CN104829492A - Preparation method of trans-N-Boc-1,3-cyclobutanediamine - Google Patents

Preparation method of trans-N-Boc-1,3-cyclobutanediamine Download PDF

Info

Publication number
CN104829492A
CN104829492A CN201510224945.6A CN201510224945A CN104829492A CN 104829492 A CN104829492 A CN 104829492A CN 201510224945 A CN201510224945 A CN 201510224945A CN 104829492 A CN104829492 A CN 104829492A
Authority
CN
China
Prior art keywords
compound
boc
trans
preparation
ethyl acetate
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
Application number
CN201510224945.6A
Other languages
Chinese (zh)
Inventor
刘雅莉
袁文蛟
刘晓磊
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hebei University of Technology
Original Assignee
Hebei University of Technology
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Hebei University of Technology filed Critical Hebei University of Technology
Priority to CN201510224945.6A priority Critical patent/CN104829492A/en
Publication of CN104829492A publication Critical patent/CN104829492A/en
Pending legal-status Critical Current

Links

Abstract

The present invention is a preparation method of trans-N-Boc-1,3-cyclobutanediamine. The method uses easily available 3-methylene-cyclobutyl carbonitrile as a starting material, and conducts 7 steps of reaction including hydrolysis, Curtius rearrangement, oxicracking, reduction, methanesulfonyl chloride protection, substitution and hydrogenation. The invention has the technical characteristics of short reaction step, total yield of up to 49.8% and high purity of the final product (>99%) (the prior art comprises at least 8 steps, and the highest total yield is up to 19%); and N-Boc-1,3-cyclobutanediamine with transconfiguration is selectively synthesized. From the perspective of chemistry, the invention has the characteristics of few steps, simple reaction, high yield, feasible purification method of intermediate and simple operation, and has wide prospect in business application.

