CN1045442C - Levo- and dextro-rotary chloroscouriline (tetrahydroprotoberberines) and application thereof - Google Patents
Levo- and dextro-rotary chloroscouriline (tetrahydroprotoberberines) and application thereof Download PDFInfo
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Abstract
The present invention relates to levo/dextro-chloroscouriline (tetrahydroprotoberberines) manufactured by applying a synthetic method. The present invention, levo-stephania and levo-tetrahydro palmatine belong to tetrahydro proto-berberine class of compounds, and pharmacology tests prove that the levo-chloroscouriline (tetrahydroprotoberberines) has stronger functions than the levo-stephania and the levo-tetrahydro and can be suitable for industrialized production.
Description
The present invention relates to the N-1 analogue, the particularly left and right chlorine Si Kuli quinoline that revolves.
L-spd [(-)-stepholidine, (-)-SPD] [I] and rotundin [(-)-tetrahydropalmatine, (-)-THP] [II] 12-chloro Si Kuli quinoline [2,9-dihydroxyl 3,10-dimethoxy-12-chloro-tetrahydrochysene berbine, THPB-18] [III], their structure is very similar, through Shanghai Pharmaceutical Inst., Chinese Academy of Sciences at first confirm they be in the brain of novel type Dopamine HCL (Dopamine, DA) receptor-blocking agent have extensive potential applicability in clinical practice.
L-spd and hyndarin are Tetrahydro-proto-berberines congener (tetrahydroprotoberberines, THPBs), rotundin is a kind of neuroleptanalgesic, loaded China pharmacopeia, left-handed stephanine clinical application is in treatment hyperkinetic syndrome and migraine, and can be used for psychotic treatment.L-spd is to separate to obtain from the piece root of Root of Japanese Stephania plant, but because plant resources sharply descends, clinical use has hidden danger, because l-spd carries out large-scale commercial production with synthetic method very big difficulty is also arranged, be necessary that therefore the congener of seeking other substitutes l-spd again.
Control the racemize of reporting with golden Tian Chongfu 2 by Japanese scientist tortoise paddy wise man, synthetic (the pharmaceutical journal 87 of 9-dihydroxyl-3-10-dimethoxy-12-chloro-tetrahydrochysene berbine, 1070 (1967)] nineteen sixty-eight is recorded in chemical abstracts, compound number is [17891-0-0-8], it is that reaction makes through 11 steps as starting raw material with isovanillin, but up to making the report of not seeing about its biological effect.
The present invention seeks to seek a kind of Tetrahydro-proto-berberines congener, it not only can be made the interior novel retarding agent of Dopamine Receptors of brain but also meets the industrial production condition.
The present invention finishes through the following steps.
Make 1 (Ber.96,1520[1962]) by isovanillin through two step reactions.
Compound 1 sulfuryl chloride chlorination; obtain 2-chloro-4-methoxyl group-5-hydroxyl phenylacetic acid (2); compound 2 usefulness iodate 1-methyl-2-bromopyridines make activator and 3-methoxyl group-4-benzyloxy phenylethylamine 3 is condensed into acid amides 4; also can be by compound 2 and 3 directly dehydration generation 4 at high temperature; the hydroxyl of compound 4 generates 5a respectively with isobutyl oxygen formyl radical or ethanoyl protection; 5b; 5a; 5b is transformed into dihydro-isoquinoline salt 6a with the Bischler-Napieralski method respectively with Phosphorus Oxychloride; 6b; in ethanol or methyl alcohol, reduce and the deacylated tRNA base with boron hydrogen sodium then; obtain tetrahydroisoquinoline 7; 7 at room temperature carry out the Mannich reaction with formaldehyde; obtain racemize 2-benzyloxy-3,10-dimethoxy-9-hydroxyl-12-chloro-tetrahydrochysene berbine (8).Compound 8 is used the hydrochloric acid debenzylation in formic acid, obtain racemize 2,9-dihydroxyl-3,10-dimethoxy-12-chloro-tetrahydrochysene berbine (III) (±-THPB-18)
Compound 8 usefulness optical activity dibenzoyl tartaric acids split into left-handed and dextral compound 8 as resolving agent, levorotatory compound 8 and dextrorotatory compound 8 obtain the levorotatory compound III with the hydrochloric acid debenzylation respectively in formic acid and the dextrorotatory compound III is (-)-THPB-18 and two compounds of (+)-THPB-18.
