CN110437228A - A kind of preparation method of Tadalafei and its intermediate - Google Patents
A kind of preparation method of Tadalafei and its intermediate Download PDFInfo
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- CN110437228A CN110437228A CN201910659063.0A CN201910659063A CN110437228A CN 110437228 A CN110437228 A CN 110437228A CN 201910659063 A CN201910659063 A CN 201910659063A CN 110437228 A CN110437228 A CN 110437228A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 71
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 54
- SATCULPHIDQDRE-UHFFFAOYSA-N piperonal Chemical compound O=CC1=CC=C2OCOC2=C1 SATCULPHIDQDRE-UHFFFAOYSA-N 0.000 claims abstract description 26
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 20
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229940081310 piperonal Drugs 0.000 claims abstract description 13
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 claims abstract description 12
- QIVBCDIJIAJPQS-SECBINFHSA-N D-tryptophane Chemical compound C1=CC=C2C(C[C@@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-SECBINFHSA-N 0.000 claims abstract description 9
- 238000000034 method Methods 0.000 claims abstract description 9
- -1 D-trp methyl esters Chemical class 0.000 claims abstract description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000000058 cyclopentadienyl group Chemical group C1(=CC=CC1)* 0.000 claims abstract description 6
- ZSWFCLXCOIISFI-UHFFFAOYSA-N endo-cyclopentadiene Natural products C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 6
- 239000001257 hydrogen Substances 0.000 claims abstract description 6
- 230000032050 esterification Effects 0.000 claims abstract description 5
- 238000005886 esterification reaction Methods 0.000 claims abstract description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000011938 amidation process Methods 0.000 claims abstract description 4
- 238000010719 annulation reaction Methods 0.000 claims abstract description 3
- 239000007858 starting material Substances 0.000 claims abstract description 3
- 238000007171 acid catalysis Methods 0.000 claims abstract 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 90
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 42
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 29
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 8
- 238000002425 crystallisation Methods 0.000 claims description 6
- 230000008025 crystallization Effects 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- 101000654381 Homo sapiens Sodium channel protein type 8 subunit alpha Proteins 0.000 claims description 5
- 102100031371 Sodium channel protein type 8 subunit alpha Human genes 0.000 claims description 5
- DFWFIQKMSFGDCQ-UHFFFAOYSA-N deethylatrazine Chemical compound CC(C)NC1=NC(N)=NC(Cl)=N1 DFWFIQKMSFGDCQ-UHFFFAOYSA-N 0.000 claims description 5
- 239000000010 aprotic solvent Substances 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- 238000012805 post-processing Methods 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 2
- ZOOGRGPOEVQQDX-KHLHZJAASA-N cyclic guanosine monophosphate Chemical compound C([C@H]1O2)O[P@](O)(=O)O[C@@H]1[C@H](O)[C@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-KHLHZJAASA-N 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 3
- 239000013037 reversible inhibitor Substances 0.000 abstract description 2
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 abstract 1
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 abstract 1
- 230000001681 protective effect Effects 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 25
- 230000015572 biosynthetic process Effects 0.000 description 24
- 238000003786 synthesis reaction Methods 0.000 description 24
- 238000004128 high performance liquid chromatography Methods 0.000 description 21
- 239000000843 powder Substances 0.000 description 20
- 238000001035 drying Methods 0.000 description 19
- 238000005119 centrifugation Methods 0.000 description 17
- 238000001514 detection method Methods 0.000 description 11
- 238000010438 heat treatment Methods 0.000 description 11
- 239000007787 solid Substances 0.000 description 8
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 238000009413 insulation Methods 0.000 description 5
- 101100189582 Dictyostelium discoideum pdeD gene Proteins 0.000 description 4
- 101150098694 PDE5A gene Proteins 0.000 description 4
