Benzyl isoquinoline compound as well as preparation method and application thereof

Abstract

The invention provides a benzylisoquinoline compound as well as a preparation method and application thereof, and belongs to the field of chemical medicines. The structure of the benzylisoquinoline compound is shown as a formula (I). The benzylisoquinoline compound has the advantages that the effect is fast when the benzylisoquinoline compound is taken once, the super-short-acting non-depolarized muscle relaxation effect can be realized only by depending on the metabolism of an organism, the recovery time is short, the muscle relaxation residue is avoided, and the benzylisoquinoline compound can be used as a super-short-acting non-depolarized muscle relaxation medicine to be clinically applied, and has a good application prospect. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of chemical medicines, and specifically relates to a benzylisoquinoline compound and a preparation method and application thereof. Background Art

[0002] Neuromuscular blockers (also known as muscle relaxants) are used to relax skeletal muscles during endotracheal intubation and surgical operations, and are important adjuvant drugs for anesthesia in surgical operations. Muscle relaxants are divided into two categories based on their mechanism of action: depolarizing and non-depolarizing muscle relaxants. Based on their duration of action, they can be divided into four categories: ultra-short-acting, short-acting, medium-acting, and long-acting (Anesthesiology, 82(1), 33a, 1995). The commonly used depolarizing muscle relaxant is succinylcholine, which has a good interaction with the membrane cholinergic receptors of nerves and muscles, and is not easily decomposed by cholinesterase at the neuromuscular junction, thus producing a relatively long-lasting depolarizing effect. However, due to its special mechanism of action, succinylcholine has serious side effects, such as increased blood potassium, malignant hyperthermia, arrhythmia, increased intraocular pressure, and gastric tension. Despite its obvious side effects, succinylcholine is still the only ultra-short-acting muscle relaxant currently used in clinical practice. In humans, it lasts for 10 minutes and takes effect quickly. Ultra-short durations of action are extremely important in emergency situations to avoid the serious brain damage or even death that may be caused by the use of longer-duration drugs.

[0003] Nondepolarizing muscle relaxants compete with acetylcholine for N at the neuromuscular junction. M Receptors, competitively blocking the depolarizing effect of acetylcholine, relaxing skeletal muscles, and thus exerting a muscle relaxant effect. Due to different mechanisms of action, non-depolarizing muscle relaxants avoid the side effects of depolarizing muscle relaxants and are considered to be safer muscle relaxants in clinical practice. However, all non-depolarizing muscle relaxants currently used in clinical practice do not have ultra-short-acting characteristics (meaning that the duration of muscle relaxation after a single dose is less than 10 minutes). Among them, the non-depolarizing muscle relaxant mivacurium with the shortest duration of action lasts for 15 to 20 minutes when used once, and the other non-depolarizing muscle relaxants have a longer duration of action, such as cisatracurium and rocuronium, which last for 40 to 60 minutes after a single use, and pancuronium, which lasts for more than 60 minutes after a single use.

[0004] An ideal muscle relaxant should have the characteristics of rapid onset, short duration, rapid recovery, and no adverse cardiovascular reactions. Therefore, it is of great significance to research and develop ultra-short-acting non-depolarizing muscle relaxants with similar onset and duration of action as succinylcholine. Summary of the invention

[0005] The purpose of the present invention is to provide a benzyl isoquinoline compound and a preparation method and use thereof.

[0006] The present invention provides a compound, its stereoisomer, its tautomer, its isotope substitute, its solvate or its metabolite, wherein the structure of the compound is shown in formula (I):

[0007]

[0008] in,

[0009] R1, R2, R3, and R4 are independently selected from hydrogen or C 1-8 Alkoxy;

[0010] R5 and R6 are independently selected from C 1-8 Alkyl, L 31 R9, C 2-8 Alkenyl or C 2-8 Alkynyl; L 31 None or C 1-8 Alkylene, R9 is a 3-8 membered cycloalkyl;

[0011] L0 is selected from

[0012] L1 and L2 are independently selected from C 1-8 Alkylene, C 2-8 Alkenylene or C 2-8 Alkyne;

[0013] L3 and L4 are independently selected from the following groups which are unsubstituted or substituted by one or more R7: 1-8 Alkylene, C 2-8 Alkenyl, C 2-8 Alkynyl, 6-10 membered aryl, 6-10 membered biaryl, 3-8 membered cycloalkyl, 3-8 membered bicycloalkyl; each R7 is independently selected from halogen, hydroxyl, amino, nitro, C 1-8 Alkyl, C 2-8 Alkenyl or C 2-8 Alkynyl;

[0014] M is a pharmaceutically acceptable anion;

[0015] And the compound is not

[0016] Furthermore, the structure of the compound is shown in formula (II):

[0017]

[0018]

[0019] in,

[0020] R1, R2, R3, and R4 are independently selected from hydrogen or C 1-4 Alkoxy;

[0021] R5 and R6 are independently selected from C 1-4 Alkyl, L 31 R9, C 2-6 Alkenyl or C 2-6 Alkynyl; L 31 None or C 1-4 Alkylene, R9 is a 3-6 membered cycloalkyl;

[0022] L1 and L2 are independently selected from C 1-4 Alkylene, C 2-6 Alkenylene or C 2-6 Alkynylidene;

[0023] L4 is selected from the following groups which are unsubstituted or substituted by one or more R7: 1-6 Alkylene, C 2-6 Alkenyl, C 2-6 Alkynyl, phenyl, biphenyl, 3-6 membered cycloalkyl, 3-6 membered bicycloalkyl; each R7 is independently selected from halogen, hydroxyl, amino, nitro, C 1-4 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;

[0024] M is a pharmaceutically acceptable anion.

[0025] Further,

[0026] R1, R2, R3, and R4 are each independently selected from hydrogen or methoxy;

[0027] R5 and R6 are independently selected from C 1-2 Alkyl, L 31 R9, C 2-3 Alkenyl or C 2-3 Alkynyl; L 31 None or C 1-2 Alkylene, R9 is a 3-4 membered cycloalkyl;

[0028] L1 and L2 are independently selected from C 1-3 Alkylene, C 2-3 Alkenylene or C 2-3 Alkynylidene;

[0029] L4 is selected from the following groups which are unsubstituted or substituted by one or more R7: 1-4 Alkylene, C 2-4 Alkenyl, C 2-4 Alkynyl, phenyl, biphenyl, 3-6 membered cycloalkyl, 3-6 membered bicycloalkyl; each R7 is independently selected from halogen or C1-4 alkyl;

[0030] M is selected from chloride, bromide, iodide, sulfonate, methanesulfonate, benzenesulfonate or p-toluenesulfonate;

[0031] Preferably,

[0032] L4 is selected from C 1-4 Alkylene,

[0033] Furthermore, the structure of the compound is shown in formula (IIa):

[0034]

[0035] in,

[0036] L4 is selected from C3 alkylene,

[0037] M is selected from chloride, bromide, iodide, sulfonate, methanesulfonate, benzenesulfonate or p-toluenesulfonate.

[0038] Furthermore, the structure of the compound is shown in formula (III):

[0039]

[0040] in,

[0041] R1, R2, R3, and R4 are independently selected from hydrogen or C 1-4 Alkoxy;

[0042] R5 and R6 are independently selected from C 1-4 Alkyl, L 31 R9, C 2-6 Alkenyl or C 2-6 Alkynyl; L 31 None or C 1-4 Alkylene, R9 is a 3-6 membered cycloalkyl;

[0043] L1 and L2 are independently selected from C 1-4 Alkylene, C 2-6 Alkenylene or C 2-6 Alkyne;

[0044] L3 is selected from the following groups which are unsubstituted or substituted by one or more R7: 1-6 Alkylene, C 2-6 Alkenyl, C 2-6 Alkynyl, Phenyl, biphenyl, 3-6 membered cycloalkyl, 3-6 membered bicycloalkyl; each R7 is independently selected from halogen, hydroxyl, amino, nitro, C 1-4 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;

[0045] M is a pharmaceutically acceptable anion;

[0046] And the compound is not

[0047] Further,

[0048] Said R1, R2, R3, and R4 are independently selected from hydrogen or methoxy;

[0049] R5 and R6 are independently selected from C 1-2 Alkyl, L 31 R9, C 2-3 Alkenyl or C 2-3 Alkynyl; L 31 None or C 1-2 Alkylene, R9 is a 3-4 membered cycloalkyl;

[0050] L1 and L2 are independently selected from C 1-3 Alkylene, C 2-3 Alkenylene or C 2-3 Alkyne;

[0051] L3 is selected from the following groups which are unsubstituted or substituted by one or more R7: 1-4 Alkylene, C 2-6 Alkenyl, C 2-6 Alkynyl, Phenyl, biphenyl, 3-6 membered cycloalkyl, 3-6 membered bicycloalkyl; each R7 is independently selected from halogen or C 1-4 alkyl;

[0052] M is selected from chloride, bromide, iodide, sulfonate, methanesulfonate, benzenesulfonate or p-toluenesulfonate;

[0053] Preferably,

[0054] The R5 and R6 are independently selected from methyl, ethyl,

[0055] L3 is C 1-4 Alkylene,

[0056] Furthermore, the structure of the compound is shown in formula (IIIa):

[0057]

[0058] in,

[0059] The R5 and R6 are independently selected from methyl, ethyl,

[0060] L3

[0061] M is selected from chloride, bromide, iodide, sulfonate, methanesulfonate, benzenesulfonate or p-toluenesulfonate.