The chemical property of (-)-THPB-18 compound:
The chiral carbon of (-)-THPB-18 is C14, and specific rotation is [α]
D 11.5=-223.19 ° of (CHCl
3, C=0.14), fusing point 161-162 ℃ (decomposition), C
2And C
3The position has hydroxyl, C
3And C
10The position has methoxyl group; Color is a dark brown red, is dissolved in dilute sulphuric acid and methyl alcohol, organic solvents such as chloroform, silica gel thin-layer chromatography, (solvent systems is an ethyl acetate), R
rBe worth consistent with (±)-THPB-18.
Ultimate analysis (C
19H
20NO
4Cl)
Calculated value: C 63.07
H 5.57
N 3.87
Cl 9.80
Experimental value C 62.86
H 5.92
N 8.66
Cl 9.66
HNMR (400 megacycle), CF
3COOD, δ 3.91,4.01 (each 3H, 2s, CH
3O-); 6.88,7.10,7.13 (each 1H, 3s are aromatic nucleus hydrogen) ppm;
IR(KBr)3510,3400,2930,2834,1615,1510,1487,1435,1290,1240,1142,1106,1025,830cm
-1
The chemical feature of (+)-THPB-18:
The specific rotation of (+)-THPB-18 [α]
D 115+ 222.53 ° of (CHCl
3, C=0.12), other physico-chemical properties are identical with (-)-THPB-18 in addition, calculated value: C, and 63.07 H, 5.57 N, 3.87 Cl, 9.80, measured value C, 62.83, H, 5.72 N, 3.62Cl 9.99
Method of the present invention is that raw material reacts synthetic racemize 2 through 9 steps with the isovanillin, 9-dihydroxyl-3, and 10-dimethoxy-12-chloro-tetrahydrochysene berbine, more easier than the method in Gui Gu and golden field.
(-)-THPB-18, (+)-THPB-18 (±)-THPB-18 and (-)-SPD compare the avidity of DA receptors bind:
Use D
1And D
2Two kinds of DA receptor binding assays, prove (-)-THPB-18 and (±)-THPB-18 be to D
1And D
2Look and power [K1] all on the nM level, wherein (-)-THPB-18 is to D
1And D
2Effect stronger slightly than (±)-THPB-18, yet (-)-THPB-18 and (±)-THPB-18 are to D
1Effect than (+)-THPB-18 15-25 eager to excel in whatever one does doubly, they are to D
2Effect than the strong 953-1605 of (+)-THPB-18 doubly (-)-THPB-18 to D
1Effect and (-) SPD similar.Yet the former is to D
2Effect stronger approximately 14 times than (-)-SPD, show thus (-)-effect of THPB-18 is stronger than (-)-SPD.
Table 1 THPB-18 optically active isomer and (-) SPD are right
The comparison radioreceptor of DA receptor acting avidity is in conjunction with test (-)-SPD THPB-18 (±) THPB-18 (+)-THPD-18[
*H] S △ H28890 D1 Ki (nM) 80 8 89 135[
*H]-Syiyemme D2 Ki (nM) 80.0 8 96 9160 D2/D1 ratio 9 1.07 67 (-)-THPB-18 are to the pharmacodynamics test (table 2) of DA acceptor retardation: from suppressing the minimizing of spontaneous activity in mice, the antagonism amphetamine is to the mouse excitation activity and draw together anti-Apomorphinum to typing active action of mouse etc., the test of three DA nervous system activities shows that (-)-THPB-18 has retardation to DA acceptor in the brain, the effect of antagonism presynaptic and postsynaptic DA receptor simultaneously, action intensity is similar to (-) SPD or strong slightly.
By the DA neurone discharge activities test of record black substance dense area (SNC), prove (-)-THPB-18 can antagonism D
2And D
1The effect of receptor stimulant, show (-)-THPB-18 has the action characteristic of DA receptor-blocking agent stronger slightly than the effect of (-)-SPD.
Rat circling behavior and GTP regulate D
1The test of acceptor high-affinity demonstrates (-)-THPB-18 to D
1Acceptor has agonism, and this action characteristic is identical with (-) SPD.In the DA receptor-blocking agent, have D concurrently
1The compound of receptor agonism has only (-)-SPD at present, and this agonism may be to weaken the cataleptic major reason of (-)-SPD, becomes (-)-big characteristics of SPD effect.Similarly, (-)-THPB-18 also has such action characteristic.
According to the chemical structure of (-)-THPB-18 and similarity inference (-)-THPB of pharmacological action feature and (-)-SPD, the clinical application of (±)-THPB has the indication similar to (-) SPD probably.
