HK40019965A - Method for preparing oxaspirocycle derivative, and intermediate thereof - Google Patents

Description

Preparation method and intermediate of oxaspiro derivative

The present application claims priority from chinese patent application CN201710896555.2 filed 2017, 9, 28. The present application refers to the above-mentioned chinese patent application in its entirety.

Technical Field

The invention relates to a preparation method of an oxaspiro derivative and an intermediate thereof.

Background

Postoperative pain is the most common acute pain, and the commonly used drugs are opioids, such as fentanyl, morphine, pethidine, oxycodone, etc., and the pharmacological activity of analgesia is achieved by activating G α i protein receptors (μ opioid receptors, MOR) expressed on cell membranes of the central nervous system and gastrointestinal tract, and inhibiting nerve fiber hyperpolarization. Opioid receptors are important G Protein Coupled Receptors (GPCRs), are target points for combination of endogenous opioid peptides and opioid drugs, have a regulating effect on nervous system immunity and endocrine system after being activated, and are the strongest and commonly used central analgesics at present. Endogenous opioid peptides are opioid active substances naturally produced in mammals, and currently known endogenous opioid peptides are roughly classified into enkephalins, endorphins, dynorphins and neokephalins (Pharmacol Rev 2007; 59: 88-123). The central nervous system has its corresponding opioid receptors, i.e., μ (MOR), δ (DOR), κ (KOR), etc. MOR is the target of action of opioid analgesics such as endogenous enkephalin and morphine.

Opioid drugs, when used for a long period of time, produce tolerance and side effects such as respiratory depression and constipation, which have been shown to be closely related to the function of β -arrestin. In order to reduce the side effect of opioid, a drug can be designed based on negative beta-arrestin preferential ligand of MOR, so that the beta-arrestin mediated side effect is reduced, and the treatment effect is enhanced, and in the research of the oxaspiro derivative as MOR selective drug, TrevenaInc. researches find that the activity is poor when aryl benzyl is substituted (J.Med.chem.2013,56, 8019-one 8031); patent application WO2017063509a1 (published japanese 2017-04-20) discloses a single configuration MOR compound (shown in formula (III)) with the chemical name (1S,4S) -4-ethoxy-N- (2- ((R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) -1,2,3, 4-tetrahydronaphthalen-1-amine, which is prepared as follows,

the method has the problems of small batch, chiral chromatographic column separation and purification, thin-layer chromatography purification, low yield and the like in a post-treatment method, wherein the reaction yield of the preparation compound 19 is only 35 percent; the reducing agent DIBAL used in the preparation of the compound 5a is a dangerous and flammable reagent, and relatively large impurities are generated during the reaction, which is not favorable for industrial scale-up, and there is a need for an improved preparation method thereof.

Disclosure of Invention

The invention provides a method for preparing a compound shown as D1 or a salt thereof,

it includes: a step of chiral resolution of the compound shown in the formula D or the salt thereof, wherein the chiral resolution method is preferably selected from a chromatographic resolution method (such as chiral High Performance Liquid Chromatography (HPLC)) or a chemical resolution method (such as resolution by using a chiral resolving agent),

wherein R is selected from aryl OR heteroaryl, said aryl OR heteroaryl being optionally substituted with one OR more substituents selected from alkyl, haloalkyl, halogen, amino, nitro, cyano, oxo, alkenyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, OR³、C(O)R³、C(O)OR³、S(O)_mR³Or NR⁴R⁵Is substituted with one or more substituents of (1);

R³selected from hydrogen atom, alkyl, deuterated alkyl and aminoAlkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of alkyl, halogen, hydroxy, amino, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

R⁴and R⁵Each independently selected from the group consisting of hydrogen, alkyl, alkoxy, hydroxyalkyl, hydroxy, amino, carboxylate, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of alkyl, halogen, hydroxy, amino, carboxylate, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

m is 0, 1 or 2.

In some embodiments, the resolving agent used in the chiral resolution method is a basic chiral resolving agent, which can be S-phenylethylamine, quinidine, cinchonidine, or arginine.