[0062] Furthermore, the compound is selected from:

[0063]

[0064]

[0065]

[0066] The present invention also provides a pharmaceutical composition, which is prepared by using the aforementioned compound, its stereoisomer, its tautomer, its isotope substitute, its solvate or its metabolite as an active ingredient and adding pharmaceutically acceptable excipients.

[0067] Furthermore, the pharmaceutically acceptable auxiliary material includes a pharmaceutically acceptable excipient.

[0068] Furthermore, the pharmaceutically acceptable excipients include one or more of diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, thickeners, antioxidants, preservatives, stabilizers, surfactants, and buffers.

[0069] The present invention also provides the use of the aforementioned compound, its stereoisomer, its tautomer, its isotope substitute, its solvate or its metabolite in the preparation of muscle relaxants;

[0070] Preferably, the muscle relaxant is a non-depolarizing muscle relaxant;

[0071] More preferably, the non-depolarizing muscle relaxant is an ultra-short-acting non-depolarizing muscle relaxant.

[0072] Definitions of terms used in the present invention: Unless otherwise stated, the initial definitions provided for groups or terms in this document apply to the groups or terms throughout the specification; for terms that are not specifically defined in this document, the meaning that a person skilled in the art can give them should be given based on the disclosure and context.

[0073] The minimum and maximum carbon atom content in a hydrocarbon group is indicated by a prefix, for example, the prefix C a-b Alkyl refers to any alkyl group containing from "a" to "b" carbon atoms. 1-8 Alkyl refers to a straight or branched chain alkyl group containing 1 to 8 carbon atoms; 1-8 The alkylene group refers to a straight chain or branched chain alkylene group containing 1 to 8 carbon atoms.

[0074] "Alkenyl" refers to an aliphatic hydrocarbon group having at least one carbon-carbon double bond. The alkenyl group may be straight chain or branched. When the alkenyl group is preceded by a carbon atom number, for example, "C 2-8 The term "alkenyl" refers to a straight or branched chain alkenyl group having 2 to 8 carbon atoms.

[0075] "Alkynyl" refers to an aliphatic hydrocarbon group having at least one carbon-carbon triple bond. The alkynyl group may be straight chain or branched. When the alkynyl group is preceded by a carbon atom number specification, for example, "C 2-8 The term "alkynyl" refers to a straight or branched chain alkynyl group having 2 to 8 carbon atoms.

[0076] "Cycloalkyl" refers to a saturated or unsaturated cyclic hydrocarbon substituent. For example, "3-8 membered cycloalkyl" refers to a cycloalkyl group having 3 to 8 ring carbon atoms.

[0077] "Bicyclic alkyl" refers to a polycyclic cycloalkyl group in which two rings are connected by a single bond. For example, the structure of a 6-membered cycloalkyl group is

[0078] "Biphenyl" refers to a bicyclic alkyl group in which the cycloalkyl group is phenyl, for example,

[0079] "Halogen" is fluorine, chlorine, bromine or iodine.

[0080] Compared with the prior art, the present invention has the following beneficial effects:

[0081] The benzylisoquinoline compound of formula (I) provided by the present invention has a rapid onset of action after a single administration, can achieve an ultra-short-acting non-depolarizing muscle relaxant effect by relying only on the body's own metabolism, has a fast recovery time, and has no residual muscle relaxant. It can be used as an ultra-short-acting non-depolarizing muscle relaxant in clinical practice, and has a good application prospect.

[0082] Obviously, according to the above contents of the present invention, in accordance with common technical knowledge and customary means in the art, without departing from the above basic technical ideas of the present invention, other various forms of modification, replacement or change may be made.

[0083] The above contents of the present invention are further described in detail below through specific implementation methods in the form of embodiments. However, this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention. DETAILED DESCRIPTION

[0084] The raw materials and equipment used in the specific embodiments of the present invention are all known products and are obtained by purchasing commercially available products.

[0085] Room temperature in the present invention refers to 5-30°C.

[0086] Example 1 Preparation of Compound 1

[0087]

[0088] Step 1) Preparation of compound 1-2

[0089] 10.0 g of compound 1-1, 3.20 g of dichlorothionyl and 50 ml of dichloromethane were put into a container, reacted at room temperature for 5 h, concentrated to dryness under reduced pressure at 45 ° C, and the concentrate was dissolved in 50 ml of dichloromethane. Under nitrogen protection, 1.06 g of 2,4-hexadiyn-1,6-diol and 3.10 g of potassium carbonate were added to react for 21 h. 40 ml of water was added to the reaction solution, and the pH was adjusted to 8 with 3N NaOH solution. The organic phase was washed with water twice, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 45 ° C. The residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 99 / 1 to 96 / 4) to obtain 4.75 g of compound 1-2.

[0090] Step 2) Preparation of Compound 1

[0091] 4.75 g of compound 1-2 was dissolved in 30 ml of acetonitrile, 4.24 g (5.0 eq) of methyl benzenesulfonate was added, and the mixture was protected by nitrogen. The temperature was raised to 60 °C for reaction for 20 h. The reaction solution was concentrated to dryness under reduced pressure at 45 °C. The concentrate was dissolved in 8 ml of dichloromethane and added to 110 ml of ether under stirring to precipitate a solid. After solid-liquid separation, 10 ml of dichloromethane was added to the solid to dissolve it. The solid was added to a mixed solution of 150 ml of ethyl acetate and 50 ml of ether under stirring to precipitate a solid. The solid was filtered and the filter cake was dried. The solid was separated by reverse phase preparative chromatography to obtain 0.82 g of compound 1.

[0092] 1H NMR (400MHz, CDCl3) δ7.81–7.75(m,4H),7.33–7.22(m,6H),6.61–6.49(m,2H),6.30–6.17(m,4H),5.93–5.72(m,2H),5.07–4.6 2(m,6H),4.23–4.17(m,1H),4.01–3.95(m,1H),3.83–3.50(m,32H),3.39–3.30(m,8H),3.22–2.89(m,10H),2.84–2.68(m,4H).

[0093] 13 C NMR (101MHz, CDCl3) δ169.54,169.15,153.20,149.30,149.19,147.04,146. 74,136.94,130.46,129.49,128.17,125.74,121.65,120.44,111.96,110.55 ,107.69,107.53,77.44,74.44,74.13,70.71,70.58,60.76,58.55,56.24,56.00,55.97,55.68,55.61,53.50,53.36,53.30,46.35,38.16,27.62,23.29.

[0094] HRMS (ESI-TOF) m / z: [M–anion] 2+ Calculate for C 56 H 70 N2O 14 :497.2408; found497.2418.

[0095] Example 2 Preparation of Compound 2

[0096]

[0097] Step 1) Preparation of compound 2-1

[0098] 10.0 g of compound 1-1, 3.20 g of dichlorothionyl and 50 ml of dichloromethane were put into a container, reacted at room temperature for 5 h, concentrated to dryness under reduced pressure at 45 ° C, the concentrate was dissolved in 50 ml of dichloromethane, protected by nitrogen, 2.38 g of trans-2,3-dibromo-2-butene-1,4-diol and 3.10 g of potassium carbonate were added to react for 21 h, 40 ml of water was added to the reaction solution, the pH was adjusted to 8 with 3N NaOH solution, the liquids were separated, the organic phase was washed with water twice, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 45 ° C. The residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 99 / 1 to 96 / 4) to obtain 5.0 g of compound 2-1.

[0099] Step 2) Preparation of Compound 2

[0100] 5.0 g of compound 2-1 was dissolved in 30 ml of acetonitrile, 3.91 g of methyl benzenesulfonate was added, nitrogen protection was applied, the temperature was raised to 60 °C for reaction for 20 h, the reaction solution was concentrated to dryness under reduced pressure at 45 °C, the concentrate was dissolved in 8 ml of dichloromethane, and added to 110 ml of ether with stirring to precipitate a solid, solid-liquid separation was performed, 10 ml of dichloromethane was added to the solid to dissolve it, and it was added to a mixed solution of 150 ml of ethyl acetate and 50 ml of ether with stirring to precipitate a solid, which was filtered with suction and dried. The solid was separated by reverse phase preparative chromatography to obtain 1.05 g of compound 2.