The pharmacological action of table 2 (-)-THPB-18 and (-)-SPD relatively
Test (-)-THPB-18 (-)-SPD1. suppresses spontaneous activity in mice effect 20,30-60 minutes 20,30-60 minute time length 2., the antagonism amphetamine was to mouse excitement 20,30 minutes 20,30 minutes active action time length 3. antagonism Apomorphinum suppresses black substance and causes neural discharge off activity (to the effect of D2 acceptor) (the μ g/kg of 77 14 close district DA 10 of mouse～20 15～30 typing active actions, 4. upset Apomorphinums, iv) 5. upset SKF38393 are to inhibition (effect of D1 acceptor) (the μ g/kg of reserpinization 500 520 back black substance DA neurone discharges, iv) D1 receptor agonism (mg/kg, ip) the dibit point combination of 7. pairs of D1 acceptors of rotation 25 behaviors of 6.6-OHDA damage rat
(n?mol/L)
High affine R
H0.04 2.4
Low affine R
L80.0 68.3
GTP regulation and control R 17 338. causes catalepsy (mg/kg, ip) 15 20
It is of short duration to act on of short duration effect
The immeasurable effect relationship 9. chmice acute LD50 of no dose-effect relationship (mg/kg, ip) 149 358
(7 days) (3 days) are clinical indication not test (N.T.) migraine 10.
Infer hyperkinetic syndrome
There are the similar effect 11. clinical effective reduction intraocular pressure 12. clinical plans examination illnesss of trembling not try schizophrenia
This shows with left and right and revolve the preparation of chlorine Si Kuli quinoline as the application in treatment hyperkinetic syndrome, migraine, the schizophrenia drug.
The preparation of embodiment 1:2-chloro-4-methoxyl group-5-hydroxyl phenylacetic acid (1):
3-hydroxyl-4-methoxyl group-toluylic acid 5 grams, be dissolved in 30 milliliters in Glacial acetic acid, slowly add 2.4 milliliters of sulfuryl chlorides, continue to stir 1.5 hours in room temperature then in room temperature with under stirring, decompression (water pump) boils off acetic acid, the residual sugar soup compound is dissolved in water, and pressure reducing and steaming water gets white solid again, adding less water embathes, filter is assembled brilliant, and dry back weighs 5 grams (84.1%), fusing point 145-147 °.δH(CD
3COCD
3):3.61(2H,s),3.88(3H,s),6.89(1H,s),6.96(1H,s)ppm。Must not be further purified and promptly can be used for next step reaction.
The preparation of embodiment 2:3-methoxyl group-4-benzyloxy-phenylethylamine (3):
10.2 gram is mixed with 0.4 milliliter of methyl alcohol, 0.4 milliliter of benzyl chloride and sodium hydroxide 0.12 gram, under agitation reflux is 2.5 hours, about 0.04 gram (water-soluble 3) of hydro-oxidation sodium, reheat refluxes and stirred 3 hours, pressure reducing and steaming solvent and unnecessary benzyl chloride add water, after the aqueous solution is washed with chloroform, with diatomite is the flocculating aids suction strainer, clear filtrate is with the salt acidifying, and the crystallization that the filter collection is separated out weighs 0.2 gram after the drying, use recrystallizing methanol, fusing point 151-152 ° of ultimate analysis (C
16H
16O
4Cl; Calculated value, C, 62.44; H, 5.24; Cl, 11.52.Measured value, C, 82.50; H, 4.93; Cl, 11.48.δ H (CDCl
3), 3.66 (2H, s), 3.84 (3H, s), 5.07 (2H, s), 6.79,6.87 (2H, 2s), 7.34 (5H, wide s) ppm.
Embodiment 3:
N-(3 '-methoxyl group-4 '-the benzyloxy styroyl)-preparation of 2-chloro-4-methoxyl group-5-hydroxyl-phenylacetamide (4):
Method 1.3-methoxyl group-4-benzyloxy-phenylethylamine (3) 1.3 grams, 2-chloro-4-methoxyl group-5-hydroxyl-toluylic acid (2) 1.08 grams, iodate 1-methyl-2-bromopyridine 1.8 grams, tri-n-butylamine 2.3 grams, in 50 milliliters of methylene dichloride, under agitation reflux is 3 hours, boils off most of solvent with rotatory evaporator.Add vinyl acetic monomer and water, divide and get organic layer, water, dilute hydrochloric acid, water, sodium bicarbonate aqueous solution are used anhydrous sodium sulfate drying after washing in succession.Filter, filtrate is used the rotatory evaporator solvent evaporated, and residue embathes with benzene, filter collection solid, and dry back weighs 0.6 gram (27.4%), uses ethyl alcohol recrystallization, fusing point 152-153 °.Ultimate analysis (C
25H
20NO
5Cl); Calculated value, C, 65.85; H, 5.75; N, 3.07; Cl, 7.78.Measured value, C, 66.02; H, 5.81; N, 3.11; Cl, 7.77 δ H (CDCl
3, HMDS is a standard): 2.62 (2H, t, J=7Hz), 3.36 (2H, t, J=7Hz) 3.47 (2H, s), 5.06 (2H, s), 6.40-7.74 (10H, m) ppm.
