Alpha-chloro-beta-hydroxy phosphate compound as well as synthesis method and application thereof

Abstract

The invention belongs to the technical field of asymmetric catalysis, and particularly discloses a fosfomycin key intermediate alpha-chloro-beta-hydroxy phosphate compound as well as a synthesis method and application of the fosfomycin key intermediate alpha-chloro-beta-hydroxy phosphate compound. The alpha-chloro-beta-hydroxyl phosphate is shown as a formula II in the specification. The synthesis method comprises the following step: in the presence of a catalyst, reacting a compound as shown in a structural formula I with the catalyst, an organic solvent and a hydrogen source to obtain a compound as shown in a formula II. According to the invention, alpha-chloro-beta-carbonyl phosphate is reduced by an asymmetric catalytic transfer hydrogenation method, and the hydrogenated product can be used as a key intermediate for synthesis of fosfomycin or a fosfomycin derivative. The product obtained by the synthesis method has excellent yield and enantioselectivity. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the technical field of asymmetric catalysis, and particularly provides a chiral α-chloro-β-hydroxy phosphate compound, a synthesis method thereof, and an application thereof. Background Art

[0002] Chiral compounds widely exist in natural products, bioactive molecules, and clinical drug molecules (or their key intermediates). In the field of new drug research, among more than 1,200 drugs under research, 820 are chiral molecules, accounting for nearly 70%. The research on chiral drugs has been very rapid in recent years, and major drug research and development companies have developed small molecule drugs. The proportion of single-chiral compounds is gradually increasing. The importance of chiral research is self-evident.

[0003] Fosfomycin is a broad-spectrum antibiotic initially isolated from Streptomyces fradiae, with a unique chemical structure and significant antibacterial activity. Its core structure is an epoxy phosphonate, which contains a phosphonic acid group and an epoxyethyl group and can inhibit the synthesis of bacterial cell walls.

[0004]

[0005] Fosfomycin mainly inhibits the activity of uridine diphosphate glucuronic acid amide by interfering with the early steps of bacterial cell wall synthesis, thereby effectively preventing the construction of bacterial cell walls and causing bacterial cell death. Fosfomycin is mainly used clinically to treat bacterial infections such as urinary tract infections, especially having strong effects against common pathogenic bacteria such as Escherichia coli, Klebsiella, and Enterococcus. In addition, fosfomycin is also used to treat drug-resistant bacterial infections, such as multi-drug-resistant Staphylococcus aureus. Fosfomycin is administered orally or by intravenous injection and is widely used clinically. At present, a method for synthesizing fosfomycin using α-chloro-β-hydroxy phosphonate as a raw material has been reported by C.P. Morocco et al. in the journal "Tetrahedron Asymmetry", and the specific synthesis route is as follows:

[0006]

[0007] Literature "Dynamic kinetic resolution ofa-chloro b-keto estersandphosphonates:hemisynthesis of "Through Ru-DIFLUORPHOS Asymmetric Hydrogenation" reveals a method for the efficient synthesis of α-chloro-β-hydroxyphosphonates, using a ruthenium catalyst for asymmetric hydrogenation reactions. However, the reaction process is sensitive to temperature and pressure conditions. Although a higher temperature may increase the reaction rate, it is prone to cause side reactions of dechlorination, affecting the purity and yield of the product. The selection of hydrogen pressure is also crucial. While ensuring the reaction efficiency, it is necessary to avoid the operational complexity and increased costs brought about by excessive pressure. The synthesis method of fosfomycin faces certain challenges, especially how to efficiently obtain the key intermediate of α-chloro-β-hydroxyphosphate with excellent enantioselectivity and diastereoselectivity.

[0008] In recent years, asymmetric synthesis methods based on catalytic transfer hydrogenation and dynamic kinetic resolution have gradually been developed, providing a more efficient and safe route for the industrial synthesis of fosfomycin. Among all chiral compounds, chiral alcohols belong to a common type of chiral molecules and are widely used in the fields of small molecule drugs, pesticides, natural compounds, and functional materials. Organometallic-catalyzed asymmetric hydrogenation reactions have the advantages of mild reaction conditions, high efficiency and selectivity, and a wide range of substrate applicability, and have received extensive attention and in-depth research. Summary of the Invention

[0009] The object of the present invention is to provide an α-chloro-β-hydroxyphosphate compound, its synthesis method and application, in order to screen out α-chloro-β-hydroxyphosphates with excellent enantioselectivity and diastereoselectivity as important intermediates for the synthesis of fosfomycin or its derivatives. The synthesis method provided by the present invention has easily available raw materials, good substrate applicability, and excellent reaction activity and enantioselectivity at a relatively high turnover number. During the reaction process, it exhibits excellent reaction activity and enantioselectivity and has broad application prospects. To achieve the above object, in the first aspect of the present invention, an α-chloro-β-hydroxyphosphate compound is proposed, as shown in Formula II,

[0010]

[0011] R 1 is selected from methyl, ethyl, n-propyl, substituted or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic groups;

[0012] R 2 is selected from methyl, ethyl or n-propyl;

[0013] The carbon atoms marked with * are independently R configuration or S configuration, or achiral carbon atoms.

[0014] In some specific embodiments, the substituted or unsubstituted aryl is selected from substituted or unsubstituted C 6-10 aryl or substituted or unsubstituted C11-14 Polycyclic aryl group.

