Catalytic synthesis of a class of leteprinim drugs and intermediates thereof

Abstract

The application provides a synthesis method of a lenabre drug intermediate, a structural general formula of the lenabre drug intermediate is shown as formula 15, and the catalytic synthesis method is that a compound shown as formula 12, a compound shown as formula 13 and a compound shown as formula 14 are contacted and reacted under the action of a nickel catalyst and a chiral double nitrogen ligand to form a compound shown as formula 15. The synthesis method provided in the application is simple in operation, high in universality, fast in synthesis and good in stereoselectivity.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis, and in particular to a method for synthesizing a levofloxacin drug and its intermediates. Background Technology

[0002] SGLT, short for sodium-dependent glucose cotransporter, is a crucial transport protein in the human body responsible for glucose reabsorption. It utilizes the electrochemical potential of sodium ions to transport glucose against its concentration gradient. Among the SGLT protein family in the human body, SGLT1 and SGLT2 are the most critical for glucose absorption and homeostasis. SGLT1 is widely distributed in the renal cortex, intestines, heart, and lungs, while SGLT2 is expressed almost exclusively in the renal cortex.

[0003] Inhibiting the glucose transport function of SGLT2 prevents SGLT2 from reabsorbing glucose from the renal tubules, leading to the excretion of excess glucose in the urine and thus indirectly lowering blood glucose levels. However, inhibition of SGLT1 can cause glucose-lactose malabsorption. Due to the unique distribution characteristics of SGLT2 and its insulin-independent hypoglycemic effect, SGLT2 inhibitors have attracted much attention in recent years.

[0004] Currently, several SGLT2 inhibitors have been used in the clinical treatment of type 2 diabetes, such as dapagliflozin, empagliflozin, canagliflozin, and ipragliflozin. In addition, dozens of companies have been approved for clinical trials of these derivatives. The Chinese market for SGLT2 inhibitors is expected to exceed several billion yuan, and research and development enthusiasm is high.

[0005]

[0006] Currently marketed SGLT2 inhibitors are mainly β-C-aryl glycosides, meaning that the aryl group is linked to the 1 position of the sugar backbone via a carbon glycosidic bond. Their synthesis methods can be classified according to the raw materials into gluconolactone method, glycosyl leaving group method, and gluconolactone epoxide method.

[0007] Gluconolactone method: An addition reaction is performed between an aryl metal reagent (such as aryllithium) and a protected gluconolactone (2). The resulting compound (3) is then reacted with methanol to prepare a ketal compound (4). Finally, β-C-aryl glucoside compounds (6) are obtained through reduction, resolution, and other steps. Empagliflozin, canagliflozin, dapagliflozin, and epagliptin were initially synthesized using this method (see WO2004063209, WO2006117359, US2010094025, WO2005012326).

[0008]

[0009] Glycosyl leaving group method: Electron-withdrawing groups such as bromine, chlorine, and sulfonate esters are installed at position 1 of the glycosyl backbone to prepare electron-deficient glycosyl compounds (7). Then, nucleophilic substitution is performed on them using aryl metal reagents (such as aryl lithium reagent, aryl magnesium reagent, aryl zinc reagent, etc.). After subsequent deprotection and other reactions, aryl glycosides are obtained (see CN103980263, CN105859672, CN106188022, CN105294624).

[0010]

[0011] Grape epoxide method: 1,2-glucene epoxide (10) is nucleophilically substituted and ring-opened using an aryl nucleophile, and then deprotected to obtain aryl glycosides. However, this method is rarely used and is currently mainly used for the preparation of apagliflozin (see US7847074; WO2015177083; J.Org.Chem.2015,80,9328-9335).

[0012]

[0013] In summary, the conventional methods for preparing C-aryl glycosides currently have several drawbacks. Specifically, these include (1) a lack of stereoselectivity in the formation of the desired C-aryl glycoside, making it impossible to achieve selective control of the product; and (2) relatively long synthetic routes and resolution processes resulting in low reaction yields and atom economy.

[0014] Therefore, in order to achieve efficient development of SGLT2 inhibitor hypoglycemic drugs, it is necessary to establish a synthetic method that is simple to operate, highly universal, rapid to synthesize, and has good stereoselectivity. Summary of the Invention

[0015] In view of the shortcomings of the prior art described above, the purpose of this invention is to provide a catalytic synthesis method for glibenclamide drug intermediates to solve the problems in the prior art.

[0016] To achieve the above and other related objectives, the present invention is implemented by including the following technical solutions.