In some embodiments, the resolving agent used in the chiral resolution process is S-phenylethylamine.

Further, the process for producing the compound represented by D1 or a salt thereof further comprises the step of producing the compound represented by formula D from the compound represented by formula E, preferably under a reaction condition selected from the group consisting of basic hydrolysis,

wherein R is defined in the compound shown in the formula D.

In some embodiments, the base used for the hydrolysis reaction is selected from sodium hydroxide, potassium hydroxide, or lithium hydroxide, among others.

In some embodiments, the compound of formula D1 is:

the preparation method comprises the following steps:

in some embodiments, a method of making a compound represented by D1, or a salt thereof, comprises:

wherein R is defined in the compound shown in the formula D.

In a preferred embodiment, a process for preparing a compound represented by D2 or a salt thereof, comprises:

the invention also provides a compound shown as a formula D1 or a salt thereof,

wherein R is as defined above.

In some embodiments, the compound of formula D1 is:

in some embodiments, the salt of the compound of formula D1 is:

wherein M is selected from S-phenylethylamine, quinidine, cinchonidine or arginine.

In a preferred embodiment, the salt of the compound of formula D1 is

The present invention also provides a process for preparing a compound of formula D1-1, comprising: comprises the step of reacting a compound shown as a formula D with a chiral resolving agent M to obtain a compound shown as a formula D1-1, wherein the chiral resolving agent is preferably an alkaline chiral resolving agent, more preferably S-phenylethylamine, quinidine, cinchonidine or arginine,

wherein R is as defined in formula D1.

Further, the method for preparing the compound shown as the formula D1-1 further comprises the following steps:

wherein, R is as defined in formula D1.

In some embodiments, R isM is S-phenylethylamine, and the preparation method comprises the following steps:

further, still include:

the present invention also provides a process for preparing a compound represented by formula B or a stereoisomer thereof, comprising: a step of preparing a compound shown as a formula B or a stereoisomer thereof by one-step or more than one-step reaction of a compound shown as a formula D or the stereoisomer thereof,

wherein R is as defined for the compound of formula D1, preferably from

In some embodiments, the compound of formula B is:

the preparation method comprises the following steps:

in the art, there are many well-known methods for obtaining a compound containing an aldehyde group by reduction of a compound containing a carboxyl group, and the compound containing an aldehyde group is generally prepared by a one-step reaction, a two-step reaction or a reaction of two or more steps, and the compound containing an aldehyde group is preferably prepared by a two-step reaction according to the present invention.

In some embodiments, a method of making a compound of formula B, or a stereoisomer thereof, comprises:

wherein R is as defined for the compound of formula D1, preferably from

Preferably, in some embodiments, the compound of formula B or a stereoisomer thereof is

The preparation method comprises the following steps:

wherein R is preferably selected from

In some embodiments, the compound of formula B or a stereoisomer thereof is

The preparation method comprises the following steps:

further, in some embodiments, a method of making a compound of formula B, or a stereoisomer thereof, comprises:

wherein R is as defined for the compound represented by formula D1.

In some embodiments, the method of making a compound of formula B or a stereoisomer thereof further comprises the aforementioned method step of making a compound of formula D1 or a salt thereof.

In other embodiments, the compound of formula B or a stereoisomer thereof is

The preparation method comprises the following steps:

wherein R is as defined for the compound represented by formula D1.

In other embodiments, the compound of formula B or a stereoisomer thereof is

The preparation method comprises the following steps:

the invention also provides a compound shown as a formula C,

wherein R is as defined for the compound of formula D1, preferably from

In some embodiments, the compound of formula C is:

wherein R is as defined for the compound of formula D1, preferably from

In some embodiments, the compound of formula C is:

the present invention also provides a process for preparing a compound of formula C, comprising:

wherein R is as defined for the compound represented by formula D1.

In some embodiments, the compound of formula C is:

the preparation method comprises the following steps:

in some embodiments, the method of preparing a compound of formula C1 further comprises the steps of the method of preparing a compound of formula D1 as described above.

