Preparation method of (S, S)-2, 8-diazabicyclo [4, 3, 0] nonane and intermediate of (S, S)-2, 8-diazabicyclo [4, 3, 0] nonane

Abstract

The invention relates to a preparation method of (S, S)-2, 8-diazabicyclo [4, 3, 0] nonane and an intermediate of the (S, S)-2, 8-diazabicyclo [4, 3, 0] nonane. Specifically, the invention discloses a method for preparing (S, S)-2, 8-diazabicyclo [4, 3, 0] nonane from a cheap raw material 2-chloronicotinic acid through an esterification reaction, a substitution reaction, a reduction reaction and an asymmetric hydrogenation reaction, and the method is novel in route, simple to operate, high in product yield, good in purity, safe, environment-friendly and very suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the field of raw material drug intermediate synthesis, and specifically relates to a preparation method of (S,S)-2,8-diazabicyclo[4,3,0]nonane and an intermediate thereof. Background Art

[0002] Moxifloxacin is a fourth-generation fluoroquinolone antibacterial drug with a broad antimicrobial spectrum, strong antimicrobial potency, high bioavailability, high efficacy, and low toxicity. It is widely used to treat various bacterial infections, demonstrating broad-spectrum antimicrobial activity against Gram-positive and Gram-negative bacteria, anaerobic bacteria, acid-fast bacteria, and atypical microorganisms such as mycoplasmas, chlamydia, and Legionella. Moxifloxacin was launched in Germany and the United States in 1999 and subsequently in many other countries and regions worldwide, demonstrating its wide application and high economic value.

[0003]

[0004] (S,S)-2,8-diazabicyclo[4,3,0]nonane (the compound shown in Formula I) is a key intermediate in the synthesis of moxifloxacin. Currently, there are numerous reports of industrial synthesis methods for (S,S)-2,8-diazabicyclo[4,3,0]nonane, but these primarily use 2,3-pyridinedicarboxylic acid as the starting material. For example, patent EP0350733B1 reports a process using 2,3-pyridinedicarboxylic acid as the starting material. First, acetic anhydride is dehydrated, followed by cyclization with benzylamine. This is followed by hydrogenation of the pyridine ring, dicarboximide reduction, salt resolution, and hydrogenodebenzylation to produce the product. Patent WO9415938 reports a process using 2,3-pyridinedicarboxylic acid as the starting material. Following methyl esterification, the product is reduced with lithium aluminum hydride, hydroxyl chlorinated, and p-toluenesulfonamide ring closed. Pd / C catalytic hydrogenation is then followed by resolution, and finally deprotection with hydrobromic acid to obtain the product. The method using 2,3-pyridinedicarboxylic acid as the starting material has a long synthesis route. In particular, in the dicarboximide reduction step, expensive reagents such as lithium aluminum hydride or red aluminum are required, or a large amount of reducing agents such as borane or sodium borohydride are used, resulting in high production costs and great safety risks.

[0005] Therefore, there is an urgent need in the art to develop a method for preparing (S,S)-2,8-diazabicyclo[4,3,0]nonane with cheap raw materials, simple operation, safety, environmental protection and suitability for industrial production. Summary of the Invention

[0006] The object of the present invention is to provide a method for preparing moxifloxacin side chain (S,S)-2,8-diazabicyclo[4,3,0]nonane, which has a novel process route, uses cheap and readily available raw materials, and is easy to achieve industrial large-scale production.

[0007] The first aspect of the present invention provides a method for preparing a compound of formula I, comprising the following steps:

[0008] a) in an inert solvent, in the presence of a metal catalyst, subjecting the compound of formula V to a hydrogenation reduction reaction and an intramolecular ring closure reaction, thereby preparing a compound of formula IV;

[0009] b) in an inert solvent, in the presence of a metal catalyst, subjecting the compound of formula IV to a hydrogenation reduction reaction to prepare a compound of formula III;

[0010] c) subjecting the compound of formula III to an asymmetric hydrogenation reduction reaction in an inert solvent in the presence of a chiral catalyst to prepare a compound of formula II;

[0011] d) In an inert solvent, the compound of formula II is subjected to a reduction reaction under the action of a reducing agent to prepare a compound of formula I.