[0015] In some specific embodiments, the substituted or unsubstituted aromatic heterocyclic group is selected from a substituted or unsubstituted 5- to 6-membered aromatic heterocyclic group, a substituted or unsubstituted 8- to 10-membered fused aromatic heterocyclic group, or a substituted or unsubstituted 7- to 10-membered bridged aromatic heterocyclic group.

[0016] In some embodiments, the substituted or unsubstituted C 6-10 aryl group is selected from: a substituted or unsubstituted C6 aryl group, a substituted or unsubstituted C7 aryl group, a substituted or unsubstituted C8 aryl group, a substituted or unsubstituted C9 aryl group, a substituted or unsubstituted C 10 aryl group.

[0017] In some specific embodiments, the substituted or unsubstituted C 11-14 polycyclic aryl group is selected from: a substituted or unsubstituted C 11 polycyclic aryl group, a substituted or unsubstituted C 12 polycyclic aryl group, a substituted or unsubstituted C 13 polycyclic aryl group, a substituted or unsubstituted C 14 polycyclic aryl group.

[0018] In some specific embodiments, the substituted or unsubstituted 5- to 6-membered aromatic heterocyclic group is selected from: a substituted or unsubstituted 5-membered aromatic heterocyclic group, a substituted or unsubstituted 6-membered aromatic heterocyclic group.

[0019] In some specific embodiments, the substituted or unsubstituted 8- to 10-membered fused aromatic heterocyclic group is selected from: a substituted or unsubstituted 8-membered fused aromatic heterocyclic group, a substituted or unsubstituted 9-membered fused aromatic heterocyclic group, a substituted or unsubstituted 10-membered fused aromatic heterocyclic group.

[0020] In some specific embodiments, the substituted or unsubstituted 7- to 10-membered bridged aromatic heterocyclic group is selected from: a substituted or unsubstituted 7-membered bridged aromatic heterocyclic group, a substituted or unsubstituted 8-membered bridged aromatic heterocyclic group, a substituted or unsubstituted 9-membered bridged aromatic heterocyclic group, a substituted or unsubstituted 10-membered bridged aromatic heterocyclic group.

[0021] In some specific embodiments, the substitution in the substituted or unsubstituted aryl group means that at least one hydrogen atom on the aryl group is substituted by a methyl group, a methoxy group, a fluorine atom, a chlorine atom, or a bromine atom.

[0022] In some specific embodiments, the substitution in the substituted or unsubstituted aromatic heterocyclic group means that at least one hydrogen atom on the aromatic heterocyclic group is substituted by a methyl group, a methoxy group, a fluorine atom, a chlorine atom, or a bromine atom.

[0023] In some specific embodiments, the compound represented by Formula II is selected from compounds having the following structures:

[0024]

[0025] The second aspect of the present invention provides a method for synthesizing a compound represented by Formula II, comprising:

[0026] Under an inert gas or nitrogen atmosphere, the compound represented by Formula I is fully mixed with a catalyst, an organic solvent, and a hydrogen source to form a reaction system, and after the reaction, the compound represented by Formula II is obtained; the reaction formula is as follows:

[0027]

[0028] In Formulas I and II, R 1 and R 2 are respectively the same as R 1 and R 2 of the α-chloro-β-hydroxy phosphate compound described in the first aspect.

[0029] In some specific embodiments, the inert gas is selected from at least one of neon, helium, argon, krypton, and xenon.

[0030] In some specific embodiments, the compound represented by Formula I is selected from compounds having the following structures:

[0031]

[0032] The synthesis method of the above compound represented by Formula I can refer to the prior art, for example, it can be prepared by strategies such as asymmetric catalytic hydrogenation [1] or dynamic kinetic resolution [2].

[0033] [1]Tetrahedron:Asymmetry 2011,22(18-19),1784-1789.

[0034] [2]Tetrahedron:Asymmetry 2010,21(11-12),1436-1446.

[0035] In some specific embodiments, the catalyst is obtained by complexing a ligand with a transition metal precursor.

[0036] In some specific embodiments, the molar ratio of the catalyst to the compound represented by Formula I in the feed is 0.0001:1 to 0.1:1.

[0037] In some specific embodiments, the molar ratio of the catalyst to the compound represented by Formula I is 0.0001:1, 0.0002:1, 0.0003:1, 0.0004:1, 0.0005:1, 0.0006:1, 0.0007:1, 0.0008:1, 0.0009:1, 0.001:1, 0.002:1, 0.003:1, 0.004:1, 0.005:1, 0.006:1, 0.007:1, 0.008:1, 0.009:1, 0.01:1, 0.02:1, 0.03:1, 0.04:1, 0.05:1, 0.06:1, 0.07:1, 0.08:1, 0.09:1 or 0.1:1.

[0038] In some specific embodiments, the reaction temperature of the reaction system is 10 to 80 °C, preferably 20 to 50 °C.

[0039] In some specific embodiments, the reaction temperature of the reaction system is 20 °C, 21 °C, 22 °C, 23 °C, 24 °C, 25 °C, 26 °C, 27 °C, 28 °C, 29 °C, 30 °C, 31 °C, 32 °C, 33 °C, 34 °C, 35 °C, 36 °C, 37 °C, 38 °C, 39 °C, 40 °C, 41 °C, 42 °C, 43 °C, 44 °C, 45 °C, 46 °C, 47 °C, 48 °C, 49 °C or 50 °C.

