CN102320981B - Chiral intermediate (S)-1-cyclobutyl ethylamine hydrochloride as well as preparation method and application thereof - Google Patents
Chiral intermediate (S)-1-cyclobutyl ethylamine hydrochloride as well as preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to the field of medical chemistry, and discloses a chiral intermediate (S)-1-cyclobutyl ethylamine hydrochloride as well as a preparation method thereof. The preparation method comprises the following steps of: reacting 1-cyclobutane ethyl ketone and (R)-tert-butyl sulfenamide with tetraisopropyl titanate to obtain (R,Z)-N-(1-cyclobutylene)-2-tert-butyl sulfenamide; then reacting with lithium tri-sec-butyl borohydride to obtain (R)-N-((S)-1-cyclobutyl-ethyl)-2-tert-butyl-sulfenamide; and then reacting with a hydrochloric acid alcohol solution to separate out a precipitate namely the (S)-1-cyclobutyl ethylamine hydrochloride. The obtained product is an important medical intermediate, and can be used for synthesizing chronic renal failure accepter ligands and intermediates of cephalo antibiotics, or can be used for synthesizing novel chiral phosphine ligands. The preparation method has the advantages of simplicity, mild reaction conditions, easily available raw materials and high yield.
Description
Technical field
The invention belongs to and the present invention relates to medicinal chemistry arts, especially the preparation field of medicine intermediate chiral drug molecule.Particularly relate to a kind of preparation for can be used for chiral intermediate (the S)-1-cyclobutyl ethylamine hydrochloride synthesizing chronic accepting agent part, cephalosporin analog antibiotic and Novel phosphine ligand.
Background technology
At present, the total number of drugs used in the world is at present about 1900 kinds of chiral drugs and accounts for more than 50%, and in clinical 200 kinds of conventional medicines, chiral drug reaches 114 kinds.
Phosphine ligands is the focus of catalyst research at present, and a lot of chiral phosphine ligand can be used for transition metal-catalyzed asymmetric synthesis.The substituent structure of (S)-1-cyclobutyl-ethylamino is there is in chiral phosphine ligand.
In addition, chronic accepting agent part 7-(6-methoxypyridine)-imidazoles [4,5-b] pyridine derivate, or also there is this kind of structure in the structural formula preparing cephalosporin analog antibiotic intermediate.By various reactions such as replacement or reduction, this substituting group is joined in above-mentioned chiral molecules structure.Therefore, need a kind of intermediate, above-mentioned reaction can be completed.Vigorous gradually to the demand of this kind of intermediate.
For achieving the above object, the present invention has designed and synthesized a kind of novel molecular " (S)-1-cyclobutyl ethylamine hydrochloride ", can be used as chiral intermediate, for decorating molecule, prepares multiple product.
Summary of the invention
The present invention aims to provide a kind of medicine intermediate (S)-1-cyclobutyl ethylamine hydrochloride.
Present invention also offers the preparation method of above-mentioned (S)-1-cyclobutyl ethylamine hydrochloride.
This (S)-1-cyclobutyl ethylamine hydrochloride is chiral intermediate, and structure is:
Preparation method is obtained by reacting (R, Z)-N-(1-cyclobutyl subunit)-2-t-butyl sulfonamide with 1-tetramethylene ethyl ketone, (R)-t-butyl sulfonamide and titanium isopropylate; React with 3-sec-butyl lithium borohydride again and generate (R)-N-((S)-1-CYCLOBUTYLETHYL)-2-t-butyl sulfonamide; React with hydrochloric acid alcoholic solution, separate out precipitation and obtain (S)-1-cyclobutyl ethylamine hydrochloride.
