CN103980275B - The preparation method of PDE5 inhibitor tadanafil - Google Patents
The preparation method of PDE5 inhibitor tadanafil Download PDFInfo
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- CN103980275B CN103980275B CN201410201172.5A CN201410201172A CN103980275B CN 103980275 B CN103980275 B CN 103980275B CN 201410201172 A CN201410201172 A CN 201410201172A CN 103980275 B CN103980275 B CN 103980275B
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- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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Abstract
The present invention relates to the preparation method of PDE5 inhibitor tadanafil; with D tryptophan methyl ester hydrochloride as initiation material; obtaining tadanafil crude product through reacting with piperonal cyclization, acylated, the amine solution cyclization of N etc., tadanafil crude product is recrystallized to give tadanafil finished product.What the present invention provided prepares tadanafil method, and reaction condition is gentle, and the response time is shorter, and yield is high, and product stability is good, it is simple to industrialized production.
Description
Technical field
The present invention relates to the preparation method of a kind of PDE5 inhibitor, more particularly it relates to di-phosphate ester
The preparation method of enzyme 5 inhibitor tadanafil.
Background technology
11 families of the phosphodiesterase (PDE) in human body, they biological functions in body are different.Di-phosphate ester
Enzyme 5 (PDE5) is present in corpus cavernosum smooth muscle, blood vessel and visceral smooth muscle, skeletal muscle, platelet, kidney, lung and big
A kind of enzyme in brain, PDE5 has specific expressed in cavernous body of penis and vascular smooth muscle cell.Normal erection is
Cause when sexual stimulus parasympathetic nervous excited, promote non-adrenergic, non-cholinergic neuronal release nitric oxide (NO),
Activating cavernous body of penis and the guanylate cyclase of vascular smooth muscle cell, GTP (guanosine triphosphate) (GTP) metabolism is ring phosphorus by this enzyme
Acid guanosine (cGMP), makes testosterone relax, produces and erect.CGMP is hydrolyzed by specific PDE 5, becomes inactive phosphoric acid
Guanosine (GMP), then occurs erection to disappear.PDE5 inhibitor energy competitive inhibition PDE5 thus suppress the hydrolysis of cGMP, strengthen
The diastole cavernous body of penis effect of the cGMP of NO inductive formation, reaches to treat the effect of ED.
Tadanafil is the selectivity of cGMP specific PDE 5, reversible inhibitor.Penis sponge is caused when there being sexual stimulus
During the release NO of body local, PDE5 is suppressed by tadanafil, and in making penis vessel and Corpus cavernous smooth muscle cells, cGMP level carries
Height, causes smooth muscle loosening, and blood flows into corpus cavernosum tissue, produces and erects.If without sexual stimulus, tadanafil does not occurs
Effect.
Tadanafil belongs to chiral drug, and chiral drug refers in molecular structure containing chiral centre (being also asymmetric center)
Medicine, chirality is a kind of base attribute of nature, composition organism a lot of basic structural units all there is chirality, chirality
The different stereoisomers of medicine all there may be difference at aspects such as drug effect, medicine generation and toxicitys, therefore, and the solid of chiral drug
Chemical purity is critically important at medicinal applications.
Chiral drug typically can be obtained by extraction from natural product, racemate resolution method, but these methods
Complexity, costly, also can cause secondary pollution.The most increasing chiral drug is obtained by the method for asymmetric synthesis,
Along with the progress of biotechnology and biotechnology and the fusion of organic synthesis technology, biosynthesis technology also becomes acquirement chirality
The important means of medicine.
Tadanafil chemistry entitled (6R-12aR)-6-(1,3-benzodioxole-5-base)-2-methyl-2,3,6,7,12,
12a-hexahydro pyrazine also [1', 2'-1,6]-pyrido [3,4-b] indole-Isosorbide-5-Nitrae-diketone, its structural formula is as follows.