[0012]

[0013] In another preferred embodiment, the method further comprises the following steps before step a):

[0014] a-1) in an alcohol solvent, the compound of formula VII undergoes a substitution reaction to prepare a compound of formula VI;

[0015] a-2) In an inert solvent, the compound of formula VI reacts with compound M to prepare a compound of formula V.

[0016]

[0017] in,

[0018] R is a C1-C6 alkyl group;

[0019] Compound M is selected from the group consisting of NaCN, KCN, Zn(CN)2, CuCN, Cu(CN)2, or a combination thereof.

[0020] In another preferred embodiment, the compound M is CuCN.

[0021] In another preferred embodiment, the metal catalyst in step a) is selected from the group consisting of Raney nickel, palladium on carbon, palladium hydroxide on carbon, ruthenium on carbon, rhodium on carbon, platinum on carbon, platinum dioxide, or a combination thereof; preferably, Raney nickel.

[0022] In another preferred embodiment, the inert solvent in step a) is selected from the group consisting of water, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO), sulfolane, toluene, acetonitrile, alcohol solvents, ether solvents, ketone solvents, ester solvents, or combinations thereof.

[0023] In another preferred embodiment, the alcohol solvent is a C1-C8 alcohol, preferably methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, or a combination thereof.

[0024] In another preferred embodiment, the inert solvent in step a) is selected from the group consisting of water, methanol, ethanol, or a combination thereof.

[0025] In another preferred embodiment, the amount of the metal catalyst in step a) is 0.1-50 wt % of the compound of formula V, preferably 3 wt %.

[0026] In another preferred embodiment, the hydrogen pressure in step a) is 2-100 atmospheres, preferably 5-15 atmospheres.

[0027] In another preferred embodiment, the volume of the inert solvent in step a) is 1 to 20 times the volume of the compound of formula V, preferably 10 times the volume.

[0028] In another preferred embodiment, the reaction temperature of step a) is 30-180°C, preferably 50-100°C.

[0029] In another preferred embodiment, the chiral catalyst is selected from the following group: (R)-Ru(OAc)2(BINAP), (R)-Ru(OAc)2(Tol-BINAP), (R)-Ru(OAc)2(xyl-BINAP), (R)-Ru(OAc)2(H8-BINAP), (R)-Ru(OAc)2(SegPhos), [(R,R)-(Et-DuPhos)Rh(COD)]BF4, [(R,R)-(Me-DuPhos)Rh(COD)]BF4, [(R,R)-(Me-BPE)Rh(COD)]BF4, [(R)-

[0030] (PhanePhos)Rh(COD)]BF4, [(R,R)-(Ph-BPE)Rh(COD)]BF4, [(R)-(Tol-Binap)Rh(COD)]BF4, [(R)-(xyl-Binap)Rh(COD)]BF4, [(R,S)-

[0031] (JosiPhos)Rh(COD)]BF4, [(R)-(Monophos)Rh(COD)]BF4, or a combination thereof; preferably [(R,R)-(Et-DuPhos)Rh(COD)]BF4.

[0032] In another preferred embodiment, the inert solvent in step c) is selected from the group consisting of water, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO), sulfolane, toluene, acetonitrile, alcohol solvents, ether solvents, ketone solvents, ester solvents, or combinations thereof.

[0033] In another preferred embodiment, the alcohol solvent is a C1-C8 alcohol, preferably methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, or a combination thereof.

[0034] In another preferred embodiment, the ether solvent is selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, or a combination thereof.

[0035] In another preferred embodiment, the inert solvent in step c) is selected from the group consisting of methanol, ethanol, or a combination thereof.

[0036] In another preferred embodiment, the amount of the chiral catalyst is 0.001-20 mol%, preferably 0.1 mol%, of the compound of formula III.

[0037] In another preferred embodiment, the hydrogen pressure in step c) is 1-100 atmospheres, preferably 20-30 atmospheres.

