The invention relates to N, N, Napos; , Napos, Napos; preparation method of-tetra (3-aminopropyl)-1, 4-butanediamine and intermediate thereof

Abstract

The invention discloses a preparation method of [formula (I)] and its intermediate, 1, 4-butanediamine (SM1) and amido-protected propylamine derivative (SM2) are used as raw materials, and substitution and deprotection reactions are carried out to obtain the formula (I) or its salt. The synthesis route is simple, the initial raw materials are cheap and easy to obtain, the operation is simple, the reaction condition is mild, the yield is high, the product purity is high, industrialization is easy to realize, high-temperature and high-pressure hydrogenation reaction conditions and the use of an allyl cyanide toxic reagent in the existing preparation method are avoided, and the generation of toxic three wastes is reduced. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the fields of pharmaceuticals, electrochemistry, and multifunctional materials, and particularly to the synthesis process of pharmaceutical intermediates, and specifically to a method for preparing a key intermediate of bixalomer. Background Art

[0002] Hyperphosphatemia is one of the most common complications in the late stage of chronic kidney disease (CKD). Conventional treatment measures for hyperphosphatemia mainly include dietary control, dialysis, and the use of phosphate binders, etc. Early phosphate binders mainly contained calcium and aluminum. Among them, aluminum-containing phosphate binders have relatively large adverse reactions after being taken by patients, and are currently less used clinically. The use of calcium-containing phosphate binders and the extensive use of high-calcium dialysis fluid during dialysis have led to a significant increase in side effects such as elevated serum calcium levels and vascular calcification in patients. Therefore, new non-calcium and non-aluminum phosphate binders have become the first choice for treating hyperphosphatemia. Currently, the newly marketed non-calcium and non-aluminum phosphate binders mainly include sevelamer hydrochloride (Renagel), sevelamer carbonate (Renvela), lanthanum carbonate (Fosrenol), colestilan (BindRen), bixalomer (Kiklin), sucroferric oxyhydroxide (Velphoro), ferric citrate (Auryxia), etc.

[0003] Among them, bixalomer (CAS: 851373-13-2, alias: Bixalomer (JAN / USAN / INN), trade name: Kiklin) is a new non-calcium and non-aluminum phosphate binder developed by Astellas Pharma, and is currently only on the market in Japan for clinical use in improving hyperphosphatemia in dialysis patients with chronic renal failure.

[0004] Currently, there is only one reported synthetic route for bixalomer, that is, it is prepared by the polymerization reaction of the key intermediate N,N,N',N'-tetrakis(3-aminopropyl)-1,4-butanediamine and epichlorohydrin. This key intermediate is not industrially produced in China, and there are mainly 3 reported synthetic methods:

[0005] 1) Bao Jinyuan et al. (Patent No.: CN105111089B, Route 2) used 3,3'-diaminodipropylamine as the raw material, reacted with benzyl chloroformate under the action of an acid-binding agent to obtain 3,3'-dibenzyloxymethylamidodipropylamine, and then reacted with 1,4-dibromobutane or 1,4-dichlorobutane under the action of an acid-binding agent potassium carbonate or sodium carbonate and a catalyst potassium iodide or sodium iodide through a substitution reaction to obtain the compound N,N,N',N'-tetra(3-benzyloxymethylamino)-1,4-butanediamine. After that, it was subjected to a pressurized hydrogenation reaction under the catalysis of Pd-C and deprotection to obtain the key intermediate N,N,N',N'-tetra(3-aminopropyl)-1,4-butanediamine; this patent requires the use of the dangerous chemical reaction of Pd-C hydrogenation.

[0006] 2) Bao Jinyuan et al. (Patent No.: CN105061216A, Route 3) used allyl bromide as the starting material, obtained 3-azido-1-propene under the action of sodium azide, and 3-azido-1-propene and 1,4-butanediamine underwent an addition reaction to obtain the intermediate N,N,N',N'-tetra(3-aminopropyl)-1,4-butanediamine, and then carried out a hydrogenation reaction to obtain the key intermediate N,N,N',N'-tetra(3-aminopropyl)-1,4-butanediamine. This patent requires the use of the dangerous chemical reaction of Pd-C hydrogenation and the use of the highly toxic and explosive reagent sodium azide.

[0007] 3) Si Ge et al. (Chinese Journal of Medicinal Chemistry, VOl.30, 419-422, Route 4) used 1,4-butanediamine as the starting material, and obtained the intermediate N,N,N',N'-tetra(3-aminopropyl)-1,4-butanediamine through reaction with acrylonitrile and hydrogenation reduction. This article requires the use of a high-temperature and high-pressure hydrogenation reaction and the use of highly toxic acrylonitrile.

[0008] Among the above three methods for preparing the key intermediate N,N,N',N'-tetrakis(3-aminopropyl)-1,4-butanediamine, the first two methods have relatively high raw material costs. Moreover, 1,4-dihalobutane and allyl bromide are genotoxic substances, and sodium azide is an explosive. Acrylonitrile belongs to category 2B carcinogens and is volatile, posing significant safety hazards. The "three wastes" generated need to be specially treated, which is not conducive to labor protection and not suitable for industrial production. In addition, all of the above three methods use the reaction conditions of "hydrogenation at high temperature and high pressure", which have high requirements for industrial production equipment. According to the "Notice on Announcing the Catalogue of the First Batch of Key Supervised Hazardous Chemical Processes" (An Jian Zong Guan San

[2009] No. 116) issued by the State Administration of Work Safety Supervision on June 15, 2009, fifteen hazardous chemical processes need to be included in national or local key supervision. Among them, the "hydrogenation process" belongs to hazardous chemical processes. Therefore, the "hydrogenation at high temperature and high pressure reaction" used in the above existing technologies belongs to the chemical processes that need to be key supervised by each province as stipulated in the first batch of national regulations. In addition, according to the "Catalogue of Hazardous Chemicals" published in February 2015, both "sodium azide" and "halohydrocarbons (such as 1,4-dihalobutane and allyl bromide)" belong to hazardous chemicals. Therefore, this poses more stringent requirements and challenges for the existing industrial production of besalom and related intermediates. Through a large amount of research and exploration, the patented technology effectively avoids the use of hazardous chemical processes and hazardous chemicals such as "hydrogenation at high temperature and high pressure reaction" and "hazardous chemicals" that need to be key supervised by each province in the preparation process. This not only greatly reduces the production cost, but more importantly, greatly reduces the potential production safety hazards. The implementation of this patented technology has great social value and application value in the chemical industry.

[0009]

[0010]

[0011] Therefore, under the general guiding principle of national work safety, how to effectively avoid the use of hazardous chemical processes and hazardous chemicals such as "hydrogenation at high temperature and high pressure reaction" and "hazardous chemicals" that need to be key supervised by each province in the preparation process, and prepare besalom and its intermediates with low cost and high efficiency is an issue to be solved. Summary of the Invention

[0012] The purpose of the present invention is to overcome the deficiencies of the prior art and provide a production process that is safer and can achieve the preparation of high-quality key intermediates of besalom under normal pressure and mild conditions.

[0013] Therefore, we have developed the following methods for safely and low-cost synthesizing the intermediate N,N,N',N'-tetrakis(3-aminopropyl)-1,4-butanediamine and its hydrochloride.

[0014] The object of the present invention can be achieved by the following technical solutions:

[0015] A new method for synthesizing N,N,N',N'-tetrakis(3-aminopropyl)-1,4-butanediamine and its hydrochloride, a key intermediate of besalomer. The synthetic route is as follows:

[0016]

[0017] An embodiment of the present invention discloses a method for preparing a compound of formula (III) and its salts, hydrates, and solvates. The structural formula of the compound of formula (III) is as follows:

[0018]

[0019] The method for preparing the compound of formula (III) and its salts, hydrates, and solvates includes the following reaction:

[0020]

[0021] Wherein, X is a functional group capable of undergoing a nucleophilic substitution reaction with an amino group; X is selected from F, Cl, Br, I, MsO, Tos, TfO, NsO, PhSO 3 , AcO, PCl4O, POCl 2 , PCl 2 O, NaOSO 3 , preferably Br or MsO.

[0022] PG is a protecting group for the amino group, and PG is selected from Cbz, Boc, Fmoc, Alloc, Teoc, methoxy(ethoxy)carbonyl, Pht, Tos, Tfa, Trt, PMB, Bn, preferably Boc, methoxy(ethoxy)carbonyl, Fmoc, Bn, Cbz, Alloc, Pht, Tos, Tfa.

