Preparation method of chiral amine compound and intermediate thereof

Abstract

The present invention discloses a method for preparing a chiral amine compound and an intermediate thereof. The present invention provides a method for preparing a chiral amine compound 1, comprising the following steps: (1) using D-(+)-p-methyldibenzoyltartaric acid or N-acetyl-L-leucine as a resolving agent to split IM-1 to obtain IM-1(S); (2) protecting IM-1(S) with SM-3 and reacting with SM2, and deprotecting under acidic conditions to obtain the chiral amine compound 1. The preparation method of the present invention has one or more of the following advantages: the reagents used are more economical and safe, the route is short, the yield is high, the preparation cost is low, and the post-processing is simple, which is suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to a method for preparing a chiral amine compound and an intermediate thereof, and in particular to a method for preparing (S)-N'-(1H-benzimidazol-2-ylmethyl)-N'-(5,6,7,8-tetrahydroquinoline-8-yl)butane-1,4-diamine and an intermediate thereof. Background Art

[0002] The chemical name of Mavorixafor is: (S)-N'-(1H-benzimidazol-2-ylmethyl)-N'-(5,6,7,8-tetrahydroquinolin-8-yl)butane-1,4-diamine, and the structural formula is shown in Formula 1 below. Mavorixafor is a chemokine CXCR4 receptor antagonist developed by X4 Pharmaceuticals. Mavorixafor is currently in Phase III clinical trials as a drug for the treatment of WHIM syndrome (WHIM syndrome is a rare autosomal dominant hereditary disease characterized by warts, hypogammaglobulinemia, bacterial infection, and tetralogy of ineffective chronic myeloid deficiency). In addition, Mavorixafor has been shown to be effective for renal clear cell carcinoma, congenital severe neutropenia, Diseases such as macroglobulinemia and triple-negative breast cancer are also in clinical research stages.

[0003]

[0004] In 2018 and 2019, Mavorixafor received Orphan Drug and Breakthrough Therapy designations for the treatment of WHIM syndrome in the U.S. and Orphan Drug status for the same indication in the EU. In 2020, the product received Fast Track designation in the U.S. for the treatment of WHIM syndrome in adults.

[0005] Currently, there are mainly three generations of synthesis processes in the preparation of Mavorixafor, as follows: First generation synthesis process: (Organic Process Research & Development 2008, 12, 823–830).

[0006]

[0007] Second generation synthesis process: (WO2020047410A).

[0008]

[0009] Third-generation synthesis process: (WO2020047410A).

[0010] The third generation synthesis process is basically the same as the second generation synthesis process except that p-hydroxybenzoic acid is omitted to purify compound 1.

[0011]

[0012] The three generations of synthesis processes all adopt a convergent synthesis of three fragments, namely fragment 3, fragment 5 and aldehyde compounds whose amino groups are protected by different protecting groups. The required fragment 3(S) is prepared by nitrosation reaction of the benzyl position near the N atom with compound SM1-1 5,6,7,8-tetrahydroquinoline as the starting material to obtain compound 2. This step uses dangerous reagent n-butyl lithium and reagent LDA with high environmental requirements, and has high requirements for production and operation equipment. Compound 2 is then reduced by zinc powder to obtain compound 3. This step requires a large amount of zinc powder and causes serious environmental pollution. Compound 3 is then prepared by enzyme resolution to obtain a single isomer 3(S). The hydrochloride of 3(S) is separated by hydrochloride formation and then freed to obtain 3(S). Although it is an enzyme resolution, it still requires a salt formation and freeing step. Therefore, the current production processes of chiral center fragments have the disadvantages of complex operation, high equipment requirements, and serious environmental pollution. The common fragment 5 of the three processes is obtained from compound 4 by protecting the secondary amine with Boc2O.

[0013] In addition, the first generation production process has 11 steps to synthesize Mavorixafor. Compound 6 is prepared by protecting the amino group with o-phthalic acid imine to obtain compound 7; compound 7 is substituted to obtain acyl chloride compound 8; compound 8 is reduced by palladium / carbon catalyzed hydrogen to obtain aldehyde fragment 9. This step has problems such as high production equipment requirements and dangerous operation. Compound 9 and fragment 3 (S) are subjected to reductive amination to obtain compound 10. The reductive amination step is relatively complicated; compound 10 and compound 5 are subjected to substitution reaction and then the Boc protective group is removed to obtain compound 11 in two steps; finally, compound 11 is removed from the o-phthalic acid imine protective group under the action of the genotoxic reagent hydrazine hydrate to obtain Mavorixafor. This reaction step is the last step in the synthesis of API. The genotoxic reagent hydrazine hydrate is used, which is not conducive to the quality control of the raw material drug and requires silica gel purification. Therefore, in addition to the disadvantages of synthesizing 3 (S), the first generation synthesis process also has the disadvantages of long synthesis route, complex operation, high production equipment requirements, certain dangers, and the large-scale use of genotoxic reagents in the last step.

[0014] Compared with the second generation production process, the third generation synthesis process is basically the same as the second generation synthesis process except that the purification step of compound 1 with p-hydroxybenzoic acid is omitted. Although the salt purification step in the second generation production process is omitted, more than 10 steps of reaction are still required to synthesize Mavorixafor. Both use the expensive acetal compound 13 as the starting material, and two Boc protecting groups are added to the amino group in two steps to prepare compound 15. The second protecting group of compound 14 uses a Grignard reagent. This step of reaction has high environmental requirements, complex operation and certain dangers; compound 15 is hydrolyzed to obtain compound 16, and compound 16 is aminated and reduced in two steps to obtain compound 18. Finally, compound 18 is deprotected to obtain Mavorixafor. Therefore, in addition to the disadvantages of synthesizing 3(S), the second and third generation production processes still have the disadvantages of long reaction routes, high production costs, complex operations, high requirements for production equipment and certain dangers.

[0015] It can be seen that the existing synthesis method of (S)-N'-(1H-benzimidazol-2-ylmethyl)-N'-(5,6,7,8-tetrahydroquinolin-8-yl)butane-1,4-diamine has the defects of using expensive reagents, high cost, long route, complicated operation, high requirements for reaction environment, certain danger and unsuitability for industrialization. These problems need to be solved urgently. Summary of the invention

[0016] The technical problem to be solved by the present invention is to provide a novel method for preparing chiral amine compounds and intermediates thereof. The preparation method of the present invention has one or more of the following advantages: the reagents used are more economical and safe, the route is short, the yield is high, the preparation cost is low, and the post-treatment is simple, which is suitable for industrial production.

[0017] The present invention solves the above-mentioned technical problems through the following technical solutions.

[0018] The present invention provides a method for preparing a compound represented by formula IM-1(S) by splitting, which comprises the following steps:

[0019] (i) reacting compound IM-1 with a resolving agent in a solvent to form a salt to obtain a salt of the compound represented by formula IM-1(S) and the resolving agent;

[0020]

[0021] (ii) subjecting the salt obtained in step (i) to a free reaction under the action of a base to obtain a compound represented by formula IM-1(S);

[0022] The compound IM-1 is a mixture of a compound represented by formula IM-1(S) and a compound represented by formula IM-1(R);

[0023]

[0024] The resolving agent is D-(+)-p-methyldibenzoyltartaric acid or N-acetyl-L-leucine;

[0025] The salt formed by the compound of formula IM-1(S) and the resolving agent has a molecular composition of IM-1(S): resolving agent of 1:1-1:3;

[0026] In some embodiments, the compound IM-1 is preferably a mixture of a compound represented by formula IM-1(S) and a compound represented by formula IM-1(R) in a molar ratio of (2:3) to (3:2) (eg, 1:1).

[0027] In step (i), a suitable solvent is selected to precipitate the salt formed by the compound represented by formula IM-1(S) and the resolving agent, while the compound represented by formula IM-1(R) remains in the solvent.

[0028] When the resolving agent is D-(+)-p-methyldibenzoyltartaric acid, the salt formed by the compound of formula IM-1(S) and the resolving agent is preferably

[0029] When the resolving agent is N-acetyl-L-leucine, the salt formed by the compound of formula IM-1(S) and the resolving agent is preferably

[0030] When the resolving agent is D-(+)-p-methyldibenzoyltartaric acid, the solvent may be an alcohol solvent or a "mixed solvent of an alcohol solvent and water". The alcohol solvent may be one or more of methanol, ethanol, and isopropanol, preferably ethanol. In the mixed solvent of the alcohol solvent and water, the volume ratio of the alcohol solvent to water is preferably 5:1-8:1.

[0031] When the resolving agent is D-(+)-p-methyldibenzoyltartaric acid, the solvent is preferably ethanol, methanol / ethanol, or isopropanol / water / ethanol, wherein " / " indicates a mixed solvent.

[0032] When the resolving agent is N-acetyl-L-leucine, the solvent may be a mixed solvent of an aprotic solvent and a protic solvent. The aprotic solvent is preferably an ether solvent, and the ether solvent is preferably one or more of tetrahydrofuran, 2-methyltetrahydrofuran and dioxane. The protic solvent is preferably an alcohol solvent, water or a "mixed solvent of an alcohol solvent and water"; the alcohol solvent is preferably one or more of methanol, ethanol and isopropanol. When the resolving agent is N-acetyl-L-leucine, the solvent is preferably tetrahydrofuran / methanol.