[0038] In another preferred embodiment, the volume of the inert solvent in step c) is 1 to 20 times the volume of the compound of formula III, preferably 10 times the volume.

[0039] In another preferred embodiment, the reaction temperature of step c) is 30-180°C, preferably 60-90°C.

[0040] In another preferred embodiment, the reducing agent in step d) is selected from the group consisting of borane tetrahydrofuran, borane dimethyl sulfide, borane pyridine, borane triethylamine, lithium aluminum hydride, red aluminum, sodium borohydride / boron trifluoride ethyl ether, sodium borohydride / zinc chloride, sodium borohydride / nickel chloride, sodium borohydride / zirconium chloride, sodium borohydride / cobalt chloride, or a combination thereof.

[0041] In another preferred embodiment, the reducing agent in step d) is sodium borohydride / boron trifluoride etherate.

[0042] In another preferred embodiment, the inert solvent in step d) is selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, methyl tert-butyl ether, toluene, or a combination thereof; preferably tetrahydrofuran.

[0043] In another preferred embodiment, the amount of the reducing agent in step d) is 100-400 mol %, preferably 150 mol %, of the compound of formula II.

[0044] In another preferred embodiment, the volume of the inert solvent in step d) is 1 to 20 times the volume of the compound of formula II, preferably 10 times the volume.

[0045] In another preferred embodiment, the reaction temperature of step d) is 30-180°C, preferably 60-90°C.

[0046] In another preferred embodiment, the metal catalyst in step b) is selected from the group consisting of Raney nickel, palladium on carbon, palladium hydroxide on carbon, ruthenium on carbon, rhodium on carbon, platinum on carbon, platinum dioxide, or a combination thereof; preferably palladium on carbon.

[0047] The inert solvent in step b) is selected from the group consisting of water, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO), sulfolane, toluene, acetonitrile, alcohol solvents, ether solvents, ester solvents, or combinations thereof.

[0048] In another preferred embodiment, the ester solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, isobutyl acetate, tert-butyl acetate, n-propyl acetate, methyl acetate, or a combination thereof.

[0049] In another preferred embodiment, the alcohol solvent is methanol, ethanol, or a combination thereof.

[0050] In another preferred embodiment, the amount of the metal catalyst in step b) is 0.1-30 wt %, preferably 2 wt %, of the compound of formula IV.

[0051] In another preferred embodiment, the hydrogen pressure in step b) is 2-100 atmospheres, preferably 10-30 atmospheres.

[0052] In another preferred embodiment, the volume of the inert solvent in step b) is 1 to 20 times the volume of the compound of formula IV, preferably 10 times the volume.

[0053] In another preferred embodiment, the reaction temperature of step b) is 30-180°C, preferably 60-90°C.

[0054] In another preferred embodiment, the alcohol solvent in step a-1) is R-OH; wherein R is as defined above.

[0055] In another preferred embodiment, the alcohol solvent is selected from the group consisting of methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, tert-butanol, or a combination thereof.

[0056] In another preferred embodiment, the volume of the alcohol solvent in step a-1) is 1 to 20 times the volume of the raw material 2-chloronicotinic acid (compound of formula VII), preferably 5 to 10 times the volume.

[0057] In another preferred embodiment, the equivalent of sulfuric acid in step a-1) is 0.01-5 times the equivalent of the raw material 2-chloronicotinic acid, preferably 0.05-0.2 times the equivalent.

[0058] In another preferred embodiment, the reaction temperature of step a-1) is 20-100 degrees, preferably 50-80 degrees.

[0059] In another preferred embodiment, the reaction time of step a-1) is 2-20 hours, preferably 5-7 hours.

[0060] In another preferred embodiment, the inert solvent in step a-2) is selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, DMF, DMSO, DMAc, NMP, sulfolane, acetonitrile, toluene, or a combination thereof, preferably DMF or DMSO.

[0061] In another preferred embodiment, the volume of the inert solvent in step a-2) is 1-20 times, preferably 10 times, of the compound of formula VI.