[0101] 1 H NMR (400MHz, CDCl3) δ7.85–7.76(m,4H),7.32–7.25(m,6H),6.59–6.51(m,2H),6.29–6.16(m,4H),5.97–5.69(m,2H),5. 14–4.85(m,6H),4.28–4.20(m,1H),4.04–3.95(m,1H),3.87–3.50(m,34H),3.38(s,6H),3.13(s,6H),3.07–2.66(m,8H).

[0102] 13C NMR (101MHz, CDCl3) δ169.35,168.93,153.22,149.23,147.14,146.78,13 7.01,136.92,130.30,129.46,128.16,125.82,121.61,121.17,120.46,1 19.58,119.31,111.93,110.56,107.70,107.44,70.83,70.64,68.13,60. 79,58.49,56.24,55.98,55.65,53.51,53.37,46.39,38.24,27.65,23.30.

[0103] HRMS (ESI-TOF) m / z: [M–anion] 2+ calculated for C 54 H 70 Br2N2O 14 :565.1581; found565.1586.

[0104] Example 3 Preparation of Compound 3

[0105]

[0106] Step 1) Preparation of compound 3-1

[0107] 7.0 g of compound 1-1, 2.24 g of dichlorothionyl and 40 ml of dichloromethane were put into a container, reacted at room temperature for 4 h, concentrated to dryness under reduced pressure at 45 ° C, the concentrate was dissolved in 50 ml of dichloromethane, protected by nitrogen, 0.60 g of cis-2-butene-1,4-diol was added to react for 16 h, 30 ml of water was added to the reaction solution, the pH was adjusted to 10-11 with 3N NaOH solution, the liquids were separated, the organic phase was washed with water twice, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 45 ° C. The residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 99 / 1 to 96 / 4) to obtain 4.4 g of compound 3-1.

[0108] Step 2) Preparation of compound 3

[0109] 4.4 g of compound 3-1 was dissolved in 44 ml of acetonitrile, 4.02 g of methyl benzenesulfonate was added, nitrogen protection was applied, the temperature was raised to 60 °C for reaction for 24 h, the reaction solution was concentrated to dryness at 45 °C under reduced pressure, the concentrate was dissolved in 5 ml of dichloromethane, added to 100 ml of methyl tert-butyl ether with stirring, a solid was precipitated, solid-liquid separation was performed, 4 ml of dichloromethane was added to the solid to dissolve, the solid was added to a mixed solution of 150 ml of ethyl acetate and 50 ml of methyl tert-butyl ether with stirring, a solid was precipitated, filtered, and the filter cake was dried. The obtained solid was separated by reverse phase preparative chromatography to obtain 1.10 g of compound 3.

[0110] 1 H NMR(400MHz, CDCl3)δ7.86–7.76(m,4H),7.33–7.24(m,6H),6.60–6.49(m,2H),6.29–6.15(m,4H),5.97–5.6 7(m,4H),5.04–4.81(m,2H),4.81–4.53(m,4H),4.30–3.84(m,4H),3.83–3.48(m,32H),3.46–2.70(m,20H).

[0111] 13 C NMR (101MHz, CDCl3) δ169.98,169.65,153.27,149.24,147.16,146.73,137.04,130.37,129.44,129.01,128.12,125. 84,121.71,121.22,120.44,111.82,110.78,107.38,70.84,60.57,56.22,55.95,55.65,46.46,38.33,27.97,23.36.

[0112] HRMS (ESI-TOF) m / z: [M–anion] 2+ calculated for C 54 H 72 N2O 14 :486.2486; found486.2488.

[0113] Example 4 Preparation of Compound 4

[0114]

[0115] Step 1) Preparation of compound 4-1

[0116] 7.0 g of compound 1-1, 2.24 g of dichlorothionyl and 40 ml of dichloromethane were put into a container, reacted at room temperature for 4 h, concentrated to dryness under reduced pressure at 45 °C, 50 ml of dichloromethane was added to the obtained concentrate to dissolve, nitrogen protection, cooled to 0 °C and stirred for 30 min, 0.58 g of 2-butyne-1,4-diol was added and reacted for 20 min, then moved to room temperature to react for 16 h, 30 ml of water was added to the reaction solution, the pH was adjusted to 10-11 with 3N NaOH solution, the liquids were separated, the organic phase was washed with water twice, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 45 °C. The obtained residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 99 / 1 to 96 / 4) to obtain 5.6 g of compound 4-1.

[0117] Step 2) Preparation of compound 4

[0118] 5.6 g of compound 4-1 was dissolved in 56 ml of acetonitrile, 5.12 g of methyl benzenesulfonate was added, nitrogen protection was applied, the temperature was raised to 60 °C for reaction for 24 h, the reaction solution was concentrated to dryness at 45 °C under reduced pressure, the concentrate was dissolved in 5 ml of dichloromethane, added to 100 ml of methyl tert-butyl ether with stirring, solid was precipitated, solid-liquid separation was performed, 4 ml of dichloromethane was added to the solid to dissolve, and it was added to a mixed solution of 150 ml of ethyl acetate and 50 ml of methyl tert-butyl ether with stirring, solid was precipitated, filtered, and the filter cake was dried. The obtained solid was separated by reverse phase preparative chromatography to obtain 1.30 g of compound 4.

[0119] 1 H NMR (400MHz, CDCl3) δ7.87–7.72(m,4H),7.35–7.22(m,6H),6.63–6.46(m,2H),6.32–6.15(m,4H),5.99–5.64(m,2H),5.07–4.5 5(m,6H),4.23–4.15(m,1H),4.04–3.97(m,1H),3.83–3.48(m,32H),3.46–3.16(m,10H),3.14–3.09(m,4H),3.07–2.68(m,8H).

[0120] 13C NMR (101MHz, CDCl3) δ169.63,169.26,153.21,149.28,149.17,147.05,146.78,136. 94,130.56,130.44,129.49,128.17,125.80,121.68,121.19,120.45,120.39,111.9 3,110.49,107.65,107.47,81.15,80.86,70.67,70.46,60.81,60.75,58.52,56.26,56.22,55.99,55.93,55.63,53.32,53.07,52.83,46.31,38.20,27.84,27.66,23.30.

[0121] HRMS (ESI-TOF) m / z: [M–anion] 2+ calculated for C 54 H 70 N2O 14 :485.2408; found485.2411.

[0122] Example 5 Preparation of Compound 5

[0123]

[0124] Step 1) Preparation of compound 5-1

[0125] 7.0 g of compound 1-1, 2.24 g of dichlorothionyl and 40 ml of dichloromethane were put into a container, reacted at room temperature for 4 h, concentrated to dryness under reduced pressure at 45 ° C, and the concentrate was dissolved in 50 ml of dichloromethane. Under nitrogen protection, the temperature was lowered to 0 ° C and stirred for 30 min. 0.70 g of neopentyl glycol was added and reacted for 20 min, then moved to room temperature to react for 16 h. 30 ml of water was added to the reaction solution, and the pH was adjusted to 10-11 with 3N NaOH solution. The organic phase was separated, and the organic phase was washed with water twice, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure at 45 ° C, and the residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 99 / 1 to 96 / 4) to obtain 4.5 g of compound 5-1.

[0126] Step 2) Preparation of Compound 5

[0127] 4.5 g of compound 5-1 was dissolved in 45 ml of acetonitrile, 4.04 g of methyl benzenesulfonate was added, nitrogen protection was applied, the temperature was raised to 60 °C for reaction for 24 h, the reaction solution was concentrated to dryness under reduced pressure at 45 °C, the concentrate was dissolved in 5 ml of dichloromethane, added to 100 ml of methyl tert-butyl ether with stirring, solid was precipitated, solid-liquid separation was performed, 4 ml of dichloromethane was added to the solid to dissolve, the solid was added to a mixed solution of 150 ml of ethyl acetate and 50 ml of methyl tert-butyl ether with stirring, solid was precipitated, filtered, the filter cake was dried, and the solid was separated by reverse phase preparative chromatography to obtain 1.08 g of compound 5.

[0128] 1 H NMR(400MHz, CDCl3)δ7.90–7.79(m,4H),7.37–7.29(m,6H),6.63–6.51(m,2H),6.29–6.13(m,4H),5.95–5.66(m,2H),5.03–4.79 (m,2H),4.22–3.85(m,8H),3.83–3.44(m,34H),3.39(d,J=5.0Hz,6H),3.35–3.10(m,6H),3.02–2.64(m,6H),1.07–0.83(m,6H).

[0129] 13 C NMR (101MHz, CDCl3) δ170.32,170.21,153.28,153.21,149.37,149.25,14 7.20,147.13,146.65,137.07,136.99,130.25,129.46,128.12,125.84,1 21.70,120.41,111.80,110.55,107.64,107.32,71.12,70.12,60.79,58. 91,56.22,56.17,55.94,55.64,46.42,38.29,35.04,27.82,23.36,21.94.

[0130] HRMS (ESI-TOF) m / z: [M–anion] 2+ Calculate for C 55 H 76 N2O 14 :494.2643; found494.2645.