In some embodiments, a method of making a compound of formula C1 comprises:

wherein R is as defined for the compound represented by formula D1.

In some embodiments, the compound of formula C is:

the preparation method comprises the following steps:

in some embodiments, the method of preparing a compound of formula C2 further comprises the steps of the method of preparing a compound of formula D-1 described above.

In some embodiments, a method of making a compound of formula C2 comprises:

the invention also provides a method for preparing the compound shown in the formula I or the salt thereof, which comprises the steps of reacting the compound shown in the formula D or the stereoisomer thereof to obtain the compound shown in the formula B or the stereoisomer thereof, reacting the compound shown in the formula B or the stereoisomer thereof with the compound shown in the formula A or the stereoisomer thereof to obtain the compound shown in the formula I,

wherein R1 is selected from a hydrogen atom or an alkyl group; r2 is selected from optionally substituted aryl OR heteroaryl groups selected from hydrogen atoms, alkyl groups, haloalkyl groups, halogen, amino groups, nitro groups, cyano groups, oxo groups, alkenyl groups, haloalkoxy groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, heteroaryl groups, -OR3, -c (o) R3, -c (o) OR3, -s (o) mR3 OR-NR 4R5, wherein said alkyl, alkoxy, alkenyl, haloalkyl, cycloalkyl, heterocyclyl groups, aryl groups and heteroaryl groups are optionally substituted with one OR more substituents selected from deuterium atoms, alkyl groups, haloalkyl groups, halogen, amino groups, nitro groups, cyano groups, hydroxy groups, alkoxy groups, haloalkoxy groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups OR heteroaryl groups; n is selected from 0, 1,2 or 3; r, R3, R4, R5 and m are defined as the compound shown in formula D1.

In some embodiments, the process for preparing a compound of formula I or a salt thereof further comprises:

wherein R is as defined for the compound represented by formula D1.

Further, the method for preparing the compound shown in the formula I or the salt thereof further comprises the following steps:

in some embodiments, the method of preparing a compound of formula I or a salt thereof further comprises the aforementioned method step of preparing a compound of formula D1 or a salt thereof.

In some embodiments, the method of making a compound of formula I or a salt thereof further comprises the aforementioned method step of making a compound of formula B or a stereoisomer thereof.

In some embodiments, the compound of formula I is

The preparation method comprises the following steps:

further, the method for preparing the compound shown in the formula II comprises the following steps:

in some embodiments, the compound of formula I is

The preparation method comprises the following steps:

in some embodiments, a method for preparing a compound of formula III comprises:

preferably, a process for preparing a compound of formula III, comprising:

first step, Synthesis of intermediate D-1

Reacting the compound shown in the formula (E) with alkali in an organic solvent, and hydrolyzing to obtain a compound shown in a formula D-1; the alkaline condition is preferably sodium hydroxide, potassium hydroxide or ammonia.

Second step, Synthesis of intermediate D2-1

Reacting the compound shown as the formula D-1 with a chiral resolving reagent in an alcohol solvent to generate a compound shown as a formula D2-1; the chiral resolving agent is preferably an alkaline chiral resolving agent, and more preferably S-phenylethylamine, quinidine, cinchonidine or arginine; the alcohol solvent is preferably methanol, ethanol or isopropanol.

Third step, synthesis of intermediate D2

Dissociating the compound shown as the formula D2-1 under the alkaline condition to obtain a compound shown as a formula D2; the alkaline condition is preferably sodium hydroxide, potassium hydroxide or ammonia.

Fourth step, Synthesis of intermediate C2

Reacting the compound shown in the formula D2 with N, O-dimethylhydroxylamine hydrochloride, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 4-dimethylaminopyridine under an alkaline condition to obtain a compound shown in a formula C2; the basic conditions are preferably N, N-diisopropylethylamine, triethylamine or diisopropylamine.

Fifth step, Synthesis of intermediate B2

Reacting the compound shown as the formula C2 with a reducing agent to obtain a compound shown as a formula B2; the reducing agent is preferably red aluminum.