Method 2.2-chloro-4-methoxyl group-5-hydroxyl-toluylic acid (2) 4.0 grams, mixed with 3-methoxyl group-4-benzyloxy-phenylethylamine (3) 5.2 grams, the oil bath with 180 °-185 ° under nitrogen protection was heated 2.5 hours.Glassy product dissolves with chloroform, and it is inferior to give a baby a bath on the third day after its birth with dilute hydrochloric acid, and it is inferior to give a baby a bath on the third day after its birth with sodium bicarbonate aqueous solution again, uses anhydrous sodium sulfate drying.Filter, filtrate is used the rotatory evaporator solvent evaporated, and residue is dissolved in benzene under heating.The crystallization that filter next day collection is separated out, dry back weighs 6.12 grams (72.7%).Use ethyl alcohol recrystallization, mp, 152-153 °.
Embodiment 4:
N-(3 '-methoxyl group-4 '-benzyloxy-styroyl)-preparation of 2-chloro-4-methoxyl group-5-isobutyl oxygen methanoyl-phenylacetamide (5a):
N-(3 '-methoxyl group-4 '-benzyloxy-styroyl)-2-chloro-4-methoxyl group-5-hydroxyl-phenylacetamide (4) 1 grams, be fused to 20 milliliters of dry tetrahydrofuran, add 0.6 milliliter of pyridine, stirring and ice-cooled 0.8 milliliter of the isobutyl chlorocarbonate that slowly adds down, continuation is stirred under frozen water cooling hour, then at 3 quarters of stirring at room.Boil off solvent with rotatory evaporator, add benzene and water.The benzene layer washes with water to neutrality after washing with dilute hydrochloric acid, uses anhydrous sodium sulfate drying, filters, and filtrate is used the rotatory evaporator evaporate to dryness.Residual syrup thing becomes crystallization when placing.Embathe with methyl alcohol, filter collection solid, the heavy 1g (79.1%) in dry back uses ethyl alcohol recrystallization, fusing point 119-121 °.Ultimate analysis (C
30H
34NO
7Cl): calculated value, C, 64.80; H, 6.16; N, 2.52; Cl, 6.38.Measured value, C, 64.80; H, 6.14; N, 2.32; Cl, 6.27.δ H (CDCl
3, be standard with HMDS): 0.93 (6H, d, J=6Hz), 2.60 (2H, t, J=7Hz), 3.32 (2H, t, J=7Hz), 3.46 (2H, s), 3.76 (6H, s), 3.95 (2H, d, J=6Hz), 5.04 (2H, s), 5.38 (1H, m), 6.36-7.44 (10H, m) ppm.
Embodiment 5:
N-(3 '-methoxyl group-4 '-benzyloxy-styroyl)-preparation of 2-chloro-4-methoxyl group-5-acetoxyl group-phenylacetamide (5b)
N-(3 '-methoxyl group-4 '-benzyloxy-styroyl)-2-chloro-4-methoxyl group-5-hydroxyl-phenylacetamide (4) 6.12 grams, with 42 milliliters of methylene dichloride, 4.2 milliliters of pyridines, a little is mixed for the 4-Dimethylamino pyridine, adds 4.2 milliliters of aceticanhydrides, shakes spoon, the solid dissolving, room temperature is placed to next day, adds methyl alcohol 15ml, after 0.5 hour, boil off solvent with rotatory evaporator, debris adds water, separates out crystallization, the filter collection, wash with water, dry back recrystallizing methanol gets product 5.72g (85.6%), fusing point 133-134 ° of ultimate analysis (C
27H
26NO
3Cl); Calculated value, C, 65.12; H, 5.67; N, 2.81; Cl, 7.12. measured value, C, 65.12; H, 5.63; N, 2.73; Cl, 7.12 δ H (CDCl
3, be standard with HMDS): 2.20 (3H, s), 2.53 (2H, t, J=6Hz), 3.16,3.44 (5H, a plurality of peaks), 3.65 (3H, s), 3.69 (3H, s), 4.97 (2H, s), 5.30 (1H, m), 6.24-6.80 (5H, m), 7.16 (5H, m) ppm.