Description

A kind of preparation method of trans N-Boc-1,3-ring butanediamine
Technical field
The present invention relates to a kind of high efficiency preparation method of trans N-Boc-1,3-ring butanediamine compounds, belong to the technology of preparing of pharmaceutical intermediate.
Background technology
1,3-ring butanediamine, as important molecular skeleton, is widely used in novel drugs molecular designing.As having 1,3-ring butanediamine derivative CDK1 (Engelhardt, H. of kinase inhibitory activity; WO2007115999), CDK2, GSK-3 (Ahlijanian, M.K.; And PLK (Stadtmueller, H. WO0210141); WO 2006021544); Phosphodiesterase inhibitor PDE4 (Kuang, R.; WO 2005116009) and glycine transport enzyme inhibitors GLyT-1 (Lowe, J.A.; WO 2008065500).In addition, the derivative being skeleton with 1,3-ring butanediamine is also designed to sterilant and removes mite agent.As the basic raw material of synthesis 1,3-ring butanediamine derivative, the synthetic method report of trans N-Boc-1,3-ring butanediamine is less.Wherein preparation method (Avram, M.; Chem.Ber, 90,1424 – 1427,1957) be that starting raw material is obtained by reacting the suitable back mixing compound of 1,3-ring butanediamine through 10 Walk with bromopropylene oxide, this method steps is long, yield is low, and can not obtain single cis or trans product.Another kind method (Radchenko, D.S.; Journal of Organic Chemistry, 75 (17), 5941 – 5952,2010) be obtained by reacting trans N-Boc-1,3-ring butanediamine through 8 Walk, total recovery only has 19%, and reaction raw materials is not easy to obtain.
Be difficult to commercialization in view of the method steps of existing preparation trans N-Boc-1,3-ring butanediamine is long, yield is low, the invention provides the method that one is easy to business-like efficient preparation trans N-Boc-1,3-ring butanediamine.
Summary of the invention
The object of the invention is the deficiency for current techniques, provide a kind of preparation method of trans N-Boc-1,3-ring butanediamine, the method is trans N-Boc-1, the 3-ring butanediamine of single protection by simple, reliable 7 Walk chemical reactive synthesis.Synthetic route design is ingenious, efficiently builds cis-configuration by means of only simple reductive agent 3-sec-butyl lithium borohydride (L-selectride), and the substitution reaction then through classical SN2 type obtains trans N-Boc-1,3-ring butanediamine.Mild condition of the present invention, yield is high, and purifying is simple, is easy to extensive preparation.
Technical scheme of the present invention is:
A kind of preparation method of trans N-Boc-1,3-ring butanediamine, is characterized by and comprise the following steps:
Step one), 3-methylene radical cyclobutyl formonitrile HCN is dissolved in the mixing solutions of second alcohol and water, then adds potassium hydroxide, after back flow reaction 1-5 hour, with the pH=2 of hydrochloric acid conditioning solution; Filtered by the white solid of separating out, washing, drying obtains compound 2;
Wherein, material mol ratio is 3-methylene radical cyclobutyl formonitrile HCN: potassium hydroxide=1:1 ~ 10; Volume ratio is ethanol: water=1 ~ 5:5 ~ 1;
Step 2) successively alkali, trinitride and compound 2 is dissolved in the trimethyl carbinol at 83 DEG C, then reflux 0.5-12 hour; To go out reaction with shrend, when solution being concentrated into 1/5 of original volume, in surplus solution, add ethyl acetate; Organic phase is through washing, and saturated common salt is washed, dry, obtains compound 3 after being spin-dried for;
Wherein, material mol ratio is alkali: triazo-compound: compound 2=1 ~ 3:1 ~ 3:1; Every mole compound 2 adds 2L ethyl acetate;