[0062] In another preferred embodiment, the reaction temperature of step a-2) is 60-150°C, preferably 80-120°C.

[0063] The second aspect of the present invention further provides a method for preparing the compound of formula II, comprising the following steps:

[0064] b-1) in an inert solvent, in the presence of a metal catalyst, subjecting the compound of formula IV to a pyridine ring reduction reaction to prepare a compound of formula IV-a;

[0065] b-2) In an inert solvent, in the presence of a chiral acid, the compound of formula IV-a is salified and then resolved to prepare a compound of formula II.

[0066]

[0067] In another preferred embodiment, the chiral acid is selected from the group consisting of D-tartaric acid, D-malic acid, D-mandelic acid, D-dibenzoyltartaric acid, D-di-p-methylbenzoyltartaric acid, D-camphorsulfonic acid, D-gluconic acid, DN-acetylalanine, DN-acetylphenylalanine, or a combination thereof, preferably D-tartaric acid.

[0068] In another preferred embodiment, the metal catalyst in step b-1) is selected from the group consisting of Raney nickel, palladium on carbon, palladium hydroxide on carbon, ruthenium on carbon, rhodium on carbon, platinum on carbon, platinum dioxide, or a combination thereof, preferably platinum on carbon.

[0069] In another preferred embodiment, the inert solvent in step b-1) is selected from the following group: water, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO), sulfolane, toluene, acetonitrile, alcohol solvents, ether solvents, ester solvents, or combinations thereof.

[0070] In another preferred embodiment, the ether solvent is selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, or a combination thereof.

[0071] In another preferred embodiment, the ester solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, isobutyl acetate, tert-butyl acetate, n-propyl acetate, methyl acetate, or a combination thereof.

[0072] In another preferred embodiment, the alcohol solvent is a C1-C8 alcohol, preferably methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, or a combination thereof, more preferably ethanol, isopropanol, or a combination thereof.

[0073] In another preferred embodiment, the amount of the metal catalyst in step b-1) is 0.1-30 wt %, preferably 3 wt %, of the compound of formula IV.

[0074] In another preferred embodiment, the hydrogen pressure in step b-1) is 2-100 atmospheres, preferably 20-30 atmospheres.

[0075] In another preferred embodiment, the volume of the inert solvent in step b-1) is 1 to 20 times the volume of the compound of formula IV, preferably 10 times the volume

[0076] In another preferred embodiment, the reaction temperature of step b-1) is 30-180°C, preferably 60-120°C.

[0077] In another preferred embodiment, the chiral acid in step b-2) is 10-500 mol %, preferably 100 mol %, of the compound of formula VI-a.

[0078] In another preferred embodiment, the inert solvent in step b-2) is selected from the group consisting of water, DMF, NMP, DMAc, DMSO, acetonitrile, toluene, dichloromethane, methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, ethyl acetate, isopropyl acetate, isobutyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, or a combination thereof.

[0079] In another preferred embodiment, the inert solvent in step b-2) is selected from the group consisting of water, isopropyl alcohol, or a combination thereof.

[0080] In another preferred embodiment, the volume of the inert solvent in step b-2) is 1 to 20 times the volume of the compound of formula VI-a, preferably 10 times the volume.

[0081] In another preferred embodiment, the salt formation temperature in step b-2) is 0-50°C, preferably 10-20°C.

[0082] The third aspect of the present invention provides a compound of formula III,

[0083]

[0084] The fourth aspect of the present invention provides the use of a compound of formula III in preparing a compound of formula I,

[0085]

[0086] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. DETAILED DESCRIPTION

[0087] After extensive and in-depth research, the inventors unexpectedly discovered that a compound of Formula III can be prepared using 2-chloronicotinic acid as a starting material through a series of reactions, followed by asymmetric hydrogenation and amide reduction in the presence of a chiral catalyst to produce a compound of Formula I. The present invention also provides a method for preparing a compound of Formula I by hydrogenating the compound of Formula III and then resolving it into salts. This method is simple to operate, has a high yield, produces minimal waste, and is highly suitable for industrial production. Based on this, the inventors completed the present invention.