Embodiment 6:
Hydrochloric acid 1-(2 '-chloro-4 '-methoxyl group-5 '-isobutyl oxygen methanoyl) benzyl-6-methoxyl group-7-benzyloxy-3, the preparation of 4-dihydro-isoquinoline (6a):
N-(3 '-methoxyl group-4 '-benzyloxy-styroyl)-2-chloro-4-methoxyl group-5-isobutyl oxygen methanoyl phenylacetamide (5a) 0.8 gram, 5 milliliters of dry benzene, 2.5 milliliters of Phosphorus Oxychlorides, reflux 2 hours, be chilled to room temperature, add 60 milliliters of sherwood oils (60-90 °), separate out syrup, put, topple over liquid to next day, the residual sugar soup compound embathes three times with sherwood oil, add methyl alcohol 10 milliliters of dissolvings, separate out yellow crystal during placement, add diethyl ether again, filter is assembled brilliant, wash with ether, dry back weighs 0.66 gram (79.8%), fusing point 200-202 ° (decomposition).δ H (CDCl
3, be standard with HMDS): 0.90 (6H, d, J=6Hz), 3.75,3.90 (6H, s), 4.55 (2H, s), 4.95 (2H, s), 6.70-7.35 (m, 9H, m) ppm.
Embodiment 7
1-(2 '-chloro-4 '-methoxyl group-5-hydroxyl) benzyl-6-methoxyl group-7-benzyloxy-1,2,3, the preparation of 4-tetrahydroisoquinoline (7a)
Method 1. hydrochloric acid 1-(2 '-chloro-4 '-methoxyl group-5 '-isobutyl oxygen methanoyl) benzyl-6-methoxyl group-7-benzyloxy-3,4-dihydro-isoquinoline (6a) 0.57 gram, be dissolved in 35 milliliters of ethanol, under stirring at room, slowly add boron hydrogen sodium 0.8 gram, reflux 3 hours.Boil off ethanol with rotatory evaporator, add water and add the neutralization of biphosphate potassium solution, the solid chloroform extraction, extracting solution washes the back anhydrous sodium sulfate drying with water, filters, and filtrate boils off chloroform with rotatory evaporator, get white crystals 0.40 gram (91.6%), use the methanol-water recrystallization, fusing point 204-206 ° m/z (FD): 440 (M+1), δ H (CDCl
3+ CD
3SOCD
3), 3.76 (6H, s), 4.91 (2H, s), 6.56 (2H, s), 6.72,6.80 (2H, 2s), 7.28 (5H, wide s) ppm.
Method 2, N-(3 '-methoxyl group-4 '-benzyloxy-styroyl)-2-chloro-4-methoxyl group-5-acetoxyl group-phenylacetamide (5b) 0.94g, mixed with dried benzene 6ml of sodium and 3 milliliters of new distillatory Phosphorus Oxychlorides, under agitation reflux is 2 hours, adds 70 milliliters of sherwood oils (60-90 °), shakes spoon, be placed to next day, topple over liquid, cull shape thing is dissolved in methyl alcohol 60ml after giving a baby a bath on the third day after its birth time with sherwood oil, under the frozen water cooling and stirring, slowly add boron hydrogen sodium 1.2 grams, reflux 3 hours is under agitation separated out solid in the reaction process then, places in refrigerator and spends the night, filter collection solid, wash the heavy 0.83g (100%) in dry back, fusing point 204-206 ° with water.
Embodiment 8:
Racemize 2-benzyloxy-3, the preparation of 4-dimethoxy-9-hydroxyl-12-chloro-tetrahydrochysene berbine 3:
1-(2 '-chloro-4 '-methoxyl group-6 '-hydroxyl) benzyl-6-methoxyl group-7-benzyloxy-1,2,3,4-tetrahydroisoquinoline 1.85 gram, floatingly be suspended from 40 milliliters of chloroforms, add some ethanol solution of hydrogen chloride, jolting make the solid dissolving.Imitative with rotatory evaporator evaporate to dryness oxygen, residue is dissolved in 92 milliliters of methyl alcohol, add 56 milliliters of 36% formaldehyde solutions, add 37 milliliters in water then, placed 2 days under the room temperature, boil off methyl alcohol with rotatory evaporator, residue adds the sodium bicarbonate aqueous solution neutralization, use chloroform extraction, use anhydrous sodium sulfate drying after extracting solution washes with water.Filter, filtrate is used the rotatory evaporator solvent evaporated.Residue is dissolved in small amount of methanol, separates out crystallization very soon, the filter collection, to wash with methyl alcohol, dry back weighs 1.84 grams (94.3%) and uses recrystallizing methanol, fusing point 165-166 ° (decomposition).Ultimate analysis (C
26H
26NO
4Cl) calculated value, C, 69.10; H, 5.80; N, 3.10; Cl, 7.84 measured values, C, 69.03; H, 5.65; N, 3.18; Cl, 7.82.M/z 451 (M
+, δ H (CDCl
3, be standard with HMDS): 3.77,3.81 (6H, 2s are overlapped), 5.09 (2H, s), 6.55 (1H, S), 6.70 (2H, s), 7.12-7.46 (5H, m).