Tadanafil has beta-tetrahydro carboline ring in molecular structure to contain two chiral carbon atoies, and configuration is respectively 6R, 12aR,
The outer substituent group of the ring of chiral carbon atom is in cis (cis) configuration.Chinese patent CN1070492C discloses the two of tadanafil
Bar synthetic route.
Route 1: with D-trp methyl ester as initiation material, dichloromethane is solvent, under the catalysis of trifluoroacetic acid and recklessly
Green pepper aldehyde carries out Pickett-Shi Penggele reaction, reacts 5 days, column chromatography for separation, cis (cis) product obtained and trans at 4 DEG C
(trans) product is than for 3:4.
Route 2: generate (R)-N with Fructus Piperis acyl chloride reaction with D-trp methyl esterα-(3,4-methylenedioxyphenyl carbonyl)
After tryptophan methyl ester, form thioamides, thioamides elder generation and iodomethane effect cyclization with Lawson (Lawesson) reagent effect,
Sodium borohydride reduces at-78 DEG C, then reacts to obtain tadanafil with chloracetyl chloride, methylamine.
Revell JD reports two syntheti c routes of tadanafil,
Route 1:D-tryptophan methyl ester hydrochloride and piperonal reaction, almost obtain quantitative stable imines after recrystallization
Compound, this group with imine moiety is lower with N-fluorenes carbometoxyl sarcosyl chlorine (Fmoc-in DMAP (DMAP) catalysis
Sar-Cl) there is Pickett-Shi Penggele reaction, obtain the mixture of cis and trans product with the total recovery of 60%, both ratios
Example is 1.1:1, and column chromatography for separation isomer, after sloughing protection group, at room temperature obtains tadanafil in cyclization.
Route 2: be the improvement of the route 1 to him, in this route, replaces costliness with chloracetyl chloride cheap and easy to get
Fmoc-Sar-Cl, the Pickett-Shi Penggele occurred under DMAP is catalyzed reaction, obtains the total recovery of cis and trans product
Bringing up to 78%, cis and trans selectivity brings up to 1.3:1.
WO2007110734 discloses after reacting prepared amide with D-trp methyl ester for raw material and methylamine, amide and Fructus Piperis
Aldehyde generation Pickett-Shi Penggele reacts, and obtains cis and trans mixture, after gained mixture reacts with chloracetyl chloride, and alkali
Changing, partial solvent be evaporated off to there being solid to separate out, filter to obtain cis-product, trans product is stayed in mother solution, and this cis-product is in fourth
Under the effect of base lithium, cyclization prepares tadanafil.
The corrosivity of trifluoroacetic acid used by CN1070492C route 1 is strong, and the response time is long, sets operator and reaction
Standby requirement height；CN1070492C route 2 reactions steps is long, and Lawesson reagent is expensive and abnormal smells from the patient is difficult to hear；The two of Revell JD
Bar route, stereo selectivity is poor, there is not crystallization induced asymmetric sex reversal, and yield is low, separates complexity.These 4 syntheti c routes
It is required for by column chromatography for separation intermediate.The synthetic route of WO2007110734 uses butyl lithium, severe reaction conditions, yield
Low.
CN1070492C route 1 step is shorter, and initiation material has been commercially produced.CN100430395C is at this route base
Process modification has been carried out: Pickett-Shi Penggele reaction utilizes crystallization induction asymmetric transformation, it is to avoid diastereo-isomerism on plinth
The fractionation of body, ee value ＜ 99%；N-acylation reaction tetrahydrofuran aqueous solution makees reaction dissolvent；Amine solution-ring-closure reaction is also with four
Hydrogen furan makees solvent；Oxolane reclaims difficulty, price, and three-protection design bothers, and purifying tadalafil uses glacial acetic acid, finished product
Baking temperature is high.
Summary of the invention
The present invention provides the preparation method of a kind of PDE5 inhibitor tadanafil, and the method syntheti c route is short, the response time
Shortening, easy to operate, three-protection design is simple, it is simple to industrialized production.