- 102100029175 cGMP-specific 3',5'-cyclic phosphodiesterase Human genes 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 208000010228 Erectile Dysfunction Diseases 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 201000001881 impotence Diseases 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- WOXKDUGGOYFFRN-IIBYNOLFSA-N tadalafil Chemical compound C1=C2OCOC2=CC([C@@H]2C3=C(C4=CC=CC=C4N3)C[C@H]3N2C(=O)CN(C3=O)C)=C1 WOXKDUGGOYFFRN-IIBYNOLFSA-N 0.000 description 3
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- CEAJFNBWKBTRQE-UHFFFAOYSA-N methanamine;methanol Chemical compound NC.OC CEAJFNBWKBTRQE-UHFFFAOYSA-N 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 229960000835 tadalafil Drugs 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 101710134988 Esterase-5 Proteins 0.000 description 1
- 102100034343 Integrase Human genes 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 229940082638 cardiac stimulant phosphodiesterase inhibitors Drugs 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 229940117229 cialis Drugs 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- SEGLCEQVOFDUPX-UHFFFAOYSA-N di-(2-ethylhexyl)phosphoric acid Chemical compound CCCCC(CC)COP(O)(=O)OCC(CC)CCCC SEGLCEQVOFDUPX-UHFFFAOYSA-N 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000009200 high fat diet Nutrition 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000005360 mashing Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 239000002571 phosphodiesterase inhibitor Substances 0.000 description 1
- 208000002815 pulmonary hypertension Diseases 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000008771 sex reversal Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- ZXLDQJLIBNPEFJ-UHFFFAOYSA-N tetrahydro-beta-carboline Natural products C1CNC(C)C2=C1C1=CC=C(OC)C=C1N2 ZXLDQJLIBNPEFJ-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of selectivity of cyclic guanosine monophosphate (cGMP) specific phosphodiesterase enzyme 5 (PDE5), the preparation method of reversible inhibitor Tadalafei, the following steps are included: using D-trp as starting material, it reacts, generates D-trp methyl esters (intermediate 1) with methanol esterification under sulfuric acid catalysis；Then (1R, 3R) -1- (1,3- benzo two dislikes cyclopentadienyl -5- base) -2 is prepared through Pickett - Shi Penggele (P-S) reaction with piperonal, 3, -1 hydrogen of 4,9- tetrahydro - pyrido [3,4-b] indole -3-carboxylic acid methyl ester hydrochloride (intermediate 2)；Then (1R is prepared with chloracetyl chloride amidation process; 3R) (1-1-; 3- benzo two dislikes cyclopentadienyl-5- base)-2- (2- chloracetyl)-2; 3; 4; -1 hydrogen of 9- tetrahydro-pyrido [3,4-b] indole -3-carboxylic acid methyl ester's (intermediate 3), last and methylamine alcohol solution annulation obtain Tadalafei.This method raw material is easy to get, easy to operate, environmentally protective, low in cost, is suitble to industrialized production.
Description
Technical field
The invention belongs to chemical pharmaceutical technology fields, and in particular to the preparation method of Tadalafei and its intermediate.
Background technique
Tadalafei, entitled (6R-12aR) -6- (1,3- benzo two dislikes cyclopentadienyl -5- the base) -2- methyl -2,3 of chemistry, 6,7,12,
12a- hexahydro pyrazine simultaneously [1', 2'-1,6]-pyrido [3,4-b] indoles-Isosorbide-5-Nitrae-diketone is white crystalline powder, indissoluble
Yu Shui.The general entitled Tadalafil of English, trade name have: Cialis (Xi Aili), Tadalafil, sharp scholar etc..Its structural formula
It is as follows:
Tadalafei is the specific di(2-ethylhexyl)phosphate of cyclic guanosine monophosphate (cGMP) of U.S. Ai Kesi and Li Lai company joint development
The selectivity of esterase 5 (PDE5), reversible inhibitor, belong to second generation phosphodiesterase inhibitors, it passes through Reverse transcriptase
CGMP and PDE5 is combined, and is inactivated PDE5, is reduced the hydrolysis of cGMP, and cGMP concentration is made to increase the work for reaching erection function enhancing
With.
2003, FDA ratified it and lists in the U.S., and indication is male erectile dysfunction (ED)；China was in 2005
Ratify it to list at home.The oral recommended dose 10-20mg/d of Tadalafei, compared with similar drugs, this product is to PDE5's
Selectivity is higher, smaller to visual impact, works rapidly, duration of efficacy is long, long half time, is in current ED therapeutic agent
The drug not influenced by alcohol and high fat diet intake uniquely, belongs to typical cookle grade drug.In addition, Tadalafei is also
The successive granted treatment for pulmonary hypertension and benign prostatic hyperplasis.