[0088] the term

[0089] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0090] As used herein, the terms "comprise," "include," and "contain" are used interchangeably to include not only closed definitions but also semi-closed and open definitions. In other words, the terms include "consisting of," "consisting essentially of."

[0091] The "inert solvent" described in the present invention refers to a solvent that does not react with the compounds in the reaction system.

[0092] As used herein, the terms "the method of the present invention", "the preparation method of the present invention" and "the industrial preparation method of the present invention" can be used interchangeably to refer to the method described in the first aspect of the present invention.

[0093] In the present invention, "C1-C6 alkyl" refers to a straight or branched chain alkyl group containing 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl, tert-pentyl, or the like.

[0094] The "alcohol solvent" in the present invention refers to an organic solvent containing a hydroxyl group (-OH), wherein "C1-C8 alcohol" refers to an alcohol solvent containing 1 to 8 carbon atoms, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, etc.

[0095] The "ether solvent" mentioned in the present invention refers to an organic solvent containing an ether functional group (-O-), such as dimethyl ether, diethyl ether, tetrahydrofuran, methyl tert-butyl ether, dioxane, ethylene glycol dimethyl ether, etc.

[0096] The "ketone solvent" mentioned in the present invention refers to an organic solvent containing a ketone carbonyl group (C=O), such as acetone, butanone, cyclohexanone, etc.

[0097] The "ester solvent" mentioned in the present invention refers to a type of organic solvent synthesized by reacting an alcohol solvent with an organic acid, such as methyl formate, methyl acetate, ethyl acetate, etc.

[0098] Compounds and preparation methods

[0099] The compound of formula I described in the present invention, "(S,S)-2,8-diazabicyclo[4,3,0]nonane", is one of the important intermediates for preparing moxifloxacin.

[0100]

[0101] The present invention also provides one of the important intermediates for preparing the compound of formula I, whose structural formula is as follows:

[0102]

[0103] The preparation method of the compound of formula I of the present invention is described in more detail below, but these specific methods do not constitute any limitation to the present invention. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily carried out by those skilled in the art.

[0104] Typically, the preparation method of the compound of formula I of the present invention is as follows, wherein the raw materials and reagents used can be purchased through commercial channels unless otherwise specified.

[0105] The present invention provides a method for preparing (S,S)-2,8-diazabicyclo[4,3,0]nonane, which comprises the following steps:

[0106]

[0107] wherein R is as defined above.

[0108] a-1) esterifying the compound of formula VII (2-chloronicotinic acid) to obtain the compound of formula VI;

[0109] a-2) the compound of formula VI undergoes cyano substitution reaction to obtain a compound of formula V;

[0110] a) subjecting the compound of formula V to a hydrogenation reduction reaction and an intramolecular ring closure reaction to obtain a compound of formula IV;

[0111] b) hydrogenating the compound of formula IV to obtain the compound of formula III;

[0112] c) asymmetric hydrogenation of the compound of formula III to obtain a compound of formula II;

[0113] d) The compound of formula II is subjected to reduction reaction to obtain the compound of formula I with the moxifloxacin side chain (S,S)-2,8-diazabicyclo[4,3,0]nonane.

[0114] Specifically, the method steps of the present invention are as follows:

[0115] a-1) This step is an esterification reaction, in which the compound of formula VII reacts in a certain amount of alcohol solvent under the catalysis of sulfuric acid at a certain temperature to obtain the compound of formula VI.

[0116]

[0117] Wherein, R is a C1-C6 alkyl group.

[0118] a-2) This step is a substitution reaction, in which the compound of formula VI reacts with compound M in an organic solvent to obtain a compound of formula V;

[0119]

[0120] Wherein, R is a C1-C6 alkyl group;

[0121] Compound M is selected from the group consisting of NaCN, KCN, Zn(CN)2, CuCN, Cu(CN)2, or a combination thereof.

[0122] In another preferred embodiment, the compound M is CuCN.

