CN114230490A - Preparation method of N-alkylated diamine - Google Patents
Preparation method of N-alkylated diamine Download PDFInfo
- Publication number
- CN114230490A CN114230490A CN202111632053.1A CN202111632053A CN114230490A CN 114230490 A CN114230490 A CN 114230490A CN 202111632053 A CN202111632053 A CN 202111632053A CN 114230490 A CN114230490 A CN 114230490A
- Authority
- CN
- China
- Prior art keywords
- compound
- solvent
- formula
- temperature
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
Abstract
The invention provides a preparation method of N-alkylated diamine, which takes amino alkanol as a starting material, amino-protected amino alkanol is prepared by amidation, hydroxyl protection is carried out by acyl halide, and amino-protected diamine is prepared by substitution of phthalimide potassium salt; or the amino-protected aminoalcohol is substituted by phthalimide to prepare amino-protected diamine; adding halogenated alkane or halogenated aromatic hydrocarbon into diamine protected by amino in the presence of sodium hydride to prepare N-substituted amide, performing hydrazinolysis to obtain N-protected and substituted diamine, and salifying to obtain the diamine. The invention takes the amino alkanol as the initial raw material, reasonably designs the reaction route, optimizes the production process of each step, avoids high-risk reactions such as high-pressure hydrogenation and the like, greatly improves the total yield of products, and greatly reduces the production cost and the generation quantity of three wastes.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to a preparation method of N-alkylated diamine.
Background
N-alkylated diamines are important pharmaceutical intermediates for the synthesis of medicaments for the treatment or prevention of diseases related to the orexin subtype 1 receptor (OX 1R): n- [ (pyrimidinylamino) propyl ] -and N- [ (pyridinylamino) -propylarylcarboxamide derivatives. Orexin is a hypothalamic neuropeptide that plays an important role in the regulation of many physiological behaviors, such as arousal, appetite, food intake, cognition, motivational behavior, reward, mood, and stress. Sleep induction by orexin receptor antagonists is primarily mediated through OX2R, while other physiological states such as mood and reward are regulated by impulse control of autonomic and neuroendocrine functions. Arousal and alertness are regulated by OX 1R. Due to their sleep-inducing effects, OX1R and OX2R are not suitable for disorders associated with a deficiency in impulse control, such as in addiction (e.g., substance use disorders), personality disorders (e.g., borderline personality disorders), eating disorders (e.g., binge eating disorders), or attention deficit (e.g., hyperactivity disorders). Thus, it plays an important role in the regulation of many physiological behaviors, and it is desirable to provide OX1R selective antagonists for use in treating penetration control deficiencies.
In the prior art (WO2017178343), the synthetic route of N-alkylated diamine is to prepare N-substituted aminoalkanol by continuously reductive amination of aminoalkanol, and then to prepare N-alkylated diamine by amino protection, Mitsunobu reaction and hydrazinolysis in sequence. The route has long production steps, difficult separation and purification, low total yield, large production amount of three wastes and high production risk.
Disclosure of Invention
In view of the above, the present invention provides a method for preparing N-alkylated diamine, which aims to overcome the defects in the prior art.
In order to achieve the purpose, the technical scheme of the invention is realized as follows:
a preparation method of N-alkylated diamine comprises the following synthetic route:
wherein n is 1; r1X is an acyl halide, R2X is a halogenated alkane, X is Cl, Br or I, R1Is Ts or Ms, R2Is methyl, ethyl, propyl, butyl or benzyl; the Acid is one or more of formic Acid, acetic Acid, propionic Acid, citric Acid, oxalic Acid, hydrochloric Acid and sulfuric Acid.
The method specifically comprises the following steps:
s1: amino alkanol is used as a starting material, and amino-protected amino alkanol is prepared through amidation:
s2: hydroxyl protection is carried out on amino alkanol protected by amino through acyl halide, and then the amino protected diamine is prepared through substitution of phthalimide potassium salt;
or S2: substituting amino alkanol protected by amino with phthalimide to prepare diamine protected by amino;
s3: and (4) adding halogenated alkane or halogenated aromatic hydrocarbon into the diamine with the amino protection obtained in the step (S2) in the presence of sodium hydride to prepare N-substituted amide, performing hydrazinolysis to obtain N-protected and substituted diamine, and salifying to obtain the diamine.
Preferably, the step S1 specifically includes the following steps:
reacting the compound shown in the formula 1 with di-tert-butyl dicarbonate in the presence of an organic base by using a solvent A as a medium and controlling the temperature to be 0-30 ℃, concentrating the filtrate under reduced pressure until the reaction is finished, adding a solvent B, pulping, controlling the temperature to be 0-30 ℃, stirring, filtering, drying and concentrating the filter cake under reduced pressure to obtain the compound shown in the formula 2.
Preferably, solvent a is dichloromethane.
Preferably, the volume weight ratio of the solvent A to the compound of the formula 1 is 3-30 v.
More preferably, the volume to weight ratio of solvent a to the compound of formula 1 is 4 v.
Preferably, the molar ratio of the compound of formula 1, di-tert-butyl dicarbonate and organic base is 1: (1-2): (1-3).
More preferably, the molar ratio of the compound of formula 1, di-tert-butyl dicarbonate and organic base is 1: 1.05: 1.2.
preferably, the organic base is triethylamine.
Preferably, the reaction temperature is 15-25 ℃.
Preferably, the pulping solvent B is petroleum ether.
Preferably, the volume weight ratio of the pulping solvent B to the compound of the formula 1 is 2-5 v.
More preferably, the volume weight ratio of the beating solvent B to the compound of formula 1 is 2 v.
Preferably, the step S2 specifically includes the following steps:
s21: reacting a compound shown in a formula 2 with acyl halide in the presence of organic alkali by using 4-dimethylaminopyridine as a catalyst and a solvent C as a medium at a temperature of 0-30 ℃, filtering insoluble substances after the reaction is finished, washing the filtrate with an aqueous solution of acid and an aqueous solution of saturated sodium bicarbonate in sequence, or washing with water, drying, and concentrating under reduced pressure to obtain a compound shown in a formula 3;
s22: and (2) reacting the compound of the formula 3 with phthalimide potassium salt in a polar aprotic solvent X at the temperature of 30-50 ℃, cooling to 0-20 ℃ after the reaction is finished, filtering out insoluble substances, dropwise adding water into the filtrate for crystallization, filtering to obtain a filter cake, and drying to obtain the compound of the formula 4.
In step S21: preferably, solvent C is dichloromethane.
Preferably, the volume weight ratio of the solvent C to the compound of the formula 2 is 5-20 v.
More preferably, the volume weight ratio of the solvent C to the compound of the formula 2 is 5-8 v.
Preferably, the compound of formula 2, acyl halide, organic base and 4-dimethylaminopyridine are in a molar ratio of 1: (1-2): (1-3): (0.01-0.2).
More preferably, the molar ratio of the compound of formula 2, acid halide, organic base, 4-dimethylaminopyridine is 1: (1.05-1.1): 1.5: 0.05.
preferably, the organic base is triethylamine.
And further, the reaction temperature is 0-10 ℃.
In step S22:
preferably, the polar aprotic solvent X is DMF.
Preferably, the volume weight ratio of the polar aprotic solvent X to the compound of formula 3 is 5-15 v.
More preferably, the volume to weight ratio of the polar aprotic solvent X to the compound of formula 3 is 10 v.
Preferably, the molar ratio of the compound of formula 3 to the potassium phthalimide salt is 1:1.0 to 1.5.
More preferably, the molar ratio of the compound of formula 3 to the potassium phthalimide salt is 1: 1.1.
Preferably, the reaction temperature is 35-50 ℃.
More preferably, the reaction temperature is 40-45 ℃.
Preferably, the volume weight ratio of the water to the compound of the formula 3 is 5-15 v.
More preferably, the volume to weight ratio of water to the compound of formula 3 is 10 v.
Preferably, the volume weight ratio of the pulping water to the compound of the formula 3 is 5-15 v.
More preferably, the volume weight ratio of the pulping water to the compound of formula 3 is 10 v.
Preferably, the drying temperature of the compound of formula 3 is 40-55 ℃.
More preferably, the drying temperature of the compound of formula 3 is 40-45 ℃.