Sixth step, Synthesis of Compound represented by formula (III)

Reacting the compound shown as the formula B2 with the compound shown as the formula A1 to obtain the compound shown as the formula III.

In some embodiments, the compound of formula I is

The preparation method comprises the following steps:

in some embodiments, a method for preparing a compound of formula IV comprises:

the invention also provides application of the compound shown in the formula D1 and the compound shown in the formula C or salt thereof in preparing the compound shown in the formula I,

in some embodiments, the compound of formula I is:

in some embodiments, the compound of formula I is:

the invention also provides a method for preparing pharmaceutically acceptable salts of the compounds shown in the formulas I, II, III and IV, which comprises the steps in the scheme and the step of preparing the pharmaceutically acceptable salts of the compounds shown in the formulas I, II, III and IV by reacting the compounds shown in the formulas I, II, III and IV with acid, wherein the acid is selected from organic acid or inorganic acid, preferably organic acid; the organic acid is selected from acetic acid, maleic acid, fumaric acid, tartaric acid, citric acid, methanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid, preferably fumaric acid; the inorganic acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid.

The terms: the "halogen or halogen atom" as used herein means a fluorine atom, chlorine atom, bromine atom, iodine atom or the like.

The "alkyl" as used herein refers to a straight or branched chain alkyl group containing 1 to 20 carbon atoms, including, for example, "C_1-6Alkyl group "," C_1-4Alkyl "and the like, specific examples include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylPentyl, 2-methylpentyl, 1-methylpentyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 1, 2-dimethylpropyl, and the like.

The "alkenyl group" as used herein means a straight or branched chain group having 2 to 20 carbon atoms and containing at least one double bond, and includes, for example, "C_2-6Alkenyl radical, C_2-4Alkenyl groups "and the like. Examples include, but are not limited to: vinyl, propenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, and the like.

"haloalkyl" as used herein refers to a group derived from one or more "halogen atoms" substituted for one or more hydrogen atoms of an "alkyl", said "halogen atoms" and "alkyl" being as defined above.

As used herein, "hydroxyalkyl or hydroxyalkyl" refers to a group derived from one or more "hydroxy groups" substituted for one or more hydrogen atoms of an "alkyl group" as defined above.

The term "alkoxy, haloalkoxy, alkylcarbonyl, alkoxycarbonyl, carbonylalkoxy, alkylcarbonylamino, alkylaminocarbonyl, alkylamino, dialkylamino, alkylsulfonylamino or alkylsulfonyl" as used herein refers to the alkyl group-O-, haloalkyl-O-, alkyl-C (O) -, alkyl-O-C (O) -, C (O) -alkyl-O-, alkyl-C (O) -NH-, alkyl-NH-C (O) -, alkyl-NH-, (alkyl)₂-N-, alkyl-S (O)₂-NH-or alkyl-S (O)₂-a group attached in a manner wherein "alkyl, haloalkyl" is as defined above.

The "oxo" group in the present invention means ═ O.

As used herein, "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent comprising 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably a cycloalkyl ring comprising 3 to 10 carbon atoms, and most preferably a cycloalkyl ring comprising 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl and the like, with cyclopropyl, cyclohexenyl being preferred. Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.

As used herein, "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably a 6 to 10 membered aryl group, more preferably a phenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indenyl or fluorenyl group, and most preferably a phenyl group.

"Heterocyclyl" as referred to herein means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms, wherein at least one ring atom is a heteroatom such as a nitrogen atom, an oxygen atom or a sulfur atom, and the remaining ring atoms are carbon; optionally, a ring atom (e.g., a carbon atom, a nitrogen atom, or a sulfur atom) in the cyclic structure may be oxidized. Preferably 3 to 12 ring atoms or 5 to 12 ring atoms of which 1-4 are heteroatoms, more preferably the heterocyclyl ring comprises 3 to 8 ring atoms, more preferably the heterocyclyl ring comprises 5 to 6 ring atoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, dihydrofuranyl, tetrahydrofuranyl and the like. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.

