CN101519374B - Method for synthesizing derivatives of chiral pyridyl aminoalcohols, and intermediate products and final products of same - Google Patents
Method for synthesizing derivatives of chiral pyridyl aminoalcohols, and intermediate products and final products of same Download PDFInfo
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Abstract
The invention relates to a method for synthesizing the derivatives of chiral pyridyl aminoalcohols, and intermediate products and final products of the same. Initial materials are selected from commercial raw materials on the market or easy-to-prepare raw materials of halogenated pyridine alkyl ketone or aromatic ring ketones, wherein X is F or Cl, R1 is C1 to C8 alkyls or C3 to C8 cycloalkyls; and final products are obtained through a process of chemical reactions under mild conditions, wherein R1 is C1 to C8 alkyls or C3 to C8 naphthene base, R2 is H or C1 to C8 alkyls, or C3 to C8 cycloalkyls or C7 to C9 benzyls, and chiral centers of alcohols have an S or R structure. The method provides a new thought and means for preparing the derivatives of chiral pyridyl aminoalcohols; the intermediate products are that the chiral centers of alcohols have an S or R structure; and the final products are that the chiral centers of alcohols have an S or R structure.
Description
(1) technical field:
The present invention relates to a kind of synthetic method and partial intermediate and final product of derivative of chiral pyridyl class aromatic ring amino alcohol.
(2) background technology:
The derivative of chiral pyridyl class aromatic ring amino alcohol is introduced in peptide medicament in order to the modified peptides chain structure, strengthens its stability in living organisms and active; Also can be used as in addition inhibitor or antioxidant, prevention is as malignant proliferation sexual maladjustment diseases such as lung cancer, mammary cancer, prostate cancer, arteriosclerosis, thereby arrival is used for treating the purpose of cancer, tumour; Such as, 1-S-(PA-3-yl)-1-propyl alcohol is used in synthesizing of mitotic kinesin inhibitor (drug patent EP1942899), and this type of drug candidates is the important medicine that is used for the treatment of cell proliferation disorders.
Present stage, the method for preparing this compounds mainly contains following two classes:
With
Be raw material, carry out chiral reduction with the CBS of chirality, then carry out the catalytic hydrogenation debenzylation; But due to the impact of nitrogen-atoms, with chirality CBS reduction, the purity of the enantiomorph of the alcohol that obtains (ee) only has 50～60%, and practice is worth little.
With
Be raw material, obtain racemic alcohol with NaBH4 reduction, then split, but owing to being benzyl position alcohol, be easy to racemization in split process, substantially without the value of industrial applications.
Above two class synthetic methods are because splitting condition is difficult to control, thereby purity (ee) value of the easy racemization of the product that obtains or enantiomorph is not high, is not suitable for large-scale production.Therefore, for solving a difficult problem that exists in prior art, suddenly wait the practicable synthetic route that finds to carry out large-scale production.
(3) summary of the invention:
Technical problem to be solved by this invention is to provide a kind of synthetic method of derivative of chiral pyridyl class aromatic ring amino alcohol; the method raw material is easy to get; the reaction purity and yield is higher; stable process conditions; simple to operate; be applicable to large-scale production, for the derivative for preparing chiral pyridyl class aromatic ring amino alcohol has supplied a kind of new thinking and method.
Another technical problem to be solved by this invention is to provide partial intermediate and the final product of synthetic method of the derivative of above-mentioned chiral pyridyl class aromatic ring amino alcohol.