[0017] This invention first provides a catalytic synthesis method for intermediates of levofloxacin drugs, the general structural formula of which is shown in Formula 15. The catalytic synthesis method is as follows: under the action of a nickel catalyst and a chiral dinitrogen ligand, the compounds shown in Formula 12, Formula 13, and Formula 14 are contacted and reacted to form the compound shown in Formula 1. The synthetic route is as follows:

[0018]

[0019] Wherein, R is selected from one or more of hydrogen, straight-chain or branched alkoxy, cycloalkoxy, substituted or unsubstituted arylmethoxy, substituted or unsubstituted arylformyloxy, and sulfonic acid oxy; preferably, R is benzoxy or methoxymethoxy (-OMOM).

[0020] R 1 It is selected from one or more of straight-chain or branched alkyl, cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic aryl, preferably, R 1 It is p-tert-butylphenyl.

[0021] In this application, the chirality of the sugar phosphate ester C1 in the compound represented by Formula 12 is selected from α and β, wherein the α configuration is relatively more stable and easier to prepare. Therefore, the compound represented by Formula 12 is preferably the α configuration.

[0022] X is selected from Cl, Br, and I, and preferably X is I.

[0023] Ar represents substituted or unsubstituted aryl groups, or substituted or unsubstituted heterocyclic aryl groups.

[0024] More preferably, the general structural formula of Ar is as follows:

[0025]

[0026] Where R 4 R is a halogen atom, a substituted or unsubstituted alkyl group. 5 The aryl group may be substituted or unsubstituted, or a heterocyclic aryl group may be substituted or unsubstituted. More preferably, the R... 4 It is selected from F, Cl, Br, and I.

[0027] More preferably, Ar is any one of the structures in formulas I-IV.

[0028] The product obtained at this time is an intermediate for scutellarin-type drugs with clear commercial value.

[0029] R 2 It is selected from one of straight-chain or branched alkyl, cycloalkyl, substituted or unsubstituted aryl, and alkylsilyl groups.

[0030] Preferably, R 2 It is an alkylsilyl group, and its general structural formula is shown below:

[0031]

[0032] Among them, R 6 R 7 R 8It is independently selected from one of straight-chain or branched alkyl, cycloalkyl, substituted or unsubstituted aryl, or alkylsilyl groups.

[0033] More preferably, R 6 R 7 R 8 Both are methyl groups. At this point, R... 2 It is trimethylsilyl (TMS).

[0034] R 3 It is selected from one of straight-chain or branched alkyl, cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl.

[0035] Preferably, R 3 The phenyl group may be substituted or unsubstituted. More preferably, R 3 It is one or more of alkylphenyl and alkoxyphenyl. The substitution site is one or more of ortho, meta, and para on the aromatic ring. Most preferably, R 3 It is a phenyl group.

[0036] Preferably, the nickel catalyst is selected from one or more of nickel bromide, nickel iodide, nickel chloride, di(cyclooctadiene) nickel, ethylene glycol dimethyl ether nickel bromide, ethylene glycol dimethyl ether nickel chloride, and di(acetylacetone) nickel. More preferably, the nickel catalyst is ethylene glycol dimethyl ether nickel bromide (NiBr2·DME).

[0037] Preferably, the chiral dinitrogen ligand is selected from one or more of the following structural formulas:

[0038]

[0039]

[0040] Correspondingly, when one of (S,S)-L1 to (S,S)-L16 is used as a ligand, the product is mainly a β-C-aryl glycoside; when one of (R,R)-L1 to (R,R)-L11 is used as a ligand, the product is mainly an α-C-aryl glycoside. Preferably, when (S,S)-L16 is used to prepare β-C-aryl glycosides, the α:β ratio is ≤15.6:84.4; when (R,R)-L3 is used to prepare α-C-aryl glycosides, the α:β ratio is ≥83.3:16.7.

[0041] Preferably, the amount of the compound shown in Formula 13 is 75% to 200% of the amount of the compound shown in Formula 12, such as 75%, 80%, 85%, 90%, 95%, 100%, 105%, 110%, 115%, 120%, 125%, 130%, 135%, 140%, 145%, 150%, 155%, 160%, 165%, 170%, 175%, 180%, 185%, 190%, 195%, etc.

[0042] Preferably, the amount of the chiral dinitrogen ligand is 1 to 20% of the molar amount of the compound shown in Formula 12, such as 1%, 3%, 5%, 8%, 10%, 13%, 15%, 18%, 20%, etc.

[0043] Preferably, the amount of nickel catalyst used is 1 to 20% of the molar amount of the compound shown in Formula 12, such as 1%, 3%, 5%, 8%, 10%, 13%, 15%, 18%, 20%, etc.

[0044] Preferably, the amount of the compound shown in Formula 14 is 75% to 200% of the molar amount of the compound shown in Formula 12, such as 75%, 80%, 85%, 90%, 95%, 100%, 105%, 110%, 115%, 120%, 125%, 130%, 135%, 140%, 145%, 150%, 155%, 160%, 165%, 170%, 175%, 180%, 185%, 190%, 195%, etc.

