CN105130951A - Chiral ND-322, ND-364 or ND-364 sulfoxide analog and preparation method therefor - Google Patents

Chiral ND-322, ND-364 or ND-364 sulfoxide analog and preparation method therefor Download PDF

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CN105130951A
CN105130951A CN201510532246.8A CN201510532246A CN105130951A CN 105130951 A CN105130951 A CN 105130951A CN 201510532246 A CN201510532246 A CN 201510532246A CN 105130951 A CN105130951 A CN 105130951A
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phenyl
phenoxy group
thiirane
ethanamide
methylene radical
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CN105130951B (en
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张颖杰
徐文方
闫玉刚
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Zhongchuang Hecheng Shandong Pharmaceutical Technology Co ltd
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Shandong University
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D331/00—Heterocyclic compounds containing rings of less than five members, having one sulfur atom as the only ring hetero atom
    • C07D331/02—Three-membered rings

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Abstract

The invention relates to a chiral ND-322, ND-364 or ND-364 sulfoxide analog and a preparation method therefor, and belongs to the technical field of pharmaceutical active compound synthesis. The chiral ND-322, ND-364 or ND-364 sulfoxide analog takes chiral glycidol as a starting material, and finally the chiral ND-322, ND-364 or ND-364 sulfoxide analog is prepared. The preparation method is simple in process and high in yield, is suitable for industrial production, and is beneficial to developing more specific pharmaceutical active study.

Description

Chirality ND-322, ND-364 or ND-364 sulfoxide analogue and preparation method thereof
Technical field
The invention belongs to chemosynthesis technical field, particularly chirality ND-322, ND-364 or ND-364 sulfoxide analogue and preparation method thereof.
Background technology
Matrix metalloproteinase is zine ion dependency endopeptidase, and its function is for regulating cell to be matrix.Under pathological state, with tumor growth, metastases, angiogenesis, sacroiliitis, connective tissue disease (CTD), inflammation, cardiovascular disorder, DPN is relevant with autoimmune disease.Up to the present, found that wherein, gelatinase is relevant to various diseases, causes great attention more than 26 hypotypes.Wherein, ND-322 and ND-364 is effective as selective gelatinase inhibitor.But the compound reported is raceme, and structural formula is as follows:
The preparation method reported in prior art only relates to the synthesis of raceme ND-322 and ND-364, optically active ND-322 and ND-364 can not be prepared, and ND-364 sulfoxide analogue, not open about optically active ND-322 and ND-364 in prior art yet, and the enlightenment of ND-364 sulfoxide analogue and preparation.
Summary of the invention
The invention provides chirality ND-322, ND-364 or ND-364 sulfoxide analogue and preparation method, the method technique is simple, cost is low, productive rate is higher, suitability for industrialized is produced.
Technical scheme of the present invention is as follows:
Chirality ND-322, ND-364 or ND-364 sulfoxide analogue of the present invention is respectively:
(S)-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) aniline salt hydrochlorate (8),
(R)-4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) anilinechloride (9),
(S)-N-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) ethanamide (12),
(R)-N-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) ethanamide (13),
N-(4-(4-((S)-(((S)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (16),
N-(4-(4-((R)-(((S)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (17),
N-(4-(4-((S)-(((R)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (18),
N-(4-(4-((R)-(((R)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (19).
Structural formula is as follows:
The preparation method of chirality ND-322, ND-364 or ND-364 sulfoxide analogue:
1. the preparation method of (S)-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) aniline salt hydrochlorate (8) and (R)-4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) anilinechloride (9), step is as follows:
(1) (R)-Racemic glycidol and Tosyl chloride generation chlorosulfonation react to obtain compound 2;
Compound 2
(2) reacting to obtain compound 3 with thiohydroquinone again, this step, there is nucleophilic substitution reaction with the C-3 of (R)-Racemic glycidol in sulfydryl, and three-dimensional arrangement keeps;
Compound 3
(3) under the existence of mineral alkali cesium carbonate, react with p-fluoronitrobenzene and form oxyethane one step and complete to obtain compound 4;
Compound 4
(4), under acidic conditions, after zinc powder reduction nitro, after alkalization, amino the compound 5 of BOC acid anhydrides protection is directly added;
Compound 5
(5) compound 6 is oxidized to obtain through over cure after;
Compound 6
(6) oxyethane changes into thiirane and obtains compound 7;
Compound 7
(7) N-Boc deprotection obtains end product (S)-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) aniline salt hydrochlorate (8); When oxyethane changes into thiirane, steric configuration reverses;
(8) preparation method of end product (R)-4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) anilinechloride (9) and (S)-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) aniline salt hydrochlorate (8) is similar, and just starting raw material is (S)-Racemic glycidol.
Preferred according to the present invention: the preparation method of (S)-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) aniline salt hydrochlorate (8) and (R)-4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) anilinechloride (9), concrete preparation process is as follows:
(1) preparation of (S)-ethylene oxide-2-methylene radical 4-toluene sulfonic acide ester (2)
Tosyl chloride is dissolved in the methylene dichloride heavily steamed, and (R)-Racemic glycidol is added solution.At 0 DEG C, be added drop-wise to by triethylamine in reaction solution, reaction 2-5 hour, evaporate to dryness, crosses post.Obtain white (S)-ethylene oxide-2-methylene radical 4-toluene sulfonic acide ester solid; Wherein, Tosyl chloride is 1:1-2:1 with the molar ratio of (R)-Racemic glycidol;
(2) preparation of (R)-2-hydroxyl-3-((4-hydroxyphenyl) sulfo-) propyl group 4-toluene sulfonic acide ester (3)
(S)-ethylene oxide-2-methylene radical 4-toluene sulfonic acide ester, 4-mercapto-phenol is dissolved in anhydrous methylene chloride, at 0 DEG C, drip triethylamine.After dropwising, remove ice bath, room temperature reaction 4-5 hour, evaporate to dryness, cross post; Obtain white (R)-2-hydroxyl-3-((4-hydroxyphenyl) sulfo-) propyl group 4-toluene sulfonic acide ester solid; Wherein, the molar ratio of (S)-ethylene oxide-2-methylene radical 4-toluene sulfonic acide ester and 4-mercapto-phenol is 1:1-2:3;
(3) preparation of (R)-2-(((4-(4-nitrophenoxy) phenyl) sulfo-) methyl) oxyethane (4)
(R)-2-hydroxyl-3-((4-hydroxyphenyl) sulfo-) propyl group 4-toluene sulfonic acide ester is dissolved in anhydrous dimethyl formamide, and under room temperature, 4-nitrophenols and cesium carbonate join in reaction solution, reaction 10-15 hour; Add suitable quantity of water, extraction into ethyl acetate, organic layer washes three times by saturated nacl aqueous solution, anhydrous magnesium sulfate drying, filters, evaporate to dryness, crosses post; Obtain faint yellow oily (R)-2-(((4-(4-nitrophenoxy) phenyl) sulfo-) methyl) oxyethane; Wherein, the molar ratio of (R)-2-hydroxyl-3-((4-hydroxyphenyl) sulfo-) propyl group 4-toluene sulfonic acide ester and 4-nitrophenols is 1:1-1:2;
(4) preparation of the tertiary butyl (R)-(4-(4-((ethylene oxide-2-methylene radical) sulfo-) phenoxy group) phenyl) carbamate (5)
(R)-2-(((4-(4-nitrophenoxy) phenyl) sulfo-) methyl) oxyethane is dissolved in anhydrous tetrahydro furan.Ice bath, adds zinc powder, drips acetic acid; React 15 minutes, filter, add anhydrous methanol in filtrate, under ice bath, add triethylamine, react 5 minutes; Add two dimethyl dicarbonate butyl esters and react half an hour, remove ice bath, room temperature reaction 24 hours; Evaporate to dryness, crosses post, obtains the faint yellow oily tertiary butyl (R)-(4-(4-((ethylene oxide-2-methylene radical) sulfo-) phenoxy group) phenyl) carbamate; Wherein, the molar ratio of (R)-2-(((4-(4-nitrophenoxy) phenyl) sulfo-) methyl) oxyethane and two dimethyl dicarbonate butyl esters is 1:1-1:10;
(5) preparation of the tertiary butyl (R)-(4-(4-((ethylene oxide-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) carbamate (6)
The tertiary butyl (R)-(4-(4-((ethylene oxide-2-methylene radical) sulfo-) phenoxy group) phenyl) carbamate is dissolved in anhydrous methylene chloride, add tetraisopropoxy titanium, under room temperature, drip cumyl hydroperoxide, reaction 1-2 hour; Post is crossed with ethyl acetate/petroleum ether system flash, evaporate to dryness, vacuum-drying, obtains the white solid tertiary butyl (R)-(4-(4-((ethylene oxide-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) carbamate; Wherein, the tertiary butyl (R)-(4-(4-((ethylene oxide-2-methylene radical) sulfo-) phenoxy group) phenyl) carbamate; Wherein, the tertiary butyl (R)-(4-(4-((ethylene oxide-2-methylene radical) sulfo-) phenoxy group) phenyl) carbamate, the molar ratio of tetraisopropoxy titanium and cumyl hydroperoxide is 1:1:1-1:2:3;
(6) preparation of the tertiary butyl (S)-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) carbamate (7)
The tertiary butyl (R)-(4-(4-((ethylene oxide-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) carbamate is dissolved in anhydrous methylene chloride and anhydrous methanol, and add thiocarbamide, reaction is spent the night; Flash post is crossed by ethyl acetate/petroleum ether system, evaporate to dryness, vacuum-drying obtains the white solid tertiary butyl (S)-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) carbamate, wherein, the molar ratio of the tertiary butyl (R)-(4-(4-((ethylene oxide-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) carbamate and thiocarbamide is 1:1-1:10;
(7) preparation of (S)-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) aniline salt hydrochlorate (8)
The tertiary butyl (S)-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) carbamate is dissolved in saturated Hydrochloride/ethyl acetate, reaction is spent the night, filtering solids, vacuum-drying obtains white solid (S)-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) aniline salt hydrochlorate;
(8) preparation of (R)-4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) anilinechloride (9)
Preparation (R)-4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) anilinechloride method and preparation (S)-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) aniline salt Barbiturates seemingly; just starting raw material makes (S)-Racemic glycidol into, and (R)-4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) anilinechloride is white powder.
