CN102234276A - Preparation method of optical isomer of stepholidine or its derivative and intermediate used in the method - Google Patents
Preparation method of optical isomer of stepholidine or its derivative and intermediate used in the method Download PDFInfo
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Abstract
The invention relates to a preparation method of an optical isomer of stepholidine or its derivatives and an intermediate used in the method. The method constructs a chiral carbon configuration by an addition reaction of metal lithium salts and chiral imines, and comprises the following steps: performing hydrogen abstraction of o-cyanotoluene compounds as shown in the following general formula I under the action of an alkali to form a metal lithium salt, performing an addition reaction of the metal lithium salt and sulfinamide compounds with an S or R configuration as shown in following general formula II to obtain a compound III with a corresponding S or R configuration, performing de-protection, an intramolecular cyclization reaction, a reduction reaction, and de-protection of the compound III to obtain sinistral or dextral stepholidine. The invention uses sulfinamides with an S or R configuration as raw materials respectively, and can prepare sinistral or dextral stepholidine or its derivatives by a consistent reaction route and operation method.
Description
Technical field
The invention belongs to pharmaceutical chemistry and asymmetric synthesis chemical field, more specifically, relate to chemical synthesis process with the active natural product Stopholidine of antipsychotic or derivatives thereof optical isomer, especially l-spd (L-stepholidine, L-SPD) chemical synthesis process of or derivatives thereof optical isomer, and the new intermediate that uses in the method.
Background technology
Schizophrenia is a kind of serious mental disorder, and its clinical treatment does not obtain satisfied the solution as yet.In the last few years, neuroscientists the were verified dopamine D of schizophreniac's pallium prefrontal lobe
1Function of receptors is low relevant with negative symptoms, the D of structure under the cortex
2Function of receptors hyperfunction relevant (Okubo, Y., Nature, 1997,385:634 with positive symptom; Abi-Dargham, A., Eur.Psychiatry, 2005,20:15).Therefore, people to propose schizoid new nosetiology be because D
1Function of receptors downward modulation, D simultaneously
2The hyperfunction institute of receptor function controlling causes.Based on this hypothesis, has D simultaneously
1Excitement and D
2The compound of antagonism dual function should become the brand-new antipsychotics that a class can be complementary with the schizophrenia nosetiology.
Reported first compound of Tetrahydro-proto-berberines class (THPB)-l-spds (L-stepholidine is L-SPD, and its structural formula is as follows) such as Jin nation's chapter are that first has D
1Excitement and D
2The lead drug of antagonism dual function (Jin GZ, Trends in Pharmacological Science, 2002,23:4).Clinical efficacy shows that tentatively L-SPD is all effective in cure to the positive and negative symptoms, to the negative symptoms better efficacy, might become the newtype drug that meets the new hypothesis of schizophrenia.
L-SPD separates (Chin.J.Physiol.1928:203) that obtains from the piece root of Menispermaceae stephania plant " Root of Epigeal Srephaia ", its content in most of stephania plant exsiccant root, stem, leaf all is lower than 1 ‰, content is the highest also has only about 1% (Acta.Pharm.Sin., 1998,33 (7): 528～533).Synthetic (Hsuch-Ching Chiang, J.Org.Chem., 1977,42,19,3190 of SPD raceme that very early bibliographical information arranged; Hsuch-Ching Chiang, Journal of the TaiwanPharmaceutical Association, 1976,28,111-120.).Had bibliographical information now with ruthenium ligand catalysis 3, the asymmetric reduction of 4-dihydro-isoquinoline is that the method for committed step prepares L-SPD optical isomer (Jian-Jun Cheng and Yu-She Yang, J.Org.Chem., 2009,74,9225-9228; CN200910053220.X), but ruthenium part price is comparatively expensive, and the condition of catalyzed reaction is comparatively harsh, makes this route be difficult to amplify.
Because the antipsychotic activity of L-SPD uniqueness needs the optically pure compound of a large amount of preparations further to further investigate, because plant resources is exhausted at present, presses for the effective chemical synthesizing mean.
Summary of the invention
Goal of the invention
The inventor is devoted to study a kind of chirality synthetic method that can prepare the optical isomer of optically pure Stopholidine or derivatives thereof, and this method makes up the chiral carbon configuration by the addition reaction of metallic lithium salt pair chiral imines.In preparation process, the inventor designs the o-cyano toluene compounds that synthesized shown in the general formula I and the sulfinyl amine compounds shown in the general formula I I, can be synthesized the optical isomer of Stopholidine or derivatives thereof by these two kinds of raw materials.
Therefore, the purpose of this invention is to provide a kind of preparation method of Stopholidine or derivatives thereof optical isomer, it is raw material that this method adopts o-cyano toluene compounds and the sulfinyl amine compounds shown in the general formula I I shown in the general formula I;
Another purpose of the present invention provides the intermediate compound III～VI that uses among the preparation method of above-mentioned Stopholidine or derivatives thereof optical isomer;
A further object of the present invention provides sulfinyl amine compounds shown in the general formula I I and preparation method thereof;
An also purpose of the present invention provides o-cyano toluene compounds shown in the general formula I and preparation method thereof.
Technical scheme
According to an aspect of the present invention, the invention provides a kind of preparation method of Stopholidine or derivatives thereof optical isomer, it is raw material that this method adopts the sulfinyl amine compounds shown in o-cyano toluene compounds shown in the following general formula I and the general formula I I, wherein the o-cyano toluene compounds shown in the general formula I:
Wherein, R
1Be sec.-propyl, benzyl, 4-methoxy-benzyl, 3,4-dimethoxy-benzyl, methoxymethyl or benzyloxymethyl, and preferred sec.-propyl;
Sulfinyl amine compounds shown in the general formula I I:
Wherein, R
2Be sec.-propyl, benzyl, 4-methoxy-benzyl, 3,4-dimethoxy-benzyl, methoxymethyl or benzyloxymethyl, and preferred sec.-propyl; R
3For trimethyl silicon based, triethyl is silica-based, tertiary butyl dimethyl is silica-based, tert-butyl diphenyl is silica-based, benzyl, 4-methoxy-benzyl or 3,4-dimethoxy-benzyl, and the silica-based or benzyl of preferred tertiary butyl dimethyl; R
4Be the tertiary butyl, p-methylphenyl or naphthyl, and the preferred tertiary butyl; And in the sulfinyl amine structure, the chirality of sulphur atom can be S type or R type, wavy line
Represent that this chemical bond can be solid line or dotted line;
The preparation method of described Stopholidine or derivatives thereof optical isomer comprises the steps:
Step 1: the o-cyano toluene compounds shown in the general formula I is seized hydrogen under the effect of alkali, form the metal lithium salts, sulfinyl amine compounds with the S configuration shown in the general formula I I carries out addition reaction then, obtain the compound III of S configuration, perhaps the sulfinyl amine compounds with the R configuration shown in the general formula I I carries out addition reaction, obtains the compound III of R configuration;
Its reaction formula is as follows:
Step 2: the compound III that step 1 obtains the S configuration removes protecting group R
3And R
4S (O)-, obtain the compound of the S configuration shown in the general formula I V, perhaps step 1 compound III that obtains the R configuration removes protecting group R
3And R
4S (O)-, obtain the compound of the R configuration shown in the general formula I V;
Its reaction formula is as follows:
Step 3: the compound of the S configuration shown in the general formula I V issues addition and the hydrolysis reaction of living intramolecularly amido to cyano group in alkali effects such as sodium hydroxide or potassium hydroxide, obtain the lactam analog compound V of the S configuration shown in the general formula V, perhaps the compound of the R configuration shown in the general formula I V issues addition and the hydrolysis reaction of living intramolecularly amido to cyano group in alkali effects such as sodium hydroxide or potassium hydroxide, obtains the lactam analog compound V of the R configuration shown in the general formula V;
Its reaction formula is as follows:
Step 4: make alcoholic extract hydroxyl group and SULPHURYL CHLORIDE reaction among the lactam analog compound V of the S configuration that step 3 obtains generate sulphonate, resulting then sulphonate under the effect of alkali with amide group generation internal nucleophilic substitution further cyclisation be the compound of the S configuration shown in the general formula VI; Perhaps the reaction of alcoholic extract hydroxyl group among the lactam analog compound V of R configuration and SULPHURYL CHLORIDE generates sulphonate, and the cyclisation further with amide group generation internal nucleophilic substitution under the effect of alkali of resulting then sulphonate is the compound of the R configuration shown in the general formula VI,
Its reaction formula is as follows:
Step 5: make the compound of the S configuration shown in the general formula VI that step 4 obtains under the reductive agent effect, be reduced to the compound of the S configuration shown in the general formula VII, perhaps make the compound of the R configuration shown in the general formula VI that step 4 obtains under the reductive agent effect, be reduced to the compound of the R configuration shown in the general formula VII;
Its reaction formula is as follows:
Step 6: the compound of the S configuration shown in the general formula VII removes R
1, R
2, obtain l-spd, perhaps the compound of the R configuration shown in the general formula VII removes R
1, R
2, obtain the dextrorotation Stopholidine;
Its reaction formula is as follows:
Synthetic method of the present invention is more specifically described below:
In step 1, described alkali can be lithium diisopropyl amido, two (trimethyl silicon based) amido lithium, n-Butyl Lithium, s-butyl lithium or tert-butyl lithium etc., and preferred lithium diisopropyl amido; The consumption of alkali is 1 to 3 equivalent with respect to the o-cyano toluene compounds shown in the general formula I; Solvent for use is tetrahydrofuran (THF), ether, methyl tertiary butyl ether, glycol dimethyl ether or diethylene glycol dimethyl ether etc.; Temperature of reaction is-80 ℃ to-20 ℃; The time of o-cyano toluene compounds shown in the general formula I and alkali effect is 10 to 60 minutes; The consumption of the sulfinyl amine compounds shown in the general formula I I is 0.9 to 1.5 equivalent with respect to the o-cyano toluene compounds shown in the general formula I, and the reaction times behind the adding sulfinyl amine compounds is 30 to 120 minutes.