For solving the problems of the technologies described above technical scheme of the present invention:
A kind of synthetic method of derivative of chiral pyridyl class aromatic ring amino alcohol is selected business-like raw material or the haloperidid alkyl ketone of easily preparation or the raw material of aromatic ring ketone on market
Be initial feed, wherein X is F or C1, and R1 is the cycloalkyl of alkyl or the C3～C8 of C1～C8, and the chemical reaction process of process mild condition obtains final product
Wherein R1 is the cycloalkyl of alkyl or the C3～C8 of C1～C8, and R2 is alkyl or the cycloalkyl of C3～C8 or the benzyl of C7～C9 of H or C1～C8; The alcohol chiral centre is S or R configuration; Concrete preparation process is as follows:
(1) under ether solvent and reductive agent, catalyzer exist, raw material
Generate
Wherein R1 is the cycloalkyl of alkyl or the C3～C8 of C1～C8, and pure chiral centre can S or R; The ether solvent consumption is every gram main raw material
10～40mL; Raw material
With the mol ratio consumption of reductive agent be 1: 0.7～2; Raw material
With the catalyst molar ratio consumption be 1: 0.02～0.1: reduction reaction temperature is 25 ± 5 ℃;
(2) under alcoholic solvent and ammoniation agent existence,
By ammonification, generate
Wherein R1 is the cycloalkyl of alkyl or the C3～C8 of C1～C8, and R2 is alkyl or the cycloalkyl of C3～C8 or the benzyl of C7～C9 of H or C1～C8; The alcohol chiral centre can S or R; The aminating reaction temperature is 35 ± 5 ℃;
With the mole dosage of ammoniation agent be 1: 5～20, permissible error＜5%; The alcoholic solvent consumption is every gram
The derivative of chiral pyridyl class aromatic ring amino alcohol of the present invention mainly refers to
With
This a pair of enantiomorph.
In above-mentioned steps (1), the ether solvent consumption is every gram main raw material
20～35mL; Raw material
With the mol ratio consumption of reductive agent be 1: 0.8～1.6; Raw material
With the catalyst molar ratio consumption be 1: 0.04～0.08: reduction reaction temperature is 25 ± 3 ℃; In step (2), the aminating reaction temperature is 35 ± 3 ℃;
With the mole dosage of ammoniation agent be 1: 8～18, permissible error＜5%; The alcoholic solvent consumption is every gram
In above-mentioned steps (1), the ether solvent consumption is every gram main raw material
Be 22～30mL; Raw material
With the mol ratio consumption of reductive agent be 1: 0.9～1.2; Raw material
With the catalyst molar ratio consumption be 1: 0.05～0.07: reduction reaction temperature is 25 ± 1 ℃; In step (2), the aminating reaction temperature is 35 ± 1 ℃;
With the mole dosage of ammoniation agent be 1: 10～12, permissible error＜5%; The alcoholic solvent consumption is every gram
Be 10～16ml.
In above-mentioned steps (1), ether solvent comprises ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, methyl tertiary butyl ether or phenyl ether; Reductive agent comprises borine dimethyl sulphide or diborane; Catalyzer comprises S-Jia Ji oxazole borine or R-Jia Ji oxazole borine; In step (2), alcoholic solvent comprises methyl alcohol, ethanol, propyl alcohol, Virahol or butanols; Ammoniation agent comprises liquefied ammonia, ammoniacal liquor, methylamine, ethamine or benzylamine.
In above-mentioned steps (1), ether solvent is tetrahydrofuran (THF), and reductive agent is the borine dimethyl sulphide; Alcoholic solvent in step (2) is methyl alcohol, and ammoniation agent is liquefied ammonia or methylamine.
In above-mentioned steps (1)
R1 is ethyl, and X is fluorine, namely
The alcohol chiral centre is S or R configuration;
The intermediate product of the synthetic method of the derivative of above-mentioned a kind of chiral pyridyl class aromatic ring amino alcohol is 1-S-(2-fluorine pyridin-3-yl)-1-propyl alcohol,
H-NMR:(300MHZ, CDCl3), δ 0.688 (CH3, t), δ 1.352 (with H, the m on the CH2 that is connected on CH3), δ 4.418 (be connected with hydroxyl-H, m on CH), the δ 5.099 (H on OH, d), δ 7.425 (pyridine ring 5 upper H, m), δ 8.121 (4 upper H of pyridine ring, d), δ 8.391 (pyridine ring 6 upper H, d).