It is preferred further,
In above-mentioned steps (1), Tosyl chloride is 3:2 with the molar ratio of (R)-Racemic glycidol;
In above-mentioned steps (2), the molar ratio of (S)-ethylene oxide-2-methylene radical 4-toluene sulfonic acide ester and 4-mercapto-phenol is 5:6;
In above-mentioned steps (3), the molar ratio of (R)-2-hydroxyl-3-((4-hydroxyphenyl) sulfo-) propyl group 4-toluene sulfonic acide ester and 4-nitrophenols is 5:6;
In above-mentioned steps (4), the molar ratio of (R)-2-(((4-(4-nitrophenoxy) phenyl) sulfo-) methyl) oxyethane and two dimethyl dicarbonate butyl esters is 1:5;
In above-mentioned steps (5), the tertiary butyl (R)-(4-(4-((ethylene oxide-2-methylene radical) sulfo-) phenoxy group) phenyl) carbamate, the molar ratio of tetraisopropoxy titanium and cumyl hydroperoxide is 5:6:10;
In above-mentioned steps (6), the molar ratio of the tertiary butyl (R)-(4-(4-((ethylene oxide-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) carbamate and thiocarbamide is 1:5.
2. the preparation method of (S)-N-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) ethanamide (12) and (R)-N-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) ethanamide (13), step is as follows:
(9) reducing compound 4, acetylated compound 10 then;
Compound 10
(10) through over cure oxidation after, compound 11 is obtained;
Compound 11
(11) oxyethane changes into thiirane and obtains compound (S)-N-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) ethanamide (12); When oxyethane changes into thiirane, steric configuration reverses;
(12) preparation method of end product (R)-N-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) ethanamide (13) and (S)-N-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) ethanamide (12) is similar, is just (S)-Racemic glycidol by starting raw material.
Preferred according to the present invention; (S) preparation method of-N-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) ethanamide (12) and (R)-N-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) ethanamide (13), concrete preparation process is as follows:
(9) preparation of (R)-N-(4-(4-((ethylene oxide-2-methylene radical) sulfo-) phenoxy group) phenyl) ethanamide (10)
(S)-2-(((4-(4-nitrophenoxy) phenyl) sulfo-) methyl) oxyethane is dissolved in anhydrous tetrahydro furan; Ice bath, adds zinc powder, drips acetic acid; React 15 minutes, filter, add anhydrous methanol in filtrate, under ice bath, add triethylamine, react 5 minutes; Be added dropwise to Acetyl Chloride 98Min., react 15 minutes, evaporate to dryness, add water, ethyl acetate extracts three times, has the saturated sodium sulfide solution of basic unit to wash three times, anhydrous magnesium sulfate drying, evaporate to dryness, crosses post, obtains faint yellow solid (R)-N-(4-(4-((ethylene oxide-2-methylene radical) sulfo-) phenoxy group) phenyl) ethanamide; Wherein, the molar ratio of (S)-2-(((4-(4-nitrophenoxy) phenyl) sulfo-) methyl) oxyethane and Acetyl Chloride 98Min. is 1:1-1:100;
(10) preparation of (R)-N-(4-(4-((ethylene oxide-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) ethanamide (11)
(R)-N-(4-(4-((ethylene oxide-2-methylene radical) sulfo-) phenoxy group) phenyl) ethanamide is dissolved in anhydrous methylene chloride, add tetraisopropoxy titanium, under room temperature, drip cumyl hydroperoxide, react 1 hour; Cross flash post by ethyl acetate/petroleum ether system, evaporate to dryness, vacuum-drying, obtain white solid (R)-N-(4-(4-((ethylene oxide-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) ethanamide; Wherein, (R)-N-(4-(4-((ethylene oxide-2-methylene radical) sulfo-) phenoxy group) phenyl) ethanamide, the molar ratio of tetraisopropoxy titanium and cumyl hydroperoxide is 1:1:1-1:2:3;
(11) preparation of (S)-N-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) ethanamide (12)
Under room temperature, (R)-N-(4-(4-((ethylene oxide-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) ethanamide is dissolved in anhydrous tetrahydro furan and anhydrous methanol, and add thiocarbamide, reaction is spent the night; Flash post is crossed by ethyl acetate/petroleum ether system, evaporate to dryness, vacuum-drying, obtain white solid (S)-N-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) ethanamide, wherein, the molar ratio of (R)-N-(4-(4-((ethylene oxide-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) ethanamide and thiocarbamide is 1:1-1:10;
(12) preparation of (R)-N-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) ethanamide (13)
Ethanamide seemingly for preparation (R)-N-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) ethanamide (13) method and preparation (S)-N-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl); just starting raw material makes (S)-Racemic glycidol into, and (R)-N-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) ethanamide is white solid.
It is preferred further,
In above-mentioned steps (9), the molar ratio of (S)-2-(((4-(4-nitrophenoxy) phenyl) sulfo-) methyl) oxyethane and Acetyl Chloride 98Min. is 1:50;
In above-mentioned steps (10), (R)-N-(4-(4-((ethylene oxide-2-methylene radical) sulfo-) phenoxy group) phenyl) ethanamide, the molar ratio of tetraisopropoxy titanium and cumyl hydroperoxide is 5:6:10;
In above-mentioned steps (11), the molar ratio of (R)-N-(4-(4-((ethylene oxide-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) ethanamide and thiocarbamide is 1:5.
3.N-(4-(4-((S)-(((S)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (16), N-(4-(4-((R)-(((S)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (17), the preparation method of N-(4-(4-((S)-(((R)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (18) and N-(4-(4-((R)-(((R)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (19), step is as follows:
(13), at catalyzer tetraisopropoxy titanium, under the existence of part D-(-)-diethyl tartrate, cumyl hydroperoxide (tech.80%) oxygenated compound 10 obtains compound 14;
Compound 14
(14) change into thiirane through oxyethane after and obtain compound N-(4-(4-((S)-(((S)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (16); When oxyethane changes into thiirane, steric configuration reverses;
(15) end product N-(4-(4-((R)-(((S)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (17) is similar with the preparation method of compound 16, just changes part into L-(+)-diethyl tartrate.
(16) end product N-(4-(4-((S)-(((R)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (18) is similar respectively at the preparation method of compound 16, and just starting raw material is (S)-Racemic glycidol.
(17) preparation method of end product N-(4-(4-((R)-(((R)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (19) and compound 17 is similar, and just starting raw material is (S)-Racemic glycidol.