There are many synthetic method of Tadalafei at present, and United States Patent (USP) US5859006 first reported the synthesis of Tadalafei,
First using D-trp methyl esters as raw material, in methylene chloride, addition trifluoroacetic acid is catalyst, and it is anti-to complete P-S with piperonal
Answer, then by column chromatograph method separating-purifying required for cis- tetrahydro-beta-carboline compound, cis- carboline compound with
Chloracetyl chloride reaction, triethylamine catalysis reaction, finally and methylamine synthesizes Tadalafei in tetrahydrofuran, and it is not right which passes through
Claiming synthesis building carboline compound is a common step, but can generate cis- and transisomer, and needs column chromatography point
From not only causing the loss of product, improve cost, and be unfavorable for industrialized green production.
United States Patent (USP) US7550479 discloses a kind of new process, P-S reaction is carried out by solvent of isopropanol, through CIAT mistake
Journey (crystallization induced asymmetric sex reversal), makes unwanted diastereoisomer be transformed into required cis-compound, but its
Still it cannot make its conversion completely,
The country also improves its process at present, such as patent CN201710120730.9,
CN201510502098.5, CN201310518973.X, CN201310472456.3 etc. are optimized it, but still
So there is cost of material height, preparation process is complicated, it is difficult to large-scale production is realized, the disadvantages of causing serious pollution to the environment.
Summary of the invention
The present invention primarily directed to the deficiencies in the prior art, propose a kind of Tadalafei suitable for industrialized production and
The wherein green synthesis method of mesosome.This method is raw material using D-trp, and by using dilute hydrochloric acid, through CIAT, (crystallization is induced
Asymmetry transformation) trans- carboline compound is converted to cis- carboline intermediate by process, and preparation process is more applicable for industry
Metaplasia produces, and to more environment-friendly, post-processing is simple, and total recovery and purity are higher.
A kind of preparation method of Tadalafei and its intermediate, which comprises the following steps:
Step 1: using D-trp as starting material, esterification occurs with methanol, generates D-trp methyl esters (intermediate
1)；
Step 2: intermediate 1 and piperonal prepare (1R, 3R) -1- (1,3- benzene through Pickett-Shi Penggele (P-S) reaction
And two dislike cyclopentadienyl -5- base) -1 hydrogen of -2,3,4,9- tetrahydro-pyrido [3,4-b] indole -3-carboxylic acid methyl ester hydrochloride (intermediate 2)；
Step 3: intermediate 2 and chloracetyl chloride amidation process prepare (1R, 3R) -1- (1,3- benzo two dislikes cyclopentadienyl -5- base) -
- 1 hydrogen of 2- (2- chloracetyl) -2,3,4,9- tetrahydro-pyrido [3,4-b] indole -3-carboxylic acid methyl ester's (intermediate 3)；
Step 4: intermediate 3 and methylamine alcohol solution annulation obtain Tadalafei.
Reaction route figure is as shown in Fig. 1 in synthesis process:
Specifically, in the step 1: carrying out esterification, the sulfuric acid and D-trp as catalyst using sulfuric acid
Molar ratio be 1:0.03~0.08, preferably 0.05；Instead of thionyl chloride, the discharge of exhaust gas and hydrogen chloride gas is reduced.
In the step 2: using the mixed solvent of aprotic solvent and dilute hydrochloric acid as reaction reagent, hydrochloric acid is as catalysis
Agent and CIAT solvent, P-S reaction is carried out under counterflow condition can directly be made cis-product.
In the step 2: aprotic solvent is methylene chloride, ethyl acetate, n-hexane, toluene, wherein it is preferred that toluene, first
Benzene dosage is 1-10 times of 1 mass of intermediate, wherein it is preferred that 6 times of amounts；Dilute hydrochloric acid concentration is 1mol/L-6mol/L, wherein it is preferred that
3mol/L, dosage are 1-2 times, preferably 1.05 times of 1 molal quantity of intermediate.
In the step 3: intermediate 2 and chloracetyl chloride amidation process, using triethylamine as acid binding agent, methylene chloride is molten
Agent.
In the step 3: using washing dichloromethane layer, the post-processing approach for the direct crystallization that cools down, water consumption is dichloro
0.5-3 times of methane volumetric, preferably 1 times；Treatment temperature is -10-10 DEG C, preferably -5 DEG C.