[0023] Furthermore, the reaction is carried out in the presence of a base, and the base is selected from at least one of cesium carbonate, potassium carbonate, potassium phosphate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, triethylamine, DBU, DIPEA, sodium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide, preferably at least one of potassium carbonate, lithium hydroxide, sodium bicarbonate, pyridine.

[0024] Furthermore, the reaction is carried out in the presence of a catalyst, and the catalyst is selected from at least one of sodium iodide, potassium iodide, sodium dodecyl sulfate, 18-crown-6, 15-crown-5, cyclodextrin, benzyltriethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium hydrogen sulfate, trioctylmethylammonium chloride, dodecyltrimethylammonium chloride, tetradecyltrimethylammonium chloride, preferably at least one of sodium iodide, potassium iodide, tetrabutylammonium bromide.

[0025] Further, the molar ratio of SM1 to SM2 in this reaction is 1:4.0 to 6.0, preferably 1:4.1 to 4.5.

[0026] Further, the molar ratio of SM1 to the base in this reaction is 1:1.5 to 20.0, preferably 1:1.5 to 15.

[0027] Further, the temperature of this method is -10°C to 110°C, preferably -10°C to 60°C, more preferably -5°C to 50°C.

[0028] Further, the solvent used in the method for preparing the compound of formula (III) and its salts, hydrates, and solvates is selected from at least one of pentane, hexane, octane, toluene, xylene, cyclohexane, cyclohexanone, toluene cyclohexanone, dichloromethane, chloroform, 1,1,1-trifluoroethane, methanol, ethanol, ethylene glycol, propylene glycol, isopropanol, ether, propylene oxide, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, acetone, butanone, methyl isobutyl ketone, methyl acetate, ethyl acetate, propyl acetate, acetonitrile, pyridine, phenol, DMF, DMSO, tetrahydrofuran, and water; preferably at least one of DMF, DMSO, acetonitrile, tetrahydrofuran, methanol, ethanol, dichloromethane, acetone, water, ethyl acetate, isopropanol, and acetone; more preferably at least one of DMF, acetonitrile, ethyl acetate, tetrahydrofuran, methanol, and water.

[0029] Further, the salts of the compound of formula (III) are selected from those with formic acid, acetic acid, propionic acid, benzoic acid, salicylic acid, oxalic acid, succinic acid, citric acid, fumaric acid, malic acid, tartaric acid, maleic acid, lactic acid, succinic acid, mandelic acid, ascorbic acid, malonic acid, stearic acid, palmitic acid, triphenylacetic acid, trifluoroacetic acid, glycolic acid, butanedisulfonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, p-toluenesulfinic acid, TFA, HCl, H 2 SO 4 、H 3 PO 4 、HNO 3 、HBr、H 2 CO 3 、H 3 BO 3 、H 2 SiO 3 、HMnO 4Salts formed by HF, HI; The hydrates or solvates of the compound of formula (III) are selected from hydrates or solvates formed with one of pentane, hexane, octane, toluene, xylene, cyclohexane, cyclohexanone, toluene cyclohexanone, dichloromethane, chloroform, 1,1,1-trifluoroethane, methanol, ethanol, ethylene glycol, propylene glycol, isopropanol, ether, propylene oxide, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, acetone, butanone, methyl isobutyl ketone, methyl acetate, ethyl acetate, propyl acetate, acetonitrile, pyridine, phenol, DMF, DMSO, tetrahydrofuran, water.

[0030] An embodiment of the present invention discloses a preparation method of the compound of formula (II) and its hydrates and solvates, including the following reaction:

[0031]

[0032] PG is selected from Cbz, Boc, methoxy (ethoxy) carbonyl, Trt, PMB, Tfa, Tos, preferably Boc, methoxy (ethoxy) carbonyl, Trt, Tfa, Tos; n = 0.5 - 10, preferably n = 0.5 - 6.0; more preferably n = 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0; This reaction is carried out in the presence of an acid, and the acid is selected from at least one of TFA, HCl, H 2 SO 4 、H 3 PO 4 、CH 3 SO 3 H, HBr, TsOH, HOAc, preferably HCl, H 2 SO 4 、HBr, TsOH; HA is the corresponding acid in acidic conditions; In particular, when HA is HCl or HBr, n = 4 - 6; when HA is TsOH, n = 0.5 - 3.

[0033] Among them, the corresponding relationship for removing the amine protecting group under acidic conditions used in formula (III) is: TFA or HBr removes Cbz; H 2 SO 4 or H 3 PO 4 or CH 3 SO 3 H or HCl or TFA or TsOH removes Boc; HBr removes methoxy (ethoxy) carbonyl; HBr removes Tos; HCl removes Tfa; HCl or TFA removes Trt; TFA removes PMB.

[0034] Furthermore, the molar ratio of compound (III) to acid in this reaction is 1:4 - 60, preferably 1:4 - 20.

[0035] Further, the solvent used in this method is selected from at least one of methanol, ethanol, tetrahydrofuran, ethyl acetate, acetonitrile, DMF, dichloromethane, isopropanol, water, dioxane, preferably at least one of methanol, ethanol, dichloromethane, water, and hydrobromic acid.

[0036] Further, the temperature of this method is 10°C to 120°C.

[0037] An embodiment of the present invention discloses a preparation method of the compound of formula (I), including the following reaction:

[0038]

[0039] Wherein, PG is selected from piperidine of Fmoc, methyl (ethyl) oxycarbonyl, Pht, Tfa, Trt, PMB, Bn, Teoc, Dmb, Cbz, Boc, Alloc, preferably Boc, Fmoc, methyl (ethyl) oxycarbonyl, Cbz, Alloc.

[0040] Further, one of the conditions of this reaction is carried out in the presence of a base, and the base is selected from at least one of piperidine, sodium hydroxide, ethanolamine, cyclohexylamine, morpholine, pyrrolidone, DBU, potassium hydroxide, potassium carbonate, ammonia water, hydrazine hydrate, sodium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide, preferably at least one of sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide. Among them, potassium tert-butoxide is used to remove Boc, piperidine is used to remove Fmoc, potassium hydroxide is used to remove methyl (ethyl) oxycarbonyl, hydrazine hydrate is used to remove Pht, potassium carbonate, potassium hydroxide, NH 3 is used to remove Tfa.

[0041] Further, the molar ratio of the compound of formula (III) to the base in the feed is 1:4 - 20.

[0042] Further, the solvent used in this method is selected from at least one of methanol, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, acetonitrile, DMF, dichloromethane, isopropanol, water, dioxane, toluene, preferably at least one of tetrahydrofuran, 2-methyltetrahydrofuran.

[0043] Further, the second condition of this reaction is carried out in the presence of hydrogenation and a metal reagent, or a hydrogen source reagent and a metal reagent, and the conditions are selected from H 2 / Pd, H 2 / Pd(OH) 2 、H 2 / Pd-C、HCO 2 H / Pd-C、HCO 2 H / Pd、HCO 2 H / Pd(OH) 2, HCO 2 NH 3 / Pd-C, HCO 2 NH 3 / Pd, HCO 2 NH 3 / Pd(OH) 2 at least one of, preferably H 2 / Pd(OH) 2 , H 2 / Pd-C, HCO 2 H / Pd-C, HCO 2 NH 3 / Pd-C; wherein, H 2 / Pd-C is used to remove Cbz, H 2 / Pd is used to remove Trt, HCO 2 H / Pd-C or H 2 / Pd(OH) 2 is used to remove PMB, HCO 2 H / Pd-C / or H 2 / Pd(OH) 2 is used to remove Bn. The solvent used in this method is selected from at least one of methanol, tetrahydrofuran, ethyl acetate, acetonitrile, DMF, dichloromethane, isopropanol, water, dioxane, toluene, preferably at least one of methanol, toluene, tetrahydrofuran.