The "heteroaryl group" as referred to herein means a 5-to 14-membered aryl group having 1 to 4 heteroatoms as ring atoms, the remaining ring atoms being carbon, wherein the heteroatoms include oxygen, sulfur or nitrogen. Preferably 5 to 10-membered heteroaryl, more preferably 5 to 6-membered heteroaryl, and specific examples include, but are not limited to, furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,3, 4-oxadiazolyl, pyridyl, dihydroindolyl, 2-pyridonyl, 4-pyridonyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2, 3-triazinyl, 1,3, 5-triazinyl, 1,2,4, 5-tetrazinyl, azepinotrienyl, 1, 3-diazacycloheptyltrienyl, etc, Azacyclooctatetraenyl and the like; the heteroaryl group may also be fused to an aryl, heterocyclyl or cycloalkyl ring.

The "carbon atom, nitrogen atom or sulfur atom is oxo/oxo" in the present invention means that C O, N-O, S-O or SO is formed₂The structure of (1).

The term "alcoholic solvent" as used herein means a compound in which one or more "hydroxyl groups" are substituted for "C_1-6Radicals derived from one or more hydrogen atoms of alkyl radicals, said "hydroxy" and "C_1-6Alkyl "is as defined above, specific examples include, but are not limited to: methanol, ethanol, isopropanol, n-propanol, isoamyl alcohol or trifluoroethanol.

The term "stereoisomerism" as used herein is intended to include conformational and configurational isomerism, as well as cis-trans isomerism and optical isomerism (or enantiomers). Conformational isomerism is a stereoisomerism phenomenon in which organic molecules having a certain configuration are rotated or twisted due to carbon and carbon single bonds, so that atoms or atom groups of the molecules generate different arrangement modes in space, and the common structures include structures of alkanes and cycloalkanes, such as chair conformation and ship conformation which appear in cyclohexane structure. "optical isomers (or enantiomers)", when the compounds of the invention contain one or more asymmetric centers, are intended to be racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The compounds of the present invention have asymmetric centers that each independently produce two optical isomers, and the scope of the present invention includes all possible optical isomers and diastereomeric mixtures and pure or partially pure compounds. The compounds of the present invention, if they contain an olefinic double bond, include both cis-and trans-isomers, unless otherwise specified. The compounds of the present invention may exist in tautomeric forms having different points of attachment of hydrogen through one or more double bond shifts. For example, a ketone and its enol form are keto-enol tautomers. Each tautomer and mixtures thereof are included in the present invention. Enantiomers, diastereomers, racemates, meso, cis-trans isomers, tautomers, geometric isomers, epimers and mixtures thereof are included within the scope of the present invention.

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shifts are given in units of 10-6 (ppm). NMR was measured using a Bruker AVANCE-400 NMR spectrometer using deuterated reagents as the solvent and Tetramethylsilane (TMS) as the internal standard.

MS was determined using a FINNIGAN LCQAD (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).

The HPLC measurement uses Agilent 1200DAD high pressure liquid chromatograph and Waters 2695-2996 high pressure liquid chromatograph, and uses octadecylsilane chemically bonded silica as chromatographic column packing.

Detailed Description

The present invention will be further described with reference to the following examples, which are not intended to limit the scope of the present invention.

The preparation of 2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) acetonitrile (compound of formula (E1)) can be referred to the method in patent application WO2012129495A1 (published Japanese 2012-09-27),

EXAMPLE 1 preparation of (1S,4S) -4-ethoxy-N- (2- ((R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl) ethyl) -1,2,3, 4-tetrahydronaphthalen-1-amine

First step, Synthesis of intermediate (D-1)

The compound represented by the formula (E1) (25g), potassium hydroxide (22.4g) and ethylene glycol (150mL) were mixed and stirred at 150 ℃ for 16 hours to terminate the reaction. The reaction was cooled to room temperature, diluted with water (150mL), extracted with dichloromethane (150mL × 2), the aqueous phase adjusted to pH 6-7 with 3M hydrochloric acid, extracted with dichloromethane (200mL × 4), the organic phases combined, washed with saturated sodium chloride solution (200mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the product (26.1g, pale yellow oil) in 97.4% yield and 92% purity by HPLC.