[0040] In some specific embodiments, the transition metal precursor is selected from at least one of the precursors of Rh, the precursors of Ir or the precursors of Ru.

[0041] In some specific embodiments, the catalyst is selected from at least one of the following compounds:

[0042]

[0043] wherein R3 is selected from a hydrogen atom (to obtain catalyst 6a), a methyl group (to obtain catalyst 6b), a methoxy group (to obtain catalyst 6c), a fluorine atom (to obtain catalyst 6d) or a trifluoromethyl group (to obtain catalyst 6e).

[0044] In some specific embodiments, the organic solvent is selected from at least one of alcohol solvents, ethyl acetate, tetrahydrofuran, and halogenated solvents.

[0045] In some specific embodiments, the alcohol solvent is selected from at least one of methanol, ethanol, and isopropanol.

[0046] In some specific embodiments, the halogenated solvent is selected from at least one of dichloromethane, dichloroethane, and chloroform.

[0047] In some specific embodiments, the reaction system may optionally contain a basic reagent.

[0048] In some specific embodiments, the basic reagent is selected from at least one of organic bases and inorganic basic reagents.

[0049] In some specific embodiments, the organic base is selected from at least one of triethylamine, diisopropylethylamine, triethylenediamine, 4-dimethylaminopyridine, sodium methoxide, sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide.

[0050] In some specific embodiments, the inorganic basic reagent is selected from at least one of sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium hydroxide, potassium hydroxide, sodium phosphate, and potassium phosphate.

[0051] In some specific embodiments, the hydrogen source is selected from transfer hydrogenation reagents or hydrogen gas.

[0052] In some specific embodiments, when the hydrogen source is a transfer hydrogenation reagent, the transfer hydrogenation reagent is selected from at least one of formic acid, sodium formate, and ammonium formate.

[0053] In some specific embodiments, the molar ratio of the transfer hydrogenation reagent to the basic reagent in the feed is 5.0:1.0 to 5.0:5.0, preferably 5.0:2.0.

[0054] In some specific embodiments, the molar ratio of the transfer hydrogenation reagent to the basic reagent in the feed is 5.0:1.0, 5.0:2.0, 5.0:3.0, 5.0:4.0, or 5.0:5.0.

[0055] In some specific embodiments, when the hydrogen source is hydrogen gas, the reaction system further includes an additive, and the additive is selected from at least one of silver hexafluoroantimonate and silver tetrafluoroborate.

[0056] In some specific embodiments, the molar ratio of the additive to the substrate represented by Formula I in the feed is 1:5 to 1:10, preferably 1:10.

[0057] In some specific embodiments, the molar ratio of the additive to the substrate represented by Formula I in the feed is 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10.

[0058] In some specific embodiments, the pressure of the hydrogen gas is 1 atm to 10 atm.

[0059] In some specific embodiments, the hydrogen gas pressure is 1 atm, 2 atm, 3 atm, 4 atm, 5 atm, 6 atm, 7 atm, 8 atm, 9 atm, or 10 atm.

[0060] The third aspect of the present invention provides an application of the α-chloro-β-hydroxy phosphate compound II-a as described in the first aspect or the α-chloro-β-hydroxy phosphate compound II-a prepared by the preparation method described in the second aspect in the reaction for synthesizing fosfomycin or its derivatives.

[0061] Beneficial effects:

[0062] Compared with the prior art, at least one embodiment of the present invention has at least one of the following beneficial effects:

[0063] (1) The catalyst used in the preparation method provided by the present invention can efficiently catalyze the compound shown in Formula I to obtain the compound shown in Formula II. This method is simple to operate, has high catalytic efficiency, mild reaction conditions, and is suitable for large-scale production. It exhibits excellent reaction activity and enantioselectivity during the synthesis process, can complete the reaction in a short time, has a wide substrate applicability, easily available raw materials, and a high reaction yield, effectively reducing production costs and improving economic benefits.

[0064] (2) The compound shown in Formula II prepared by the preparation method provided by the present invention has a product with high optical purity, and its enantioselectivity value is not less than 95%. More importantly, the reaction exhibits high enantioselectivity, and the diastereomeric ratio of the obtained product exceeds 99:1. In addition, the yield of this reaction is usually higher than 90%, ensuring good synthesis efficiency and low raw material waste.

[0065] (3) The compound shown in Formula II provided by the present invention can be used as an important intermediate in the synthesis of fosfomycin or its derivatives and has significant application prospects. The synthesized fosfomycin or its derivatives not only have high optical purity, but also can simplify the purification steps, reduce the generation of by-products, and improve the overall synthesis efficiency. Due to the mild reaction conditions and simple operation, this method is suitable for large-scale production, and the raw materials are easily available and the production cost is low. Therefore, this method has wide application value in the industrial production of fosfomycin or its derivatives.