[0044] Furthermore, the third condition of this reaction is carried out in the presence of at least one of the following other reagents, and the reagents are selected from tetrabutylammonium fluoride, tetraethylammonium fluoride, tetramethylammonium fluoride, sodium borohydride, benzaldehyde / cyanoborohydride, ammonium cerium nitrate, boron tribromide, trimethylsilyl iodide, tetracarbonylnickel, tetrakistriphenylphosphine palladium / tri-n-butyltin hydride, 2,3-dichloro-5,6-dicyanobenzoquinone. Among them, tetrabutylammonium fluoride and tetraethylammonium fluoride are used to remove Teoc, sodium borohydride is used to remove Pht, benzaldehyde / cyanoborohydride is used to remove Dmb, ammonium cerium nitrate is used to remove PMB, boron tribromide is used to remove Cbz, trimethylsilyl iodide is used to remove methoxy (ethoxy) carbonyl and Boc, hexafluoroisopropanol is used to remove Boc, tetracarbonylnickel or tetrakistriphenylphosphine palladium / tri-n-butyltin hydride is used to remove Alloc, 2,3-dichloro-5,6-dicyanobenzoquinone is used to remove PMB.

[0045] Furthermore, the solvent used in this method is selected from at least one of methanol, tetrahydrofuran, ethyl acetate, acetonitrile, DMF, dichloromethane, isopropanol, water, dioxane, toluene, preferably at least one of methanol, tetrahydrofuran, toluene, acetonitrile.

[0046] Further, the compound of formula (I) in this reaction is obtained by vacuum distillation. The distillation temperature is 150°C to 180°C, and the distillation vacuum degree is

[0047] -0.05 MPa to -0.095 MPa.

[0048] Another embodiment of the present invention also discloses a method for preparing the compound of formula (I), including the following reaction:

[0049]

[0050] Among them, preferably n = 0.5 - 6.0; more preferably n = 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0;

[0051] HA is TFA, HCl, H 2 SO 4 、H 3 PO 4 、CH 3 SO 3 H, HBr, TsOH, HOAc, preferably HCl, H 2 SO 4 、TFA, HBr, TsOH; In particular, when HA is HCl or HBr, n = 4 - 6; when HA is TsOH, n = 0.5 - 3.

[0052] Further, this reaction is carried out in the presence of a base. The base is selected from at least one of cesium carbonate, potassium carbonate, potassium phosphate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, triethylamine, DIPEA, piperidine, ethanolamine, cyclohexylamine, morpholine, pyrrolidone, DBU, ammonia water, hydrazine hydrate, sodium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide, preferably at least one of sodium hydroxide, potassium hydroxide, triethylamine, and sodium methoxide.

[0053] Further, the molar ratio of the base to the compound of formula (II) is 1:0.5 - 8, preferably 1:1 - 5.

[0054] Further, the solvent used in this method is selected from at least one of methanol, tetrahydrofuran, ethyl acetate, acetonitrile, DMF, dichloromethane, isopropanol, water, dioxane, toluene, and preferably the reaction solvent is ethanol, water, and tetrahydrofuran.

[0055] The present invention also discloses a method for directly preparing besalomer from the compound of formula (II) as a raw material. The structural formula of the compound of formula (II) is shown as follows:

[0056]

[0057] n = 0.5 - 10, preferably n = 0.5 - 6.0; more preferably n = 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0;

[0058] HA is TFA, HCl, H 2 SO 4 、H 3 PO 4 、CH 3 SO 3 H、HBr、TsOH、HOAc, preferably HCl, H 2 SO 4 、TFA、HBr; in particular, when HA is HCl or HBr, n = 4 - 6; when HA is TsOH, n = 0.5 - 3.

[0059] The present invention also provides a synthesis method of formula (II), including the following reactions:

[0060] (SM1)+(SM2)→(III)→(II), that is:

[0061]

[0062] The present invention also provides a synthesis method of formula (I), including the following reactions:

[0063] (SM1)+(SM2)→(III)→(I), that is:

[0064]

[0065] (SM1)+(SM2)→(III)→(II)→(I), that is:

[0066]

[0067] The present invention also provides a synthesis method of besalomer, including the following reactions:

[0068] (III)→(II)→besalomer, that is:

[0069]

[0070] (SM1)+(SM2)→(III)→(II)→besalomer, that is:

[0071]

[0072] In the reaction routes for preparing the compounds of formula (II), formula (I) and besalomer through the above multi-step reactions, the reaction conditions for each step (including the selection of catalysts, acids, bases and other reagents, molar ratio of feedstocks, reaction solvents, reaction temperature, etc.) are the same as those of the corresponding single-step reactions described above.

[0073] The present invention also provides a compound of formula (III), and the structural formula of formula (III) is as follows:

[0074]

[0075] Wherein, PG is selected from Cbz, Boc, Fmoc, Alloc, Teoc, methoxy (ethoxy) carbonyl, Pht, Tos, Tfa, Trt, PMB, Bn, preferably Boc, methoxy (ethoxy) carbonyl, Fmoc.

[0076] Definitions of abbreviations and key terms in the present invention:

[0077]

[0078]

[0079]

[0080] The beneficial effects of the present invention are as follows:

[0081] On the premise of ensuring the preparation of high-quality compound (II), the synthesis reaction steps are not increased, which can avoid increasing the industrial production cycle. The starting material for preparing compound (III) is adjusted from "allyl cyanide" to "N-Boc-3-aminopropyl bromide", which greatly reduces the industrial production risk of compound (I), avoids the use of toxic reagents and the generation of toxic "three wastes", as well as the environmental protection pressure brought by the subsequent treatment of "three wastes". Compound (II) can be prepared under normal pressure and mild conditions, with cheap reagent costs and simple post-treatment, changing the unfavorable situation of high-temperature and high-pressure metal-catalyzed reactions in previous patents, effectively reducing the production barrier, and realizing the favorable situation that compound (II) can also be produced in China. It can maximize the cost and improve the market competitiveness of besalomer to the greatest extent.

[0082] In summary, this method route greatly reduces the synthesis difficulty of compound (I) and also significantly reduces its cost, thereby ensuring the high quality of besalomer while improving the competitiveness of besalomer products. Detailed implementation manners

[0083] In order to more clearly illustrate the technical problems solved by the present invention and the effects of its technical solutions, the present invention will be further described in conjunction with the following examples.

[0084] In the following examples, unless otherwise specified, the specific conditions of the experimental methods are usually carried out under conventional conditions; the raw materials and reagents are all purchased from commercial products; the ratios, ratios, percentages or parts are all calculated by weight.

[0085] Preparation of (III):

[0086] Example 1

[0087]

[0088] In a 10 L three-necked round-bottom flask, 5 L of DMF, 100.00 g (1.13 mol) of SM1, 1.25 Kg (9.04 mol) of potassium carbonate, and 17.00 g (0.10 mol) of sodium iodide were successively added and stirred. Nitrogen was displaced three times, and 1.10 KG of SM2 (4.63 mol) was added in batches. After the addition was completed, the temperature was kept at 30 °C and the reaction was continued for 24 hours. 2 L of purified water was added, stirred, and 2.5 L of ethyl acetate was added for extraction twice. The organic phase was washed with water 4 times, dried, concentrated, and the concentrated solution was purified by crystallization with a mixed solvent of ethyl acetate and n-heptane, filtered, and dried to obtain 654.14 g of compound (III) with a purity of 97.26% and a yield of 80.42%.

[0089] MS(m / z): [M+H] + = 717.5, [M+Na] + = 739.5. 1 H-NMR(400MHz, CCl 3 D)(ppm): 5.29(m, 4H), 3.15(d, J = 5.8Hz, 8H), 2.43(t, J = 6.6Hz, 8H), 2.37(s, 4H), 1.66–1.58(m, 8H), 1.43(s, 36H), 1.39(s, 4H).