Second step, Synthesis of intermediate (D2-1)

Dissolving the compound (28g) shown in the formula (D-1) in absolute ethyl alcohol (100mL), heating to 50 ℃, dissolving a resolving reagent S-phenethylamine (6.2g) in absolute ethyl alcohol (100mL), dripping the S-phenethylamine solution into the solution at 50 ℃, heating to reflux, and stirring for 2 hours. Naturally cooling to 10 ℃, separating out solid, filtering and washing to obtain a product (13g, solid), wherein the ee value: 96.7 percent;

and (3) recrystallization: adding 13g of solid into absolute ethyl alcohol (80mL), heating to reflux, stirring for 6 hours, naturally cooling to 10 ℃, separating out the solid, filtering, washing and drying to obtain a product (10.6g), wherein the ee value: 99.0 percent.

Third step, Synthesis of intermediate (D2)

KOH (2.18g) was dissolved in water (120mL), the compound represented by formula (D2-1) was dissolved in the solution, extracted with dichloromethane (100 mL. times.3), the pH of the aqueous phase was adjusted to 6 to 7 with 1N HCl solution, extracted with dichloromethane (150 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the product (7g) in 50% yield. ee value: 99.4 percent

MS m/z(ESI):276.71[M+H]⁺，298.68[M+Na]⁺

1H NMR(400MHz,CDCl3)δ8.50-8.51(m,1H),7.73-7.77(m,1H),7.51-7.53(d,1H),7.21-7.24(m,1H),3.73-3.84(m,2H),2.78-2.81(d,1H),2.58-2.63(m,1H),2.53-2.56(d,1H),2.39-2.43(m,1H),1.98-2.02(d,1H),1.87-1.94(m,1H),1.76-1.80(m,1H),1.61-1.65(m,1H),1.39-1.58(m,4H),1.14-1.19(m,1H),(m,1H),(m,1H).

Fourth step, Synthesis of intermediate (C2)

Adding dichloromethane (8.5kg) into a reaction bottle, adding raw materials (R) -2- (9- (pyridine-2-yl) -6-oxaspiro [4.5] decane-9-yl) acetic acid (350g), N, O-dimethylhydroxylamine hydrochloride (148.8g), EDCI (292.3g) and DMAP (15.5g) under stirring, stirring for 15-25 min, adding DIPEA (492.4g), protecting with argon, stirring at room temperature for 16-18 h, adding a saturated ammonium chloride aqueous solution (2.8kg) into a reaction liquid, stirring for 5-10 min, and separating liquid; the organic phase was washed with a saturated aqueous solution of ammonium chloride (2.8 kg. times.2), a saturated brine (2.7kg), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure, followed by addition of dichloromethane (2.5kg) and further concentration under reduced pressure to dryness to give an oil (372.03g) in 92.0% yield.

MS m/z(ESI):319.1[M+H]+，341.3[M+Na]+

1H NMR(400MHz,CDCl3)δ8.50-8.51(m,1H),7.66-7.71(m,1H),7.43-7.45(d,1H),7.15-7.18(m,1H),3.63-3.66(m,2H),3.47(s,3H),2.86-2.88(d,3H),2.62-2.65(d,1H),2.50-2.57(m,1H),2.36-2.39(d,1H),1.96-2.00(d,1H),1.80-1.86(m,1H),1.68-1.72(m,1H),1.48-1.55(m,1H),1.31-1.46(m,4H),1.03-1.07(m,1H),0.63-0.71(m,1H).