[0066] (4) Compared with compound I-p in which the R 2 group is selected from isopropyl, R 2 group is selected from tert-butyl is compound I-q or R 1Compound I-r in which the group is selected from isopropyl, when used as a substrate for synthesizing the compound shown in Formula II, has more excellent yield, enantioselectivity value and diastereomeric ratio than using the compound shown in Formula I provided by the present invention as a substrate for synthesizing the compound shown in Formula II, and has unexpected excellent technical effects. When using hydrogen as the hydrogen source, compared with reacting without adding or adding Additive 1 or Additive 2, the present invention reacts with silver hexafluoroantimonate or silver tetrafluoroborate added when using hydrogen as the hydrogen source, greatly improving the yield, enantioselectivity value and diastereomeric ratio of the compound shown in Formula II, and having unexpected excellent technical effects. Description of the Drawings

[0067] Figure 1 is the 1H NMR spectrum of Compound II-a; Figure 2 is the 13C NMR spectrum of Compound II-a; Figure 3 is the liquid chromatogram of Compound II-a; Figure 4 is the liquid chromatogram of Compound II-a.

[0072] Term Explanation

[0073] Unless otherwise specified, the following terms and phrases as used herein are intended to have the following meanings:

[0074] In the present invention, expressions such as "Compound II" and "the compound shown in Formula II" refer to the same compound.

[0075] The term "atm" represents standard atmospheric pressure. For example, 1 atm represents 1 standard atmospheric pressure (101.325 kPa).

[0076] The term "and / or" should be understood to mean any one of the alternatives or a combination of any two or more of the alternatives.

[0077] The terms "optionally", "optional" or "optionally" mean that the subsequent described event or situation may but does not necessarily occur. For example, "Optionally, the heteroatoms in the heterocycle include at least one selected from nitrogen, oxygen, and sulfur" means that the situation that "the heteroatoms in the heterocycle include at least one selected from nitrogen, oxygen, and sulfur" may or may not exist.

[0078] In various parts of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to group types or ranges. Specifically noted, the present invention includes each independent secondary combination of each member of these group types and ranges. For example, the term "C1-C6 alkyl" specifically refers to methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl independently disclosed.

[0079] In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variables listed for that group should be understood as the linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl", then it should be understood that the "alkyl" or "aryl" represents a linked alkylene group or arylene group, respectively.

[0080] "Room temperature" in the present invention refers to the ambient temperature, with the temperature ranging from about 10 °C to about 40 °C. In some embodiments, "room temperature" refers to the temperature ranging from about 20 °C to about 30 °C; in other embodiments, "room temperature" refers to the temperature ranging from about 25 °C to about 30 °C; in still other embodiments, "room temperature" refers to 10 °C, 15 °C, 20 °C, 25 °C, 30 °C, 35 °C, 40 °C, etc.

[0081] "Alkyl" is a hydrocarbon containing primary, secondary, tertiary, or cyclic carbon atoms. For example, an alkyl can have 1 to 20 carbon atoms (i.e., C1-C 20(alkyl), from 1 to 8 carbon atoms (i.e., C1-C8 alkyl) or from 1 to 6 carbon atoms (i.e., C1-C6 alkyl). Examples of suitable alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (i-Pr, i-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3 or n-octyl (-(CH2)7CH3).

[0082] The term "alkylene" refers to a saturated divalent hydrocarbon radical obtained by removing two hydrogen atoms from a saturated straight-chain or branched-chain hydrocarbon radical. Unless otherwise specified in detail, the alkylene radical contains 1-12 carbon atoms. In one embodiment, the alkylene radical contains 1-6 carbon atoms; in another embodiment, the alkylene radical contains 1-4 carbon atoms; in yet another embodiment, the alkylene radical contains 1-3 carbon atoms; still in one embodiment, the alkylene radical contains 1-2 carbon atoms. Such examples include methylene (-CH2-), ethylene (-CH2CH2-), isopropylidene (-CH(CH3)CH2-), and the like. The alkylene radical is optionally substituted with one or more substituents described in the present invention.

[0083] The term "aryl" refers to a monocyclic, bicyclic, and tricyclic carbocyclic system containing 6-20 ring atoms, or 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring system is aromatic, and each ring system contains a ring composed of 3-7 atoms. The aryl group is usually, but not necessarily, connected to the parent molecule through the aromatic ring of the aryl group. The term "aryl" can be used interchangeably with the terms "aromatic ring" or "aromatic ring". Examples of aryl groups can include groups derived from benzene (e.g., phenyl), substituted benzene, naphthalene, anthracene, biphenyl, and the like. The aryl group is optionally substituted with one or more substituents described in the present invention.

[0084] The term "heteroaryl" or "aromatic heterocyclic group" refers to a monocyclic, bicyclic, and tricyclic system containing 4-20 ring atoms, or 4-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, and each ring system contains a ring composed of 4-7 atoms and has one or more attachment points connected to the rest of the molecule. The term "heteroaryl" can be used interchangeably with the terms "aromatic heterocyclic group", "heteroaromatic ring", or "heteroaromatic compound". The heteroaryl group is optionally substituted with one or more substituents described in the present invention. In one embodiment, the heteroaryl composed of 4-20 ring atoms contains 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N.

[0085] Examples of heteroaryl groups or aromatic heterocyclic groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (such as 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, pyrazinyl, 1,3,5-triazinyl; also included are the following bicyclics, but by no means limited to these bicyclics: benzimidazolyl, benzofuryl, benzothienyl, indolyl (such as 2-indolyl), purinyl, quinolinyl (such as 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (such as 1-isoquinolinyl, 3-isoquinolinyl or 4-isoquinolinyl), imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridyl, and so on.