[0091] Example 2

[0092] In a 10 L three-necked round-bottom flask, 5 L of DMF, 100.00 g (1.13 mol) of SM1 and 379.13 g (9.04 mol) of lithium hydroxide, and 17.00 g (0.10 mol) of sodium iodide were successively added under stirring conditions and stirred. Nitrogen was displaced three times, and 1.10 KG (4.63 mol) of SM2 was added in batches. After the addition was completed, the temperature was kept at 30 °C and the reaction was continued for 24 hours. 2 L of purified water was added, stirred, and 2.5 L of ethyl acetate was added for extraction twice. The organic phase was washed with water 4 times, dried, concentrated, and the concentrated solution was purified by crystallization with a mixed solvent of ethyl acetate and n-heptane, filtered, and dried to obtain 672.35 g of compound (III) with a purity of 97.14% and a yield of 82.66%. MS(m / z): [M+H]+ = 717.5, [M+Na] + = 739.5。 1 H-NMR(400 MHz, CCl 3 D)(ppm): 5.29 (m, 4H), 3.15 (d, J = 5.8 Hz, 8H), 2.43 (t, J = 6.6 Hz, 8H), 2.37 (s, 4H), 1.66–1.58 (m, 8H), 1.43 (s, 36H), 1.39 (s, 4H)。

[0093] Example 3

[0094] In a 10 L three-necked round-bottom flask, 5 L of acetonitrile, 100.00 g (1.13 mol) of SM1, 914.75 g (9.04 mol) of triethylamine, and 17.00 g (0.10 mol) of sodium iodide were successively added under stirring, and stirred. Nitrogen was displaced three times, and 1.10 KG (4.63 mol) of SM2 was added in batches. After the addition was completed, the temperature was maintained at 30 °C, and the reaction was continued for 24 hours. 1 L of purified water was added, stirred, and extracted twice with 2.5 L of ethyl acetate. The organic phase was washed twice with water, dried, concentrated, and the concentrated solution was purified by crystallization with a mixed solvent of ethyl acetate and n-heptane, filtered, and the material was dried to obtain 489.50 g of compound (III) with a purity of 95.42% and a yield of 60.18%. MS (m / z): [M+H] + = 717.5, [M+Na] + = 739.5。 1 H-NMR(400 MHz, CCl 3 D)(ppm): 5.29 (m, 4H), 3.15 (d, J = 5.8 Hz, 8H), 2.43 (t, J = 6.6 Hz, 8H), 2.37 (s, 4H), 1.66–1.58 (m, 8H), 1.43 (s, 36H), 1.39 (s, 4H)。

[0095] Example 4

[0096] In a 10 L three-necked round-bottom flask, 5 L of acetonitrile, 100.00 g (1.13 mol) of SM1, 2.95 Kg (9.04 mol) of cesium carbonate, and 17.00 g (0.10 mol) of sodium iodide were successively added under stirring, and stirred. Nitrogen was displaced three times, and 1.10 KG of SM2 (4.63 mol) was added in batches. After the addition was completed, the temperature was maintained at 30 °C, and the reaction was continued for 24 hours. The temperature was lowered, 3 L of purified water was added, and the mixture was stirred and crystallized for 6 h, filtered, washed with water, and dried. The crude product was dissolved by heating with 1.5 L of acetonitrile, 1.5 L of purified water was added, and crystallization was carried out at low temperature, filtered, and the material was dried to obtain 534.74 g of compound (III) with a purity of 99.57% and a yield of 65.99%. MS (m / z):

[0097] [M + H] + = 717.5, [M + Na] + = 739.5。 1 H-NMR(400 MHz, CCl 3 D)(ppm): 5.29(m, 4H), 3.15(d, J = 5.8 Hz, 8H), 2.43(t, J = 6.6 Hz, 8H), 2.37(s, 4H), 1.66–1.58(m, 8H), 1.43(s, 36H), 1.39(s, 4H)。

[0098] Example 5

[0099] In a 10 L three-necked round-bottom flask, 5 L of purified water, 100.00 g (1.13 mol) of SM1, 32.58 g (0.11 mol) of sodium dodecyl sulfate, and 732.60 g (9.04 mol) of sodium bicarbonate were successively added under stirring conditions. Nitrogen was displaced three times, the temperature was raised to 80 °C, and the reaction was maintained for 30 min. Then 1.10 KG (4.63 mol) of SM2 was added and stirred, and the reaction continued for 24 hours. 3 L of ethyl acetate was added for extraction twice, and the organic phase was washed with water twice, dried, and concentrated to 1 L. The concentrated solution was stirred and crystallized at low temperature, filtered, and the product was dried to obtain 563.42 g of compound (III) with a purity of 99.46% and a yield of 69.54%. MS(m / z): [M + H] + = 717.5, [M + Na] + = 739.5。 1 H-NMR(400 MHz, CCl 3 D)(ppm): 5.29(m, 4H), 3.15(d, J = 5.8 Hz, 8H), 2.43(t, J = 6.6 Hz, 8H), 2.37(s, 4H), 1.66–1.58(m, 8H), 1.43(s, 36H), 1.39(s, 4H)。

[0100] Example 6

[0101] In a 10 L three-necked round-bottom flask, 5 L of DMF, 100.00 g (1.13 mol) of SM1, 1.92 Kg (9.04 mol) of potassium phosphate, and 36.42 g (0.10 mol) of tetrabutylammonium bromide were successively added under stirring conditions, and then stirred. Nitrogen was displaced three times, and 1.10 KG (4.63 mol) of SM2 was added in batches. After the addition was completed, the temperature was maintained at 30 °C and the reaction was continued for 24 hours. 3 L of purified water was added, stirred, and then extracted twice with 3 L of ethyl acetate. The organic phase was washed 4 times with water, dried, concentrated, and the concentrated solution was purified by crystallization with a mixed solvent of ethyl acetate and n-heptane, filtered, and dried to obtain 462.01 g of compound (III) with a purity of 95.59% and a yield of 56.80%. MS (m / z): [M+H] + = 717.5, [M+Na] + = 739.5. 1 H-NMR (400 MHz, CCl 3 D) (ppm): 5.29 (m, 4H), 3.15 (d, J = 5.8 Hz, 8H), 2.43 (t, J = 6.6 Hz, 8H), 2.37 (s, 4H), 1.66–1.58 (m, 8H), 1.43 (s, 36H), 1.39 (s, 4H).

[0102] Example 7

[0103]

[0104] In a 10 L three-necked round-bottom flask, 5 L of THF, 100.00 g (1.13 mol) of 1,4-butanediamine, and 1.14 kg of triethylamine (11.26 mol) were successively added under stirring conditions, and then stirred. Nitrogen was displaced three times, and the temperature was lowered to -10 °C. 1.17 KG (4.63 mol) of 3-((tert-butoxycarbonyl)amino)propyl methanesulfonate was added in batches. After the addition was completed, the temperature was maintained at -10 °C to 5 °C and the reaction was carried out for 2 hours. 2 L of purified water was added, stirred, and then extracted twice with 3 L of ethyl acetate. The organic phase was washed 2 times with water, dried, concentrated, and the concentrated solution was purified by crystallization with a mixed solvent of ethyl acetate and n-heptane, filtered, and dried to obtain 671.95 g of compound (III) with a purity of 97.06% and a yield of 82.61%. MS (m / z): [M+H] + = 717.5, [M+Na] + = 739.5. 1 H NMR (400 MHz, CCl 3D) (ppm): 5.29 (m, 4H), 3.15 (d, J = 5.8 Hz, 8H), 2.43 (t, J = 6.6 Hz, 8H), 2.37 (s, 4H), 1.66–1.58 (m, 8H), 1.43 (s, 36H), 1.39 (s, 4H).

[0106] Example 8

[0107]

[0108] In a 10 L three-necked round-bottom flask, 5 L of DMF, 100.00 g (1.13 mol) of 1,4-butanediamine, and 587.72 g (10.87 mol) of sodium methoxide were successively added under stirring. After stirring and displacing nitrogen three times, 1.38 kg (4.97 mol) of benzyl 3-bromopropylcarbamate was added in batches. After the addition was completed, the temperature was maintained at 70 °C to 80 °C for 10 hours. Then, 2 L of purified water was added, and after stirring, 3 L of ethyl acetate was added for extraction twice. The organic phase was washed with water twice, dried, concentrated, and the concentrated solution was purified by crystallization using a mixed solvent of ethyl acetate and n-heptane. After filtration and drying, 671.95 g of N,N,N',N'-tetrakis(benzyl 3-aminopropylcarbamate)-1,4-butanediamine was obtained, with a purity of 92.41% and a yield of 77.41%. MS (m / z): [M+H] + = 853.4. 1 1H NMR (400 MHz, CCl3D) (ppm): 7.29–7.24 (m, 20H): 5.60, (m, 4H), 5.03 (d, 8H), 3.18 - 3.16 (t, 12H), 1.58–1.55 (m, 8H), 1.35 (s, 4H).