[0033] When the resolving agent is D-(+)-p-methyldibenzoyltartaric acid, the amount of the solvent used is the conventional amount used in this type of reaction in the art; preferably, the volume mass ratio of the solvent to IM-1 is 10 to 80 ml / g, preferably 10 to 30 ml / g.

[0034] When the resolving agent is D-(+)-p-methyldibenzoyltartaric acid, the molar ratio of the resolving agent to compound IM-1 is 1:1 or more, preferably 3:1 or more, more preferably (3:1) to (3.5:1), for example 3:1.

[0035] When the resolving agent is N-acetyl-L-leucine, the amount of the solvent used is the conventional amount used in this type of reaction in the art. Preferably, the volume mass ratio of the solvent to compound IM-1 is 5 to 20 ml / g.

[0036] When the resolving agent is N-acetyl-L-leucine, the molar ratio of the resolving agent to compound IM-1 is greater than 0.5:1, preferably (0.5-3):1, more preferably (0.5-0.7):1, for example 0.7:1.

[0037] The temperature of the salt-forming reaction may be a temperature commonly used in such reactions in the art, preferably 60-100° C. In some embodiments, the temperature of the salt-forming reaction is the reflux temperature of the solvent used in the salt-forming reaction.

[0038] In some embodiments, in step (i), after the salt-forming reaction is completed, a crystallization step is further included. The crystallization method can be conventional in the art, preferably cooling crystallization, for example, directly cooling the reaction solution of the salt-forming reaction for crystallization. The cooling crystallization can be by lowering the temperature to 20-30°C.

[0039] In some embodiments, in step (i), after the crystallization step, a step of separating the precipitated solid is further included, and the separated solid is the salt formed by the compound represented by formula IM-1(S) and the resolving agent.

[0040] In step (ii), the operation and conditions of the freeing reaction are conventional in the art.

[0041] In step (ii), the base may be an alkali metal hydroxide and / or an alkali metal carbonate, such as one or more of sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate, preferably sodium hydroxide.

[0042] In step (ii), the temperature of the freeing reaction can be a temperature commonly used for such reactions in the art, preferably 10-40°C.

[0043] In step (ii), the freeing reaction is preferably carried out in water.

[0044] In step (ii), the operation of the free reaction may include the following steps: adjusting the pH of the aqueous solution of the salt obtained in step (i) to alkaline (e.g., about 10) with a base, extracting the resulting aqueous solution with an organic solvent (e.g., dichloromethane), and concentrating the organic phase to obtain a compound represented by formula IM-1(S).

[0045] In the method for preparing the compound represented by formula IM-1(S), the method for preparing the compound IM-1 may include the following steps: in an organic solvent, compound SM1 and 1,4-butanediamine undergo the following substitution reaction;

[0046]

[0047] In the substitution reaction, the organic solvent may be a commonly used solvent in such substitution reactions in the art, preferably acetonitrile and / or N,N-dimethylformamide; more preferably acetonitrile.

[0048] In the substitution reaction, the molar ratio of the 1,4-butanediamine to SM-1 can be 5:1 to 15:1, preferably 10:1.

[0049] In the substitution reaction, the reaction temperature may be a temperature commonly used in such substitution reactions in the art. Preferably, the substitution reaction temperature is 25 to 40°C, preferably 30 to 35°C.

[0050] The time of the substitution reaction can be the time until the completion of the reaction is detected by conventional detection means, for example, 20 to 25 hours.

[0051] After the substitution reaction is completed, the reaction can be treated by conventional post-treatment steps for such reactions in the art.

[0052] The present invention also provides an application of D-(+)-p-methyldibenzoyltartaric acid or N-acetyl-L-leucine in splitting IM-1 to prepare a compound represented by formula IM-1(S), wherein the compound IM-1 is a mixture of the compound represented by formula IM-1(S) and the compound represented by formula IM-1(R);

[0053]

[0054] The present invention also provides a compound represented by formula IM-3:

[0055]

[0056] The present invention provides a method for preparing a compound of formula IM-3, comprising the following steps: in a solvent, subjecting compound IM-1 to a salt-forming reaction with a resolving agent, D-(+)-p-methyldibenzoyltartaric acid, to obtain a compound of formula IM-3;

[0057]

[0058] The compound IM-1 is a mixture of a compound represented by formula IM-1(S) and a compound represented by formula IM-1(R);

[0059]

[0060] In the method for preparing the compound of formula IM-3, the conditions and operation of the salt-forming reaction can be the same as those described in step (i) of the method for preparing the compound of formula IM-1(S) by resolution.

[0061] The present invention also provides a compound represented by formula IM-4:

[0062]

[0063] The present invention provides a method for preparing a compound of formula IM-4, comprising the following steps: in a solvent, subjecting compound IM-1 to a salt-forming reaction with a resolving agent, N-acetyl-L-leucine, to obtain a compound of formula IM-4;

[0064]

[0065] The compound IM-1 is a mixture of a compound represented by formula IM-1(S) and a compound represented by formula IM-1(R);

[0066]

[0067] In the method for preparing the compound of formula IM-4, the conditions and operation of the salt-forming reaction can be the same as those described in step (i) of the method for preparing the compound of formula IM-1(S) by resolution.

[0068] The present invention also provides a method for preparing compound IM-1, which comprises the following steps: in an organic solvent, compound SM1 and 1,4-butanediamine are subjected to the following substitution reaction; the conditions and operation of the substitution reaction can be the same as described above;

[0069]

[0070] The present invention also provides a method for preparing compound 1, which comprises the following steps:

[0071] (1) In an organic solvent, the compound represented by formula IM-5 is subjected to a substitution reaction with SM2 in the presence of a base to obtain a compound represented by formula IM-6;

[0072] (2) removing the Boc and imine protecting groups from the compound represented by formula IM-6 obtained in step (1) under the action of an acid to obtain compound 1;

[0073] Where n is 0, 1 or 2;

[0074]

[0075] Preferably, in step (1), the organic solvent is one or more of methanol, ethanol, isopropanol and acetonitrile, preferably acetonitrile.

[0076] Preferably, in step (1), the volume mass ratio of the organic solvent to the compound SM2 is 8 to 15 mL / g;

[0077] Preferably, in step (1), the base may be one or more of triethylamine, N,N-diisopropylethylamine and 4-dimethylaminopyridine, preferably N,N-diisopropylethylamine.

[0078] Preferably, the substitution reaction temperature in step (1) is 30-100°C, more preferably 35-45°C.

[0079] Preferably, the product obtained after the substitution reaction in step (1) is directly used in step (2) without purification. For example, after the substitution reaction in step (1) is completed, the solid in the reaction solution is removed, the solvent is removed from the obtained solution, and the obtained residue is directly used in step (2).

[0080] Preferably, in step (2), the acid may be one or more of hydrochloric acid, sulfuric acid and trifluoroacetic acid, preferably hydrochloric acid.

[0081] Preferably, in step (2), the deprotection reaction is carried out in water.

[0082] Preferably, in step (2), the operation of the deprotection reaction may include the following steps: adjusting the pH of the aqueous solution of the compound represented by formula IM-6 to 1-2 with acid and then performing the deprotection reaction.

[0083] Preferably, in step (2), the temperature of the deprotection reaction is 38-42°C.

[0084] Preferably, the method for preparing compound 1 may include the following steps:

[0085] (1) In an organic solvent, a compound represented by formula IM-5 is subjected to a substitution reaction with SM2 in the presence of a base; after the substitution reaction is completed, the solid in the reaction solution is removed, and the solvent is removed from the obtained solution to obtain a residue;

[0086] (2) The residue of step (1) is reacted with an acid to remove the Boc and imine protecting groups to obtain compound 1.

[0087] Preferably, The fragment is Preferably

[0088] In the method for preparing compound 1, the method for preparing the compound represented by formula IM-5 may include the following steps:

[0089] (A) In an organic solvent, the compound represented by formula IM-1(S) is reacted with compound SM-3 to obtain a compound represented by formula IM-5; n is as defined above;

[0090]

[0091] Preferably, in step (A), the organic solvent is one or more of methanol, ethanol, isopropanol and acetonitrile, preferably ethanol.

[0092] Preferably, in step (A), the molar ratio of compound SM-3 to the compound represented by formula IM-1(S) is 1:1-1.5:1.

[0093] Preferably, in step (A), the reaction temperature is 30°C-100°C, for example, the reflux temperature of the solvent used in the reaction.

[0094] Preferably, the product obtained after the reaction in step (A) is completed is directly used in step (1) without purification. For example, in step (A), after the reaction is completed, when the solvent used in the reaction in step (A) is the same as the solvent used in the reaction in step (1), the reaction solution in step (A) is directly used or used in step (1) after removing the solvent; when the solvent used in the reaction in step (A) is different from the solvent used in the reaction in step (1), the reaction solution in step (A) is used in step (1) after removing the solvent.