Preferably, the step S2 specifically includes the following steps:
dropwise adding diisopropyl azodicarboxylate in a solvent D of the compound shown in the formula 2 and phthalimide in the presence of triphenylphosphine, controlling the temperature to be 15-30 ℃ to carry out Mitsunobu reaction, after the reaction is finished, carrying out reduced pressure concentration to remove the solvent, adding a solvent E to carry out pulping, filtering out insoluble substances, carrying out reduced pressure concentration on the filtrate to dryness, and carrying out column chromatography purification on the obtained crude product to obtain the compound shown in the formula 4.
Preferably, the solvent D is tetrahydrofuran.
Preferably, the volume weight ratio of the solvent D to the compound of the formula 2 is 5-15 v;
more preferably, the volume to weight ratio of the solvent D to the compound of formula 2 is 10 v.
Preferably, the molar ratio of the compound of formula 2, phthalimide, triphenylphosphine, and diisopropyl azodicarboxylate is 1: (1.0-1.5): (1.0-1.5): (1.0 to 1.5),
more preferably, the molar ratio of the compound of formula 2 to phthalimide is 1: 1: 1:1.
preferably, the reaction temperature is 20-25 ℃.
Preferably, the solvent E for pulping is methyl tert-butyl ether.
Preferably, the volume weight ratio of the solvent E for pulping to the compound of the formula 2 is 5-10 v.
More preferably, the volume weight ratio of the solvent E for beating to the compound of formula 2 is 8 v.
Preferably, the step S3 specifically includes the following steps:
s31: the compound of formula 4 is firstly reacted with sodium hydride in a polar aprotic solvent Y at the temperature of-10-15 ℃, and then R is dripped at the temperature of-10-15 DEG C2X, after the dropwise addition, heating to 15-30 ℃, carrying out heat preservation reaction, after the reaction is finished, sequentially dropwise adding a quenching solvent, carrying out acid quenching, adding water for dilution, extracting with a solvent F, and carrying out column chromatography purification to obtain a compound shown in the formula 5;
s32: reacting the compound shown in the formula 5 with hydrazine hydrate in a solvent G at 15-35 ℃, after the reaction is finished, adding a solvent H for dilution, cooling to-5-15 ℃, filtering out insoluble substances, concentrating the filtrate under reduced pressure to dryness, adding a solvent I for pulping, filtering out the insoluble substances, and repeating for multiple times until no solid exists in the concentrate to obtain the compound shown in the formula 6;
s33: dissolving the compound shown in the formula 6 into a solvent J or a mixture of the solvent J and a solvent K, dropwise adding a solution of an acid solvent L at the temperature of 15-35 ℃, controlling the temperature of 15-35 ℃ for reaction, cooling to-5-10 ℃ for crystallization after the reaction is finished, filtering, pulping and purifying a filter cake by using alcohol, and drying to obtain a compound 7, or concentrating a reaction solution under reduced pressure until the reaction solution is dry, pulping a concentrated residue by using a solvent M, filtering, and drying to obtain the compound 7.
In step S31:
preferably, the polar aprotic solvent Y is DMF.
Preferably, the volume weight ratio of the polar aprotic solvent Y to the compound of formula 4 is 5-10 v.
More preferably, the volume weight ratio of the polar aprotic solvent Y to the compound of formula 4 is 6-7 v.
Preferably, the molar ratio of the compound of formula 4 to sodium hydride is 1: (1.0-3.0).
More preferably, the molar ratio of the compound of formula 4 to sodium hydride is 1: (1.5-2.0).
Preferably, R2X is methyl bromide, ethyl bromide, propyl bromide or butyl bromide.
Preferably, sodium hydride and R2The feeding temperature of-X is-5 ℃.
Preferably, the reaction temperature is 15-25 ℃.
Preferably, the quenching temperature is-5 to 25 ℃.
More preferably, the quenching temperature is-5 to 20 ℃.
Preferably, the quenching solvent is an alcohol. More preferably, the quenching solvent is methanol.
Preferably, the acid for quenching is one or more of formic acid, acetic acid, propionic acid, citric acid, oxalic acid, hydrochloric acid and sulfuric acid.
More preferably, the quenching acid is acetic acid.
Preferably, the volume weight ratio of the dilution water to the compound of formula 4 is 1-3 v.
More preferably, the volume to weight ratio of the dilution water to the compound of formula 4 is 1 v.
Preferably, the solvent F for extraction is one or more of ethyl acetate, methyl tert-butyl ether, petroleum ether and n-heptane.
In step S32:
preferably, the solvent G is one or more of DMF, DMSO, methanol, ethanol, propanol, butanol and isopropanol.
More preferably, the solvent G is ethanol.
Preferably, the molar ratio of the compound of formula 5 to hydrazine hydrate is 1: (1.0-4.0).
More preferably, the molar ratio of the compound of formula 5 to hydrazine hydrate is 1: 2.5.
preferably, the reaction temperature is 20-30 ℃.
Preferably, the solvent for dilution H is methyl tert-butyl ether.
Preferably, the volume weight ratio of the solvent H for dilution to the compound of the formula 5 is 2-5 v.
Preferably, the volume weight ratio of the solvent I for pulping to the compound of the formula 5 is 1-5 v.
In step S33:
preferably, the solvent J for dissolving the compound of formula 6 is one or more of ethyl acetate, methyl tert-butyl ether and dichloromethane, and the solvent K is one or more of methanol, ethanol and propanol.
More preferably, solvent J, which dissolves the compound of formula 6, is methyl tert-butyl ether and solvent K is methanol.
Preferably, the solvent M for pulping is ethanol or methyl tert-butyl ether.
Preferably, the acid used for salt formation is oxalic acid.
Compared with the prior art, the invention has the following advantages:
the invention provides a new N-alkylated diamine process route, takes amino alkanol as a starting material, reasonably designs a reaction route, optimizes the production process of each step, avoids high-risk reactions such as high-pressure hydrogenation and the like, greatly improves the total yield of products, greatly reduces the production cost, greatly reduces the generation quantity of three wastes, simplifies the operation of each intermediate step, and avoids high-risk and harsh reaction conditions.
Drawings
FIG. 1 is a HNMR map of Compound 2 prepared in example 1 of the present invention;
FIG. 2 is an MS spectrum of Compound 2 prepared in example 1 of the present invention;
FIG. 3 is a HNMR map of compound 3a prepared in example 2 of the present invention;
FIG. 4 is a HNMR map of compound 3b prepared in example 3 of the present invention;
FIG. 5 is a HNMR map of Compound 4 prepared in example 4 of the present invention;
FIG. 6 is an MS spectrum of Compound 4 prepared in example 5 of the present invention;
FIG. 7 is a HNMR map of Compound 4 prepared in example 6 of the present invention;
FIG. 8 is a HNMR map of compound 5a prepared in example 7 of the present invention;
FIG. 9 is an MS spectrum of Compound 5a prepared in example 7 of the present invention;
FIG. 10 is a HNMR map of compound 5b prepared in example 8 of the present invention;
FIG. 11 is an MS spectrum of Compound 5b prepared in example 8 of the present invention;
FIG. 12 is a HNMR map of compound 5c prepared in example 9 of the present invention;
FIG. 13 is an MS spectrum of compound 5c prepared in example 9 of the present invention;
FIG. 14 is a HNMR map of compound 5d prepared in example 10 of the present invention;
FIG. 15 is an MS spectrum of compound 5d prepared in example 10 of the present invention;
FIG. 16 is a HNMR map of compound 5e prepared in example 11 of the present invention;
FIG. 17 is an MS spectrum of compound 5e prepared in example 11 of the present invention;
FIG. 18 is a HNMR map of Compound 6a prepared in example 12 of the present invention;
FIG. 19 is an MS spectrum of Compound 6a prepared in example 12 of the present invention;
FIG. 20 is a HNMR map of compound 6b prepared in example 13 of the present invention;
FIG. 21 is an MS spectrum of compound 6b prepared in example 13 of the present invention;
FIG. 22 is a HNMR map of compound 6c prepared in example 14 of the present invention;
FIG. 23 is an MS spectrum of compound 6c prepared in example 14 of the present invention;
FIG. 24 is a HNMR map of compound 6d prepared in example 15 of the present invention;
FIG. 25 is an MS spectrum of compound 6d prepared in example 15 of the present invention;
FIG. 26 is a HNMR map of compound 6e prepared in example 16 of the present invention;
FIG. 27 is an MS spectrum of compound 6e prepared in example 16 of the present invention;
FIG. 28 is a HNMR map of compound 7a prepared in example 17 of the present invention;
FIG. 29 is a HNMR map of compound 7b prepared in example 18 of the present invention;
FIG. 30 is a HNMR map of compound 7c prepared in example 19 of the present invention;
FIG. 31 is an MS spectrum of compound 7c prepared in example 19 of the present invention;
FIG. 32 is a HNMR map of compound 7d prepared in example 20 of the present invention;
FIG. 33 is an MS spectrum of compound 7d prepared in example 20 of the present invention;
FIG. 34 is a HNMR map of compound 7e, prepared according to example 21 of the present invention;
FIG. 35 is an MS spectrum of compound 7e prepared in example 21 of the present invention.