[0086] The term "substituted" or "substitution" means that one or more hydrogen atoms in the structure are replaced by specific substituents. Unless otherwise indicated, a substituted group can have a substituent at each substitutable position of the group. When more than one position in the given structural formula can be substituted by one or more substituents selected from a specific group, the substituents can be the same or different at each position.

[0087] The term "unsubstituted" means that the specified group does not carry a substituent.

[0088] The term "substituted" in relation to alkyl, aryl, arylalkyl, aromatic heterocyclic group, carbocyclic group, etc., such as "substituted C1-C 10 alkyl", "substituted C6-C 20 aryl", "substituted arylalkyl", "substituted C1-C 20 aromatic heterocyclic group" and "substituted carbocyclic group" respectively mean C1-C in which one or more hydrogen atoms are each independently replaced by a non-hydrogen substituent 10 alkyl, C6-C 20Aryl, arylalkyl, C1-C 20 Aromatic heterocyclic group, carbocyclic group. Unless otherwise indicated, when the term "substituted" is used in connection with a group having two or more moieties capable of being substituted, such as arylalkyl, the substituents may be attached to the aryl moiety, the alkyl moiety, or both.

[0089] The term "composed of j-k atoms" or "j-k membered" means that the cyclic group is composed of j-k ring atoms, which include carbon atoms and / or heteroatoms such as O, N, S, P, etc.; j and k are each independently any non-zero natural number, and k > j; the "j-k" includes j, k, and any natural number between the two. For example, "composed of 3-8 atoms" or "3-8 membered", "composed of 3-6 atoms" or "3-6 membered", "composed of 5-10 atoms" or "5-10 membered", "composed of 5-6 atoms" or "5-6 membered" means that the cyclic group is composed of 3-8 (i.e., 3, 4, 5, 6, 7, or 8), 3-6 (i.e., 3, 4, 5, or 6), 5-10 (i.e., 5, 6, 7, 8, 9, or 10), or 5-6 (i.e., 5 or 6) ring atoms, which include carbon atoms and / or heteroatoms such as O, N, S, P, etc. For another example, piperidinyl is a heterocyclic group composed of 6 atoms or a 6-membered heterocyclic group, and pyridinyl is a heteroaryl group composed of 6 atoms or a 6-membered heteroaryl group.

[0090] The terms "j-k", "j-k membered", or "C j -C k " in which j and k are each independently any non-zero natural number, and k > j; for example, "1-4" means 1, 2, 3, or 4, "4-6 membered" means 4-membered, 5-membered, or 6-membered; "C3-C6" means C3, C4, C5, or C6. And so on.

[0091] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0092] Whenever a compound described herein is substituted by more than one identical designated group (e.g., "R" or "R 1 "), it should be understood that these groups may be the same or different, i.e., each group is independently selected. Detailed Description of the Invention

[0093] To enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting examples are further disclosed below to further illustrate the present invention in detail.

[0094] In the following examples, "NMR" refers to nuclear magnetic resonance, which is a technique based on the magnetic behavior of atomic nuclei in a magnetic field and analyzes the structure and properties of substances by measuring the energy of electromagnetic waves absorbed or released by atomic nuclei.

[0095] The object of the present invention is to provide an α-chloro-β-hydroxy phosphate compound, its synthesis method and application, so as to screen out α-chloro-β-hydroxy phosphates with excellent enantioselectivity and diastereoselectivity as important intermediates for synthesizing fosfomycin or its derivatives. The chiral α-chloro-β-hydroxy phosphate compound is prepared by the reaction described in the present invention, and the reaction formula is as follows:

[0096]

[0097] R 1 is selected from methyl, ethyl, n-propyl, substituted or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic groups, and R 2 is selected from methyl, ethyl or n-propyl.

[0098] Example 1:

[0099] (1) Synthesis of the chiral alcohol shown in Structural Formula II-a

[0100] Under a nitrogen atmosphere, 0.1 mmol of the compound shown in I-a, 0.001 mmol of Catalyst 1, 0.2 mL of dichloromethane, and 0.05 mL of a formic acid triethylamine mixture (the molar ratio of formic acid to triethylamine in the feed is 5:2) were added to a hydrogenation flask. After stirring at room temperature for two hours, the reaction solution was separated by column chromatography to obtain the chiral alcohol shown in II-a (colorless oil).

[0101] By 1 HNMR and 13 13C NMR spectra to determine the structure of the hydrogenation product, use high-performance liquid chromatography to determine the enantioselectivity value of the product, and conduct yield analysis through nuclear magnetic resonance hydrogen spectrum. The nuclear magnetic resonance analysis results show that the yield is 91%, the enantioselectivity value is 97%, and the diastereomeric excess is >99:1.

[0102]

[0103] Catalyst 1 used in this example has the following structure:

[0104]

[0105] (2) Experimental results

[0106] The NMR data of the product II-a are as follows:

[0107] 11H NMR (600 MHz, Chloroform-d) δ 4.35 (tt, J = 8.7, 6.3 Hz, 1H), 4.31 - 4.15 (m, 4H), 3.85 (dd, J = 12.5, 2.4 Hz, 1H), 1.42 - 1.32 (m, 9H).

[0108] 13 13C NMR (151 MHz, Chloroform-d) δ 66.19, 63.93, 57.17, 20.12, 16.41.