For the problems referred to above, applicant have passed through numerous studies test.Development test finds, uses isopropanol and second
Nitrile mixed solvent, carries out Pickett-Shi Penggele reaction, can effectively utilize crystallization induction asymmetric transformation, i.e. utilize two kinds
Diastereomer dissolubility difference in above-mentioned mixed solvent, makes the isomer of needs precipitate in the solution, makes need not
Diastereomer dissolve in the solution, thus constantly convert to required product, chiral purity can be improved, it is to avoid diastereomeric
The fractionation of isomer, ee value ＞ 99%.Specifically Pickett-Shi Penggele reaction is carried out in isopropanol and acetonitrile mixed solvent,
Initiation material D-trp methyl ester hydrochloride rather than D-trp methyl ester.
Present invention provide the technical scheme that the preparation method of PDE5 inhibitor tadanafil, comprise the following steps:
(1) with D-trp methyl ester hydrochloride (II) and piperonal (III) as raw material, isopropanol and acetonitrile are reaction dissolvent,
(1R, 3R)-1,2,3,4-tetrahydrochysene-1-(3,4-methylenedioxyphenyl)-9H-is reacted through Pickett-Shi Penggele
Pyrido [3,4-b] indole-3-carboxylic acid methyl ester's hydrochlorate (IV)；
(2) compounds Ⅳ is in organic solvent, under the effect of acid binding agent after stirring reaction, then carries out N-with chloracetyl chloride
Acylation reaction, obtains (1R, 3R)-1 through isopropanol, first alcohol and water purification, and (3,4-is sub-for 2,3,4-tetrahydrochysene-2-chloracetyl-1-
Methyl dioxy phenyl)-9H-pyrido [3,4-b] indole-3-carboxylic acid methyl ester (V)；
(3) compound V and methylamine carry out amine solution-ring-closure reaction and obtain (6R-12aR)-6-(1,3-benzodioxole-5-
Base)-2-methyl-2,3,6,7,12,12a-hexahydro pyrazine also [1', 2'-1,6]-pyrido [3,4-b] indole-1,4-diketone
I.e. tadanafil.
(4) tadanafil finished product is obtained after tadanafil is purified.
In above-mentioned steps (1), the reaction temperature of Pickett-Shi Penggele reaction is solvent reflux temperature, reflux time
Being 11～13 hours, the molar ratio of D-trp methyl ester hydrochloride and piperonal is 1:1～1.3, D-trp methyl ester salt
Hydrochlorate is 1:45～55 with the mass ratio that feeds intake that the mass ratio that feeds intake is 1:7～9, wherein isopropanol and acetonitrile of mixed solvent.Step
Suddenly the purification solvent isopropanol in (2), the mass ratio that feeds intake of first alcohol and water are 1:3～5:1～2.
Organic solvent in above-mentioned steps (2) is dichloromethane or chloroform, preferably dichloromethane；Acid binding agent selects carbon
Acid potassium or triethylamine, preferably triethylamine.
Amine solution-ring-closure reaction in step (3) is to carry out in lower alcohol solvent, and described lower alcohol is methanol, ethanol, different
Propanol, propanol or butanol, preferably methanol, ethanol, more selects methanol.
Tadanafil purification in step (4) uses methanol and the mixed solvent of acetone, and methanol with the mass ratio of acetone is
1:5～10, preferably methanol and acetone quality are than for 1:6～8；The mass ratio of tadanafil crude product and mixed solvent be 1:28～
33。
The technology of the present invention route is as follows:
The present invention utilizes the commercial D-trp methyl ester hydrochloride being easy to get rather than D-trp methyl ester and piperonal
Pickett-Shi Penggele reacts, it is to avoid use trifluoroacetic acid, carries out crystallization induction asymmetric transformation, ee value ＞ 99%.
Compounds Ⅳ is dissolved in the dichloromethane solution adding triethylamine by the present invention, in 10 after stirring 10～30 minutes
Drip chloracetyl chloride at DEG C, react complete, add solution of potassium carbonate, separate, be dried, remove solvent, residue isopropanol methanol
Purifying aqueous solutions, can go the removal of impurity well, and product purity can reach more than 99%.