Step 3) compound 3 is dissolved in solvent, then add oxygenant; After question response is complete, after extraction, drying and distillation, obtain compound 4; Mol ratio is compound 3: oxygenant=1:1 ~ 10;
Wherein, solvent is the mixing solutions of methylene dichloride and methyl alcohol, and volume ratio is (10 ~ 1): (1 ~ 10);
Step 4) at-78 DEG C-0 DEG C, reductive agent is added in the tetrahydrofuran solution of compound 4, drip rear room temperature and continue again to stir 0.5-12 hour; After will reacting cancellation, stir after then adding water and ethyl acetate successively in reaction solution, organic phase is through washing, and saturated common salt is washed, dry, obtains compound 5 after being spin-dried for;
Wherein, mol ratio is compound 4: reductive agent=1:1 ~ 10; Volume ratio is tetrahydrofuran (THF): water: ethyl acetate=1 ~ 10:1 ~ 10:1 ~ 10;
Step 5) compound 5 and triethylamine are dissolved in methylene dichloride, at-78 DEG C ~ 5 DEG C, Methanesulfonyl chloride is dropped in above-mentioned reaction solution; After dropwising, this reaction solution is after stirring at room temperature 0.5-12 hour, and this organic phase is through washing, and saturated common salt is washed, dry, obtains white solid and compound 6 after being spin-dried for;
Wherein, mol ratio is compound 5: triethylamine: Methanesulfonyl chloride=1:1 ~ 3:1 ~ 3;
Step 6) compound 6 and sodium azide are dissolved in solvent, this reaction solution adds ethyl acetate and water after stirring 0.5-12 hour at 5 DEG C ~ 180 DEG C; Organic phase is through washing, and saturated common salt is washed, dry, obtains white solid and compound 7 after being spin-dried for;
Wherein, mol ratio is compound 6: sodium azide=1:1 ~ 10; Every g of compound 6 adds ethyl acetate 13 ~ 18mL, volume ratio ethyl acetate: water=1:1;
Step 7) in hydriding reactor, Pd/C is added in the ethanolic soln of compound 7, at 15-150Psi hydrogen, stirring reaction is 0.5 ~ 1 hour at 5 DEG C ~ 100 DEG C, then by after Pd/C filtering, concentrate and obtain light yellow liquid, after rectifying, obtain trans N-Boc-1,3-ring butanediamine;
Wherein, mass ratio is compound 7:Pd/C=1:0.1% ~ 10%.
Step 2) described alkali is the one to multiple kind of triethylamine, pyridine, DIPEA, salt of wormwood, sodium carbonate.
Step 2) described triazo-compound is NaN 3, KN 3, Ca (N 3) 2, TMSN 3with diphenyl phosphate azide (DPPA).
Step 3) described oxygenant is one to multiple kind in ruthenium trichloride, perosmic anhydride, sodium periodate, peroxy tert-butyl alcohol, hydrogen peroxide, chromic oxide, potassium permanganate, oxygen and ozone.
Step 4) described reductive agent is lithium borohydride, sodium borohydride and 3-sec-butyl lithium borohydride (L-selectride).
Step 6) described solvent is the one to multiple kind of toluene, hexanaphthene, chloroform, tetracol phenixin, acetonitrile, DMF, dimethyl sulfoxide (DMSO), tetramethylene sulfone and tetrahydrofuran (THF).Wherein temperature of reaction is preferably 110 DEG C.
Beneficial effect of the present invention is: with the 3-methylene radical cyclobutyl formonitrile HCN be easy to get for starting raw material, through hydrolysis, Curtius resets, oxicracking, reduction, Methanesulfonyl chloride is protected, replace and hydro-reduction, step only needs short 7 Walk (in current techniques the shortest step 8 Walk), total recovery 49.8% (in current techniques the highest total recovery 19%) and purity >99% are all far away higher than current techniques (see background introduction), simply reacted by 7 Walk, synthesize the N-Boc-1 with transconfiguration cleverly, 3-ring butanediamine is core content of the present invention.Therefore, the present invention be chemically angle to emphasize to have step short, reaction is simple, and the features such as yield is high, and purification of intermediate method is simple, easy and simple to handle, have wide commercial application prospect.