[0131] Example 6 Preparation of Compound 6

[0132]

[0133] Step 1) Preparation of compound 6-1

[0134] 10.0 g of compound 1-1, 3.20 g of dichlorothionyl and 50 ml of dichloromethane were put into a container, reacted at room temperature for 5 h, concentrated to dryness under reduced pressure at 45 °C, the concentrate was dissolved in 50 ml of dichloromethane, protected by nitrogen, 1.08 g of 2,2-difluoropropane-1,3-diol and 3.10 g of potassium carbonate were added to react for 21 h, 40 ml of water was added to the reaction solution, the pH was adjusted to 8 with 3N NaOH solution, the liquids were separated, the organic phase was washed with water twice, dried with stirring over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 45 °C. The residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 99 / 1 to 96 / 4) to obtain 2.7 g of compound 6-1.

[0135] Step 2) Preparation of Compound 6

[0136] 2.7 g of compound 6-1 was dissolved in 27 ml of acetonitrile, 2.4 g of methyl benzenesulfonate was added, nitrogen protection was applied, the temperature was raised to 60 °C for reaction for 24 h, the reaction solution was concentrated to dryness under reduced pressure at 45 °C, the concentrate was dissolved in 5 ml of dichloromethane, and added to 100 ml of ether with stirring to precipitate a solid, solid-liquid separation was performed, 5 ml of dichloromethane was added to the solid to dissolve it, and it was added to a mixed solution of 100 ml of ethyl acetate and 50 ml of ether with stirring to precipitate a solid, which was filtered with suction and dried. The solid was separated by reverse phase preparative chromatography to obtain 0.18 g of compound 6.

[0137] 1 H NMR (400MHz, CDCl3) δ7.84–7.75(m,4H),7.34–7.22(m,6H),6.58–6.46(m,2H),6.25–6.11(m,4H),5.90–5.67(m,2H),4.98–4.7 7(m,2H),4.67–4.33(m,4H),4.33–3.91(m,4H),3.84–3.48(m,34H),3.39–3.34(m,6H),3.29–2.86(m,10H),2.79–2.65(m,2H).

[0138] 13C NMR (101MHz, CDCl3) δ169.43,153.24,149.25,147.12,146.56,137.04,130.32,1 29.54,128.18,125.77,121.63,121.12,120.46,120.38,120.25(t,J=182.1Hz), 111.88,110.56,107.64,107.45,71.14,62.71(t,J=36.0Hz),60.81,60.75,58.5 8,56.22,56.18,56.00,55.94,55.61,55.60,53.15,46.35,38.19,27.60,23.27.

[0139] HRMS (ESI-TOF) m / z: [M–anion] 2+ Calculate for C 53 H 70 F2N2O 14 :498.2392; found498.2394.

[0140] Example 7 Preparation of Compound 7

[0141]

[0142] Step 1) Preparation of compound 7-1

[0143] 7.0g of compound 1-1, 2.24g of thionyl chloride and 40ml of dichloromethane were put into a container, reacted at room temperature for 4h, concentrated to dryness under reduced pressure at 45℃, dissolved in 50ml of dichloromethane, protected by nitrogen, cooled to 0℃ and stirred for 30min, added 0.61g of 1,4-butanediol and reacted for 20min, then moved to room temperature and reacted for 16h. 30ml of water was added to the reaction solution, the pH was adjusted to 10-11 with 3N NaOH solution, separated, the organic phase was washed with water twice, dried by stirring with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 45℃. The residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 99 / 1 to 96 / 4) to obtain 4.7g of compound 7-1.

[0144] Step 2) Preparation of Compound 7

[0145] 4.7 g of compound 7-1 was dissolved in 47 ml of acetonitrile, 4.28 g of methyl benzenesulfonate was added, nitrogen protection was applied, the temperature was raised to 60 °C for reaction for 24 h, the reaction solution was concentrated to dryness at 45 °C under reduced pressure, the concentrate was dissolved in 5 ml of dichloromethane, added to 100 ml of methyl tert-butyl ether with stirring, a solid was precipitated, solid-liquid separation was performed, 4 ml of dichloromethane was added to the solid to dissolve it, and it was added to a mixed solution of 150 ml of ethyl acetate and 50 ml of methyl tert-butyl ether with stirring, a solid was precipitated, and it was filtered. The solid was separated by reverse phase preparative chromatography to obtain 1.12 g of compound 7.

[0146] 1 H NMR (400MHz, CDCl3) δ7.88–7.78(m,4H),7.34–7.28(m,6H),6.62–6.51(m,2H),6.29–6.15(m,4H),5.95–5.69(m,2H), 4.99–4.79(m,2H),4.29–4.07(m,6H),3.95–3.55(m,34H),3.42–3.37(m,6H),3.35–2.72(m,14H),1.89–1.61(m,4H).

[0147] 13 C NMR (101MHz, CDCl3) δ170.24,153.29,153.24,149.28,147.19,146.77,137.09,130.31,129.43,128.10,125.84,121.65,120.49,111.80, 110.61,107.63,107.38,70.94,70.50,65.04,60.86,60.74,56.27,5 6.22,56.02,55.97,55.67,55.64,46.46,38.35,27.94,25.15,23.37.

[0148] HRMS (ESI-TOF) m / z: [M–anion] 2+ Calculate for C 54 H 74 N2O 14 :487.2565; found487.2565.

[0149] Example 8 Preparation of Compound 8

[0150]

[0151] Step 1) Preparation of compound 8-1

[0152] 7.0g of compound 1-1, 2.24g of thionyl chloride and 40ml of dichloromethane were put into a container, reacted at room temperature for 4h, concentrated to dryness under reduced pressure at 45℃, dissolved in 50ml of dichloromethane, protected by nitrogen, cooled to 0℃ and stirred for 30min, added 0.51g of 1,3-propylene glycol and reacted for 20min, then moved to room temperature to react for 16h. 30ml of water was added to the reaction solution, the pH was adjusted to 10-11 with 3N NaOH solution, separated, the organic phase was washed with water twice, dried with stirring over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 45℃. The residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 99 / 1 to 96 / 4) to obtain 4.5g of compound 8-1.

[0153] Step 2) Preparation of Compound 8

[0154] 4.5 g of compound 8-1 was dissolved in 45 ml of acetonitrile, 4.16 g of methyl benzenesulfonate was added, nitrogen protection was applied, the temperature was raised to 60 °C for reaction for 24 h, the reaction solution was concentrated to dryness at 45 °C under reduced pressure, the concentrate was dissolved in 5 ml of dichloromethane, added to 100 ml of methyl tert-butyl ether with stirring, a solid was precipitated, solid-liquid separation was performed, 4 ml of dichloromethane was added to the solid to dissolve, and it was added to a mixed solution of 150 ml of ethyl acetate and 50 ml of methyl tert-butyl ether with stirring, a solid was precipitated, and it was filtered off. The solid was separated by reverse phase preparative chromatography to obtain 1.20 g of compound 8.

[0155] 1 H NMR (400MHz, CDCl3) δ7.89–7.80(m,4H),7.36–7.29(m,6H),6.61–6.50(m,2H),6.31–6.16(m,4H),5.96–5.67(m,2H),5.07– 4.80(m,2H),4.33–3.86(m,8H),3.84–3.42(m,34H),3.38(s,4H),3.30–3.25(m,4H),3.16–2.61(m,8H),2.10–1.86(m,2H).

[0156] 13C NMR (101MHz, CDCl3) δ170.27,169.90,153.27,149.34,149.22,147.25,147.18, 146.70,137.03,136.96,130.30,129.46,128.12,125.82,121.75,121.20,120. 38,120.18,111.80,110.48,107.59,107.32,70.97,63.88,60.84,60.78,58.93,56.23,56.18,56.03,55.94,55.63,46.50,46.40,38.32,27.91,27.57,23.36.

[0157] HRMS (ESI-TOF) m / z: [M–anion] 2+ Calculate for C 53 H 72 N2O 14 :480.2486; found480.2489.

[0158] Example 9 Preparation of Compound 9

[0159]

[0160] Step 1) Preparation of compound 9-1

[0161] 4.0g of compound 1-1, 1.18g of thionyl chloride and 30ml of dichloromethane were put into a container, reacted at room temperature for 3h, concentrated to dryness under reduced pressure at 45℃, dissolved in 30ml of dichloromethane, protected by nitrogen, cooled to 0℃ and stirred for 30min, added 0.47g of 1,6-hexanediol and reacted for 20min, then moved to room temperature to react for 16h. 20ml of water was added to the reaction solution, the pH was adjusted to 10-11 with 3N NaOH solution, separated, the organic phase was washed with water twice, dried with stirring over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 45℃. The residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 99 / 1 to 96 / 4) to obtain 2.4g of compound 9-1.