Detailed Description
Unless defined otherwise, technical terms used in the following examples have the same meanings as commonly understood by one of ordinary skill in the art to which the present invention belongs. The test reagents used in the following examples, unless otherwise specified, are all conventional biochemical reagents; the experimental methods are conventional methods unless otherwise specified.
The invention will be described in detail with reference to the following examples.
The invention provides a preparation method of N-alkylated diamine, which comprises the following synthetic route:
EXAMPLE 1 preparation of tert-butyl (S) - (1-hydroxypropan-2-yl) carbamate (Compound 2)
To the reaction flask were added 520.0g of L-aminopropanol, 841.7g of triethylamine and 2080.0ml of dichloromethane. A solution of di-tert-butyl dicarbonate (1586.6g) in methylene chloride (530.0ml) was added dropwise at 20 ℃ while controlling the temperature. After the dropwise addition, preserving the heat for 1 hour; after the reaction, the reaction solution is decompressed and concentrated to be dry, and the petroleum ether is pulped for 1 hour at the temperature of 20 ℃. Filtering, and drying a filter cake at 40 ℃ under reduced pressure to obtain a compound 2: 1106.1g, GC: 98.8%, Yield: 91.1 percent.
The HNMR results of compound 2 are shown in FIG. 1, the GCMS results are shown in FIG. 2, and the specific data are as follows:
1HNMR(400MHz,DMSO),δ＝4.63(S,1H),δ＝3.78～3.76(m,1H),δ＝3.66～3.63(m,1H),δ＝3.53～3.49(m,1H),δ＝1.45(s,9H),δ＝1.15(d,J＝6.8Hz,3H).
MS(EI)m/z,calcd for C8H17NO3,175.23；found 175.10.
example 2 preparation of (S) -2- ((tert-butoxycarbonyl) amino) propyl 4-methylbenzenesulfonate (Compound 3a)
To a reaction flask were added compound 2(100.0g), dichloromethane 0.8L, 4-dimethylaminopyridine 3.4g and triethylamine 86.6g in this order. A solution of p-toluenesulfonyl chloride (114.6g) in dichloromethane (0.2L) was added dropwise to the reaction mixture while controlling the temperature at 5 ℃; after the dropwise addition, the temperature was raised to 20 ℃ and kept for 12 hours. Cooling the reaction solution to 5 ℃ and stirring for 30 minutes under the condition of heat preservation, filtering, washing the filtrate with 10% citric acid aqueous solution and saturated sodium bicarbonate aqueous solution in sequence, drying the organic phase with anhydrous sodium sulfate, and concentrating under reduced pressure to dryness to obtain a compound 3a as an off-white solid with the yield of 170.1 g: 90.5%, HPLC: 92.2 percent.
The HNMR results of compound 3a are shown in fig. 3, and the specific data are as follows:
1H NMR(400MHz,DMSO),δ＝7.78(d,J＝8.4Hz,2H),δ＝7.53(d,J＝8.4Hz,2H),δ＝3.90～3.87(m,1H),δ＝3.86～3.82(m,1H),δ＝3.68～3.65(m,1H),δ＝1.34(s,9H),δ＝0.98(d,J＝6.8Hz,3H).
example 3 preparation of (S) -2- ((tert-butoxycarbonyl) amino) propyl methanesulfonate (Compound 3b)
Compound 2(160.0g), 5.7g of 4-dimethylaminopyridine, 138.8g of triethylamine and 800.0ml of dichloromethane are sequentially added into a reaction bottle, 115.1g of methanesulfonyl chloride is added dropwise at 5 ℃ while controlling the internal temperature, and after the addition is finished, the temperature is controlled at 5 ℃ to react for 30 min. Filtration, washing of the filtrate with water, drying over anhydrous sodium sulfate, and concentration to dryness under reduced pressure gave compound 3b as an off-white solid, 206.8g, in 89.3% yield.
The HNMR results of compound 3b are shown in fig. 4, with the following specific data:
1H NMR(400MHz,DMSO),δ＝4.63(s,1H),δ＝4.24～4.22(m,1H),δ＝4.17～4.14(m,1H),δ＝3.98～3.94(m,1H),δ＝3.04(s,3H),δ＝1.45(s,9H),δ＝1.24(d,J＝6.8Hz,3H).
EXAMPLE 4 preparation of tert-butyl (S) - (1- (1, 3-Dioxoisoindolin-2-yl) propan-2-yl) carbamate (Compound 4) from Compound 3a
To a reaction flask was added compound 3a (110.0g), and 1100.0ml of N, N-dimethylformamide and 68.0g of potassium phthalimide were added. After the addition, the temperature is raised to 40-45 ℃ and kept for 12 hours. After the reaction is finished, cooling to 0-5 ℃, and stirring for 30 minutes under the condition of heat preservation. Filtering, controlling the temperature to be 25 ℃, and dropwise adding 1100.0ml of water into the filtrate. After the addition, the mixture was stirred for 30 minutes. Filtration and the filter cake slurried with 1100.0ml of water for 30 minutes. Filtering, and drying the filter cake at 45 ℃ to obtain the compound 4 which is a white solid with the yield of 32.3g, 31.8 percent and 99.9 percent.
The HNMR results of compound 4 are shown in fig. 5, with the following specific data:
1H NMR(400MHz,CDCl3) δ 7.86(d, J1.4 Hz,2H), δ 7.84(dd, J1.4 Hz,5.2Hz,2H), δ 3.94(m,1H), δ 3.70 to 3.67(m,2H), δ 1.25(s,9H), δ 1.21(d, J6.8 Hz,3H), internal standard: 1,3, 5-trimethoybenzene, δ ═ 6.09(s,3H), δ ═ 3.77(s,3H).
EXAMPLE 5 preparation of tert-butyl (S) - (1- (1, 3-Dioxoisoindolin-2-yl) propan-2-yl) carbamate (Compound 4) from Compound 3b
To a reaction flask was added compound 3b (50.0g), and 500.0ml of N, N-dimethylformamide and 40.2g of potassium phthalimide were added. After the addition, heating to 40-45 ℃ and reacting for 12 hours under the condition of heat preservation. After the reaction, the reaction solution was cooled to 5 ℃ and stirred for 30 minutes under heat preservation. Filtering, controlling the temperature to be 25 ℃, and dropwise adding 500.0ml of water into the filtrate. After the completion of the dropwise addition, the mixture was stirred for 30 minutes. Filtration and slurrying of the filter cake with 500.0ml of water for 30 minutes. Filtering, drying filter cake at 45 deg.C to obtain compound 4 as off-white solid, 32.0g, yield 53.3%, yield 99.6%.
The MS results for compound 4 are shown in fig. 6, with the following specific data:
MS(ESI)m/z,calcd for C16H20N2O4-H-；304.35；found 303.1.
EXAMPLE 6 preparation of tert-butyl (S) - (1- (1, 3-Dioxoisoindolin-2-yl) propan-2-yl) carbamate (Compound 4) from Compound 2
To a reaction flask, 500.0ml of THF500, compound 2(50.0g), 64.5g of triphenylphosphine, 36.2g of phthalimide, and 3 times with nitrogen were added. 49.8g of diisopropyl azodicarboxylate was added dropwise at 25 ℃ under nitrogen protection. After the dropwise addition, the reaction was carried out at 25 ℃ for 12 hours. After the reaction is finished, concentrating under reduced pressure to remove the solvent, adding 296.7g of methyl tert-butyl ether, controlling the temperature to be 5 ℃, pulping for 1 hour, filtering, concentrating the filtrate under reduced pressure to be dry to obtain yellow oily matter, purifying by column chromatography, eluting by ethyl acetate-petroleum ether (v: v ═ 1:10) to obtain a product which is a white-like solid, 37.0g of HPLC (high performance liquid chromatography), 63.1 percent of yield, yield: 45.2 percent.