In above-mentioned steps (2)
R1 is ethyl, and R2 is H, namely
The alcohol chiral centre is S or R configuration.
The final product of the synthetic method of the derivative of above-mentioned a kind of chiral pyridyl class aromatic ring amino alcohol is 1-S-(PA-3-yl)-1-propyl alcohol,
H-NMR:(300MHZ, CDCl3), δ 0.672 (CH3, t), δ 1.261 (CH2, m), δ 4.418 (be connected with hydroxyl-H, m on CH), δ 5.099 (H, d on OH), δ 6.351 (NH2, s),
δ 6.531 (pyridine ring 5 upper H, m), δ 7.351 (pyridine ring 4 upper H, d), δ 8.001 (pyridine ring 6 upper H, d).
Above-mentioned final product can be introduced in peptide medicament in order to the modified peptides chain structure, strengthens its stability in living organisms and active; Can be used as inhibitor or antioxidant, for the preparation of the medicine of prevention as malignant proliferation sexual maladjustment diseases such as lung cancer, mammary cancer, prostate cancer, arteriosclerosis.
Superiority of the present invention:
1, the raw material of the present invention's employing all is easy to get, and low price; Raw materials used business-like raw material or the easy raw material of preparation of being can satisfy the needs of large-scale production;
2, the present invention adopts is synthetic method with chiral source, has obtained at present optical purity 98～99.8% target products;
3, chemical reaction condition of the present invention is gentle, reaction in whole technological process, all without pyroreaction, can directly obtain the product of the purity (ee) of high chemical purity, high antimer after reaction, product need not recrystallization or column chromatography obtains, and ripe on this Technology, possess the ability of large-scale production;
(4) description of drawings:
Fig. 1: synthetic
The chemical reaction process of (pure chiral centre is S or R)
Can understand more intuitively the technical scheme of foregoing invention in conjunction with Fig. 1.
(5) embodiment:
(for the interval range that occurs in embodiment, be due to carry out meeting appearance certain float of temperature in single test with reaction process.)
Embodiment 1:
(1) preparation 1-S-(2-fluorine pyridin-3-yl)-1-propyl alcohol,
Add 1.7kg tetrahydrofuran (THF) (25mL/g), 34.2g borine dimethyl sulphide (0.9eq.) to the 5L reaction flask, add 8.3gS-Jia Ji oxazole borine (0.06eq.) to system, reinforced complete, 25～26 ℃ are stirred 30min; Begin to drip 76.6g 2-fluoro-3-propionyl pyridine (1eq), drip 1/s of speed, dropwise; HPLC tracks to reaction to be finished; add 1.2kg methyl alcohol (20mL/g) termination reaction, the contracting dry system, residue is added to the water; 2.3kg methylene dichloride (23mL/g) extraction; organic phase is done in contracting, obtains product 73.7g, yield 95%; liquid chromatography purity (HPLC): 98.8%, the purity of enantiomorph (ee): 98.5%.
H-NMR:(300MHZ, CDCl3), δ 0.688 (CH3, t), δ 1.352 (with H, the m on the CH2 that is connected on CH3), δ 4.418 (be connected with hydroxyl-H, m on CH), the δ 5.099 (H on OH, d), δ 7.425 (pyridine ring 5 upper H, m), δ 8.121 (4 upper H of pyridine ring, d), δ 8.391 (pyridine ring 6 upper H, d).