[0109] Example 9

[0110]

[0111] In a 10 L three-necked round-bottom flask, 5 L of acetone, 100.00 g (1.13 mol) of 1,4-butanediamine, and 452.00 g (11.30 mol) of sodium hydroxide were successively added under stirring. After stirring and displacing nitrogen three times, 1.10 kg (4.97 mol) of N-Boc-3-aminopropyl allyl ester was added in batches. After the addition was completed, the temperature was maintained at 30 °C to 40 °C for 12 hours. Then, 2 L of purified water was added, and after stirring, 3 L of ethyl acetate was added for extraction twice. The organic phase was washed with water twice, dried, concentrated, and the concentrated solution was purified by crystallization using a mixed solvent of ethyl acetate and n-heptane. After filtration and drying, 322.24 g of N,N,N',N'-tetrakis(3-aminopropyl allyl ester)-1,4-butanediamine was obtained, with a purity of 89.62% and a yield of 76.00%. MS (m / z): [M+H]+ = 653.4。 1 H NMR(400 MHz, CCl 3 D)(ppm): 5.90–5.84 (m, 4H), 5.63 (m, 4H), 5.27–5.22 (d, 4H), 5.16–5.13 (d, 4H), 4.51–4.50 (m, 8H), 3.21 - 3.16 (t, 8H), 2.41 - 2.38 (m, 12H), 1.63–1.57 (m, 8H), 1.38 (m, 4H)。

[0113] Example 10

[0114]

[0115] In a 10 L three-necked round-bottom flask, 5 L of DMSO, 100.00 g (1.13 mol) of 1,4-butanediamine, and 453.13 g (8.07 mol) of potassium hydroxide were successively added under stirring conditions. After stirring and replacing nitrogen three times, 1.33 KG (4.97 mol) of N-(3-bromopropyl)phthalimide was added in batches. After the addition was completed, the temperature was maintained at 70 °C - 80 °C and the reaction was carried out for 8 hours. Then, 2 L of purified water was added, and after stirring, 3 L of ethyl acetate was added for extraction twice. The organic phase was washed with water twice, dried, concentrated, and the concentrated solution was recrystallized with a mixed solvent of ethyl acetate and n-heptane. After filtration and drying, 708.80 g of compound N,N,N',N'-tetrakis(3-aminopropylphthalimide)-1,4-butanediamine was obtained, with a purity of 93.44% and a yield of 75.00%. MS(m / z): [M+H] + = 837.3. 1 HNMR(400 MHz, CCl 3 D)(ppm): 7.92–7.79 (m, 8H), 7.7–7.65 (m, 8H), 5.29 (m, 4H), 3.15 (d, 8H), 2.43 (t, 8H), 2.37 (s, 4H), 1.66–1.58 (m, 8H), 1.43 (s, 36H), 1.39 (s, 4H)。

[0117] Example 11

[0118]

[0119] In a 10 L three-necked round-bottom flask, 5 L of DMF, 100.00 g (1.13 mol) of 1,4-butanediamine, and 453.13 g (8.07 mol) of potassium hydroxide were successively added under stirring conditions. After stirring and replacing nitrogen three times, 1.45 kg (4.97 mol) of N-Boc-3-aminopropyl tosyl was added in batches. After the addition was completed, the temperature was maintained at 70 °C to 80 °C, and the reaction was carried out for 2 hours. Then, 2 L of purified water was added, and after stirring, 3 L of ethyl acetate was added for extraction twice. The organic phase was washed with water twice, dried, concentrated, and the concentrated solution was recrystallized with a mixed solvent of ethyl acetate and n-heptane. After filtration and drying, 962.94 g of compound N,N,N',N'-tetrakis(3-aminopropyl tosyl)-1,4-butanediamine was obtained, with a purity of 92.34% and a yield of 77.01%. MS (m / z): [M+H] + = 933.3. 1 HNMR(400MHz, CCl 3 D)(ppm): 7.27–7.67(d,8H),7.25–7.23(d,8H),2.94–2.91(m,8H),2.74–2.71(m,12H), 2.40(s,12H),1.76–1.74(m,12H).

[0120] Example 12

[0121]

[0122] In a 10 L three-necked round-bottom flask, 5 L of acetonitrile, 100.00 g (1.13 mol) of 1,4-butanediamine, and 892.70 g (11.28 mol) of pyridine were successively added under stirring conditions. After stirring and replacing nitrogen three times, 1.16 kg (4.97 mol) of N-Boc-3-aminopropyl trifluoromethanesulfonyl was added in batches. After the addition was completed, the temperature was maintained at 70 °C to 80 °C, and the reaction was carried out for 2 hours. Then, 2 L of purified water was added, and after stirring, 3 L of ethyl acetate was added for extraction twice. The organic phase was washed twice with 1% hydrochloric acid aqueous solution, dried, concentrated, and the concentrated solution was recrystallized with a mixed solvent of ethyl acetate and n-heptane. After filtration and drying, 589.62 g of compound N,N,N',N'-tetrakis(3-aminopropyl trifluoromethanesulfonyl)-1,4-butanediamine was obtained, with a purity of 74.52% and a yield of 82.61%. MS (m / z): [M+H] + = 701.2. 1 H NMR(400MHz, CCl 3D) (ppm): 7.79 (s, 4H), 3.46 - 3.36 (m, 8H), 2.53–2.49 (m, 8H), 2.41 (d, 4H), 1.75–1.68 (m, 8H), 1.45 - 1.14 (s, 4H); F NMR (400 MHz, CCl 3 D) (ppm): -75.62 to 76.33.

[0123] (Preparation of (II)):

[0124] Example 13

[0125]

[0126] In a 5 L round-bottom flask, 2.5 L of ethanol and 500 g (697.34 mmol) of compound (III) were successively added, and 500 ml (6 mol) of concentrated hydrochloric acid was added dropwise. During the addition, the temperature was controlled at 20 °C - 30 °C. After the addition was completed, the reaction was carried out at 20 °C - 30 °C for 24 h; the stirring was stopped, and the mixture was filtered. The filter cake was rinsed once with ethanol. The filter cake was dried at 40 °C - 45 °C for 12 h to obtain 364.12 g of compound N,N,N',N'-tetrakis(3-aminopropyl)-1,4-butanediamine hexahydrochloride (calculated as 6 hydrochloric acids by titration), with a purity of 98.10% and a yield of 97.55%.

[0127] MS (m / z): [M + H] + = 317.4. 1 H-NMR (400 MHz, D 2 O) (ppm): 3.39 (dd, J = 9.2, 7.5 Hz, 12H), 3.25–3.11 (m, 8H), 2.31–2.15 (m, 8H), 1.90 (q, 4H).

[0129] Example 14

[0130]

[0131] In a 5 L round-bottom flask, 2.5 L of acetonitrile and 500 g (697.34 mmol) of compound (III) were successively added, and 1.20 kg of p-toluenesulfonic acid (6.97 mol) was added. The reaction was carried out at 20 °C - 30 °C for 24 h; the stirring was stopped, and the mixture was filtered. The filter cake was rinsed once with acetonitrile. The filter cake was dried at 40 °C - 45 °C for 12 h to obtain 414.78 g of compound N,N,N',N'-tetrakis(3-aminopropyl)-1,4-butanediamine 1.7 p-toluenesulfonates (the hydrogen spectrum showed complexation with 1.7 TsOH), with a purity of 99.10% and a yield of 90.07%.

[0132] MS (m / z): [M + 172 + H]+ = 489.4; [M + 172 + 172 + 42] + = 702.1. 1 H-NMR(400MHz, D 2 O)(ppm): 7.59(d, J = 8.2Hz, 3.4H), 7.27(d, J = 8.0Hz, 3.4H), 2.71(t, J = 7.3Hz, 8H), 2.46(dd, J = 15.9, 7.8Hz, 12H), 2.30(s, 5.3H), 1.69–1.57(m, 8H), 1.36(q, 4H).

[0134] Example 15

[0135]

[0136] In a 1 L round-bottom flask, 50 g (53.63 mmol) of the compound N,N,N',N'-tetrakis(3-aminopropyl p-toluenesulfonyl)-1,4-butanediamine and 1.0 g of phenol were successively added, and 500 mL of 48% hydrobromic acid (2.96 mol) was added dropwise. During the addition, the temperature was controlled at 20 °C to 30 °C. After the addition was completed, the reaction was carried out at 80 °C to 90 °C for 24 h; stirring was stopped, the temperature was lowered, and the mixture was filtered. The filter cake was washed once with acetonitrile. The filter cake was dried at 40 °C to 45 °C for 12 h to obtain 79.41 g of the compound N,N,N',N'-tetrakis(3-aminopropyl)-1,4-butanediamine hexahydrobromide (calculated by titration to be 6 hydrobromic acids), with a purity of 95.78% and a yield of 92.33%.