The HNMR results of compound 4 are shown in fig. 7, with the following specific data:
1H NMR(400MHz,CDCl3),δ＝7.88(d,J＝1.4Hz,2H),δ＝7.85(dd,J＝1.4Hz,5.2Hz,2H),δ＝6.32(s,1H),δ＝5.01～4.95(m,1H),δ＝4.11(m,1H),δ＝3.72～3.64(m,1H),δ＝1.25(s,9H),δ＝1.22(d,J＝6.4Hz,3H).
example 7 preparation of tert-butyl (S) - (1- (1, 3-dioxoisoindolin-2-yl) propan-2-yl) (methyl) carbamate (Compound 5a)
Nitrogen was replaced three times, and 66.7ml of N, N-dimethylformamide, Compound 4(10.0g), was added to the reaction flask, and nitrogen was replaced three times. The temperature is reduced to 0 ℃, and 60 percent NaH 2.6g is added in batches at the temperature of 0 ℃. After the addition, the temperature is kept for reaction for 30 minutes, the temperature is controlled to be 0 ℃, 14.0g of methyl iodide is dropwise added, after the addition, the temperature is kept for reaction for 1 hour, the temperature is raised to 20 +/-5 ℃, and the temperature is kept for reaction for 1 hour. After the reaction is finished, cooling the reaction liquid to 0 ℃, controlling the temperature to be 0 ℃, dropwise adding 4.0g of methanol and 4.0g of methanol solution of acetic acid (4.0g), controlling the temperature to be below 20 ℃, dropwise adding 10.0ml of water for quenching, then adding the quenched reaction liquid into water for diluting, extracting with ethyl acetate, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and purifying a crude product by column chromatography to obtain a compound 5a which is a white-like granular solid with the yield of 6.0g of 57.4%. HPLC 99.5%.
The HNMR results of compound 5a are shown in fig. 8, and the MS results are shown in fig. 9, with the following data:
1H NMR(400MHz,CDCl3),δ＝7.78(d,2H),δ＝7.85(dd,J＝2.8Hz,20.4Hz,2H),δ＝4.71～4.56(m,1H),δ＝3.83～3.76(m,1H),δ＝3.54～3.47(m,1H),δ＝2.75(d,J＝14.8Hz,3H).δ＝1.22(d,J＝6.8Hz,3H).δ＝1.12(s,9H)。
MS(ESI)m/z,calcd for C17H22N2O4+H+,319.16；found+318.9.
example 8 preparation of tert-butyl (S) - (1- (1, 3-dioxoisoindolin-2-yl) propan-2-yl) (ethyl) carbamate (Compound 5b)
Adding 250.0ml of N, N-dimethylformamide and a compound 4(50.0g) into a reaction bottle, replacing the mixture with nitrogen for three times, cooling to 0 ℃, controlling the temperature to be 0, adding 9.8g of 60% NaH in batches, and keeping the temperature to be 0 ℃ for reacting for 1 hour after the addition is finished. Controlling the temperature to be 0 ℃, dropwise adding 71.6g of bromoethane into the reaction solution, keeping the temperature to be 0 ℃ after adding, reacting for 1 hour, returning the temperature to be 25 ℃, and keeping the temperature to react for 3 hours. 60.4g of methanol, 9.8g of acetic acid and 550.0g of water were successively dropped into the reaction flask, and the reaction solution was extracted 3 times equally with a mixed solution of 172.5g of methyl t-butyl ether and 517.5g of n-heptane. Mixing organic phases, washing with water, drying with anhydrous sodium sulfate, filtering the filtrate with silica gel, eluting with n-heptane-methyl tert-butyl ether (4:1), concentrating under reduced pressure to dryness, pulping with n-heptane at 20 deg.C for 12 hr, cooling to 0 deg.C, and crystallizing for 1 hr. Filtering, vacuum drying filter cake at 25 deg.C to constant weight under reduced pressure to obtain compound 5b as white solid 31.0g, HPLC: 100.0%, yield: 56.8 percent.
The HNMR results of compound 5b are shown in FIG. 10, the LCMS results are shown in FIG. 11, and the specific data are as follows:
1H NMR(400MHz,MeOD),δ＝7.77～7.67(m,4H),δ＝4.55～4.25(m,1H),δ＝3.74～3.71(m,1H),δ＝3.45～3.40(m,1H),δ＝3.04(dd,J＝7.2Hz,86.4Hz,2H).δ＝1.35(d,J＝5.2Hz,3H).δ＝1.05(s,9H),δ＝1.00(t,J＝7.2Hz,3H).
MS(ESI)m/z,calcd for C18H24N2O4-C5H9O2+H+,(M-101+H)+233.40；found 233.1.
example 9 preparation of tert-butyl (S) - (1- (1, 3-dioxoisoindolin-2-yl) propan-2-yl) (propyl) carbamate (Compound 5c)
Nitrogen was replaced three times, and 40.0ml of N, N-dimethylformamide and Compound 4(8.0g) were added to the reaction flask. The temperature is reduced to 0 ℃, and 60 percent NaH 2.1g is added in batches at the temperature of 0 ℃. After the addition, the reaction was carried out at 0 ℃ for 30 minutes. Controlling the temperature to be 0 ℃, dropwise adding 12.9g of n-propyl bromide, keeping the temperature at 0 ℃ for reacting for 1 hour after the addition is finished, heating to 20 ℃, and keeping the temperature for reacting for 1 hour. After the reaction is finished, the temperature of the reaction liquid is reduced to 0 ℃, the temperature is controlled to be 0 ℃, 3.4g of methanol and 3.6g of acetic acid (3.6g) solution in methanol are sequentially dripped, 8.0ml of water is dripped to quench the reaction liquid at the temperature controlled to be below 20 ℃, then the reaction liquid is added into 6.4g of methanol and 88.0ml of water to dilute the solution, ethyl acetate is used for extraction, water is used for washing, anhydrous sodium sulfate is used for drying, the solvent is removed by decompression concentration, and then column chromatography purification is carried out to obtain a compound 5c which is yellow oily matter, 4.4g of the compound, and the yield is 48.3%. HPLC 97.3%.
The HNMR results of compound 5c are shown in fig. 12, and the MS results are shown in fig. 13, with the following data:
1H NMR(400MHz,CDCl3),δ＝7.83(m,2H),δ＝7.69(d,J＝10.8Hz,2H),δ＝4.54～4.24(m,1H),δ＝3.91～3.81(m,1H),δ＝3.59～3.56(m,1H),δ＝3.14～2.82(m,2H).δ＝1.62(m,2H),δ＝1.28(s,9H),δ＝1.20(d,3H).δ＝0.90(t,3H).
MS(ESI)m/z,calcd for C19H26N2O4+H+,347.19；found 346.9.
EXAMPLE 10 preparation of tert-butyl (S) -butyl (1- (1, 3-dioxoisoindolin-2-yl) propan-2-yl) carbamate (Compound 5d)
Nitrogen was replaced three times, and 50.0ml of N, N-dimethylformamide and Compound 4(10.0g) were added to the reaction flask. The temperature is reduced to 0 ℃, and 60 percent NaH 2.7g is added in batches at the temperature of 0 ℃. After the addition, the reaction was carried out at 0 ℃ for 30 minutes. Controlling the temperature to be 0 ℃, dropwise adding 18.1g of bromobutane, keeping the temperature at 0 ℃ for reaction for 1 hour after the addition is finished, and heating to 20 ℃ for reaction for 1 hour. Cooling the reaction liquid to 0 ℃, sequentially dropwise adding methanol (4.2 g) and a methanol (8.0g) solution of acetic acid (4.0g), then dropwise adding water (110.0 ml) at the temperature of below 20 ℃, extracting with ethyl acetate, washing with water, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and purifying by column chromatography to obtain a compound 5d which is a light yellow oily substance with the yield of 43.1 g. HPLC 98.6%.
The HNMR results of compound 5d are shown in fig. 14, and the MS results are shown in fig. 15, with the following data:
1HNMR(400MHz,CDCl3),δ＝7.83～7.72(m,2H),δ＝7.71(d,J＝10.8Hz,2H),δ＝4.54～4.24(m,1H),δ＝3.91～3.81(m,1H),δ＝3.59～3.56(m,1H),δ＝3.14～2.82(m,2H).δ＝1.63(m,2H),δ＝1.43～1.40(m,2H),δ＝1.28(s,9H),δ＝1.20(d,3H).δ＝0.90(t,3H).