[0045] Preferably, the reaction solvent is one or more selected from tetrahydrofuran, toluene, methylcyclopentanehexane ether, 2-methoxytetrahydrofuran, methyl tert-butyl ether, and benzene.

[0046] Preferably, the reaction temperature is -20 to 50°C, more preferably 25°C.

[0047] Preferably, the reaction time is 4-36 hours.

[0048] As mentioned above, when the corresponding aryl iodine and chiral dinitrogen ligand are used, key intermediates for serotonin drugs can be obtained.

[0049] The second aspect of this invention also discloses a method for synthesizing an intermediate compound of dapagliflozin, the synthetic route being as follows:

[0050] Under the action of a nickel catalyst and a chiral dinitrogen ligand, the compounds shown in Formula 16, Formula 17, and Formula 18 are contacted and reacted to form the compound shown in Formula 19. The synthetic route is as follows:

[0051]

[0052] Among them, R9 The group is selected from one or more of straight-chain or branched alkyl, cycloalkyl, substituted or unsubstituted arylmethyl, substituted or unsubstituted arylformyl, and sulfonic acid groups, preferably, R 9 It is benzyl or methoxymethyl (-MOM);

[0053] R 10 It is selected from one or more of alkyl, cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic aryl, preferably p-tert-butylphenyl;

[0054] R 11 It is selected from alkyl, cycloalkyl, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclic aryl. Specifically, when R... 11 When the phenyl group is substituted, the substituent can be one or more of alkyl, alkoxy, etc., and the substitution site can be one or more of ortho, meta, and para on the aromatic ring. Preferably, R 11 It is a phenyl group.

[0055] A third aspect of this invention also discloses a method for synthesizing an intermediate compound of empagliflozin, wherein, under the action of a nickel catalyst and a chiral dinitrogen ligand, the compounds shown in Formula 16, Formula 20, and Formula 18 are contacted and reacted to form the compound shown in Formula 21. The synthetic route is as follows:

[0056]

[0057] Among them, R 9 The group is selected from one or more of straight-chain or branched alkyl, cycloalkyl, substituted or substituted arylmethyl, substituted or unsubstituted arylformyl, and sulfonic acid groups, preferably, R 9 It is benzyl or methoxymethyl (-MOM);

[0058] R 10 It is selected from one or more of straight-chain or branched alkyl, cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic aryl, preferably, R 10 It is p-tert-butylphenyl;

[0059] R 11 It is selected from straight-chain or branched alkyl, cycloalkyl, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclic aryl; preferably, R 11 It is a phenyl group.

[0060] The fourth aspect of this invention also discloses a method for synthesizing an intermediate compound of canagliflozin, wherein, under the action of a nickel catalyst and a chiral dinitrogen ligand, the compounds shown in Formula 16, Formula 22, and Formula 18 are contacted and reacted to form the compound shown in Formula 23. The synthetic route is as follows:

[0061]

[0062] Among them, R 9 It is selected from one or more of straight-chain or branched alkyl, cycloalkyl, substituted or substituted arylmethyl, substituted or unsubstituted arylformyl, sulfonic acid group, preferably benzyl or methoxymethyl (-MOM);

[0063] R 10 It is selected from one or more of straight-chain or branched alkyl, cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, preferably p-tert-butylphenyl;

[0064] R 11 It is selected from straight-chain or branched alkyl, cycloalkyl, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclic aryl; preferably, R 11 It is a phenyl group.

[0065] Preferably, in the above-described method for synthesizing intermediate compounds of dapagliflozin, empagliflozin, and canagliflozin:

[0066] The nickel catalyst is selected from one or more of nickel bromide, nickel iodide, nickel chloride, di(cyclooctadiene) nickel, ethylene glycol dimethyl ether nickel bromide, ethylene glycol dimethyl ether nickel chloride, and di(acetylacetone) nickel;

[0067] The reaction also uses a reaction solvent, which is one or more selected from tetrahydrofuran, toluene, methylcyclopentanehexane ether, 2-methoxytetrahydrofuran, methyl tert-butyl ether, and benzene;

[0068] The reaction temperature is -20 to 50°C.

[0069] Preferably, in the above-described method for synthesizing intermediate compounds of dapagliflozin, empagliflozin, and canagliflozin: the chiral dinitrogen ligand is selected from one or more of the following structural formulas:

[0070]

[0071]

[0072] Preferably, in the above-described method for synthesizing intermediate compounds of dapagliflozin, empagliflozin, and canagliflozin:

[0073] The amount of the compound shown in Formula 17 is 75% to 200% of the molar amount of the compound shown in Formula 16;

[0074] And / or, the amount of the compound shown in Formula 20 is 75 to 200% of the molar amount of the compound shown in Formula 16;

[0075] And / or, the amount of the compound shown in Formula 22 is 75 to 200% of the molar amount of the compound shown in Formula 16;

[0076] And / or, the amount of the nickel catalyst used is 1 to 20% of the molar amount of the compound shown in Formula 16;

[0077] And / or, the amount of the compound shown in Formula 18 is 75 to 200% of the molar amount of the compound shown in Formula 16.