In step 2, work as R
3For trimethyl silicon based, triethyl is silica-based, tertiary butyl dimethyl is silica-based or tert-butyl diphenyl when silica-based, sulfinyl R
4S (O)-with R
3Remove together, the mixture that deprotection reaction is formed with methyl alcohol, ethanol, Virahol, water or water and above-mentioned alcohol is a solvent, under effect such as hydrochloric acid, sulfuric acid, acetic acid or trifluoracetic acid, temperature of reaction be-20 ℃ to the solvent refluxing temperature, the reaction times is 1 to 24 hour; Work as R
3Be benzyl, remove sulfinyl R with preceding method earlier
4S (O)-, be catalyzer with palladium carbon or palladium hydroxide/carbon etc. again, be that hydrogen donor removes benzyl with hydrogen, formic acid or tetrahydrobenzene etc.; Work as R
3Be 4-methoxy-benzyl or 3, during the 4-dimethoxy-benzyl, remove sulfinyl R with preceding method earlier
4S (O)-, the mode with ceric ammonium nitrate (CAN) or DDQ (DDQ) oxidation removes 4-methoxy-benzyl or 3, the 4-dimethoxy-benzyl again;
In step 3, reaction solvent is the mixture that methyl alcohol, ethanol, Virahol, water or water and alcohol are formed, and the alkali that reacts used is sodium hydroxide or potassium hydroxide, temperature of reaction be-20 ℃ to the solvent refluxing temperature, the reaction times is 4 to 48 hours;
In step 4, cyclisation is reacted in two steps and is carried out.The first step with lactam analog compound V and SULPHURYL CHLORIDE react sulphonate: used SULPHURYL CHLORIDE is methylsulfonyl chloride, trifluoromethanesulfchloride chloride, Tosyl chloride or m-nitrobenzene sulfonyl chloride etc., reaction solvent can be pyridine, methylene dichloride, chloroform, tetrahydrofuran (THF), ether or methyl tertiary butyl ether etc., the acid binding agent that reacts used is pyridine, to dimethylamino pyridine, triethylamine or diisopropyl ethyl amine etc., temperature of reaction be-20 ℃ to the solvent refluxing temperature, the reaction times is 4 to 48 hours; The sulphonate of second step with the first step gained is converted into the compound shown in the general formula VI under the alkali effect: reaction is made solvent with tetrahydrofuran (THF), ether, methyl tertiary butyl ether etc., with sodium hydride, hydrolith, lithium diisopropyl amido, two (trimethyl silicon based) amido lithium etc. is alkali, temperature of reaction be-20 ℃ to solvent refluxing, the reaction times is 1 to 24 hour;
In step 5, the reaction make solvent with tetrahydrofuran (THF), ether or methyl tertiary butyl ether etc., be reductive agent with lithium aluminium hydride, borane complexes, POTASSIUM BOROHYDRIDE or sodium borohydride etc., temperature of reaction be-20 ℃ to solvent refluxing, the reaction times is 1 to 24 hour;
In step 6, according to R
1, R
2Difference choose appropriate means and remove.For example, work as R
1=R
2During=sec.-propyl, be reaction solvent with methylene dichloride, chloroform, tetrahydrofuran (THF), ether or methyl tertiary butyl ether etc., preferred methylene dichloride; Compound shown in the general formula VII and boron trichloride or aluminum chloride reaction remove sec.-propyl; Temperature of reaction be-80 ℃ to room temperature, the reaction times is 1 to 24 hour.Work as R
1=R
2During=benzyl, reaction is a solvent with methyl alcohol, ethanol, tetrahydrofuran (THF), water or their mixture, is catalyzer with palladium carbon, palladium hydroxide/carbon etc., is that hydrogen donor removes with hydrogen, formic acid or tetrahydrobenzene etc.; Or be solvent with hydrochloric acid, reflux removes; Or the compound shown in the general formula VII and boron trichloride or aluminum chloride reaction, be solvent with methylene dichloride, chloroform etc., remove to the temperature of room temperature at-80 ℃.
According to another aspect of the invention, the invention provides the preparation method of the sulfinyl amine compounds shown in o-cyano toluene compounds shown in the general formula I and the general formula I I.As follows respectively:
(1) the o-cyano toluene compounds shown in the general formula I can be prepared by following method:
Wherein, R
1Definition is the same; R
5Be methyl, ethyl, sec.-propyl, the tertiary butyl or phenyl.
Step I: in the presence of alkali, phenyl aldehyde A and dimethylamine hydrochloride and sodium borohydride or POTASSIUM BOROHYDRIDE are carried out reductive amination process, obtain dimethyl benzyl amine B; Wherein, this reaction solvent for use is methyl alcohol, ethanol or Virahol etc., and reacting used alkali is triethylamine or diisopropyl ethyl amine etc., and temperature of reaction is 0 ℃ to 50 ℃, and the reaction times is 8 to 24 hours;
Step I i: in the presence of alkali, dimethyl benzyl amine B and chloro-formic ester reaction obtain benzyl chlorine C; Wherein, this reaction solvent for use is tetrahydrofuran (THF), ether or methyl tertiary butyl ether etc., used alkali is lithium diisopropyl amido, two (trimethyl silicon based) amido lithium, n-Butyl Lithium, s-butyl lithium or tert-butyl lithium, described chloro-formic ester is methyl-chloroformate, Vinyl chloroformate, isopropyl chlorocarbonate, the chloroformic acid tert-butyl ester or phenyl chloroformate, and the consumption of chloro-formic ester is 2 to 4 equivalents with respect to dimethyl benzyl amine B, temperature of reaction be-80 ℃ to room temperature, the reaction times is 1 to 24 hour;
Step I ii: benzyl chlorine C is reduced to o-toluic acid ester D by reduction reaction; Wherein, this reduction reaction is a solvent with methyl alcohol, ethanol, tetrahydrofuran (THF), water or their mixture, is catalyzer with palladium carbon or palladium hydroxide/carbon etc., is that hydrogen donor carries out with hydrogen, formic acid or tetrahydrobenzene etc., temperature of reaction be-20 ℃ to room temperature, the reaction times is 1 to 24 hour;
Step I v: o-toluic acid ester D is hydrolyzed to o-toluic acid E in the presence of acid or alkali; This hydrolysis reaction solvent for use is methyl alcohol, ethanol, tetrahydrofuran (THF), water or their mixture, described acid is hydrochloric acid or sulfuric acid etc., described alkali is sodium hydroxide, potassium hydroxide, yellow soda ash or salt of wormwood, temperature of reaction be room temperature to the solvent refluxing temperature, the reaction times is 1 to 48 hour;
Step v: o-toluic acid E is converted into benzamide F by two-step reaction: the first step, and o-toluic acid E and oxalyl chloride or sulfur oxychloride reaction are converted into acyl chlorides, and this temperature of reaction is that room temperature is to the solvent refluxing temperature; In second step, the water of resulting acyl chlorides and ammonia, methyl alcohol or ethanolic soln react, and obtain benzamide F, this temperature of reaction be-20 ℃ to room temperature, the reaction times is 1 to 24 hour;
Step vi: benzamide F dewaters under the dewatering agent effect, obtains the o-cyano toluene compounds shown in the general formula I.This reacts available dewatering agent is sulfur oxychloride or Cynuric Chloride.When being dewatering agent with the sulfur oxychloride, can methylene dichloride or chloroform etc. be solvent, or solubilizing agent not; When being dewatering agent with the Cynuric Chloride, use N, dinethylformamide or N,N-dimethylacetamide are solvent.Temperature of reaction be-20 ℃ to room temperature, the reaction times is 6 to 24 hours.