(2) preparation 1-S-(PA-3-yl)-1-propyl alcohol;
Disposable 2.5kg methyl alcohol (10mL/g), the 374g liquefied ammonia (11eq) of adding in the 5L autoclave, 310.4g main raw material 1-S-(2-fluorine pyridin-3-yl)-1-propyl alcohol (1eq) starts stirring, be warming up to 35～36 ℃, after the reaction of sampling spot plate finishes, the extrusion system, concentrated, be added to the water, with 8.3kg methylene dichloride (20mL/g) extraction, contracting is done, obtain product 273.9g, without repurity; Yield 90%, the purity of enantiomorph (ee): 99.1%, liquid chromatography purity (HPLC): 99%;
1H-NMR:(300MHZ, CDCl3), δ 0.672 (CH3, t), δ 1.261 (CH2, m), δ 4.418 (be connected with hydroxyl-H, m on CH), the δ 5.099 (H on OH, d), δ 6.351 (NH2, s), δ 6.51 (pyridine ring 5 upper H, m), δ 7.351 (4 upper H of pyridine ring, d), δ 8.001 (pyridine ring 6 upper H, d).
Embodiment 2:
(1) preparation 1-R-(2-chloropyridine-3-yl)-1-cyclopropyl-carbinol;
Add 375.7g 2-methyltetrahydrofuran (30mL/g), 7.3g borine dimethyl sulphide (1.2eq.) to the 1L reaction flask, add 1.5g R-Jia Ji oxazole borine (0.07eq.) to system, reinforced complete, 29～30 ℃ are stirred 40min; Begin to drip 14.6g 2-chloro-3-cyclopropyl formyl radical pyridine (1eq), 1/s, dropwise; HPLC tracks to reaction to be finished; add 172.6g ethanol (15mL/g) to stop, the contracting dry system, residue is added to the water; methylene dichloride 484.2g (25mL/g) extraction; receive and do organic phase, obtain product 13.4g, yield 91%; liquid chromatography purity (HPLC): 98%, the purity of enantiomorph (ee): 99%.
1H-NMR:(300MHZ, CDCl3), δ 0.561 (cyclopropyl CH2, m), 4.398 (be connected with hydroxyl-H, s on CH), δ 4.499 (the H on OH, s), δ 7.615 (pyridine ring 5 upper H, m), δ 8.119 (4 upper H of pyridine ring, d), δ 8.491 (pyridine ring 6 upper H, d).
(2) preparation 1-R-(PA-3-yl)-1-cyclopropyl-carbinol:
Disposable 232.0g ethanol (16mL/g), the 225.0g ammoniacal liquor (18eq) of adding in the 1L autoclave, 18.6g main raw material 1-R-(2-chloropyridine-3-yl)-1-cyclopropyl-carbinol (1eq) starts stirring, is warming up to 39～40 ℃, reaction finishes, the extrusion system, after concentrate system, add the saturated common salt water washing, then after using 297.3g ethyl acetate (18mL/g) extraction, the organic phase drying, filter, obtain product 14.8g after concentrating, without repurity; Yield 90%, the purity of enantiomorph (ee): 99%, liquid chromatography purity (HPLC): 99%;
1H-NMR:(300MHZ, CDCl3), δ 0.579 (cyclopropyl CH2, m), 4.398 (be connected with hydroxyl-H, s on CH), δ 4.499 (H, s on OH), δ 6.411 (NH2, s), δ 6.591 (pyridine ring 5 upper H, m), δ 7.499 (4 upper H of pyridine ring, d), δ 8.002 (pyridine ring 6 upper H, d).
Embodiment 3:
(1) preparation 1-S-(2-chloropyridine-3-yl)-1-propyl alcohol;
Add 242.8g ether (40mL/g), 1.0g diborane (0.7eq.) to the 1L reaction flask, add 1.1g S-Jia Ji oxazole borine (0.08eq.) to system, reinforced complete, 25～26 ℃ are stirred 35min; Begin to drip 8.5g 2-chloro-3-propionyl pyridine (1eq), 1/s, dropwise; HPLC tracks to reaction to be finished; add 147.7g methyl alcohol (22mL/g) termination reaction, receive dry system, residue is added to the water; 229.5g ethyl acetate extraction (30mL/g); organic phase is done in contracting, obtains product 7.6g, yield 88%; liquid chromatography purity (HPLC): 98%, the purity of enantiomorph (ee): 99%.
