CN105524062B - The synthetic method of Tadalafei - Google Patents
The synthetic method of Tadalafei Download PDFInfo
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- CN105524062B CN105524062B CN201511014807.1A CN201511014807A CN105524062B CN 105524062 B CN105524062 B CN 105524062B CN 201511014807 A CN201511014807 A CN 201511014807A CN 105524062 B CN105524062 B CN 105524062B
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- 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
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Abstract
The invention discloses the synthetic method in terms of a kind of Tadalafei.The present invention is with 3,4 4-dihydroxy benzaldehydes, D tryptophan methyl ester hydrochlorides for initiation material, and through being condensed cyclization, chloroacetylation, aminolysis cyclization, methyl ring-closure reaction are final obtains product.The present invention with 3,4 4-dihydroxy benzaldehydes is raw material, is condensed ring-closure reaction and makees solvent with nitrile, lower alcohol, nitroparaffins, makees solvent in chlorine acetylation with ethyl acetate or dichloromethane, aminolysis ring-closure reaction has used cheap lower alcohol to make solvent.Compared with other routes, the route have isolate and purify easy, reaction condition is simple, each step high income (often walking yield ＞ 80%), process stabilizing, the shorter production cycle the characteristics of；And avoid using easy drugs piperonal processed, it is not required to, using purge processes such as column chromatographies, be suitable for industrialized production.
Description
Technical field
The present invention relates to technical field of organic synthesis, more particularly, to a kind of synthetic method of Tadalafei.
Background technology
Tadalafei (Tadalafil) is a kind of Phosphodiesterase V type (PDE 5) inhibitor, by GlaxoSmithKline PLC company
(GSK) initially research and development, ratify for 2003 through FDA, and the medicine as treatment male erectile dysfunction (ED) lists in the U.S..By
There is high selectivity in clinical treatment ED in Tadalafei, long half time, the advantages that patient's bigger independence, and have uniqueness
Pharmacological action, domestic and international expert conduct extensive research to chemical synthesis Tadalafei, and achieve certain achievement.
United States Patent (USP) US5859006 report synthetic route, the route be using tryptophan methyl ester and piperonal as raw material, with
Dichloromethane is solvent, and P-S reactions (Pictet-Spengler) reaction occurs under the catalysis of trifluoroacetic acid, passes through column chromatography
Isolated cis carboline intermediate reacts synthesis acylate intermediate with chloracetyl chloride again；Finally react to obtain him with methylamine again
Da Lafei.
Revell et al. report Two concise synthesis of cialis via the N-acyliminium
D-trp methyl ester hydrochloride and pepper aldehyde reaction are given birth in the route mentioned in the texts of Pictet-Spengler reaction mono-
Into after imines, then promote imines molecule cyclization with Fmoc-Sar-Cl, reacted after column chromatography for separation intermediate with methylamine and generate him
Da Lafei, slough protection group and obtain Tadalafei, total recovery 28%.
As can be seen here, the principal synthetic routes for synthesizing Tadalafei are using D-trp methyl ester hydrochloride and piperonal to rise
Beginning raw material, the route synthesized through condensation and cyclization, acylation, aminolysis cyclization, it is whole to build beta-tetrahydro carboline ring by asymmetric syntheses
The key of individual synthetic route, on the one hand, Pictet-Spengler (condensation cyclization) reactions are that structure beta-tetrahydro carboline ring is most effective
And conventional means, but this reaction is easily caused the generation of cis and trans isomers, it usually needs by column chromatography for separation or
The cumbersome processing such as recrystallization obtains the cis carboline intermediate of high-purity, on the other hand, important source material piperonal belong to by《Danger
Dangerous chemical producting safety management rules》、《Regulation on Management of Drug-Making Chemicals》The chemicals of control.Therefore, a high selection is probed into
Property the diastereomeric synthesis cis carboline of Tadalafei intermediate preparation method, find a kind of control initiation material that substitutes and reached for him
Draw non-synthesis most important to industrialized production.
The content of the invention
The technical problem to be solved in the present invention is the deficiency for existing synthesis Tadalafei technology, there is provided a kind of new conjunction
Into the method for Tadalafei.Instant invention overcomes prior art using piperonal as raw material, because of the purchase of raw material and using not
Easily to obstacle caused by synthetically produced, and the yield for overcoming prior art processes is low, route is cumbersome, severe reaction conditions etc. lack
Point and deficiency, there is provided a high income, post processing is simple, yield is higher, reaction condition is gentle, safety and environmental protection is easy to industrialize
The syntheti c route of production.
