CN105524062A - A synthetic method of tadalafil - Google Patents
A synthetic method of tadalafil Download PDFInfo
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- CN105524062A CN105524062A CN201511014807.1A CN201511014807A CN105524062A CN 105524062 A CN105524062 A CN 105524062A CN 201511014807 A CN201511014807 A CN 201511014807A CN 105524062 A CN105524062 A CN 105524062A
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- tadalafei
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
A synthetic method of tadalafil is disclosed. The method adopts 3,4-dihydroxybenzaldehyde and methyl D-tryptophanate hydrochloride as initial raw materials, and prepares a product by condensation-cyclization, chloroacetylation, aminolysis-cyclization and methyl cyclization. The 3,4-dihydroxybenzaldehyde is adopted as the raw material. Nitrile, lower alcohol and nitroalkane are adopted as solvents for the condensation-cyclization. Ethyl acetate or dichloromethane is adopted as a solvent for the chloroacetylation. Lower alcohol which is cheap is adopted as a solvent for the aminolysis-cyclization. Compared with other routes, the method is characterized by simple and convenient separation and purification, simple reaction conditions, a high yield of each step (with the yield of each step being higher than 80%), a stable process and a short production period. The method is free of heliotropin with which narcotics can be prepared easily, is free of column chromatography and other purification processes and is suitable for industrial production.
Description
Technical field
The present invention relates to technical field of organic synthesis, more specifically, relate to a kind of synthetic method of Tadalafei.。
Background technology
Tadalafei (Tadalafil) is a kind of Phosphodiesterase V type (PDE5) inhibitor, researched and developed at first by GlaxoSmithKline PLC company (GSK), within 2003, through FDA approval, the medicine as treatment male erectile dysfunction (ED) goes on the market in the U.S..Because Tadalafei has highly selective at clinical treatment ED, long half time, the advantages such as the autonomy that patient is larger, and have unique pharmacological action, domestic and international expert conducts extensive research chemosynthesis Tadalafei, and achieves certain achievement.
The synthetic route that US Patent No. 5859006 is reported, this route is for raw material with tryptophan methyl ester and piperonylaldehyde, take methylene dichloride as solvent, occur under the catalysis of trifluoroacetic acid P-S reaction (Pictet-Spengler) reaction, by column chromatography for separation obtain cis carboline intermediate again with chloroacetyl chloride Reactive Synthesis acylate intermediate; Finally be obtained by reacting Tadalafei with methylamine again.
After the people such as Revell report in the route mentioned in TwoconcisesynthesisofcialisviatheN-acyliminiumPictet-Spe nglerreaction mono-literary composition and D-trp methyl ester hydrochloride and piperonylaldehyde are reacted and generate imines; then promote that imines molecule closes ring with Fmoc-Sar-Cl; react with methylamine after column chromatography for separation intermediate and generate Tadalafei; slough protecting group and obtain Tadalafei, total recovery is 28%.
As can be seen here, the principal synthetic routes of synthesis Tadalafei is for starting raw material with D-trp methyl ester hydrochloride and piperonylaldehyde, through condensation and cyclization, acidylate, the route of aminolysis cyclization synthesis, the key that beta-tetrahydro carboline ring is whole synthetic route is built by asymmetric synthesis, on the one hand, Pictet-Spengler(condensation cyclization) reaction builds beta-tetrahydro carboline ring the most effectively and conventional means, but this reaction easily causes the generation of cis and trans-isomer(ide), usually need to obtain highly purified cis carboline intermediate by the loaded down with trivial details process such as column chromatography for separation or recrystallization, on the other hand, important source material piperonylaldehyde belongs to by " safety management of dangerous chemical products regulations ", the chemical of " regulation on Management of Drug-Making Chemicals " control.Therefore, probe into the preparation method of a highly selective diastereomeric synthesis Tadalafei intermediate cis carboline, find a kind of alternative control starting raw material most important to suitability for industrialized production for the synthesis of Tadalafei.