[0078] The catalytic synthesis method in this application has the following main advantages:

[0079] (1) The substrate preparation is simple and the operation method is simplified. The sugar substrate preparation is simple and relatively stable, and there is no need to prepare aryl metal reagents at low temperatures.

[0080] (2) It can synthesize C-aryl glycosides in batches and efficiently, which is suitable for drug development and screening.

[0081] (3) By adjusting the aryl and sugar skeleton structures in the reactants, C-aryl glycosides with different aryl substitutions can be obtained, and this has been confirmed by adjusting the arylization reagent to prepare key intermediates of existing SGLT2 inhibitors.

[0082] (4) By adjusting the stereostructure of the chiral ligand, C-aryl glycosides with different chiralities can be obtained with high yield and selectivity, and this arylation method has been confirmed by adjusting the chiral ligand. Attached Figure Description

[0083] Figure 1 The image shown is the nuclear magnetic resonance spectrum of the product in Example 1 of this invention.

[0084] Figure 2 The image shown is the nuclear magnetic resonance spectrum of the product in Example 2 of this invention.

[0085] Figure 3 The image shown is the nuclear magnetic resonance spectrum of the product in Example 3 of this invention.

[0086] Figure 4 The image shown is the nuclear magnetic resonance spectrum of the product in Example 4 of this invention. Detailed Implementation

[0087] The following specific examples illustrate the implementation of the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention from the content disclosed in this specification. The present invention can also be implemented or applied through other different specific embodiments, and various details in this specification can also be modified or changed based on different viewpoints and applications without departing from the spirit of the present invention.

[0088] The following compounds and intermediates were characterized by liquid chromatography-mass spectrometry (LC-MS) and nuclear magnetic resonance (NMR). The starting materials and reagents used in the preparation of these compounds were available from suppliers or prepared by methods known to those skilled in the art. The following general synthetic routes are merely illustrative of methods by which the compounds of the present invention can be synthesized, and various modifications to these synthetic routes are possible and inspired by those skilled in the art who have referred to this disclosure.

[0089] The term "contact" as used herein should be interpreted broadly, encompassing any method that enables at least two reactants to undergo a chemical reaction, such as mixing two reactants under appropriate conditions. If necessary, reactants requiring contact can be mixed under stirring; therefore, the type of stirring is not particularly limited, such as mechanical stirring, i.e., stirring under mechanical force.

[0090] Example 1

[0091] This embodiment describes a non-stereoselective catalytic synthesis method for dapagliflozin intermediates, specifically including the following processes:

[0092]

[0093] Under a nitrogen atmosphere, NiBr2·DME (0.005 mmol, 5.0 mol%, 1.54 mg) and rac-L1 (0.005 mmol, 5.0 mol%, 1.66 mg) were dissolved in 0.8 mL of tetrahydrofuran solution and stirred for 30 min to form a complex solution. Glycosyl phosphate (24, 0.1 mmol, 88.5 mg, 1.0 equiv.) and aryl iodine (17, 0.1 mmol, 37.3 mg, 1.0 equiv.) were dissolved in 0.4 mL of tetrahydrofuran and then added to the pre-complex solution. Organozirconium metal (25, 0.17 mmol, 79.5 mg, 1.7 equiv.) was then added, the mixture was sealed, and stirred at 25 °C for 18 h. The reaction was quenched with 0.5 mL of methanol at room temperature. The reaction solution was evaporated to dryness and purified by silica gel column chromatography (PE:EA = 20:1 → 5:1) to give 26,72.3 mg of the product.

[0094] Product 26 was a colorless liquid in its α configuration and a white solid in its β configuration, with a total yield of 94%. The two products were characterized by liquid chromatography-mass spectrometry (LC-MS) and nuclear magnetic resonance (NMR) and confirmed to be consistent with standards. The stereoselectivity was confirmed by NMR as α:β = 56.1:43.9. The stereoselectivity characterization chromatogram is shown below. Figure 1 As shown.