In the step 4: using methanol as reaction reagent, being reacted using the methanol solution of 30% methylamine, reaction solution
It can be with recovery.
Compared with prior art, the present invention has the following advantages: thionyl chloride is replaced using the sulfuric acid of catalytic amount in step 1,
It avoids generating sulfur dioxide and hydrogen chloride gas, reduce costs；The mixed solvent of toluene and dilute hydrochloric acid is taken in step 2, is passed through
CIAT makes trans- carboline compound be transformed into cis- carboline intermediate, and transisomer is soluble in the mixed solvent,
And gained intermediate 2 is insoluble, improves yield, simplifies operation, while can be continuous by water during the reaction using toluene
Ground separates, and carries out reaction to the right, improves reaction rate；The post-processing approach of washing directly cooling crystallization is taken in step 3,
It changes distilled dichloromethane into crystallization filtering, can directly be applied after methylene chloride mother liquor liquid separation, reduce solvent loss, reduce
Cost simplifies operation；Step 4 uses the methanol solution of methylamine, cools down and can directly filter after the 6h that flows back, is conducive to operation.
The technological operation is simple, and cost is lower, is more advantageous to industrialized production, to more environment-friendly.
Detailed description of the invention
Fig. 1 Tadalafei and its intermediate reaction route map.
Specific embodiment
Above content of the invention is described in further details by the following examples, but does not therefore limit this hair
Bright content.
Embodiment 1
The synthesis of intermediate 1
By D-trp (25kg, 123mol), methanol 125L is added 500L reaction kettle, is stirred at room temperature, sulfuric acid is slowly added dropwise
(588g, 6mol), drop finish, are heated to flowing back, and insulation reaction 2h, HPLC detection is completed, and remove methanol under reduced pressure, ethyl acetate is added
175L is beaten 2h, and centrifugation, product is dry through bipyramid, obtains off-white powder 31kg, yield 99.4%, purity 99.1%.
Embodiment 2
The synthesis of intermediate 1
By D-trp (25kg, 123mol), methanol 125L is added 500L reaction kettle, is stirred at room temperature, sulfuric acid is slowly added dropwise
(362g, 3.7mol), drop finish, are heated to flowing back, and insulation reaction 3h, HPLC detection is completed, and remove methanol under reduced pressure, acetic acid second is added
Ester 175L is beaten 2h, centrifugation, and product drying obtains 1 off-white powder 30.8kg of intermediate, yield 98.9%, purity 99%.
Embodiment 3
The synthesis of intermediate 1
By D-trp (25kg, 123mol), methanol 125L is added 500L reaction kettle, is stirred at room temperature, sulfuric acid is slowly added dropwise
(960g, 9.8mol), drop finish, are heated to flowing back, and insulation reaction 2h, HPLC detection is completed, and remove methanol under reduced pressure, acetic acid second is added
Ester 175L is beaten 2h, centrifugation, and product drying obtains 1 off-white powder 30.9kg of intermediate, yield 99.2%, purity 98.9%.
Embodiment 4
The synthesis of intermediate 2
By intermediate 1 (25.5kg, 100mol), piperonal (15.7kg, 105mol), toluene 150L, 3mol/L hydrochloric acid
35L is added in 500L reaction kettle, and heating stirring goes out moisture in reflux course to flowing back, and reacts 15h, HPLC detection reaction
It finishes, reaction solution cools to 25 DEG C -30 DEG C, and centrifugation, product drying obtains 2 off-white powder 37.4kg of intermediate, yield
96.2%, purity 99.6%.
Embodiment 5
The synthesis of intermediate 2
By intermediate 1 (25.5kg, 100mol), piperonal (15.7kg, 105mol), toluene 100L, 3mol/L hydrochloric acid
35L is added in 500L reaction kettle, and heating stirring goes out moisture in reflux course to flowing back, and reacts 16h, HPLC detection reaction
It finishes, reaction solution cools to 25 DEG C -30 DEG C, and centrifugation, product drying obtains 2 off-white powder 37.2kg of intermediate, yield
95.8%, purity 99.3%.