The present invention utilizes prior art to be reacted under the boiling point less than methanol with methylamine in methanol by compound V, condition
Gentle, it is not necessary to using pressue device, methylamine volatilization is few.
Reaction dissolvent isopropanol in the present invention, acetonitrile, dichloromethane, methanol, recrystallization solvent methanol, isopropanol etc. are all
Environmental pollution can be reduced with recovery.
The present invention relates to the preparation method of a kind of PDE5 inhibitor tadanafil, specifically Pickett-Shi Penggele reaction
Isopropanol with the mixed solvent of acetonitrile are carried out, initiation material D-trp methyl ester hydrochloride rather than D-trp first
Ester, effectively utilizes reactant, utilizes crystallization induction asymmetric transformation, i.e. utilizes two kinds of diastereomers molten in above-mentioned mixing
Dissolubility difference in agent, makes the isomer of needs precipitate in the solution, makes unwanted diastereomer the most molten
Solve, thus constantly convert to required product, improve chiral purity (ee value ＞ 99.5%)；N-acylation reaction dichloromethane is made
Reaction dissolvent, products therefrom isopropanol methanol aqueous solution is purified, and can go the removal of impurity well；Amine solution-ring-closure reaction first
Reaction dissolvent made by alcohol；Tadanafil purification acetone methanol mixed solvent makees recrystallization solvent, these solvents can with recovery,
Achieve environmentally friendly production.
Detailed description of the invention
Embodiment 1:
1,1R, 3R)-1,2,3,4-tetrahydrochysene-1-(3,4-methylenedioxyphenyl)-9H-pyrido [3,4-b] Yin
The preparation of diindyl-3-carboxylate methyl ester hydrochlorate (compounds Ⅳ):
D-trp methyl ester hydrochloride (100 grams, 0.39 mole), isopropanol 20 milliliters, acetonitrile 1000ml, piperonal (65
Gram, 0.43 mole) mix and blend reflux 11～13 hours, be cooled to room temperature, filter, isopropanol wash, be dried to obtain 144.0 grams
(94.9%) compounds Ⅳ, ee value 99.6%, [α]D 20=+82.00(c1, CH3OH).
2, (1R, 3R)-1,2,3,4-tetrahydrochysene-2-chloracetyl-1-(3,4-methylenedioxyphenyl)-9H-pyrido
The preparation of [3,4-b] indole-3-carboxylic acid methyl ester (compound V):
Compounds Ⅳ (48 grams, 0.12 mole) is suspended in 1.0 liters of dichloromethane, adds 50 milliliters of triethylamines, stirs 30 minutes,
At cooling down 10 DEG C, dropping chloracetyl chloride (14 milliliters, 0.18 mole), then stirring 1.5 hours, add 10wt% solution of potassium carbonate
500 milliliters, separating, obtain organic layer, anhydrous magnesium sulfate is dried.Filter, solvent is distilled off, residue 43ml isopropanol,
177ml methanol, 46ml purifying aqueous solutions, obtain 48.2 grams of (91.0%) compounds V, purity 99.5%, [α]D 20=-122.00(c1,
CH2Cl2).
3, (6R-12aR)-6-(1,3-benzodioxole-5-base)-2-methyl-2,3,6,7,12,12a-hexahydro pyrazine
And the i.e. tadanafil of [1', 2'-1,6]-pyrido [3,4-b] indole-1,4-diketone (compounds I)
Compound V (39 grams, 0.09 mole), methanol 700 milliliters, methylamine alcohol solution (64 milliliters, 0.43 mole), mixing,
Stirring heats up, and at 45～55 DEG C, stirring reaction 8～11 hours, are cooled to room temperature, filter, and water, methanol wash, and are dried, obtain 32.0
Gram (90.0%) tadanafil crude product.