Embodiment 9:
Left-handed and dextrorotation 2-benzyloxy-3, the preparation of 10-dimethoxy-9-hydroxyl-12-chloro-tetrahydrochysene berbine (8a, 8b);
Racemize 2-benzyloxy-3; 10-dimethoxy-9-hydroxyl-12-chloro-tetrahydrochysene berbine (8) 1.04 grams and hydration dibenzoyl-L-tartrate 0.86 gram; reflux is 2 hours in the 70ml ethyl acetate; placed again after cold 2 hours; filter is assembled brilliant; wash with acetate ethanol; the heavy 1.46g in dry back, fusing point 163-164 ° (is dissolved in 80 ml methanol earlier, boils off about 65 ml methanol with methyl alcohol-ethyl alcohol recrystallization under reflux; add 50 milliliters of ethanol; shake spoon, boil off about 30 milliliters of solvents again, placement is spent the night; filter is assembled brilliant, washes with ethanol.) secondary, 180～181 ° of fusing points (decomposition), heavy 0.81g (recrystallization, fusing point does not raise) again.Ultimate analysis (C
44H
40NO
19Cl): calculated value, C, 65.22; H, 4.98; N, 1.73; Cl, 4.38.Measured value, C, 65.37; H, 5.00; N, 1.76; Cl, 4.46.Get 0.79 gram, mixed with sodium bicarbonate aqueous solution, add chloroform, stirring is spent the night.Chloroform extracted solution washes once back anhydrous sodium sulfate drying with water, filters, and filtrate concentrates back column chromatography (silica gel, ethyl acetate) purifying, and effluent liquid steams in solvent with rotatory evaporator, and residual reddish-brown glassy mass weighs 0.45 gram,
1HMR, thin-layer chromatography (silica gel, methylene dichloride-ethyl acetate [1: 1]) Rf and racemize 2-benzyloxy-3,10-dimethoxy-9-hydroxyl-12-chloro-tetrahydrochysene berbine is in full accord.[α]
D 27.5=-250.9°(CHCl
3,C=0.11)。The mother liquor for preparing this salt and this salt of recrystallization merges; boil off solvent with rotatory evaporator; residue and sodium bicarbonate aqueous solution are mixed; use chloroform extraction; extracting solution washes the back anhydrous sodium sulfate drying with water; filter; filtrate is used the rotatory evaporator solvent evaporated, and the heavy 0.68g of residue is dissolved in the 35ml ethyl acetate; add hydration dibenzoyl-D-tartrate 0.57 gram; reflux 2 hours, filter next day is assembled brilliant, and dry back weighs 0.97 gram; with heavy 0.78 gram behind methyl alcohol-ethyl alcohol recrystallization secondary, fusing point 180-181 ° (decomposition).Ultimate analysis (C
44H
40NO
12Cl); Calculated value, C, 65.22; H, 4.98; N, 1.73; Cl, 4.38.Measured value, C, 65.39; H, 4.96; N, 1.75; Cl, 4.49 (from the mother liquor of recrystallization, can obtain-2-benzyloxy-3 10-dimethoxy-9-hydroxyl-12-chloro-tetrahydrochysene berbine, dibenzoyl-L-tartaric acid salt 0.12 gram again) by similarity method.Be transformed into free alkali, reddish-brown, glassy,
1HNMR, thin-layer chromatography (silica gel, methylene dichloride-ethyl acetate [1: 1]) Rf and racemize 2-benzyloxy-3,10-dimethoxy-9-hydroxyl-12-chloro-tetrahydrochysene berbine is in full accord.[α]
D 27.5=+250.6；(CHCl
3,C=0.11)。
Embodiment 10:
Racemize 2,9-dihydroxyl-3, the preparation of 10-dimethoxy-12-chloro-tetrahydrochysene berbine (9, contain crystallization methyl alcohol)
Racemize 2-benzyloxy-3,10-dimethoxy-9-hydroxyl-12-chloro-tetrahydrochysene berbine 0.71 gram, be dissolved in 80 milliliters in 88% formic acid, add 24 milliliters of concentrated hydrochloric acids, reflux 2 hours in 140 °-150 ° oil bath under agitation, the crystallization (hydrochloride) that filter next day collection is separated out is after water, ethanol wash in succession, add excess bicarbonate and chloroform, stirring is spent the night.After washing with water, chloroform layer uses anhydrous sodium sulfate drying.Filtration, after filtrate was used the rotatory evaporator solvent evaporated, residue added the dissolving of 5 ml methanol, separated out crystallization, filter assembly crystalline substance soon, washed with methyl alcohol, and the drying back weighs 0.44 gram (71%), uses recrystallizing methanol for fusing point 136-138 °, and fusing point is constant.Ultimate analysis (C
19H
20NO
4CH
3OH); Calculated value: C, 60.99; H, 6.14; N, 3.56; Cl, 9.00.Measured value, C, 61.16; H, 6.10, N, 3.47; Cl, 9.01.