Preferred according to the present invention, N-(4-(4-((S)-(((S)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (16), N-(4-(4-((R)-(((S)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (17), the preparation method of N-(4-(4-((S)-(((R)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (18) and N-(4-(4-((R)-(((R)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (19), concrete preparation process is as follows:
(13) preparation of N-(4-(4-((S)-(((R)-ethylene oxide-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (14)
(R)-N-(4-(4-((ethylene oxide-2-methylene radical) sulfo-) phenoxy group) phenyl) ethanamide is dissolved in anhydrous methylene chloride, add tetraisopropoxy titanium and D-(-)-diethyl tartrate, react 5 minutes under room temperature, 0 DEG C drips cumyl hydroperoxide, reacts 24 hours; Flash post is crossed by ethyl acetate/petroleum ether system, evaporate to dryness, vacuum-drying obtains white solid, N-(4-(4-((S)-(((R)-ethylene oxide-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide; Wherein, (R)-N-(4-(4-((ethylene oxide-2-methylene radical) sulfo-) phenoxy group) phenyl) ethanamide, D-(-)-diethyl tartrate, the molar ratio of tetraisopropoxy titanium and cumyl hydroperoxide is 1:1:1:1-1:8:6:6;
(14) preparation of N-(4-(4-((S)-(((S)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (16)
N-(4-(4-((S)-(((R)-ethylene oxide-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide is dissolved in anhydrous tetrahydro furan and anhydrous methanol, add thiocarbamide, reaction is spent the night; Flash post is crossed by ethyl acetate/petroleum ether system, evaporate to dryness, vacuum-drying obtains white solid N-(4-(4-((S)-(((S)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide; Wherein, the molar ratio of N-(4-(4-((S)-(((R)-ethylene oxide-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide and thiocarbamide is 1:1-1:10;
(15) preparation of N-(4-(4-((R)-(((S)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (17)
Prepare N-(4-(4-((R)-(((S)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide and prepare compound 16 similar, just change the part in preparation process into L-(+)-diethyl tartrate (L-DET), final N-(4-(4-((R)-(((S)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide white solid;
(16) preparation of N-(4-(4-((S)-(((R)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (18)
N-(4-(4-((S)-(((R)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide is with to prepare compound 16 similar, just change starting raw material into (S)-Racemic glycidol, final N-(4-(4-((S)-(((R)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide white solid;
(17) preparation of N-(4-(4-((R)-(((R)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (19)
N-(4-(4-((R)-(((R)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide is with to prepare compound 17 similar; just change starting raw material into (S)-Racemic glycidol, final N-(4-(4-((R)-(((R)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide white solid.
It is preferred further,
In above-mentioned steps (13), (R)-N-(4-(4-((ethylene oxide-2-methylene radical) sulfo-) phenoxy group) phenyl) ethanamide, D-(-)-diethyl tartrate, the molar ratio of tetraisopropoxy titanium and cumyl hydroperoxide is 2:8:3:4;
In above-mentioned steps (14), the molar ratio of N-(4-(4-((S)-(((R)-ethylene oxide-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide and thiocarbamide is 1:5.
Detailed Description Of The Invention:
The preparation method of chirality ND-322, ND-364 or ND-364 sulfoxide analogue of the present invention, step is as follows:
(1) preparation of end product (S)-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) aniline salt hydrochlorate (8) and (R)-4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) anilinechloride (9), its syntheti c route is as follows:
Syntheti c route: (R)-Racemic glycidol and Tosyl chloride generation chlorosulfonation react to obtain compound 2, compound 3 is reacted to obtain again with thiohydroquinone, this step, there is nucleophilic substitution reaction with the C-3 of (R)-Racemic glycidol in sulfydryl, three-dimensional arrangement keeps; Under the existence of mineral alkali cesium carbonate, react and formed the compound 4 that oxyethane one step completes with p-fluoronitrobenzene, under acidic conditions, after zinc powder reduction nitro, after alkalization, directly add the compound 5 that the protection of BOC acid anhydrides is amino; Be oxidized through over cure afterwards, oxyethane changes into thiirane, and N-Boc deprotection obtains end product (S)-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) aniline salt hydrochlorate (8); When oxyethane changes into thiirane, steric configuration reverses; The preparation method of end product (R)-4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) anilinechloride (9) and (S)-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) aniline salt hydrochlorate (8) is similar, is just (S)-Racemic glycidol by starting raw material.
Syntheti c route reaction formula is as follows:
Reagent in above-mentioned syntheti c route reaction formula: (a) Tosyl chloride, triethylamine, methylene dichloride, 0 DEG C of (b) thiohydroquinone, triethylamine, methylene dichloride, 0 DEG C of (c) p-fluoronitrobenzene, cesium carbonate, N, dinethylformamide, room temperature (d) zinc powder, acetic acid, tetrahydrofuran (THF), 0 DEG C, BOC acid anhydrides, triethylamine, 0 DEG C-room temperature (e) tetraisopropoxy titanium, cumyl hydroperoxide (tech.80%), methylene dichloride, room temperature (f) thiocarbamide, methylene dichloride, methyl alcohol, room temperature (g) saturated salt acid ethyl acetate solution, room temperature.
(2) preparation of end product (S)-N-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) ethanamide (12) and (R)-N-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) ethanamide (13), its syntheti c route is as follows:
Syntheti c route: reducing compound 4, then acetylated compound 10, afterwards through over cure oxidation, oxyethane changes into thiirane and obtains compound (S)-N-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) ethanamide (12); When oxyethane changes into thiirane, steric configuration reverses.The preparation method of end product (R)-N-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) ethanamide (13) and (S)-N-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) ethanamide (12) is similar, is just (S)-Racemic glycidol by starting raw material.Syntheti c route reaction formula is as follows:
Reagent in above-mentioned syntheti c route reaction formula: (a) zinc powder, acetic acid, tetrahydrofuran (THF), 0 DEG C, Acetyl Chloride 98Min., triethylamine, methyl alcohol, 0 DEG C-room temperature (b) tetraisopropoxy titanium, cumyl hydroperoxide (tech.80%), methylene dichloride, room temperature (c) thiocarbamide, tetrahydrofuran (THF), methyl alcohol, room temperature.
(3) end product N-(4-(4-((S)-(((S)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (16), N-(4-(4-((R)-(((S)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (17), the preparation of N-(4-(4-((S)-(((R)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (18) and N-(4-(4-((R)-(((R)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (19), its syntheti c route is as follows:
Syntheti c route: at catalyzer tetraisopropoxy titanium; part D-(-)-diethyl tartrate; under the existence of oxygenant cumyl hydroperoxide (tech.80%); react to obtain compound 14 with compound 10, change into thiirane through oxyethane afterwards and obtain compound N-(4-(4-((S)-(((S)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (16).When oxyethane changes into thiirane, steric configuration reverses.End product N-(4-(4-((R)-(((S)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (17) is similar with the preparation method of compound 16, just changes part into L-(+)-diethyl tartrate.End product N-(4-(4-((S)-(((R)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (18) and N-(4-(4-((R)-(((R)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (19) similar respectively at the preparation method of compound 16 and compound 17, just starting raw material is (S)-Racemic glycidol.
Syntheti c route reaction formula is as follows:
Reagent in above-mentioned syntheti c route reaction formula: (a) tetraisopropoxy titanium, D-(-)-diethyl tartrate, cumyl hydroperoxide (tech.80%), methylene dichloride, room temperature-0 DEG C (b) tetraisopropoxy titanium, L-(+)-diethyl tartrate, cumyl hydroperoxide (tech.80%), methylene dichloride, room temperature-0 DEG C (c) thiocarbamide, tetrahydrofuran (THF), methyl alcohol, room temperature.
Technical characterstic of the present invention and excellent results as follows:
1, the present invention take chiral glycidol as starting raw material, has finally prepared chirality ND-322, ND-364 and ND-364 sulfoxide analogue, and technique is simple, and cost is low, step is short, is applicable to suitability for industrialized production.
2, preparation method's productive rate of the present invention is higher, often walks productive rate all more than 75%.
3, agents useful for same clean environment firendly of the present invention, is conducive to environment protection.
Embodiment
Further explain and describe content of the present invention by the following examples.But the embodiment provided should not be understood to be construed as limiting scope.Described room temperature refers to 10 DEG C ~ 30 DEG C.
The preparation method 1 of embodiment 1, (S)-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) aniline salt hydrochlorate (8) and (R)-4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) anilinechloride (9), the preparation of (S)-ethylene oxide-2-methylene radical 4-toluene sulfonic acide ester (2)
Tosyl chloride (25.0g) is dissolved in the methylene dichloride (250mL) heavily steamed, and (R)-Racemic glycidol (6.0mL) is added solution.At 0 DEG C, triethylamine (36.0mL) is added drop-wise in reaction solution, reacts 3 hours, evaporate to dryness, cross post.Obtain 17.6g white solid, productive rate 85.0%.Fusing point: 44-46 DEG C; [α] 25 d=+18.3 (c1.7, acetonitrile) .IR (KBr) 1598,1363,1177,969,666,556. 1hNMR (400MHz, DMSO-d 6) δ 7.83 (d, J=8.1Hz, 2H), 7.52 – 7.46 (m, 2H), 4.43 (d, J=11.6Hz, 1H), 3.85 (dddd, J=7.0,5.7,3.7,1.9Hz, 1H), 3.26 – 3.17 (m, 1H), 2.78 (t, J=4.6Hz, 1H), 2.66 – 2.58 (m, 1H), 2.42 (s, 3H) .ESI-MSm/z:251.2 [M+Na] +.