1H-NMR:(300MHZ, CDCl3), δ 0.688 (CH3, t), δ 1.252 (CH2, m), δ 4.418 (H, the m that are connected with hydroxyl), δ 4.499 (OH, d), δ 7.425 (pyridine ring 5 upper H, m), δ 8.121 (4 upper H of pyridine ring, d), δ 8.391 (pyridine ring 6 upper H, d).
(2) preparation 1-S-(2-methylamino pyridin-3-yl)-1-propyl alcohol,
Disposable 535.7g Virahol (8mL/g), the 93.2g methylamine (6eq) of adding in the 1L autoclave, 85.3g main raw material 1-S-(2-chloropyridine-3-yl)-1-propyl alcohol (1eq) starts stirring, be warming up to 31～32 ℃, after sampling spot plate detection reaction finishes, extrusion system, contracting dry system, be added to the water, with 1.2kg ethyl acetate (15mL/g) extraction, get product 71.7g after organic phase is concentrated, without repurity; Yield 87%, the purity of enantiomorph (ee): 98.3%, liquid chromatography purity (HPLC): 99%;
H-NMR:(300MHZ, CDCl3), δ 0.672 (CH3, t), δ 1.361 (CH2, m), δ 2.375 (be connected with NH-hydrogen of CH3, d), δ 3.915 (H, the m that are connected with NH), the δ 4.415 (H that is connected with hydroxyl, m), δ 4.599 (OH, d), δ 6.51 (pyridine ring 5 upper H, m), δ 7.351 (4 upper H of pyridine ring, d), δ 8.001 (pyridine ring 6 upper H, d).
Embodiment 4
(1) preparation 1-S-(2-chloropyridine-3-yl)-1-hexanol;
Add 172.6g methyl tertiary butyl ether (22mL/g), 1.4g diborane (1eq.) to the 1L reaction flask, add 0.3gS-Jia Ji oxazole borine (0.02eq.) to system, reinforced complete, 25～26 ℃ are stirred 45min; Begin to drip 10.6g2-chloro-3-caproyl pyridine (1eq), drip 1/s of speed, dropwise; HPLC tracks to reaction to be finished; add 167.5g methyl alcohol (20mL/g) termination reaction, the contracting dry system, residue is added to the water; 152.6g ethyl acetate (16mL/g) extraction; organic phase is done in contracting, obtains product 9.3g, yield 87%; liquid chromatography purity (HPLC): 98.7%, the purity of enantiomorph (ee): 98.3%.
1H-NMR:(300MHZ, CDCl3), (hexyl 6 is the 3H on upper-CH3 to δ 0.896, t), δ 1.189 (H, m on CH2-CH2-), δ 1.689 (H, m on 2-CH2-of hexyl), δ 4.445 (be connected with hydroxyl-H on CH, m), δ 5.107 (H, s on OH), δ 7.623 (pyridine ring 5 upper H, m), δ 8.102 (4 upper H of pyridine ring, d), δ 8.501 (pyridine ring 6 upper H, d).
(2) preparation 1-S-(2-benzamido group pyridin-3-yl)-1-hexanol,
Disposable 169.0g methyl alcohol (5mL/g), the 342.8g benzyl ammonia 16eq of adding in the 1L autoclave, 42.8g main raw material 1-S-(2-chloropyridine-3-yl)-1-hexanol (1eq) starts stirring, be warming up to 30～31 ℃, after the HPLC detection reaction finishes, extrusion system, contracting dry system, be added to the water, with 1.7kg methylene dichloride (30mL/g) extraction, get product 48.3g after organic phase is concentrated, without repurity; Yield 85%, the purity of enantiomorph (ee): 98.3%, liquid chromatography purity (HPLC): 98.8%;
1H-NMR:(300MHZ, CDCl3), (hexyl 6 is the 3H on upper-CH3 to δ 0.896, t), δ 1.189 (the H on CH2-CH2-, m), δ 1.689 (the H on 2-CH2-of hexyl, m), δ 4.232 is (with the H the on-upper CH2-that is connected of NH, d), δ 4.445 (be connected with hydroxyl-H on CH, m), δ 5.107 (the H on OH, s), δ 6.545 (5 upper H of pyridine ring, m), δ 6.999 is (on phenyl ring 2, the H of 6, dd), δ 7.245 (the H of 4 on phenyl ring, m), δ 7.253 is (on phenyl ring 3, H on 5, dd), δ 7.495 (4 upper H of pyridine ring, d), δ 8.0011 (6 upper H of pyridine ring, d).