Summary of the invention
The technical problem to be solved in the present invention is the deficiency for existing synthesis Tadalafei technology, provides a kind of method of synthesis Tadalafei newly.Instant invention overcomes prior art adopts piperonylaldehyde as raw material, because of raw material purchase and use and not easily the obstacle that causes produced to synthesis, and the shortcoming and defect such as the yield overcoming prior art processes is low, route is loaded down with trivial details, severe reaction conditions, yield is high, aftertreatment simple, yield is higher, reaction conditions is gentle, the syntheti c route being easy to suitability for industrialized production of safety and environmental protection to provide one.
Goal of the invention of the present invention is achieved by the following technical programs:
A kind of synthetic method of Tadalafei is provided, comprises the following steps:
S1. be that raw material obtains (1R, 3R)-methyl isophthalic acid-(3,4-dihydroxy phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] Indole-3-Carboxylic Acid (compound 1) through condensation cyclization with 3,4-Dihydroxy benzaldehyde, D-trp methyl ester hydrochloride;
S2.(1R, 3R)-methyl isophthalic acid-(3,4-dihydroxy phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] Indole-3-Carboxylic Acid and chloroacetyl chloride generation chlorine acetylation generate (1R, 3R)-2-(2-chloracetyl)-1-(3,4-dihydroxy phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] Indole-3-Carboxylic Acid (compound 2);
S3.(1R, 3R)-2-(2-chloracetyl)-1-(3,4-dihydroxy phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] aqueous solution generation aminolysis ring-closure reaction of Indole-3-Carboxylic Acid and methylamine or alcohol generates (6R, 12aR)-6-(3,4-dihydroxy phenyl)-2-methyl-methyl-2,3,6,7,12,12a-hexahydro-pyrazine also [1', 2'-1,6]-pyrido [3,4-b] indoles-Isosorbide-5-Nitrae-diketone (compound 3);
S4. (6R, 12aR)-6-(3,4-dihydroxy phenyl)-2-methyl-methyl-2,3,6,7,12,12a-hexahydro-pyrazine also [1', 2'-1,6]-pyrido [3,4-b] indoles-Isosorbide-5-Nitrae-diketone reacts with methylene bromide in the basic conditions and prepares Tadalafei.
Tadalafei prepared by the present invention for starting raw material, through condensation and cyclization, chloroacetylation, aminolysis cyclization, methyl cyclization, obtains Tadalafei with D-trp methyl ester hydrochloride, 3,4-Dihydroxy benzaldehydes.
The first step condensation cyclization Pictet-Spengler reacts, and the Tadalafei of described preparation for starting raw material, avoids the raw material piperonylaldehyde used by public security department's control with D-trp methyl ester hydrochloride, 3,4-Dihydroxy benzaldehydes, and raw material is bought more convenient.
Condensation cyclization Pictet-Spengler reacts, and selects lower alcohol, nitrile or nitroparaffins to make solvent, and isomer generates few, and target configuration proportion of products is high, and aftertreatment is simple, filters to obtain chemical compounds I.
Cis Si Qing Ka Lin intermediate of the present invention is prepared by starting raw material by D-trp methyl ester hydrochloride, 3,4-Dihydroxy benzaldehydes.Cis tetrahydrochysene click beautiful jade Intermediate Preparation of the present invention, without the need to catalyzer, is made solvent directly prepare with lower alcohol, nitrile, nitroparaffins, and reaction terminates rear cooling and filters, and obtain product, molar yield is 90 ~ 97%.
In chlorine acetylation of the present invention, make solvent with ethyl acetate or methylene dichloride, do alkali with DIPEA or triethylamine, temperature control-10 ~ 30 DEG C, drip the chloroacetyl chloride of 1.0 ~ 4.0 molar equivalents.
In aminolysis ring-closure reaction of the present invention, directly use aqueous methylamine solution or alcoholic solution, molar equivalent 2.0 ~ 6.0, lower alcohol 2 ~ 20 volume multiple makees solvent.Reacting by heating 1 ~ 6 hour, direct filtration, with lower alcohol washing, filters to obtain compound III.