Embodiment
Technical spirit of the present invention and invention advantage fully can be understood in order to make the public; applicant will describe in detail the specific embodiment of the present invention below; but applicant is not the restriction to technical scheme to the description of embodiment, any changing in the form rather than substance according to the present invention's design all should be considered as protection scope of the present invention.
Principle of the present invention is as shown in following reaction formula:
Embodiment 1
Step one:
Potassium hydroxide (2408g, 43mol) is added in the ethanol (5L) and water (5L) solution of 3-methylene radical cyclobutyl formonitrile HCN (400g, 4.3mol).Reflux after 2 hours, with the pH=2 of concentrated hydrochloric acid regulator solution.Filtered by the white solid of separating out, washing, drying obtains compound 2 (450g), yield 93.4%.Hydrogen nuclear magnetic resonance spectrum (400MHz, CDCl 3) δ: 2.67-3.56 (5H, m), 4.68-4.98 (2H, m), 10.73 (1H, br, s), illustrate to obtain target product.Its molecular weight is 112.13.
Step 2:
Successively by triethylamine (590g, 5.9mol), diphenyl phosphate azide (DPPA) (1273g, 4.7mol) be dissolved in the trimethyl carbinol (8L) with compound 2 (440g, 3.9mol) reflux temperature 83 DEG C, then reflux 12 hours.With water (2L) cancellation reaction, after solution being concentrated into 1/5 of original volume, in surplus solution, add ethyl acetate (7.8L).Organic phase is through washing, and saturated common salt is washed, dry, obtains white solid and compound 3 (649g), yield 91% after being spin-dried for.Hydrogen nuclear magnetic resonance spectrum (400MHz, CDCl 3) δ: 1.36 (9H, s), 2.56-2.65 (2H, m), 2.97-3.18 (2H, m), 4.05-4.23 (1H, m), 4.05-4.23 (1H, m), 4.85 (1H, br s), 5.08 (2H, m), target product is described to obtain.Its molecular weight is 183.25.
Step 3:
Compound 3 (800g, 4.4mol) is dissolved in methylene dichloride (12L) and methyl alcohol (3L).At-78 DEG C, pass into ozone gas, until solution becomes blueness (illustrating that in reaction solution, compound 3 disappears, and is all converted into compound 4) from light yellow.Dimethyl sulphide (2L) joins in reaction solution, is then naturally warming up to room temperature.Solvent steams and removes by underpressure distillation, obtains white solid and compound 4 (706.4g), yield 88.3%.Hydrogen nuclear magnetic resonance spectrum (400MHz, CDCl 3) δ: 1.40 (9H, s), 2.97-3.04 (2H, m), 3.26-3.33 (2H, m), 4.18-4.37 (1H, m), illustrate to obtain target product.Its molecular weight is 185.22.
Step 4:
At-20 DEG C, slowly by 3-sec-butyl lithium borohydride (L-selectride) (2700mL, 1M, 2.7mol) drop to compound 4 (420g, in tetrahydrofuran (THF) (10L) solution 2.3mol), after dripping, at room temperature continue stirring 1 hour.After saturated aqueous ammonium chloride (2.5L) will react cancellation, in reaction solution, add water (10L) and ethyl acetate (10L) successively.Organic phase is through washing, and saturated common salt is washed, dry, obtains yellow oily liquid and compound 5 (383.7g), yield 88.3% after being spin-dried for.Hydrogen nuclear magnetic resonance spectrum (400MHz, CDCl 3) δ: 1.42 (9H, s), 1.79 (2H, br s), 2.43 (1H, br s), 2.73 (2H, br s), 3.63 (1H, br s), 3.99 (1H, quint, J=6.9Hz), 4.72 (1H, br s), illustrate to obtain target product.Its molecular weight is 187.24.