1HNMR (400 megacycle): δ (CF
8COOD) 3.63 (s, CH
8OH), 3.92,3.34 (each 3H, 2s, CH
3O), 3.96 (s is with 3.63 peak additions 3H altogether, CF
3COOCH
3, be methyl alcohol and solvent esterification and generate), 6.83,7.06,7.09 (each 1H, 3s, fragrant H) [R (KBr): 3400,3180,2928,2830,1629,1490,1438,1288,1245,1143,1110,1015,830cm
-1
Embodiment 11:
Left-handed 2,9-dihydroxyl-3, the preparation of 10-dimethoxy-12-chloro-tetrahydrochysene berbine (9):
By preparation racemize 2,9-dihydroxyl-3, the method for 10-dimethoxy-12-chloro-tetrahydrochysene berbine is by left-handed 2-benzyloxy-3, and 10-dimethoxy-9-hydroxyl-12-chloro-tetrahydrochysene berbine makes, and uses recrystallizing methanol, uses P
2O
5Room temperature vacuum-drying, fusing point 161-162 ° (decomposition), [α]
D 11.8=223 19 ° (CHC)
3, C=0.14), thin-layer chromatography (silica gel, ethyl acetate) Rf and racemize 2,9-dihydroxyl 3,10-dimethoxy-12-chloro-tetrahydrochysene berbine unanimity.Ultimate analysis (C
19H
20NO
4Cl) calculated value, C, 63.07; H, 5.57; N, 3.87; Cl, 980.Measured value, C, 62.86 H, 5.92; N, 3.66, Cl, 9.66.
1HNMR (400 megacycle): δ (CF
3COOD) 3.91,4.01 (each 3H, 2s, CH
3O), 6.88,7.10,7.13 (each 1H, 3s, fragrant H) ppm[R (KBr); 3510,3400,2930,2834,1615,1510,1487,1435,1290,1240,1142,1106,1025,830cm
-1
Embodiment 12:
Dextrorotation 2,9-dihydroxyl-3, the preparation of 10-dimethoxy-12-chloro-tetrahydrochysene berbine (9):
By preparation racemize 2,9-dihydroxyl-3, the method for 10-dimethoxy-12-chloro-tetrahydrochysene berbine is by dextrorotation 2-benzyloxy-3, and 10-dimethoxy-9-hydroxyl-12-chloro-tetrahydrochysene berbine makes, and uses recrystallizing methanol, uses P
2O
5Room temperature vacuum-drying, fusing point 161-162 ° (decomposition), [α]
D 11.6=+222.53 ° of (CHCl
3, C=0.12), thin-layer chromatography (silica gel, ethyl acetate) Rf and racemize and left-handed 2,9-dihydroxyl-3, the consistent ultimate analysis (C of 10-dimethoxy-12-chloro-tetrahydrochysene berbine
18H
20NO
4Cl): calculated value, C63.07; H, 5.57; N, 3.87; Cl, 9.80 measured values, C, 62.83; H, 5.72; N, 3.62; Cl, 9.99.
1HNMR (400 megacycle) and IR (KBr) be with left-handed 2,9-dihydroxyl-3,10-dimethoxy-12-chloro-tetrahydrochysene berbine unanimity.