(2) the sulfinyl amine compounds shown in the general formula I I can be prepared by following method:
Wherein, R
2, R
3, R
4Definition the same;
Step I: substituted phenylacetic acid a is reduced to substituted benzene ethanol b, this reacts with tetrahydrofuran (THF), ether or methyl tertiary butyl ether etc. as solvent, with lithium aluminium hydride, borane complexes, POTASSIUM BOROHYDRIDE or sodium borohydride etc. is reductive agent, temperature of reaction be-20 ℃ to the solvent refluxing temperature, the reaction times is 1 to 24 hour;
Step I i: substituted benzene ethanol b passes through bromo-reaction, obtain the compound c of o-brominated, this reaction is with chloroform, N, dinethylformamide or N, the N-N,N-DIMETHYLACETAMIDE is a solvent, with the N-bromo-succinimide is brominated reagent, temperature of reaction be-20 ℃ to the solvent refluxing temperature, the reaction times is 2 to 24 hours;
Step I ii: compound c is carried out the alcoholic extract hydroxyl group protection, obtains compound d, works as R
3For trimethyl silicon based, triethyl is silica-based, tertiary butyl dimethyl is silica-based or tert-butyl diphenyl when silica-based, in the presence of at imidazoles, pyridine, to alkali such as dimethylamino pyridine, triethylamine or diisopropyl ethyl amines, compound c and corresponding chlorosilane reaction obtain compound d; Work as R
3Be benzyl, 4-methoxy-benzyl or 3, during the 4-dimethoxy-benzyl, at acetone, tetrahydrofuran (THF) or N, in the N-N,N-DIMETHYLACETAMIDE equal solvent, in the presence of alkali such as salt of wormwood, yellow soda ash, sodium hydride or hydrolith, compound c and corresponding benzyl chlorine or benzyl bromine reaction obtain compound d;
Step I v: with tetrahydrofuran (THF), ether or methyl tertiary butyl ether is solvent, under alkali lithium diisopropyl amido, two (trimethyl silicon based) amido lithium, n-Butyl Lithium, s-butyl lithium or tert-butyl lithium effect, the bromine atoms of compound d carries out metal-halogen exchange, to N, dinethylformamide carries out addition, makes benzaldehyde compound e.This temperature of reaction be-80 ℃ to room temperature, the reaction times is 1 to 4 hour;
Step v: in the presence of condensing agent metatitanic acid tetra isopropyl ester or tetraethyl titanate, the R of benzaldehyde compound e and S configuration
4S (O) NH
2Sulfinyl amine carries out condensation reaction, obtains the sulfinyl amine compounds shown in the general formula I I of S configuration; The perhaps R of benzaldehyde compound e and R configuration
4S (O) NH
2Sulfinyl amine carries out condensation reaction, obtains the sulfinyl amine compounds shown in the general formula I I of R configuration.This reaction solvent for use is tetrahydrofuran (THF), ether or methyl tertiary butyl ether etc.; Temperature of reaction be room temperature to the solvent refluxing temperature, the reaction times is 4 to 16 hours.The R of S and R configuration wherein
4S (O) NH
2Commercialization, commercially available obtaining.
Beneficial effect
Addition reaction by the optically pure sulfinyl amine of metallic lithium salt pair makes up the chiral carbon configuration, and method provided by the invention can be synthesized the optical isomer of Stopholidine or derivatives thereof.Utilize the sulfinyl amine of S or R configuration to be raw material respectively, the reaction scheme of available unanimity and working method prepare the optical isomer of left-handed or dextral Stopholidine or derivatives thereof respectively.
Embodiment
The invention will be further elaborated below in conjunction with embodiment, but these embodiment never are any limitation of the invention.Illustrate the present invention with L-SPD, be described below:
In all embodiments, fusing point all uses MEL-TEMP fusing point instrument to measure, and thermometer is not calibrated;
1H-NMR uses Varian Mercury Plus 300MHz nmr determination,
13C-NMR uses Varian Mercury Plus 400MHz nmr determination, and chemical shift is represented with δ (ppm); EI uses Finnigan MAT 95 mass spectrographs to measure, and ESI uses Kratos MS 80 mass spectrographs to measure; Separation is 200～300 orders with silica gel.
Route 1:
Preparation R
1The compound of Formula I of=sec.-propyl (being compound 7), route is as follows:
The preparation of embodiment 1 compound 2: the reductive amination process of vanillin food grade,1000.000000ine mesh isopropyl ether
Vanillin food grade,1000.000000ine mesh isopropyl ether 1 (77.7g, 0.40mol), triethylamine (112mL, 0.80mol), dimethylamine hydrochloride (65.2g, 0.80mol), Ti (Oi-Pr)
4(238mL 0.80mol) mixes with ethanol (400mL), and stirring reaction is 16 hours under the room temperature.Then, in reaction system, add NaBH
4(24g 0.60mol), continues to stir 14 hours.After reaction is finished, in the mixture (2L) with reaction solution slow impouring 2N ammoniacal liquor and ice, left standstill 1 hour.Filter, filter residue washs with methylene dichloride (300mL), and with this dichloromethane extraction filtrate, repeats above-mentioned washing, extracting operation three times.Resulting dichloromethane solution is merged, with saturated common salt washing (300mL * 2), anhydrous Na
2SO
4Drying is filtered, and concentrates, and gets white semi-solid compound 2,73.2g, yield 82.0%.
1H?NMR(300MHz，CDCl
3)：6.86(d，1H，J＝2.0Hz)，6.82(d，1H，J＝8.0Hz)，6.76(dd，1H，J＝8.0，2.0Hz)，4.52-4.44(m，1H)，3.84(s，3H)，3.33(s，2H)，2.22(s，6H)，1.34(d，6H，J＝6.6Hz)；
13C?NMR(300MHz，CDCl
3)：150.2，146.2，131.8，121.1，115.4，112.7，71.3，64.2，55.9，45.2(×2)，22.0(×2)；
EI-MS：m/z(％)137(100)，138(18)，163(16)，180(15)，223(26)；
HRMS: theoretical value C
13H
21NO
2: 223.1572, measured value: 223.1573.
Embodiment 2 compounds 2 are converted into benzyl chlorine 3
Compound 2, promptly (32g 0.14mol) is dissolved in anhydrous THF (300mL) nitrogen protection to substituted benzyl dimethylamine 2, is cooled to-10 ℃, and (1.6M 100mL), finishes and stirred 1 hour in hexane to drip n-Butyl Lithium.Then, be cooled to-78 ℃, (27.5mL 0.35mol), stirs and slowly rises to stirred overnight at room temperature after 15 minutes to add methyl-chloroformate.Frozen water cooling adds the shrend reaction of going out, and reaction solution extracts with methyl tertiary butyl ether, and extraction liquid merges, the saturated common salt washing, and anhydrous sodium sulfate drying, concentrating under reduced pressure, the resistates rapid column chromatography must red oil benzyl chlorine 3,35g, yield 92%.
1H?NMR(300MHz，CDCl
3)：7.06(d，1H，J＝8.5Hz)，6.90(d，1H，J＝8.5Hz)，4.59-4.51(m，3H)，3.94(s，3H)，3.87(s，3H)，1.35(d，6H，J＝6.1Hz)；
13C?NMR(100MHz，CDCl
3)：167.3，151.2，147.7，128.9，127.2，125.5，116.4，71.1，61.3，52.4，43.6，21.9(×2)；
EI-MS：m/z(％)163(81)，198(100)，200(34)，230(42)，232(13)，272(41)，274(14)；
HRMS: theoretical value C
13H
17ClO
4: 272.0815, measured value: 272.0818.