Step comprises:
(1) (R is prepared, Z)-N-(1-cyclobutyl subunit)-2-t-butyl sulfonamide: be the 1-tetramethylene ethyl ketone of 1:1 ~ 1.2:2 ~ 2.5, (R)-t-butyl sulfonamide and titanium isopropylate and solvent by mol ratio, stirring and refluxing 15 ~ 24 hours under protection of inert gas; Except after desolventizing, washing is dry; Solvent is THF or acetonitrile;
(2) (R)-N-((S)-1-CYCLOBUTYLETHYL)-2-t-butyl sulfonamide is prepared :-60 ~-70 DEG C, 3-sec-butyl lithium borohydride solution is added drop-wise to (R under nitrogen or protection of inert gas condition, Z) in-N-(1-cyclobutyl subunit)-2-t-butyl sulfonamide solution, and stir; React 1 ~ 4 hour under being warmed up to room temperature;
The mol ratio of 3-sec-butyl lithium borohydride and (R, Z)-N-(1-cyclobutyl subunit)-2-t-butyl sulfonamide is 1.1 ~ 1.3:1;
Concentrated remove solvent after product methylene dichloride or acetic acid ethyl dissolution and wash;
Collect organic phase, concentrated after dry, obtain the crude product of (R)-N-((S)-1-CYCLOBUTYLETHYL)-2-t-butyl sulfonamide;
(3) by the dissolving crude product of (R)-N-((S)-1-CYCLOBUTYLETHYL)-2-t-butyl sulfonamide in excessive methanol hydrochloride solution, at 10 ~ 15 DEG C stir 0.5 ~ 2 hour;
Then concentrated removal alcohol; Ethyl acetate or sherwood oil is added in remaining mixture, by the solid by filtration separated out, drying obtains (S)-1-cyclobutyl ethylamine hydrochloride; In methanol hydrochloride solution, the content of HCl is 3 ~ 5mol/L.
The present invention preparation-obtained (S)-1-cyclobutyl ethylamine hydrochloride is a kind of important chiral medicinal intermediate, can be used as intermediate, preparation chirality 7-(6-methoxypyridine)-imidazoles [4,5-b] pyridine derivate, this is the effective constituent of chronic accepting agent part.
Can be used in addition preparing multiple cancer therapy drug, or the intermediate of synthesis cephalosporin analog antibiotic, or for the synthesis of Novel phosphine ligand.
Molecule of the present invention, as intermediate, is connected in the structure of multiple chiral molecules product or intermediate by addition or substitution reaction etc.; Preparation method is simple, and reaction conditions is gentle, raw material be easy to get and also productive rate high, be a kind of novel method preparing chiral medicinal intermediate.
Accompanying drawing explanation
Fig. 1 is prepared (R, Z)-N-(1-cyclobutyl the subunit)-2-t-butyl sulfonamide of embodiment 1
1h NMR collection of illustrative plates
Fig. 2 ~ 4 are the different retention time collection of illustrative plates of LCMS of prepared (R)-N-((S)-1-CYCLOBUTYLETHYL)-2-t-butyl sulfonamide of embodiment 3
Fig. 5 is prepared (the S)-1-cyclobutyl ethylamine hydrochloride of embodiment 4
1h NMR collection of illustrative plates
Fig. 6 is the HPLC collection of illustrative plates of prepared (the S)-1-cyclobutyl ethylamine hydrochloride of embodiment 4
Fig. 7 is the MS collection of illustrative plates of prepared (the S)-1-cyclobutyl ethylamine hydrochloride of embodiment 4
Fig. 8 is the SFC collection of illustrative plates of prepared (the S)-1-cyclobutyl ethylamine hydrochloride of embodiment 4
Embodiment
Below in conjunction with embodiment, the present invention is described in further detail and completely:
Embodiment 1
1-tetramethylene ethyl ketone (109g is added successively in the tetrahydrofuran (THF) of 1.5L; 1.11mol), (R)-t-butyl sulfonamide 1.11mol and titanium isopropylate 2.3mol; this reaction mixture is stirred under nitrogen protection backflow (reflux temperature 70 ~ 85 DEG C), and back flow reaction 18 hours.
After question response is complete, reactant being cooled to room temperature, being spin-dried for by tetrahydrofuran (THF) with revolving to steam, the methylene dichloride (or ethyl acetate) of remaining mixture 1L and the water dilution of 500ml, fall solid filtering.By methylene dichloride (or ethyl acetate) flush cake 4 times, each 1L.Reaction formula:
Organic phase is merged rear anhydrous sodium sulfate drying; Cross concentrated (R, Z)-N-(1-cyclobutyl the subunit)-2-t-butyl sulfonamide (weak yellow liquid, productive rate 80%) obtaining 187g after filtering anhydrous sodium sulphate.