[0109] The enantioselectivity values and diastereomeric excess were obtained by high performance liquid chromatography analysis. Chiral OD-H column, 230 nm, 25 °C, n Hexane: i PrOH = 90:10; flow 1.0 mL / min; t1 (minor) = 5.56 min, t2 (minor) = 5.85 min, t3 (minor) = 7.99 min, t4 (major) = 10.53 min.

[0110] Examples 2 - 34: Screening of catalysts, solvents, and organic bases

[0111] Examples 2 - 34 were carried out as follows: Chiral alcohols shown in Structural Formulas II-a to II-o were synthesized. Under a nitrogen atmosphere, 0.1 mmol of the compound (raw materials shown in Table 1) was mixed with 0.001 mmol of the catalyst (shown in Table 1), 0.2 mL of the organic solvent (shown in Table 1), and 0.05 mL of the transfer hydrogenation reagent / base mixture (the molar ratio of the transfer hydrogenation reagent to the base was 5:2). After stirring at room temperature for two hours, the reaction solution was separated by column chromatography to obtain the chiral alcohol shown in II.

[0112] The following catalysts were used in the following examples:

[0113]

[0114] Among them, in Compound 6, R 3 was selected from a hydrogen atom (catalyst 6a), a methyl group (catalyst 6b), a methoxy group (catalyst 6c), a fluorine atom (catalyst 6d), or a trifluoromethyl group (catalyst 6e).

[0115] By 1 1H NMR and 13 13C NMR spectra, the structure of the hydrogenation product was determined. The enantioselectivity values of the product were determined by high performance liquid chromatography, and the yield was analyzed by 1H NMR, as shown in Table 1.

[0116] Table 1 Comparison Table of Synthesis Conditions and Yields of α-Chloro-β-Hydroxy Phosphate Compounds

[0117]

[0118]

[0119]

[0120] The structures of the compounds Ⅰ-a to Ⅰ-o are as follows respectively:

[0121]

[0122] The structures of the compounds Ⅱ-a to Ⅱ-o are as follows respectively:

[0123]

[0124] Examples 35 to 37: Exploration of the Dosage of the Catalyst

[0125] Examples 35 to 37 are carried out as follows: Under a nitrogen atmosphere, 0.1 mmol of the compound shown in Ⅰ-a, the catalyst 6c with different dosages (see Table 2), 0.2 mL of dichloromethane, and 0.05 mL of a mixture of triethylamine formate (the molar ratio of formic acid to triethylamine is 5:2) are mixed. After stirring at room temperature for two hours, the reaction solution is separated by column chromatography to obtain the chiral alcohol shown in Ⅱ-a.

[0126] Through 1 HNMR and 13 C NMR spectra to determine the structure of the hydrogenation product, using high-performance liquid chromatography to determine the enantioselectivity value of the product, and analyzing the yield through nuclear magnetic resonance hydrogen spectrum, as shown in Table 2.

[0127] Table 2 Table of the Dosage of the Catalyst 6c and the Reaction Results

[0128] Feeding amount of catalyst 6c mmol Yield % Enantioselectivity value % Diastereomeric ratio Example 35 0.0001 85 99 >99:1 Example 36 0.001 97 99 >99:1 Example 37 0.01 98 99 >99:1

[0129] Examples 38 to 41: Exploration of the Molar Ratio of the Transfer Hydrogenation Reagent and the Base

[0130] Examples 38 to 41 are carried out as follows: Under a nitrogen atmosphere, 0.1 mmol of the compound shown in Ⅰ-a, 0.001 mmol of the catalyst 6c, 0.2 mL of dichloromethane, and 0.05 mL of a mixture of triethylamine formate with different molar ratios (see Table 3) are mixed. After stirring at room temperature for two hours, the reaction solution is directly separated by column chromatography to obtain the chiral alcohol shown in Ⅱ-a.

[0131] Through 1 HNMR and 13The structure of the hydrogenated product was determined by 13C NMR spectra, the enantioselectivity value of the product was determined by high performance liquid chromatography, and the yield was analyzed by 1H NMR spectra, as shown in Table 3.

[0132] Table 3 Reaction results of formic acid - triethylamine under different feeding ratios

[0133]

[0134] Examples 42 - 57: Screening of catalysts and solvents when the hydrogen source is hydrogen

[0135] Examples 42 - 57 were carried out as follows: Under a nitrogen atmosphere, 0.1 mmol of the compound shown in I-a, 0.001 mmol of the catalyst (see Table 4), and 0.2 mL of the organic solvent (see Table 4) were mixed and hydrogen was introduced. The hydrogen pressure in the reaction system was maintained at 5 atm, and 0.01 mmol of silver hexafluoroantimonate was added. After stirring at room temperature for two hours, the reaction solution was directly separated by column chromatography to obtain the chiral alcohol shown in II-a.

[0136] By 1 1H NMR and 13 13C NMR spectra determined the structure of the hydrogenated product, high performance liquid chromatography was used to determine the enantioselectivity value of the product, and 1H NMR spectra were used for yield analysis, as shown in Table 4.

[0137] Table 4 Synthesis conditions and reaction results of α-chloro-β-hydroxy phosphate compounds when the hydrogen source is hydrogen

[0138]

[0139] Note: ND means not detected.