Fifth step, Synthesis of intermediate (B2)

Dissolving a compound (334.4g) shown as a formula (C2) in toluene (2.2kg) in a reaction bottle, cooling to-45 to-35 ℃, carrying out argon protection, controlling the dropping temperature to-45 to-35 ℃, dropping red aluminum (348.76g), stirring and reacting for 3-4 h at-45 to-35 ℃, then dropping 10% citric acid aqueous solution (1kg) into the reaction liquid at-45 to-35 ℃, adding concentrated hydrochloric acid solution to adjust the pH to 2-3, adding ethyl acetate (1.8kg), stirring, standing and layering, adjusting the pH of the aqueous phase to 11-13 by using 5N sodium hydroxide solution, extracting by dichloromethane (3.3kg multiplied by 2), combining dichloromethane layers, washing by using saturated sodium chloride solution (2.7kg), drying by using anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, adding dichloromethane (3.3kg), continuously concentrating under reduced pressure, obtaining light red oily matter, and directly putting the oily matter into the next reaction.

Sixth step, Synthesis of Compound represented by formula (III)

Adding the oily matter into a reaction bottle, adding dichloromethane (8.5kg) and a compound (134.56g) shown as a formula (A1) into the reaction bottle, stirring for reaction for 2-3 h, adding sodium triacetoxyborohydride (373.86g) into a reaction liquid, stirring for reaction for 16-18 h at room temperature, adding a saturated sodium carbonate solution (2.66kg), adjusting the pH to 11-13 with a 5N sodium hydroxide aqueous solution, layering, washing an organic phase with a saturated ammonium chloride aqueous solution (2.83kg), washing with a saturated sodium chloride aqueous solution (2.74kg), drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness, adding acetonitrile (120g), stirring for crystallization for 16-18 h at room temperature, filtering, drying to obtain a product (206.87g), and obtaining the yield of 68.0%.

MS m/z(ESI):435.3[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ9.74(d,1H),9.58(d,1H),8.94(d,1H),8.37(d,1H),7.94(d,1H),7.67(d,1H),7.52(d,1H),7.47(t,1H),4.46-4.49(m,1H),4.30-4.33(m,1H),3.84-3.87(m,1H),3.66-3.70(m,2H),3.53-3.56(m,2H),2.82-2.85(d,2H),2.67(s,2H),2.39-2.41(m,4H),2.30-2.33(m,4H),1.85(s,2H),1.48-1.52(m,6H),1.27(m,3H).

Example 2

First step, Synthesis of intermediate (D-1)

The compound represented by the formula (E1) (13.5 Kg; 1.0eq), potassium hydroxide (2.6 Kg; 2.0eq) and ethylene glycol (135L; 10vol) were mixed, and the reaction was stopped by stirring at 110 ℃ for 24 hours. Concentrating under reduced pressure to remove ethanol; dichloromethane (26L dissolved with stirring) was added to the residue; washed twice with saturated sodium chloride solution (5L), dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure to give the product (13kg, yellow oil) in 90% yield and 95% purity by HPLC.

Second step, Synthesis of intermediate (D2-1)

Dissolving the product (13Kg) in ethylene glycol (65L; 5vol), heating to 50 deg.C, dissolving resolving agent S-phenethylamine (5.7 Kg; 1.0eq) in ethylene glycol (1L), dropping the S-phenethylamine solution into the above solution at 50 deg.C, heating to reflux, and stirring for 3 hr. Naturally cooling to room temperature, separating out solid, filtering, washing to obtain product (6600g, solid),

and (3) recrystallization: 6600g of solid was added to ethylene glycol (3L), warmed to reflux, stirred for 6 hours, cooled to room temperature naturally, solid precipitated, filtered, washed and dried to give the product (4700g), ee: 99.0 percent.

Third step, Synthesis of intermediate (D2)

4700g of the solid was dissolved in water, followed by 1.2eq potassium hydroxide, extraction with 30L by 3 Dichloromethane (DCM), removal of the organic phase, pH adjustment of the aqueous phase to 6-7 with hydrochloric acid, 30L by 5 with DCM, combination of the organic phases, drying and concentration to provide 3200g of product, ee: 99.42%, purity: 99 percent.

Although specific embodiments of the present invention have been described above, it will be appreciated by those skilled in the art that these are merely illustrative and that various changes or modifications may be made without departing from the principles and spirit of the invention. The scope of the invention is therefore defined by the appended claims.