The goal of the invention of the present invention is achieved by the following technical programs：
A kind of synthetic method of Tadalafei is provided, comprised the following steps：
S1. using 3,4- 4-dihydroxy benzaldehydes, D-trp methyl ester hydrochloride as raw material through be condensed cyclization obtain (1R, 3R)-
1- (1,2- dihydroxyphenyl -4- bases) -2,3,4,9- tetrahydrochysene -1H- pyridos [3,4-b] indole -3-carboxylic acid methyl ester's hydrochloride (chemical combination
Thing I)；
S2. (1R, 3R) -1- (1,2- dihydroxyphenyl -4- bases) -2,3,4,9- tetrahydrochysene -1H- pyrido [3,4-b] indoles -3-
With chloracetyl chloride chlorine acetylation generation (1R, 3R) -1- (1,2- dihydroxyphenyl -4- bases) -2- occurs for carboxylate methyl ester hydrochloride
Chloracetyl -2,3,4,9- tetrahydrochysene -1H- pyridos [3,4-b] indole -3-carboxylic acid methyl ester's (compound ii)；
S3. (1R, 3R) -1- (1,2- dihydroxyphenyl -4- bases) -2- chloracetyl -2,3,4,9- tetrahydrochysene -1H- pyridos [3,
4-b] aqueous solution of indole -3-carboxylic acid methyl ester and methylamine or the alcoholic solution of methylamine occur aminolysis ring-closure reaction generation (6R, 12aR)-
6- (1,2- dihydroxyphenyl -4- bases) -2- methyl -2,3,6,7,12,12a- hexahydros pyrazine simultaneously [1', 2'-1,6]-pyrido [3,
4-b] indoles -1,4- diketone (compound III)；
S4. (6R, 12aR) -6- (1,2- dihydroxyphenyl -4- bases) -2- methyl -2,3,6,7,12,12a- hexahydros pyrazine is simultaneously
[1', 2'-1,6]-pyrido [3,4-b] indoles -1,4- diketone is prepared him with methylene bromide reaction in the basic conditions and reached
Draw non-.
Tadalafei prepared by the present invention with D-trp methyl ester hydrochloride, 3,4- 4-dihydroxy benzaldehydes for initiation material,
Through condensation and cyclization, chloroacetylation, aminolysis cyclization, methyl cyclization, Tadalafei is obtained.
First step condensation cyclization Pictet-Spengler reactions, the Tadalafei of the preparation is with D-trp methyl esters salt
Hydrochlorate, 3,4- 4-dihydroxy benzaldehydes are initiation material, are avoided using the raw material piperonal by public security department's control, and raw material is purchased
Buy more convenient.
Cyclization Pictet-Spengler reactions are condensed, make solvent, isomers generation from lower alcohol, nitrile or nitroparaffins
Few, target configuration proportion of products is high, and post processing is simple, and filtering can obtain chemical compounds I.
The cis Si Qing Ka Lin intermediates of the present invention are starting by D-trp methyl ester hydrochloride, 3,4- 4-dihydroxy benzaldehydes
It is prepared by raw material.The cis tetrahydrochysene click beautiful jade intermediate of the present invention is prepared without catalyst, makees solvent with lower alcohol, nitrile, nitroparaffins
Directly prepare, reaction cools after terminating filters, and produces product, and molar yield is 90~97%.
In chlorine acetylation of the present invention, solvent is made with ethyl acetate or dichloromethane, with DIPEA or
Triethylamine does alkali, temperature control -10~30 DEG C, the chloracetyl chloride of 1.0~4.0 molar equivalents of dropwise addition.
In aminolysis ring-closure reaction of the present invention, methylamine water solution or alcoholic solution are directly used, molar equivalent 2.0~6.0 is rudimentary
The volume multiple of alcohol 2~20 makees solvent.Heating response 1~6 hour, directly filter, washed with lower alcohol, filtering can obtain compound
Ⅲ。
1~10 equivalent of cesium carbonate, potassium carbonate or sodium carbonate are added in methyl ring-closure reaction of the present invention at room temperature as alkali, then
Addition dimethyl sulfoxide (DMSO), DMF make solvent, stir the lower methylene bromide for adding 1~4.0 equivalent, are heated to 40
~80 DEG C are reacted 4~14 hours, and cooling, reaction solution is poured into 10~30 times of water, are stirred 30~60 minutes, and filtering, filter cake is first used
15~40 times of water washings, then washed with 1~4 times of ethanol.