Embodiment 5
(1) preparation 1-R-(2-chloropyridine-3-yl)-1-hexalin,
Add 248.6g methyl tertiary butyl ether (15mL/g), 4.2g diborane (1.5eq.) to the 1L reaction flask, add 1.2gR-Jia Ji oxazole borine (0.04eq.) to system, reinforced complete, 20～21 ℃ are stirred 50min; Begin to drip 22.4g 2-chloro-3-hexamethylene acyl pyridine (1eq), drip 1/s of speed, dropwise; HPLC tracks to reaction to be finished; add 265.4g methyl alcohol (15mL/g) termination reaction, the contracting dry system, residue is added to the water; 595.8g dichloromethane extraction (20mL/g); organic phase is done in contracting, obtains product 19.4g, yield 86%; liquid chromatography purity (HPLC): 98.8%, the purity of enantiomorph (ee): 98.9%.
1H-NMR:(300MHZ, CDCl3), δ 1.189～δ 1.900 (11 H on cyclohexyl, m, δ 4.399 (H, the s that are connected with hydroxyl), δ 5.101 (the H on OH, d), δ 7.346 (pyridine ring 5 H, m), δ 7.659 (4 upper H of pyridine ring, d), δ 8.235 (pyridine ring 6 upper H, d).
(2) preparation 1-R-(2-phenylethylamine yl pyridines-3-yl)-1-hexalin,
Disposable 347.1g ethanol (13mL/g), the 163.6g β-phenylethylamine (9eq) of adding in the 1L autoclave, 33.8g main raw material 1-R-(2-chloropyridine-3-yl)-1-hexalin (1eq) starts stirring, be warming up to 35～36 ℃, after sampling spot plate detection reaction finishes, extrusion system, contracting dry system, be added to the water, with 1.1kg methylene dichloride (25mL/g) extraction, get product 38.6g after organic phase is concentrated, without repurity; Yield 83%, the purity of enantiomorph (ee): 98.4%, liquid chromatography purity (HPLC): 98.8%;
1H-NMR:(300MHZ, CDCl3), δ 1.189～δ 1.900 (11 H on cyclohexyl, m, δ 2.678 (on benzyl-CH2 H, t), δ 3.299 (the H on NH-CH2, m), δ 4.399 (H, the s that are connected with hydroxyl), δ 5.101 (the H on OH, d), δ 6.631 (pyridine ring 5 upper H, m), δ 7.239～7.251 (5 H on phenyl ring, H), δ 7.379 (H, t on NH), δ 7.499 (4 upper H of pyridine ring, d), δ 8.001 (pyridine ring 6 upper H, d).
Embodiment 6:
(1) preparation 1-R-(2-fluorine pyridin-3-yl)-1-propyl alcohol,
Add 340.4g tetrahydrofuran (THF) (25mL/g), 6.8g borine dimethyl sulphide (0.9eq.) to the 1L reaction flask, add 1.4gR-Jia Ji oxazole borine (0.05eq.) to system, reinforced complete, 25～28 ℃ are stirred 40min; Begin to drip 15.3g 2-fluoro-3-propionyl pyridine (1eq), drip 1/s of speed, dropwise; HPLC tracks to reaction to be finished; add 241.7g methyl alcohol (20mL/g) termination reaction, the contracting dry system, residue is added to the water; 508.7g methylene dichloride (25mL/g) extraction; organic phase is done in contracting, obtains product 13.8g, yield 89%; liquid chromatography purity (HPLC): 98.4%, the purity of enantiomorph (ee): 98.1%.