[0095] Preferably, the method for preparing compound 1 may include the following steps:

[0096] (A) reacting the compound represented by formula IM-1(S) with compound SM-3 in an organic solvent, and the product obtained after the reaction is completed is directly used in step (1) without purification;

[0097] (1) In an organic solvent, the product obtained in step (A) is subjected to a substitution reaction with SM2 in the presence of a base, and after the reaction is completed, the product obtained is directly subjected to step (2) without purification;

[0098] (2) The product obtained in step (1) is subjected to the action of an acid to remove the Boc and imine protecting groups to obtain compound 1.

[0099] In step (1), the molar ratio of SM2 to the compound represented by formula IM-1(S) in step (A) is preferably 0.95:1-1:1.

[0100] In step (1), the molar ratio of the base to the compound represented by formula IM-1(S) in step (A) is preferably 1:1-2:1.

[0101] After step (2) is completed, the conventional post-treatment steps of this type of reaction in the art can be used for treatment. Preferably, the post-treatment step includes: filtering the reaction solution of step (2), adjusting the pH of the filtrate to alkaline (e.g., pH 6) with a base, extracting with a water-insoluble organic solvent, and retaining the aqueous phase; adjusting the pH of the aqueous phase to alkaline (e.g., pH 10) with a base, extracting with a water-insoluble organic solvent, and retaining the organic phase; washing with water, drying with anhydrous sodium sulfate, filtering, and spin drying. The base can be an alkali metal hydroxide and / or an alkali metal carbonate, such as sodium hydroxide and / or sodium carbonate. The water-insoluble organic solvent can be dichloromethane.

[0102] The present invention also provides a compound represented by formula IM-5:

[0103]

[0104] The definition of n is as described above.

[0105] In some embodiments, the compound represented by formula IM-5 is:

[0106]

[0107] The present invention also provides a method for preparing the compound represented by formula IM-5, which comprises the following steps:

[0108] (A) In an organic solvent, the compound represented by formula IM-1(S) is reacted with compound SM-3 to obtain a compound represented by formula IM-5; n is as defined above; and the reaction conditions can be as described above;

[0109]

[0110] In the present invention, the SM1 is 8-chloro-5,6,7,8-tetrahydroquinoline, and the structural formula is

[0111] In the present invention, the IM-1 is N 1 -(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-butanediamine, the structural formula is

[0112] In the present invention, the IM-1(S) is N 1 -[(8S)-5,6,7,8-tetrahydro-8-quinolinyl]-1,4-butanediamine, the structural formula is

[0113] In the present invention, the SM2 is

[0114] In the present invention, the room temperature refers to 20-30°C.

[0115] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0116] The reagents and raw materials used in the present invention are commercially available.

[0117] The positive and progressive effects of the present invention are: the present invention uses 8-chloro-5,6,7,8-tetrahydroquinoline as a raw material to prepare (S)-N'-(1H-benzimidazol-2-ylmethyl)-N'-(5,6,7,8-tetrahydroquinoline-8-yl)butane-1,4-diamine, the reaction process has low danger, the reagents used are economical and safe, the preparation cost is low, and the post-treatment is simple, which is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0118] Figure 1 Single crystal diffraction structure diagram of the absolute configuration of IM-3 DETAILED DESCRIPTION

[0119] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0120] HPLC determination method for chemical purity of IM-1(S) and compound 1:

[0121] Mobile phase A: acetonitrile, mobile phase B: aqueous solution containing 1‰ trifluoroacetic acid

[0122] time Mobile phase A Mobile phase B 0mins 90％ 10％ 5mins 40％ 60％ 50mins 90％ 10％ 60mins 90％ 10％

[0123] Injection volume: 10 μL, column temperature: 25°C, flow rate: 1 mL / mins, wavelength: 268 nm

[0124] Column model: ZORBAX, inner diameter: 5μm, filler particle size 4.6mm, column length 250mm.

[0125] HPLC determination method of chiral purity of IM-1(S):

[0126] Mobile phase A: n-hexane solution containing 1‰ diethylamine, mobile phase B: ethanol solution containing 1‰ diethylamine

[0127] time Mobile phase A Mobile phase B 25mins 80％ 20％

[0128] Injection volume: 10 μL, column temperature: 35°C, flow rate: 0.6 mL / mins, wavelength: 266 nm

[0129] Column model: AY-H, inner diameter: 5μm, filler particle size 4.6mm, column length 250mm.

[0130] HPLC determination method for chiral purity of compound 1:

[0131] Mobile phase A: n-hexane solution containing 1‰ diethylamine, mobile phase B: isopropanol solution containing 1‰ diethylamine

[0132] time Mobile phase A Mobile phase B 40mins 90％ 10％

[0133] Injection volume: 20 μL, column temperature: 35°C, flow rate: 1 mL / mins, wavelength: 266 nm

[0134] Column model: OD-H, inner diameter: 5μm, filler particle size 4.6mm, column length 250mm.

[0135] Example 1

[0136] N 1 Preparation of -(5,6,7,8-tetrahydro-8-quinolyl)-1,4-butanediamine (IM-1)

[0137]

[0138] Add butanediamine (525.0 g, 5.956 mol) to a 2L reaction bottle, and add a mixed solution of SM1 (100.2 g, 0.598 mol) and 900 mL of MeCN dropwise at room temperature. After the addition is completed, react in an oil bath at 30-35°C for 23 h. TLC detection shows that the raw material has basically reacted completely. Concentrate the acetonitrile, add 1400 mL of dichloromethane, wash 5 times with 320 mL of water, concentrate the organic phase, add 400 mL of water, adjust the pH to 1-2 with concentrated hydrochloric acid, wash three times with 100 mL of dichloromethane, adjust the pH to about 12 with NaOH in the aqueous phase, extract three times with 100 mL of dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, filter, and spin dry to obtain 125.5 g of brown oil with a yield of 95.7% and HPLC purity of 98.75%.

[0139] 1 H-NMR (600MHz, CDCl3+D2O): δ8.38-8.39(dd,1H),7.37-7.38(dd,1H),7.05-7.08(q,1H),3.75-3.77(m,1H),2.69-2 .85(m,6H),2.13-2.17(m,1H),1.97-2.02(m,1H),1.71-1.79(m,2H),1.51-1.67(m,4H); MS(ESI+):m / z,220[M+H]+.

[0140] Example 2

[0141] N 1 Preparation of -(5,6,7,8-tetrahydro-8-quinolyl)-1,4-butanediamine (IM-1)

[0142]

[0143] Add butanediamine (133.6 g, 1.516 mol) to a 1 L reaction bottle, and add a mixed solution of SM1 (50.8 g, 0.303 mol) and 450 mL of MeCN dropwise at room temperature. After the addition is completed, react in an oil bath at 30-35 ° C for 23 h. TLC detection shows that the raw material is basically reacted. Concentrate the acetonitrile, add 700 mL of dichloromethane, wash 5 times with 160 mL of water, concentrate the organic phase, add 200 mL of water, adjust the pH to 1-2 with concentrated hydrochloric acid, wash three times with 50 mL of dichloromethane, add NaOH to the aqueous phase, adjust the pH to about 12, extract three times with 50 mL of dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, filter, and spin dry to obtain 50.9 g of brown oil with a yield of 76.6% and HPLC purity of 97.56%.

[0144] 1H-NMR (600MHz, CDCl3+D2O): δ8.38-8.39(dd,1H),7.37-7.38(dd,1H),7.05-7.08(q,1H),3.75-3.77(m,1H),2.69-2 .85(m,6H),2.13-2.17(m,1H),1.97-2.02(m,1H),1.71-1.79(m,2H),1.51-1.67(m,4H); MS(ESI+):m / z,220[M+H]+.

[0145] Example 3

[0146] N 1 Preparation of -(5,6,7,8-tetrahydro-8-quinolyl)-1,4-butanediamine (IM-1)

[0147]

[0148] Add butanediamine (395.16 g, 4.483 mol) to a 2L reaction bottle, and add a mixed solution of SM1 (50.1 g, 0.299 mol) and 450 mL of MeCN dropwise at room temperature. After the addition is completed, react in an oil bath at 30-35°C for 23 h. TLC detection shows that the raw material is basically reacted. Concentrate the acetonitrile, add 1000 mL of dichloromethane, wash 5 times with 160 mL of water, concentrate the organic phase, add 200 mL of water, adjust the pH to 1-2 with concentrated hydrochloric acid, wash three times with 50 mL of dichloromethane, adjust the pH to about 12 with NaOH in the aqueous phase, extract three times with 50 mL of dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, filter, and spin dry to obtain 64.1 g of brown oil with a yield of 97.8% and HPLC purity of 98.37%.

[0149] 1 H-NMR (600MHz, CDCl3+D2O): δ8.38-8.39(dd,1H),7.37-7.38(dd,1H),7.05-7.08(q,1H),3.75-3.77(m,1H),2.69-2 .85(m,6H),2.13-2.17(m,1H),1.97-2.02(m,1H),1.71-1.79(m,2H),1.51-1.67(m,4H); MS(ESI+):m / z,220[M+H]+.