MS(ESI)m/z,calcd for C20H28N2O4+H+361.20；found 360.9.
EXAMPLE 11 preparation of tert-butyl (S) -benzyl (1- (1, 3-dioxoisoindol-2-yl) propan-2-yl) carbamate (Compound 5e)
Nitrogen was replaced three times, and 30.0ml of N, N-dimethylformamide and Compound 4(6.0g) were added to the reaction flask. The temperature is reduced to 0 ℃, and 1.6g of 60 percent NaH is added in batches at the temperature of 0 ℃. After the addition, the reaction was carried out at 0 ℃ for 30 minutes. And (3) dropwise adding 13.5g of benzyl bromide at the temperature of 0 ℃, keeping the temperature of 0 ℃ for reaction for 1 hour after the addition is finished, heating to 20 ℃, and keeping the temperature for reaction for 1 hour. After the reaction is finished, the reaction solution is cooled to 0 ℃, methanol solution 2.5g and methanol solution 48.0g of acetic acid 2.4g are sequentially dripped, water is dripped to quench at the temperature of below 20 ℃, ethyl acetate is used for extraction, water washing is carried out, anhydrous sodium sulfate is used for drying, column chromatography purification is carried out after decompression and concentration, and the compound 5e is white solid, 4.7g and the yield is 60.5%. HPLC 87.9%.
The HNMR results of compound 5e are shown in fig. 16, and the MS results are shown in fig. 17, with the following data:
1H NMR(400MHz,CDCl3),δ＝7.80(d,2H),δ＝7.68(d,2H),δ＝7.39～7.12(m,5H),δ＝4.70～4.54(m,1H),δ＝4.50(s,2H)，δ＝4.11～3.96(m,1H),δ＝3.59～3.55(m,1H),δ＝1.35(d,3H).δ＝1.33～1.10(m,9H).
MS(ESI)m/z,calcd for C23H26N2O4+H+,395.19；found 395.0.
example 12 preparation of tert-butyl (S) - (1-aminopropyl-2-yl) (methyl) carbamate (Compound 6a)
90.0g of ethanol and 5a (7.5g) of the compound are added into a reaction bottle, 3.7g of 80% hydrazine hydrate is dropwise added at the temperature of 25 ℃, and after the addition is finished, the temperature is raised to 40 ℃ and the reaction is kept for 12 hours. And (5) finishing the reaction. Adding 17.0ml of methyl tert-butyl ether into the reaction solution, cooling to 0 ℃, preserving heat for 2 hours, filtering, concentrating the filtrate under reduced pressure to remove the solvent, adding 15.0ml of methyl tert-butyl ether, preserving heat for 0 ℃, stirring for 2 hours, filtering, concentrating the filtrate under reduced pressure to remove the solvent, adding 15.0ml of methyl tert-butyl ether, preserving heat for 0 +/-5 ℃, stirring for 2 hours, filtering, concentrating the filtrate under reduced pressure to remove the solvent, and obtaining a compound 6a which is a yellow liquid and has the yield of 67.5 percent and 3.0 g. And GC content is 97.7%.
The HNMR results of compound 6a are shown in fig. 18, and the GCMS results are shown in fig. 19, with the following data:
1H NMR(400MHz,CDCl3),δ＝4.21～4.02(m,1H),δ＝2.70～2.64(m,4H),δ＝1.47(s,9H),δ＝1.33～1.28(m,3H).δ＝1.07(d,3H).
GCMS(EI)m/z,calcd for C9H20N2O2,(M-CH2NH2),158.22；found 158.20.
example 13 preparation of tert-butyl (S) - (1-aminopropyl-2-yl) (ethyl) carbamate (Compound 6b)
To the reaction flask was added 750.0ml of absolute ethanol, compound 5b (50.0g, N). 23.5g of 80% hydrazine hydrate is added dropwise at a controlled temperature of 25 ℃. After the dropwise addition, the system was heated to 40 ℃ and reacted for 3 hours with heat preservation. And (5) finishing the reaction. Adding 100.0ml of methyl tert-butyl ether into the system for dilution, cooling the system to 0 ℃, preserving heat for 2 hours, filtering, and concentrating the filtrate under reduced pressure to be dry. Adding 125.0ml of methyl tert-butyl ether, cooling to 0 ℃, preserving heat, pulping for 2 hours, filtering, and concentrating the filtrate under reduced pressure to dryness. Adding 50.0ml of methyl tert-butyl ether, cooling to 0 ℃, preserving heat, pulping for 2 hours, filtering, and concentrating the filtrate under reduced pressure to dryness to obtain 30.2g of a product compound 6b which is a light yellow oily substance, and performing GC: 92.7%, yield: 99.3 percent.
The HNMR results of compound 6b are shown in fig. 20, and the GCMS results are shown in fig. 21, with the following data:
1H NMR(400MHz,CDCl3),δ＝2.71～2.62(m,2H),δ＝4.32～3.52(m,1H),δ＝3.42～3.15(m,2H),δ＝1.45(s,9H),δ＝1.26～1.22(t,J＝4.2Hz,3H),δ＝1.14～1.11(q,3H).
MS(EI)m/z,calcd for C10H22N2O2,(M),202.30；found 202.20.
example 14 preparation of tert-butyl (S) - (1-aminopropyl-2-yl) (propyl) carbamate (Compound 6c)
70.0g of ethanol and 5c (5.8g) of the compound are added into a reaction bottle, 2.6g of 80% hydrazine hydrate is dropwise added at the temperature of 25 ℃, and after the addition is finished, the temperature is raised to 40 ℃ and the reaction is kept for 12 hours. After the reaction, adding 10.0g of methyl tert-butyl ether into the reaction solution, cooling to 0 ℃, preserving heat and stirring for 2 hours, filtering, concentrating the filtrate under reduced pressure, adding 10.0g of methyl tert-butyl ether, preserving heat and stirring for 2 hours at 0 ℃, filtering, and concentrating the filtrate under reduced pressure to obtain a compound 6c which is a yellow liquid, 3.6g, with the yield of 99.7%. And GC 87.8%.
The HNMR results of compound 6c are shown in fig. 22, and the GCMS results are shown in fig. 23, with the following data:
1H NMR(400MHz,CDCl3),δ＝4.04～3.21(m,1H),δ＝3.03(s,2H),δ＝2.67～2.62(m,2H),δ＝1.62～1.51(m,2H),δ＝1.47(s,9H),δ＝1.43～1.27(m,2H),δ＝1.25(d,J＝3.8Hz,3H),δ＝0.90(t,3H).
MS(EI)m/z,calcd for C11H24N2O2,(M),216.30；found 216.30.
example 15 preparation of tert-butyl (S) - (1-aminopropyl-2-yl) (butyl) carbamate (Compound 6d)
56.4g of ethanol and 5d (4.7g) of compound are added into a reaction bottle, 2.2g of 80% hydrazine hydrate is dropwise added at the temperature of 25 ℃, and after the addition is finished, the temperature is raised to 40 ℃ and the reaction is kept for 12 hours. After the reaction, 7.0g of methyl tert-butyl ether was added to the reaction solution, the temperature was reduced to 0 ℃ and the mixture was stirred for 2 hours under heat preservation, the filtrate was filtered, 8.8g of methyl tert-butyl ether was added to the filtrate under reduced pressure, the mixture was stirred for 2 hours under heat preservation at 0 ℃ and the filtrate was concentrated under reduced pressure, 4.0g of methyl tert-butyl ether was added to the filtrate, the mixture was stirred for 2 hours under heat preservation at 0 ℃ and the filtrate was concentrated under reduced pressure to obtain compound 6d as a pale yellow liquid, 2.9g, with a yield of 96.8%. And GC 88.5%.
The HNMR results of compound 6d are shown in fig. 24, and the GCMS results are shown in fig. 25, with the following data:
1H NMR(400MHz,CDCl3),δ＝3.91～3.05(m,1H),δ＝3.06(s,2H),δ＝2.74～2.66(m,1H),δ＝2.64～2.62(m,1H),δ＝1.58～1.50(m,2H),δ＝1.49(s,9H),δ＝1.30～1.26(m,2H),δ＝1.25(d,J＝6.8Hz,3H),δ＝0.93(t,J＝7.6Hz,3H).
MS(EI)m/z,calcd for C12H26N2O2,230.35；found 230.30.