Embodiment 6
The synthesis of intermediate 2
By intermediate 1 (25.5kg, 100mol), piperonal (15.7kg, 105mol), toluene 204L, 3mol/L hydrochloric acid
35L is added in 500L reaction kettle, and heating stirring goes out moisture in reflux course to flowing back, and reacts 18h, HPLC detection reaction
It finishes, reaction solution cools to 25 DEG C -30 DEG C, and centrifugation, product drying obtains 2 off-white powder 36.98kg of intermediate, yield
95.2%, purity 99.6%.
Embodiment 7
The synthesis of intermediate 2
By intermediate 1 (25.5kg, 100mol), piperonal (15.7kg, 105mol), ethyl acetate 150L, 3mol/L salt
Sour 35L is added in 500L reaction kettle, and heating stirring reacts 25h to flowing back, and HPLC detects end of reaction, and reaction solution cools to
25 DEG C -30 DEG C, centrifugation, product drying obtains 2 off-white powder 35.6kg of intermediate, yield 91.8%, purity 95.4%.
Embodiment 8
The synthesis of intermediate 2
By intermediate 1 (25.5kg, 100mol), piperonal (15.7kg, 105mol), n-hexane 150L, 3mol/L hydrochloric acid
35L is added in 500L reaction kettle, and heating stirring reacts 32h to flowing back, and HPLC detects end of reaction, and reaction solution cools to 25
DEG C -30 DEG C, centrifugation, product drying obtains 2 off-white powder 35.8kg of intermediate, yield 92.2%, purity 94%.
Embodiment 9
The synthesis of intermediate 2
By intermediate 1 (25.5kg, 100mol), piperonal (15.7kg, 105mol), toluene 150L, 2mol/L hydrochloric acid
52.5L is added in 500L reaction kettle, and heating stirring goes out moisture in reflux course to flowing back, and reacts 25h, and HPLC detection is anti-
It should finish, reaction solution cools to 25 DEG C -30 DEG C, and centrifugation, product drying obtains 2 off-white powder 35.6kg of intermediate, yield
91.7%, purity 96.8%.
Embodiment 10
The synthesis of intermediate 2
By intermediate 1 (25.5kg, 100mol), piperonal (15.7kg, 105mol), toluene 150L, 6mol/L hydrochloric acid
17.5L is added in 500L reaction kettle, and heating stirring goes out moisture in reflux course to flowing back, and reacts 16h, and HPLC detection is anti-
It should finish, reaction solution cools to 25 DEG C -30 DEG C, and centrifugation, product drying obtains 2 off-white powder 37.1kg of intermediate, yield
95.5%, purity 98.6%.
Embodiment 11
The synthesis of intermediate 2
By intermediate 1 (25.5kg, 100mol), piperonal (15.7kg, 105mol), toluene 150L, 3mol/L hydrochloric acid
33L is added in 500L reaction kettle, and heating stirring goes out moisture in reflux course to flowing back, and reacts 21h, HPLC detection reaction
It finishes, reaction solution cools to 25 DEG C -30 DEG C, and centrifugation, product drying obtains 2 off-white powder 37.2kg of intermediate, yield
95.8%, purity 98.6%.
Embodiment 12
The synthesis of intermediate 2
By intermediate 1 (25.5kg, 100mol), piperonal (15.7kg, 105mol), toluene 150L, 3mol/L hydrochloric acid
50L is added in 500L reaction kettle, and heating stirring reacts 18h to flowing back, and HPLC detects end of reaction, and reaction solution cools to 25
DEG C -30 DEG C, centrifugation, product drying obtains 2 off-white powder 36.9kg of intermediate, yield 95%, purity 97.9%.
Embodiment 13
The synthesis of intermediate 3
By intermediate 2 (20kg, 52mol), methylene chloride 160L is added in 500L reaction kettle, is stirred at room temperature, and is added three
Ethamine (13.6kg, 134mol) stirs 10min, and the dichloromethane solution 10L of chloracetyl chloride (8.2kg, 73mol), drop is added dropwise
Finishing, reacts at room temperature 1h, HPLC detects end of reaction, and 170L water is added, and a large amount of solids are precipitated, -5 DEG C of stirring 0.5h-1h are cooled to,
Centrifugation, a small amount of methylene chloride are washed, and product drying obtains 3 off-white powder 20.98kg of intermediate, yield 95.1%, purity 99.6%.