[0140] Examples 58 - 61: Exploration of the feeding amount of additives when the hydrogen source is hydrogen

[0141] Examples 58 - 61 were carried out as follows: Under a nitrogen atmosphere, 0.1 mmol (1.0 equivalent) of the compound shown in I-a, 0.001 mmol of catalyst 6c, and 0.2 mL of dichloromethane were mixed and hydrogen was introduced. The hydrogen pressure in the reaction system was maintained at 5 atm, and additives with different feeding amounts (see Table 5) (see Table 5) were added. After stirring at room temperature for two hours, the reaction solution was directly separated by column chromatography to obtain the chiral alcohol shown in II-a. By 1 1H NMR and 13 13C NMR spectra determined the structure of the hydrogenated product, high performance liquid chromatography was used to determine the enantioselectivity value of the product, and 1H NMR spectra were used for yield analysis, as shown in Table 5.

[0142] Table 5 Feeding amounts of different additives and reaction results

[0143]

[0144]

[0145] Example 62: Investigation of Hydrogen Pressure When the Hydrogen Source is Hydrogen

[0146] Under a nitrogen atmosphere, 0.1 mmol of the compound shown in I-a, 0.001 mmol of catalyst 6c, and 0.2 mL of dichloromethane were mixed and hydrogen was introduced. The hydrogen pressure in the reaction system was maintained at 10 atm, and 0.01 mmol of silver hexafluoroantimonate was added. After stirring at room temperature for two hours, the reaction solution was directly separated by column chromatography to obtain the chiral alcohol shown in II-a.

[0147] By 1 HNMR and 13 13C NMR spectra to determine the structure of the hydrogenation product, high performance liquid chromatography to determine the enantioselectivity value of the product, and 1H NMR for yield analysis. The nuclear magnetic resonance analysis results showed a colorless oil, yield: 96%, enantioselectivity value: 96%, >99:1 diastereomeric excess.

[0148] Conclusion: In the above examples of the present invention, the chiral alcohols shown in II-a to II-o were respectively synthesized using the ketones shown in I-a to I-o. The synthesis method of the present invention has the advantages of inexpensive and easily available raw materials, simple operation steps, high catalytic efficiency, high yield, and high enantioselectivity of the product.

[0149] Comparative Examples 1 - 3: Synthesis of II-p to II-r

[0150] Under a nitrogen atmosphere, 0.1 mmol of the compound (see Table 6), 0.001 mmol of catalyst 6c, 0.05 mL of a mixture of triethylamine formate (the molar ratio of formic acid to triethylamine in the feed is 5:2), and 0.2 mL of dichloromethane were mixed. After stirring at room temperature for two hours, the reaction solution was separated by column chromatography to obtain the chiral alcohol shown in II.

[0151] By 1 HNMR and 13 13C NMR spectra to determine the structure of the hydrogenation product, high performance liquid chromatography to determine the enantioselectivity value of the product, and 1H NMR for yield analysis, as shown in Table 6.

[0152] Table 6 Overview of the yield, enantioselectivity value, and diastereomeric excess of the product

[0153] Substrate type Chiral alcohol Yield % Enantioselectivity value % Diastereomeric ratio Comparative example 1 Ⅰ-p Ⅱ-p 46 98 >99:1 Comparative example 2 Ⅰ-q II-q 38 83 86:14 Comparative example 3 Ⅰ-r II-r 58 98 >99:1

[0154] In this example, the chemical structural formulas of I-p, I-q, I-r and II-p, II-q, II-r are shown in the following figure.

[0155]

[0156] Conclusion: Compared with using R 2 Compound I-p in which the group is selected from isopropyl, R 2 Compound I-q in which the group is selected from tert-butyl or R 1 Compound I-r in which the group is selected from isopropyl as the substrate for synthesizing the compound shown in Formula II, using the compound shown in Formula I provided by the present invention as the substrate for synthesizing the compound shown in Formula II, has more excellent yield, enantioselectivity value and diastereomeric ratio, and has unexpected excellent technical effects.

[0157] Comparative Examples 4-8: Exploration of additives when the hydrogen source is hydrogen

[0158] Under a nitrogen atmosphere, 0.1 mmol of the compound shown in I-a, 0.001 mmol of catalyst 6c and 0.2 mL of dichloromethane were mixed and hydrogen was introduced, and the hydrogen pressure in the reaction system was maintained at 5 atm. After stirring at room temperature for two hours, the reaction was directly separated by column chromatography to obtain the chiral alcohol shown in II-a.

[0159] By 1 HNMR and 13 13C NMR spectra to determine the structure of the hydrogenation product, using high performance liquid chromatography to determine the enantioselectivity value of the product, and analyzing the yield by nuclear magnetic resonance hydrogen spectrum, as shown in Table 7.

[0160] Table 7 Table of feed amounts of different additives and reaction results

[0161]

[0162] Conclusion: When using hydrogen as the hydrogen source, compared with reacting without adding or adding silver trifluoroacetate, silver hexafluorophosphate and silver trifluoromethanesulfonate, adding silver hexafluoroantimonate or silver tetrafluoroborate when using hydrogen as the hydrogen source in the present invention greatly improves the yield, enantioselectivity value and diastereomeric ratio of the compound shown in Formula II, and has unexpected excellent technical effects.