Step 5:
Compound 5 (320g, 1.7mol) and triethylamine (260g, 2.6mol) are dissolved in methylene dichloride (10L).At 0 DEG C, heavy steamed Methanesulfonyl chloride (230g, 2.0mol) is dropped in above-mentioned reaction solution.After dropwising, this reaction solution is in stirring at room temperature after 2 hours, and this organic phase is through washing, and saturated common salt is washed, dry, obtains white solid and chemical combination 6 (380g), yield 84.8% after being spin-dried for.Hydrogen nuclear magnetic resonance spectrum (400MHz, CDCl 3) δ: 1.37 (9H, s), 2.08-2.92 (2H, m), 2.83-2.91 (2H, m), 2.92 (3H, s), 3.76 (1H, s), illustrate to obtain target product.Its molecular weight is 265.33.
Step 6:
DMF (4L), compound 6 (190g, 0.72mol) and sodium azide (56g, 0.86mol) is added successively in reactor.This reaction solution adds ethyl acetate (3L) and water (3L) after stirring 2 hours at 110 DEG C.Organic phase is through washing, and saturated common salt is washed, dry, obtains white solid and compound 7 (189g), yield 98.1% after being spin-dried for.Hydrogen nuclear magnetic resonance spectrum (400MHz, CDCl 3) δ: 1.39 (9H, s), 2.21 (2H, br s), 2.46 (2H, br s), 4.08 (1H, m), 4.18 (1H, br s), 4.65 (1H, br s), illustrate to obtain target product.Its molecular weight is 212.25.
Step 7:
The Pd/C (9.5g) that ethanol (5L), compound 7 (95g, 0.45mol) and charge capacity are 5% is added in hydriding reactor.At the stirring under hydrogen 1 hour of 50Psi pressure.After Pd/C filtering, concentrate and obtain light yellow liquid, obtain trans N-Boc-1,3-ring butanediamine (75g) after rectifying, yield 90%.Hydrogen nuclear magnetic resonance spectrum (400MHz, CDCl 3) δ: 1.37 (9H, s), 2.04-2.05 (2H, m), 2.12-2.13 (2H, m), 3.57 (1H, s), 4.14 (1H, s), illustrate to obtain target product.Its molecular weight is 186.25.
Embodiment 2
Step one:
With step one in embodiment 1.
Step 2:
Successively by salt of wormwood (814g, 5.9mol), NaN 3(305.5g, 4.7mol) and compound 2 (440g, 3.9mol) is dissolved in the trimethyl carbinol (8L) reflux temperature 83 DEG C, then refluxes 12 hours.With water (2L) cancellation reaction, after solvent concentration, in surplus solution, add ethyl acetate (7.8L).Organic phase is through washing, and saturated common salt is washed, dry, obtains white solid and compound 3 (520.6g), yield 73% after being spin-dried for.Hydrogen nuclear magnetic resonance spectrum (400MHz, CDCl 3) δ: 1.36 (9H, s), 2.56-2.65 (2H, m), 2.97-3.18 (2H, m), 4.05-4.23 (1H, m), 4.05-4.23 (1H, m), 4.85 (1H, br s), 5.08 (2H, m).
Step 3:
Compound 3 (8.0g, 0.044mol) is dissolved in methylene dichloride (50mL) and water (50mL).Then, RuCl is added to this reaction solution 3(0.32g), NaIO 4(14.1g, 0.066mol).Aqueous phase, after 1 hour, separates by stirring at room temperature, and organic phase is after washing, saturated common salt washing, dry, and solvent steams and removes by underpressure distillation, obtains white solid and compound 4 (5.4g), yield 69.1%.Hydrogen nuclear magnetic resonance spectrum (400MHz, CDCl 3) δ: 1.40 (9H, s), 2.97-3.04 (2H, m), 3.26-3.33 (2H, m), 4.18-4.37 (1H, m).
Step 4:
At 0 DEG C, slowly lithium borohydride (0.588g, 0.027mol) is added in tetrahydrofuran (THF) (100mL) solution of compound 4 (4.20g, 0.023mol) in batches, after dripping, at room temperature continue stirring 1 hour.After saturated aqueous ammonium chloride (2.5L) will react cancellation, in reaction solution, add water (100mL) and ethyl acetate (100mL) successively.Organic phase is through washing, and saturated common salt is washed, dry, obtains yellow oily liquid, obtain compound 5 (0.43g), yield 9.8% after purification by column chromatography after being spin-dried for.Hydrogen nuclear magnetic resonance spectrum (400MHz, CDCl 3) δ: 1.42 (9H, s), 1.79 (2H, br s), 2.43 (1H, br s), 2.73 (2H, br s), 3.63 (1H, br s), 3.99 (1H, quint, J=6.9Hz), 4.72 (1H, br s).