[0095] The characterization data of product 26(α) are as follows:

[0096] R f =0.2(petroleum ether:EtOAc,5:1)

[0097] 1 H-NMR(500MHz, CDCl3)δp.pm7.51(s,1H),7.49–7.45(m,1H),,7.32–7.14(m,19H),7.07–6.99(m,4H),6.6 4(d,J=8.5Hz,2H),5.08(d,J=5.2Hz,1H),4.76–4.70(m,2H),4.67–4.63(m,1H),4.62–4.58(m,2H),4.57–4 .52(m,2H),4.42–4.37(m,2H),3.95–3.89(m,3H),3.86–3.75(m,5H),3.64(dd,J=9.7,8.0Hz,1H),3.59(d d,J=10.6,4.0Hz,1H),3.51(dd,J=10.6,2.3Hz,1H),3.38(ddd,J=9.7,4.0,2.3Hz,1H),2.04–1.94(m,2H);

[0098] 13 C-NMR (125MHz, CDCl3) δ156.0,139.1,138.6,138.2,138.1,136.7,133.2,131.9,130.8,130.3,129.5,128.6,128.5,128.2,128.0 3,127.95,127.9,127.8,127.7,115.4,81.9,81.2,78.3,77.3,75.3,74.9,73.5,73.4,73.20,73.14,72.5,69.0,67.3,38.5,33.1;

[0099] IR(ATR):

[0100] HRMS(ESI) Calculation for [M+H] + :811.3396m / z, found:811.3399m / z; [α] D 17 =83.4 (c=4.0, CHCl3).

[0101] The characterization data of product 26(β) are as follows:

[0102] R f =0.4(petroleum ether:EtOAc,5:1)

[0103] 1 H-NMR(500MHz, CDCl3)δp.pm7.39–7.28(m,14H),7.25–7.16(m,7H),7.05–7.01(m,2H),6.91–6.8 7(m,2H),6.75–6.71(m,2H),4.93–4.84(m,3H),4.64–4.59(m,2H),4.53(d,J=12.2Hz,1H),4.39(d ,J=10.5Hz,1H),4.16(d,J=9.5Hz,1H),4.07(d,J=15.4Hz,1H),3.98–3.92(m,3H),3.82(d,J=10.5 Hz,1H),3.77–3.70(m,4H),3.56(dd,J=6.9,3.0Hz,1H),3.46–3.40(m,1H),1.38(t,J=6.9Hz,3H);

[0104] 13 C-NMR (125MHz, CDCl3) δ157.5,139.1,138.7,138.5,138.3,137.7,134.0,131.4,130.6,129.9,129.7,128.6,128.5,128.4,12 8.2,127.93,127.87,127.9,127.7,126.8,114.6,86.8,84.3,81.1,79.5,78.4,75.9,75.3,75.1,73.6,69.2,63.5,38.5,15.0;

[0105] IR(ATR):

[0106] HRMS(ESI)Calcd for C 49 H 49 ClO6[M+NH4]+:786.3557m / z,found:786.3556m / z;[α] D 18 = +21.5 (c = 1.3, CHCl3).

[0107] Example 2

[0108] This embodiment describes a catalytic synthesis method for dapagliflozin intermediates, specifically including the following processes:

[0109]

[0110] Under a nitrogen atmosphere, NiBr2·DME (0.005 mmol, 5.0 mol%, 1.54 mg) and (S,S)-L16 (0.005 mmol, 5.0 mol%, 1.74 mg) were dissolved in 0.8 mL of tetrahydrofuran solution and stirred for 30 min to form a complex solution. Glycosyl phosphate (24, 0.1 mmol, 88.5 mg, 1.0 equiv.) and aryl iodine (17, 0.1 mmol, 37.3 mg, 1.0 equiv.) were dissolved in 0.4 mL of tetrahydrofuran and added to the pre-complex solution. Then, organozirconium metal (25, 0.17 mmol, 79.5 mg, 1.7 equiv.) was added, the mixture was sealed, and stirred at 25 °C for 18 h. The reaction was quenched with 0.5 mL of methanol at room temperature. The reaction solution was then evaporated to dryness and purified by silica gel column chromatography (PE:EA = 20:1 → 5:1) to obtain the dapagliflozin intermediate (26.53.1 mg).

[0111] The dapagliflozin intermediate was a white solid, and its consistency with the standard was confirmed by liquid chromatography-mass spectrometry (LC-MS) and nuclear magnetic resonance (NMR). The separation yield was 69%, and the stereoselectivity was confirmed by NMR as α:β = 6.3:93.7. The stereoselectivity characterization chromatogram is shown below. Figure 2 As shown.

[0112] The characterization data of dapagliflozin intermediate 26(β) obtained in this embodiment are consistent with those in Example 1.

[0113] Example 3

[0114] This embodiment describes a catalytic synthesis method for empagliflozin intermediates, specifically including the following processes:

[0115]

[0116] Under a nitrogen atmosphere, NiBr2·DME (0.005 mmol, 5.0 mol%, 1.54 mg) and (S,S)-L16 (0.005 mmol, 5.0 mol%, 1.74 mg) were dissolved in 0.8 mL of tetrahydrofuran solution and stirred for 30 min to form a complex solution. Glycosyl phosphate (24, 0.1 mmol, 88.5 mg, 1.0 equiv.) and aryl iodine (20, 0.1 mmol, 41.5 mg, 1.0 equiv.) were dissolved in 0.4 mL of tetrahydrofuran and added to the pre-complex solution. Then, organozirconium metal (25, 0.17 mmol, 79.5 mg, 1.7 equiv.) was added, the mixture was sealed, and stirred at 25 °C for 18 h. The reaction was quenched with 0.5 mL of methanol at room temperature. The reaction solution was then evaporated to dryness and purified by silica gel column chromatography (PE:EA = 20:1 → 5:1) to obtain empagliflozin intermediate (27.56.0 mg).