[0123] a) This step is a hydrogenation reduction and cyclization reaction. The compound of formula V is heated in a solvent under the action of a metal catalyst and a hydrogen atmosphere of a certain pressure to react, and cyanide reduction and ring closure reactions occur in one step to prepare the compound of formula IV.

[0124]

[0125] b) This step is a hydrogenation reduction reaction, wherein the compound of formula IV undergoes a hydrogenation reduction reaction in a solvent under the action of a metal catalyst and a hydrogen atmosphere of a certain pressure to obtain the compound of formula III.

[0126]

[0127] c) This step is an asymmetric hydrogenation reaction. The compound of formula IIII undergoes an asymmetric hydrogenation reduction reaction in a solvent under the action of a chiral catalyst and a hydrogen atmosphere of a certain pressure to obtain the compound of formula II.

[0128]

[0129] d) This step is a reduction reaction, in which the compound of formula II undergoes a reduction reaction in a solvent under the action of a reducing agent to obtain the compound of formula I.

[0130]

[0131] The present invention also provides a method for preparing a compound of formula II from a compound of formula IV:

[0132] b-1) This step is a hydrogenation reduction reaction, wherein the compound of formula IV undergoes pyridine ring reduction in a solvent under the action of a metal catalyst and a hydrogen atmosphere of a certain pressure to prepare a compound of formula IV-a.

[0133]

[0134] b-2) This step is chiral resolution. The compound of formula IV-a is dissolved in a certain solvent, and a chiral acid is added to form a salt at a certain temperature. After the salt formation is completed, the target chiral salt is filtered to obtain the target chiral salt, which is then freed with sodium hydroxide aqueous solution to obtain the compound of formula II.

[0135]

[0136] Compared with the prior art, the main advantages of the present invention are:

[0137] 1. The present invention provides a novel method for preparing the moxifloxacin side chain (S,S)-2,8-diazabicyclo[4,3,0]nonane using inexpensive 2-chloronicotinic acid as a raw material.

[0138] 2. In step c) of the method of the present invention, the compound of formula II with high chiral purity is directly prepared by asymmetric hydrogenation reaction under the action of a chiral catalyst.

[0139] 3. In step d) of the method of the present invention, only one carbonyl group needs to be reduced, which greatly reduces the amount of reducing agent, reduces production costs and reduces safety risks.

[0140] 4. The present invention provides a preparation method with high reaction yield, few impurities and good product purity.

[0141] 5. The raw materials of the present invention are easily available, the operation is simple, the conditions are relatively mild, and it is suitable for industrial production.

[0142] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0143] Example 1

[0144]

[0145] Under nitrogen, methanol (5000 mL), 25 g of concentrated sulfuric acid, and 500 g of 2-chloronicotinic acid were added to a reactor equipped with a stirrer and temperature controller. The temperature was raised to reflux and the reaction was allowed to react for 16 hours. After the reaction was complete, the mixture was cooled to room temperature and partitioned with dichloromethane and water. The aqueous phase was extracted once with dichloromethane, and the organic phase was washed once with aqueous sodium bicarbonate solution. The mixture was concentrated to dryness to obtain methyl 2-chloronicotinate (515 g) in a 95% yield.

[0146] Example 2

[0147]

[0148] Under nitrogen, DMF (2000 mL), cuprous cyanide (116 g), and methyl 2-chloronicotinate (200 g) were added to a reactor equipped with a stirrer and temperature controller. The temperature was raised to reflux and the reaction was allowed to proceed for 18 hours. After completion of the reaction, the mixture was cooled to room temperature, partitioned with ethyl acetate and water, and then extracted with ethyl acetate and washed twice with water. The organic phase was washed once with saturated brine and concentrated to dryness to yield methyl 2-cyanonicotinate (170 g) in a 90% yield.

[0149] Example 3

[0150]

[0151] Methanol (1500 mL), methyl 2-cyanonicotinate (150 g), and Raney nickel (25 g) were added to a hydrogenation reactor and reacted at a hydrogen pressure of 10 atm and a reaction temperature of 80°C for 8 h. After the reaction, the Raney nickel was filtered off and the product was concentrated to dryness to obtain Compound IV (106 g) with a yield of 86.0%.