H-NMR:(300MHZ, CDCl3), δ 0.688 (CH3, t), δ 1.352 (with H, the m on the CH2 that is connected on CH3), δ 4.418 (be connected with hydroxyl-H, m on CH), the δ 5.099 (H on OH, d), δ 7.425 (pyridine ring 5 upper H, m), δ 8.121 (4 upper H of pyridine ring, d), δ 8.391 (pyridine ring 6 upper H, d).
(2) preparation 1-R-(PA-3-yl)-1-propyl alcohol;
Disposable 429.0g methyl alcohol (10mL/g), the 65.5g liquefied ammonia (11eq) of adding in the 1L autoclave, main raw material 54.3g 1-R-(2-fluorine pyridin-3-yl)-1-propyl alcohol (1eq) starts stirring, be warming up to 35～36 ℃, after the reaction of sampling spot plate finishes, the extrusion system, concentrated, be added to the water, with 1.4kg methylene dichloride (20mL/g) extraction, contracting is done, obtain product 48.5g, without repurity; Yield 91%, the purity of enantiomorph (ee): 98.2%, liquid chromatography purity (HPLC): 99.1%;
1H-NMR:(300MHZ, CDCl3), δ 0.672 (CH3, t), δ 1.261 (CH2, m), δ 4.418 (be connected with hydroxyl-H, m on CH), the δ 5.099 (H on OH, d), δ 6.351 (NH2, s), δ 6.51 (pyridine ring 5 upper H, m), δ 7.351 (4 upper H of pyridine ring, d), δ 8.001 (pyridine ring 6 upper H, d).
This shows, in the present invention, the synthetic method of the derivative of disclosed chiral pyridyl class aromatic ring amino alcohol can obtain the high target product of purity, the products obtained therefrom optical purity is stabilized in more than 98.2%, the raw material that described synthetic method adopts is easy to get, method is simple, chemical reaction condition is gentle, the purity of yield and enantiomorph (ee) value is all very high, in whole production process, simple to operate, synthesis technique feasible, that pollution is lower, for the derivative for preparing chiral pyridyl class aromatic ring amino alcohol provides a kind of new thinking and method.
Claims (9)
1. the synthetic method of the derivative of a chiral pyridyl class aromatic ring amino alcohol, is characterized in that; Select
Be initial feed, the chemical reaction process of process mild condition obtains final product
Concrete preparation process is as follows:
(1) under the existence of ether solvent and reductive agent, catalyst S-Jia Ji oxazole borines or R-Jia Ji oxazole borine, raw material
Generate
Wherein the ether solvent consumption is every gram main raw material
10～40mL; Raw material
With the mol ratio consumption of reductive agent be 1: 0.7～2; Raw material
Yu oxazole boranes catalyst molar ratio consumption be 1: 0.02～0.1: reduction reaction temperature is 25 ± 5 ℃;
(2) under alcoholic solvent and ammoniation agent existence,
By ammonification, generate
The aminating reaction temperature is 35 ± 5 ℃;
With the mole dosage of ammoniation agent be 1: 5～20, permissible error＜5%; The alcoholic solvent consumption is every gram
5～22mL;
Wherein, X is F or Cl;
R1 is the cycloalkyl of alkyl or the C3～C8 of C1～C8; R2 is alkyl or the cycloalkyl of C3～C8 or the benzyl of C7～C9 of H or C1～C8; The alcohol chiral centre is S or R configuration.