[0137] MS(m / z): [M + H] + = 317.4. 1 H-NMR(400MHz, D 2 O)(ppm): 3.39(dd, J = 9.2, 7.5Hz, 12H), 3.25–3.11(m, 8H), 2.31–2.15(m, 8H), 1.90(q, 4H).

[0139] Example 16

[0140]

[0141] In a 5 L round-bottom flask, 2.5 L of methanol and 500 g (713.70 mmol) of the compound N,N,N',N'-tetrakis(3-aminopropyltrifluoromethanesulfonyl)-1,4-butanediamine were successively added. 309.3 ml of concentrated hydrochloric acid (3.71 mol) was added, and the reaction was carried out at a controlled temperature of 40 °C to 50 °C for 24 h. Stirring was stopped, and the mixture was filtered. The filter cake was rinsed once with methanol. The filter cake was dried at 40 °C to 45 °C for 12 h to obtain 350.02 g of the compound (II) (complexed with 6 hydrochloric acids calculated by chloride ion titration), with a purity of 98.69% and a yield of 91.62%.

[0142] MS(m / z):[M+H] + =317.4. 1 H-NMR(400MHz,D 2 O)(ppm):3.39(dd,J=9.2,7.5Hz,12H),3.25–3.11(m,8H),2.31–2.15(m,8H),1.90(q,4H).

[0144] Preparation of formula (I):

[0145] Example 17

[0146]

[0147] In a 5 L round-bottom flask, 5 L of 2-methyltetrahydrofuran and 500 g (697.34 mmol) of the compound (III) were successively added. 938.98 g (8.37 mol) of potassium tert-butoxide was added, and 12.56 g (697.34 mmol) of water was added. During the addition process, the temperature was controlled at 20 °C to 30 °C. After the addition was completed, the mixture was heated to reflux and reacted for 24 h. Stirring was stopped, and the mixture was filtered. The filter cake was rinsed once with acetonitrile, and the filtrate was concentrated. The concentrated solution was distilled under reduced pressure (distillation temperature: 150 °C to 180 °C, distillation vacuum: -0.05 MPa to -0.095 MPa) to obtain 160.41 g of the compound (I), with a purity of 98.65% and a yield of 72.71%.

[0148] MS(m / z):[M+H] + =317.4. 1 H-NMR(400MHz,CCl 3 D)(ppm):2.53(t,J=6.9Hz,8H),2.29–2.23(m,8H),2.21(t,J=6.8Hz,4H),1.43–1.34(m,8H),1.26-1.19(m,4H),1.09(s,8H).

[0150] Example 18

[0151]

[0152] In a 5 L round-bottom flask, 5 L of methanol and 500 g (586.11 mmol) of the compound N,N,N',N'-tetrakis(3-aminopropylcarbobenzoxy)-1,4-butanediamine were added successively. 500 g of 10% Pd / C was added. During the addition process, the temperature was controlled at 20 °C to 30 °C. After the addition was completed, the hydrogen was replaced three times, and the reaction was carried out at room temperature for 16 h; the Pd / C was removed by filtration, and the methanol was removed by rotary evaporation to obtain 162.18 g of the compound (I), with a purity of 92.89% and a yield of 87.42%.

[0153] MS(m / z): [M+H] + = 317.4. 1 H-NMR(400 MHz, CCl 3 D)(ppm): 2.53 (t, J = 6.9 Hz, 8H), 2.29–2.23 (m, 8H), 2.21 (t, J = 6.8 Hz, 4H), 1.43–1.34 (m, 8H), 1.26 - 1.19 (m, 4H), 1.09 (s, 8H).

[0155] Example 19

[0156]

[0157] In a 5 L round-bottom flask, 5 L of tetrahydrofuran and 300 g (459.53 mmol) of the compound N,N,N',N'-tetrakis(3-aminopropylallyl)-1,4-butanediamine were added successively. 26.5 g (22.97 mmol) of Pd(PPh 3 ) 4 was added, and 802 g (2.75 mol) of tri-n-butyltin hydride was added. During the addition process, the temperature was controlled at 20 °C to 30 °C. After the addition was completed, the temperature was raised to reflux for 24 h; the stirring was stopped, and the mixture was filtered. The filter cake was washed once with tetrahydrofuran, and the filtrate was concentrated. The concentrated solution was distilled under reduced pressure (distillation temperature: 150 °C to 180 °C, distillation vacuum: -0.05 MPa to -0.095 MPa) to obtain 104.47 g of the compound (I), with a purity of 95.10% and a yield of 71.83%.

[0158] MS(m / z): [M+H] + = 317.4. 1 H-NMR(400 MHz, CCl 3 D)(ppm): 2.53 (t, J = 6.9 Hz, 8H), 2.29–2.23 (m, 8H), 2.21 (t, J = 6.8 Hz, 4H), 1.43–1.34 (m, 8H), 1.26 - 1.19 (m, 4H), 1.09 (s, 8H)

[0160] Preparation of formula (I):

[0161] Example 20

[0162]

[0163] In a 250 mL round-bottom flask, 100.0 mL of purified water and 100.00 g (183.87 mmol) of compound (II) were successively added, 30 mL (75 mmol) of 5% aqueous sodium hydroxide solution was added dropwise, and the mixture was stirred for 10 min. The concentrated solution was distilled under reduced pressure (distillation temperature: 150 °C to 180 °C, distillation vacuum degree: -0.05 MPa to -0.095 MPa) to obtain 160.41 g of compound (I) with a purity of 98.65% and a yield of 72.71%.

[0164] MS (m / z): [M+H] + = 317.4. 1 H-NMR (400 MHz, CCl 3 D) (ppm): 2.53 (t, J = 6.9 Hz, 8H), 2.29–2.23 (m, 8H), 2.21 (t, J = 6.8 Hz, 4H), 1.43–1.34 (m, 8H), 1.26 - 1.19 (m, 4H), 1.09 (s, 8H).

[0166] Preparation of Bishalom (API):

[0167] Example 21

[0168] Method for preparing API with reference to Patent WO2009023544A2 to verify the feasibility of preparing API from compound (I). The specific steps are as follows: Dissolve 94.8 g (299.48 mmol) of compound (I) prepared in Example 20 in 57.6 g of purified water and cool the temperature to 20 °C. Dropwise add 59.0 g of 37% hydrochloric acid, controlling the temperature at 25 °C ± 5 °C during the dropping process, and controlling the dropping time within 0.5 h. Dropwise add an aqueous solution of branched dodecylbenzenesulfonate to the reaction system (8.7 g, 30% by weight), control the temperature at 25 °C ± 5 °C, and stir at 290 rmp for 10 min. Add 282 g of toluene to the reaction system, heat up to 75 °C, and dropwise add 65.1 g of epichlorohydrin to the reaction solution, controlling the temperature at 75 °C during the dropping process. Keep the reaction at 75 °C for 1 h to precipitate a solid. Stir the solid with 4 L of purified water, 4 L of methanol, 4 L of 1% hydrochloric acid by mass fraction, 4.5 L of 5% sodium hydroxide by mass fraction, and 9 L of purified water for 5 min each in sequence, and then filter. After washing the product, rotary evaporate and dry the material at 48 °C to 53 °C for 48 h to obtain 116 g of a white solid with a spherical microscopic morphology. The swelling index of the API is 1.9 (the reported swelling index in Document CN106432719A is 1.9 - 2.0); 2) the phosphate binding rate is 5.5 mmol / g (reported in Document CN106432719A as 3.5 - 5.5 mmol / g), the chlorine content is 0.3% (reported in Document CN106432719A as 1.1% - 1.3%), and the yield is 72.53%. 1 H-NMR (solid state) (ppm) -1.28 to 0.18 (m). 13 C-NMR (solid state) δ: 26.2, 41.0, 55.3, 64.4, 158.2, 163.9. Elemental analysis: N,N,N',N'-tetrakis(3-aminopropyl)-1,4-butanediamine: epichlorohydrin = 1:2.1 - 2.4, that is, y / x = 2.1 - 2.4, C / N = (192X + 36Y) / 84X = 3.18 - 3.31, measured value (%): C 53.03, H 10.42, N 16.18, C / N = 3.27.