The preparation of 2, (R)-2-hydroxyl-3-((4-hydroxyphenyl) sulfo-) propyl group 4-toluene sulfonic acide ester (3)
(S)-ethylene oxide-2-methylene radical 4-toluene sulfonic acide ester (9.0g), 4-mercapto-phenol (5.0g) is dissolved in anhydrous methylene chloride (150mL), drips triethylamine (11.1mL) at 0 DEG C.After dropwising, remove ice bath, room temperature reaction 4-5 hour, evaporate to dryness, cross post.Obtain 5.9g white solid, productive rate 81.5%.Fusing point: 96-98 DEG C; [α] 25 d=+24.3 (c0.6, acetonitrile) .IR (KBr) 3372,3146,1597,1582,1495,1365,1257,1190,1177,1097,1074,988,905,829,815,792,665,555. 1hNMR (400MHz, DMSO-d 6) δ 9.58 (s, 1H), 7.76 (d, J=8.3Hz, 2H), 7.48 (d, J=8.1Hz, 2H), 7.15 (d, J=8.6Hz, 2H), 6.71 (d, J=8.6Hz, 2H), 5.42 (d, J=5.2Hz, 1H), 4.06 (dd, J=10.1,3.3Hz, 1H), 3.92 (dd, J=10.1,6.3Hz, 1H), 3.69-3.59 (m, 1H), 2.77 (d, J=6.5Hz, 2H), 2.43 (s, 3H) .ESI-MSm/z:377.4 [M+Na] +.ESI-MSm/z:353.4 [M-H] -.
The preparation of 3, (R)-2-(((4-(4-nitrophenoxy) phenyl) sulfo-) methyl) oxyethane (4)
(R)-2-hydroxyl-3-((4-hydroxyphenyl) sulfo-) propyl group 4-toluene sulfonic acide ester (3.0g) is dissolved in anhydrous dimethyl formamide (50mL), under room temperature, 4-nitrophenols (3.0g) and cesium carbonate (8.1g) join in reaction solution, react 12 hours.Add suitable quantity of water, extraction into ethyl acetate, organic layer washes three times by saturated nacl aqueous solution, anhydrous magnesium sulfate drying, filters, evaporate to dryness, crosses post.Obtain the faint yellow oil of 4.15g.Productive rate: 83.0%; [α] 25 d=-3.5 (c0.5, acetonitrile) .IR (KBr) 1582,1487,1343,1243,877,846,751. 1hNMR (400MHz, DMSO-d 6) δ 8.29 – 8.23 (m, 2H), 7.57 – 7.51 (m, 2H), 7.19 – 7.12 (m, 4H), 3.24 – 3.11 (m, 3H), 2.78 – 2.74 (m, 1H), 2.59 (dd, J=5.1,2.2Hz, 1H) .ESI-MSm/z:304.4 [M+H] +.ESI-MSm/z:348.4 [M+HCOO] -.
4, the preparation of the tertiary butyl (R)-(4-(4-((ethylene oxide-2-methylene radical) sulfo-) phenoxy group) phenyl) carbamate (5)
(R)-2-(((4-(4-nitrophenoxy) phenyl) sulfo-) methyl) oxyethane (3.7g) is dissolved in anhydrous tetrahydro furan (60mL).Under ice bath, add zinc powder (32g), drip acetic acid (13.9mL).React 15 minutes, filter, add anhydrous methanol (60mL) in filtrate, under ice bath, add triethylamine (37mL), react 5 minutes.Add two dimethyl dicarbonate butyl esters (12.8g) and react half an hour, remove ice bath, room temperature reaction 24 hours.Evaporate to dryness, crosses post and obtains the faint yellow oil of product 3.7g, productive rate 81.1%.Fusing point: 82-84 DEG C; [α] 25 d=-0.39 (c1.0, acetonitrile) .IR (KBr) 3345,3298,2978,2918,1718,1488,1229,1155,1053,852,826,771,738. 1hNMR (400MHz, DMSO-d 6) δ 9.37 (s, 1H), 7.50 – 7.40 (m, 4H), 7.00 – 6.87 (m, 4H), 3.13 – 3.02 (m, 3H), 2.75 – 2.70 (m, 1H), 2.53 – 2.51 (m, 1H), 1.48 (s, 9H) .ESI-MSm/z:374.4 [M+H] +.ESI-MSm/z:372.3 [M-H] -.
5, the preparation of the tertiary butyl (R)-(4-(4-((ethylene oxide-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) carbamate (6)
The tertiary butyl (R)-(4-(4-((ethylene oxide-2-methylene radical) sulfo-) phenoxy group) phenyl) carbamate (3.5g) is dissolved in anhydrous methylene chloride (30mL), add tetraisopropoxy titanium (3.8mL), under room temperature, drip cumyl hydroperoxide (80%, 2.2mL), react 1 hour.Cross post with ethyl acetate/petroleum ether system flash, evaporate to dryness, vacuum-drying obtains 3.3g white solid, productive rate 87.3%.Fusing point: 118-120 DEG C; [α] 25 d=-14.1 (c0.6, acetonitrile) .IR (KBr) 3334,2980,1699,1527,1490,1407,1368,1312,1234,1143,850,834,767,566. 1hNMR (400MHz, DMSO-d 6) δ 9.47 (s, 1H), 7.89 – 7.83 (m, 2H), 7.55 (d, J=8.9Hz, 2H), 7.13 – 7.06 (m, 4H), 3.68 (dd, J=14.6,4.3Hz, 1H), 3.50 (dd, J=14.6,7.1Hz, 1H), 3.158 – 3.113 (m, 1H), 2.72 (dd, J=5.2,4.1Hz, 1H), 2.44 (dd, J=5.3,2.5Hz, 1H), 1.48 (s, 9H) .ESI-MSm/z:428.4 [M+Na] +.ESI-MSm/z:404.6 [M-H] -.
6, the preparation of the tertiary butyl (S)-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) carbamate (7)
The tertiary butyl (R)-(4-(4-((ethylene oxide-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) carbamate (2.0g) is dissolved in anhydrous methylene chloride (15mL) and anhydrous methanol (30mL); add thiocarbamide (2.0g), reaction is spent the night.Cross flash post by ethyl acetate/petroleum ether system, evaporate to dryness, vacuum-drying obtains 1.76g white solid, productive rate 84.5%.Fusing point: 158-160 DEG C; [α] 25 d=-0.7 (c0.14, acetonitrile) .IR (KBr) 3325,2979,1698,1530,1310,1239,1140,851,834,768,565,550,515. 1hNMR (400MHz, DMSO-d 6) δ 9.47 (s, 1H), 7.92 – 7.84 (m, 2H), 7.54 (d, J=8.9Hz, 2H), 7.14 – 7.06 (m, 4H), 3.62 (d, J=6.7Hz, 2H), 2.98 (dd, J=6.4,5.5Hz, 1H), 3.013 – 2.951 (m, 1H), 2.19 (dd, J=5.3,1.2Hz, 1H), 1.48 (s, 9H) .ESI-MSm/z:444.5 [M+Na] +.ESI-MSm/z:420.3 [M-H] -.
Compound 8, the synthetic method of 9 is similar.
7, the preparation of (S)-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) aniline salt hydrochlorate (8)
The tertiary butyl (S)-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) carbamate (1.7g) is dissolved in the saturated Hydrochloride/ethyl acetate of 20mL.Reaction is spent the night.Filtering solids, vacuum-drying obtains 1.28g white solid, productive rate 89.0%.Fusing point: 192-194 DEG C; 96.2%ee [pillar, CHIRALPAKIA (4.6mmI.D. × 250mm.5um); Moving phase, normal hexane/ethanol=50/50 (V/V); Flow velocity, 0.8mL/min; Detect, UV244nm; Temperature, room temperature]; [α] 25 d=+5.2 (c0.7, methyl alcohol) .IR (KBr) 2850,2595,1586,1501,1488,1314,1254,1142,1085,876,860,826,780,516. 1hNMR (400MHz, DMSO-d 6) δ 10.23 (br, 3H), 7.95 – 7.90 (m, 2H), 7.48 – 7.43 (m, 2H), 7.30 – 7.24 (m, 2H), 7.23 – 7.18 (m, 2H), 3.72 – 3.59 (m, 2H), 3.05 – 2.95 (m, 1H), 2.56 (dd, J=6.3,1.1Hz, 1H), 2.20 (dd, J=5.3,1.2Hz, 1H) .ESI-MSm/z:344.4 [M+Na] +.ESI-MSm/z:320.3 [M-H] -.HRMSm/z:calcdforC 15h 15nO 3s 2[M+H] +322.0493, found:322.0566.