EXAMPLE 16 preparation of tert-butyl (S) - (1-aminopropyl-2-yl) (benzyl) carbamate (Compound 6e)
74.4g of ethanol and 5e (6.2g) are added into a reaction bottle, 2.9g of 80% hydrazine hydrate is dropwise added at the temperature of 25 ℃, and after the addition is finished, the temperature is raised to 40 ℃ and the reaction is kept for 12 hours. After the reaction, 9.2g of methyl tert-butyl ether was added to the reaction solution, the temperature was reduced to 0 ℃ and the mixture was stirred for 2 hours under heat preservation, the mixture was filtered, the filtrate was concentrated under reduced pressure, 38.0g of methyl tert-butyl ether was added to the mixture, the mixture was stirred for 2 hours under heat preservation at 0 ℃ and the filtrate was concentrated under reduced pressure, 18.0g of methyl tert-butyl ether was added to the mixture, the mixture was stirred for 2 hours under heat preservation at 0 ℃ and the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 6e as a pale yellow liquid, 3.0g, with a yield of 72.3%. And GC 92.3%.
The HNMR results of compound 6e are shown in fig. 26, and the GCMS results are shown in fig. 27, with the following data:
1H NMR(400MHz,CDCl3),δ＝7.36～7.21(m,5H),δ＝4.35(s,2H)，δ＝4.15～3.45(m,1H),δ＝2.77～2.72(m,1H),δ＝2.62～2.59(m,1H),δ＝1.42(s,9H).δ＝1.07(d,2H).
MS(EI)m/z,calcd for C15H24N2O2,(M)264.37；found 264.15.
example 17 preparation of tert-butyl (S) - (1-aminopropyl-2-yl) (methyl) carbamate oxalate (Compound 7a)
To the reaction flask were added compound 6a (3.3g) and methyl t-butyl ether (9.0 ml), and the mixture was stirred to dissolve completely. A methanol (14.0ml) solution of oxalic acid dihydrate (2.2g) was added dropwise to the reaction flask while controlling the temperature at 20 ℃. After the dropwise addition, the temperature was controlled at 20 ℃ to react for 2 hours. Cooling the reaction solution to 0 ℃, carrying out heat preservation and crystallization for 2 hours, filtering, washing a filter cake with methyl tert-butyl ether, and drying at 45 ℃ under reduced pressure to obtain a compound 7a, 3.3g, HPLC: 99.9%, yield: 67.7 percent.
The HNMR results for compound 7a are shown in fig. 28, with the following specific data:
1H NMR(400MHz,DMSO),δ＝7.76(s,3H),δ＝4.26～4.15(m,1H),δ＝2.96～2.91(m,1H),δ＝2.84～2.80(m,1H)，δ＝2.66(s,3H),δ＝1.41(s,9H),δ＝1.08(d,J＝6.8Hz,2H).
EXAMPLE 18 preparation of tert-butyl (S) - (1-aminopropyl-2-yl) (ethyl) carbamate oxalate (Compound 7b)
To the reaction flask were added compound 6b (110.0g), methyl t-butyl ether 860.0 ml. A solution of oxalic acid dihydrate (68.5g) in methanol (660.0ml) was added dropwise to the reaction kettle while controlling the temperature at 25 ℃. After the dropwise addition, the temperature was controlled at 25 ℃ to react for 2 hours. Filtering, and leaching filter cake with methyl tert-butyl ether. The filter cake is pulped for 1 hour by 440.0ml of absolute ethyl alcohol at the temperature of 25 ℃, cooled to 5 ℃ and crystallized for 1 hour under the condition of heat preservation. Filtration, cake rinsing with methyl tert-butyl ether and drying at 45 ℃ under reduced pressure gave compound 7b, 100.1g, HPLC: 99.8%, yield: 63.0 percent.
The HNMR results of compound 7b are shown in fig. 29, with the following specific data:
1H NMR(400MHz,DMSO),δ＝5.97(s,2H),δ＝4.04～3.82(m,1H),δ＝3.11～3.01(m,2H),δ＝2.99～2.96(m,1H),δ＝2.88～2.83(m,1H),δ＝1.41(s,9H),δ＝1.17(d,J＝6.8Hz,3H),δ＝1.05(t,J＝6.8Hz,3H).
example 19 preparation of tert-butyl (S) - (1-aminopropyl-2-yl) (propyl) carbamate oxalate (Compound 7c)
To a reaction flask were added compound 6c (3.6g), methyl t-butyl ether (10.0ml), and methanol (6.0 ml), and the mixture was stirred to dissolve completely. A methanol (16.0ml) solution of oxalic acid dihydrate (2.1g) was added dropwise to the reaction flask while controlling the temperature at 20 ℃. After the dropwise addition, the temperature was controlled at 20 ℃ to react for 2 hours. The reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was slurried with 10.0ml of methyl t-butyl ether at a controlled temperature of 20 ℃ for 2 hours. Filtration and drying of the filter cake under reduced pressure at 45 ℃ gave compound 7c as a white solid, 1.5g, HPLC: 99.9%, yield: 29.0 percent.
The HNMR results of compound 7c are shown in fig. 30, and the MS results are shown in fig. 31, with the following data:
1H NMR(400MHz,DMSO),δ＝7.73(s,2H),δ＝3.93～3.76(m,1H),δ＝3.08～2.88(m,3H),δ＝2.86～2.85(m,1H),δ＝1.49～1.44(m,2H),δ＝1.41(s,9H).δ＝1.18(d,J＝6.8Hz,3H),δ＝0.84(t,J＝7.2Hz,3H),
MS(ESI)m/z,freebase calcd for C11H24N2O2+H+,217.18.；
found.217.4.
EXAMPLE 20 preparation of tert-butyl (S) - (1-aminopropyl-2-yl) (butyl) carbamate oxalate (Compound 7d)
To a reaction flask were added compound 6d (2.7g), methyl t-butyl ether (8.0 ml), and methanol (8.0 ml), and the mixture was stirred to dissolve completely. A methanol (10.0ml) solution of oxalic acid dihydrate (1.5g) was added dropwise to the reaction flask while controlling the temperature at 20 ℃. After the dropwise addition, the temperature was controlled at 20 ℃ to react for 2 hours. The reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was slurried with 20.0ml of methyl t-butyl ether at a controlled temperature of 20 ℃ for 2 hours. Filtration and drying of the filter cake under reduced pressure at 45 ℃ gave compound 7d, 2.0g, HPLC: 99.8%, yield: 53.2 percent.
The HNMR results of compound 7d are shown in fig. 32, and the MS results are shown in fig. 33, with the following data:
1H NMR(400MHz,CDCl3),freebaseδ＝4.08～3.75(m,1H),δ＝3.28～3.09(m,6H),δ＝1.50～1.48(m,2H),δ＝1.43(s,9H),δ＝1.32～1.27(m,2H),δ＝1.25～1.24(m,3H),δ＝0.89(t,J＝7.2Hz,3H).
MS(ESI)m/z,freebase calcd for C12H26N2O2+H+231.20；found 231.3.
example 21 preparation of tert-butyl (S) - (1-aminopropyl-2-yl) (benzyl) carbamate oxalate (Compound 7e)
To a reaction flask were added compound 6e (3.0g), methyl t-butyl ether 9.0ml, and methanol 6.0ml, and the mixture was stirred to dissolve completely. A methanol (10.0ml) solution of oxalic acid dihydrate (1.4g) was added dropwise to the reaction flask while controlling the temperature at 20 ℃. After the dropwise addition, the temperature was controlled at 20 ℃ to react for 2 hours. The reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was slurried with 20.0ml of methyl t-butyl ether at a controlled temperature of 20 ℃ for 2 hours. Filtration and drying of the filter cake under reduced pressure at 45 ℃ gave compound 7e, HPLC: 98.3%, yield: 82.1 percent.
The HNMR results of compound 7e are shown in fig. 34, and the MS results are shown in fig. 35, with the following data:
1H NMR(400MHz,DMSO),δ＝8.53(s,2H),δ＝7.36～7.23(m,5H),δ＝4.59～4.42(m,1H),δ＝4.25～3.84(m,2H),δ＝3.08～3.01(m,1H),δ＝2.88～2.83(m,1H),δ＝1.41(s,9H),δ＝1.00(d,2H).
MS(ESI)m/z,freebase calcd for C15H24N2O2+H+265.18；found 265.4.
the above description is only for the purpose of illustrating the preferred embodiments of the present invention and should not be taken as limiting the invention, so that any modifications, equivalents, improvements and the like, which are within the spirit and principle of the present invention, should be included in the scope of the present invention.