Preferably, it is condensed described in step S1 in ring-closure reaction, makees solvent from isopropanol, acetonitrile or propionitrile.
Preferably, it is that solvent is done with ethyl acetate or dichloromethane in chlorine acetylation described in step S2, with N, N- bis-
Wopropyl ethyl amine or triethylamine do alkali.
Preferably, the last handling process of chlorine acetylation product described in step S2 includes revolving removing solvent, and use is low
Level alcohol washing and filtering impurity elimination, further, the lower alcohol is methanol or ethanol.
Preferably, aminolysis ring-closure reaction described in step S3, the methylamine solution of selection are the aqueous solution or alcoholic solution, further
For 30%~40% methylamine water solution.
Preferably, aminolysis ring-closure reaction described in step S3, the solvent of selection is lower alcohol, and further is methanol or second
Alcohol.
Preferably, aminolysis ring-closure reaction described in step S3, reaction is washed after terminating through filtering and solvent can obtain high-purity
(6R, 12aR) -6- (1,2- dihydroxyphenyl -4- bases) -2- methyl -2,3,6,7,12,12a- hexahydros pyrazine simultaneously [1', 2'-1,
6]-pyrido [3,4-b] indoles -1,4- diketone.
Preferably, step S4 is to do alkali with carbonate.
It is further preferred that carbonate described in step S4 is sodium carbonate, potassium carbonate or cesium carbonate.
Preferably, step S4 is with N, and N- dimethyl sulfoxide (DMSO)s or DMF are solvent, (6R, 12aR) -6-
(1,2- dihydroxyphenyl -4- bases) -2- methyl -2,3,6,7,12,12a- hexahydros pyrazine simultaneously [1', 2'-1,6]-pyrido [3,4-
B] indoles -1,4- diketone and methylene bromide react directly obtained high-purity Tadalafei.
Beneficial effects of the present invention：
(1) present invention avoids use with 3,4- 4-dihydroxy benzaldehydes for initiation material《Safety management of dangerous chemical products bar
Example》、《Regulation on Management of Drug-Making Chemicals》The piperonal of control is as initiation material.
(2) three-step reaction condition of the present invention is not harsh, easily realizes, no HTHP is easy to operate, the easy recovery set of waste liquid
With.
(3) post processing of present invention process route is simple, avoids the loss of cumbersome processing.
(4) present invention prepares cis tetrahydrochysene click beautiful jade intermediate without the lower direct high-purity in high yield of catalysis.
(5) chloracetyl intermediate of the present invention directly participates in the next step without purifying.
(6) in aminolysis ring-closure reaction of the present invention, directly using methylamine solution, reaction is filtered after terminating can obtain product.
(7) present invention process often walks yield all more than 80%, purity more than 98%, creates one from D-trp first
For ester hydrochloride to the complete process of Tadalafei, technique is simple, and cost is relatively low, safety and environmental protection, meets industrialized production.
Brief description of the drawings
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 Tadalafeis of the present invention.
The nuclear-magnetism qualification result of Fig. 5 chemical compounds Is.
The nuclear-magnetism qualification result of Fig. 6 compound iis.
The nuclear-magnetism qualification result of Fig. 7 compound IIIs.
The nuclear-magnetism qualification result of Fig. 8 Tadalafeis.
Embodiment
The present invention is further described with specific embodiment below in conjunction with the accompanying drawings.Unless stated otherwise, the present invention is implemented
The various raw materials that example uses can obtain by the way that routine is purchased in market, or be prepared according to the conventional method of this area, used to set
Standby is experiment common equipment.Unless otherwise defined or described herein, all specialties used herein and scientific words and this area
Meaning is identical known to person skilled in the art.
Embodiment 1
25.5 grams of D-trp methyl ester hydrochlorides are added in reaction bulb, add 150 milliliters of isopropanols at room temperature, are stirred,
Add 1.2 equivalents 3,4- 4-dihydroxy benzaldehydes, react 8 hours at 85 DEG C, until raw material fundamental reaction is complete, be cooled to room temperature,
Filtering, solid are washed with 50 milliliters of isopropanols, are then dried to constant weight in an oven.Obtain 34.6 g of compound I, yield
92%.Shown in synthetic route chart as accompanying drawing 1.