Claims (21)

1. A process for preparing a compound of formula D1 or a salt thereof,

   it includes: a step of carrying out chiral resolution on the compound shown in the formula D or the salt thereof, wherein the chiral resolution method is preferably selected from a chromatographic resolution method or a chemical resolution method,

   wherein R is selected from aryl OR heteroaryl, said aryl OR heteroaryl being optionally substituted with one OR more substituents selected from alkyl, haloalkyl, halogen, amino, nitro, cyano, oxo, alkenyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, OR³、C(O)R³、C(O)OR³、S(O)_mR³Or NR⁴R⁵Is substituted with one or more substituents of (1);

   R³selected from the group consisting of hydrogen, alkyl, deuterated alkyl, amino, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, whereinAlkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted with one or more substituents selected from alkyl, halogen, hydroxy, amino, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

   R⁴and R⁵Each independently selected from the group consisting of hydrogen, alkyl, alkoxy, hydroxyalkyl, hydroxy, amino, carboxylate, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of alkyl, halogen, hydroxy, amino, carboxylate, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

   m is 0, 1 or 2.
2. The process as claimed in claim 1, wherein the resolving agent used in the chemical resolution process is a basic chiral resolving agent, preferably selected from the group consisting of S-phenylethylamine, quinidine, cinchonidine and arginine.
3. The method of claim 1 or 2, further comprising: a step of preparing a compound shown as a formula D from a compound shown as a formula E, wherein the reaction condition is preferably alkaline hydrolysis,

   wherein R is as defined in claim 1.
4. The method of any one of claims 1-3, wherein the compound of formula D1 is:
5. the method of any one of claims 1-4, which is:
6. a compound of formula D1 or a salt thereof,

   wherein R is as defined in claim 1.
7. The compound of claim 6 which is
8. The compound according to claim 6, which is a salt thereof:

   wherein M is selected from S-phenylethylamine, quinidine, cinchonidine or arginine, preferably from S-phenylethylamine.
9. A process for preparing a compound of formula B or a stereoisomer thereof,

   it includes: a step of preparing a compound shown as a formula B or a stereoisomer thereof by one-step or more than one-step reaction of a compound shown as a formula D or the stereoisomer thereof,

   wherein R is as defined in claim 1, preferably from
10. The method of claim 9, which is:

    wherein R is as defined in claim 1, preferably from
11. The method of claim 9 or 10, wherein the compound of formula B is:
12. the method according to any of claims 9-11, further comprising the method steps according to any of claims 1-5.
13. A compound represented by the formula C, wherein,

    wherein R is as defined in claim 1, preferably from
14. The compound of claim 13 which is
15. A process for preparing a compound of formula I or a salt thereof, which comprises the step of reacting a compound of formula D or a stereoisomer thereof to obtain a compound of formula B or a stereoisomer thereof, reacting the compound of formula B or a stereoisomer thereof with a compound of formula A or a stereoisomer thereof to obtain a compound of formula I,

    wherein R is¹Selected from a hydrogen atom or an alkyl group; r²Selected from optionally substituted aryl OR heteroaryl groups, said substituents being selected from hydrogen atoms, alkyl groups, haloalkyl groups, halogen, amino groups, nitro groups, cyano groups, oxo groups, alkenyl groups, haloalkoxy groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, heteroaryl groups, -OR³、-C(O)R³、-C(O)OR³、-S(O)mR³or-NR⁴R⁵Wherein said alkyl, alkoxy, alkenyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more substituents selected from deuterium atoms, alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; n is selected from 0, 1,2 or 3; r, R³、R⁴、R⁵M is as defined in claim 1.
16. The method of claim 15, further comprising the method steps of any one of claims 1-5 or the method steps of any one of claims 9-12.
17. The method of claim 15 or 16, wherein the compound of formula I is
18. The method of claim 15 or 16, wherein the compound of formula I is:
19. a process for preparing a compound of formula III, comprising:
20. a process for preparing a compound of formula IV, comprising:
21. use of a compound according to any one of claims 6 to 8, 13 or 14, or a salt thereof, in the preparation of a compound of formula I,

    wherein, R, R¹、R²N is as defined in claim 15.