[0162] Step 2) Preparation of compound 9

[0163] 2.4 g of compound 9-1 was dissolved in 24 ml of acetonitrile, and 2.2 g of methyl benzenesulfonate was added. The mixture was protected by nitrogen and heated to 60 °C for 24 h. The reaction solution was concentrated to dryness under reduced pressure at 45 °C. The concentrate was dissolved in 5 ml of dichloromethane and added to 100 ml of methyl tert-butyl ether with stirring to precipitate a solid. After solid-liquid separation, 4 ml of dichloromethane was added to the solid to dissolve it. The solid was added to a mixed solution of 150 ml of ethyl acetate and 50 ml of methyl tert-butyl ether with stirring to precipitate a solid. The solid was filtered and separated by reverse phase preparative chromatography to obtain 1.15 g of compound 9.

[0164] 1 H NMR (400MHz, CDCl3) δ7.91–7.80(m,4H),7.36–7.25(m,6H),6.65–6.50(m,2H),6.34–6.16(m,4H),6.00–5.68(m,2H), 5.06–4.75(m,2H),4.28–3.97(m,6H),3.91–3.52(m,34H),3.45–3.30(m,8H),3.30–2.70(m,12H),1.73–1.28(m,8H).

[0165] 13 C NMR (101MHz, CDCl3) δ170.60,169.91,153.28,149.35,149.25,147.18,147.10,146.74,137 .05,136.95,130.49,130.29,129.41,128.09,125.84,121.69,121.22,120.51,120.25,111. 80,110.60,107.62,107.30,71.18,70.76,65.76,65.52,60.85,60.78,58.90,56.22,56.17,56.03,55.94,55.67,55.64,46.55,46.48,38.35,27.98,27.78,25.79,25.50,23.49,23.36.

[0166] HRMS (ESI-TOF) m / z: [M–anion] 2+ Calculate for C 53 H 72 N2O 14 :501.2721; found501.2722.

[0167] Example 10 Preparation of Compound 10

[0168]

[0169] Take 3.00g of compound 10-1, 0.60g of 1,4-phenylene oxalic acid, 1.53g of DCC, and 0.022g of DMAP and add them to 30mL of dichloromethane, heat and reflux for 24h, cool to room temperature and filter, the filtrate is concentrated to dryness under reduced pressure at 40°C to obtain 5.14g of solid. Dissolve it with 200mL of dichloromethane, add 7% NaCl solution to wash 5 times, 16mL each time, and separate the liquids. Add 150mL of water to the organic layer and extract it, separate the liquids. Wash the water layer with chloroform twice, 16mL each time, and separate the liquids. Add 20.08g of solid sodium chloride to the water layer, stir evenly, add dichloromethane to extract twice, 100mL each time, combine the two dichloromethanes, dry the dichloromethane layer with anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness under reduced pressure at 40°C to obtain 0.81g of compound 10.

[0170] 1 H NMR (400MHz, CDCl3) δ7.25–7.05(m,4H),6.72-6.62(m,2H),6.56–6.16(m,4H),5.80–5.54(m,2H),5.15–4.62(m,2H),4.17–3. 99(m,4H),3.99–3.62(m,34H),3.62–3.46(m,6H),3.46–3.35(m,8H),3.32–3.00(m,6H),2.96–2.61(m,2H),2.45–2.15(m,4H).

[0171] 13 C NMR (101MHz, CDCl3) δ171.50,171.31,153.30,153.23,149.43,149.36,147.00,146.7 3,137.19,136.95,132.89,130.59,130.25,129.67,121.24,120.84,120.57,120.12, 111.79,111.71,110.81,110.73,107.97,107.57,70.50,70.19,60.81,60.71,58.45,56.63,56.53,56.09,55.99,55.63,53.94,49.35,46.48,40.66,38.34,23.46,22.47.

[0172] HRMS (ESI-TOF) m / z: [M–anion] 2+ Calculate for C 60 H 78 N2O 14:525.2721; found525.2725.

[0173] Example 11 Preparation of Compound 11

[0174]

[0175] Take 2.50g of compound 10-1, 0.35g of glutaric acid, 1.30g of DCC, and 0.02g of DMAP and add them to 25mL of dichloromethane, heat and reflux for 24h, cool to room temperature and filter, the filtrate is concentrated to dryness under reduced pressure at 40°C to obtain 3.75g of solid. Dissolve it with 150mL of dichloromethane, add 7% NaCl solution to wash 5 times, 12mL each time, and separate the liquids. Add 100mL of water to the organic layer and extract it, separate the liquids. Wash the water layer with chloroform twice, 12mL each time, and separate the liquids. Add 17g of solid sodium chloride to the water layer, stir evenly, add dichloromethane to extract twice, 50mL each time, combine the two dichloromethanes, dry the dichloromethane layer with anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness under reduced pressure at 40°C to obtain 1.23g of compound 11.

[0176] 1 H NMR(400MHz, CDCl3)δ6.67(d,J=5.7Hz,2H),6.54–6.25(m,4H),5.83–5.67(m,2H),5.18–4.79(m,2H),4.19–3.63 (m,40H),3.42(d,J=6.1Hz,6H),3.33(d,J=5.3Hz,4H),3.26–3.11(m,4H),2.90–2.20(m,10H),1.94–1.63(m,2H).

[0177] 13 C NMR (101MHz, CDCl3) δ172.84,172.72,153.32,153.24,149.40,149.34,147.0 0,146.88,137.19,136.97,130.55,130.40,121.30,121.21,120.45,120.16, 111.76,110.77,107.91,107.64,76.85,70.22,60.80,60.73,58.48,56.61,56.55,56.07,56.00,55.61,53.82,49.34,38.40,33.05,23.57,22.51,19.72.

[0178] HRMS (ESI-TOF) m / z: [M–anion] 2+ Calculate for C55 H 76 N2O 14 :494.2643; found494.2646.

[0179] Example 12 Preparation of Compound 12

[0180]

[0181] Take 2.50g of compound 10-1, 0.38g of adipic acid, 1.30g of DCC, and 0.02g of DMAP and add them to 25mL of dichloromethane, heat and reflux for 24h, cool to room temperature and filter, the filtrate is concentrated to dryness under reduced pressure at 40℃ to obtain 3.77g of solid. Dissolve it with 150mL of dichloromethane, add 7% NaCl solution to wash 5 times, 12mL each time, and separate the liquids. Add 100mL of water to the organic layer and extract it, separate the liquids. Wash the water layer with chloroform twice, 12mL each time, and separate the liquids. Add 17g of solid sodium chloride to the water layer, stir evenly, add dichloromethane to extract twice, 50mL each time, combine the two dichloromethanes, dry the dichloromethane layer with anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness under reduced pressure at 40℃ to obtain 1.18g of compound 12.

[0182] 1 H NMR (400MHz, CDCl3) δ6.67 (d, J = 2.4Hz, 2H), 6.55–6.25 (m, 4H), 5.78–5.69 (m, 2H), 5.09–4.79 (m, 2H), 4.08–3.64(m,40H),3.42(d,J=6.1Hz,6H),3.36–2.94(m,8H),2.89–2.20(m,10H),1.71–1.45(m,4H).

[0183] 13 C NMR (101MHz, CDCl3) δ173.55,173.23,153.38,153.27,149.42,149.39,147.04,146.92,137.27,137.02,130.56,121.32,121.13,120.12,111. 80,110.82,107.94,107.62,70.26,60.82,60.75,58.52,56.63,56.57, 56.09,56.02,55.65,55.62,49.44,49.37,38.45,33.48,23.92,23.57.

[0184] HRMS (ESI-TOF) m / z: [M–anion] 2+ Calculate for C56 H 78 N2O 14 :501.2721; found501.2722.

[0185] Example 13 Preparation of Compound 13

[0186]

[0187] 5.00 g of compound 13-1, 1.61 g of 3-chloro-propylene and 50 mL of acetonitrile were put into a container and refluxed for 6 h. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 10 / 1) to obtain 6.61 g of compound 13-2.

[0188] 6.60 g of compound 13-2 and 3.73 g of 1,3-propylene glycol cyclic sulfate were taken and refluxed in 50 mL of acetonitrile for 24 h. The reaction solution was decompressed to dryness. The obtained crude product was crystallized with 50 mL of acetone, filtered, and the filter cake was dried to obtain 6.12 g of compound 13-3.

[0189] Take 6.12 g of compound 13-3, add 60 mL of acetonitrile for recrystallization (configuration resolution), filter with suction, and dry the filter cake to obtain 3.12 g of compound 13-4.

[0190] Take 2.90g of compound 13-4, add 60mL of methyl acetate hydrogen chloride methanol solution (39.50g of acetyl chloride is dripped into 350mL of methanol at 0-10°C and stirred for 10min), and stir at room temperature for 15h. The reaction solution is quenched with sodium bicarbonate, filtered, and the filtrate is concentrated to dryness under reduced pressure. The obtained solid is dispersed with dichloromethane, filtered, and the filtrate is concentrated to dryness under reduced pressure to obtain 2.96g of compound 13-5.