1h NMR spectrogram and nuclear magnetic spectrogram are as shown in Figure 1.
1h NMR: compound 2 (R, Z)-N-(1-cyclobutyl subunit)-2-t-butyl sulfonamide (CDCl
3, 400MHz) and 3.10-3.20 (m, 1H); 2.22 (s, 3H); 2.10-2.20 (m, 4H); 1.70-2.00 (m, 2H); 1.17 (s, 9H).
Embodiment 2
1-tetramethylene ethyl ketone consumption is 1.11mol, and (R)-t-butyl sulfonamide consumption is 1.3mol, titanium isopropylate 2.5mol, and replaces tetrahydrofuran (THF) with acetonitrile, and reacting reflux time is 20 hours, and reflux temperature is 90-100 DEG C; All the other are with embodiment 1, obtain (R, Z)-N-(1-cyclobutyl subunit)-2-t-butyl sulfonamide 158g, productive rate 67.6%.
Embodiment 3
In nitrogen or argon shield; at the temperature of-65 DEG C; 550ml concentration 1mol/L 3-sec-butyl lithium borohydride THF solution is added drop-wise to containing the prepared (R of 92g (0.46mol) embodiment 1 or 2; in anhydrous tetrahydro furan (800ml) solution of Z)-N-(1-cyclobutyl subunit)-2-t-butyl sulfonamide, the time controling of dropping is within 2-3 hour.After dropwising, reaction mixture continues to stir 15 minutes at-65 DEG C DEG C, and under being then warming up to room temperature, (10 ~ 30 DEG C) reaction 4 ~ 5 is little of reacting completely.Then fallen by solvent concentration, remaining mixture 1L methylene dichloride (or ethyl acetate) dissolves, and washs 3 ~ 4 times with water (100ml).Reaction formula:
Collect organic phase, with anhydrous sodium sulfate drying; After filtering anhydrous sodium sulphate removal, the concentrated crude product obtaining (R)-N-((S)-1-CYCLOBUTYLETHYL)-2-t-butyl sulfonamide.This crude product does not need to be further purified, and directly throws in next step reaction.
LCMS assay as shown in figs. 2 to 4.
In above-mentioned reaction, the consumption of 1mol/L 3-sec-butyl lithium borohydride THF solution can be 500 ~ 600ml.
Embodiment 4
The crude product 0.93mol of (R)-N-((S)-1-CYCLOBUTYLETHYL)-2-t-butyl sulfonamide is dissolved in 1L hydrochloric acid methanol (HCl content 4mol/L) solution, stirs 1 hour at the temperature of 10 ~ 15 DEG C.The preparation method of methanol hydrochloride solution is that HCl gas is passed into anhydrous methanol.Reaction formula:
Concentrated removal methyl alcohol, adds ethyl acetate in remaining mixture, and taken out by the solid filtering of separating out, drying obtains 38g (S)-1-cyclobutyl ethylamine hydrochloride (0.7mol), productive rate 75%.Purity:
HPLC:Compound4(purity:99.85％)
SFC:Compound4(ee:99.6％)
MS:Compound4(M+1:100.12)
1h NMR:(S)-1-cyclobutyl ethylamine hydrochloride (S)-1-cyclobutylethanamine hydrochloride (DMSO-d6,400MHz) 8.05 (b, 3H); 3.04 (s, 1H); 2.28-2.45 (m, 1H); 1.63-2.00 (m, 6H); 1.00-1.10 (d, J=6.4Hz, 3H).
1h NMR, HPLC, MS and SFC collection of illustrative plates as shown in figures 5-8.
Embodiment 5
By (the S)-1-cyclobutyl ethylamine hydrochloride prepared, react with compound chloropyridine thing (formula 1 compound), preparation 7-(6-methoxypyridine)-imidazoles [4,5-b] pyridine derivate (formula 4 compound).Reaction formula is as follows:
For the situation of R1=H, R2=H, preparation process is as follows:
(1) substitution reaction:
By chloro-for 1.0mmol2-3-nitro-4-(6-methoxypyridine)-pyridinium dissolution in acetonitrile, reflux at adding 1.1mmol (S)-1-cyclobutyl ethylamine hydrochloride 80 DEG C 48hr, after reacting completely, washing, obtain after being spin-dried for compound 2 ((S)-N-(1-CYCLOBUTYLETHYL)-6-methoxyl group-3'-nitro-[3,4 '-bipyridyl]-2 '-amine) (yield is about 82%).