[0150] Example 4

[0151] N 1 Preparation of -(5,6,7,8-tetrahydro-8-quinolyl)-1,4-butanediamine (IM-1)

[0152]

[0153] Add butanediamine (524.5 g, 5.950 mol) to a 2L reaction bottle, and add a mixed solution of SM1 (100.0 g, 0.597 mol) and 900 mL of acetonitrile dropwise at room temperature. After the addition is completed, react in an oil bath at 30-35°C for 23 h. TLC detection shows that the raw material has basically reacted completely. Concentrate the acetonitrile, add 1400 mL of dichloromethane, wash 5 times with 320 mL of water, concentrate the organic phase, add 400 mL of water, adjust the pH to 1-2 with concentrated hydrochloric acid, wash three times with 100 mL of dichloromethane, adjust the pH to about 12 with NaOH in the aqueous phase, extract three times with 100 mL of dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, filter, and spin dry to obtain 112.7 g of brown oil with a yield of 86.1% and HPLC purity of 98.79%.

[0154] 1 H-NMR (600MHz, CDCl3+D2O): δ8.38-8.39(dd,1H),7.37-7.38(dd,1H),7.05-7.08(q,1H),3.75-3.77(m,1H),2.69-2 .85(m,6H),2.13-2.17(m,1H),1.97-2.02(m,1H),1.71-1.79(m,2H),1.51-1.67(m,4H); MS(ESI+):m / z,220[M+H]+.

[0155] Example 5

[0156] N 1 Preparation of -[(8S)-5,6,7,8-tetrahydro-8-quinolinyl]-1,4-butanediamine (IM-1(S), Method 1)

[0157] D-(+)-p-Toluoyl tartaric acid (49.733 g, 0.129 mol) and 300 mL of ethanol were added to a 1000 mL reaction bottle, stirred at room temperature until dissolved, IM-1 (10.051 g, 45.826 mmol) was dissolved in 180 mL of ethanol and added dropwise to the reaction bottle at room temperature, heated under reflux in an oil bath to dissolve, stirred at room temperature for crystallization overnight, filtered and dried to obtain 22.011 g of off-white solid powder, with a yield of 34.8% (HPLC chemical purity: 99.88%, HPLC optical purity: 99.91%), and the single crystal diffraction confirmed the configuration, and the single crystal result was as follows: Figure 1 shown.

[0158] 1H-NMR (600MHz, DMSO-d6+D2O): δ8.45-8.46(dd,1H),7.85-7.87(m,12H),7.62-7.63(dd,1H),7.34-7.35(d,12H),5.67(s,6H),4.33-4.36 (m,1H),2.99-3.04(m,1H),2.88-2.93(m,1H),2.71-2.77(m,4H),2.37(s,18H),2.23-2.28(m,1H),1.88-1.92(m,1H),1.52-1.80(m,7H).

[0159] The above N 1 -[(8S)-5,6,7,8-tetrahydro-8-quinolinyl]-1,4-butanediamine·3D-(+)-p-methyldibenzoyl tartrate was dissolved in 30 mL of water, the pH was adjusted to about 10 with sodium hydroxide, extracted three times with 10 mL of dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain N 1 -[(8S)-5,6,7,8-tetrahydro-8-quinolyl]-1,4-butanediamine 3.502 g, yield 100%, 99.82% ee,

[0160] Example 6

[0161] N 1 Preparation of -[(8S)-5,6,7,8-tetrahydro-8-quinolinyl]-1,4-butanediamine (IM-1(S), Method 1)

[0162] D-(+)-p-Toluoyltartaric acid (30.863 g, 79.884 mmol) and 300 mL of ethanol were added to a 500 mL reaction bottle, and the mixture was stirred at room temperature until dissolved. IM-1 (5.006 g, 22.824 mmol) was dissolved in 50 mL of ethanol and added dropwise to the reaction bottle at room temperature. The mixture was heated under reflux in an oil bath until dissolved. The mixture was stirred at room temperature and crystallized overnight. The mixture was filtered and dried to obtain 10.986 g of an off-white solid powder with a yield of 34.9% (HPLC chemical purity: 99.86%, HPLC optical purity: 99.63%).

[0163] 1H-NMR (600MHz, DMSO-d6+D2O): δ8.45-8.46(dd,1H),7.85-7.87(m,12H),7.62-7.63(dd,1H),7.34-7.35(d,12H),5.67(s,6H),4.33-4.36 (m,1H),2.99-3.04(m,1H),2.88-2.93(m,1H),2.71-2.77(m,4H),2.37(s,18H),2.23-2.28(m,1H),1.88-1.92(m,1H),1.52-1.80(m,7H).

[0164] The above N 1 -[(8S)-5,6,7,8-tetrahydro-8-quinolinyl]-1,4-butanediamine·3D-(+)-p-methyldibenzoyl tartrate was dissolved in 20 mL of water, the pH was adjusted to about 10 with sodium hydroxide, extracted three times with 5 mL of dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain N 1 -[(8S)-5,6,7,8-tetrahydro-8-quinolyl]-1,4-butanediamine 1.748 g, yield 100%, 99.26% ee, The NMR data are the same as IM-1.

[0165] Example 7

[0166] N 1 Preparation of -[(8S)-5,6,7,8-tetrahydro-8-quinolinyl]-1,4-butanediamine (IM-1(S), Method 1)

[0167] D-(+)-p-Toluoyltartaric acid (25.356 g, 65.630 mmol) and 100 mL of methanol were added to a 500 mL reaction bottle, and the mixture was stirred at room temperature to dissolve. IM-1 (5.128 g, 23.380 mmol) was dissolved in 100 mL of ethanol and added dropwise to the reaction bottle at room temperature. The mixture was heated under reflux in an oil bath to dissolve. The mixture was stirred at room temperature and crystallized overnight. The mixture was filtered and dried to obtain 10.591 g of an off-white solid powder with a yield of 32.9% (HPLC chemical purity: 99.78%, HPLC optical purity: 99.59%).

[0168] 1H-NMR (600MHz, DMSO-d6+D2O): δ8.45-8.46(dd,1H),7.85-7.87(m,12H),7.62-7.63(dd,1H),7.34-7.35(d,12H),5.67(s,6H),4.33-4.36 (m,1H),2.99-3.04(m,1H),2.88-2.93(m,1H),2.71-2.77(m,4H),2.37(s,18H),2.23-2.28(m,1H),1.88-1.92(m,1H),1.52-1.80(m,7H).

[0169] The above N 1 -[(8S)-5,6,7,8-tetrahydro-8-quinolinyl]-1,4-butanediamine·3D-(+)-p-methyldibenzoyl tartrate was dissolved in 20 mL of water, the pH was adjusted to about 10 with sodium hydroxide, extracted three times with 5 mL of dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain N 1 -[(8S)-5,6,7,8-tetrahydro-8-quinolyl]-1,4-butanediamine 1.675 g, yield 99.3%, 99.18% ee, The NMR data are the same as IM-1.

[0170] Example 8

[0171] N 1 Preparation of -[(8S)-5,6,7,8-tetrahydro-8-quinolinyl]-1,4-butanediamine (IM-1(S), Method 1)

[0172] D-(+)-p-Toluoyltartaric acid (25.016 g, 64.750 mmol), 200 mL of isopropanol and 40 mL of H2O were added to a 500 mL reaction bottle and stirred at room temperature to dissolve. IM-1 (5.108 g, 23.289 mmol) was dissolved in 50 mL of ethanol and added dropwise to the reaction bottle at room temperature. The mixture was heated to reflux in an oil bath to dissolve. The mixture was stirred at room temperature and crystallized overnight. The mixture was filtered and dried to obtain 11.562 g of an off-white solid powder with a yield of 36.0% (HPLC chemical purity: 99.83%, HPLC optical purity: 99.62%).

[0173] 1H-NMR (600MHz, DMSO-d6+D2O): δ8.45-8.46(dd,1H),7.85-7.87(m,12H),7.62-7.63(dd,1H),7.34-7.35(d,12H),5.67(s,6H),4.33-4.36 (m,1H),2.99-3.04(m,1H),2.88-2.93(m,1H),2.71-2.77(m,4H),2.37(s,18H),2.23-2.28(m,1H),1.88-1.92(m,1H),1.52-1.80(m,7H).

[0174] The above N 1 -[(8S)-5,6,7,8-tetrahydro-8-quinolinyl]-1,4-butanediamine·3D-(+)-p-methyldibenzoyl tartrate was dissolved in 20 mL of water, the pH was adjusted to about 10 with sodium hydroxide, extracted three times with 5 mL of dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain N 1 -[(8S)-5,6,7,8-tetrahydro-8-quinolyl]-1,4-butanediamine 1.832 g, yield 99.6%, 99.24% ee, The NMR data are the same as IM-1.

[0175] Example 9

[0176] N 1 Preparation of -[(8S)-5,6,7,8-tetrahydro-8-quinolyl]-1,4-butanediamine (IM-1(S), method 2) To a 500 mL reaction bottle, add N-acetyl-L-leucine (11.052 g, 63.807 mmol), 200 mL of tetrahydrofuran, IM-1 (20.0 g, 91.168 mmol) and 20 mL of MeOH, heat to reflux in an oil bath to dissolve, stir at room temperature for crystallization overnight, filter and dry to obtain 12.675 g of off-white solid powder, with a yield of 35.4% (HPLC chemical purity: 99.92%, HPLC optical purity: 99.98%).