The preparation of 8, (R)-4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) anilinechloride (9)
Prepare (R)-4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) anilinechloride (9) method and prepare compound 8 similar; just starting raw material makes (S)-Racemic glycidol into, and compound 9 is white powder.Productive rate: 87.4%; Fusing point: 152-154 DEG C; 96.2%ee [pillar, CHIRALPAKIA (4.6mmI.D. × 250mm.5um); Moving phase, normal hexane/ethanol=50/50 (V/V); Flow velocity, 0.8mL/min; Detect, UV244nm; Temperature, room temperature]; [α] 25 d=-14.5 (c1.0, methyl alcohol) .IR (KBr) 2853,2579,1590,1508,1489,1313,1259,1143,1087,877,853,831,549,519. 1hNMR (400MHz, DMSO-d 6) δ 10.15 (br, 3H), 7.95 – 7.90 (m, 2H), 7.48 – 7.43 (m, 2H), 7.31 – 7.25 (m, 2H), 7.24 – 7.18 (m, 2H), 3.72 – 3.58 (m, 2H), 3.04 – 2.95 (m, 1H), 2.56 (dd, J=6.3,1.1Hz, 1H), 2.20 (dd, J=5.3,1.2Hz, 1H) .ESI-MSm/z:344.4 [M+Na] +.ESI-MSm/z:320.3 [M-H] -.HRMSm/z:calcdforC 15h 15nO 3s 2[M+H] +322.0493, found:322.0565.
The preparation method 9 of embodiment 2, (S)-N-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) ethanamide (12) and (R)-N-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) ethanamide (13), the preparation of (R)-N-(4-(4-((ethylene oxide-2-methylene radical) sulfo-) phenoxy group) phenyl) ethanamide (10)
(S)-2-(((4-(4-nitrophenoxy) phenyl) sulfo-) methyl) oxyethane (3.0g) is dissolved in anhydrous tetrahydro furan (50mL).Under ice bath, add zinc powder (26g), drip acetic acid (11.3mL).React 15 minutes, filter, add anhydrous methanol (50mL) in filtrate, under ice bath, add triethylamine (30mL), react 5 minutes.Be added dropwise to Acetyl Chloride 98Min. (7.0mL) and react 15 minutes, evaporate to dryness, add water, ethyl acetate extracts three times, has the saturated sodium sulfide solution of basic unit to wash three times, anhydrous magnesium sulfate drying, evaporate to dryness, crosses post and obtains product 2.4g faint yellow solid, productive rate 78.1%.Fusing point: 96-98 DEG C; [α] 25 d=-4.8 (c0.3, acetonitrile) .IR (KBr) 3286,1659,1552,1525,1507,1490,1277,1256,819,516. 1hNMR (400MHz, DMSO-d 6) δ 9.95 (s, 1H), 7.59 (d, J=8.9Hz, 2H), 7.43 (d, J=8.7Hz, 2H), 6.99 (d, J=8.9Hz, 2H), 6.92 (d, J=8.7Hz, 2H), 3.14 – 3.05 (m, 3H), 2.76 – 2.70 (m, 1H), 2.53 (d, J=2.2Hz, 1H), 2.03 (s, 3H) .ESI-MSm/z:316.4 [M+H] +.
The preparation of 10, (R)-N-(4-(4-((ethylene oxide-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) ethanamide (11)
(R)-N-(4-(4-((ethylene oxide-2-methylene radical) sulfo-) phenoxy group) phenyl) ethanamide (0.5g) is dissolved in anhydrous methylene chloride (15mL), add tetraisopropoxy titanium (0.47mL), under room temperature, drip cumyl hydroperoxide (tech.80%, 1.0mL), react 1 hour.Cross flash post by ethyl acetate/petroleum ether system, evaporate to dryness, vacuum-drying obtains 0.5g white solid, productive rate: 91.0%.[α] 25 d=-9.3 (c0.4, acetonitrile) .IR (KBr) 3301,1665,1531,1506,1488,1314,1296,1245,1137,839,788,680,595,554,526,508. 1hNMR (400MHz, DMSO-d 6) δ 10.04 (s, 1H), 7.92 – 7.84 (m, 2H), 7.70 – 7.65 (m, 2H), 7.19 – 7.07 (m, 4H), 3.72 – 3.40 (m, 3H), 3.159 – 3.114 (m, 1H), 2.72 (dd, J=5.2,4.2Hz, 1H), 2.44 (dd, J=5.3,2.5Hz, 1H), 2.06 (s, 3H) .ESI-MSm/z:348.4 [M+H] +.
Compound 12, the synthetic method of 13 is similar.
The preparation of 11, (S)-N-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) ethanamide (12)
Under room temperature; (R)-N-(4-(4-((ethylene oxide-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) ethanamide (0.4g) is dissolved in anhydrous tetrahydro furan (8mL) and anhydrous methanol (4mL); add thiocarbamide (0.4g), reaction is spent the night.Cross flash post by ethyl acetate/petroleum ether system, evaporate to dryness, vacuum-drying obtains 0.39g white solid, productive rate 92.5%.Fusing point: 162-164 DEG C; 92.9%ee [pillar, CHIRALPAKIA (4.6mmI.D. × 250mm.5um); Moving phase, normal hexane/ethanol/tetrahydrofuran (THF)=65/35/5 (V/V/V); Flow velocity, 1mL/min; Detect, UV251nm; Temperature, room temperature]; [α] 25 d=+1.1 (c0.4, acetonitrile) .IR (KBr) 3298,3258,3197,3138,3093,2927,1663,1615,1584,1557,1505,1489,1244,1225,1145,1087,874,858,839,755,586,542,525,511. 1hNMR (400MHz, DMSO-d 6) δ 10.05 (s, 1H), 7.88 (d, J=8.9Hz, 2H), 7.67 (d, J=8.9Hz, 2H), 7.17 – 7.09 (m, 4H), 3.63 (d, J=6.7Hz, 2H), 3.03 – 2.93 (m, 1H), 2.55 (d, J=5.5Hz, 1H), 2.19 (d, J=5.2Hz, 1H), 2.05 (s, 3H) .HRMSm/z:calcdforC 17h 17nO 4s 2[M+H] +364.0599, found:364.0674.
The preparation of 12, (R)-N-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) ethanamide (13)
Synthesis (R)-N-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) ethanamide (13) method and synthetic compound 12 similar; just starting raw material makes (S)-Racemic glycidol into, and compound 13 is white solid.Productive rate: 91.4%; Fusing point: 162-164 DEG C; 93.6%ee [pillar, CHIRALPAKIA (4.6mmI.D. × 250mm.5um); Moving phase, normal hexane/ethanol/tetrahydrofuran (THF)=65/35/5 (V/V/V); Flow velocity, 1mL/min; Detect, UV251nm; Temperature, room temperature]; [α] 25 d=-5.7 (c0.5, acetonitrile) .IR (KBr) 3298,3258,3198,3138,3093,2927,1663,1615,1557,1505,1489,1244,1145,874,859,839,755,586,542,525,511. 1hNMR (400MHz, DMSO-d 6) δ 10.05 (s, 1H), 7.88 (d, J=8.9Hz, 2H), 7.67 (d, J=8.9Hz, 2H), 7.17 – 7.08 (m, 4H), 3.63 (d, J=6.7Hz, 2H), 3.03 – 2.94 (m, 1H), 2.55 (d, J=5.5Hz, 1H), 2.19 (d, J=5.3Hz, 1H), 2.06 (s, 3H) .HRMSm/z:calcdforC 17h 17nO 4s 2[M+H] +364.0599, found:364.0683.