[0117] The empagliflozin intermediate was a white solid, characterized by consistency with standards as determined by liquid chromatography-mass spectrometry (LC-MS) and nuclear magnetic resonance (NMR). The separation yield was 69%, and the stereoselectivity was confirmed by NMR to be α:β = 10.4:89.6. The stereoselectivity characterization chromatogram is shown below. Figure 3 As shown.

[0118] The characterization data of empagliflozin intermediate 27(β) are as follows:

[0119] R f =0.2(petroleum ether:EtOAc,5:1)

[0120] 1 H-NMR(500MHz, CDCl3)δp.pm7.30(d,J=8.2Hz,1H),7.27–7.11(m,20H),7.00–6.96(m,2H),6.87–6.79(m, 2H),6.65–6.61(m,2H),4.86–4.78(m,3H),4.75(ddt,J=6.4,4.5,2.3Hz,1H),4.58–4.53(m,2H),4.47(d,J =12.3Hz,1H),4.34(d,J=10.5Hz,1H),4.10(d,J=9.5Hz,1H),4.01(d,J=15.4Hz,1H),3.91–3.84(m,4H),3. 83–3.75(m,2H),3.73–3.65(m,4H),3.50(dd,J=7.3,2.0Hz,1H),3.36(d,J=9.0Hz,1H),2.11–2.00(m,2H);

[0121] 13 C-NMR (125MHz, CDCl3) δ156.0,138.9,138.7,138.4,138.28,138.25,137.7,134.0,131.9,130.6,130.0,129.7,128.6,128.5,128.4,128.2, 128.0,127.9,127.83,127.80,127.7,126.8,115.5,86.8,84.3,81.1, 79.5,78.4,77.4,75.9,75.3,75.1,73.6,73.3,69.2,67.3,38.4,33.1;

[0122] IR(ATR):

[0123] HRMS(ESI)Calcd for C 51 H 51 ClO7[M+NH4]+:828.3662m / z,found:828.3663m / z;[α] D 18 =

[0124] +8.8 (c=7.1, CHCl3).

[0125] Example 4

[0126] This embodiment describes a catalytic synthesis method for canagliflozin, specifically including the following processes:

[0127]

[0128] Perform the following steps in sequence:

[0129] Under a nitrogen atmosphere, NiBr2·DME (0.05 mmol, 5.0 mol%, 15.4 mg) and (S,S)-L16 (0.05 mmol, 5.0 mol%, 17.4 mg) were dissolved in 8.0 mL of tetrahydrofuran solution and stirred for 30 min to form a complex solution. Glycosyl phosphate (28, 1.0 mmol, 588.5 mg, 1.0 equiv.) and aryl iodine (22, 0.1 mmol, 408.3 mg, 1.0 equiv.) were dissolved in 4.0 mL of tetrahydrofuran and then added to the pre-complex solution. Then, organozirconium metal (25, 1.7 mmol, 794.7 mg, 1.7 equiv.) was added, the mixture was sealed, and stirred at 25 °C for 18 h. The reaction was quenched with 5.0 mL of methanol at room temperature. The reaction solution was then evaporated to dryness and purified by silica gel column chromatography (PE:EA = 20:1 → 5:1) to obtain the canagliflozin intermediate (29,465.5 mg).

[0130] Canagliflozin intermediate 29(β) was a white solid, characterized by consistency with standards as determined by liquid chromatography-mass spectrometry (LC-MS) and nuclear magnetic resonance (NMR). The reaction yield was 75%, and the stereoselectivity was confirmed by NMR to be α:β = 10.0:90.0. The stereoselectivity characterization chromatogram is shown below. Figure 4 As shown.

[0131] The characterization data of canagliflozin intermediate 29(β) are as follows:

[0132] R f =0.5(petroleum ether:EtOAc,2:1)

[0133] 1 H-NMR(500MHz, CDCl3)δp.pm7.50–7.42(m,2H),7.24(d,J=1.8Hz,1H),7.20(dd,J=7.7, 1.8Hz,1H),7.14(d,J=7.7Hz,1H),7.06–6.97(m,3H),6.71–6.60(m,1H),4.94–4.89(m, 2H),4.87(d,J=6.3Hz,1H),4.78(d,J=6.3Hz,1H),4.68–4.62(m,2H),4.35(d,J=6.4Hz, 1H),4.14(d,J=9.4Hz,1H),4.10(s,2H),4.02(d,J=6.4Hz,1H),3.94–3.89(m,1H),3.77–