[0177] 1H-NMR (600MHz, DMSO-d6): δ8.35-8.36(dd,1H),7.49-7.51(dd,1H),7.17-7.19(m,1H),3.95-3.97(brs,1H),2.69-2.76(m,4H),2.60-2.68(m,2H), 2.00-2.04(m,1H),1.87-1.90(m,1H),1.79(s,3H),1.63-1.67(m,2H),1. 49-1.59(m,5H),1.43-1.18(m,1H),1.30-1.35(m,1H),0.81-0.83(t,6H).

[0178] The above N 1 -[(8S)-5,6,7,8-tetrahydro-8-quinolinyl]-1,4-butanediamine·N-acetyl-L-leucine salt was dissolved in 15 mL of water, the pH was adjusted to about 10 with sodium hydroxide, extracted three times with 10 mL of dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain N 1 -[(8S)-5,6,7,8-tetrahydro-8-quinolyl]-1,4-butanediamine 7.082 g, yield 100.0%, 99.96% ee, The NMR data are the same as IM-1.

[0179] Example 10

[0180] N 1 Preparation of -[(8S)-5,6,7,8-tetrahydro-8-quinolinyl]-1,4-butanediamine (IM-1(S), Method 2)

[0181] To a 500 mL reaction bottle, add N-acetyl-L-leucine (11.050 g, 63.795 mmol), 200 mL of tetrahydrofuran, IM-1 (20.0 g, 91.168 mmol) and 5 mL of MeOH, heat to reflux in an oil bath to dissolve, stir at room temperature to crystallize overnight, filter and dry to obtain 12.826 g of off-white solid powder, with a yield of 35.8% (HPLC chemical purity: 99.97%, HPLC optical purity: 100.00%).

[0182] 1H-NMR (600MHz, DMSO-d6): δ8.35-8.36(dd,1H),7.49-7.51(dd,1H),7.17-7.19(m,1H),3.95-3.97(brs,1H),2.69-2.76(m,4H),2.60-2.68(m,2H), 2.00-2.04(m, 1H), 1.87-1.90(m, 1H), 1.79(s, 3H), 1.63-1.67(m, 2H), 1. 49-1.59(m,5H),1.43-1.18(m,1H),1.30-1.35(m,1H),0.81-0.83(t,6H).

[0183] The above N 1 -[(8S)-5,6,7,8-tetrahydro-8-quinolinyl]-1,4-butanediamine·N-acetyl-L-leucine salt was dissolved in 15 mL of water, the pH was adjusted to about 10 with sodium hydroxide, extracted three times with 10 mL of dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain N 1 -[(8S)-5,6,7,8-tetrahydro-8-quinolyl]-1,4-butanediamine 7.166 g, yield 100.0%, 100.00% ee, The NMR data are the same as IM-1.

[0184] Embodiment 11

[0185] N 1 Preparation of -[(8S)-5,6,7,8-tetrahydro-8-quinolinyl]-1,4-butanediamine (IM-1(S), Method 2)

[0186] To a 500 mL reaction bottle, add N-acetyl-L-leucine (4.053 g, 23.40 mmol), 200 mL of tetrahydrofuran, IM-1 (10.107 g, 46.081 mmol) and 20 mL of MeOH, heat to reflux in an oil bath to dissolve, stir at room temperature to crystallize overnight, filter and dry to obtain 5.020 g of off-white solid powder, with a yield of 27.8% (HPLC chemical purity: 99.82%, HPLC optical purity: 99.51%).

[0187] 1H-NMR (600MHz, DMSO-d6): δ8.35-8.36(dd,1H),7.49-7.51(dd,1H),7.17-7.19(m,1H),3.95-3.97(brs,1H),2.69-2.76(m,4H),2.60-2.68(m,2H), 2.00-2.04(m,1H),1.87-1.90(m,1H),1.79(s,3H),1.63-1.67(m,2H),1. 49-1.59(m,5H),1.43-1.18(m,1H),1.30-1.35(m,1H),0.81-0.83(t,6H).

[0188] The above N 1 -[(8S)-5,6,7,8-tetrahydro-8-quinolinyl]-1,4-butanediamine·N-acetyl-L-leucine salt was dissolved in 50 mL of water, the pH was adjusted to about 10 with sodium hydroxide, extracted three times with 10 mL of dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain N 1 -[(8S)-5,6,7,8-tetrahydro-8-quinolyl]-1,4-butanediamine 2.800 g, yield 99.6%, 99.02% ee, The NMR data are the same as IM-1.

[0189] Example 12

[0190] N 1 Preparation of -[(8S)-5,6,7,8-tetrahydro-8-quinolinyl]-1,4-butanediamine (IM-1(S), Method 2)

[0191] To a 500 mL reaction bottle, add N-acetyl-L-leucine (6.378 g, 36.82 mmol), 200 mL of tetrahydrofuran, IM-1 (10.107 g, 46.081 mmol) and 20 mL of MeOH, heat to reflux in an oil bath to dissolve, stir at room temperature to crystallize overnight, filter and dry to obtain 4.068 g of off-white solid powder, with a yield of 22.7% (HPLC chemical purity: 99.01%, HPLC optical purity: 99.06%).

[0192] 1H-NMR (600MHz, DMSO-d6): δ8.35-8.36(dd,1H),7.49-7.51(dd,1H),7.17-7.19(m,1H),3.95-3.97(brs,1H),2.69-2.76(m,4H),2.60-2.68(m,2H), 2.00-2.04(m,1H),1.87-1.90(m,1H),1.79(s,3H),1.63-1.67(m,2H),1. 49-1.59(m,5H),1.43-1.18(m,1H),1.30-1.35(m,1H),0.81-0.83(t,6H).

[0193] The above N 1 -[(8S)-5,6,7,8-tetrahydro-8-quinolinyl]-1,4-butanediamine·N-acetyl-L-leucine salt was dissolved in 50 mL of water, the pH was adjusted to about 10 with sodium hydroxide, extracted three times with 10 mL of dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain N 1 -[(8S)-5,6,7,8-tetrahydro-8-quinolyl]-1,4-butanediamine 2.259 g, yield 99.4%, 99.03% ee, The NMR data are the same as IM-1.

[0194] Embodiment 13

[0195] Preparation of (S)-N'-(1H-benzimidazol-2-ylmethyl)-N'-(5,6,7,8-tetrahydroquinolin-8-yl)butane-1,4-diamine (Compound 1)

[0196]

[0197] To a 50 mL reaction bottle, add 1.902 g IM-1(S) (1.902 g, 8.672 mmol), 20 mL ethanol, and p-nitrobenzaldehyde (1.446 g, 9.569 mmol), reflux for 2 h, and then concentrate for later use.

[0198] Add 25 mL of acetonitrile solution of the above-mentioned standby concentrate, SM2 (2.314 g, 8.676 mmol), and DIPEA (1.685 g, 13.037 mmol) to another 50 mL reaction bottle, and react in an oil bath at 38-41°C for 14 h. Stop heating, cool to room temperature, filter, concentrate, add 20 mL of water, adjust pH to 1-2 with concentrated hydrochloric acid, stir in an oil bath at 38-42°C for 4 h, filter, the filter cake is a small polar aldehyde compound, adjust pH of the filtrate to about 6 with saturated sodium carbonate aqueous solution, and extract 3 times with 10 mL of dichloromethane. A small amount of NaOH was continued to be added to the aqueous phase to adjust the pH to about 10, and extracted three times with 20 mL of dichloromethane. The organic phases were combined, washed twice with 10 mL of water, dried over anhydrous sodium sulfate, filtered, spin-dried, and pulled dry with an oil pump to obtain 3.072 g of a black colloidal solid. Column chromatography purification afforded 2.728 g, with a yield of 90.0%, HPLC chemical purity: 99.96%, HPLC optical purity: 100.00%.

[0199] 1 H-NMR (600MHz, CDCl3+D2O): δ8.54-8.55(d,1H),7.56-7.59(m,2H),7.39-7. 42(dd,1H),7.11-7.20(d,3H),3.95-4.08(m,3H),2.79-2.86(m,1H),2.64-2 .74(m,2H),2.45-2.54(m,3H),2.16-2.22(m,1H),1.99-2.01(m,1H),1.84-1 .95(m,1H),1.65-1.72(m,1H),1.31-1.48(m,4H); MS(ESI+):m / z,350[M+H]+.

[0200] Embodiment 14

[0201] Preparation of (S)-N'-(1H-benzimidazol-2-ylmethyl)-N'-(5,6,7,8-tetrahydroquinolin-8-yl)butane-1,4-diamine (Compound 1)

[0202] IM-1(S) (2.000 g, 9.229 mmol), 20 mL of ethanol, and 2,4-dinitrobenzaldehyde (1.991 g, 10.152 mmol) were added to a 50 mL reaction bottle, and the mixture was refluxed for 2 h and then concentrated for later use.