1 ~ 10 equivalent of cesium carbonate, salt of wormwood or sodium carbonate is added as alkali under room temperature in methyl ring-closure reaction of the present invention, add dimethyl sulfoxide (DMSO), N again, dinethylformamide makees solvent, adds the methylene bromide of 1 ~ 4.0 equivalent under stirring, is heated to 40 ~ 80 DEG C of reactions 4 ~ 14 hours, cooling, reaction solution is poured in 10 ~ 30 times of water, stirs 30 ~ 60 minutes, filters, 15 ~ 40 times of water washings first used by filter cake, then use 1 ~ 4 times of washing with alcohol.
Preferably, in condensation ring-closure reaction described in step S1, Virahol, acetonitrile or propionitrile is selected to make solvent.
Preferably, in chlorine acetylation described in step S2, be make solvent with ethyl acetate or methylene dichloride, do alkali with DIPEA or triethylamine.
Preferably, the last handling process of chlorine acetylation resultant described in step S2 comprises revolving and steams except desolventizing, and with the impurity elimination of lower alcohol washing and filtering, further, described lower alcohol is methyl alcohol or ethanol.
Preferably, aminolysis ring-closure reaction described in step S3, the methylamine solution selected is the aqueous solution or alcoholic solution, is further 30% ~ 40% aqueous methylamine solution.
Preferably, aminolysis ring-closure reaction described in step S3, the solvent selected is lower alcohol, is further methyl alcohol or ethanol.
Preferably, aminolysis ring-closure reaction described in step S3, reaction terminate after through filter and solvent wash high purity (6R, 12aR)-6-(3,4-dihydroxy phenyl)-2-methyl-methyl-2,3,6,7,12,12a-hexahydro-pyrazine also [1', 2'-1,6]-pyrido [3,4-b] indoles-Isosorbide-5-Nitrae-diketone.
Preferably, step S4 does alkali with carbonate.
Further preferably, carbonate described in step S4 is sodium carbonate, salt of wormwood or cesium carbonate.
Preferably, step S4 is with N, N-dimethyl sulfoxide (DMSO) or N, dinethylformamide is solvent, (6R, 12aR)-6-(3,4-dihydroxy phenyl)-2-methyl-methyl-2,3,6,7,12,12a-hexahydro-pyrazine also [1', 2'-1,6]-pyrido [3,4-b] indoles-Isosorbide-5-Nitrae-diketone and methylene bromide react directly obtained high purity Tadalafei.
Beneficial effect of the present invention:
(1) the present invention with 3,4-Dihydroxy benzaldehyde for starting raw material, avoid use " safety management of dangerous chemical products regulations ", " regulation on Management of Drug-Making Chemicals " control piperonylaldehyde as starting raw material.
(2) three-step reaction condition of the present invention is not harsh, easily realizes, and without High Temperature High Pressure, easy and simple to handle, waste liquid is easy to recovery of applied.
(3) aftertreatment of present invention process route is simple, avoids the loss of loaded down with trivial details process.
(4) the present invention prepares cis tetrahydrochysene click beautiful jade intermediate without high yield high purity direct under catalysis.
(5) chloracetyl intermediate of the present invention is without the need to purifying, participates in the next step directly.
(6) in aminolysis ring-closure reaction of the present invention, directly use methylamine solution, after reaction terminates, filter to obtain product.
(7) present invention process often walks yield all more than 80%, purity more than 98%, creates one from D-trp methyl ester hydrochloride to the complete process of Tadalafei, and technique is simple, and cost is lower, safety and environmental protection, meets suitability for industrialized production.
Accompanying drawing explanation
The synthetic route chart of Fig. 1 the compounds of this invention I.
The synthetic route chart of Fig. 2 the compounds of this invention II.
The synthetic route chart of Fig. 3 the compounds of this invention III.
The synthetic route chart of Fig. 4 Tadalafei of the present invention.
The nuclear-magnetism qualification result of Fig. 5 chemical compounds I.
The nuclear-magnetism qualification result of Fig. 6 compound ii.
The nuclear-magnetism qualification result of Fig. 7 compound III.