Embodiment 2
25.5 grams of D-trp methyl ester hydrochlorides are added in reaction bulb, 250 milliliters of propionitrile is added at room temperature, stirring, adds
Enter 1.5 equivalents 3,4- 4-dihydroxy benzaldehydes, react 16 hours at 85 DEG C, until raw material fundamental reaction is complete, be cooled to room temperature, mistake
Filter, solid are washed with 50 milliliters of isopropanols, are then dried to constant weight in an oven.Obtain 34.2 g of compound I, yield 97%.
Shown in synthetic route chart as accompanying drawing 1.
Embodiment 3
25.5 grams of D-trp methyl ester hydrochlorides are added in reaction bulb, add 375 ml methanols at room temperature, stirs, adds
Enter 1.5 equivalents 3,4- 4-dihydroxy benzaldehydes, react 24 hours at 60 DEG C, until raw material fundamental reaction is complete, be cooled to room temperature, mistake
Filter, solid are washed with 50 ml methanols, are then dried to constant weight in an oven.Obtain 33.8 g of compound I, yield 90%.Close
See shown in accompanying drawing 1 into route map.
Embodiment 4
25.5 grams of D-trp methyl ester hydrochlorides are added in reaction bulb, 150 milliliters of butanol is added at room temperature, stirring, adds
Enter 1.2 equivalents 3,4- 4-dihydroxy benzaldehydes, react 8 hours at 120 DEG C, until raw material fundamental reaction is complete, be cooled to room temperature, mistake
Filter, solid are washed with 50 milliliters of butanol, are then dried to constant weight in an oven.Obtain 34.1 g of compound I, yield 91%.Close
Into shown in route map as accompanying drawing 1.
Embodiment 5
25.5 grams of D-trp methyl ester hydrochlorides are added in reaction bulb, 250 milliliters of acetonitriles is added at room temperature, stirring, adds
Enter 1.0 equivalents 3,4- 4-dihydroxy benzaldehydes, react 10 hours at 80 DEG C, until raw material fundamental reaction is complete, be cooled to room temperature, mistake
Filter, solid are washed with 50 milliliters of acetonitriles, are then dried to constant weight in an oven.Obtain 35.6 g of compound I, yield 96%.Close
Into shown in route map as accompanying drawing 1.
Embodiment 6
25.5 grams of D-trp methyl ester hydrochlorides are added in reaction bulb, 150 milliliters of nitromethanes is added at room temperature, stirs
Mix, add 1.2 equivalents 3,4- 4-dihydroxy benzaldehydes, react 6 hours at 100 DEG C, until raw material fundamental reaction is complete, be cooled to room
Temperature, filtering, solid are washed with 50 milliliters of nitromethanes, are then dried to constant weight in an oven.Obtain 35.9 chemical compounds Is, yield
95%.Shown in synthetic route chart as accompanying drawing 1.
Gained chemical compounds I is carried out nuclear-magnetism identification by the gained chemical compounds I purity of embodiment 1 to 6 respectively more than 98%,
Data are as follows：1H NMR(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 the gained gained chemical compounds I of embodiment 1 to 6 is (1R, 3R) -1- (1,2- dihydroxyphenyls
Base -4- bases) -2,3,4,9- tetrahydrochysene -1H- pyridos [3,4-b] indole -3-carboxylic acid methyl ester's hydrochlorides, structural formula such as formula (I) institute
Show, nuclear-magnetism qualification result is as shown in Figure 5.
Embodiment 7
The Compound Compound I that the present embodiment is prepared with any embodiment of embodiment 1 to 6 prepares synthesis for raw material
Acylate intermediate (1R, 3R) -1- (1,2- dihydroxyphenyl -4- bases) -2- chloracetyl -2,3,4,9- tetrahydrochysene -1H- pyridos
[3,4-b] indole -3-carboxylic acid methyl ester.Syntheti c route is as shown in Figure 2.
30.8 g of compound I are added in reaction bulb, add 500 milliliters of ethyl acetate at room temperature, lower addition 2.5 is stirred and works as
Triethylamine is measured, ice bath, the chloracetyl chloride of 1.0 equivalents is then slowly added dropwise, continues reaction 2 hours after dripping off, solvent evaporated, adds
90 milliliters of ethanol, stir 20 minutes, filtering, filter cake is washed with 30 milliliters of ethanol, is dried, is obtained 28.3 g of compound II, yield
83%, purity more than 98%.