The preparation of embodiment 3 compounds 4: the catalytic hydrogenation of compound 3 (being benzyl chlorine 3)
(17.5g 64mmol) is dissolved in anhydrous methanol (200mL) to benzyl chlorine 3, adds 10% palladium carbon (1.8g), the logical H-H reaction of room temperature normal pressure 8 hours.Then, filtering palladium carbon, filtrate concentrates, and gets product compound 4,14.1g, yield 92%.
1H?NMR(300MHz，CDCl
3)：6.85(d，1H，J＝8.5Hz)，6.83(d，1H，J＝8.6Hz)，4.53-4.42(m，1H)，3.90(s，3H)，3.85(s，3H)，2.21(s，3H)，1.32(d，6H，J＝6.1Hz)；
13C?NMR(100MHz，CDCl
3)：168.4，148.4，147.4，129.3，127.8，125.3，117.8，71.5，61.2，52.0，22.0(×2)，18.4；
EI-MS：m/z(％)164(100)，196(48)，207(14)，238(30)；
HRMS: theoretical value C
13H
18O
4: 238.1205, measured value: 238.1200.
The hydrolysis of embodiment 4 compounds 4
Methyl benzoate is that (7.9g 33mmol) is dissolved in ethanol (100mL) and the 20wt% aqueous sodium hydroxide solution (100mL) back flow reaction 4 hours to compound 4.Then, be cooled to room temperature, remove ethanol under reduced pressure, remaining alkali lye is washed with ether, the frozen water cooling, ethyl acetate extraction is used in the concentrated hydrochloric acid acidifying, combining extraction liquid, and wash with saturated common salt, anhydrous sodium sulfate drying, concentrating under reduced pressure get faint yellow solid compound 5,6.95g, yield 94%.
1H?NMR(300MHz，CDCl
3)：6.94(d，1H，J＝8.4Hz)，6.90(d，1H，J＝8.4Hz)，4.53(m，1H)，3.95(s，3H)，2.40(s，3H)，1.36(d，6H，J＝6.0Hz)；
13C?NMR(100MHz，CDCl
3)：170.1，148.5，148.2，130.4，126.5，126.3，118.6，71.6，61.7，22.1(×2)，19.9；
EI-MS：m/z(％)121(26)，135(28)，136(32)，164(100)，165(21)，182(53)，207(27)，224(36)；
HRMS: theoretical value C
12H
16O
4: 224.1049, measured value: 224.1049.
Embodiment 5 is a feedstock production acid amides 6 with benzoic acid compounds 5
(10.0g 44.6mmol) is dissolved in oxalyl chloride (50mL) to benzoic acid compounds 5, refluxes and stirs 2 hours.Then, concentrating under reduced pressure, resistates add toluene (20mL), concentrating under reduced pressure once more, and it is standby that resistates is dissolved in ether (50mL).
Strong aqua (100mL) places three-necked bottle, and frozen water cools off, and drips the diethyl ether solution of above-mentioned acyl chlorides, finishes and stirs 1 hour.The reaction finish after, in system, add normal hexane (100mL), the after-filtration that stirs, solid with the washing, sherwood oil is washed, dry 8.8g, promptly acid amides 6, yield 88%.
Embodiment 6 acid amides 6 prepare compound 7 with the Cynuric Chloride dehydration
Under the nitrogen protection, (8.8g 39.4mmol) adds in the dry DMF (100mL) benzamide 6, and the frozen water cooling adds Cynuric Chloride (0.1mol), stirring at room 16 hours.Cool off with frozen water after reaction is finished, add shrend and go out, remove DMF under reduced pressure, resistates is washed with acetic acid ethyl dissolution, the saturated common salt washing, and anhydrous sodium sulfate drying concentrates the back column chromatography, gets colorless oil compounds 7,7.7g, yield 95%.
1H?NMR(300MHz，CDCl
3)：7.01(d，1H，J＝8.5Hz)，6.90(d，1H，J＝8.5Hz)，4.54-4.42(m，1H)，3.98(s，3H)，2.42(s，3H)，1.34(d，6H，J＝6.2Hz)；
13C?NMR(100MHz，CDCl
3)：152.9，148.3，134.6，125.0，120.9，115.5，108.3，72.0，61.4，22.0(×2)，19.7；
EI-MS：m/z(％)120(26)，148(26)，163(100)，205(15)；
HRMS: theoretical value C
12H
15NO
2: 205.1103, measured value: 205.1096.
Route 2:
The preparation of the sulfinyl amine compounds shown in the general formula I I (is R
2=sec.-propyl, R
3=tertiary butyl dimethyl is silica-based, R
4The general formula I I compound-compound 13 of=tertiary butyl)
Synthetic route is as follows:
The preparation of embodiment 73-methoxyl group-4-isopropoxy phenylethyl alcohol (compound 9)
Under the nitrogen protection, LiAlH
4(11.4g, 0.30mol) be suspended in anhydrous THF (500mL), be cooled to 0 ℃, drip 3-methoxyl group-4-isopropoxy toluylic acid (compound 8) (44.8g, 0.20mol) THF (200mL) solution, finish and refluxed 1 hour, be cooled to 0 ℃, carefully add entry (30mL), 10wt%NaOH (30mL) and water (100mL) successively.Then, left standstill 1 hour, filter, filtrate is with extracted with diethyl ether, and extraction liquid merges, and anhydrous sodium sulfate drying, concentrating under reduced pressure get colorless oil compounds 9,41.2g, yield 98%.
1H?NMR(300MHz，CDCl
3)：6.84(d，1H，J＝10.4Hz)，6.76-6.70(m，2H)，4.51-4.43(m，1H)，3.86-3.76(m，5H)，2.80(t，2H，J＝6.6Hz)，1.35(d，6H，J＝6.1Hz)；
13C?NMR(100MHz，CDCl
3)：150.4，145.9，131.4，120.9，116.2，112.9，71.5，63.7，55.9，38.7，22.1(×2)；
EIMS：m/z?137(100.0)，138(9.23)，168(20.24)，210(13.63)；
HRMS-EI (theoretical value C
12H
18O
3): 210.1256, measured value 210.1263.
The bromo of embodiment 83-methoxyl group-4-isopropoxy phenylethyl alcohol (compound 9) is with preparation compound 10
3-methoxyl group-4-isopropoxy phenylethyl alcohol (44.2g 0.21mol) is dissolved in DMF (200mL), frozen water cooling, add in batches N-bromo-succinimide (NBS) (41.1g, 0.23mol), stirred overnight at room temperature.Then, add Na
2S
2O
3The solution cancellation, concentrating under reduced pressure, resistates dissolves with methylene dichloride, washing, the saturated common salt washing, anhydrous sodium sulfate drying, concentrating under reduced pressure gets brown oil, and the rapid column chromatography purifying gets yellow oily compounds 10,59.3g, yield 98%.
1H?NMR(400MHz，CDCl
3)：7.03(s，1H)，6.77(s，1H)，4.50-4.46(m，1H)，3.86(t，2H，J＝6.6Hz)，3.83(s，3H)，2.94(t，2H，J＝6.6Hz)，1.36(d，6H，J＝6.0Hz)；
13C?NMR(100MHz，CDCl
3)：149.6，146.6，130.0，119.7，114.4，114.2，71.9，62.2，56.1，39.0，21.9(×2)；
EI-MS：m/z(％)215(100)，217(97)，246(33)，248(31)，288(18)，300(17)；
HRMS: theoretical value C
12H
17BrO
3: 288.0361, measured value: 288.0356.
Embodiment 9 compounds 10 hydroxyl protections are tertiary butyl dimethyl-silicon ether 11
Compound 10 (10.4g 36mmol) is dissolved in anhydrous methylene chloride (200mL), add imidazoles (4.9g, 72mmol), stir moments later add TERT-BUTYL DIMETHYL CHLORO SILANE (8.1g, 54mmol), stirring at room 1 hour.Then, the dilute reaction solution that adds methylene chloride, washing, the saturated common salt washing, dried over sodium sulfate, concentrating under reduced pressure, the resistates column chromatography gets yellow oily compounds 11,13.9g, yield 96%.