[0152] Example 4

[0153]

[0154] Methanol (1000 mL), compound IV (100 g), and palladium on carbon (2 g) were added to a hydrogenation reactor and reacted at a hydrogen pressure of 20 atm and a reaction temperature of 50°C for 24 h. After the reaction, the catalyst was filtered off and the mixture was concentrated to dryness to obtain compound III (103 g) with a yield of 100.0%.

[0155] MS (ESI+) m / z: 139 [M+H + ].

[0156] 1 H NMR (400MHz, DMSO) δ6.52(s,1H),6.49(s,1H),3.67(s,2H),3.16-3.12(m,2H),2.05-2.02(t,2H),1.70-1.64(m,2H).

[0157] Example 5

[0158]

[0159] Methanol (500 mL), compound III (50 g), and chiral catalyst [(R,R)-(Et-DuPhos)Rh(COD)]BF4 (0.25 g) were added to a hydrogenation reactor. The reaction was carried out at a hydrogen pressure of 30 atm and a temperature of 90°C for 16 hours. After completion of the reaction, the mixture was concentrated to dryness and recrystallized from ethyl acetate and n-heptane to obtain compound II (42 g) with a yield of 82.0%. The purity was 98.6% as determined by GC, and the chiral purity was 99.6%.

[0160] Example 6

[0161]

[0162] Tetrahydrofuran (600 mL), compound II (60 g), and sodium borohydride (36 g) were added to a hydrogenation kettle. Boron trifluoride etherate (180 g) was added dropwise at a temperature of 60-66°C. After addition, the mixture was refluxed for 12 h. After completion of the reaction, 10% aqueous sodium hydroxide solution was added to quench the reaction. The aqueous phase was then extracted three times with ethyl acetate. The organic phase was concentrated and the product was distilled off under reduced pressure to obtain compound I (46 g) with a yield of 85%. The purity was 99.0% as determined by GC, and the chiral purity was 99.6%.

[0163] Example 7

[0164]

[0165] Methanol (1000 mL), compound IV (100 g), and platinum on carbon (3 g) were added to a hydrogenation reactor and reacted at a hydrogen pressure of 30 atm and a reaction temperature of 100°C for 24 h. After the reaction, the catalyst was filtered off and the product was concentrated to dryness to obtain compound IV-a (97 g) with a yield of 93%.

[0166] Example 8

[0167]

[0168] 75% isopropanol (800 mL), compound IV-a (80 g), and D-tartaric acid (52 g) were added to a hydrogenation kettle, the temperature was raised to 85-90°C to dissolve, the temperature was slowly lowered to 10-20°C, and the mixture was filtered. The wet product was then added to dichloromethane and aqueous sodium carbonate solution, the layers were separated, and the organic phase was concentrated to dryness and recrystallized from ethyl acetate and n-heptane to obtain compound II (28 g) with a yield of 35%. The purity was 99.7% as determined by GC, and the chiral purity was 99.8%.

[0169] Therefore, the benefit of the present invention lies in its novel route, which uses cheap 2-chloropyridinecarboxylic acid as a starting material, and obtains a lactam intermediate through carboxylic acid methylation, cyano substitution, and catalytic hydrogenation ring closure. In the subsequent reduction process, compared with the need to reduce two carbonyl groups in obtaining a dicarboximide intermediate from 2,3-pyridinedicarboxylic acid, this route only reduces a single carbonyl group, has a high yield, and greatly reduces the amount of reducing agent used, thereby effectively reducing costs and safety risks.

[0170] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A method for preparing a compound of formula I, comprising the following steps: a) in an inert solvent, in the presence of a metal catalyst, subjecting the compound of formula V to a hydrogenation reduction reaction and an intramolecular ring closure reaction, thereby preparing a compound of formula IV; b) in an inert solvent, in the presence of a metal catalyst, subjecting the compound of formula IV to a hydrogenation reduction reaction to prepare a compound of formula III; c) subjecting the compound of formula III to an asymmetric hydrogenation reduction reaction in an inert solvent in the presence of a chiral catalyst to prepare a compound of formula II; d) In an inert solvent, the compound of formula II is subjected to a reduction reaction under the action of a reducing agent to prepare a compound of formula I.