[0191] Take 2.96g of compound 13-5, 0.52g (E)-oct-4-ene-1,8-diacid, 1.50g DCC, 0.02g DMAP, 30mL dichloromethane, heat and reflux for 24h, cool to room temperature and filter, the filtrate is concentrated to dryness under reduced pressure at 40°C, the residue is dissolved with 150mL dichloromethane, added with 7% NaCl solution and washed 5 times, separated, the organic layer is extracted with 150mL of water, separated. The water layer is washed with chloroform twice, 15mL each time, separated. Add 22.00g of solid sodium chloride to the water layer, stir evenly, add dichloromethane to extract twice, 75mL each time, combine the dichloromethane layers, dry over anhydrous sodium sulfate, filter, the filtrate is concentrated to dryness under reduced pressure at 40°C, the residue is freeze-dried to obtain 1.80g of compound 13.

[0192] 1H NMR (400MHz, CDCl3) δ6.67 (s, 2H), 6.38 (s, 4H), 6.25 (tt, J = 13.6, 7.0Hz, 2H), 6.03 (d, J =16.8Hz,2H),5.81(d,J=10.1Hz,2H),5.70(s,2H),5.29(t,J=3.3Hz,2H),5.20(dd,J=1 4.2,7.0Hz,2H),4.89(dd,J=10.6,3.7Hz,2H),4.63(dd,J=14.2,7.1Hz,2H),4.19–3.71 (m,34H),3.42–3.08(m,12H),3.00–2.79(m,4H),2.55–2.29(m,4H),2.22–2.09(m,8H).

[0193] 13 C NMR (101MHz, CDCl3) δ172.47,153.19,149.44,146.96,137.04,130.42,129.36,129.24,124.50,121.10,120.53,111.87,111.81, 110.77,107.90,69.75,61.72,60.81,60.75,56.53,56.47,56.08,56.01,55.63,54.21,51.77,38.25,33.68,27.37,23.35,22.29.

[0194] HRMS (ESI-TOF) m / z: [M–anion] 2+ Calculate for C 62 H 84 N2O 14 :540.2956; found540.2959.

[0195] Example 14 Preparation of Compound 14

[0196]

[0197] The preparation method is the same as that of Example 13, except that no configurational resolution is performed.

[0198] 1H NMR(400MHz, CDCl3)δ6.68(d,J=7.6Hz,2H),6.40–6.27(m,4H),6.17(ddt,J=17.2,10.1,7.2Hz,2H),5.97–5.78(m,2H),5.75–5.51(m,4H), 5.49–5.34(m,2H),5.24–4.86(m,2H),4.36–3.64(m,42H),3.45(d,J= 2.2Hz,4H),3.34–3.10(m,4H),3.08–2.86(m,4H),2.70–2.07(m,12H).

[0199] 13 C NMR (101MHz, CDCl3) δ172.83,153.24,149.46,147.11,137.17,130.27,129.43,128.68,124.50,121.23,120.49,112.3 1,110.73,107.76,69.09,61.23,60.74,59.17,56.49,55.98,55.74,53.49,51.91,38.17,33.88,27.46,23.41,22.21.

[0200] HRMS (ESI-TOF) m / z: [M–anion] 2+ Calculate for C 62 H 84 N2O 14 :540.2956; found540.2960.

[0201] Example 15 Preparation of Compound 15

[0202]

[0203] 4.00 g of compound 13-1, 1.08 g of cyclobutylcarboxaldehyde, 4.54 g of sodium triacetoxyborohydride, and 40 mL of dichloromethane were placed in a container, stirred at room temperature for 8 h, washed with 30 mL of 10% sodium hydroxide aqueous solution, separated, the organic phase was washed with water 3 times, 30 mL each time, separated, the organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain 4.21 g of compound 15-1;

[0204] 4.20 g of compound 15-1, 2.00 g of 1,3-propylene glycol cyclic sulfate, and 0.40 g of sodium carbonate were refluxed in 40 mL of acetonitrile for 24 h, filtered, and the filter cake was dried to obtain 2.80 g of compound 15-2;

[0205] Take 2.80g of compound 15-2, 30mL of methyl acetate hydrogen chloride methanol solution (39.50g of acetyl chloride is dropped into 350mL of methanol at 0-10°C and stirred for 10min), and stir at room temperature for 15h. The reaction solution is quenched with sodium bicarbonate, filtered, and the filtrate is decompressed to dryness and then dispersed with dichloromethane, filtered, and the filtrate is decompressed and concentrated to dryness to obtain 2.20g of compound 15-3;

[0206] Take 2.00g of compound 15-3, 0.32g (E)-oct-4-ene-1,8-diacid, 0.92g DCC, 0.02g DMAP, 20mL dichloromethane, heat and reflux for 24h, cool to room temperature and filter, the filtrate is concentrated to dryness under reduced pressure at 40°C to obtain 2.80g of solid. Dissolve it with 120mL of dichloromethane, add 7% NaCl solution to wash 5 times, 10mL each time, and separate the liquids. Add 90mL of water to the organic phase for extraction and separate the liquids. Wash the water layer with chloroform twice, 10mL each time, and separate the liquids. Add 15.00g of solid sodium chloride to the water layer, stir evenly, add dichloromethane to extract twice, 45mL each time, combine the dichloromethane layers, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness under reduced pressure at 40°C to obtain 1.00g of compound 15.

[0207] 1 H NMR (400MHz, CDCl3) δ6.67(s,2H),6.37(s,4H),5.86(s,2H),5.28(t,J=3.4Hz,2H),5.09(dd,J=10.2,4.0Hz,2H),4 .31(dd,J=14.4,4.5Hz,2H),4.03–3.70(m,36H),3.44(s,6H),3.38–2.87(m,12H),2.63(s,2H),2.41–2.02(m,22H).

[0208] 13 C NMR (101MHz, CDCl3) δ172.50,153.28,149.49,147.18,137.20,130.24,129.27,121.26,120.47,112.01,107.90,69.75,69.67,64.28,60. 86,60.76,56.62,56.52,56.12,56.02,55.80,55.77,54.47,53.50,5 2.31,38.24,33.72,29.55,29.13,27.64,27.40,23.31,22.59,19.16.

[0209] HRMS (ESI-TOF) m / z: [M–anion] 2+ Calculate for C66 H 92 N2O 14 :568.3269; found568.3273.

[0210] Example 16 Preparation of Compound 16

[0211]

[0212] Take 2.50g of compound 10-1, 0.55g of 3-3'-dimethylglutaric acid, 1.30g of DCC, 0.02g of DMAP, and 25mL of dichloromethane and put them into a container. Heat and reflux for 24h, cool to room temperature and filter, and the filtrate is concentrated to dryness under reduced pressure at 40°C to obtain 3.72g of solid. Stir it with 150mL of dichloromethane to dissolve it, add 7% NaCl solution to wash 5 times, 12mL each time, and separate the liquids. Add 100mL of water to the organic phase and extract it, and separate the liquids. Wash the water layer with chloroform twice, 12mL each time, and separate the liquids. Add 17g of solid sodium chloride to the water layer, stir evenly, add dichloromethane to extract twice, 50mL each time, combine the dichloromethane layers, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness under reduced pressure at 40°C. The residue is separated by reverse phase preparative chromatography to obtain 1.08g of compound 16.

[0213] 1 H NMR(400MHz, CDCl3)δ6.67(d,J=1.9Hz,2H),6.54–6.25(m,4H),5.86–5.65(m,2H),5.12–4.82(m,2H ),4.10–3.60(m,40H),3.48–3.38(m,6H),3.38–3.10(m,8H),2.89–2.10(m,10H),1.10–0.78(m,6H).

[0214] 13 C NMR (101MHz, CDCl3) δ171.82,171.53,153.23,149.34,146.98,146.88,137.21,1 36.97,130.58,130.40,121.34,121.30,120.52,120.19,111.80,111.71,110.83 ,110.76,107.91,107.62,76.83,70.18,60.81,60.72,58.54,56.62,56.53,56.07,55.96,55.63,55.60,49.43,44.21,38.38,32.44,32.25,28.43,23.55,22.57.

[0215] HRMS (ESI-TOF) m / z: [M–anion] 2+ Calculate for C 57 H 80 N2O 14 :508.2799; found508.2804.

[0216] Example 17 Preparation of Compound 17

[0217]

[0218] 10.00 g of compound 13-1, 4.38 g of ethyl bromide and 230 mL of acetone were placed in a container and refluxed for 18 h. The reaction solution was concentrated to dryness under reduced pressure. The residue was separated and purified by column chromatography (dichloromethane / methanol (v / v) = 50 / 1) to obtain 8.72 g of compound 17-1.

[0219] 8.70 g of compound 17-1 and 5.50 g of 1,3-propylene glycol cyclic sulfate were refluxed in 50 mL of acetonitrile for about 8 h. The reaction solution was concentrated to dryness under reduced pressure. The residue was crystallized with 10 times the mass of acetonitrile / ethyl acetate = 1:1 system, filtered, and dried. The solid was slurried with 8 times the mass of acetonitrile at room temperature, filtered, and dried to obtain 5.84 g of compound 17-2.