Embodiment 8
The present embodiment prepares synthesis acylate using the chemical compounds I that any embodiment of embodiment 1 to 6 is prepared as raw material
Intermediate (1R, 3R) -1- (1,2- dihydroxyphenyl -4- bases) -2- chloracetyl -2,3,4,9- tetrahydrochysene -1H- pyridos [3,4-b]
Indole -3-carboxylic acid methyl ester.Syntheti c route is as shown in Figure 2.
30.8 g of compound I are added in reaction bulb, add 500 milliliters of dichloromethane at room temperature, lower addition 2.5 is stirred and works as
DIPEA is measured, then the chloracetyl chloride of 4.0 equivalents is slowly added dropwise at 30 DEG C in control temperature, continue after dripping off anti-
Answer 2 hours, rotate solvent evaporated, add 90 ml methanols, stir 20 minutes, filtering, filter cake is washed with 30 ml methanols, is done
It is dry, obtain 27.8 g of compound II, yield 82%, purity more than 98%.
Embodiment 9
The present embodiment prepares synthesis acylate using the chemical compounds I that any embodiment of embodiment 1 to 6 is prepared as raw material
Intermediate (1R, 3R) -1- (1,2- dihydroxyphenyl -4- bases) -2- chloracetyl -2,3,4,9- tetrahydrochysene -1H- pyridos [3,4-b]
Indole -3-carboxylic acid methyl ester.Syntheti c route is as shown in Figure 2.
30.8 g of compound I are added in reaction bulb, add 500 milliliters of dichloromethane at room temperature, lower addition 2.5 is stirred and works as
Triethylamine is measured, then the chloracetyl chloride of 2.0 equivalents is slowly added dropwise at -10 DEG C in control temperature, dripping off rear room temperature, to continue reaction 2 small
When, solvent evaporated is rotated, adds 90 milliliters of ethanol, is stirred 20 minutes, filtering, filter cake is washed with 30 ml methanols, is dried, is obtained
29.5 g of compound II, yield 87%, purity more than 98%.
Embodiment 10
Other are the same as embodiment 7.The difference is that the addition of triethylamine is 2.0 equivalents.The present embodiment yield 79%, purity
More than 98%.
Embodiment 11
Other are the same as embodiment 8.The difference is that dripping off room temperature after chloracetyl chloride continues stirring 1 hour.The present embodiment yield
81%, purity more than 98%.
The compound ii of any gained of embodiment 7 to 11 is subjected to nuclear-magnetism identification, data are：1H NMR(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 is as shown in Figure 6.
Shown in the structural formula of compound ii such as formula (II)：
Embodiment 12
Using the compound ii that any embodiment of embodiment 7 to 11 is prepared as raw material, synthesis key intermediate is prepared
(6R, 12aR) -6- (1,2- dihydroxyphenyl -4- bases) -2- methyl -2,3,6,7,12,12a- hexahydros pyrazine simultaneously [1', 2'-1,
6]-pyrido [3,4-b] indoles -1,4- diketone.Syntheti c route is as shown in Figure 3.
28.0 g of compound II are added in reaction bulb, add 300 ml methanols at room temperature, stir 2.0 equivalents of lower addition
30% methylamine water solution, it is heated to 65 DEG C and reacts 6 hours, cooling, decompression filters, and is washed with 50 ml methanols, oven drying,
Obtain 22.7 grams of compound III, yield 89%, purity more than 98%.
Embodiment 13
Using the compound ii that any embodiment of embodiment 7 to 11 is prepared as raw material, synthesis key intermediate is prepared
(6R, 12aR) -6- (1,2- dihydroxyphenyl -4- bases) -2- methyl -2,3,6,7,12,12a- hexahydros pyrazine simultaneously [1', 2'-1,
6]-pyrido [3,4-b] indoles -1,4- diketone.Syntheti c route is as shown in Figure 3.
28.0 g of compound II are added in reaction bulb, add 300 ml methanols at room temperature, stir 3.0 equivalents of lower addition
30% methylamine alcohol solution, it is heated to 50 DEG C and reacts 1 hour, cooling, decompression filters, and is washed with 50 milliliters of ethanol, oven drying,
Obtain 23.0 grams of compound III, yield 90%, purity more than 98%.