Embodiment 14
The synthesis of intermediate 3
By intermediate 2 (20kg, 52mol), methylene chloride 160L is added in 500L reaction kettle, is stirred at room temperature, and is added three
Ethamine (13.6kg, 134mol) stirs 10min, and the dichloromethane solution 10L of chloracetyl chloride (8.2kg, 73mol), drop is added dropwise
Finishing, reacts at room temperature 1h, HPLC detects end of reaction, and 85L water is added, and a large amount of solids are precipitated, -5 DEG C of stirring 0.5h-1h are cooled to,
Centrifugation, a small amount of methylene chloride are washed, and product drying obtains 3 off-white powder 20.85kg of intermediate, yield 94.5%, purity 98.2%.
Embodiment 15
The synthesis of intermediate 3
By intermediate 2 (20kg, 52mol), methylene chloride 160L is added in 500L reaction kettle, is stirred at room temperature, and is added three
Ethamine (13.6kg, 134mol) stirs 10min, and the dichloromethane solution 10L of chloracetyl chloride (8.2kg, 73mol), drop is added dropwise
Finishing, reacts at room temperature 1h, HPLC detects end of reaction, and 340L water is added, and a large amount of solids are precipitated, -5 DEG C of stirring 0.5h-1h are cooled to,
Centrifugation, a small amount of methylene chloride are washed, and product drying obtains 3 off-white powder 20.96kg of intermediate, yield 95%, purity 99.6%.
Embodiment 16
The synthesis of intermediate 3
By intermediate 2 (20kg, 52mol), methylene chloride 160L is added in 500L reaction kettle, is stirred at room temperature, and is added three
Ethamine (13.6kg, 134mol) stirs 10min, and the dichloromethane solution 10L of chloracetyl chloride (8.2kg, 73mol), drop is added dropwise
Finishing, reacts at room temperature 1h, HPLC detects end of reaction, and 170L water is added, and a large amount of solids are precipitated, 10 DEG C of stirring 0.5h-1h, centrifugation,
A small amount of methylene chloride is washed, and product drying obtains 3 off-white powder 17.7kg of intermediate, yield 80.2%, purity 99.7%.
Embodiment 17
The synthesis of intermediate 3
By intermediate 2 (20kg, 52mol), methylene chloride 160L is added in 500L reaction kettle, is stirred at room temperature, and is added three
Ethamine (13.6kg, 134mol) stirs 10min, and the dichloromethane solution 10L of chloracetyl chloride (8.2kg, 73mol), drop is added dropwise
Finish, react at room temperature 1h, HPLC detects end of reaction, and 170L water is added, and a large amount of solids are precipitated, and 0 DEG C of stirring 0.5h-1h is centrifuged, few
Amount methylene chloride is washed, and product drying obtains 3 off-white powder 20.67kg of intermediate, yield 93.7%, purity 99.6%.
Embodiment 18
The synthesis of intermediate 3
By intermediate 2 (20kg, 52mol), methylene chloride 160L is added in 500L reaction kettle, is stirred at room temperature, and is added three
Ethamine (13.6kg, 134mol) stirs 10min, and the dichloromethane solution 10L of chloracetyl chloride (8.2kg, 73mol), drop is added dropwise
Finish, react at room temperature 1h, HPLC detects end of reaction, and 170L water is added, and a large amount of solids are precipitated, -10 DEG C of stirring 0.5h-1h, slightly sticky
Thick, centrifugation, a small amount of methylene chloride is washed, and product drying obtains 3 off-white powder 21kg of intermediate, yield 95.2%, purity 99.1%.
Embodiment 19
The synthesis of intermediate 3
By intermediate 2 (20kg, 52mol), methylene chloride 160L is added in 500L reaction kettle, is stirred at room temperature, and is added three
Ethamine (13.6kg, 134mol) stirs 10min, and the dichloromethane solution 10L of chloracetyl chloride (8.2kg, 73mol), drop is added dropwise
Finish, react at room temperature 1h, HPLC detects end of reaction, is directly evaporated methylene chloride, and acetone/water (2:1) 180L mashing is added, stirs
2h is mixed, is centrifuged, a small amount of methylene chloride is washed, and it is faint yellow to off-white powder 18.7kg, yield that product drying obtains intermediate 3
93.2%, purity 98.5%.