Embodiment 3, N-(4-(4-((S)-(((S)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (16), N-(4-(4-((R)-(((S)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (17), the preparation method of N-(4-(4-((S)-(((R)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (18) and N-(4-(4-((R)-(((R)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (19)
The preparation of 13, N-(4-(4-((S)-(((R)-ethylene oxide-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (14)
(R)-N-(4-(4-((ethylene oxide-2-methylene radical) sulfo-) phenoxy group) phenyl) ethanamide (1.0g) is dissolved in anhydrous methylene chloride (25mL), add tetraisopropoxy titanium (0.94mL) and D-(-)-diethyl tartrate (2.2mL), react 5 minutes under room temperature, 0 DEG C drips cumyl hydroperoxide (0.64mL), reacts 24 hours.Cross flash post by ethyl acetate/petroleum ether system, evaporate to dryness, vacuum-drying obtains 0.79g white solid, productive rate 75.2%.Fusing point: 86-88 DEG C; [α] 25 d=-43.8 (c0.6, acetonitrile) .IR (KBr) 3262,3198,3132,3066,2965,2920,1686,1545,1507,1489,1256,1021,852,834,523. 1hNMR (400MHz, DMSO-d 6) δ 10.01 (s, 1H), 7.71 – 7.60 (m, 4H), 7.11 (d, J=8.7Hz, 2H), 7.06 (d, J=8.9Hz, 2H), 3.26 – 3.17 (m, 1H), 3.14 – 2.99 (m, 2H), 2.84 – 2.73 (m, 1H), 2.61 (ddd, J=20.0,5.2,2.4Hz, 1H), 2.05 (s, 3H) .ESI-MSm/z:332.5 [M+H] +.
Compound 16,17, the preparation method of 18,19 and the preparation method of compound 16 similar.
The preparation of 14, N-(4-(4-((S)-(((S)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (16)
N-(4-(4-((S)-(((R)-ethylene oxide-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (0.52g) is dissolved in anhydrous tetrahydro furan (10.4mL) and anhydrous methanol (5.2mL); add thiocarbamide (0.52g), reaction is spent the night.Cross flash post by ethyl acetate/petroleum ether system, evaporate to dryness, vacuum-drying obtains 0.49g white solid, productive rate 89.4%.Fusing point: 134-136 DEG C; 23:76:1dr [pillar, CHIRALPAKIA (4.6mmI.D. × 250mm.5um); Moving phase, normal hexane/ethanol/tetrahydrofuran (THF)=74/25/1 (V/V/V); Flow velocity, 1mL/min; Detect, UV255nm; Temperature, room temperature]; [α] 25 d=-36.3 (c0.3, acetonitrile) .IR (KBr) 3297,1658,1506,1488,1245,1021,834,524. 1hNMR (400MHz, DMSO-d 6) δ 10.01 (s, 1H), 7.74 – 7.61 (m, 4H), 7.17 – 7.04 (m, 4H), 3.31 – 2.81 (m, 3H), 2.61 (d, J=6.3Hz, 1H), 2.35 (dd, J=54.8,5.2Hz, 1H), 2.05 (s, 3H) .HRMSm/z:calcdforC 17h 17nO 3s 2[M+H] +348.0650, found:348.0719.
The preparation of 15, N-(4-(4-((R)-(((S)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (17)
Prepare N-(4-(4-((R)-(((S)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide and prepare compound 16 similar; just change the part in preparation process into L-DET, final N-(4-(4-((R)-(((S)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide white solid.Productive rate: 87.2%; Fusing point: 114-116 DEG C; 60:38:2dr [pillar, CHIRALPAKIA (4.6mmI.D. × 250mm.5um); Moving phase, normal hexane/ethanol/tetrahydrofuran (THF)=74/25/1 (V/V/V); Flow velocity, 1mL/min; Detect, UV255nm; Temperature, room temperature]; [α] 25 d=+24.4 (c0.5, acetonitrile) .IR (KBr) 3297,1678,1659,1548,1507,1488,1255,1022,833,523. 1hNMR (400MHz, DMSO-d 6) δ 10.01 (s, 1H), 7.76 – 7.56 (m, 4H), 7.14 – 7.06 (m, 4H), 3.32 – 3.12 (m, 2H), 3.12 – 2.80 (m, 1H), 2.61 (d, J=6.1Hz, 1H), 2.35 (dd, J=54.6,5.2Hz, 1H), 2.05 (s, 3H) .HRMSm/z:calcdforC 17h 17nO 3s 2[M+H] +348.0650, found:348.0720.
The preparation of 16, N-(4-(4-((S)-(((R)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (18)
N-(4-(4-((S)-(((R)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide is with to prepare compound 16 similar; just change starting raw material into (S)-Racemic glycidol, final N-(4-(4-((S)-(((R)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide white solid.Productive rate: 88.9%; Fusing point: 150-152 DEG C; 1:67:32dr [pillar, CHIRALPAKIA (4.6mmI.D. × 250mm.5um); Moving phase, normal hexane/ethanol/tetrahydrofuran (THF)=74/25/1 (V/V/V); Flow velocity, 1mL/min; Detect, UV255nm; Temperature, room temperature]; [α] 25 d=-47.2 (c0.4, acetonitrile) .IR (KBr) 3296,1662,1617,1557,1505,1488,1242,1222,1035,836,520. 1hNMR (400MHz, DMSO-d 6) δ 10.01 (s, 1H), 7.72 – 7.61 (m, 4H), 7.14 – 7.05 (m, 4H), 3.31 – 3.12 (m, 2H), 3.12 – 2.82 (m, 1H), 2.61 (d, J=6.0Hz, 1H), 2.35 (dd, J=54.7,5.2Hz, 1H), 2.05 (s, 3H) .HRMSm/z:calcdforC 17h 17nO 3s 2[M+H] +348.0650, found:348.0720.
The preparation of 17, N-(4-(4-((R)-(((R)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (19)
N-(4-(4-((R)-(((R)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide is with to prepare compound 17 similar; just change starting raw material into (S)-Racemic glycidol, final N-(4-(4-((R)-(((R)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide white solid.Productive rate: 86.4%; Fusing point: 136-138 DEG C; 2:27:71dr [pillar, CHIRALPAKIA (4.6mmI.D. × 250mm.5um); Moving phase, normal hexane/ethanol/tetrahydrofuran (THF)=74/25/1 (V/V/V); Flow velocity, 1mL/min; Detect, UV255nm; Temperature, room temperature]; [α] 25 d=+20.1 (c0.4, acetonitrile) .IR (KBr) 3297,1656,1552,1507,1258,1021,834,524. 1hNMR (400MHz, DMSO-d 6) δ 10.01 (s, 1H), 7.75 – 7.57 (m, 4H), 7.17 – 7.03 (m, 4H), 3.32 – 3.12 (m, 2H), 3.12 – 2.81 (m, 1H), 2.61 (d, J=6.3Hz, 1H), 2.35 (dd, J=54.7,5.1Hz, 1H), 2.05 (s, 3H) .HRMSm/z:calcdforC 17h 17nO 3s 2[M+H] +348.0650, found:348.0737.

Claims (10)

1. chirality ND-322, ND-364 or ND-364 sulfoxide analogue, is characterized in that,
Described ND-322 is the compound with formula 8 or formula 9 structure:
Formula 8:
Formula 9:
Described ND-364 is the compound with formula 12 or formula 13 structure:
Formula 12:
Formula 13:
Described ND-364 sulfoxide analogue is the compound with formula 16, formula 17, formula 18 or formula 19 structure:
Formula 16:
Formula 17:
Formula 18:
Formula 19:
2. chirality ND-322 as claimed in claim 1; the preparation method of ND-364 or ND-364 sulfoxide analogue; wherein; (S) preparation method of-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) aniline salt hydrochlorate (8) and (R)-4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) anilinechloride (9), step is as follows:
(1) (R)-Racemic glycidol and Tosyl chloride generation chlorosulfonation react to obtain compound 2;
Compound 2
(2) reacting to obtain compound 3 with thiohydroquinone again, this step, there is nucleophilic substitution reaction with the C-3 of (R)-Racemic glycidol in sulfydryl, and three-dimensional arrangement keeps;
Compound 3
(3) under the existence of mineral alkali cesium carbonate, react with p-fluoronitrobenzene and form oxyethane one step and complete to obtain compound 4;
Compound 4
(4), under acidic conditions, after zinc powder reduction nitro, after alkalization, amino the compound 5 of BOC acid anhydrides protection is directly added;
Compound 5
(5) compound 6 is oxidized to obtain through over cure after;
Compound 6
(6) oxyethane changes into thiirane and obtains compound 7;
Compound 7
(7) N-Boc deprotection obtains end product (S)-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) aniline salt hydrochlorate (8); When oxyethane changes into thiirane, steric configuration reverses;
(8) preparation method of end product (R)-4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) anilinechloride (9) and (S)-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) aniline salt hydrochlorate (8) is similar, and just starting raw material is (S)-Racemic glycidol.