1H?NMR(400MHz，CDCl
3)：7.03(s，1H)，6.78(s，1H)，4.51-4.42(m，1H)，3.86-3.74(m，5H)，2.87(t，2H，J＝6.7Hz)，1.34(d，6H，J＝6.1Hz)，0.86(s，9H)，-0.03(s，6H)；
13C?NMR(100MHz，CDCl
3)：149.4，146.2，130.8，119.6，114.8，114.0，71.8，62.6，55.9，39.2，25.8(×3)，21.9(×2)，18.2，-5.5(×2)；
EI-MS：m/z(％)73(41)，223(47)，345(100)，347(96)，402(6)，404(6)；
HRMS: theoretical value C
18H
31SiBrO
3: 402.1226, measured value: 402.1218.
Embodiment 10 compounds 11 are converted into benzaldehyde compound 12
Under nitrogen protection; compound 11 (8.07g; 20mmol) be dissolved in anhydrous THF (200mL), be cooled to-78 ℃, (1.6M is in hexane to drip n-Butyl Lithium; 16mL); finish and stir half an hour, and dropping DMF (2.3mL, 30mmol); add saturated ammonium chloride solution after stirring half an hour, rise to room temperature.Add water (100mL), use extracted with diethyl ether, extraction liquid merges, the saturated common salt washing, and anhydrous sodium sulfate drying, concentrating under reduced pressure, the resistates column chromatography gets yellow oily compounds 12,6.4g, yield 91%.
1H?NMR(300MHz，CDCl
3)：10.15(s，1H)，7.39(s，1H)，6.74(s，1H)，4.47-4.58(m，1H)，3.91(s，3H)，3.83(t，2H，J＝6.3Hz)，3.17(t，2H，J＝6.3Hz)，1.37(d，6H，J＝6.0Hz)，0.82(s，9H)，0.09(s，6H).
13C?NMR(100MHz，CDCl
3)：190.4，154.8，145.9，137.4，127.4，115.4，114.2，71.4，64.4，56.0，34.9，25.8(×3)，21.9(×2)，18.2，-5.6(×2).
EI-MS：m/z(％)75(31)，214(31)，216(31)，221(32)，295(100)，352(1)；
HRMS: theoretical value C
19H
32SiO
4: 352.2070, measured value: 352.2081.
Embodiment 11 benzaldehyde compounds 12 and the condensation of S-tertiary butyl sulfinyl amine
Under nitrogen protection, benzaldehyde compound 12 (3.6g 10mmol) is dissolved in anhydrous THF (100mL), add S-tertiary butyl sulfinyl amine (1.27g, 10.5mmol), Ti (Oi-Pr)
4(7.4mL 25mmol), refluxes and stirred 4 hours.Then, the cooling reaction solution adds water (10mL), left standstill after stirring 1 hour, and filtered, filter cake washs with THF, filtrate concentrates, and with dichloromethane extraction, extraction liquid merges, the saturated common salt washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, the resistates column chromatography, get red thickness oily compounds 13,3.8g, yield 95%.
[α]
20 D+41.5(c0.53，CHCl
3)；
1H?NMR(300MHz，CDCl
3)：8.72(s，1H)，7.50(s，1H)，6.76(s，1H)，4.62-4.51(m，1H)，3.91(s，1H)，3.86-3.71(m，2H)，3.16-3.05(m，2H)，1.36(d，1H，J＝6.3Hz)，1.24(s，9H)，0.81(s，9H)，-0.09(s，6H)；
13C?NMR(100MHz，CDCl
3)：160.2，153.3，145.7，135.6，124.7，115.4，114.2，71.4，64.2，57.4，55.8，35.6，25.8(×3)，22.5(×3)，21.9，21.7，18.2，-5.6(×2)；
EI-MS：m/z(％)73(65)，177(100)，219(63)，267(72)，399(84)，455(3)；
HRMS: theoretical value C
23H
41NO
4SSi:455.2526, measured value: 455.2558.
Route 3:
With compound 7 and compound 13 is feedstock production L-SPD, and route is as follows:
Embodiment 12 is a feedstock production compound 14 with compound 7 and 13
Under argon shield, (2M 5.0mL) adds anhydrous THF (20mL) dilution to lithium diisopropyl amido in THF; be cooled to-78 ℃; stir after 5 minutes and to drip raw material o-cyano toluene compound 7 (1.03g, anhydrous THF (5mL) solution 5mmol) finish-78 ℃ and stirs half an hour.(-78 ℃ are stirred half an hour for 2.28g, anhydrous THF (5mL) solution 5mmol) to drip raw material group with imine moiety 13.Add saturated ammonium chloride solution cancellation reaction, rise to room temperature, extracted with diethyl ether.Extraction liquid merges, the saturated common salt washing, and anhydrous sodium sulfate drying, column chromatography behind the concentrating under reduced pressure (methylene dichloride: methyl alcohol=100: 1, by volume), obtain compound 14, be yellow thickness oily matter 1.70g, yield 52%.
[α]
20 D+34.5(c?0.80，CHCl
3)；
1H?NMR(300MHz，CDCl
3)：6.99(d，1H，J＝8.5Hz)，6.94(s，1H)，6.89(d，1H，J＝8.5Hz)，6.68(s，1H)，4.78-4.70(m，1H)，4.56-4.42(m，2H)，3.95(s，3H)，3.81(s，3H)，3.79-3.68(m，2H)，3.46(d，1H，J＝4.4Hz)，3.34(dd，1H，J＝14.1，6.6Hz)，3.11(dd，1H，J＝14.1，6.6Hz)，2.84-2.66(m，2H)，1.38-1.28(m，12H)，1.11(s，9H)，0.84(s，9H)，-0.09(s，6H)；
13C?NMR(100MHz，CDCl
3)：152.7，149.7，149.1，145.8，134.2，131.1，129.8，125.7，120.2，115.5，114.8，114.2，109.0，71.7(×2)，64.0，61.4，56.1，55.8，55.7，41.2，35.4，25.9(×3)，22.4(×3)，22.1(×2)，21.9(×2)，18.3，-5.3(×2)；
ESI-MS：683.1(M+Na)；
HRMS：683.3524(C
35H
56N
2O
6NaSSi，M+Na).
To as yet not the crude product of column chromatography carry out LC-MS de value test (C18 post, 250 * 4.6mm, CH
3CN/H
2O from 10/90 to 90/10 gradient elution after 20 minutes with 90/10 wash-out), diastereomer RT
1=26.6min (3%); Principal product: RT
2=27.0min (97%);
The structure of its diastereomer is:
Embodiment 13 compounds 14 remove protecting group, obtain compound 15
(0.50g 0.82mmol) is dissolved in the methyl alcohol (20mL) compound 14, adds concentrated hydrochloric acid (1.0mL), stirring at room 2 hours.Remove methyl alcohol under reduced pressure, resistates alkalizes with 10wt% sodium hydroxide, dichloromethane extraction, and extraction liquid merges, the saturated common salt washing, anhydrous sodium sulfate drying, concentrating under reduced pressure get white solid compound 15,0.27g, yield 81%.
[α]
20 D-4.7(c?0.95，CHCl
3)
1H?NMR(300MHz，CDCl
3)：7.05(s，1H)，7.02(d，1H，J＝8.5Hz)，6.92(d，1H，J＝8.5Hz)，6.68(s，1H)，4.58-4.42(m，3H)，4.00(s，3H)，3.86-3.75(m，4H)，3.73-3.64(m，1H)，3.22-3.12(m，1H)，3.04-2.73(m，3H)，1.38-1.29(m，12H)；
13C?NMR(100MHz，CDCl
3)：153.0，149.6，149.2，145.8，135.1，134.1，130.2，125.8，120.1，115.7，113.8(×2)，107.9，71.7(×2)，63.9，61.5，55.9，51.1，43.1，35.6，22.1(×4)；
ESI-MS：442.9(M+H)；
HRMS：465.2363(C
25H
34N
2O
5Na，M+Na).
15 cyclisation of embodiment 14 compounds are lactan 16
(0.35g 0.79mmol) is dissolved in the ethanol (15mL) compound 15, adds 20wt% potassium hydroxide solution (15mL), refluxes and stirs 12 hours.Be cooled to room temperature, remove ethanol under reduced pressure, remaining alkali lye is with dichloromethane extraction, and extraction liquid merges, the saturated common salt washing, and anhydrous sodium sulfate drying, concentrating under reduced pressure, column chromatography gets lactam compound 16,0.30g, yield 87%.