The nuclear-magnetism qualification result of Fig. 8 Tadalafei.
Embodiment
The present invention is further described below in conjunction with the drawings and specific embodiments.Unless stated otherwise, the various raw materials that the embodiment of the present invention uses all can be obtained by conventional commercial, or prepare according to the ordinary method of this area, and equipment used is experiment common equipment.Unless otherwise defined or described herein, all specialties used herein and scientific words and those skilled in the art the same meaning be familiar with.
Embodiment 1
25.5 grams of D-trp methyl ester hydrochlorides are added in reaction flask, 150 milliliters of Virahols are added under room temperature, stir, add 1.2 equivalent 3,4-Dihydroxy benzaldehydes, react 8 hours at 85 DEG C, until raw material primitive reaction is complete, cool to room temperature, filters, solid 50 milliliters of washed with isopropyl alcohol, then dry in an oven to constant weight.Obtain 34.6 g of compound I, yield 92%.Synthetic route chart is shown in shown in accompanying drawing 1.
Embodiment 2
25.5 grams of D-trp methyl ester hydrochlorides are added in reaction flask, 250 milliliters of propionitrile are added under room temperature, stir, add 1.5 equivalent 3,4-Dihydroxy benzaldehydes, react 16 hours at 85 DEG C, until raw material primitive reaction is complete, cool to room temperature, filters, solid 50 milliliters of washed with isopropyl alcohol, then dry in an oven to constant weight.Obtain 34.2 g of compound I, yield 97%.Synthetic route chart is shown in shown in accompanying drawing 1.
Embodiment 3
25.5 grams of D-trp methyl ester hydrochlorides are added in reaction flask, 375 ml methanol are added under room temperature, stir, add 1.5 equivalent 3,4-Dihydroxy benzaldehydes, react 24 hours at 60 DEG C, until raw material primitive reaction is complete, cool to room temperature, filters, solid 50 ml methanol are washed, and then dry in an oven to constant weight.Obtain 33.8 g of compound I, yield 90%.Synthetic route chart is shown in shown in accompanying drawing 1..
Embodiment 4
25.5 grams of D-trp methyl ester hydrochlorides are added in reaction flask, 150 milliliters of butanols are added under room temperature, stir, add 1.2 equivalent 3,4-Dihydroxy benzaldehydes, react 8 hours at 120 DEG C, until raw material primitive reaction is complete, cool to room temperature, filters, solid 50 milliliters of butanols wash, and then dry in an oven to constant weight.Obtain 34.1 g of compound I, yield 91%.Synthetic route chart is shown in shown in accompanying drawing 1.
Embodiment 5
25.5 grams of D-trp methyl ester hydrochlorides are added in reaction flask, 250 milliliters of acetonitriles are added under room temperature, stir, add 1.0 equivalent 3,4-Dihydroxy benzaldehydes, react 10 hours at 80 DEG C, until raw material primitive reaction is complete, cool to room temperature, filters, solid 50 milliliters of acetonitrile wash, then dry in an oven to constant weight.Obtain 35.6 g of compound I, yield 96%.Synthetic route chart is shown in shown in accompanying drawing 1.
Embodiment 6
25.5 grams of D-trp methyl ester hydrochlorides are added in reaction flask, 150 milliliters of Nitromethane 99Min.s are added under room temperature, stir, add 1.2 equivalent 3,4-Dihydroxy benzaldehydes, react 6 hours at 100 DEG C, until raw material primitive reaction is complete, cool to room temperature, filters, solid 50 milliliters of Nitromethane 99Min.s wash, and then dry in an oven to constant weight.Obtain 35.9 chemical compounds Is, yield 95%.Synthetic route chart is shown in shown in accompanying drawing 1.