Claims (10)
1. A method for preparing N-alkylated diamine is characterized in that: the synthetic route is as follows:
wherein n is 1; r1X is an acyl halide, R2X is a halogenated alkane, X is Cl, Br or I, R1Is Ts or Ms, R2Is methyl, ethyl, propyl, butyl or benzyl; the Acid is one or more of formic Acid, acetic Acid, propionic Acid, citric Acid, oxalic Acid, hydrochloric Acid and sulfuric Acid.
The method specifically comprises the following steps:
s1: amino alkanol is used as a starting material, and amino-protected amino alkanol is prepared through amidation:
s2: hydroxyl protection is carried out on amino alkanol protected by amino through acyl halide, and then the amino protected diamine is prepared through substitution of phthalimide potassium salt;
or S2: substituting amino alkanol protected by amino with phthalimide to prepare diamine protected by amino;
s3: and (4) adding halogenated alkane or halogenated aromatic hydrocarbon into the diamine with the amino protection obtained in the step (S2) in the presence of sodium hydride to prepare N-substituted amide, performing hydrazinolysis to obtain N-protected and substituted diamine, and salifying to obtain the diamine.
2. The process for the preparation of an N-alkylated diamine according to claim 1, characterized in that: the step S1 specifically includes the following steps:
reacting the compound shown in the formula 1 with di-tert-butyl dicarbonate in the presence of an organic base by using a solvent A as a medium and controlling the temperature to be 0-30 ℃, concentrating the filtrate under reduced pressure until the reaction is finished, adding a solvent B, pulping, controlling the temperature to be 0-30 ℃, stirring, filtering, drying and concentrating the filter cake under reduced pressure to obtain the compound shown in the formula 2.
3. The process for the preparation of an N-alkylated diamine according to claim 2, characterized in that: the solvent A in the step S1 is dichloromethane; preferably, the volume weight ratio of the solvent A to the compound of the formula 1 is 3-30 v, and more preferably 4 v; preferably, the molar ratio of the compound of formula 1, di-tert-butyl dicarbonate and organic base is 1: (1-2): (1-3) more preferably 1: 1.05: 1.2; preferably, the organic base is triethylamine; preferably, the reaction temperature is 15-25 ℃; preferably, the solvent B for pulping is petroleum ether; preferably, the volume weight ratio of the pulping solvent to the compound of formula 1 is 2-5 v, and more preferably 2 v.
4. The process for the preparation of an N-alkylated diamine according to claim 1, characterized in that: the step S2 specifically includes the following steps:
s21: reacting a compound shown in a formula 2 with acyl halide in the presence of organic alkali by using 4-dimethylaminopyridine as a catalyst and a solvent C as a medium at a temperature of 0-30 ℃, filtering insoluble substances after the reaction is finished, washing the filtrate with an aqueous solution of acid and an aqueous solution of saturated sodium bicarbonate in sequence, or washing with water, drying, and concentrating under reduced pressure to obtain a compound shown in a formula 3;
s22: and (2) reacting the compound of the formula 3 with phthalimide potassium salt in a polar aprotic solvent X at the temperature of 30-50 ℃, cooling to 0-20 ℃ after the reaction is finished, filtering out insoluble substances, dropwise adding water into the filtrate for crystallization, filtering to obtain a filter cake, and drying to obtain the compound of the formula 4.
5. The process according to claim 3 for the preparation of N-alkylated diamines, characterized in that: in step S21: preferably, solvent C is dichloromethane; preferably, the volume weight ratio of the solvent C to the compound of the formula 2 is 5-20 v, and more preferably 5-8 v; preferably, the compound of formula 2, acyl halide, organic base and 4-dimethylaminopyridine are in a molar ratio of 1: (1-2): (1-3): (0.01 to 0.2); more preferably 1: (1.05-1.1): 1.5: 0.05; preferably, the organic base is triethylamine, and preferably, the reaction temperature is 0-10 ℃.
6. The process according to claim 3 for the preparation of N-alkylated diamines, characterized in that: in step S22: the polar aprotic solvent X is DMF; preferably, the volume weight ratio of the polar aprotic solvent X to the compound of formula 3 is 5-15 v, more preferably 10 v; the molar ratio of the compound of formula 3 to the phthalimide potassium salt is 1: 1.0-1.5, more preferably 1: 1.1; preferably, the reaction temperature is 35-50 ℃, and more preferably 40-45 ℃; preferably, the volume weight ratio of the water to the compound of the formula 3 is 5-15 v; more preferably 10 v; preferably, the volume weight ratio of the pulping water to the compound of the formula 3 is 5-15 v, and more preferably 10 v; preferably, the drying temperature of the compound of formula 3 is 40-55 ℃, more preferably 40-45 ℃.
7. The process for the preparation of an N-alkylated diamine according to claim 1, characterized in that: the step S2 specifically includes the following steps:
dropwise adding diisopropyl azodicarboxylate in a solvent D of the compound shown in the formula 2 and phthalimide in the presence of triphenylphosphine, controlling the temperature to be 15-30 ℃ to carry out Mitsunobu reaction, after the reaction is finished, carrying out reduced pressure concentration to remove the solvent, adding a solvent E to carry out pulping, filtering out insoluble substances, carrying out reduced pressure concentration on the filtrate to dryness, and carrying out column chromatography purification on the obtained crude product to obtain the compound shown in the formula 4.
8. The process according to claim 5 for the preparation of N-alkylated diamines, characterized in that: the solvent D is tetrahydrofuran; preferably, the volume weight ratio of the solvent D to the compound of the formula 2 is 5-15 v; more preferably the ratio is 10 v; preferably, the molar ratio of the compound of formula 2, phthalimide, triphenylphosphine, and diisopropyl azodicarboxylate is 1: (1.0-1.5): (1.0-1.5): (1.0 to 1.5), more preferably 1: 1: 1: 1; preferably, the reaction temperature is 20-25 ℃; preferably, the pulping solvent E is methyl tert-butyl ether; preferably, the volume weight ratio of the pulping solvent E to the compound of the formula 2 is 5-10 v, and more preferably 8 v.
9. The process for the preparation of an N-alkylated diamine according to claim 1, characterized in that: the step S3 specifically includes the following steps:
s31: the compound of formula 4 is firstly reacted with sodium hydride in a polar aprotic solvent Y at the temperature of-10-15 ℃, and then R is dripped at the temperature of-10-15 DEG C2X, after the dropwise addition, heating to 15-30 ℃, carrying out heat preservation reaction, after the reaction is finished, sequentially dropwise adding a quenching solvent, carrying out acid quenching, adding water for dilution, extracting with a solvent F, and carrying out column chromatography purification to obtain a compound shown in the formula 5;
s32: reacting the compound shown in the formula 5 with hydrazine hydrate in a solvent G at 15-35 ℃, after the reaction is finished, adding a solvent H for dilution, cooling to-5-15 ℃, filtering out insoluble substances, concentrating the filtrate under reduced pressure to dryness, adding a solvent I for pulping, filtering out the insoluble substances, and repeating for multiple times until no solid exists in the concentrate to obtain the compound shown in the formula 6;
s33: dissolving the compound shown in the formula 6 into a solvent J or a mixture of the solvent J and a solvent K, dropwise adding a solution of an acid solvent L at the temperature of 15-35 ℃, controlling the temperature of 15-35 ℃ for reaction, cooling to-5-10 ℃ for crystallization after the reaction is finished, filtering, pulping and purifying a filter cake by using alcohol, and drying to obtain a compound 7, or concentrating a reaction solution under reduced pressure until the reaction solution is dry, pulping a concentrated residue by using a solvent M, filtering, and drying to obtain the compound 7.