2. the synthetic method of the derivative of a kind of chiral pyridyl class aromatic ring amino alcohol according to claim 1 is characterized in that: wherein in step (1), the ether solvent consumption is every gram main raw material
20～35mL; Raw material
With the mol ratio consumption of reductive agent be 1: 0.8～1.6; Raw material
Yu oxazole boranes catalyst molar ratio consumption be 1: 0.04～0.08: reduction reaction temperature is 25 ± 3 ℃; In step (2), the aminating reaction temperature is 35 ± 3 ℃;
With the mole dosage of ammoniation agent be 1: 8～18, permissible error＜5%; The alcoholic solvent consumption is every gram
8～18ml.
3. the synthetic method of the derivative of a kind of chiral pyridyl class aromatic ring amino alcohol according to claim 2 is characterized in that: wherein in step (1), the ether solvent consumption is every gram main raw material
Be 22～30mL; Raw material
With the mol ratio consumption of reductive agent be 1: 0.9～1.2; Raw material
Yu oxazole boranes catalyst molar ratio consumption be 1: 0.05～0.07: reduction reaction temperature is 25 ± 1 ℃; In step (2), the aminating reaction temperature is 35 ± 1 ℃;
With the mole dosage of ammoniation agent be 1: 10～12, permissible error＜5%; The alcoholic solvent consumption is every gram
Be 10～16ml.
4. the synthetic method of the derivative of a kind of chiral pyridyl class aromatic ring amino alcohol according to claim 1 is characterized in that: wherein in step (1), ether solvent comprises ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, methyl tertiary butyl ether or phenyl ether; Reductive agent comprises borine dimethyl sulphide or diborane; In step (2), alcoholic solvent comprises methyl alcohol, ethanol, propyl alcohol, Virahol or butanols; Ammoniation agent comprises liquefied ammonia, ammoniacal liquor, methylamine, ethamine or benzylamine.
5. the synthetic method of the derivative of according to claim 1 or 4 described a kind of chiral pyridyl class aromatic ring amino alcohols is characterized in that: wherein in step (1), ether solvent is tetrahydrofuran (THF), and reductive agent is the borine dimethyl sulphide; Alcoholic solvent in step (2) is methyl alcohol, and ammoniation agent is liquefied ammonia or methylamine.
6. the synthetic method of the derivative of one of according to claim 1～4 described a kind of chiral pyridyl class aromatic ring amino alcohols is characterized in that the intermediate product in step (1) wherein
R1 is ethyl, and X is fluorine, namely
The alcohol chiral centre is S or R configuration.
7. the synthetic method of the derivative of a kind of chiral pyridyl class aromatic ring amino alcohol according to claim 6, it is characterized in that: described intermediate product is 1-S-(2-fluorine pyridin-3-yl)-1-propyl alcohol,
H-NMR:(300MHZ, CDCl3), δ 0.688 (CH3, t), δ 1.352 (with H, the m on the CH2 that is connected on CH3), δ 4.418 (be connected with hydroxyl-H, m on CH), the δ 5.099 (H on OH, d), δ 7.425 (pyridine ring 5 upper H, m), δ 8.121 (4 upper H of pyridine ring, d), δ 8.391 (pyridine ring 6 upper H, d).
8. the synthetic method of the derivative of one of according to claim 1～4 described a kind of chiral pyridyl class aromatic ring amino alcohols is characterized in that: the final product in step (2) wherein
Be ethyl, R2 is H, namely
The alcohol chiral centre is S or R configuration.
9. the synthetic method of the derivative of a kind of chiral pyridyl class aromatic ring amino alcohol according to claim 8, it is characterized in that: described final product is 1-S-(PA-3-yl)-1-propyl alcohol,
H-NMR:(300MHZ, CDCl3), δ 0.672 (CH3, t), δ 1.261 (CH2, m), δ 4.418 (be connected with hydroxyl-H, m on CH),
δ 5.099 (H, d on OH), δ 6.351 (NH2, s),
δ 6.531 (pyridine ring 5 upper H, m), δ 7.351 (pyridine ring 4 upper H, d),
δ 8.001 (pyridine ring 6 upper H, d).
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