Embodiment 1 to 6 gained chemical compounds I purity is all more than 98%, and gained chemical compounds I is carried out nuclear-magnetism qualification respectively, and data are as follows:
1hNMR (400MHz, DMSO): 10.83 (s, 1H), 10.40 (s, 1H), 9.89 (s, 1H), 9.40 (s, 1H), 9.24 (s, 1H), 7.54 (d, 1H, J=7.8Hz), 7.30 (d, 1H, J=8.0Hz), 7.14-7.09 (m, 1H), 7.05 (dd, 1H, J=11.0,3.9Hz), 6.84 (q, 3H, J=8.0Hz), 5.75 (m, 1H), 4.74 (m, 1H), 3.85 (s, 3H), 3.33 (m, 1H), 3.29-3.15 (m, 1H).Prove that embodiment 1 to 6 gained gained chemical compounds I is (1R, 3R)-methyl isophthalic acid-(3,4-dihydroxy phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] Indole-3-Carboxylic Acid, structural formula as shown in formula I, nuclear-magnetism qualification result as shown in Figure 5:
（Ⅰ）。
Embodiment 7
The Compound Compound I that the present embodiment prepares with embodiment 1 to 6 any embodiment for raw material, preparation synthesis acylate intermediate (1R, 3R)-2-(2-chloracetyl)-1-(3; 4-dihydroxy phenyl)-2,3,4; 9-tetrahydrochysene-1H-pyrido [3,4-b] Indole-3-Carboxylic Acid.Syntheti c route as shown in Figure 2.
In reaction flask, add 30.8 g of compound I, add 500 milliliters of ethyl acetate under room temperature, under stirring, add 2.5 eq of triethylamine, ice bath, then slowly drips the chloroacetyl chloride of 1.0 equivalents, drips off rear continuation reaction 2 hours, solvent evaporated, adds 90 milliliters of ethanol, stirs 20 minutes, filter, filter cake 30 milliliters of washing with alcohol, dry, obtain 28.3 g of compound II, productive rate 83%, purity more than 98%.
Embodiment 8
The chemical compounds I that the present embodiment prepares with embodiment 1 to 6 any embodiment for raw material, preparation synthesis acylate intermediate (1R, 3R)-2-(2-chloracetyl)-1-(3; 4-dihydroxy phenyl)-2,3,4; 9-tetrahydrochysene-1H-pyrido [3,4-b] Indole-3-Carboxylic Acid.Syntheti c route as shown in Figure 2.
In reaction flask, add 30.8 g of compound I, under room temperature, add 500 milliliters of methylene dichloride, under stirring, add 2.5 equivalent N, N-diisopropylethylamine, control temperature, at 30 DEG C, then slowly drips the chloroacetyl chloride of 4.0 equivalents, drip off rear continuation reaction 2 hours, revolve steaming solvent evaporated, add 90 ml methanol, stir 20 minutes, filter, filter cake 30 ml methanol are washed, dry, obtain 27.8 g of compound II, productive rate 82%, purity more than 98%.
Embodiment 9
The chemical compounds I that the present embodiment prepares with embodiment 1 to 6 any embodiment for raw material, preparation synthesis acylate intermediate (1R, 3R)-2-(2-chloracetyl)-1-(3; 4-dihydroxy phenyl)-2,3,4; 9-tetrahydrochysene-1H-pyrido [3,4-b] Indole-3-Carboxylic Acid.Syntheti c route as shown in Figure 2.
In reaction flask, add 30.8 g of compound I, add 500 milliliters of methylene dichloride under room temperature, under stirring, add 2.5 eq of triethylamine, control temperature, at-10 DEG C, then slowly drips the chloroacetyl chloride of 2.0 equivalents, drips off rear room temperature and continues reaction 2 hours, revolve steaming solvent evaporated, add 90 milliliters of ethanol, stir 20 minutes, filter, filter cake 30 ml methanol are washed, dry, obtain 29.5 g of compound II, productive rate 87%, purity more than 98%.
Embodiment 10
Other are with embodiment 7.Add-on unlike triethylamine is 2.0 equivalents.The present embodiment productive rate 79%, purity more than 98%.
Embodiment 11
Other are with embodiment 8.Stirring 1 hour is continued unlike dripping off room temperature after chloroacetyl chloride.The present embodiment productive rate 81%, purity more than 98%.