[0220] 5.84 g of compound 17-2 was slurried with 10 times the mass of acetonitrile at room temperature, filtered, and dried. The obtained solid was slurried with 6 times the mass of acetonitrile at 40°C, filtered hot, and dried to obtain 3.01 g of compound 17-3;

[0221] Take 3.00g of compound 17-3, 30mL of methyl acetate hydrogen chloride methanol solution (39.50g of acetyl chloride was dropped into 350mL of methanol at 0-10°C and stirred for 10min), and stir at room temperature for 15h. The reaction solution was quenched with sodium bicarbonate, filtered, and the filtrate was concentrated to dryness under reduced pressure and then dispersed with dichloromethane, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain 2.63g of compound 17-4;

[0222] Take 2.30g of compound 17-4, 0.40g (E)-oct-4-ene-1,8-diacid, 1.15g DCC, 0.02g DMAP, 25mL dichloromethane, heat and reflux for 24h, cool to room temperature and filter, the filtrate is concentrated to dryness under reduced pressure at 40°C to obtain 3.01g of solid. Stir it with 120mL dichloromethane to dissolve it, add 7% NaCl solution to wash 5 times, 10mL each time, and separate the liquids. Add 90mL of water to the organic layer and extract it, separate the liquids. Wash the water layer with chloroform twice, 10mL each time, and separate the liquids. Add 15.00g of solid sodium chloride to the water layer, stir evenly, add dichloromethane to extract twice, 45mL each time, combine the dichloromethane layers, dry with anhydrous sodium sulfate and filter, and concentrate the filtrate to dryness under reduced pressure at 40°C to obtain 1.21g of compound 17.

[0223] 1 H NMR(400MHz,Chloroform-d)δ6.68(s,2H),6.31(s,4H),5.83(s,2H),5.27(t,J=3.5Hz,2H),4.93(dd,J=10.8,3.8Hz,2H),4.34–4.20(m,2H), 4.13–3.89(m,10H),3.85–3.71(m,24H),3.51–3.31(m,10H),3.31–3.1 0(m,4H),2.97–2.80(m,4H),2.44–2.08(m,12H),1.64(t,J=7.0Hz,6H).

[0224] 13 C NMR (101MHz, CDCl3) δ172.52,153.28,149.49,147.08,137.19,130.21,129.27,121.16,120.68,112.09,110.74,107.81,69.54,60.85,60. 79,56.53,56.47,56.11,56.05,55.72,55.70,54.81,53.03,51.69,38.18,33.74,27.39,23.44,22.27,8.25.HRMS(ESI-TOF)m / z:[M–anion] 2+ Calculate for C 60 H 84 N2O 14 :528.2956; found 528.2962.

[0225] Example 18 Preparation of Compound 18

[0226]

[0227] The preparation method is the same as that of Example 17, except that no configurational resolution is performed.

[0228] 1 H NMR (400MHz, CDCl3) δ6.71–6.62(m,2H),6.38–6.24(m,4H),5.92–5.77(m,2H),5.38–5.24(m,2H),5. 09–4.84(m,2H),4.12–3.69(m,34H),3.57–2.75(m,20H),2.49–2.07(m,12H),1.55(t,J=6.9Hz,6H).

[0229] 13 C NMR (101MHz, CDCl3) δ172.96,172.53,153.27,149.48,147.07,137.20,130.22,129.28,121.16,120.71,112.19,1 10.79,107.80,69.53,60.85,56.55,56.12,56.04,55.71,53.03,51.68,38.19,33.81,27.42,23.45,22.30,8.27.

[0230] HRMS (ESI-TOF) m / z: [M–anion] 2+ Calculate for C 60 H 84 N2O 14 :528.2956; found528.2964.

[0231] Example 19 Preparation of Compound 19

[0232]

[0233] The preparation method is the same as that of Example 12, except that the raw materials used are compound 19-1 and (E)-oct-4-ene-1,8-dioic acid.

[0234] 1H NMR (400MHz, CDCl3) δ6.61 (s, 2H), 6.30 (s, 4H), 5.71 (s, 2H), 5.22 (t, J = 3.1Hz, 2H), 4.9 6(dd,J=10.6,3.9Hz,2H),4.49(dd,J=14.2,5.0Hz,2H),4.00–3.91(m,6H),3.79–3.64( m,26H),3.59–3.51(m,2H),3.51–3.40(m,4H),3.35(s,6H),3.27–3.04(m,4H),2.89–2. 67(m,4H),2.46–2.17(m,4H),2.16–2.01(m,8H),1.26–1.15(m,2H),0.94–0.60(m,8H).

[0235] 13 C NMR (101MHz, CDCl3) δ172.48,153.19,149.45,147.03,137.07,130.38,129.24,121.24,120.61,111.97,111.91,110.71,107.94,69.5 0,63.95,60.81,60.74,56.57,56.51,56.09,56.01,55.72,55.70,54.17,51.96,38.13,33.68,27.37,23.26,22.52,6.08,4.71,4.17.

[0236] HRMS (ESI-TOF) m / z: [M–anion] 2+ Calculate for C 64 H 88 N2O 14 :554.3112; found554.3121.

[0237] Example 20 Preparation of Compound 20

[0238]

[0239] Compound 20-1

[0240] The preparation method is the same as that of Example 19, except that the raw material used is compound 20-1.

[0241] 1H NMR(400MHz, CDCl3)δ6.73–6.61(m,2H),6.43–6.24(m,4H),5.90–5.73(m,2H),5.41–5.27(m,2H),5.19–4.91(m,2H), 4.09–3.95(m,6H),3.85–3.41(m,38H),3.31–2.85(m,8H),2.53–2.09(m,12H),1.29–1.21(m,2H),1.08–0.48(m,8H).

[0242] 13 C NMR (101MHz, CDCl3) δ172.53,153.23,149.48,147.07,137.13,130.37,129.28,121.27,120.67,112.01,110.79,107.93,69 .56,63.96,60.75,56.61,56.50,56.14,56.01,55.76,55.72,54.19,51.99,38.16,33.71,27.41,23.31,22.59,6.14,4.22.

[0243] HRMS (ESI-TOF) m / z: [M–anion] 2+ Calculate for C 64 H 88 N2O 14 :554.3112; found554.3114.

[0244] Example 21 Preparation of Compound 21

[0245]

[0246] Take 3.00g of compound 10-1, 0.90g of 2,2'-biphenyldicarboxylic acid, 2.50g of DCC, 0.02g of DMAP, and 30mL of dichloromethane, heat and reflux for 24h, cool to room temperature and filter, the filtrate is concentrated to dryness under reduced pressure at 40°C to obtain 5.13g of solid. Dissolve it with 200mL of dichloromethane, add 7% NaCl solution to wash 5 times, 15mL each time, and separate the liquids. Add 150mL of water to the organic layer and extract it, separate the liquids. Wash the water layer with chloroform twice, 15mL each time, and separate the liquids. Add 20.00g of solid sodium chloride to the water layer, stir evenly, add dichloromethane to extract twice, 100mL each time, combine the dichloromethane layers, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness under reduced pressure at 40°C. The obtained solid is freeze-dried to obtain 1.02g of compound 21.

[0247] 1H NMR(400MHz, CDCl3)δ8.16–7.35(m,5H),7.31–7.00(m,3H),6.71–6.56(m,2H),6.55–6.19(m,4H),5.85–5.6 6(m,2H),5.23–4.72(m,2H),4.08–3.66(m,40H),3.47–3.37(m,6H),3.34–2.73(m,10H),2.48–2.17(m,4H).

[0248] 13 C NMR (101MHz, CDCl3) δ166.70,166.22,153.29,149.34,147.10,146.98,143.05,142.63,137 .09,131.92,131.83,130.52,130.34,129.68,128.97,128.47,127.59,127.28,121.40,121 .24,119.91,111.95,110.92,110.79,107.99,70.42,70.25,60.78,56.62,56.48,56.01,55 .96,55.66,55.64,53.48,49.46,38.46,38.39,23.54,22.51.HRMS(ESI-TOF)m / z:[M–anion] 2+ Calculate for C 64 H 78 N2O 14 :549.2721; found 549.2723.

[0249] The beneficial effects of the present invention are described below through test examples.

[0250] Test Example 1 Muscle Relaxation Effect Test

[0251] 1. Experimental Methods

[0252] Adult New Zealand white rabbits weighing 3.0 to 3.5 kg were used as experimental animals for muscle relaxation experiments. Experimental protocol: propofol was administered intravenously to induce anesthesia, with an induction dose of 10 mg / kg and a maintenance dose of 80-100 mg / (kg h). Tracheal intubation was performed and respiratory support was given. The compound of the present invention or mivacurium was administered intravenously, and muscle relaxation was continuously monitored using a muscle relaxation detector (TOF), and the onset time (the time from the start of administration to the maximum or complete blockade, Time 1), the maximum blockade efficacy (the peak muscle relaxation intensity, R%), the effective blockade time (the maximum blockade time and the time to recover to 25%, Time25%, i.e., the maintenance time of muscle relaxation), and the complete recovery time (the time for muscle relaxation to recover from 25% to 90%, Time90%) were recorded. The results are shown in Table 1.