(2) reduction reaction:
Step (1) product is dissolved in the mixed solvent of dioxane and water (by 1:1 volume), adds excess of sulfur sodium thiosulfate 1.5 ~ 2mmol and 2 ~ 3mol ammoniacal liquor (20wt% ~ 30wt%), at 25 DEG C, stirs 18h; After having reacted, filter, washing, obtains compound 3 ((S)-N2'-(1-CYCLOBUTYLETHYL)-6-methoxyl group-3 [3,4 '-bipyridyl]-2', 3'-diamines) after being extracted with ethyl acetate and being spin-dried for.
(3) Guan Huan:
Step (2) product is dissolved in toluene, add propionic acid, back flow reaction 18hr, after reacting completely, aftertreatment (be spin-dried for, wash, column chromatography for separation, concentrated) obtains having 7-(6-the methoxypyridine)-imidazoles [4 of formula 4 structure, 5-b] pyridine derivate (yield is approximately 32-42%), this is the effective constituent of chronic accepting agent part.
Claims (2)
1. the preparation method of chiral intermediate (S)-1-cyclobutyl ethylamine hydrochloride, is characterized in that, comprise the steps:
(1) (R is prepared, Z)-N-(1-cyclobutyl subunit)-2-t-butyl sulfonamide: be the 1-tetramethylene ethyl ketone of 1:1 ~ 1.2:2 ~ 2.5, (R)-t-butyl sulfonamide and titanium isopropylate and solvent by mol ratio, stirring and refluxing 15 ~ 24 hours under protection of inert gas; Except after desolventizing, washing is dry; Described solvent is THF or acetonitrile;
(2) (R)-N-((S)-1-CYCLOBUTYLETHYL)-2-t-butyl sulfonamide is prepared :-60 ~-70 DEG C, 3-sec-butyl lithium borohydride solution is added drop-wise to (R under nitrogen or protection of inert gas condition, Z) in-N-(1-cyclobutyl subunit)-2-t-butyl sulfonamide solution, and stir; React 1 ~ 4 hour under being warmed up to room temperature;
The mol ratio of 3-sec-butyl lithium borohydride and (R, Z)-N-(1-cyclobutyl subunit)-2-t-butyl sulfonamide is 1.1 ~ 1.3:1;
Concentrated remove solvent after product methylene dichloride or acetic acid ethyl dissolution and wash;
Collect organic phase, concentrated after dry, obtain the crude product of (R)-N-((S)-1-CYCLOBUTYLETHYL)-2-t-butyl sulfonamide;
(3) by the dissolving crude product of (R)-N-((S)-1-CYCLOBUTYLETHYL)-2-t-butyl sulfonamide in excessive methanol hydrochloride solution, at 10 ~ 15 DEG C stir 0.5 ~ 2 hour; In described methanol hydrochloride solution, the content of HCl is 3 ~ 5mol/L;
Then concentrated removal alcohol; Ethyl acetate is added in remaining mixture, by the solid by filtration separated out, drying obtains (S)-1-cyclobutyl ethylamine hydrochloride.
2. the preparation method of chiral intermediate described in claim 1 (S)-1-cyclobutyl ethylamine hydrochloride, it is characterized in that, 3-sec-butyl lithium borohydride and (R, Z)-N-(1-cyclobutyl subunit)-2-t-butyl sulfonamide is dissolved respectively with acetonitrile or tetrahydrofuran (THF) in step (2).
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| EP2143709A1 (en) * | 2007-04-27 | 2010-01-13 | Sumitomo Chemical Company, Limited | Amide compound and use thereof |
| WO2009066790A1 (en) * | 2007-11-20 | 2009-05-28 | Sumitomo Chemical Company, Limited | N-cycl0alkylmethyl-2-amin0thiaz0le-5-carb0xamides for use in plant disease control |
| CN101878205A (en) * | 2007-11-30 | 2010-11-03 | 诺瓦提斯公司 | Phenyl-oxetanyl-derivatives |
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