The compound ii of arbitrary for embodiment 7 to 11 routine gained is carried out nuclear-magnetism qualification, and data are:
1hNMR (400MHz, DMSO): 10.87 (s, 1H), 8.82 (d, 2H, J=47.1Hz), 7.53 (d, 1H, J=7.6Hz), 7.28 (d, 1H, J=7.9Hz), 7.06 (dt, 2H, J=28.8,7.2Hz), 6.73 (s, 1H), 6.69-6.53 (m, 2H), 6.35 (d, 1H, J=8.1Hz), 5.26-5.12 (m, 1H), 4.84 (d, 1H, J=13.8Hz), 4.43 (d, 1H, J=13.8Hz), 3.44 (t, 1H, J=16.4Hz), 3.13-2.96 (m, 4H).Nuclear-magnetism qualification result as shown in Figure 6.
The structural formula of compound ii is as shown in formula II:
（Ⅱ）。
Embodiment 12
The compound ii prepared with embodiment 7 to 11 any embodiment is for raw material, and key intermediate (6R, 12aR)-6-(3 is synthesized in preparation, 4-dihydroxy phenyl)-2-methyl-methyl-2,3,6,7,12,12a-hexahydro-pyrazine is [1', 2'-1,6]-pyrido [3 also, 4-b] indoles-Isosorbide-5-Nitrae-diketone.Syntheti c route as shown in Figure 3.
28.0 g of compound II are added at reaction flask, 300 ml methanol are added under room temperature, add the aqueous methylamine solution of 2.0 equivalents 30% under stirring, be heated to 65 DEG C of reactions 6 hours, cooling, decompress filter, with 50 ml methanol washings, oven drying, obtains the compound III of 22.7 grams, productive rate 89%, purity more than 98%.
Embodiment 13
The compound ii prepared with embodiment 7 to 11 any embodiment is for raw material, and key intermediate (6R, 12aR)-6-(3 is synthesized in preparation, 4-dihydroxy phenyl)-2-methyl-methyl-2,3,6,7,12,12a-hexahydro-pyrazine is [1', 2'-1,6]-pyrido [3 also, 4-b] indoles-Isosorbide-5-Nitrae-diketone.Syntheti c route as shown in Figure 3.
28.0 g of compound II are added at reaction flask, 300 ml methanol are added under room temperature, add the methylamine alcohol solution of 3.0 equivalents 30% under stirring, be heated to 50 DEG C of reactions 1 hour, cooling, decompress filter, by 50 milliliters of washing with alcohol, oven drying, obtains the compound III of 23.0 grams, productive rate 90%, purity more than 98%.
Embodiment 14
The compound ii prepared with embodiment 7 to 11 any embodiment is for raw material, and key intermediate (6R, 12aR)-6-(3 is synthesized in preparation, 4-dihydroxy phenyl)-2-methyl-methyl-2,3,6,7,12,12a-hexahydro-pyrazine is [1', 2'-1,6]-pyrido [3 also, 4-b] indoles-Isosorbide-5-Nitrae-diketone.Syntheti c route as shown in Figure 3.
28.0 g of compound II are added at reaction flask, 300 milliliters of ethanol are added under room temperature, add the aqueous solution of the methylamine of 4.0 equivalents 40% under stirring, be heated to 60 DEG C of reactions 6 hours, cooling, decompress filter, with 50 ml methanol washings, oven drying, obtains the compound III of 23.4 grams, productive rate 92%, purity more than 98%.
Embodiment 15
The compound ii prepared with embodiment 7 to 11 any embodiment is for raw material, and key intermediate (6R, 12aR)-6-(3 is synthesized in preparation, 4-dihydroxy phenyl)-2-methyl-methyl-2,3,6,7,12,12a-hexahydro-pyrazine is [1', 2'-1,6]-pyrido [3 also, 4-b] indoles-Isosorbide-5-Nitrae-diketone.Syntheti c route as shown in Figure 3.
28.0 g of compound II are added at reaction flask, 300 milliliters of ethanol are added under room temperature, add the aqueous solution of the methylamine of 6.0 equivalents 40% under stirring, be heated to 40 DEG C of reactions 5 hours, cooling, decompress filter, by 50 milliliters of washing with alcohol, oven drying, obtains the compound III of 22.9 grams, productive rate 90%, purity more than 98%.