All the other steps are with embodiment 1.
Embodiment 3
Step one:
With step one in embodiment 1.
Step 2:
Successively by DIPEA (762.5g, 5.9mol), TMSN 3(541.4g, 4.7mol) and compound 2 (440g, 3.9mol) is dissolved in the trimethyl carbinol (8L) reflux temperature 83 DEG C, then refluxes 12 hours.With water (2L) cancellation reaction, after solvent concentration, in surplus solution, add ethyl acetate (7.8L).Organic phase is through washing, and saturated common salt is washed, dry, obtains white solid and compound 3 (534.8g), yield 75% after being spin-dried for.Hydrogen nuclear magnetic resonance spectrum (400MHz, CDCl 3) δ: 1.36 (9H, s), 2.56-2.65 (2H, m), 2.97-3.18 (2H, m), 4.05-4.23 (1H, m), 4.05-4.23 (1H, m), 4.85 (1H, br s), 5.08 (2H, m).
Step 3:
Compound 3 (8.0g, 0.044mol) is dissolved in DMF (80mL).Then, OsO is added to this reaction solution 4(0.11g) with peroxy tert-butyl alcohol (26.1g, 0.176mol).Stirring at room temperature, after 3 hours, adds ethyl acetate (100mL) and water (100mL).Separated by aqueous phase, organic phase is after washing, saturated common salt washing, dry, and solvent steams and removes by underpressure distillation, obtains white solid and compound 4 (5.4g), yield 69.1%.Hydrogen nuclear magnetic resonance spectrum (400MHz, CDCl 3) δ: 1.40 (9H, s), 2.97-3.04 (2H, m), 3.26-3.33 (2H, m), 4.18-4.37 (1H, m).
Step 4:
At 0 DEG C, slowly sodium borohydride (1.74g, 0.046mol) is added in methyl alcohol (100mL) solution of compound 4 (4.20g, 0.023mol) in batches, after dripping, at room temperature continue stirring 1 hour.After saturated aqueous ammonium chloride (2.5L) will react cancellation, in reaction solution, add water (100mL) and ethyl acetate (100mL) successively.Organic phase is through washing, and saturated common salt is washed, dry, obtains yellow oily liquid, obtain compound 5 (0.33g), yield 7.6% after purification by column chromatography after being spin-dried for.Hydrogen nuclear magnetic resonance spectrum (400MHz, CDCl 3) δ: 1.42 (9H, s), 1.79 (2H, br s), 2.43 (1H, br s), 2.73 (2H, br s), 3.63 (1H, br s), 3.99 (1H, quint, J=6.9Hz), 4.72 (1H, br s).
All the other steps are with embodiment 1.
Embodiment 4
Step 3:
Compound 3 (8.0g, 0.044mol) is dissolved in acetone (100mL).Then, OsO is added to this reaction solution 4(0.11g) with chromium trioxide (15.4g, 0.154mol).Stirring at room temperature, after 12 hours, adds ethyl acetate (100mL) and water (100mL).Separated by aqueous phase, organic phase is after washing, saturated common salt washing, dry, and solvent steams and removes by underpressure distillation, obtains white solid and compound 4 (4.0g), yield 50.9%.Hydrogen nuclear magnetic resonance spectrum (400MHz, CDCl 3) δ: 1.40 (9H, s), 2.97-3.04 (2H, m), 3.26-3.33 (2H, m), 4.18-4.37 (1H, m).
All the other steps are with embodiment 1.
The foregoing is only the preferred embodiments of the present invention, be not limited to the present invention, for a person skilled in the art, the present invention can have various modifications and variations.Within the spirit and principles in the present invention all, any amendment done, equivalent replacement, improvement etc., all should be included within protection scope of the present invention.
Unaccomplished matter of the present invention is known technology.