3. the preparation method of (S)-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) aniline salt hydrochlorate (8) as claimed in claim 2 and (R)-4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) anilinechloride (9), concrete preparation process is as follows:
(1) preparation of (S)-ethylene oxide-2-methylene radical 4-toluene sulfonic acide ester (2)
Tosyl chloride is dissolved in the methylene dichloride heavily steamed, and (R)-Racemic glycidol is added solution; At 0 DEG C, be added drop-wise to by triethylamine in reaction solution, reaction 2-5 hour, evaporate to dryness, crosses post; Obtain white (S)-ethylene oxide-2-methylene radical 4-toluene sulfonic acide ester solid; Wherein, Tosyl chloride is 1:1-2:1 with the molar ratio of (R)-Racemic glycidol;
(2) preparation of (R)-2-hydroxyl-3-((4-hydroxyphenyl) sulfo-) propyl group 4-toluene sulfonic acide ester (3)
(S)-ethylene oxide-2-methylene radical 4-toluene sulfonic acide ester, 4-mercapto-phenol is dissolved in anhydrous methylene chloride, at 0 DEG C, drip triethylamine; After dropwising, remove ice bath, room temperature reaction 4-5 hour, evaporate to dryness, cross post; Obtain white (R)-2-hydroxyl-3-((4-hydroxyphenyl) sulfo-) propyl group 4-toluene sulfonic acide ester solid; Wherein, the molar ratio of (S)-ethylene oxide-2-methylene radical 4-toluene sulfonic acide ester and 4-mercapto-phenol is 1:1-2:3;
(3) preparation of (R)-2-(((4-(4-nitrophenoxy) phenyl) sulfo-) methyl) oxyethane (4)
(R)-2-hydroxyl-3-((4-hydroxyphenyl) sulfo-) propyl group 4-toluene sulfonic acide ester is dissolved in anhydrous dimethyl formamide, and under room temperature, 4-nitrophenols and cesium carbonate join in reaction solution, reaction 10-15 hour; Add suitable quantity of water, extraction into ethyl acetate, organic layer washes three times by saturated nacl aqueous solution, anhydrous magnesium sulfate drying, filters, evaporate to dryness, crosses post; Obtain faint yellow oily (R)-2-(((4-(4-nitrophenoxy) phenyl) sulfo-) methyl) oxyethane; Wherein, the molar ratio of (R)-2-hydroxyl-3-((4-hydroxyphenyl) sulfo-) propyl group 4-toluene sulfonic acide ester and 4-nitrophenols is 1:1-1:2;
(4) preparation of the tertiary butyl (R)-(4-(4-((ethylene oxide-2-methylene radical) sulfo-) phenoxy group) phenyl) carbamate (5)
(R)-2-(((4-(4-nitrophenoxy) phenyl) sulfo-) methyl) oxyethane is dissolved in anhydrous tetrahydro furan; Ice bath, adds zinc powder, drips acetic acid; React 15 minutes, filter, add anhydrous methanol in filtrate, under ice bath, add triethylamine, react 5 minutes; Add two dimethyl dicarbonate butyl esters and react half an hour, remove ice bath, room temperature reaction 24 hours; Evaporate to dryness, crosses post, obtains the faint yellow oily tertiary butyl (R)-(4-(4-((ethylene oxide-2-methylene radical) sulfo-) phenoxy group) phenyl) carbamate; Wherein, the molar ratio of (R)-2-(((4-(4-nitrophenoxy) phenyl) sulfo-) methyl) oxyethane and two dimethyl dicarbonate butyl esters is 1:1-1:10;
(5) preparation of the tertiary butyl (R)-(4-(4-((ethylene oxide-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) carbamate (6)
The tertiary butyl (R)-(4-(4-((ethylene oxide-2-methylene radical) sulfo-) phenoxy group) phenyl) carbamate is dissolved in anhydrous methylene chloride, add tetraisopropoxy titanium, under room temperature, drip cumyl hydroperoxide, reaction 1-2 hour; Post is crossed with ethyl acetate/petroleum ether system flash, evaporate to dryness, vacuum-drying, obtains the white solid tertiary butyl (R)-(4-(4-((ethylene oxide-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) carbamate; Wherein, the tertiary butyl (R)-(4-(4-((ethylene oxide-2-methylene radical) sulfo-) phenoxy group) phenyl) carbamate; Wherein, the tertiary butyl (R)-(4-(4-((ethylene oxide-2-methylene radical) sulfo-) phenoxy group) phenyl) carbamate, the molar ratio of tetraisopropoxy titanium and cumyl hydroperoxide is 1:1:1-1:2:3;
(6) preparation of the tertiary butyl (S)-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) carbamate (7)
The tertiary butyl (R)-(4-(4-((ethylene oxide-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) carbamate is dissolved in anhydrous methylene chloride and anhydrous methanol, and add thiocarbamide, reaction is spent the night; Flash post is crossed by ethyl acetate/petroleum ether system, evaporate to dryness, vacuum-drying obtains the white solid tertiary butyl (S)-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) carbamate, wherein, the molar ratio of the tertiary butyl (R)-(4-(4-((ethylene oxide-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) carbamate and thiocarbamide is 1:1-1:10;
(7) preparation of (S)-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) aniline salt hydrochlorate (8)
The tertiary butyl (S)-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) carbamate is dissolved in saturated Hydrochloride/ethyl acetate, reaction is spent the night, filtering solids, vacuum-drying obtains white solid (S)-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) aniline salt hydrochlorate;
(8) preparation of (R)-4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) anilinechloride (9)
Preparation (R)-4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) anilinechloride method and preparation (S)-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) aniline salt Barbiturates seemingly; just starting raw material makes (S)-Racemic glycidol into, and (R)-4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) anilinechloride is white powder.
4. the preparation method of (S)-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) aniline salt hydrochlorate (8) as claimed in claim 3 and (R)-4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) anilinechloride (9); it is characterized in that
In described step (1), Tosyl chloride is 3:2 with the molar ratio of (R)-Racemic glycidol;
In described step (2), the molar ratio of (S)-ethylene oxide-2-methylene radical 4-toluene sulfonic acide ester and 4-mercapto-phenol is 5:6;
In described step (3), the molar ratio of (R)-2-hydroxyl-3-((4-hydroxyphenyl) sulfo-) propyl group 4-toluene sulfonic acide ester and 4-nitrophenols is 5:6;
In described step (4), the molar ratio of (R)-2-(((4-(4-nitrophenoxy) phenyl) sulfo-) methyl) oxyethane and two dimethyl dicarbonate butyl esters is 1:5;
In described step (5), the tertiary butyl (R)-(4-(4-((ethylene oxide-2-methylene radical) sulfo-) phenoxy group) phenyl) carbamate, the molar ratio of tetraisopropoxy titanium and cumyl hydroperoxide is 5:6:10;
In described step (6), the molar ratio of the tertiary butyl (R)-(4-(4-((ethylene oxide-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) carbamate and thiocarbamide is 1:5.
5. chirality ND-322 as claimed in claim 1; the preparation method of ND-364 or ND-364 sulfoxide analogue; wherein; (S) preparation method of-N-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) ethanamide (12) and (R)-N-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) ethanamide (13), step is as follows:
(9) reducing compound 4, acetylated compound 10 then;
Compound 4
Compound 10
(10) through over cure oxidation after, compound 11 is obtained;
Compound 11
(11) oxyethane changes into thiirane and obtains compound (S)-N-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) ethanamide (12); When oxyethane changes into thiirane, steric configuration reverses;
(12) preparation method of end product (R)-N-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) ethanamide (13) and (S)-N-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) ethanamide (12) is similar, is just (S)-Racemic glycidol by starting raw material.