[0203] Add 25 mL of acetonitrile solution of the above-mentioned standby concentrate, SM2 (2.484 g, 9.313 mmol) and DIPEA (1.687 g, 13.052 mmol) to another 50 mL reaction bottle, and react in an oil bath at 38-41°C for 14 h. Stop heating, cool to room temperature, filter, concentrate, add 20 mL of water, adjust pH to 1-2 with concentrated hydrochloric acid, stir in an oil bath at 38-42°C for 4 h, filter, the filter cake is a small polar aldehyde compound, adjust pH of the filtrate to about 6 with saturated sodium carbonate aqueous solution, and extract 3 times with 10 mL of dichloromethane. A small amount of NaOH was continued to be added to the aqueous phase to adjust the pH to about 10, and the mixture was extracted three times with 20 mL of dichloromethane. The organic phases were combined, washed twice with 10 mL of water, dried over anhydrous sodium sulfate, filtered, spin-dried, and pulled dry with an oil pump to obtain 3.072 g of a black colloidal solid with a crude yield of 101.4% and an HPLC purity of 94.94%. Column chromatography purification afforded 2.628 g with a yield of 84.2%, HPLC chemical purity: 99.89%, and HPLC optical purity: 100.00%.

[0204] 1 H-NMR (600MHz, CDCl3+D2O): δ8.54-8.55(d,1H),7.56-7.59(m,2H),7.39- 7.42(dd,1H),7.11-7.20(d,3H),3.95-4.08(m,3H),2.79-2.86(m,1H),2. 64-2.74(m,2H),2.45-2.54(m,3H),2.16-2.22(m,1H),1.99-2.01(m,1H), 1.84-1.95(m,1H),1.65-1.72(m,1H),1.31-1.48(m,4H):m / z,350[M+H]+.

[0205] Embodiment 15

[0206] Preparation of (S)-N'-(1H-benzimidazol-2-ylmethyl)-N'-(5,6,7,8-tetrahydroquinolin-8-yl)butane-1,4-diamine (Compound 1)

[0207] Add IM-1(S) (2.000 g, 9.229 mmol), 20 mL of acetonitrile, and p-nitrobenzaldehyde (1.591 g, 10.528 mmol) into a 50 mL reaction bottle, reflux for 2 h, and then concentrate for later use.

[0208] Add 25 mL of acetonitrile solution of the above-mentioned standby concentrate, SM2 (2.456 g, 9.208 mmol) and DIPEA (1.683 g, 13.021 mmol) to another 50 mL reaction bottle, and react in an oil bath at 38-41°C for 14 h. Stop heating, cool to room temperature, filter, concentrate, add 20 mL of water, adjust pH to 1-2 with concentrated hydrochloric acid, stir in an oil bath at 38-42°C for 4 h, filter, the filter cake is a small polar aldehyde compound, adjust pH of the filtrate to about 6 with saturated sodium carbonate aqueous solution, and extract 3 times with 10 mL of dichloromethane. A small amount of NaOH was continued to be added to the aqueous phase to adjust the pH to about 10, and extracted three times with 20 mL of dichloromethane. The organic phases were combined, washed twice with 10 mL of water, dried over anhydrous sodium sulfate, filtered, spin-dried, and pulled dry with an oil pump to obtain 3.072 g of a black colloidal solid with a crude yield of 101.4% and an HPLC purity of 94.94%. Column chromatography purification afforded 2.516 g with a yield of 79.0%, HPLC chemical purity: 99.78%, and HPLC optical purity: 100.00%.

[0209] 1 H-NMR (600MHz, CDCl3+D2O): δ8.54-8.55(d,1H),7.56-7.59(m,2H),7.39- 7.42(dd,1H),7.11-7.20(d,3H),3.95-4.08(m,3H),2.79-2.86(m,1H),2. 64-2.74(m,2H),2.45-2.54(m,3H),2.16-2.22(m,1H),1.99-2.01(m,1H), 1.84-1.95(m,1H),1.65-1.72(m,1H),1.31-1.48(m,4H):m / z,350[M+H]+.

[0210] Comparative Example 1

[0211] N 1 Preparation of -[(8S)-5,6,7,8-tetrahydro-8-quinolinyl]-1,4-butanediamine (IM-1(S))

[0212] To a 500 mL reaction bottle, add D-(-)-tartaric acid (10.527 g, 70.138 mmol) and 200 mL of ethanol, and stir at room temperature to dissolve. IM-1 (5.137 g, 23.380 mmol) was dissolved in 50 mL of ethanol and added dropwise to the reaction bottle at room temperature. Heat under reflux in an oil bath to dissolve. Crystallize overnight under stirring at room temperature without precipitation.

[0213] Comparative Example 2

[0214] N 1Preparation of -[(8S)-5,6,7,8-tetrahydro-8-quinolinyl]-1,4-butanediamine (IM-1(S))

[0215] To a 250 mL reaction bottle, add L-(-)-dibenzoyltartaric acid (8.359 g, 23.330 mmol) and 80 mL of ethanol, stir at room temperature to dissolve, IM-1 (5.117 g, 23.330 mmol) was dissolved in 50 mL of ethanol and added dropwise to the reaction bottle at room temperature, heated under reflux in an oil bath to dissolve, and stirred at room temperature to crystallize overnight without precipitation.

[0216] Comparative Example 3

[0217] N 1 Preparation of -[(8S)-5,6,7,8-tetrahydro-8-quinolinyl]-1,4-butanediamine (IM-1(S))

[0218] To a 250 mL reaction bottle, add L-(-)-dibenzoyltartaric acid (8.360 g, 23.333 mmol) and 80 mL of ethyl acetate, stir at room temperature to dissolve, IM-1 (5.120 g, 23.334 mmol) was dissolved in 50 mL of ethyl acetate and added dropwise to the reaction bottle at room temperature, heated under reflux in an oil bath to dissolve, and stirred at room temperature to crystallize overnight to precipitate oil.

[0219] Comparative Example 4

[0220] N 1 Preparation of -[(8S)-5,6,7,8-tetrahydro-8-quinolinyl]-1,4-butanediamine (IM-1(S))

[0221] To a 500 mL reaction bottle, add L-(-)-dibenzoyltartaric acid (26.520 g, 68.830 mmol) and 260 mL of ethanol, stir at room temperature to dissolve, dissolve IM-1 (5.032 g, 22.943 mmol) in 50 mL of ethanol and add dropwise to the reaction bottle at room temperature, heat under reflux in an oil bath to dissolve, and stir at room temperature to crystallize overnight without precipitation.

[0222] Comparative Example 5

[0223] N 1 Preparation of -[(8S)-5,6,7,8-tetrahydro-8-quinolinyl]-1,4-butanediamine (IM-1(S))

[0224] To a 250 mL reaction bottle, add L-(-)-malic acid (3.079 g, 22.962 mmol) and 50 mL of ethanol, and stir at room temperature to dissolve. IM-1 (5.036 g, 22.961 mmol) was dissolved in 50 mL of ethanol and added dropwise to the reaction bottle at room temperature. Heat under reflux in an oil bath to dissolve. Crystallize overnight under stirring at room temperature without precipitation.

[0225] Comparative Example 6

[0226] N 1 Preparation of -[(8S)-5,6,7,8-tetrahydro-8-quinolinyl]-1,4-butanediamine (IM-1(S))

[0227] D-(+)-camphorsulfonic acid (5.296 g, 22.798 mmol) and 50 mL of ethanol were added to a 250 mL reaction bottle, and the mixture was stirred at room temperature to dissolve. IM-1 (5.000 g, 22.797 mmol) was dissolved in 50 mL of ethanol and added dropwise to the reaction bottle at room temperature. The mixture was heated under reflux in an oil bath to dissolve. The mixture was stirred at room temperature and crystallized overnight without precipitation.

[0228] Comparative Example 7

[0229] N 1 Preparation of -[(8S)-5,6,7,8-tetrahydro-8-quinolinyl]-1,4-butanediamine (IM-1(S))

[0230] To a 250 mL reaction bottle, add L-pyroglutamic acid (2.944 g, 22.802 mmol) and 30 mL of ethanol, stir at room temperature to dissolve, dissolve IM-1 (5.002 g, 22.806 mmol) in 50 mL of ethanol and add dropwise to the reaction bottle at room temperature, heat under reflux in an oil bath to dissolve, and crystallize overnight under stirring at room temperature without precipitation.

[0231] Comparative Example 8

[0232] Preparation of (S)-N'-(1H-benzimidazol-2-ylmethyl)-N'-(5,6,7,8-tetrahydroquinolin-8-yl)butane-1,4-diamine (Compound 1)

[0233] Add IM-1(S) (2.000 g, 9.229 mmol), 20 mL ethanol, p-nitrobenzaldehyde (1.589 g, 10.515 mmol) to a 50 mL reaction bottle, reflux for 2 h, then add SM2 (2.318 g, 8.691 mmol), 5 mL cyclohexane and K2CO3 (1.276 g, 9.232 mmol), reflux with water for 14 h. Stop heating, cool to room temperature, filter, concentrate, add 20 mL water, adjust pH to 1-2 with concentrated hydrochloric acid, stir in an oil bath at 38-42 ° C for 4 h, filter, the filter cake is a small polar aldehyde compound, adjust pH to about 6 with saturated sodium carbonate aqueous solution, and extract 3 times with 10 mL dichloromethane. A small amount of NaOH was added to the aqueous phase to adjust the pH to about 10, and the mixture was extracted three times with 20 mL of DCM. The organic phases were combined, washed twice with 10 mL of water, dried over anhydrous sodium sulfate, filtered, spin-dried, and pulled dry with an oil pump to obtain 1.812 with a yield of 56.8%, HPLC chemical purity: 99.07%, and HPLC optical purity: 100.00%.