4, tadanafil purification
Tadanafil crude product 30 grams, adds acetone 900ml, methanol 210ml, after agitating heating is dissolved, is incubated 0.5 hour,
Filtering, be dried, obtain 20 grams of tadanafil finished products, yield 66.7%, HPLC analyzes product purity 99.7%, single impurity content ＜
0.1%, ee value 99.5%.
The structural identification of tadanafil
Specific optical rotation [α]D 20=+82.00(c1, DMSO)
Elementary analysis C22H19N304(being value of calculation in bracket): C, 67.76%(67.86%), H5.108%(4.92%),
N10.81%(10.79%)；
Mass spectrum m/z=389
Ultraviolet λ max=284nm
Infrared (KBr tabletting, cm-1): 3330,3025,2926,1668,1650,1490,1436,1401,1324,1269,
1241,1151,939,746,
1HNMR(DMSO-d6) δ: 11.02 (s, 1H), 7.55-7.54 (d, 1H), 7.30-7.29 (d, 1H), 7.06-
7.00(m,2H), 6.87(s, 1H), 6.80-6.77(m,2H), 6.13(s,1H), 5.92(s,2H), 4.41-4.38(d
d,1H), 4.19-4.16(d,1H), 3.96-3.93(d,1H), 3.54-3.50(d d,1H), 3.00-2.93(m,4H)。
13CNMR (DMSO-d6) δ: 167.56,167.24,147.71,146.73,137.66,136.86,
134.62, 126.44, 121.91, 119.97, 119.54, 118.78, 111.98, 108.61, 107.64,
105.42, 101.57, 56.18, 55.95, 52.14, 33.55, 23.80。
Embodiment 2
According to embodiment 1: in step 1, reaction dissolvent uses 1000 milliliters of isopropanols to replace isopropanol and acetonitrile mixing molten
Agent, prepares compounds Ⅳ, yield 89.5%, ee value 98.1%, [α]D 20=+79.00(c1, CH3OH).
Embodiment 3
According to embodiment 1, in step 1, reaction dissolvent uses 1000 milliliters of acetonitriles to replace isopropanol and acetonitrile mixed solvent,
Prepare compounds Ⅳ, yield 91.0%, ee value 99.0%, [α]D 20=+81.00(c1, CH3OH).
Embodiment 4:
According to embodiment 1, step 2 uses the mixed solvent of 220ml isopropanol and 46ml water replace isopropanol, methanol and
The mixed solvent of water, prepares compound V, yield 87.0%, purity 99.0%, [α]D 20=-120.00(c1, CH2Cl2).
Embodiment 5:
According to embodiment 1, step 2 use the mixed solvent of 220ml methanol and 46ml water replace isopropanol, first alcohol and water
Mixed solvent, prepare compound V, yield 88.0%, purity 96.0%, [α]D 20=-115.00(c1, CH2Cl2).
Claims (4)
1. the preparation method of PDE5 inhibitor tadanafil, comprises the following steps: (1) is with 100 grams of D-trp methyl ester
Hydrochlorate, 65 grams of piperonals, 20 milliliters of isopropanols and 1000ml acetonitrile mix and blend reflux 11～13 hours, are cooled to room temperature,
Filter, isopropanol wash, be dried 114.0 grams, ee value 99.6%, [α]D 20=+82.00(1R, 3R)-1,2,3,4-tetra-
Hydrogen-1-(3,4-methylenedioxyphenyl)-9H-pyrido [3,4-b] indole-3-carboxylic acid methyl ester's hydrochlorate；(2) 48 grams (
1R, 3R)-1,2,3,4-tetrahydrochysene-1-(3,4-methylenedioxyphenyl)-9H-pyrido [3,4-b] indole-3-carboxylic acid's first
Ester hydrochloride is suspended in 1.0 liters of dichloromethane, adds 50 milliliters of triethylamines, stirs 30 minutes, at cooling down 10 DEG C, drips 14 milliliters of chlorine
Chloroacetic chloride, then stirring 1.5 hours, add 10wt% solution of potassium carbonate 500 milliliters, separates, obtains organic layer, anhydrous magnesium sulfate
Be dried, filter, solvent is distilled off, residue 43ml isopropanol, 177ml methanol, 46ml purifying aqueous solutions, obtain 48.2 grams,