[0163] Comparative Example 9: Exploration of reaction without adding base

[0164] Under a nitrogen atmosphere, 0.1 mmol of the compound shown in I-a, 0.001 mmol of catalyst 6c, 0.2 mL of dichloromethane and 0.05 mL of formic acid were added to the hydrogenation flask. After stirring at room temperature for two hours, the reactants did not undergo conversion.

[0165] The NMR data of II-a to II-o obtained in the above examples or comparative examples are shown in Table 8.

[0166] Table 8: NMR data table of II-a to II-o

[0167]

[0168]

[0169]

[0170]

[0171] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. An α-chloro-β-hydroxy phosphate compound, as shown in formula II, R 1 selected from methyl, ethyl, n-propyl, substituted or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group; Preferably, the substituted or unsubstituted aryl is selected from substituted or unsubstituted C 6-10 aryl or substituted or unsubstituted C 11-14 polycyclic aryl; Preferably, the substituted or unsubstituted aromatic heterocyclic group is selected from a substituted or unsubstituted 5- to 6-membered aromatic heterocyclic group, a substituted or unsubstituted 8- to 10-membered fused aromatic heterocyclic group, or a substituted or unsubstituted 7- to 10-membered bridged aromatic heterocyclic group; R 2 selected from methyl, ethyl or n-propyl; The carbon atoms marked with * are each independently in the R configuration or the S configuration, or are achiral carbon atoms.

2. The α-chloro-β-hydroxy phosphate compound according to claim 1, wherein The substitution in the substituted or unsubstituted aryl group means that at least one hydrogen atom on the aryl group is substituted by a methyl group, a methoxy group, a fluorine atom, a chlorine atom, or a bromine atom; Optionally, the substitution in the substituted or unsubstituted aromatic heterocyclic group means that at least one hydrogen atom on the aromatic heterocyclic group is substituted by a methyl group, a methoxy group, a fluorine atom, a chlorine atom, or a bromine atom.

3. The α-chloro-β-hydroxy phosphate compound according to any one of claims 1-2, characterized in that, The compound shown in formula II is selected from the compounds having the following structures:

4. A method for synthesizing the compound represented by Formula II in the α-chloro-β-hydroxy phosphate compound according to any one of claims 1-3, characterized in that, Including: Under an inert gas or nitrogen atmosphere, the compound shown in formula I is fully mixed with a catalyst, an organic solvent, and a hydrogen source to form a reaction system, and the compound shown in formula II is obtained after the reaction; the reaction formula is as follows: In Formula I and Formula II, R 1 and R 2 are respectively the R 1 and R 2 described in any one of Claims 1-3 for the α-chloro-β-hydroxy phosphate compound.

5. The synthesis method according to claim 4, wherein The catalyst is obtained by complexing a ligand with a transition metal precursor; and / or The molar ratio of the catalyst to the compound shown in formula I in the feed is 0.0001:1 to 0.1:1; and / or The reaction temperature of the reaction system is 10 to 80 °C, preferably 20 to 50 °C.

6. The synthesis method according to claim 4, wherein The transition metal precursor is selected from at least one of a precursor of Rh, a precursor of Ir, or a precursor of Ru; Optionally, the catalyst is selected from at least one of the following compounds: Among them, R in Compound 6 3 is selected from a hydrogen atom, a methyl group, a methoxy group, a fluorine atom or a trifluoromethyl group.

7. The method according to claim 4, characterized in that, The organic solvent is selected from at least one of an alcohol solvent, ethyl acetate, tetrahydrofuran, and a halogenated solvent; Optionally, the alcohol solvent is selected from at least one of methanol, ethanol, and isopropanol; and / or, Optionally, the halogenated solvent is selected from at least one of dichloromethane, dichloroethane, and chloroform.

8. The method according to claim 4, characterized in that, The reaction system may optionally contain a basic reagent, Optionally, the basic reagent is selected from at least one of an organic base and an inorganic basic reagent; Optionally, the organic base is selected from at least one of triethylamine, diisopropylethylamine, triethylenediamine, 4-dimethylaminopyridine, sodium methoxide, sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide; and / or, Optionally, the inorganic basic reagent is selected from at least one of sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium hydroxide, potassium hydroxide, sodium phosphate, and potassium phosphate.

9. The method according to any one of claims 4-8, characterized in that The hydrogen source is selected from a transfer hydrogenation reagent or hydrogen, Optionally, when the hydrogen source is a transfer hydrogenation reagent, the transfer hydrogenation reagent is selected from at least one of formic acid, sodium formate, and ammonium formate; Optionally, the molar ratio of the transfer hydrogenation reagent to the basic reagent in the feed is 5.0:1.0 to 5.0:5.0, preferably 5.0:2.0; Optionally, when the hydrogen source is hydrogen, the reaction system further includes an additive, and the additive is selected from at least one of silver hexafluoroantimonate and silver tetrafluoroborate; Optionally, the molar ratio of the additive to the substrate shown in formula I in the feed is 1:5 to 1:10, preferably 1:10; Optionally, the pressure of the hydrogen is 1 atm to 10 atm.

10. Use of an α-chloro-β-hydroxy phosphate compound II-a as described in any one of claims 1-3 or an α-chloro-β-hydroxy phosphate compound II-a prepared by the preparation method as described in any one of claims 4-9 in the reaction for synthesizing fosfomycin or its derivatives.

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