[0134] 3.70(m,2H),3.65–3.60(m,1H),3.58–3.52(m,2H),3.48–3.41(m,6H),3.32(s,3H),2.87(s,3H),2.30(s,3H);

[0135] 13 C-NMR(125MHz,CDCl3)δ162.2(d,J C-F =246.6Hz),143.6,141.6,138.2,136.9,136.6,131.0,130.6,129.3,127.23,127.17,126.5,126.0,122. 8,115.9,115.8,98.9,98.8,97.6,96.9,83.7,81.7,80.6,78.9,67.0,56.7,56.7,56.1,55.4,34.3,19.4;

[0136] 19 F-NMR (376MHz, CDCl3) δ-115.2;

[0137] IR(ATR):

[0138] HRMS(ESI) Calculation for [M+NH4] + :638.2794m / z, found:638.2800m / z; [α] D 17 =12.1 (c=4.0, CHCl3).

[0139] Under a nitrogen atmosphere, the canagliflozin intermediate (29, 0.75 mmol, 465.5 mg, 1.0 equiv.) was placed in 7.5 mL of methanol, and 6N hydrochloric acid (3.75 mmol, 0.62 mL, 5.0 equiv.) was added. The mixture was stirred at room temperature for 12 hours to remove protection. The reaction solution was then distilled under reduced pressure to dryness and purified by silica gel column chromatography (CH2Cl2:MeOH, 10:1) to obtain canagliflozin (30, 250.0 mg).

[0140] Canagliflozin is a white solid, and its consistency with standards was confirmed by liquid chromatography-mass spectrometry (LC-MS) and nuclear magnetic resonance (NMR). The deprotection separation yield was 75%, and the characterization data are as follows:

[0141] R f =0.4(CH2Cl2:MeOH, 10:1)

[0142] 1H-NMR(400MHz,DMSO)δp.pm7.63–7.55(m,2H),7.28(d,J=3.6Hz,1H),7.23– 7.17(m,3H),7.16–7.10(m,2H),6.80(d,J=3.6Hz,1H),4.97–4.92(m,2H),4. 75(d,J=5.7Hz,1H),4.49–4.43(m,1H),4.17–4.07(m,2H),3.96(d,J=9.3Hz, 1H),3.74–3.65(m,1H),3.48–3.40(m,1H),3.28–3.13(m,4H),2.26(s,3H).;

[0143] 13 C-NMR (100MHz, DMSO) δ 161.4 (d, J C-F =244.1Hz),143.7,140.3,138.3,137.4,135.0,130.58,130.55,129.7,129.1,127.1,12 7.0,126.4,126.3,123.5,116.1,115.9,81.4,81.3,78.5,74.7,70.5,61.5,33.5,18.9.;

[0144] 19 F-NMR (376MHz, DMSO) δ-115.1.

[0145] IR(ATR):

[0146] HRMS(ESI) Calculation for [M+NH4] + :462.1745m / z,found:462.1738m / z.

[0147] In summary, this invention achieves ligand-determined stereoselectivity control of products, enabling the synthesis of canagliflozin and intermediates of dapagliflozin and empagliflozin with high yield and selectivity, which is of great significance for the rapid, large-scale synthesis of SGLT2 inhibitors.

[0148] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any form or substance. It should be noted that those skilled in the art can make various improvements and additions without departing from the method of the present invention, and these improvements and additions should also be considered within the scope of protection of the present invention. Any modifications, alterations, and equivalent changes made by those skilled in the art based on the above-disclosed technical content without departing from the spirit and scope of the present invention are equivalent embodiments of the present invention. Furthermore, any modifications, alterations, and evolutions made to the above embodiments based on the essential technology of the present invention still fall within the scope of the technical solution of the present invention.

Claims

1. A catalytic synthesis method for a levofloxacin-based drug intermediate, characterized in that, The general structural formula of the intermediate of the levofloxacin drug is shown in Formula 15. The catalytic synthesis method is as follows: under the action of a nickel catalyst and a chiral dinitrogen ligand, the compounds shown in Formula 12, Formula 13, and Formula 14 are contacted and reacted to form the compound shown in Formula 15. The synthetic route is as follows: ； Wherein, R is selected from one or more of straight-chain alkoxy, unsubstituted arylmethoxy, and methoxymethyl; R 1 It is selected from one or more of straight-chain or branched alkyl, cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic aryl; X is selected from Cl, Br, and I; and R 2 It is trimethylsilyl; R 3 Selected from phenyl; The nickel catalyst is selected from one or more of ethylene glycol dimethyl ether nickel bromide and ethylene glycol dimethyl ether nickel chloride; The chiral dinitrogen ligand is selected from one or more of the following structural formulas: 、 、 、 、 ； The general structural formula for Ar is shown below: ; Where R 4 R is a halogen atom, a substituted or unsubstituted alkyl group. 5 It refers to substituted or unsubstituted aryl groups, or substituted or unsubstituted heterocyclic aryl groups.