Embodiment 20
The synthesis of Tadalafei
By intermediate 3 (20kg, 47mol), 30% methylamine methanol solution (25kg, 235mol), methanol 140L is added to instead
Kettle is answered, heating stirring to flowing back, be down to room temperature, be centrifuged, a small amount of methanol is washed, product by insulation reaction 3h, HPLC detection end of reaction
Dry white solid 17.3kg, yield 95.3%, purity 99.3%.1H-NMR(300MHz,DMSO-d6): 2.93 (s, 3H),
3.00 (dd, 1H), 3.54 (dd, 1H), 3.95 (d, 1H), 4.17 (d, 1H), 4.40 (dd, 1H), 5.93 (s, 2H), 6.14 (s,
1H), 6.79 (d, 2H), 6.88 (s, 1H), 7.00 (m, 1H), 7.07 (m, 1H), 7.31 (d, 1H), 7.55 (d, 1H), 11.05
(s,1H)。
Embodiment 21
The synthesis of Tadalafei
The methanol 140L of intermediate 3 (20kg, 47mol), 30% methylamine methanol solution (25kg, 235mol), recycling are added
Enter to reaction kettle, heating stirring to flowing back, be down to room temperature, be centrifuged, a small amount of methanol by insulation reaction 3h, HPLC detection end of reaction
It washes, product drying obtains white solid 17.24kg, yield 95%, purity 99.2%.
Claims (6)
1. the preparation method of a kind of Tadalafei and its intermediate, includes the following steps:
Step 1: using D-trp as starting material, reacted under sulfuric acid catalysis with methanol esterification, generation D-trp methyl esters (in
Mesosome 1)；
Step 2: and piperonal through Pickett-Shi Penggele (P-S) reaction prepares (1R, 3R) -1- (1,3- benzo two dislikes cyclopentadienyl -5-
Base) -1 hydrogen of -2,3,4,9- tetrahydro-pyrido [3,4-b] indole -3-carboxylic acid methyl ester hydrochloride (intermediate 2)；
Step 3: and chloracetyl chloride amidation process prepares (1R, 3R) -1- (1,3- benzo two dislikes cyclopentadienyl -5- base) -2- (2- chloracetyl
Base) -1 hydrogen of -2,3,4,9- tetrahydro-pyrido [3,4-b] indole -3-carboxylic acid methyl ester's (intermediate 3)；
Step 4: and methylamine alcohol solution annulation obtains Tadalafei.
2. the preparation method of a kind of Tadalafei as described in claim 1 and its intermediate, it is characterised in that: step 1: in
In the preparation of mesosome 1, esterification is carried out as catalyst using sulfuric acid, the sulfuric acid and D-trp molar ratio are 1:0.03
~0.08, preferably 0.05.
3. the preparation method of a kind of Tadalafei as described in claim 1 and its intermediate, it is characterised in that: step 2: in
In the preparation of mesosome 2, using the mixed solvent of aprotic solvent and dilute hydrochloric acid as reaction reagent, hydrochloric acid is returned as catalyst
P-S reaction is carried out under the conditions of stream, and cis- Tetrahydrocarboline is made through CIAT process in dilute hydrochloric acid.
4. the preparation method of a kind of Tadalafei as claimed in claim 3 and its intermediate, it is characterised in that: step 2: in
In the preparation of mesosome 2, aprotic solvent be methylene chloride, ethyl acetate, n-hexane, in toluene first, wherein preferred toluene, first
Benzene can take water out of, carry out reaction to product direction；Toluene dosage is 1~10 times of 1 mass of intermediate, wherein it is preferred that 6
It measures again；Dilute hydrochloric acid concentration is 1mol/L~6mol/L, wherein it is preferred that 3mol/L, dosage is 1~2 times of 1 molal quantity of intermediate, excellent
Select 1.05 times.
5. the preparation method of a kind of Tadalafei as described in claim 1 and its intermediate, it is characterised in that: step 3: in
In the preparation of mesosome 3, using the post-processing approach of the direct crystallization of washing cooling, water consumption is the 0.5~3 of methylene chloride volume
Times, preferably 1 times；Treatment temperature is -10~10 DEG C, preferably -5 DEG C.
6. the preparation method of a kind of Tadalafei as described in claim 1 and its intermediate, it is characterised in that: step 4: at him
In the preparation of Da Lafei, using methanol as reaction reagent, reacted using the methanol solution of 30% methylamine, reaction solution can return
Receipts are applied.
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