Claims (7)

1. the preparation method of a trans N-Boc-1,3-ring butanediamine, is characterized by and comprise the following steps:
Step one), 3-methylene radical cyclobutyl formonitrile HCN is dissolved in the mixing solutions of second alcohol and water, then adds potassium hydroxide, after back flow reaction 1-5 hour, with the pH=2 of hydrochloric acid conditioning solution; Filtered by the white solid of separating out, washing, drying obtains compound 2;
Wherein, material mol ratio is 3-methylene radical cyclobutyl formonitrile HCN: potassium hydroxide=1:1 ~ 10; Volume ratio is ethanol: water=1 ~ 5:5 ~ 1;
Step 2) successively alkali, trinitride and compound 2 is dissolved in the trimethyl carbinol at 83 DEG C, then reflux 0.5-12 hour; To go out reaction with shrend, when solution being concentrated into 1/5 of original volume, in surplus solution, add ethyl acetate; Organic phase is through washing, and saturated common salt is washed, dry, obtains compound 3 after being spin-dried for;
Wherein, material mol ratio is alkali: triazo-compound: compound 2=1 ~ 3:1 ~ 3:1; Every mole compound 2 adds 2L ethyl acetate;
Step 3) compound 3 is dissolved in solvent, then add oxygenant; After question response is complete, after extraction, drying and distillation, obtain compound 4; Mol ratio is compound 3: oxygenant=1:1 ~ 10;
Wherein, solvent is the mixing solutions of methylene dichloride and methyl alcohol, and volume ratio is (10 ~ 1): (1 ~ 10);
Step 4) at-78 DEG C-0 DEG C, reductive agent is added in the tetrahydrofuran solution of compound 4, drip rear room temperature and continue again to stir 0.5-12 hour; After will reacting cancellation, stir after then adding water and ethyl acetate successively in reaction solution, organic phase is through washing, and saturated common salt is washed, dry, obtains compound 5 after being spin-dried for;
Wherein, mol ratio is compound 4: reductive agent=1:1 ~ 10; Volume ratio is tetrahydrofuran (THF): water: ethyl acetate=1 ~ 10:1 ~ 10:1 ~ 10;
Step 5) compound 5 and triethylamine are dissolved in methylene dichloride, at-78 DEG C ~ 5 DEG C, Methanesulfonyl chloride is dropped in above-mentioned reaction solution; After dropwising, this reaction solution is after stirring at room temperature 0.5-12 hour, and this organic phase is through washing, and saturated common salt is washed, dry, obtains white solid and compound 6 after being spin-dried for;
Wherein, mol ratio is compound 5: triethylamine: Methanesulfonyl chloride=1:1 ~ 3:1 ~ 3;
Step 6) compound 6 and sodium azide are dissolved in solvent, this reaction solution adds ethyl acetate and water after stirring 0.5-12 hour at 5 DEG C ~ 180 DEG C; Organic phase is through washing, and saturated common salt is washed, dry, obtains white solid and compound 7 after being spin-dried for;
Wherein, mol ratio is compound 6: sodium azide=1:1 ~ 10; Every g of compound 6 adds ethyl acetate 13 ~ 18mL, volume ratio ethyl acetate: water=1:1;
Step 7) in hydriding reactor, Pd/C is added in the ethanolic soln of compound 7, at 15-150Psi hydrogen, stirring reaction is 0.5 ~ 1 hour at 5 DEG C ~ 100 DEG C, then by after Pd/C filtering, concentrate and obtain light yellow liquid, after rectifying, obtain trans N-Boc-1,3-ring butanediamine;
Wherein, mass ratio is compound 7:Pd/C=1:0.1% ~ 10%.
2. the preparation method of trans N-Boc-1,3-ring butanediamine as claimed in claim 1, is characterized by step 2) described alkali is the one to multiple kind of triethylamine, pyridine, DIPEA, salt of wormwood, sodium carbonate.
3. the preparation method of trans N-Boc-1,3-ring butanediamine as claimed in claim 1, is characterized by step 2) described triazo-compound is NaN 3, KN 3, Ca (N 3) 2, TMSN 3with diphenyl phosphate azide (DPPA).
4. trans N-Boc-1 as claimed in claim 1, the preparation method of 3-ring butanediamine, is characterized by step 3) described oxygenant is one to multiple kind in ruthenium trichloride, perosmic anhydride, sodium periodate, peroxy tert-butyl alcohol, hydrogen peroxide, chromic oxide, potassium permanganate, oxygen and ozone.
5. the preparation method of trans N-Boc-1,3-ring butanediamine as claimed in claim 1, is characterized by step 4) described reductive agent is lithium borohydride, sodium borohydride and 3-sec-butyl lithium borohydride (L-selectride).
6. trans N-Boc-1 as claimed in claim 1, the preparation method of 3-ring butanediamine, it is characterized by step 6) described solvent is the one to multiple kind of toluene, hexanaphthene, chloroform, tetracol phenixin, acetonitrile, DMF, dimethyl sulfoxide (DMSO), tetramethylene sulfone and tetrahydrofuran (THF).
7. the preparation method of trans N-Boc-1,3-ring butanediamine as claimed in claim 1, is characterized by step 6) described in temperature of reaction be preferably 110 DEG C.
CN201510224945.6A 2015-05-06 2015-05-06 Preparation method of trans-N-Boc-1,3-cyclobutanediamine Pending CN104829492A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201510224945.6A CN104829492A (en) 2015-05-06 2015-05-06 Preparation method of trans-N-Boc-1,3-cyclobutanediamine