The corresponding nuclear-magnetism appraising datum of the arbitrary routine gained key intermediate (compound III) of embodiment 12 to 15 is:
1hNMR (400MHz, DMSO): 11.03 (s, 1H), 8.74 (s, 2H), 7.56 (d, 1H, J=7.7, Hz), 7.29 (d, 1H, J=7.9Hz), 7.11-6.94 (m, 2H), 6.68 (d, 1H, J=1.6Hz), 6.64-6.55 (m, 2H), 6.11 (s, 1H), 4.83 (dd, 1H, J=11.6,4.4Hz), 4.19 (d, 1H, J=16.2Hz), (3.93 d, 1H, J=17.1Hz), 3.52 (dd, 1H, J=15.7,4.7Hz), 3.01-2.89 (m, 4H).Nuclear-magnetism qualification result as shown in Figure 7.
The structural formula of compound III is as shown in formula III:
（Ⅲ）。
Embodiment 16 synthesizes Tadalafei
In reaction flask, add 20.0 g of compound III, under room temperature, add 2.2 equivalent of cesium carbonate, then add 120 milliliters of N, dinethylformamide, adds the methylene bromide of 3.0 equivalents under stirring, be heated to 80 DEG C of reactions 8 hours, cooling, reaction solution is poured in 300 ml waters, stirs 30 minutes, filter, filter cake first with 80 ml water washings, then uses 30 milliliters of washing with alcohol, oven drying, obtain 19.2 grams of Tadalafeis, productive rate 93%, purity more than 98%.
Embodiment 17 synthesizes Tadalafei
In reaction flask, add 20.0 g of compound III, under room temperature, add 1 equivalent of cesium carbonate, then add 120 milliliters of dimethyl sulfoxide (DMSO), add the methylene bromide of 1.0 equivalents under stirring, be heated to 40 DEG C of reactions 14 hours, cooling, reaction solution is poured in 200 ml waters, stirs 40 minutes, filters, filter cake is first with 80 ml water washings, use 30 milliliters of washing with alcohol again, oven drying, obtain 18.4 grams of Tadalafeis, productive rate 89%, purity more than 98%.
Embodiment 18 synthesizes Tadalafei
In reaction flask, add 20.0 g of compound III, under room temperature, add 10 equivalent potassium carbonate, then add 120 milliliters of dimethyl sulfoxide (DMSO), add the methylene bromide of 4.0 equivalents under stirring, be heated to 60 DEG C of reactions 4 hours, cooling, reaction solution is poured in 200 ml waters, stirs 40 minutes, filters, filter cake is first with 90 ml water washings, use 30 milliliters of washing with alcohol again, oven drying, obtain 19.5 grams of Tadalafeis, productive rate 94%, purity more than 98%.