Purity 99.5%, [α]D 20=-122.00(1R, 3R)-1,2,3,4-tetrahydrochysene-2-chloracetyl-1-(3,4-methylene two
Oxygen phenyl)-9H-pyrido [3,4-b] indole-3-carboxylic acid methyl ester；(3) (1R, 3R)-1,2,3,4-tetrahydrochysene-2-chloracetyl
Base-1-(3,4-methylenedioxyphenyl)-9H-pyrido [3,4-b] indole-3-carboxylic acid methyl ester and methylamine carry out amine solution-
Ring-closure reaction obtains (6R-12aR)-6-(1,3-benzodioxole-5-base)-2-methyl-2,3,6,7,12,12a-hexahydro pyrazine
And [1', 2'-1,6]-pyrido [3,4-b] indole-1,4-diketone crude product；(4) (6R-12aR)-6-(1,3-benzodioxole-
5-yl)-2-methyl-2,3,6,7,12,12a-hexahydro pyrazine also [1', 2'-1,6]-pyrido [3,4-b] indole-1,4-two
Tadanafil finished product is obtained after ketone crude product is purified.
Method the most according to claim 1, it is characterised in that: the amine solution-ring-closure reaction in step (3) is molten at lower alcohol
Carrying out in agent, described lower alcohol is methanol, ethanol, isopropanol, propanol or butanol.
Method the most according to claim 1, it is characterised in that: the tadanafil purification in step (4) uses methanol and third
The mixed solvent of ketone, methanol is 1:5～10 with the mass ratio of acetone；Tadanafil crude product is 1:28 with the mass ratio of mixed solvent
～33.
Method the most according to claim 3, it is characterised in that: methanol and acetone quality are than for 1:6～8.
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| WO2016206097A1 (en) | 2015-06-26 | 2016-12-29 | 重庆文理学院 | Novel phosphodiesterase type-5 inhibitor and application thereof |
| CN105272981A (en) * | 2015-11-19 | 2016-01-27 | 中国药科大学 | New Tadalafil crystal form |
| CN105503866B (en) * | 2015-12-31 | 2018-05-08 | 湖南千金湘江药业股份有限公司 | Acylate intermediate and its synthetic method and the application in terms of Tadalafei is prepared |
| CN105524062B (en) * | 2015-12-31 | 2018-01-30 | 湖南千金湘江药业股份有限公司 | The synthetic method of Tadalafei |
| CN106977516B (en) * | 2017-03-02 | 2019-06-18 | 山东裕欣药业有限公司 | A kind of preparation method of Tadalafei |
| CN109053724A (en) * | 2018-08-22 | 2018-12-21 | 上海青平药业有限公司 | The purification process and purposes of the preparation method and Tadalafei of a kind of impurity prepared during Tadalafei and the impurity |
| RU2692764C1 (en) | 2019-04-26 | 2019-06-27 | Общество с ограниченной ответственностью "Балтфарма" | Method of producing tadalafil |
| CN110437228B (en) * | 2019-07-22 | 2022-06-14 | 山东省药学科学院 | Preparation method of tadalafil and intermediate thereof |
| CN113582992A (en) * | 2021-06-11 | 2021-11-02 | 山东罗欣药业集团股份有限公司 | Preparation method of phosphodiesterase inhibitor |
| CN114213414A (en) * | 2022-01-24 | 2022-03-22 | 山东安信制药有限公司 | Tadalafil preparation method |
| CN114805345B (en) * | 2022-04-27 | 2023-11-10 | 山东省药学科学院 | Preparation method of tadalafil intermediate cis-tetrahydrocarboline hydrochloride |
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| CN1671706A (en) * | 2002-07-31 | 2005-09-21 | 利利艾科斯有限公司 | Modified pictet-spengler reaction and products prepared therefrom |
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