[α]
20 D-97.1(c?0.51，CHCl
3)；
1H?NMR(300MHz，CDCl
3)：7.00(d，1H，J＝8.1Hz)，6.86(d，1H，J＝8.1Hz)，6.72(s，1H)，6.57(s，1H)，4.93(dd，1H，J＝11.6，3.3Hz)，4.53-4.45(m，2H)，3.90(s，3H)，3.86-3.75(m，5H)，3.17-3.06(m，1H)，2.92-2.76(m，3H)，1.36-1.24(m，12H)；
13C?NMR(100MHz，CDCl
3)：164.9，152.1，151.1，150.0，146.0，132.0，130.6，129.4，122.8，122.5，121.1，114.1，113.9，72.2，71.6，63.5，61.3，56.0，51.2，37.1，35.2，22.2(×4)；
ESI-MS：466.3(M+Na).
The 16 further cyclisation of embodiment 15 lactam compounds are compound 17
Lactam compound 16 (130mg 0.29mmol) is dissolved in anhydrous pyridine (10mL), and the adding Tosyl chloride (95mg, 0.5mmol), stirred overnight at room temperature.Remove solvent under reduced pressure, resistates methylene dichloride dissolving, washing, the saturated common salt washing, anhydrous sodium sulfate drying, concentrate oily matter.This oily matter is dissolved in anhydrous THF (10mL), the frozen water cooling, adding NaH (60% in mineral oil, 100mg), and stirring at room 2 hours.The frozen water cooling carefully adds shrend and goes out dichloromethane extraction.Extraction liquid merges, the saturated common salt washing, and anhydrous sodium sulfate drying, (ethyl acetate: sherwood oil=1: 2 by volume), gets faint yellow oily compounds 17,90mg, yield 72% to column chromatography behind the concentrating under reduced pressure.
[α]
20 D-247.9(c0.75，CHCl
3)；
1H?NMR(300MHz，CDCl
3)：7.03(d，1H，J＝8.2Hz)，6.92(d，1H，J＝8.2Hz)，6.73(s，1H)，6.70(s，1H)，4.72(dd，1H，J＝13.0，3.2Hz)，4.60-4.43(m，2H)，4.02(s，3H)，3.87(s，3H)，3.04-2.72(m，6H)，1.42-1.31(m，12H)；
13C?NMR(100MHz，CDCl
3)：162.7，151.8，151.2，149.4，146.0，131.7，128.2，127.6，123.8，121.9，120.2，114.3，111.9，72.0，71.9，61.3，55.9，54.8，39.2，38.1，29.4，22.1(×4)；
ESI-MS：448.1(M+Na)；
HRMS：448.2092(C
25H
31NO
5Na，M+Na).
Embodiment 16 compounds 17 are reduced to the L-SPD (18) of two sec.-propyl protections
Under nitrogen protection, (54mg 0.126mmol) is dissolved in anhydrous THF (20mL) to compound 17, adds LiAlH
4(15mg), backflow was stirred 2 hours.Frozen water cools off reaction solution, carefully adds shrend and goes out, and concentrates, and resistates is with dichloromethane extraction, and the extraction liquid saturated common salt is washed, and anhydrous sodium sulfate drying concentrates the back column chromatography, gets faint yellow solid compound 18,47mg, yield 91%.
[α]
20 D-190.5(c0.66，CHCl
3)；
1H?NMR(300MHz，CDCl
3)：6.87-6.78(m，3H)，6.63(s，1H)，4.57-4.46(m，2H)，4.24(d，1H，J＝15.9Hz)，3.88(s，3H)，3.85(s，3H)，3.62-3.50(m，2H)，3.31-3.08(m，3H)，2.88-2.61(m，3H)，1.45-1.34(m，12H)；
13C?NMR(100MHz，CDCl
3)：148.9，148.1，146.4，145.4，129.6，128.8，128.0，127.5，123.7，115.0，113.9，111.8，71.8，71.1，60.0，59.1，55.8，54.0，51.4，36.3，29.1，22.1(×4)；
ESI-MS：412.1(M+H)；
HRMS：412.2490(C
25H
34NO
4，M+H).
Embodiment 17 compounds 18 deprotections are L-SPD
Under nitrogen protection, (47mg 0.114mmol) is dissolved in anhydrous methylene chloride (10mL) to compound 18, is cooled to-78 ℃, drips BCl
3Dichloromethane solution (1M 0.5mL), finishes and slowly rises to ambient temperature overnight.Add water (3mL) cancellation reaction, add THF (5mL), tell organic phase, anhydrous sodium sulfate drying, the evaporating column chromatography gets L-SPD 32mg, yield 86%.
[α]
D 20＝-281.6(c?1.0，CH
3OH)
m.p.128-129℃；
1HNMR(CD
3OD)：δ6.78-6.66(m，3H)，6.63(s，1H)，4.15(d，J＝15.7Hz，1H)，3.79(s，3H)，3.77(s，3H)，3.50-3.38(m，2H)，3.32-2.98(m，3H)，2.74-2.52(m，3H)；
13CNMR(CD
3OD)：δ149.26，148.31，146.49，145.46，131.21，129.23，127.68，126.73，125.91，116.86，113.61，112.98，61.13，60.91，56.81，55.32，53.33，36.95，29.74；
EI-MS(m/z，％)：327(84.4)，178(100)。
Route 4:
With compound 12 and compound 7 is feedstock production D-SPD (being the enantiomer of L-SPD), and wherein, " ent-compound number " represents the enantiomer title of above-claimed cpd respectively.Route is as follows:
Embodiment 18 benzaldehyde compounds 12 get Verbindung nt-13 with the condensation of R-tertiary butyl sulfinyl amine
According to the identical method of embodiment 11, but replace S-tertiary butyl sulfinyl amine among the embodiment 11 with R-tertiary butyl sulfinyl amine, obtain Verbindung nt-13, yield, hydrogen spectrum, carbon spectrum, mass-spectrometric data are all consistent with compound 13, [α]
20 D=-41.4 (c 0.55, CHCl
3).
Embodiment 19 is feedstock production Verbindung nt-14 with compound 7 and ent-13
Experimental implementation is carried out according to embodiment 12 identical steps, prepares Verbindung nt-14, and resulting compound 14 is identical among the hydrogen spectrum of reaction yield and product, carbon spectrum, mass-spectrometric data and the embodiment 12, optical value [α]
20 D:-34.7 (c 0.82, CHCl
3).
Embodiment 20 Verbindung nt-14 remove protecting group, obtain Verbindung nt-15
Experimental implementation is carried out according to embodiment 13 identical steps, prepares Verbindung nt-15, and resulting compound 15 is identical among the hydrogen spectrum of reaction yield and product, carbon spectrum, mass-spectrometric data and the embodiment 13, optical value [α]
20 D:+4.6 (c0.92, CHCl
3).
Embodiment 21 Verbindung nt-15 cyclisation are lactan ent-16
Experimental implementation is carried out according to embodiment 14 identical steps, prepares Verbindung nt-16, and resulting compound 16 is identical among the hydrogen spectrum of reaction yield and product, carbon spectrum, mass-spectrometric data and the embodiment 14, the optical value of product [α]
20 D:+97.3 (c0.51, CHCl
3).
The further cyclisation of embodiment 22 lactam compound ent-16 is Verbindung nt-17
Experimental implementation is carried out according to embodiment 15 identical steps, prepares Verbindung nt-17, and resulting compound 17 is identical among the hydrogen spectrum of reaction yield, product, carbon spectrum, mass-spectrometric data and the embodiment 15, the optical value of product [α]
20 D:+247.2 (c 0.75, CHCl
3).
Embodiment 23 Verbindung nt-17 are reduced to the D-SPD (ent-18) of two sec.-propyl protections
Experimental implementation is carried out according to embodiment 16 identical steps, prepares Verbindung nt-18, and resulting compound 18 is identical among the hydrogen spectrum of reaction yield, product, carbon spectrum, mass-spectrometric data and the embodiment 16, the optical value of product [α]
20 D:+190.6 (c 0.65, CHCl
3).
Embodiment 24 Verbindung nt-18 deprotections are D-SPD
Experimental implementation is carried out according to embodiment 17 identical steps, prepares Compound D-SPD, and the hydrogen spectrum of reaction yield, product, carbon spectrum, mass-spectrometric data are identical with resulting compound L-SPD among the embodiment 17, optical value [α]
D 23:+281.4 (c1.0, CH
3OH).