Other embodiments do not repeat one by one at this.The corresponding nuclear-magnetism appraising datum preparing product (comprising the arbitrary routine products therefrom of embodiment 16 to 18) according to synthetic route chart shown in accompanying drawing 4 is:
1hNMR (400MHz, DMSO): 8.10 (s, 1H), 7.55 (d, 1H, J=7.7, Hz), 7.30 (d, 1H, J=8.0Hz), 7.11-6.95 (m, 2H), 6.87 (s, 1H), 6.79 (d, 2H, J=0.9Hz), 6.13 (s, 1H), 5.93 (s, 1H), 5.77 (s, 1H), 4.40 (dd, 1H, J=12.0,4.1Hz), 4.18 (d, 1H, J=15.9Hz), 3.95 (d, 1H, J=17.2Hz), 3.60-3.47 (m, 1H), 3.03-2.96 (m, 1H), 2.94 (s, 3H).Nuclear-magnetism qualification result as shown in Figure 8.The structural formula of product is as shown in formula IV:
（Ⅳ）。
Claims (10)
1. a synthetic method for Tadalafei, is characterized in that, comprises the following steps:
S1. be that raw material is obtained by reacting (1R, 3R)-methyl isophthalic acid-(3 through condensation cyclization Pictet-Spengler with 3,4-Dihydroxy benzaldehyde, D-trp methyl ester hydrochloride, 4-dihydroxy phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] Indole-3-Carboxylic Acid;
S2.(1R, 3R)-methyl isophthalic acid-(3,4-dihydroxy phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] Indole-3-Carboxylic Acid and chloroacetyl chloride generation chlorine acetylation generate (1R, 3R)-2-(2-chloracetyl)-1-(3,4-dihydroxy phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] Indole-3-Carboxylic Acid;
S3.(1R, 3R)-2-(2-chloracetyl)-1-(3,4-dihydroxy phenyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] aqueous solution generation aminolysis ring-closure reaction of Indole-3-Carboxylic Acid and methylamine or alcohol generates (6R, 12aR)-6-(3,4-dihydroxy phenyl)-2-methyl-methyl-2,3,6,7,12,12a-hexahydro-pyrazine also [1', 2'-1,6]-pyrido [3,4-b] indoles-Isosorbide-5-Nitrae-diketone;
S4. (6R, 12aR)-6-(3,4-dihydroxy phenyl)-2-methyl-methyl-2,3,6,7,12,12a-hexahydro-pyrazine also [1', 2'-1,6]-pyrido [3,4-b] indoles-Isosorbide-5-Nitrae-diketone and methylene bromide carry out reaction in the basic conditions and prepare Tadalafei.
2. the synthetic method of Tadalafei according to claim 1, is characterized in that, in condensation ring-closure reaction described in step S1, select lower alcohol, nitrile or nitroparaffins to make solvent, is preferably Virahol, acetonitrile, propionitrile or Nitromethane 99Min..
3. the synthetic method of Tadalafei according to claim 1, is characterized in that, in chlorine acetylation described in step S2, be make solvent with ethyl acetate or methylene dichloride, do alkali with DIPEA or triethylamine.
4. the synthetic method of Tadalafei according to claim 1, is characterized in that, the last handling process of chlorine acetylation resultant described in step S2 comprises evaporate to dryness except desolventizing, removes impurity with lower alcohol washing and filtering, is preferably methyl alcohol or ethanol.
5. the synthetic method of Tadalafei according to claim 1, it is characterized in that, aminolysis ring-closure reaction described in step S3, the methylamine solution selected is the aqueous solution or alcoholic solution, is further 30% ~ 40% aqueous methylamine solution.
6. the synthetic method of Tadalafei according to claim 1, is characterized in that, described in step S3
Aminolysis ring-closure reaction, the solvent selected is lower alcohol, is preferably methyl alcohol or ethanol.
7. the synthetic method of Tadalafei according to claim 1, is characterized in that, the aqueous solution of methylamine described in step S3 or the molar equivalent 2.0 ~ 6.0 of alcoholic solution, preferred molar equivalent is 2.0 ~ 3.0, reaction terminate after through filter and solvent wash high purity (6R, 12aR)-6-(3,4-dihydroxy phenyl)-2-methyl-methyl-2,3,6,7,12,12a-hexahydro-pyrazine also [1', 2'-1,6]-pyrido [3,4-b] indoles-Isosorbide-5-Nitrae-diketone.
8. the synthetic method of Tadalafei according to claim 1, it is characterized in that, step S4 does alkali with carbonate.
9. the synthetic method of Tadalafei according to claim 8, it is characterized in that, carbonate described in step S4 is sodium carbonate, salt of wormwood or cesium carbonate.
10. the synthetic method of Tadalafei according to claim 1, it is characterized in that, step S4 is with dimethyl sulfoxide (DMSO) or N, dinethylformamide is solvent, (6R, 12aR)-6-(3,4-dihydroxy phenyl)-2-methyl-methyl-2,3,6,7,12,12a-hexahydro-pyrazine also [1', 2'-1,6]-pyrido [3,4-b] indoles-Isosorbide-5-Nitrae-diketone and methylene bromide react directly obtained high purity Tadalafei.
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