[0253] 2. Experimental results

[0254] Table 1. Muscle relaxant effects of different compounds

[0255]

[0256]

[0257] As can be seen from Table 1, the compounds of the present invention can basically achieve 100% blocking efficacy, indicating that the compounds have a muscle relaxant effect, among which compound 4 did not reach 100% blocking efficacy, suggesting that the dosage needs to be increased. At the same time, the onset time of the compounds of the present invention is within 2 minutes, achieving a rapid onset effect. The muscle relaxation maintenance time (i.e., effective blocking time) of compounds 1, 2, 3, 4, 8, 13, 15, 17, 18 and 20 is lower than that of mivacurium chloride, among which the muscle relaxation maintenance time of compounds 1, 2, 4, 8, 13, and 20 is within 10 minutes, which meets the maintenance time of ultra-short-acting muscle relaxants, and can be used as a substitute for succinylcholine, and is applied to clinical surgeries that require ultra-short-acting muscle relaxant maintenance time. In addition, after administering the compounds of the present invention, the TOF1 to 4 of the test animals gradually decrease in sequence, rather than in equal proportion. This TOF change characteristic shows that the compounds of the present invention belong to typical non-depolarizing muscle relaxants.

[0258] In summary, the benzylisoquinoline compounds of formula (I) provided by the present invention have a fast onset of action after a single administration, can achieve an ultra-short-acting non-depolarizing muscle relaxant effect by relying solely on the body's own metabolism, have a fast recovery time, and have no residual muscle relaxant. They can be used as ultra-short-acting non-depolarizing muscle relaxant drugs in clinical practice, and have good application prospects.

Claims

1. A compound, its stereoisomer, its tautomer, its isotope substitution, its solvate or its metabolite, characterized in that: The structure of the compound is shown in formula (I): in, R1, R2, R3, and R4 are independently selected from hydrogen or C 1-8 Alkoxy; R5 and R6 are independently selected from C 1-8 Alkyl, L 31 R9, C 2-8 Alkenyl or C 2-8 Alkynyl; L 31 None or C 1-8 Alkylene, R9 is a 3-8 membered cycloalkyl; L0 is selected from L1 and L2 are independently selected from C 1-8 Alkylene, C 2-8 Alkenylene or C 2-8 Alkynylidene; L3 and L4 are independently selected from the following groups which are unsubstituted or substituted by one or more R7: 1-8 Alkylene, C 2-8 Alkenyl, C 2-8 Alkynyl, 6-10 membered aryl, 6-10 membered biaryl, 3-8 membered cycloalkyl, 3-8 membered bicycloalkyl; each R7 is independently selected from halogen, hydroxyl, amino, nitro, C 1-8 Alkyl, C 2-8 Alkenyl or C 2-8 Alkynyl; M is a pharmaceutically acceptable anion; And the compound is not 2. The compound according to claim 1, its stereoisomer, its tautomer, its isotope substitution, its solvate or its metabolite, characterized in that: The structure of the compound is shown in formula (II): in, R1, R2, R3, and R4 are independently selected from hydrogen or C 1-4 Alkoxy; R5 and R6 are independently selected from C 1-4 Alkyl, L 31 R9, C 2-6 Alkenyl or C 2-6 Alkynyl; L 31 None or C 1-4 Alkylene, R9 is a 3-6 membered cycloalkyl; L1 and L2 are independently selected from C 1-4 Alkylene, C 2-6 Alkenylene or C 2-6 Alkynylidene; L4 is selected from the following groups which are unsubstituted or substituted by one or more R7: 1-6 Alkylene, C 2-6 Alkenyl, C 2-6 Alkynyl, phenyl, biphenyl, 3-6 membered cycloalkyl, 3-6 membered bicycloalkyl; each R7 is independently selected from halogen, hydroxyl, amino, nitro, C 1-4 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; M is a pharmaceutically acceptable anion.

3. The compound according to claim 2, its stereoisomer, its tautomer, its isotope substitution, its solvate or its metabolite, characterized in that: R1, R2, R3, and R4 are each independently selected from hydrogen or methoxy; R5 and R6 are independently selected from C 1-2 Alkyl, L 31 R9, C 2-3 Alkenyl or C 2-3 Alkynyl; L 31 None or C 1-2 Alkylene, R9 is a 3-4 membered cycloalkyl; L1 and L2 are independently selected from C 1-3 Alkylene, C 2-3 Alkenylene or C 2-3 Alkynylidene; L4 is selected from the following groups which are unsubstituted or substituted by one or more R7: 1-4 Alkylene, C 2-4 Alkenyl, C 2-4 Alkynyl, phenyl, biphenyl, 3-6 membered cycloalkyl, 3-6 membered bicycloalkyl; each R7 is independently selected from halogen or C 1-4 alkyl; M is selected from chloride, bromide, iodide, sulfonate, methanesulfonate, benzenesulfonate or p-toluenesulfonate; Preferably, L4 is selected from C 1-4 Alkylene, 4. The compound according to claim 3, its stereoisomer, its tautomer, its isotope substitution, its solvate or its metabolite, characterized in that: The structure of the compound is shown in formula (IIa): in, L4 is selected from C3 alkylene, M is selected from chloride, bromide, iodide, sulfonate, methanesulfonate, benzenesulfonate or p-toluenesulfonate.

5. The compound according to claim 1, its stereoisomer, its tautomer, its isotope substitution, its solvate or its metabolite, characterized in that: The structure of the compound is shown in formula (III): in, R1, R2, R3, and R4 are independently selected from hydrogen or C 1-4 Alkoxy; R5 and R6 are independently selected from C 1-4 Alkyl, L 31 R9, C 2-6 Alkenyl or C 2-6 Alkynyl; L 31 None or C 1-4 Alkylene, R9 is a 3-6 membered cycloalkyl; L1 and L2 are independently selected from C 1-4 Alkylene, C 2-6 Alkenylene or C 2-6 Alkynylidene; L3 is selected from the following groups which are unsubstituted or substituted by one or more R7: 1-6 Alkylene, C 2-6 Alkenyl, C 2-6 Alkynyl, Phenyl, biphenyl, 3-6 membered cycloalkyl, 3-6 membered bicycloalkyl; each R7 is independently selected from halogen, hydroxyl, amino, nitro, C 1-4 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; M is a pharmaceutically acceptable anion; And the compound is not 6. The compound according to claim 5, its stereoisomer, its tautomer, its isotope substitution, its solvate or its metabolite, characterized in that: Said R1, R2, R3, and R4 are independently selected from hydrogen or methoxy; R5 and R6 are independently selected from C 1-2 Alkyl, L 31 R9, C 2-3 Alkenyl or C 2-3 Alkynyl; L 31 None or C 1-2 Alkylene, R9 is a 3-4 membered cycloalkyl; L1 and L2 are independently selected from C 1-3 Alkylene, C 2-3 Alkenylene or C 2-3 Alkynylidene; L3 is selected from the following groups which are unsubstituted or substituted by one or more R7: 1-4 Alkylene, C 2-6 Alkenyl, C 2-6 Alkynyl, Phenyl, biphenyl, 3-6 membered cycloalkyl, 3-6 membered bicycloalkyl; each R7 is independently selected from halogen or C 1-4 alkyl; M is selected from chloride, bromide, iodide, sulfonate, methanesulfonate, benzenesulfonate or p-toluenesulfonate; Preferably, The R5 and R6 are independently selected from methyl, ethyl, L3 is C 1-4 Alkylene, 7. The compound according to claim 6, its stereoisomer, its tautomer, its isotope substitution, its solvate or its metabolite, characterized in that: The structure of the compound is shown in formula (IIIa): in, The R5 and R6 are independently selected from methyl, ethyl, L3 M is selected from chloride, bromide, iodide, sulfonate, methanesulfonate, benzenesulfonate or p-toluenesulfonate.

8. The compound according to claim 1, its stereoisomer, its tautomer, its isotope substitution, its solvate or its metabolite, characterized in that: The compound is selected from:

9. A pharmaceutical composition, characterized in that: The pharmaceutical composition is prepared by using the compound according to any one of claims 1 to 8, its stereoisomer, its tautomer, its isotope substitute, its solvate or its metabolite as an active ingredient, and adding pharmaceutically acceptable excipients.

10. Use of the compound according to any one of claims 1 to 8, its stereoisomers, its tautomers, its isotope substitutes, its solvates or its metabolites in the preparation of muscle relaxants; Preferably, the muscle relaxant is a non-depolarizing muscle relaxant; More preferably, the non-depolarizing muscle relaxant is an ultra-short-acting non-depolarizing muscle relaxant.

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