[0169] Example 22

[0170] The method for preparing API with reference to Patent CN100551951C was used to verify the feasibility of preparing API from compound (II). The specific steps were as follows: 17.41 g (32.52 mmol) of compound (II) prepared in Example 13 was dissolved in 20.00 g of purified water and stirred until completely dissolved at room temperature. 5% sodium hydroxide solution was added dropwise to adjust the pH to 11, 0.56 g of branched dodecylbenzenesulfonate was added to the reaction solution, and 89.0 ml of toluene was added. The temperature was controlled at 20 °C to 30 °C. 6.41 g (63.18 mmol) of epichlorohydrin was added dropwise to the reaction solution. After the addition was complete, the mixture was stirred for 1 h and then heated to 75 °C to 85 °C for reaction for 1 h, and a solid product was precipitated. The solid was stirred with 200.0 ml of purified water, 200.0 ml of methanol, 200.0 ml of 1% hydrochloric acid by mass fraction, 200.0 ml of 5% sodium hydroxide by mass fraction, and 200.0 ml of purified water in sequence for 5 min and then filtered. After the product was washed, it was dried in vacuum at 48 °C to 53 °C for 48 h to obtain 13.46 g of a white solid with a spherical microscopic morphology. The swelling index of the API was 2.0 (the swelling index reported in Document CN106432719A was 1.9 - 2.0); 2) the phosphate binding rate was 5.5 mmol / g (reported in Document CN106432719A as 3.5 - 5.5 mmol / g), the chlorine content was 0.3% (reported in Document CN106432719A as 1.1% - 1.3%), and the yield was 78.34% (Document CN106432719A: the yield was 61.9% - 62.9%). 1 H-NMR (solid state) (ppm) -1.28~0.18 (m). 13 C-NMR (solid state) δ: 26.2, 41.0, 55.3, 64.4, 158.2, 163.9. Elemental analysis: N,N,N',N'-tetrakis(3-aminopropyl)-1,4-butanediamine: epichlorohydrin = 1:2.1 - 2.4, that is, y / x = 2.1 - 2.4, C / N = (192X + 36Y) / 84X = 3.18 - 3.31, measured value (%): C 53.03, H 10.42, N 16.18, C / N = 3.27.

[0171] Preparation of the salt of formula (III) in Example 23

[0172]

[0173] In a 5 L three-necked round-bottom flask, 500 mL of acetonitrile, 10.00 g (113.44 mmol) of SM1, 91.48 g (90.4 mmol) of triethylamine, and 1.70 g (11.34 mmol) of sodium iodide were successively added under stirring, and then stirred. Nitrogen was replaced three times, and 124.00 G (463 mmol) of SM2 was added in batches. After the addition was completed, the temperature was kept at 30 °C and the reaction was continued for 24 hours. 1 L of purified water was added, stirred, and then extracted twice with 1.5 L of ethyl acetate. The organic phase was washed twice with water, dried, and the desiccant was filtered off. Acetic acid was added dropwise to the organic phase under stirring, and the solid was filtered out. The solid was washed with ethyl acetate, and the filter cake was dried to obtain 32.62 g of the (III) monoacetic acid compound (judged by 1H-NMR), with a purity of 99.32% and a yield of 36.62%. MS (m / z): [M+H] + = 717.5. 1 1H-NMR (400 MHz, CCl 3 D) (ppm): 5.29 (m, 4H), 3.15 (d, J = 5.8 Hz, 8H), 2.43 (t, J = 6.6 Hz, 8H), 2.37 (s, 4H), 2.10 (s, 3H), 1.66–1.58 (m, 8H), 1.43 (s, 36H), 1.39 (s, 4H).

[0174] Preparation of the (III) hydrate in Example 24

[0175]

[0176] In a 5 L three-necked round-bottom flask, 500 mL of DMF, 10.00 g (113.44 mmol) of SM1, and 125.41 g (907.52 mmol) of potassium carbonate were successively added and stirred. Nitrogen was replaced three times, and 124.31 g of SM2 (521.82 mmol) was added in batches. After the addition was completed, the temperature was kept at 30 °C and the reaction was continued for 24 hours. 2 L of purified water was added, stirred, and then extracted twice with 1.5 L of ethyl acetate. The organic phase was washed 4 times with brine until DMF was removed, the organic phase was dried, concentrated, the concentrated solution was crystallized by freezing, filtered, and dried to obtain 53.65 g of the (III) monohydrate (obtained by TGA weight loss calculation), with a purity of 98.33% and a yield of 64.42%.

[0177] MS (m / z): [M+H] + = 717.5, [M+Na] + = 739.5. 1 1H-NMR (400 MHz, CCl 3D) (ppm): 5.29 (m, 4H), 3.15 (d, J = 5.8 Hz, 8H), 2.43 (t, J = 6.6 Hz, 8H), 2.37 (s, 4H), 1.66–1.58 (m, 10H), 1.43 (s, 36H), 1.39 (s, 4H).

[0179] Example 25 Preparation of the Solvate of Formula (III)

[0180]

[0181] In a 2 L three-necked round-bottom flask, 500 mL of acetonitrile, 10.00 g (113.44 mmol) of SM1, and 125.41 g (907.52 mmol) of potassium carbonate were successively added and stirred. Nitrogen was replaced three times, and 124.31 g of SM2 (521.82 mmol) was added in batches. After the addition was completed, the temperature was maintained at 45 °C and the reaction was continued for 24 hours. The reaction solution was filtered and the filtrate was collected. 1 L of purified water was added to the filtrate and stirred, and then extracted twice with 500 mL of ethyl acetate. The organic phase was dried and concentrated. The concentrate was diluted with ethanol and then cooled by adding water to crystallize. After filtration and drying at low temperature, 44.63 g of the alcoholate of compound (III) (judged by 1H-NMR) was obtained, with a purity of 98.33% and a yield of 51.59%.

[0182] MS (m / z): [M + H] + = 717.5, [M + Na] + = 739.5. 1 1H-NMR (400 MHz, CCl 3 D) (ppm): 5.29 (m, 4H), 3.72 (q, 3H), 3.15 (d, J = 5.8 Hz, 8H), 2.43 (t, J = 6.6 Hz, 8H), 2.37 (s, 4H), 1.66–1.58 (m, 8H), 1.43 (s, 36H), 1.39 (s, 4H), 1.32 (s, 1H), 1.25 (t, 2H).

[0184] Example 26 Preparation of the Hydrate of Formula (II)

[0185]

[0186] In a 1 L round-bottom flask, 500 mL of purified water and 50 g (69.73 mmol) of compound (III) were successively added, and 69.7 mL (836.80 mmol) of concentrated hydrochloric acid was added dropwise. During the addition, the temperature was controlled at 20 °C - 30 °C. After the addition was completed, the reaction was carried out at 20 °C - 30 °C for 48 h; the stirring was stopped, and the reaction solution was concentrated to obtain 249.52 g of compound N,N,N',N'-tetrakis(3-aminopropyl)-1,4-butanediamine hexahydrochloride monohydrate (calculated by TGA weight loss), with a purity of 95.42% and a yield of 92.13%.

[0187] MS(m / z):[M+H] + =317.4. 1 H-NMR(400MHz,D 2 O)(ppm):3.39(dd,J=9.2,7.5Hz,12H),3.25–3.11(m,8H),2.31–2.15(m,8H),1.90(q,4H).

[0189] Example 27 Preparation of the Solvate of Formula (II)

[0190]

[0191] In a 1 L round-bottom flask, 500 mL of methanol and 50.0 g (69.73 mmol) of compound (III) were successively added, and 69.73 mL (836.80 mmol) of concentrated hydrochloric acid was added dropwise. During the addition, the temperature was controlled at 20 °C - 30 °C. After the addition was completed, the reaction was carried out at 20 °C - 30 °C for 48 h; the stirring was stopped, and the reaction solution was concentrated to obtain 309.22 g of compound N,N,N',N'-tetrakis(3-aminopropyl)-1,4-butanediamine hexahydrochloride methanolate (judged by 1H-NMR), with a purity of 98.33% and a yield of 88.71%.

[0192] MS(m / z):[M+H] + =317.4. 1 H-NMR(400MHz,D 2 O)(ppm):3.49(s,3H)3.39(dd,J=9.2,7.5Hz,12H),3.25–3.11(m,8H),2.31–2.15(m,8H),1.90(q,4H).

[0194] The above specific embodiments are only used to illustrate the technical solutions of the present application and are not restrictive. Although the present application has been described in detail with reference to the examples, those of ordinary skill in the art should understand that the technical solutions of the present application can be modified or equivalently replaced without departing from the scope of the technical solutions of the present application, and they should all be covered within the scope of the claims of the present application.