Claims (3)
1. left-handed, Chloro-Scoulerine that molecular structural formula is following
2. left-handed, Chloro-Scoulerine's according to claim 1 preparation method, its feature may further comprise the steps:
A. make raw material through the reaction of two steps by isovanillin, make 3-hydroxyl-4-methoxyphenylacetic acid; Use the sulfuryl chloride chlorination, get 2-chloro-4-methoxyl group-5-hydroxyl phenylacetic acid; Again with 3-methoxyl group-4-benzyloxy-phenylethylamine condensation; Make N-(3 '-methoxyl group-4 '-benzyloxy-styroyl)-2-chloro-4-methoxyl group-5-hydroxybenzene ethanamide; Again with the hydroxyl on isobutyl oxygen formyl radical or the ethanoyl protection 5-position, with Bischler-Napieralski method and Phosphorus Oxychloride reaction being transformed into dihydroisoquinoline derivative salt; Slough acyl group simultaneously with boron hydrogen sodium reduction, tetrahydro isoquinoline derivative, again with formaldehyde carry out Mannich react racemize 2-benzyloxy-3,10-dimethoxy-9-hydroxyl-12-chloro-tetrahydrochysene berbine; Split into left-handed and the dextrorotation enantiomorph with the optical activity dibenzoyl tartaric acid; Under acidic conditions debenzylation get left-handed and dextral 2,9-dihydroxyl-3,10-dimethoxy-12-chloro-tetrahydrochysene berbine.
3. be used in preparation as the application in treatment hyperkinetic syndrome, schizophrenia, the migraine remedy according to described left-handed, the Chloro-Scoulerine of claim 1.
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| CN94112235A CN1045442C (en) | 1994-07-20 | 1994-07-20 | Levo- and dextro-rotary chloroscouriline (tetrahydroprotoberberines) and application thereof |
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| CN1045442C true CN1045442C (en) | 1999-10-06 |
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| CN100345848C (en) * | 2003-09-29 | 2007-10-31 | 中国科学院上海药物研究所 | Leavo halogenated salt and its preparation process and use |
| US8501762B2 (en) | 2005-07-08 | 2013-08-06 | Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences | Tetrahydroprotoberberine compounds, the synthetic method and the use thereof |
| CN100528872C (en) * | 2006-07-26 | 2009-08-19 | 中国科学院上海药物研究所 | Tetrahydro-proto-berberine compounds, their preparing method, composition and use |
| WO2008073390A2 (en) * | 2006-12-11 | 2008-06-19 | Mallinckrodt Inc. | Preparation of 3,4-dihydroisoquinolines from an acid and an amine |
| JP2010512391A (en) | 2006-12-12 | 2010-04-22 | マリンクロット インコーポレイテッド | Preparation of hexahydroisoquinoline from dihydroisoquinoline |
| NZ607842A (en) | 2008-09-30 | 2013-12-20 | Mallinckrodt Llc | Processes for the selective amination of ketomorphinans |
| US8946419B2 (en) | 2009-02-23 | 2015-02-03 | Mallinckrodt Llc | (+)-6-hydroxy-morphinan or (+)-6-amino-morphinan derivatives |
| ES2465066T3 (en) | 2009-06-11 | 2014-06-05 | Mallinckrodt Llc | Reduction amination of 6-keto-normorphinans by catalytic hydrogen transfer |
| PL2440562T3 (en) | 2009-06-11 | 2017-07-31 | Mallinckrodt Llc | Preparation of 6-alpha-amino n-substituted morphinans by catalytic hydrogen transfer |
| CN101921229B (en) * | 2009-06-17 | 2012-08-08 | 中国科学院上海药物研究所 | Synthesis method of stepholidine or derivative optical isomer thereof and intermediate thereof |
| US8431705B2 (en) | 2009-09-24 | 2013-04-30 | Mallinckrodt Llc | One-pot preparation of hexahydroisoquinolines from amides |
| WO2011038172A1 (en) | 2009-09-24 | 2011-03-31 | Mallinckrodt Inc. | One-pot preparation of hexahydroisoquinolines from dihydroisoquinolines |
| CN102399166B (en) * | 2010-09-10 | 2016-04-27 | 山东特珐曼药业有限公司 | The Stopholidine of optical siomerism and the preparation method of derivative thereof |
| MX2013013634A (en) | 2011-06-09 | 2013-12-12 | Mallinckrodt Llc | Reductive amination of 6-keto morphinans by catalytic hydrogen transfer. |
| JP2014526467A (en) | 2011-09-08 | 2014-10-06 | マリンクロッド エルエルシー | Preparation of alkaloids without isolation of intermediates |
| CN106518864A (en) * | 2016-10-28 | 2017-03-22 | 佑华制药（乐山）有限公司 | Method for synthesizing rotundine with berberine as raw material |
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