2. The preparation method according to claim 1, wherein Before step a), the method further comprises the following steps: a-1) in an alcohol solvent, the compound of formula VII undergoes a substitution reaction to prepare a compound of formula VI; a-2) reacting the compound of formula VI with compound M in an inert solvent to obtain a compound of formula V; in, R is a C1-C6 alkyl group; Compound M is selected from the group consisting of NaCN, KCN, Zn(CN)2, CuCN, Cu(CN)2, or a combination thereof.

3. The preparation method according to claim 1, wherein The metal catalyst in step a) is selected from the group consisting of Raney nickel, palladium carbon, palladium hydroxide carbon, ruthenium carbon, rhodium carbon, platinum carbon, platinum dioxide, or a combination thereof; Raney nickel is preferred.

4. The preparation method according to claim 1, wherein The inert solvent in step a) is selected from the group consisting of water, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO), sulfolane, toluene, acetonitrile, alcohol solvents, ether solvents, ketone solvents, ester solvents, or combinations thereof.

5. The preparation method according to claim 1, wherein The chiral catalyst is selected from the group consisting of: (R)-Ru(OAc)2(BINAP), (R)-Ru(OAc)2(Tol-BINAP), (R)-Ru(OAc)2(xyl-BINAP), (R)-Ru(OAc)2(H8-BINAP), (R)-Ru(OAc)2(SegPhos), [(R,R)-(Et-DuPhos)Rh(COD)]BF4, [(R,R)-(Me-DuPhos)Rh(COD)]BF4, [(R,R)-(Me-BPE)Rh(COD)]BF4, [(R)-(PhanePhos)Rh(COD)]BF4, [(R,R)-(Ph-BPE)Rh(COD)] BF4, [(R)-(Tol-Binap)Rh(COD)]BF4, [(R)-(xyl-Binap)Rh(COD)]BF4, [(R,S)-(JosiPhos)Rh(COD)]BF4, [(R)-(Monophos)Rh(COD)]BF4, or a combination thereof; preferably [(R,R)-(Et-DuPhos)Rh(COD)]BF4.

6. The preparation method according to claim 1, wherein The inert solvent in step c) is selected from the group consisting of water, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO), sulfolane, toluene, acetonitrile, alcohol solvents, ether solvents, ketone solvents, ester solvents, or combinations thereof.

7. The preparation method according to claim 1, wherein The reducing agent in step d) is selected from the group consisting of borane tetrahydrofuran, borane dimethyl sulfide, borane pyridine, borane triethylamine, lithium aluminum hydride, red aluminum, sodium borohydride / boron trifluoride ethyl ether, sodium borohydride / zinc chloride, sodium borohydride / nickel chloride, sodium borohydride / zirconium chloride, sodium borohydride / cobalt chloride, or a combination thereof.

8. The preparation method according to claim 1, wherein The inert solvent in step d) is selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, methyl tert-butyl ether, toluene, or a combination thereof; preferably tetrahydrofuran.

9. The preparation method according to claim 1, wherein The preparation method of the compound of formula II comprises the following steps: b-1) in an inert solvent, in the presence of a metal catalyst, subjecting the compound of formula IV to a pyridine ring reduction reaction to prepare a compound of formula IV-a; b-2) In an inert solvent, in the presence of a chiral acid, the compound of formula IV-a is salified and then resolved to prepare a compound of formula II.

10. The preparation method according to claim 9, wherein The chiral acid is selected from the group consisting of D-tartaric acid, D-malic acid, D-mandelic acid, D-dibenzoyltartaric acid, D-di-p-methylbenzoyltartaric acid, D-camphorsulfonic acid, D-gluconic acid, DN-acetylalanine, DN-acetylphenylalanine, or a combination thereof, preferably D-tartaric acid.

Images