Claims

1. A method for preparing a compound of formula (III) and its salt, hydrate or solvate, characterized in that: The reactions include: X is a functional group that can undergo a nucleophilic substitution reaction with an amine group; PG is a protecting group for an amine group.

2. The method according to claim 1, characterized in that The X is selected from F, Cl, Br, I, MsO, Tos, TfO, NsO, PhSO3, AcO, PCl4O, POCl2, PCl2O, NaOSO3, preferably Br or MsO.

3. The method according to claim 1, characterized in that The PG is selected from Cbz, Boc, Fmoc, Alloc, Teoc, methyl(ethyl)oxycarbonyl, Pht, Tos, Tfa, Trt, PMB, and Bn, preferably Boc, methyl(ethyl)oxycarbonyl, Fmoc, Bn, Cbz, Alloc, Pht, Tos, and Tfa.

4. The method according to claim 1, characterized in that: The reaction is carried out in the presence of a base, wherein the base is selected from at least one of cesium carbonate, potassium carbonate, potassium phosphate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, triethylamine, DBU, DIPEA, sodium methoxide, sodium ethoxide, potassium ethoxide, and potassium tert-butoxide, preferably at least one of potassium carbonate, lithium hydroxide, sodium bicarbonate, and pyridine.

5. The method according to claim 1, characterized in that The reaction is carried out in the presence of a catalyst, and the catalyst is selected from at least one of sodium iodide, potassium iodide, sodium dodecyl sulfate, 18-crown-6, 15-crown-5, cyclodextrin, benzyltriethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium hydrogen sulfate, trioctylmethylammonium chloride, dodecyltrimethylammonium chloride, and tetradecyltrimethylammonium chloride, preferably at least one of sodium iodide, potassium iodide, and tetrabutylammonium bromide.

6. The method according to claim 1, characterized in that The solvent used in the method for preparing the compound of formula (III) and its salt, hydrate and solvate is selected from at least one of pentane, hexane, octane, toluene, xylene, cyclohexane, cyclohexanone, toluene cyclohexanone, dichloromethane, chloroform, 1,1,1-trifluoroethane, methanol, ethanol, ethylene glycol, propylene glycol, isopropanol, ethyl ether, propylene oxide, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, acetone, butanone, methyl isobutyl ketone, methyl acetate, ethyl acetate, propyl acetate, acetonitrile, pyridine, phenol, DMF, DMSO, tetrahydrofuran and water; preferably at least one of DMF, DMSO, acetonitrile, tetrahydrofuran, methanol, ethanol, dichloromethane, acetone, water, ethyl acetate, isopropanol and acetone; more preferably at least one of DMF, acetonitrile, ethyl acetate, tetrahydrofuran, methanol and water.

7. The method according to claim 1, characterized in that The salt of the compound of formula (III) is selected from formic acid, acetic acid, propionic acid, benzoic acid, salicylic acid, oxalic acid, succinic acid, citric acid, fumaric acid, malic acid, tartaric acid, maleic acid, lactic acid, succinic acid, mandelic acid, ascorbic acid, malonic acid, stearic acid, palmitic acid, triphenylacetic acid, trifluoroacetic acid, glycolic acid, butanedisulfonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, p-toluenesulfinic acid, TFA, HCl, H2SO4, H3PO4, HNO3, HBr, H2CO3, H3BO3, H2SiO3, HMnO4, HF , HI formed; the hydrate or solvate of the compound of formula (III) is selected from the hydrate or solvate formed with pentane, hexane, octane, toluene, xylene, cyclohexane, cyclohexanone, toluene cyclohexanone, dichloromethane, chloroform, 1,1,1-trifluoroethane, methanol, ethanol, ethylene glycol, propylene glycol, isopropanol, ether, propylene oxide, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, acetone, butanone, methyl isobutyl ketone, methyl acetate, ethyl acetate, propyl acetate, acetonitrile, pyridine, phenol, DMF, DMSO, tetrahydrofuran, and water.

8. A method for preparing a compound of formula (II) and its hydrate and solvate, characterized in that: The reactions include: The PG is selected from Cbz, Boc, methyl(ethyl)oxycarbonyl, Trt, PMB, Tfa, and Tos, preferably Boc, methyl(ethyl)oxycarbonyl, Trt, Tfa, and Tos; n = 0.5-10, preferably n = 0.5-6.0; more preferably n = 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0; The method is carried out in the presence of an acid, wherein the acid is selected from TFA, HCl, H2SO4, H3PO4, CH3SO3H, HBr, TsOH, HOAc, preferably HCl, H2SO4, HBr, TsOH; the HA is the corresponding acid under acidic conditions; in particular, when HA is HCl or HBr, n=4-6; when HA is TsOH, n=0.5-3.

9. A method for preparing a compound of formula (I), characterized in that: The reactions include: The PG is selected from Fmoc, methyl(ethyl)oxycarbonyl, Pht, Tfa, Trt, PMB, Bn, Teoc, Dmb, Cbz, Boc, and Alloc, preferably Boc, Fmoc, methyl(ethyl)oxycarbonyl, Cbz, and Alloc.

10. The method according to claim 9, characterized in that The reaction is carried out in the presence of a base, wherein the base is selected from at least one of piperidine, sodium hydroxide, ethanolamine, cyclohexylamine, morpholine, pyrrolidone, DBU, potassium hydroxide, potassium carbonate, ammonia water, hydrazine hydrate, potassium tert-butoxide, and sodium tert-butoxide, preferably at least one of sodium hydroxide, potassium hydroxide, potassium tert-butoxide, and sodium tert-butoxide.

11. The method according to claim 9, characterized in that The reaction is carried out under the conditions of hydrogenation and metal reagent, or the presence of hydrogen source reagent and metal reagent, and the conditions are selected from at least one of H2 / Pd, H2 / Pd(OH)2, H2 / Pd-C, HCO2H / Pd-C, HCO2H / Pd, HCO2H / Pd(OH)2, HCO2NH3 / Pd-C, HCO2NH3 / Pd, HCO2NH3 / Pd(OH)2, preferably at least one of H2 / Pd(OH)2, H2 / Pd-C, HCO2H / Pd-C, HCO2NH3 / Pd-C.

12. The method according to claim 9, characterized in that The reaction is carried out in the presence of at least one of the following reagents, wherein the reagent is selected from tetrabutylammonium fluoride, tetraethylammonium fluoride, tetramethylammonium fluoride, sodium borohydride, benzaldehyde / sodium cyanoborohydride, cerium ammonium nitrate, boron tribromide, trimethylsilane iodide, nickel tetracarbonyl, tetratriphenylpalladium / tri-n-butyltin hydride, and 2,3-dichloro-5,6-dicyanobenzoquinone.

13. A method for preparing a compound of formula (I), characterized in that: The reactions include: n = 0.5-10, preferably n = 0.5-6.0; more preferably n = 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0; The HA is TFA, HCl, H2SO4, H3PO4, CH3SO3H, HBr, TsOH, HOAc, preferably HCl, H2SO4, TFA, HBr, TsOH; in particular, when HA is HCl or HBr, n=4-6; when HA is TsOH, n=0.5-3.

14. The method according to claim 13, characterized in that The reaction is carried out in the presence of a base, wherein the base is selected from at least one of cesium carbonate, potassium phosphate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, triethylamine, DIPEA, piperidine, ethanolamine, cyclohexylamine, morpholine, pyrrolidone, DBU, potassium carbonate, ammonia water, hydrazine hydrate, sodium methoxide, sodium ethoxide, potassium ethoxide, and potassium tert-butoxide, and preferably at least one of sodium hydroxide, potassium hydroxide, triethylamine, and sodium methoxide.

15. A method for preparing bisalom, characterized in that: Prepared from the compound of formula (II) as raw material, n = 0.5-10, preferably n = 0.5-6.0; more preferably n = 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0; The HA is TFA, HCl, H2SO4, H3PO4, CH3SO3H, HBr, TsOH, HOAc, preferably HCl, H2SO4, TFA; in particular, when HA is HCl, n=4-6; when HA is TsOH, n=0.5-3.

16. A compound of formula (III) having the following structural formula: in, PG is selected from Cbz, Boc, Fmoc, Alloc, Teoc, methyl(ethyl)oxycarbonyl, Pht, Tos, Tfa, Trt, PMB, Bn, preferably Boc, methyl(ethyl)oxycarbonyl, Fmoc.

Images