10. The process for the preparation of an N-alkylated diamine according to claim 7, characterized in that: in step S31: the polar aprotic solvent Y is DMF; preferably, the volume weight ratio of the polar aprotic solvent Y to the compound of formula 4 is 5-10 v, and more preferably 6-7 v; preferably, the molar ratio of the compound of formula 4 to sodium hydride is 1: (1.0 to 3.0), more preferably 1: (1.5-2.0); preferably, R2-X is methyl bromide, ethyl bromide, propyl bromide, butyl bromide, benzyl bromide; preferably, sodium hydride and R2-the feeding temperature of X is-5 to 5 ℃; preferably, the reaction temperature is 15-25 ℃; preferably, the quenching temperature is-5 to 25 ℃; more preferably-5 to 20 ℃; preferably, the quenching solvent is an alcohol, more preferably methanol; preferably, the acid for quenching is one or more of formic acid, acetic acid, propionic acid, citric acid, oxalic acid, hydrochloric acid and sulfuric acid, and more preferably acetic acid; preferably, the volume weight ratio of the dilution water to the compound of the formula 4 is 1-3 v, and more preferably 1 v; preferably, the solvent F for extraction is one or more of ethyl acetate, methyl tert-butyl ether, petroleum ether and n-heptane; preferably, in step S32: the solvent G is one or more of DMF, DMSO, methanol, ethanol, propanol, butanol and isopropanol, preferably ethanol; preferably, the molar ratio of the compound of formula 5 to hydrazine hydrate is 1: (1.0 to 4.0), more preferably 1: 2.5; preferably, the reaction temperature is 20-30 ℃; preferably, the solvent for dilution H is methyl tert-butyl ether; preferably, the volume weight ratio of the solvent H for dilution to the compound shown in the formula 5 is 2-5 v; the volume weight ratio of the solvent I for pulping to the compound shown in the formula 5 is 1-5 v; preferably, in step S33: the solvent J for dissolving the compound of the formula 6 is one or more of ethyl acetate, methyl tert-butyl ether and dichloromethane, and is dissolvedThe agent K is one or more of methanol, ethanol and propanol, preferably, the solvent J for dissolving the compound of the formula 6 is methyl tert-butyl ether, and the solvent K is methanol; preferably, the acid used for salt formation is oxalic acid; preferably, the solvent M for pulping is one of ethanol and methyl tert-butyl ether.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111632053.1A CN114230490A (en) | 2021-12-28 | 2021-12-28 | Preparation method of N-alkylated diamine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111632053.1A CN114230490A (en) | 2021-12-28 | 2021-12-28 | Preparation method of N-alkylated diamine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN114230490A true CN114230490A (en) | 2022-03-25 |
Family
ID=80743927
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111632053.1A Pending CN114230490A (en) | 2021-12-28 | 2021-12-28 | Preparation method of N-alkylated diamine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114230490A (en) |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102958918A (en) * | 2010-06-30 | 2013-03-06 | 富士胶片株式会社 | Novel nicotinamide derivatives or salts thereof |
| JP2013136535A (en) * | 2011-12-28 | 2013-07-11 | Fujifilm Corp | Novel nicotinamide derivative or salt thereof |
| CN103664959A (en) * | 2013-12-12 | 2014-03-26 | 惠州市莱佛士制药技术有限公司 | Preparation method of five-membered bicyclic guanidine compounds |
| WO2017178343A1 (en) * | 2016-04-15 | 2017-10-19 | Boehringer Ingelheim International Gmbh | Novel n-[(pyrimidinylamino)propanyl]-and n-[(pyridinylamino)propanyl]arylcarboxamides |
| WO2017178341A1 (en) * | 2016-04-15 | 2017-10-19 | Boehringer Ingelheim International Gmbh | Novel n-[(pyrimidinylamino)propanyl]-and n [(pyrazinylamino)propanyl]arylcarboxamides |
| US20190092738A1 (en) * | 2016-03-22 | 2019-03-28 | Merck Sharp & Dohme Corp. | N1-phenylpropane-1,2-diamine compounds with selective activity in voltage-gated sodium channels |
| CN110997660A (en) * | 2017-07-31 | 2020-04-10 | 勃林格殷格翰国际有限公司 | Novel N- [ (pyrimidinylamino) propyl ] -, N- [ (pyridinylamino) propyl ] -and N- [ (pyrazinylamino) propyl ] arylcarboxamides |
| CN111132975A (en) * | 2017-09-28 | 2020-05-08 | 勃林格殷格翰国际有限公司 | Novel N- (2, 2-difluoroethyl) -N- [ (pyrimidinylamino) propyl ] arylcarboxamides |
-
2021
- 2021-12-28 CN CN202111632053.1A patent/CN114230490A/en active Pending
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102958918A (en) * | 2010-06-30 | 2013-03-06 | 富士胶片株式会社 | Novel nicotinamide derivatives or salts thereof |
| JP2013136535A (en) * | 2011-12-28 | 2013-07-11 | Fujifilm Corp | Novel nicotinamide derivative or salt thereof |
| CN103664959A (en) * | 2013-12-12 | 2014-03-26 | 惠州市莱佛士制药技术有限公司 | Preparation method of five-membered bicyclic guanidine compounds |
| US20190092738A1 (en) * | 2016-03-22 | 2019-03-28 | Merck Sharp & Dohme Corp. | N1-phenylpropane-1,2-diamine compounds with selective activity in voltage-gated sodium channels |
| WO2017178343A1 (en) * | 2016-04-15 | 2017-10-19 | Boehringer Ingelheim International Gmbh | Novel n-[(pyrimidinylamino)propanyl]-and n-[(pyridinylamino)propanyl]arylcarboxamides |
| WO2017178341A1 (en) * | 2016-04-15 | 2017-10-19 | Boehringer Ingelheim International Gmbh | Novel n-[(pyrimidinylamino)propanyl]-and n [(pyrazinylamino)propanyl]arylcarboxamides |
| CN110997660A (en) * | 2017-07-31 | 2020-04-10 | 勃林格殷格翰国际有限公司 | Novel N- [ (pyrimidinylamino) propyl ] -, N- [ (pyridinylamino) propyl ] -and N- [ (pyrazinylamino) propyl ] arylcarboxamides |
| CN111132975A (en) * | 2017-09-28 | 2020-05-08 | 勃林格殷格翰国际有限公司 | Novel N- (2, 2-difluoroethyl) -N- [ (pyrimidinylamino) propyl ] arylcarboxamides |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP6061158B2 (en) | Synthesis intermediate of 6- (7-((1-aminocyclopropyl) methoxy) -6-methoxyquinolin-4-yloxy) -N-methyl-1-naphthamide, or a pharmaceutically acceptable salt thereof, and its use | |
| EP3318551B1 (en) | Method for producing pyrrole compound | |
| JP2013067625A (en) | Method for manufacturing 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-n-methylpyridine-2-carboxamide | |
| KR20170036677A (en) | Process for the preparation of 3-(3-chloro-1h-pyrazol-1-yl)pyridine | |
| JP6268093B2 (en) | Process for producing fused heterocyclic derivative and production intermediate thereof | |
| CN104177292A (en) | Method for industrial production of sorafenib tosylate polymorphic form I | |
| CN105541705B (en) | A kind of synthetic method of flupirtine maleate compound | |
| CN114230490A (en) | Preparation method of N-alkylated diamine | |
| TWI541235B (en) | Process of preparing a quinazoline derivative | |
| TWI511958B (en) | Process for production of aminoadamantanecarbamate derivative | |
| CN103958472A (en) | Aryl or N-heteroaryl substituted methanesulfonamide derivatives as vanilloid receptor ligands | |
| CN109232254B (en) | Synthesis method and application of compound | |
| JP2023548914A (en) | Pyrrolinone compounds and their synthesis method | |
| JP3213576B2 (en) | Substituted pyridine | |
| CN110204490B (en) | Preparation method of disubstituted 4-chloroquinoline-3-carbonitrile derivative and bosutinib | |
| CN112624968B (en) | Synthetic method of 5-amino-3-cyanopyridine methyl formate hydrochloride | |
| CN114262293B (en) | Preparation method of 2-amino-3-bromopyridine | |
| JP7315805B1 (en) | Method for producing intermediate for synthesis of monocyclic pyridine derivative | |
| EP3906235B1 (en) | Method for preparing sulfonamides drugs | |
| JP2003212861A (en) | Method for producing pyrimidinyl alcohol derivative and synthetic intermediate thereof | |
| CN110590641B (en) | Green preparation method of 3-hydroxyisoindole-1-ketone series compounds | |
| CN109608368B (en) | Synthesis and resolution method of N- [4- (1-aminoethyl) -2, 6-difluorophenyl ] methanesulfonamide | |
| EP4289828A1 (en) | Method for the preparation of a 3,6-dihydro-2h-1,3,4-oxadiazin-2-one | |
| CN110621660A (en) | Purification method of ropinirole hydrochloride | |
| EP3287448A1 (en) | Method for producing dicarboxylic acid compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |