic salts include: alkali metal salts such as sodium salt, potassium salt, and lithium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt; aliphatic amine salts such as trimethylamine salt, triethylamine salt, dicyclohexylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, procaine salt, meglumine salt, diethanolamine salt, and ethylenediamine salt; aralkylamine salts such as N,N-dibenzylethylenediamine and benethamine salt; heterocyclic aromatic amine salts such as pyridine salt, picoline salt, quinoline salt, and isoquinoline salt; quaternary ammonium salts such as tetramethylammonium salt, tetraethylammonium salt, benzyltrimethylammonium salt, benzyltriethylammonium salt, benzyltributylammonium salt, methyltrioctylammonium salt, and tetrabutylammonium salt; and basic amino acid salts such as arginine salt and lysine salt.

Examples of the acidic salts include: inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, bicarbonate, and perchlorate; organic acid salts such as acetate, propionate, lactate, maleate, fumarate, tartrate, malate, citrate, and ascorbate; sulfonates such as methanesulfonate, isethionate, benzenesulfonate, and p-toluenesulfonate; and acidic amino acids such as aspartate and glutamate.

The salt derived from the carboxyl or hydroxyl group is preferably a basic salt, more preferably an alkali metal salt. Particularly preferred examples of the salt include sodium salt, lithium salt, and potassium salt. The most preferred example of the salt includes sodium salt.

The salt derived from the amine site is preferably an acidic salt, more preferably an inorganic acid salt. Examples of preferable salts include hydrochloride and sulfate.

Following are the abbreviations used in the present specification.
Me – methyl
Et – ethyl
Bn – benzyl
Ph – phenyl
DMI – dimethylimidazolidinone

The production method of the present invention as described below.

Step A
This step is the step of reacting compound of formula III with compound of formula IV, if desired in the presence of base, to obtain a compound of formula V or salt thereof, as shown below

wherein each symbol is as defined above.

The compound of formula III may be a commercially available reagent or can be obtained by a method known in the art.

Examples of the "lower alkyloxy optionally substituted by substituent E" represented by R1 include methoxy, ethoxy, isopropoxy, trichloromethoxy, and trifluoromethoxy. Methoxy is preferred.

Examples of the "carbocyclyl lower alkyloxy optionally substituted by substituent E" represented by R1 include benzyloxy, phenethyloxy, 2,4-trifluorobenzyloxy, and 4-methoxybenzyloxy. Benzyloxy is preferred.

Examples of the "heterocyclyl lower alkyloxy optionally substituted by substituent E" represented by R1 include pyridylmethyloxy.

R1 in preferred embodiments is hydrogen, chloro, bromo, methoxy, or benzyloxy.

Examples of the "lower alkyl optionally substituted by substituent E" represented by R2 include methyl, ethyl, n-propyl, isopropyl, and tert-butyl.

Examples of the "carbocyclyl lower alkyl optionally substituted by substituent E" represented by R2 include benzyl and 4-methoxybenzyl.

Examples of the "heterocyclyl lower alkyl optionally substituted by substituent E" represented by R2 include pyridylmethyl.

R2 in preferred embodiments is methyl, ethyl, n-propyl, isopropyl, tert-butyl, benzyl, 4-methoxybenzyl, or the like.

Examples of the "lower alkyloxy optionally substituted by substituent E" represented by R3 include methoxy and ethoxy.

Examples of the "lower alkyl optionally substituted by substituent E" represented by R'' include methyl, ethyl, and trifluoromethyl.

R3 in preferred embodiments is -N(CH3)2, -OCH3, or pyrrolidinyl.

The compound of formula IV may be a commercially available reagent or can be obtained by a method known in the art.

Examples of the "lower alkyl optionally substituted by substituent E" represented by R4 include methyl, ethyl, n-propyl, isopropyl, and tert-butyl.

Examples of the "carbocyclyl lower alkyl optionally substituted by substituent E" represented by R4 include benzyl and 4-methoxybenzyl.

Examples of the "heterocyclyl lower alkyl optionally substituted by substituent E" represented by R4 include pyridylmethyl.

Examples of preferred embodiments of R4 include methyl, ethyl, n-propyl, isopropyl, tert-butyl, benzyl, and 4-methoxybenzyl. Particularly, methyl or ethyl is preferred.

Examples of the reaction solvent include acetonitrile, tetrahydrofuran, dioxane, toluene, xylene, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylimidazolidinone, N-methylmorpholine, N-methylpyrrolidinone, and mixed solvents thereof.

Examples of the base include n-butyllithium, tert-butyllithium, sodium tert-butoxide, potassium-tert-butoxide, sodium tert-pentoxide, sodium methoxide, sodium ethoxide, sodium hydride, lithium diisopropylamide, and lithium bis(trimethylsilyl)amide.

The amount of the base used is approximately 1.0 to 5.0 molar equivalents with respect to compound of formula III.

The amount of the compound of formula IV used is approximately 1.5 to 5.0 molar equivalents with respect to compound of formula III, or the compound of formula IV may be used as a solvent.

The reaction temperature is usually -80 °C to reflux temperature, preferably -20 °C to 50 °C. The reaction time is usually 30 minutes to 50 hours, preferably 10 to 20 hours.

The compound of formula V may be isolated by a general purification method (extraction, distillation, column chromatography, crystallization, etc.) or can also be used in the next reaction without being isolated.

Step B
This step is the step of reacting compound of formula V with compound of formula VI to obtain compound of formula VII or salt thereof, as shown below

wherein each symbol is as defined above.

Examples and preferred embodiments of R1 and R2 in the formula V are the same as those described above in Step A.

The compound of formula VI can be obtained as a commercially available reagent or by a method known in the art.
Examples of the "lower alkyl optionally substituted by substituent E" represented by R5 include HC(=O)-CH2-, CH(-OH)2-CH2-, CH3O-CH(-OH)-CH2-, dimethoxyethyl, diethoxyethyl, HO-CH2-CH(-OH)-CH2-,

Examples of the "lower alkenyl optionally substituted by substituent E" represented by R5 include CH2=CH-CH2-.

Examples of the reaction solvent include acetonitrile, tetrahydrofuran, dioxane, toluene, xylene, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylimidazolidinone, N-methylmorpholine, N-methylpyrrolidinone, methanol, ethanol, isopropanol, and mixed solvents thereof.

The amount of the compound of formula VI used is approximately 1.0 to 2.0 molar equivalents with respect to compound of formula V.

The reaction temperature is usually -5 °C to reflux temperature, preferably 0°C to 70 °C.

The reaction time is usually 30 minutes to 50 hours, preferably 2 to 12 hours.

When R5 in the formed compound of formula VII is not an aldehyde group or a group having an equivalent thereof, such as HC(=O)-CH2-, CH(-OH)2-CH2- or CH3O-CH(-OH)-CH2- , this moiety can be converted to HC(=O)-CH2-, CH(-OH)2-CH2- or CH3O-CH(-OH)-CH2-, which is an aldehyde group or a group having an equivalent thereof, by deprotection methods for protective groups in aldehyde groups described in Protective Groups in Organic Synthesis, Theodora W Greene (John Wiley & Sons) or a method known in the art as described in WO 2006/116764 and US 2014/0011995.

When R5 in compound of formula VII is, for example, dimethoxyethyl, this moiety can be converted to HC(=O)-CH2- by the addition of an acid to the solution containing compound of formula VII. The acid is not particularly limited and is exemplified by hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, maleic acid, and oxalic acid. The amount of the acid used is 2.0 to 10.0 molar equivalents with respect to compound (X4). Acetic acid or formic acid may be used as a solvent and may be used as a mixture with any of the acids described above.

The reaction temperature is usually approximately 0 °C to 80 °C, preferably 10 °C to 40 °C.

The reaction time is usually 30 minutes to 50 hours, preferably 2 to 12 hours.

When the amino group is protected with an amino protective group, a compound with a deprotected amino group can also be obtained by deprotection methods for protective groups in amino groups described in Protective Groups in Organic Synthesis, Theodora W Greene (John Wiley & Sons) or a method known in the art. The order of deprotection reactions can be changed appropriately.

When R5 is an amino protective group, the amino protective group in compound of formula VII can be subjected to deprotection reaction, followed by reaction with compound of formula IX in the subsequent step to obtain the compound of formula VII of interest.

wherein L is leaving group.
Examples of the "leaving group" represented by L include halogen, -O-SO2-CH3, -O-SO2-CF3, -O-SO2-Ph, and -O-SO2-Ph-CH3, preferably halogen.

The compound of formula VII may be isolated by a general purification method (extraction, distillation, column chromatography, crystallization, etc.).

The present invention is described in the following examples, however it should be noted that the scope of present invention is not limited by the examples.

Compound of formula IIIa was prepared as per the method described in US 2014/0011995. Methyl glycolate (IVa) and aminoacetaldehyde dimethyl acetal (VIa) are commercially available.

Example 1

Sodium tert-butoxide (4.95 g, 51.5 mmol) and DMI (25 ml) were added in the flask under nitrogen atmosphere followed by a solution of methyl glycolate (IVa) (4.63 g, 51.5 mmol) in DMI (10 ml). A solution of compound of formula IIIa (5.0 g, 17.1 mmol) in DMI (10 ml) was added drop wise at 0-5 °C. After stirring for 20 hours at 20-25 °C, 2N hydrochloric acid (100 ml) was added. After extraction with ethyl acetate (2 X 50 ml), the combined extracts were washed with water and brine. The solvent was distilled off and the obtained residue was purified by silica gel column chromatography (n-hexane-ethyl acetate 9:1) to obtain compound of formula Va as oil. (Yield=3.2 g; 62.5 %).
1H-NMR (CDCl3) d: 1.66 (1H, brs, D2O exchangeable), 1.87 (3H, t), 4.19 (2H, q), 4.65 (2H, s), 4.72 (2H, s), 7.33 (5H, m), 8.76 (1H, s).
Example 2

Aminoacetaldehyde dimethyl acetal (VIa) (8.29 g, 78.8 mmol) was added to a solution of compound of formula Va (12 g, 39.44 mmol) in ethanol (120 ml) at 0-5° C. The reaction mixture was stirred at 10-15 °C for 2 hours and solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane-ethyl acetate: 8:2) to obtain compound of formula VIIa (Yield=10 g; 81.2 %).
1H-NMR (CDCl3) d: 1.28 (3H, t), 3.45 (8H, m), 4.16 (2H, q), 4.42 (1H, m), 4.66 (4H, s), 7.35 (5H, m), 8.21 (1H, d).
,CLAIMS:1. A compound of formula V

wherein,
R1 is hydrogen, halogen, lower alkyloxy optionally substituted by substituent E, carbocyclyl lower alkyloxy optionally substituted by substituent E, heterocyclyl lower alkyloxy optionally substituted by substituent E, or --OSi(R')3,
R' is each independently lower alkyl optionally substituted by substituent E, carbocyclyl optionally substituted by substituent E, heterocyclyl optionally substituted by substituent E, carbocyclyl lower alkyl optionally substituted by substituent E, or heterocyclyl lower alkyl optionally substituted by substituent E,
R2 is hydrogen, lower alkyl optionally substituted by substituent E, carbocyclyl lower alkyl optionally
substituted by substituent E, or heterocyclyl lower alkyl optionally substituted by substituent E,
Substituent E: halogen, cyano, hydroxyl, carboxy, formyl, amino, oxo, nitro, lower alkyl, halogen, lower alkyl, lower alkyloxy, carbocyclyl optionally substituted by substituent F, heterocyclyl optionally substituted by substituent F, carbocyclyl lower alkyloxy optionally substituted by substituent F, heterocyclyl lower alkyloxy optionally substituted by substituent F, carbocyclyl lower alkylthio optionally substituted by substituent F, heterocyclyl lower alkylthio substituted by substituent F, carbocyclyl lower alkylamino optionally substituted by substituent F, heterocyclyl lower alkylamino optionally substituted by substituent F, carbocyclyloxy optionally substituted by substituent F, heterocyclyloxy optionally substituted by substituent F, carbocyclylcarbonyl optionally substituted by substituent F, heterocyclylcarbonyl optionally substituted by substituent F, carbocyclylaminocarbonyl optionally substituted by substituent F, heterocyclylaminocarbonyl optionally substituted by substituent F, halogen, lower alkyloxy, lower alkyloxy lower alkyl, lower alkyloxy lower alkyloxy, lower alkylcarbonyl, lower alkyloxycarbonyl, lower alkyloxy carbonylamino, lower alkylamino, lower alkylcarbonylamino, lower alkylaminocarbonyl, lower alkylsulfonyl, and lower alkylsulformylamino;
Substituent F: halogen, hydroxyl, carboxy, amino, oxo, nitro, lower alkyl, halogen lower alkyl, lower alkyloxy, and amino protecting group.

2. A compound of formula VII

wherein,
R1 and R2 are as defined in claim 1,
R5 is lower alkyl optionally substituted by substituent E, or lower alkenyl optionally substituted by substituent E.
3. A compound of formula

4. A compound of formula

5. A process for the preparation of compound of formula V

wherein,
R1 and R2 are as defined in claim 1,
comprising a step of
reacting a compound of formula III

wherein,
R1 and R2 are as defined in claim 1,
R3 is hydrogen, lower alkyloxy optionally substituted by substituent E, -N(R'')2, or -OR'',
R'' is each independently lower alkyl optionally substituted by substituent E, or two R'' in -N(R'')2 together with the adjacent nitrogen atom may form a heterocycle,
and
a wavy line means E form and/or Z form or a mixture thereof;
with a compound of formula IV

wherein,
R4 is lower alkyl optionally substituted by substituent E, carbocyclyl lower alkyl optionally substituted by substituent E, or heterocyclyl lower alkyl optionally substituted by substituent E.

6. A process for the preparation of compound of formula VII

wherein,
R1, R2 and R5 are as defined in claim 2,
comprising a step of
reacting a compound of formula V

with a compound of formula VI

wherein,
R5 is as defined in claim 2.

7. A process for the preparation of compound of formula VII

wherein,
R1, R2 and R5 are as defined in claim 2,
comprising steps of
reacting a compound of formula III

wherein,
R1 and R2 are as defined in claim 2,
R3 as defined in claim 5,
with a compound of formula IV

wherein,
R4 is as defined in claim 5,
to obtain a compound of formula V

R1 and R2 are as defined in claim 2,
and reacting a compound of formula V

wherein,
R1 and R2 are as defined in claim 2,
with a compound of formula VI

wherein,
R5 are as defined in claim 2.