2. The catalytic synthesis method according to claim 1, characterized in that, R is benzyloxy or methoxymethoxy; And / or, R 1 It is p-tert-butylphenyl; And / or, X is I; And / or, R 3 It can be a substituted or unsubstituted phenyl group; And / or, the amount of the compound shown in Formula 13 is 75% to 200% of the molar amount of the compound shown in Formula 12; And / or, the amount of the nickel catalyst used is 1 to 20% of the molar amount of the compound shown in Formula 12; And / or, the amount of the compound shown in Formula 14 is 75% to 200% of the molar amount of the compound shown in Formula 12; And / or, the reaction solvent is one or more selected from tetrahydrofuran, toluene, methylcyclopentanehexane ether, 2-methoxytetrahydrofuran, methyl tert-butyl ether, and benzene; And / or, the reaction temperature is -20~50℃.

3. The catalytic synthesis method according to claim 2, characterized in that, Ar can be any one of the structures in formulas I-IV. ； And / or, the R 2 It is trimethylsilyl; And / or, the R 3 It is p-tert-butylphenyl; And / or, R 3 It is a phenyl group.

4. A method for synthesizing an intermediate compound of dapagliflozin, characterized in that, Under the action of a nickel catalyst and a chiral dinitrogen ligand, the compounds shown in Formula 16, Formula 17, and Formula 18 are contacted and reacted to form the compound shown in Formula 19. The synthetic route is as follows: ； Among them, R 9 It is selected from one or more of straight-chain alkyl, unsubstituted arylmethyl, and methoxymethyl; R 10 It is selected from one or more of straight-chain or branched alkyl, cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic aryl; R 11 It is phenyl; The nickel catalyst is selected from one or more of ethylene glycol dimethyl ether nickel bromide and ethylene glycol dimethyl ether nickel chloride; The chiral dinitrogen ligand is selected from one or more of the following structural formulas: 、 、 、 、 。 5. A method for synthesizing an intermediate compound of empagliflozin, characterized in that, Under the action of a nickel catalyst and a chiral dinitrogen ligand, the compounds shown in Formula 16, Formula 20, and Formula 18 are contacted and reacted to form the compound shown in Formula 21. The synthetic route is as follows: ； Among them, R 9 It is selected from one or more of straight-chain alkyl groups and unsubstituted arylmethylmethoxymethyl groups; R 10 It is selected from one or more of straight-chain or branched alkyl, cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic aryl; R 11 It is phenyl; The nickel catalyst is selected from one or more of ethylene glycol dimethyl ether nickel bromide and ethylene glycol dimethyl ether nickel chloride; The chiral dinitrogen ligand is selected from one or more of the following structural formulas: 、 、 、 、 。 6. A method for synthesizing an intermediate compound of canagliflozin, characterized in that, Under the action of a nickel catalyst and a chiral dinitrogen ligand, the compounds shown in Formula 16, Formula 22, and Formula 18 are contacted and reacted to form the compound shown in Formula 23. The synthetic route is as follows: ; Among them, R 9 It is selected from one or more linear alkyl groups and unsubstituted aryl methyl groups; R 10 It is selected from one or more of straight-chain or branched alkyl, cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic aryl; R 11 It is selected from phenyl; The nickel catalyst is selected from one or more of ethylene glycol dimethyl ether nickel bromide and ethylene glycol dimethyl ether nickel chloride; The chiral dinitrogen ligand is selected from one or more of the following structural formulas: 、 、 、 、 。 7. The method according to any one of claims 4 to 6, characterized in that, The reaction also uses a reaction solvent, which is one or more selected from tetrahydrofuran, toluene, methylcyclopentanehexane ether, 2-methoxytetrahydrofuran, methyl tert-butyl ether, and benzene; And / or, the reaction temperature is -20~50℃; And / or, the R 9 It is benzyl or methoxymethyl; And / or, the R 10 It is p-tert-butylphenyl; And / or, the R 11 It is a phenyl group.

8. The method according to any one of claims 4 to 6, characterized in that, The amount of the compound shown in Formula 17 is 75% to 200% of the molar amount of the compound shown in Formula 16; And / or, the amount of the compound shown in Formula 20 is 75% to 200% of the molar amount of the compound shown in Formula 16; And / or, the amount of the compound shown in Formula 22 is 75% to 200% of the molar amount of the compound shown in Formula 16; And / or, the amount of the nickel catalyst used is 1 to 20% of the molar amount of the compound shown in Formula 16; And / or, the amount of the compound shown in Formula 18 is 75 to 200% of the molar amount of the compound shown in Formula 16.

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