[0234] 1 H-NMR (600MHz, CDCl3+D2O): δ8.54-8.55(d,1H),7.56-7.59(m,2H),7.39- 7.42(dd,1H),7.11-7.20(d,3H),3.95-4.08(m,3H),2.79-2.86(m,1H),2. 64-2.74(m,2H),2.45-2.54(m,3H),2.16-2.22(m,1H),1.99-2.01(m,1H), 1.84-1.95(m,1H),1.65-1.72(m,1H),1.31-1.48(m,4H):m / z,350[M+H]+.

[0235] Comparative Example 9

[0236] Preparation of (S)-N'-(1H-benzimidazol-2-ylmethyl)-N'-(5,6,7,8-tetrahydroquinolin-8-yl)butane-1,4-diamine (Compound 1)

[0237] Add IM-1(S) (2.000 g, 9.229 mmol), 20 mL ethanol, p-nitrobenzaldehyde (1.593 g, 10.541 mmol) to a 50 mL reaction bottle, reflux for 2 h, then add SM2 (2.470 g, 9.261 mmol) and K2CO3 (1.280 g, 9.261 mmol), and reflux for 14 h. Stop heating, cool to room temperature, filter, concentrate, add 20 mL water, adjust pH to 1-2 with concentrated hydrochloric acid, stir in an oil bath at 38-42 ° C for 4 h, filter, the filter cake is a small polar aldehyde compound, adjust the filtrate to pH 6 with saturated sodium carbonate aqueous solution, and extract 3 times with 10 mL dichloromethane. A small amount of NaOH was continued to be added to the aqueous phase to adjust the pH to about 10, and extracted three times with 20 mL of dichloromethane. The organic phases were combined, washed twice with 10 mL of water, dried over anhydrous sodium sulfate, filtered, spin-dried, pulled dry with an oil pump, and purified by column chromatography to obtain 1.364 with a yield of 42.8%, HPLC chemical purity: 99.13%, HPLC optical purity: 100.00%.

[0238] 1 H-NMR (600MHz, CDCl3+D2O): δ8.54-8.55(d,1H),7.56-7.59(m,2H),7.39- 7.42(dd,1H),7.11-7.20(d,3H),3.95-4.08(m,3H),2.79-2.86(m,1H),2. 64-2.74(m,2H),2.45-2.54(m,3H),2.16-2.22(m,1H),1.99-2.01(m,1H), 1.84-1.95(m,1H),1.65-1.72(m,1H),1.31-1.48(m,4H):m / z,350[M+H]+.

Claims

1. A method for preparing a compound represented by formula IM-1(S) by splitting, characterized in that: It includes the following steps: (i) reacting compound IM-1 with a resolving agent in a solvent to form a salt to obtain a salt of the compound represented by formula IM-1(S) and the resolving agent; (ii) subjecting the salt obtained in step (i) to a free reaction under the action of a base to obtain a compound represented by formula IM-1(S); The compound IM-1 is a mixture of a compound represented by formula IM-1(S) and a compound represented by formula IM-1(R); The resolving agent is D-(+)-p-methyldibenzoyltartaric acid or N-acetyl-L-leucine; The salt formed by the compound of formula IM-1(S) and the resolving agent has a molecular composition of IM-1(S): resolving agent of 1:1-1:

3.

2. The method for preparing the compound represented by formula IM-1(S) by splitting according to claim 1, characterized in that: It meets one or more of the following conditions: 1) The compound IM-1 is a mixture of a compound represented by formula IM-1(S) and a compound represented by formula IM-1(R) in a molar ratio of (2:3) to (3:2); 2) When the resolving agent is D-(+)-p-methyldibenzoyltartaric acid, the salt formed by the compound of formula IM-1(S) and the resolving agent is 3) When the resolving agent is N-acetyl-L-leucine, the salt formed by the compound of formula IM-1(S) and the resolving agent is 4) When the resolving agent is D-(+)-p-methyldibenzoyltartaric acid, the solvent is an alcohol solvent or a mixed solvent of an alcohol solvent and water; 5) When the resolving agent is N-acetyl-L-leucine, the solvent is a mixed solvent of an aprotic solvent and a protic solvent; 6) When the resolving agent is D-(+)-p-methyldibenzoyltartaric acid, the volume mass ratio of the solvent to IM-1 is 10 to 80 ml / g; 7) When the resolving agent is D-(+)-p-methyldibenzoyltartaric acid, the molar ratio of the resolving agent to compound IM-1 is 1:1 or more 8) When the resolving agent is N-acetyl-L-leucine, the volume mass ratio of the solvent to the compound IM-1 is 5 to 20 ml / g; 9) When the resolving agent is N-acetyl-L-leucine, the molar ratio of the resolving agent to compound IM-1 is 0.5:1 or more; 10) The temperature of the salt-forming reaction is 60-100° C.; 11) In the step (i), after the salt-forming reaction is completed, a crystallization step is also included; 12) In the step (ii), the base is an alkali metal hydroxide and / or an alkali metal carbonate; 13) In the step (ii), the temperature of the free reaction is 10 to 40°C; 14) In the step (ii), the free reaction is carried out in water; 15) In the step (ii), the free reaction comprises the following steps: adjusting the pH of the aqueous solution of the salt obtained in the step (i) to alkaline with a base, extracting the obtained aqueous solution with an organic solvent, and concentrating the organic phase to obtain the compound represented by formula IM-1(S).

3. The method for preparing the compound represented by formula IM-1(S) by splitting according to claim 2, characterized in that: It meets one or more of the following conditions: 1) The compound IM-1 is a mixture of a compound represented by formula IM-1(S) and a compound represented by formula IM-1(R) in a molar ratio of 1:1; 2) When the resolving agent is D-(+)-p-methyldibenzoyltartaric acid, the alcohol solvent is selected from one or more of methanol, ethanol and isopropanol; 3) When the resolving agent is N-acetyl-L-leucine, the aprotic solvent is an ether solvent; 4) When the resolving agent is D-(+)-p-methyldibenzoyltartaric acid, the volume mass ratio of the solvent to IM-1 is 10-30 ml / g; 5) When the resolving agent is D-(+)-p-methyldibenzoyltartaric acid, the molar ratio of the resolving agent to compound IM-1 is 3:1 or more; 6) When the resolving agent is N-acetyl-L-leucine, the molar ratio of the resolving agent to compound IM-1 is (0.5-3):1; 7) The temperature of the salt-forming reaction is the reflux temperature of the solvent used in the salt-forming reaction; 8) In the step (i), after the salt-forming reaction is completed, a step of cooling and crystallization is also included; 9) In step (ii), the base is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate; 10) In the step (ii), the freeing reaction comprises the following steps: adjusting the pH of the aqueous solution of the salt obtained in the step (i) to 10 with a base.

4. The method for preparing the compound represented by formula IM-1(S) by splitting according to claim 3, characterized in that: It meets one or more of the following conditions: 1) When the resolving agent is D-(+)-p-methyldibenzoyltartaric acid, the alcohol solvent is Ethanol; 2) When the resolving agent is N-acetyl-L-leucine, the ether solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran and dioxane; 3) When the resolving agent is D-(+)-p-methyldibenzoyltartaric acid, the molar ratio of the resolving agent to compound IM-1 is (3:1) to (3.5:1); 4) When the resolving agent is N-acetyl-L-leucine, the molar ratio of the resolving agent to compound IM-1 is (0.5-0.7):1; 5) In the step (i), after the salt-forming reaction is completed, the reaction solution of the salt-forming reaction is further cooled and crystallized; the temperature of the cooling and crystallization is reduced to 20-30°C; 6) In the step (ii), the base is sodium hydroxide; 7) In the step (ii), the free reaction comprises the following steps: adjusting the pH of the aqueous solution of the salt obtained in the step (i) to alkaline with a base, extracting the obtained aqueous solution with dichloromethane, and concentrating the organic phase to obtain the compound represented by formula IM-1(S).

5. The method for preparing the compound represented by formula IM-1(S) by splitting according to claim 2, characterized in that: It meets one or more of the following conditions: 1) When the resolving agent is D-(+)-p-methyldibenzoyltartaric acid, the volume ratio of the alcohol solvent to water in the mixed solvent of the alcohol solvent and water is 5:1-8:1; 2) When the resolving agent is N-acetyl-L-leucine, the protic solvent is an alcohol solvent, water or a "mixed solvent of an alcohol solvent and water"; 3) When the resolving agent is D-(+)-p-methyldibenzoyltartaric acid, the molar ratio of the resolving agent to compound IM-1 is 3:1; 4) When the resolving agent is N-acetyl-L-leucine, the molar ratio of the resolving agent to compound IM-1 is 0.7:

1.

6. The method for preparing the compound represented by formula IM-1(S) by splitting according to claim 5, characterized in that: It meets one or more of the following conditions: 1) When the resolving agent is D-(+)-p-methyldibenzoyltartaric acid, the solvent is ethanol, methanol / ethanol, or isopropanol / water / ethanol, wherein " / " indicates a mixed solvent; 2) When the resolving agent is N-acetyl-L-leucine, the alcohol solvent is selected from one or more of methanol, ethanol and isopropanol.