Claims (15)
1. the preparation method of a Stopholidine or derivatives thereof optical isomer, it is raw material that this method adopts the sulfinyl amine compounds shown in o-cyano toluene compounds shown in the following general formula I and the general formula I I, wherein the o-cyano toluene compounds shown in the general formula I:
In the formula, R
1Be sec.-propyl, benzyl, 4-methoxy-benzyl, 3,4-dimethoxy-benzyl, methoxymethyl or benzyloxymethyl, and preferred sec.-propyl;
Sulfinyl amine compounds shown in the general formula I I:
In the formula, R
2Be sec.-propyl, benzyl, 4-methoxy-benzyl, 3,4-dimethoxy-benzyl, methoxymethyl or benzyloxymethyl, and preferred sec.-propyl; R
3For trimethyl silicon based, triethyl is silica-based, tertiary butyl dimethyl is silica-based, tert-butyl diphenyl is silica-based, benzyl, 4-methoxy-benzyl or 3,4-dimethoxy-benzyl, and the silica-based or benzyl of preferred tertiary butyl dimethyl; R
4Be the tertiary butyl, p-methylphenyl or naphthyl, and the preferred tertiary butyl; And in the sulfinyl amine structure, the chirality of sulphur atom can be S type or R type, wavy line
Represent that this chemical bond can be solid line or dotted line;
The preparation method of described Stopholidine or derivatives thereof optical isomer comprises the steps:
Step 1: the o-cyano toluene compounds shown in the general formula I is seized hydrogen under the effect of alkali, form the metal lithium salts, sulfinyl amine compounds with the S configuration shown in the general formula I I carries out addition reaction then, obtain the compound III of S configuration, perhaps the sulfinyl amine compounds with the R configuration shown in the general formula I I carries out addition reaction, obtains the compound III of R configuration;
Its reaction formula is as follows:
Step 2: the compound III that step 1 obtains the S configuration removes protecting group R
3And R
4S (O)-, obtain the compound of the S configuration shown in the general formula I V, perhaps step 1 compound III that obtains the R configuration removes protecting group R
3And R
4S (O)-, obtain the compound of the R configuration shown in the general formula I V;
Its reaction formula is as follows:
Step 3: the compound of the S configuration shown in the general formula I V issues addition and the hydrolysis reaction of living intramolecularly amido to cyano group at sodium hydroxide or potassium hydroxide base effect, obtain the lactam analog compound V of the S configuration shown in the general formula V, perhaps the compound of the R configuration shown in the general formula I V issues addition and the hydrolysis reaction of living intramolecularly amido to cyano group at sodium hydroxide or potassium hydroxide base effect, obtains the lactam analog compound V of the R configuration shown in the general formula V;
Its reaction formula is as follows:
Step 4: make alcoholic extract hydroxyl group and SULPHURYL CHLORIDE reaction among the lactam analog compound V of the S configuration that step 3 obtains generate sulphonate, resulting then sulphonate under the effect of alkali with amide group generation internal nucleophilic substitution further cyclisation be the compound of the S configuration shown in the general formula VI; Perhaps the reaction of alcoholic extract hydroxyl group among the lactam analog compound V of R configuration and SULPHURYL CHLORIDE generates sulphonate, and the cyclisation further with amide group generation internal nucleophilic substitution under the effect of alkali of resulting then sulphonate is the compound of the R configuration shown in the general formula VI,
Its reaction formula is as follows:
Step 5: make the compound of the S configuration shown in the general formula VI that step 4 obtains under the reductive agent effect, be reduced to the compound of the S configuration shown in the general formula VII, perhaps make the compound of the R configuration shown in the general formula VI that step 4 obtains under the reductive agent effect, be reduced to the compound of the R configuration shown in the general formula VII;
Its reaction formula is as follows:
Step 6: the compound of the S configuration shown in the general formula VII removes R
1, R
2, obtain l-spd, perhaps the compound of the R configuration shown in the general formula VII removes R
1, R
2, obtain the dextrorotation Stopholidine;
Its reaction formula is as follows:
2. preparation method according to claim 1 is characterized in that, in described step 1, described alkali is lithium diisopropyl amido, two (trimethyl silicon based) amido lithium, n-Butyl Lithium, s-butyl lithium or tert-butyl lithium, and preferred lithium diisopropyl amido; The consumption of alkali is 1 to 3 equivalent with respect to the o-cyano toluene compounds shown in the general formula I; Solvent for use is tetrahydrofuran (THF), ether, methyl tertiary butyl ether, glycol dimethyl ether or diethylene glycol dimethyl ether; Temperature of reaction is-80 ℃ to-20 ℃; The time of o-cyano toluene compounds shown in the general formula I and alkali effect is 10 to 60 minutes; The consumption of the sulfinyl amine compounds shown in the general formula I I is 0.9 to 1.5 equivalent with respect to the o-cyano toluene compounds shown in the general formula I, and the reaction times behind the adding sulfinyl amine compounds is 30 to 120 minutes.
3. preparation method according to claim 1 is characterized in that, in described step 2,
Work as R
3For trimethyl silicon based, triethyl is silica-based, tertiary butyl dimethyl is silica-based or tert-butyl diphenyl when silica-based, sulfinyl R
4S (O)-with R
3Remove together, the mixture that deprotection reaction is formed with methyl alcohol, ethanol, Virahol, water or water and above-mentioned alcohol is a solvent, removes under hydrochloric acid, sulfuric acid, acetic acid or trifluoracetic acid effect;
Work as R
3Be benzyl, remove sulfinyl R with preceding method earlier
4S (O)-, be catalyzer with palladium carbon or palladium hydroxide/carbon again, be that hydrogen donor removes benzyl with hydrogen, formic acid or tetrahydrobenzene;
Work as R
3Be 4-methoxy-benzyl or 3, during the 4-dimethoxy-benzyl, remove sulfinyl R with preceding method earlier
4S (O)-, the mode with ceric ammonium nitrate or DDQ oxidation removes 4-methoxy-benzyl or 3 again, the 4-dimethoxy-benzyl.
4. preparation method according to claim 1, it is characterized in that, in described step 3, reaction solvent is the mixture that methyl alcohol, ethanol, Virahol, water or water and above-mentioned alcohol are formed, the alkali that reacts used is sodium hydroxide or potassium hydroxide, temperature of reaction be-20 ℃ to the solvent refluxing temperature, the reaction times is 4 to 48 hours.
5. preparation method according to claim 1 is characterized in that, in described step 4, cyclisation is reacted in two steps and carried out:
The first step with lactam analog compound V and SULPHURYL CHLORIDE react sulphonate, wherein used SULPHURYL CHLORIDE is methylsulfonyl chloride, trifluoromethanesulfchloride chloride, Tosyl chloride or m-nitrobenzene sulfonyl chloride, reaction solvent can be pyridine, methylene dichloride, chloroform, tetrahydrofuran (THF), ether or methyl tertiary butyl ether, the acid binding agent that reacts used is pyridine, to dimethylamino pyridine, triethylamine or diisopropyl ethyl amine, temperature of reaction be-20 ℃ to the solvent refluxing temperature, the reaction times is 4 to 48 hours;
The sulphonate of second step with the first step gained is converted into the compound shown in the general formula VI under the alkali effect, reaction is made solvent with tetrahydrofuran (THF), ether or methyl tertiary butyl ether, with sodium hydride, hydrolith, lithium diisopropyl amido or two (trimethyl silicon based) amido lithium is alkali, temperature of reaction be-20 ℃ to solvent refluxing, the reaction times is 1 to 24 hour.
6. preparation method according to claim 1 is characterized in that, in described step 5, described reduction reaction is a solvent with tetrahydrofuran (THF), ether or methyl tertiary butyl ether, is reductive agent with lithium aluminium hydride, borane complexes, POTASSIUM BOROHYDRIDE or sodium borohydride.
7. preparation method according to claim 1 is characterized in that, in described step 6,
Work as R
1=R
2During=sec.-propyl, be reaction solvent with methylene dichloride, chloroform, tetrahydrofuran (THF), ether or methyl tertiary butyl ether, preferred methylene dichloride, compound shown in the general formula VII and boron trichloride or aluminum chloride reaction remove sec.-propyl;
Work as R
1=R
2During=benzyl, reaction is a solvent with methyl alcohol, ethanol, tetrahydrofuran (THF), water or their mixture, is catalyzer with palladium carbon, palladium hydroxide/carbon, is that hydrogen donor removes with hydrogen, formic acid or tetrahydrobenzene; Or be solvent with hydrochloric acid, reflux removes; Or be solvent with methylene dichloride or chloroform, compound shown in the general formula VII and boron trichloride or aluminum chloride are-80 ℃ of reactions and removing to the temperature of room temperature.