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201510224945.6A CN104829492A (en) 2015-05-06 2015-05-06 Preparation method of trans-N-Boc-1,3-cyclobutanediamine

Publications (1)

Publication Number Publication Date
CN104829492A true CN104829492A (en) 2015-08-12

Family

ID=53807740

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201510224945.6A Pending CN104829492A (en) 2015-05-06 2015-05-06 Preparation method of trans-N-Boc-1,3-cyclobutanediamine

Country Status (1)

Country Link
CN (1) CN104829492A (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106810467A (en) * 2017-01-03 2017-06-09 苏州昊帆生物股份有限公司 Diamine compounds list Boc guard methods
CN115322106A (en) * 2022-07-19 2022-11-11 沈阳药科大学 Synthesis method of trans-3-azido-1-methylcyclobutanol and trans-3-amino-1-methylcyclobutanol

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1984901A (en) * 2004-05-18 2007-06-20 先灵公司 Substituted 2-quinolyl-oxazoles useful as PDE4 inhibitors.

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1984901A (en) * 2004-05-18 2007-06-20 先灵公司 Substituted 2-quinolyl-oxazoles useful as PDE4 inhibitors.

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DMYTRO S. RADCHENKO ET AL.: "Cyclobutane-Derived Diamines: Synthesis and Molecular Structure", 《JOURNAL OF THE ORGANIC CHEMSITRY》 *
ESSA HU ET AL.: "Discovery of Novel Imidazo[4，5‑b]pyridines as Potent and Selective Inhibitors of Phosphodiesterase 10A（PDE10A）", 《MEDICINAL CHEMISTRY LETTERS》 *
ESSA HU ET AL.: "Discovery of Novel Imidazo[4，5‑b]pyridines as Potent and Selective Inhibitors of Phosphodiesterase 10A（PDE10A）", 《MEDICINAL CHEMISTRY LETTERS》, vol. 5, 28 March 2014 (2014-03-28), pages 700 - 705 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106810467A (en) * 2017-01-03 2017-06-09 苏州昊帆生物股份有限公司 Diamine compounds list Boc guard methods
CN115322106A (en) * 2022-07-19 2022-11-11 沈阳药科大学 Synthesis method of trans-3-azido-1-methylcyclobutanol and trans-3-amino-1-methylcyclobutanol
CN115322106B (en) * 2022-07-19 2023-08-15 沈阳药科大学 Synthesis method of trans-3-azido-1-methylcyclobutanol and trans-3-amino-1-methylcyclobutanol

Similar Documents

Publication Publication Date Title
EP2647624B1 (en) Intermediates of sitagliptin and preparation process thereof
CN101157681A (en) Method for preparing 1,3 propane sultone
CN104829492A (en) Preparation method of trans-N-Boc-1,3-cyclobutanediamine
CN109081822A (en) A kind of method that simplicity prepares high purity butylene phthalide
CN101619034A (en) Diselenide compound synthesis method
CN102498102A (en) Novel method for synthesizing ivabradine and the addition salts thereof with a pharmaceutically acceptable acid
CN102712593B (en) Method for producing 2-amino-4-(trifluoromethyl)pyridine
CN104130188A (en) Preparation method of 8-chloro-1-methyl-2,3,4,5- tetrahydro -1H-3-benzoazatropylidene
CN103086959A (en) Novel process for producing 3,5,6-sodium trichloropyrindinol
CN102643264B (en) Synthesizing method of trioxymethylene
CN108633276B (en) The manufacturing method of five thia cycloheptane of 1,2,3,5,6-
CN104086487B (en) A kind of method being directly synthesized caprolactam for raw material with Ketohexamethylene
CN101239938B (en) Method for preparing (S)-4-hydroxypyrrolidone and derivatives thereof
CN113336761B (en) Preparation method of JAK inhibitor key intermediate
CN106518758A (en) Preparation method of Betrixaban intermediate N-(5-chloro-2-pyridyl)-2-(4-cyanobenzeneformamido)-5-metoxybenzamide
KR19990031451A (en) Method for Simultaneous Production of Dimethyl Ether and Methanol from Carbon Dioxide
CN102675162B (en) Method for synthesizing CLT acid
CN104854085A (en) Method for producing bis(3-aminophenyl)disulfides and 3-aminothiols
CN107652195A (en) A kind of preparation method of 1 amino cyclopropanecarboxylic acid
CN105622460A (en) Synthesis method for (R)-N-t-BOC biphenyl alaninol
CN102126967B (en) Method for producing N,N-diisopropyl ethanolamine
CN101805367B (en) Method for synthesizing PE (Phosphatidyl Ethanolamine)
CN112225739B (en) Preparation method of azetidine compound
CN108794477A (en) A kind of N2The preparation method of 9 substituted guanine class compound
CN103588638B (en) A kind of 4-(benzene butoxy) benzoic synthetic method

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
EXSB Decision made by sipo to initiate substantive examination
SE01 Entry into force of request for substantive examination
RJ01 Rejection of invention patent application after publication
RJ01 Rejection of invention patent application after publication

Application publication date: 20150812