7. The method for preparing the compound represented by formula IM-1(S) by splitting according to claim 2, characterized in that: When the resolving agent is N-acetyl-L-leucine, the solvent is tetrahydrofuran / methanol, wherein " / " indicates a mixed solvent.

8. The method for preparing the compound represented by formula IM-1(S) by splitting according to claim 2, characterized in that: The compound IM-1 is prepared by the following method: in an organic solvent, the compound SM1 is subjected to the following substitution reaction with 1,4-butanediamine; 9. The method for preparing the compound represented by formula IM-1(S) by splitting according to claim 8, characterized in that: It meets one or more of the following conditions: 1) In the substitution reaction, the organic solvent is acetonitrile and / or N,N-dimethylformamide; 2) In the substitution reaction, the molar ratio of 1,4-butanediamine to SM-1 is 5:1 to 15:1; 3) In the substitution reaction, the reaction temperature is 25-40°C; 4) The time of the substitution reaction is 20 to 25 hours.

10. The method for preparing the compound represented by formula IM-1(S) by splitting according to claim 9, characterized in that: It meets one or more of the following conditions: 1) In the substitution reaction, the organic solvent is acetonitrile; 2) In the substitution reaction, the molar ratio of 1,4-butanediamine to SM-1 is 10:1; 3) In the substitution reaction, the reaction temperature is 30-35°C.

11. Use of D-(+)-p-methyldibenzoyltartaric acid or N-acetyl-L-leucine in preparing a compound represented by formula IM-1(S) by splitting IM-1; The compound IM-1 is a mixture of a compound represented by formula IM-1(S) and a compound represented by formula IM-1(R); 12. A method for preparing compound IM-1, characterized in that: It includes the following steps: In an organic solvent, compound SM1 and 1,4-butanediamine undergo the following substitution reaction; 13. The method for preparing the compound IM-1 according to claim 12, characterized in that: The conditions and operation of the substitution reaction are the same as those described in claim 9 or 10.

14. A method for preparing compound 1, characterized in that: It includes the following steps: (1) In an organic solvent, the compound represented by formula IM-5 is subjected to a substitution reaction with SM2 in the presence of a base to obtain a compound represented by formula IM-6; (2) removing the Boc and imine protecting groups from the compound represented by formula IM-6 obtained in step (1) under the action of an acid to obtain compound 1; Where n is 0, 1 or 2; 15. The method for preparing compound 1 according to claim 14, characterized in that: It includes the following steps: (1) In an organic solvent, a compound represented by formula IM-5 is subjected to a substitution reaction with SM2 in the presence of a base; after the substitution reaction is completed, the solid in the reaction solution is removed, and the solvent is removed from the obtained solution to obtain a residue; (2) The residue of step (1) is reacted with an acid to remove the Boc and imine protecting groups to obtain compound 1.

16. The method for preparing compound 1 according to claim 14 or 15, characterized in that: It meets one or more of the following conditions: 1) In step (1), the organic solvent is one or more of methanol, ethanol, isopropanol and acetonitrile; 2) In step (1), the volume mass ratio of the organic solvent to the compound SM2 is 8 to 15 mL / g; 3) In step (1), the base is one or more of triethylamine, N,N-diisopropylethylamine and 4-dimethylaminopyridine; 4) The substitution reaction temperature in step (1) is 30 to 100° C.; 5) After the substitution reaction in step (1) is completed, the product obtained is directly subjected to step (2) without purification; 6) In step (2), the acid is one or more of hydrochloric acid, sulfuric acid and trifluoroacetic acid; 7) In step (2), the deprotection reaction is carried out in water; 8) In step (2), the deprotection reaction comprises the following steps: adjusting the pH of the aqueous solution of the compound represented by formula IM-6 to 1-2 with an acid and then performing a deprotection reaction; 9) In step (2), the temperature of the deprotection reaction is 38-42°C; 10) in the compound represented by formula IM-5 The fragment is 17. The method for preparing compound 1 according to claim 16, characterized in that: It meets one or more of the following conditions: 1) In step (1), the organic solvent is acetonitrile; 2) In step (1), the base is N,N-diisopropylethylamine; 3) The substitution reaction temperature in step (1) is 35-45°C; 4) After the substitution reaction in step (1) is completed, the solid in the reaction solution is removed, the solvent is removed from the obtained solution, and the obtained residue is directly used in step (2); 5) In step (2), the acid is hydrochloric acid; 6) The compound represented by formula IM-5 The fragment is 18. The method for preparing compound 1 according to claim 16, characterized in that: The IM-5 can be prepared by the following steps: (A) In an organic solvent, the compound represented by formula IM-1(S) is reacted with compound SM-3 to obtain a compound represented by formula IM-5; n is as defined in claim 14; 19. The method for preparing compound 1 according to claim 18, characterized in that: It meets one or more of the following conditions: 1) In step (A), the organic solvent is one or more of methanol, ethanol, isopropanol and acetonitrile; 2) In step (A), the molar ratio of compound SM-3 to the compound represented by formula IM-1(S) is 1:1-1.5:1; 3) In step (A), the reaction temperature is 30°C-100°C; 4) After the reaction in step (A) is completed, the product obtained is directly used in step (1) without purification.

20. The method for preparing compound 1 according to claim 19, characterized in that It meets one or more of the following conditions: 1) In step (A), the organic solvent is ethanol; 2) In step (A), the reaction temperature is the reflux temperature of the solvent used in the reaction; 3) After the reaction in step (A) is completed, if the solvent used in the reaction in step (A) is the same as the solvent used in the reaction in step (1), the reaction solution in step (A) is directly used in step (1) or is used in step (1) after removing the solvent; if the solvent used in the reaction in step (A) is different from the solvent used in the reaction in step (1), the reaction solution in step (A) is used in step (1) after removing the solvent.

21. A compound represented by formula IM-3, IM-4 or IM-5: The definition of n is as described in claim 14.

22. The compound of formula IM-5 according to claim 21, characterized in that It is any of the following compounds:

23. A method for preparing a compound represented by formula IM-3, IM-4 or IM-5, characterized in that: The preparation method of the compound represented by formula IM-3 comprises the following steps: in a solvent, reacting compound IM-1 with a resolving agent D-(+)-p-methyldibenzoyltartaric acid to form a salt to obtain a compound represented by formula IM-3; The preparation method of the compound represented by formula IM-4 comprises the following steps: in a solvent, subjecting compound IM-1 to a salt-forming reaction with a resolving agent, N-acetyl-L-leucine, to obtain a compound represented by formula IM-4; The compound IM-1 is a mixture of a compound represented by formula IM-1(S) and a compound represented by formula IM-1(R); The preparation method of the compound represented by formula IM-5 comprises the following steps: (A) In an organic solvent, the compound represented by formula IM-1(S) is reacted with compound SM-3 to obtain a compound represented by formula IM-5; n is defined as in claim 14; twenty four. The method for preparing the compound represented by formula IM-3, IM-4 or IM-5 as claimed in claim 23, It is characterized in that The preparation method of the compound represented by formula IM-3 comprises the following steps: In a solvent, compound IM-1 is reacted with a resolving agent, D-(+)-p-methyldibenzoyltartaric acid, to form a salt to obtain a compound represented by formula IM-3; The conditions and operation of the salt-forming reaction are as described in step (i) of the method for preparing the compound represented by formula IM-1(S) by splitting as described in any one of claims 1 to 7; The preparation method of the compound represented by formula IM-4 comprises the following steps: in a solvent, subjecting compound IM-1 to a salt-forming reaction with a resolving agent, N-acetyl-L-leucine, to obtain a compound represented by formula IM-4; The compound IM-1 is a mixture of a compound represented by formula IM-1(S) and a compound represented by formula IM-1(R); The conditions and operation of the salt-forming reaction are as described in step (i) of the method for preparing the compound represented by formula IM-1(S) by splitting as described in any one of claims 1 to 7; The preparation method of the compound represented by formula IM-5 comprises the following steps: (A) In an organic solvent, the compound represented by formula IM-1(S) is reacted with compound SM-3 to obtain a compound represented by formula IM-5; n is defined as in claim 14; the reaction conditions and operation are as described in any one of claims 17-19; 25. A method for preparing compound 1, characterized in that: It includes the following steps: (A) reacting the compound represented by formula IM-1(S) with compound SM-3 in an organic solvent, and the product obtained after the reaction is completed is directly used in step (1) without purification; (1) In an organic solvent, the product obtained in step (A) is subjected to a substitution reaction with SM2 in the presence of a base, and after the reaction is completed, the product obtained is directly subjected to step (2) without purification; (2) removing the Boc and imine protecting groups from the product obtained in step (1) under the action of an acid to obtain compound 1; n is defined as in claim 14; In the step (1), the molar ratio of SM2 to the compound represented by formula IM-1(S) in step (A) is 0.95:1-1:1; In the step (1), the molar ratio of the base to the compound represented by formula IM-1(S) in step (A) is 1:1-2:

1.

26. The method for preparing compound 1 according to claim 25, characterized in that: The reaction conditions and operation of step (A) are as described in any one of claims 18 to 20; The other reaction conditions and operations of steps (1) and (2) are as described in claim 16.

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