Embodiment 14
Using the compound ii that any embodiment of embodiment 7 to 11 is prepared as raw material, synthesis key intermediate is prepared
(6R, 12aR) -6- (1,2- dihydroxyphenyl -4- bases) -2- methyl -2,3,6,7,12,12a- hexahydros pyrazine simultaneously [1', 2'-1,
6]-pyrido [3,4-b] indoles -1,4- diketone.Syntheti c route is as shown in Figure 3.
28.0 g of compound II are added in reaction bulb, add 300 milliliters of ethanol at room temperature, stir 4.0 equivalents of lower addition
The aqueous solution of 40% methylamine, it is heated to 60 DEG C and reacts 6 hours, cooling, decompression filters, and is washed with 50 ml methanols, baking oven is done
It is dry, obtain 23.4 grams of compound III, yield 92%, purity more than 98%.Embodiment 15
Using the compound ii that any embodiment of embodiment 7 to 11 is prepared as raw material, synthesis key intermediate is prepared
(6R, 12aR) -6- (1,2- dihydroxyphenyl -4- bases) -2- methyl -2,3,6,7,12,12a- hexahydros pyrazine simultaneously [1', 2'-1,
6]-pyrido [3,4-b] indoles -1,4- diketone.Syntheti c route is as shown in Figure 3.
28.0 g of compound II are added in reaction bulb, add 300 milliliters of ethanol at room temperature, stir 6.0 equivalents of lower addition
The aqueous solution of 40% methylamine, it is heated to 40 DEG C and reacts 5 hours, cooling, decompression filters, and is washed with 50 milliliters of ethanol, baking oven is done
It is dry, obtain 22.9 grams of compound III, yield 90%, purity more than 98%.
The corresponding nuclear-magnetism appraising datum of key intermediate (compound III) is obtained by any of embodiment 12 to 15：1H
NMR(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 is as shown in Figure 7.
Shown in the structural formula of compound III such as formula (III)：
Embodiment 16 synthesizes Tadalafei
20.0 g of compound III are added in reaction bulb, add 2.2 equivalent of cesium carbonate at room temperature, add 120 milliliters of N,
Dinethylformamide, the lower methylene bromide for adding 3.0 equivalents is stirred, 80 DEG C is heated to and reacts 8 hours, cooling, reaction solution falls
Enter in 300 milliliters of water, stir 30 minutes, filtering, filter cake is washed first with 80 milliliters of water washings, then with 30 milliliters of ethanol, and baking oven is done
It is dry, obtain 19.2 grams of Tadalafeis, yield 93%, purity more than 98%.
Embodiment 17 synthesizes Tadalafei
20.0 g of compound III are added in reaction bulb, add 1 equivalent of cesium carbonate at room temperature, add 120 milliliters of diformazans
Base sulfoxide, the lower methylene bromide for adding 1.0 equivalents is stirred, 40 DEG C is heated to and reacts 14 hours, cooling, reaction solution pours into 200 millis
Rise in water, stir 40 minutes, filtering, filter cake washs first with 80 milliliters of water washings, then with 30 milliliters of ethanol, oven drying, obtains
18.4 grams of Tadalafeis, yield 89%, purity more than 98%.
Embodiment 18 synthesizes Tadalafei
20.0 g of compound III are added in reaction bulb, add 10 equivalent potassium carbonates at room temperature, add 120 milliliters of diformazans
Base sulfoxide, the lower methylene bromide for adding 4.0 equivalents is stirred, 60 DEG C is heated to and reacts 4 hours, cooling, reaction solution pours into 200 milliliters
In water, stir 40 minutes, filtering, filter cake washs first with 90 milliliters of water washings, then with 30 milliliters of ethanol, oven drying, obtains
19.5 grams of Tadalafeis, yield 94%, purity more than 98%.