6. the preparation method of (S)-N-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) ethanamide (12) as claimed in claim 5 and (R)-N-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) ethanamide (13), concrete preparation process is as follows:
(9) preparation of (R)-N-(4-(4-((ethylene oxide-2-methylene radical) sulfo-) phenoxy group) phenyl) ethanamide (10)
(S)-2-(((4-(4-nitrophenoxy) phenyl) sulfo-) methyl) oxyethane is dissolved in anhydrous tetrahydro furan; Ice bath, adds zinc powder, drips acetic acid; React 15 minutes, filter, add anhydrous methanol in filtrate, under ice bath, add triethylamine, react 5 minutes; Be added dropwise to Acetyl Chloride 98Min., react 15 minutes, evaporate to dryness, add water, ethyl acetate extracts three times, has the saturated sodium sulfide solution of basic unit to wash three times, anhydrous magnesium sulfate drying, evaporate to dryness, crosses post, obtains faint yellow solid (R)-N-(4-(4-((ethylene oxide-2-methylene radical) sulfo-) phenoxy group) phenyl) ethanamide; Wherein, the molar ratio of (S)-2-(((4-(4-nitrophenoxy) phenyl) sulfo-) methyl) oxyethane and Acetyl Chloride 98Min. is 1:1-1:100;
(10) preparation of (R)-N-(4-(4-((ethylene oxide-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) ethanamide (11)
(R)-N-(4-(4-((ethylene oxide-2-methylene radical) sulfo-) phenoxy group) phenyl) ethanamide is dissolved in anhydrous methylene chloride, add tetraisopropoxy titanium, under room temperature, drip cumyl hydroperoxide, react 1 hour; Cross flash post by ethyl acetate/petroleum ether system, evaporate to dryness, vacuum-drying, obtain white solid (R)-N-(4-(4-((ethylene oxide-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) ethanamide; Wherein, (R)-N-(4-(4-((ethylene oxide-2-methylene radical) sulfo-) phenoxy group) phenyl) ethanamide, the molar ratio of tetraisopropoxy titanium and cumyl hydroperoxide is 1:1:1-1:2:3;
(11) preparation of (S)-N-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) ethanamide (12)
Under room temperature, (R)-N-(4-(4-((ethylene oxide-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) ethanamide is dissolved in anhydrous tetrahydro furan and anhydrous methanol, and add thiocarbamide, reaction is spent the night; Flash post is crossed by ethyl acetate/petroleum ether system, evaporate to dryness, vacuum-drying, obtain white solid (S)-N-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) ethanamide, wherein, the molar ratio of (R)-N-(4-(4-((ethylene oxide-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) ethanamide and thiocarbamide is 1:1-1:10;
(12) preparation of (R)-N-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) ethanamide (13)
Ethanamide seemingly for preparation (R)-N-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) ethanamide (13) method and preparation (S)-N-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl); just starting raw material makes (S)-Racemic glycidol into, and (R)-N-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) ethanamide is white solid.
7. the preparation method of (S)-N-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) ethanamide (12) as claimed in claim 6 and (R)-N-(4-(4-((thiirane-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) ethanamide (13); it is characterized in that
In described step (9), the molar ratio of (S)-2-(((4-(4-nitrophenoxy) phenyl) sulfo-) methyl) oxyethane and Acetyl Chloride 98Min. is 1:50;
In described step (10), (R)-N-(4-(4-((ethylene oxide-2-methylene radical) sulfo-) phenoxy group) phenyl) ethanamide, the molar ratio of tetraisopropoxy titanium and cumyl hydroperoxide is 5:6:10;
In described step (11), the molar ratio of (R)-N-(4-(4-((ethylene oxide-2-methylene radical) alkylsulfonyl) phenoxy group) phenyl) ethanamide and thiocarbamide is 1:5.
8. chirality ND-322 as claimed in claim 1, the preparation method of ND-364 or ND-364 sulfoxide analogue, wherein, N-(4-(4-((S)-(((S)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (16), N-(4-(4-((R)-(((S)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (17), the preparation method of N-(4-(4-((S)-(((R)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (18) and N-(4-(4-((R)-(((R)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (19), step is as follows:
(13), at catalyzer tetraisopropoxy titanium, under the existence of part D-(-)-diethyl tartrate, cumyl hydroperoxide (tech.80%) oxygenated compound 10 obtains compound 14;
Compound 14
(14) change into thiirane through oxyethane after and obtain compound N-(4-(4-((S)-(((S)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (16); When oxyethane changes into thiirane, steric configuration reverses;
(15) end product N-(4-(4-((R)-(((S)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (17) is similar with the preparation method of compound 16, just changes part into L-(+)-diethyl tartrate;
(16) end product N-(4-(4-((S)-(((R)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (18) is similar respectively at the preparation method of compound 16, and just starting raw material is (S)-Racemic glycidol;
(17) preparation method of end product N-(4-(4-((R)-(((R)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (19) and compound 17 is similar, and just starting raw material is (S)-Racemic glycidol.
9. N-(4-(4-((S)-(((S)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (16) as claimed in claim 8, N-(4-(4-((R)-(((S)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (17), the preparation method of N-(4-(4-((S)-(((R)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (18) and N-(4-(4-((R)-(((R)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (19), concrete preparation process is as follows:
(13) preparation of N-(4-(4-((S)-(((R)-ethylene oxide-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (14)
(R)-N-(4-(4-((ethylene oxide-2-methylene radical) sulfo-) phenoxy group) phenyl) ethanamide is dissolved in anhydrous methylene chloride, add tetraisopropoxy titanium and D-(-)-diethyl tartrate, react 5 minutes under room temperature, 0 DEG C drips cumyl hydroperoxide, reacts 24 hours; Flash post is crossed by ethyl acetate/petroleum ether system, evaporate to dryness, vacuum-drying obtains white solid, N-(4-(4-((S)-(((R)-ethylene oxide-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide; Wherein, (R)-N-(4-(4-((ethylene oxide-2-methylene radical) sulfo-) phenoxy group) phenyl) ethanamide, D-(-)-diethyl tartrate, the molar ratio of tetraisopropoxy titanium and cumyl hydroperoxide is 1:1:1:1-1:8:6:6;
(14) preparation of N-(4-(4-((S)-(((S)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (16)
N-(4-(4-((S)-(((R)-ethylene oxide-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide is dissolved in anhydrous tetrahydro furan and anhydrous methanol, add thiocarbamide, reaction is spent the night; Flash post is crossed by ethyl acetate/petroleum ether system, evaporate to dryness, vacuum-drying obtains white solid N-(4-(4-((S)-(((S)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide; Wherein, the molar ratio of N-(4-(4-((S)-(((R)-ethylene oxide-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide and thiocarbamide is 1:1-1:10;
(15) preparation of N-(4-(4-((R)-(((S)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (17)
Prepare N-(4-(4-((R)-(((S)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide and prepare compound 16 similar, just change the part in preparation process into L-(+)-diethyl tartrate (L-DET), final N-(4-(4-((R)-(((S)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide white solid;
(16) preparation of N-(4-(4-((S)-(((R)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (18)
N-(4-(4-((S)-(((R)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide is with to prepare compound 16 similar, just change starting raw material into (S)-Racemic glycidol, final N-(4-(4-((S)-(((R)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide white solid;
(17) preparation of N-(4-(4-((R)-(((R)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (19)
N-(4-(4-((R)-(((R)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide is with to prepare compound 17 similar; just change starting raw material into (S)-Racemic glycidol, final N-(4-(4-((R)-(((R)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide white solid.
10. N-(4-(4-((S)-(((S)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (16) as claimed in claim 9, N-(4-(4-((R)-(((S)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (17), the preparation method of N-(4-(4-((S)-(((R)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (18) and N-(4-(4-((R)-(((R)-thiirane-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide (19), it is characterized in that,
In described step (13), (R)-N-(4-(4-((ethylene oxide-2-methylene radical) sulfo-) phenoxy group) phenyl) ethanamide, D-(-)-diethyl tartrate, the molar ratio of tetraisopropoxy titanium and cumyl hydroperoxide is 2:8:3:4;
In described step (14), the molar ratio of N-(4-(4-((S)-(((R)-ethylene oxide-2-base) methyl) sulfinyl) phenoxy group) phenyl) ethanamide and thiocarbamide is 1:5.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006125208A1 (en) * 2005-05-19 2006-11-23 Wayne State University Inhibitors of matrix metalloproteinases
WO2011109767A2 (en) * 2010-03-04 2011-09-09 University Of Notre Dame Du Lac Gelatinase inhibitors and prodrugs

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006125208A1 (en) * 2005-05-19 2006-11-23 Wayne State University Inhibitors of matrix metalloproteinases
WO2011109767A2 (en) * 2010-03-04 2011-09-09 University Of Notre Dame Du Lac Gelatinase inhibitors and prodrugs

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHRISTOPHER M. RAYNER ET AL.: "Stereoselective Synthesis of 2,3-Epoxy Sulphoxides", 《TETRAHEDRON LETTERS》 *
PEDRO N. GUIVISDALSKY ET AL.: "Glycidyl Derivatives as Chiral C3 Synthons. Ring Opening Catalyzed by BF3Etherate", 《JOURNAL OF AMERICAN CHEMIACAL SOCIETY》 *
TAMOTSU FUJISAWA ET AL.: "Optically pure (S)-3-phenylthio-1,2-propanediol Synthesis by the Yeast Reduction and Use as a Precursor of both Enantiomers of Secondary Alcohols", 《TETRAHEDRON LETTERS》 *

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