8. the compound shown in the following general formula III:
Wherein, R
1, R
2, R
3And R
4Define identical with claim 1.
9. the sulfinyl amine compounds shown in the following general formula I I:
Wherein, R
2Be sec.-propyl, benzyl, 4-methoxy-benzyl, 3,4-dimethoxy-benzyl, methoxymethyl or benzyloxymethyl, and preferred sec.-propyl; R
3For trimethyl silicon based, triethyl is silica-based, tertiary butyl dimethyl is silica-based, tert-butyl diphenyl is silica-based, benzyl, 4-methoxy-benzyl or 3,4-dimethoxy-benzyl, and the silica-based or benzyl of preferred tertiary butyl dimethyl; R
4Be the tertiary butyl, p-methylphenyl or naphthyl, and the preferred tertiary butyl; And in the sulfinyl amine structure, the chirality of sulphur atom can be S type or R type, wavy line
Represent that this chemical bond can be solid line or dotted line.
10. the preparation method of the sulfinyl amine compounds shown in the general formula I I as claimed in claim 9, this method comprises:
Wherein, R
2, R
3, R
4Definition identical with claim 9;
Step I: substituted phenylacetic acid a is reduced to substituted benzene ethanol b, and this reduction reaction is a reductive agent with lithium aluminium hydride, borane complexes, POTASSIUM BOROHYDRIDE or sodium borohydride;
Step I i: substituted benzene ethanol b obtains the compound c of o-brominated by bromo-reaction, and this bromo-reaction is with chloroform, N, and dinethylformamide or N,N-dimethylacetamide are solvent, are brominated reagent with the N-bromo-succinimide;
Step I ii: compound c is carried out the alcoholic extract hydroxyl group protection, obtains compound d, works as R
3For trimethyl silicon based, triethyl is silica-based, tertiary butyl dimethyl is silica-based or tert-butyl diphenyl when silica-based, in the presence of at imidazoles, pyridine, to dimethylamino pyridine, triethylamine or diisopropyl ethyl amine alkali, compound c and corresponding chlorosilane reaction obtain compound d; Work as R
3Be benzyl, 4-methoxy-benzyl or 3, during the 4-dimethoxy-benzyl, at acetone, tetrahydrofuran (THF) or N, in the N-dimethylacetamide solvent, in the presence of salt of wormwood, yellow soda ash, sodium hydride or hydrolith alkali, compound c and corresponding benzyl chlorine or benzyl bromine reaction obtain compound d;
Step I v: with tetrahydrofuran (THF), ether or methyl tertiary butyl ether is solvent, under alkali lithium diisopropyl amido, two (trimethyl silicon based) amido lithium, n-Butyl Lithium, s-butyl lithium or tert-butyl lithium effect, the bromine atoms of compound d carries out metal-halogen exchange, to N, dinethylformamide carries out addition, makes benzaldehyde compound e;
Step v: in the presence of condensing agent metatitanic acid tetra isopropyl ester or tetraethyl titanate, the R of benzaldehyde compound e and S configuration
4S (O) NH
2Sulfinyl amine carries out condensation reaction, obtains the sulfinyl amine compounds shown in the general formula I I of S configuration; The perhaps R of benzaldehyde compound e and R configuration
4S (O) NH
2Sulfinyl amine carries out condensation reaction, obtains the sulfinyl amine compounds shown in the general formula I I of R configuration.
11. the o-cyano toluene compounds shown in the following general formula I:
Wherein, R
1Be sec.-propyl, benzyl, 4-methoxy-benzyl, 3,4-dimethoxy-benzyl, methoxymethyl or benzyloxymethyl, and preferred sec.-propyl.
12. the preparation method of the o-cyano toluene compounds shown in the general formula I as claimed in claim 11, this method comprises:
Wherein, R
1Define identical with claim 11, R
5Be methyl, ethyl, sec.-propyl, the tertiary butyl or phenyl,
Step I: in the presence of alkali, phenyl aldehyde A and dimethylamine hydrochloride and sodium borohydride or POTASSIUM BOROHYDRIDE are carried out reductive amination process, obtain dimethyl benzyl amine B;
Step I i: in the presence of alkali, dimethyl benzyl amine B and chloro-formic ester reaction obtain benzyl chlorine C; Wherein, this reacts used alkali is lithium diisopropyl amido, two (trimethyl silicon based) amido lithium, n-Butyl Lithium, s-butyl lithium or tert-butyl lithium, and described chloro-formic ester is methyl-chloroformate, Vinyl chloroformate, isopropyl chlorocarbonate, the chloroformic acid tert-butyl ester or phenyl chloroformate;
Step I ii: benzyl chlorine C is reduced to o-toluic acid ester D by reduction reaction; Wherein, this reduction reaction is a catalyzer with palladium carbon or palladium hydroxide/carbon, is that hydrogen donor carries out with hydrogen, formic acid or tetrahydrobenzene;
Step I v: o-toluic acid ester D is hydrolyzed to o-toluic acid E in the presence of acid or alkali;
Step v: o-toluic acid E is converted into benzamide F by two-step reaction: the first step, and o-toluic acid E and oxalyl chloride or sulfur oxychloride reaction are converted into acyl chlorides; In second step, the water of resulting acyl chlorides and ammonia, methyl alcohol or ethanolic soln reaction obtain benzamide F;
Step vi: benzamide F dewaters under the dewatering agent effect, obtains the o-cyano toluene compounds shown in the general formula I, and used dewatering agent is sulfur oxychloride or Cynuric Chloride.
13. the compound shown in the following general formula I V:
Wherein, R
1And R
2Define identical with claim 1.
14. the compound shown in the following general formula V:
Wherein, R
1And R
2Define identical with claim 1.
15. the compound shown in the following general formula VI:
Wherein, R
1And R
2Define identical with claim 1.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012031573A1 (en) * | 2010-09-10 | 2012-03-15 | 山东特珐曼医药原料有限公司 | A method for preparing an optical isomeric stepholidine and derivates thereof |
| CN105294675A (en) * | 2014-06-19 | 2016-02-03 | 中国科学院上海药物研究所 | Preparation method for stepholidine and derivatives thereof |
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| CN1900075A (en) * | 2006-07-26 | 2007-01-24 | 中国科学院上海药物研究所 | Tetrahydro-proto-berberine compounds, their preparing method, composition and use |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1900075A (en) * | 2006-07-26 | 2007-01-24 | 中国科学院上海药物研究所 | Tetrahydro-proto-berberine compounds, their preparing method, composition and use |
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| Title |
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| 《Organic Letters》 20001108 Franklin A. Davis et al. Sulfinimine-Mediated Asymmetric Synthesis of 1,3-Disubstituted Tetrahydroisoquinolines: A Stereoselective Synthesis of cis- and trans-6,8-Dimethoxy-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline. 第3902页 3 第2卷, 第24期 * |
| 《The Journal of Organic Chemistry》 20020129 Franklin A. Davis et al. Asymmetric Synthesis of the Protoberberine Alkaloid (S)-(-)-Xylopinine Using Enantiopure Sulfinimines. 第1290-1296页 1-10, 13-15 第67卷, 第4期 * |
| 《The Journal of Organic Chemistry》 20091030 Jian-Jun Cheng et al. Enantioselective Total Synthesis of (-)-(S)-Stepholidine. 第9226-9227页 1-10, 13-15 第74卷, 第23期 * |
| FRANKLIN A. DAVIS ET AL.: "Asymmetric Synthesis of the Protoberberine Alkaloid (S)-(-)-Xylopinine Using Enantiopure Sulfinimines.", 《THE JOURNAL OF ORGANIC CHEMISTRY》, vol. 67, no. 4, 29 January 2002 (2002-01-29), pages 1290 - 1296 * |
| JIAN-JUN CHENG ET AL.: "Enantioselective Total Synthesis of (-)-(S)-Stepholidine.", 《THE JOURNAL OF ORGANIC CHEMISTRY》, vol. 74, no. 23, 30 October 2009 (2009-10-30), pages 9226 - 9227 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012031573A1 (en) * | 2010-09-10 | 2012-03-15 | 山东特珐曼医药原料有限公司 | A method for preparing an optical isomeric stepholidine and derivates thereof |
| CN105294675A (en) * | 2014-06-19 | 2016-02-03 | 中国科学院上海药物研究所 | Preparation method for stepholidine and derivatives thereof |
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