Other embodiment does not repeat one by one herein.According to synthetic route chart shown in accompanying drawing 4 be prepared product (including implement
Any products therefrom of example 16 to 18) corresponding nuclear-magnetism appraising datum be：1H NMR(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 is as shown in Figure 8.Shown in the structural formula of product such as formula (IV)：
Claims (9)
1. a kind of synthetic method of Tadalafei, it is characterised in that comprise the following steps：
S1. it is anti-through being condensed cyclization Pictet-Spengler as raw material using 3,4- 4-dihydroxy benzaldehydes, D-trp methyl ester hydrochloride
(1R, 3R) -1- (1,2- dihydroxyphenyl -4- bases) -2,3,4,9- tetrahydrochysene -1H- pyridos [3,4-b] indole -3-carboxylic acid should be obtained
Methyl ester hydrochloride；
S2. ((1R, 3R) -1- (1,2- dihydroxyphenyl -4- bases) -2,3,4,9- tetrahydrochysene -1H- pyridos [3,4-b] indoles -3- carboxylics
With chloracetyl chloride chlorine acetylation generation (1R, 3R) -1- (1,2- dihydroxyphenyl -4- bases) -2- chlorine occurs for acid methyl ester hydrochloride salt
Acetyl group -2,3,4,9- tetrahydrochysene -1H- pyridos [3,4-b] indole -3-carboxylic acid methyl ester；
S3. (1R, 3R) -1- (1,2- dihydroxyphenyl -4- bases) -2- chloracetyl -2,3,4,9- tetrahydrochysene -1H- pyridos [3,4-b]
Aminolysis ring-closure reaction generation (6R, 12aR) -6- occurs for the alcoholic solution of the aqueous solution or methylamine of indole -3-carboxylic acid methyl ester and methylamine
(1,2- dihydroxyphenyl -4- bases) -2- methyl -2,3,6,7,12,12a- hexahydros pyrazine simultaneously [1', 2'-1,6]-pyrido [3,4-
B] indoles -1,4- diketone；
S4. (6R, 12aR) -6- (1,2- dihydroxyphenyl -4- bases) -2- methyl -2,3,6,7,12,12a- hexahydros pyrazine simultaneously [1',
2'-1,6]-pyrido [3,4-b] indoles -1,4- diketone with methylene bromide carries out reaction he is prepared reaching in the basic conditions
Draw non-；
It is that solvent is done with ethyl acetate or dichloromethane, with DIPEA in chlorine acetylation described in step S2
Or triethylamine does alkali；
The last handling process of chlorine acetylation product described in step S2 includes being evaporated removing solvent, with lower alcohol washing and filtering
Go the removal of impurity；
Step S4 is to do alkali with carbonate；The carbonate is sodium carbonate, potassium carbonate or cesium carbonate；
Step S4 is (6R, 12aR) -6- (1,2- dihydroxyphenyl -4- using dimethyl sulfoxide (DMSO) or DMF as solvent
Base) -2- methyl -2,3,6,7,12,12a- hexahydros pyrazine simultaneously [1', 2'-1,6]-pyrido [3,4-b] indoles -1,4- diketone
High-purity Tadalafei is directly made with methylene bromide reaction.
2. the synthetic method of Tadalafei according to claim 1, it is characterised in that be condensed ring-closure reaction described in step S1
In, make solvent from lower alcohol, nitrile or nitroparaffins.
3. the synthetic method of Tadalafei according to claim 2, it is characterised in that the lower alcohol is isopropanol；It is described
Nitrile is acetonitrile or propionitrile；The nitroparaffins are nitromethane.
4. the synthetic method of Tadalafei according to claim 1, it is characterised in that the lower alcohol is methanol or ethanol.
5. the synthetic method of Tadalafei according to claim 1, it is characterised in that the aqueous solution of methylamine described in step S3 or
The mass percentage concentration of the alcoholic solution of methylamine is 30%~40%.
6. the synthetic method of Tadalafei according to claim 1, it is characterised in that aminolysis ring-closure reaction described in step S3,
The solvent of selection is lower alcohol.
7. the synthetic method of Tadalafei according to claim 6, it is characterised in that the lower alcohol is methanol or ethanol.
8. the synthetic method of Tadalafei according to claim 1, it is characterised in that the aqueous solution of methylamine described in step S3 or
The molar equivalent 2.0~6.0 of the alcoholic solution of methylamine, reaction terminate after through filtering and solvent washing can obtain high-purity (6R,
12aR) -6- (1,2- dihydroxyphenyl -4- bases) -2- methyl -2,3,6,7,12,12a- hexahydros pyrazine simultaneously [1', 2'-1,6]-pyrrole
Pyridine simultaneously [3,4-b] indoles -1,4- diketone.
9. the synthetic method of Tadalafei according to claim 8, it is characterised in that the aqueous solution of methylamine described in step S3 or
The molar equivalent of the alcoholic solution of methylamine is 2.0~3.0.
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