CN101462987A - Novel unsymmetrical preparation of tamsulosin hydrochloride - Google Patents
Novel unsymmetrical preparation of tamsulosin hydrochloride Download PDFInfo
- Publication number
- CN101462987A CN101462987A CNA2009100956419A CN200910095641A CN101462987A CN 101462987 A CN101462987 A CN 101462987A CN A2009100956419 A CNA2009100956419 A CN A2009100956419A CN 200910095641 A CN200910095641 A CN 200910095641A CN 101462987 A CN101462987 A CN 101462987A
- Authority
- CN
- China
- Prior art keywords
- ethamine
- methoxybenzenesulphoismide
- ferrocenyl
- group
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- ZZIZZTHXZRDOFM-UHFFFAOYSA-N 2-(2-ethoxyphenoxy)ethyl-[1-(4-methoxy-3-sulfamoylphenyl)propan-2-yl]azanium;chloride Chemical compound Cl.CCOC1=CC=CC=C1OCCNC(C)CC1=CC=C(OC)C(S(N)(=O)=O)=C1 ZZIZZTHXZRDOFM-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 229960003198 tamsulosin hydrochloride Drugs 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 31
- -1 amide compound Chemical class 0.000 claims abstract description 30
- 239000002904 solvent Substances 0.000 claims abstract description 24
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 18
- 150000002466 imines Chemical class 0.000 claims abstract description 17
- 238000006722 reduction reaction Methods 0.000 claims abstract description 11
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 8
- 239000003513 alkali Substances 0.000 claims abstract description 7
- 238000006482 condensation reaction Methods 0.000 claims abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 63
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 56
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 22
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 20
- 238000006243 chemical reaction Methods 0.000 claims description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 19
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 claims description 17
- 239000002994 raw material Substances 0.000 claims description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 150000008065 acid anhydrides Chemical class 0.000 claims description 9
- DLRJIFUOBPOJNS-UHFFFAOYSA-N phenetole Chemical compound CCOC1=CC=CC=C1 DLRJIFUOBPOJNS-UHFFFAOYSA-N 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 6
- 230000002829 reductive effect Effects 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 claims description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 16
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- QZYDOKBVZJLQCK-UHFFFAOYSA-N 1,2-diethoxybenzene Chemical compound CCOC1=CC=CC=C1OCC QZYDOKBVZJLQCK-UHFFFAOYSA-N 0.000 abstract 1
- WFWKNGZODAOLEO-UHFFFAOYSA-N 1-(4-Methoxyphenyl)-2-propanone Chemical compound COC1=CC=C(CC(C)=O)C=C1 WFWKNGZODAOLEO-UHFFFAOYSA-N 0.000 abstract 1
- 150000008064 anhydrides Chemical class 0.000 abstract 1
- 229940124530 sulfonamide Drugs 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- 239000012141 concentrate Substances 0.000 description 15
- 239000012043 crude product Substances 0.000 description 15
- 238000000746 purification Methods 0.000 description 13
- 239000011734 sodium Substances 0.000 description 13
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- 238000004458 analytical method Methods 0.000 description 12
- 238000001035 drying Methods 0.000 description 12
- 238000003810 ethyl acetate extraction Methods 0.000 description 12
- 238000010898 silica gel chromatography Methods 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000001816 cooling Methods 0.000 description 9
- 239000003480 eluent Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 244000124209 Crocus sativus Species 0.000 description 6
- DRHKJLXJIQTDTD-OAHLLOKOSA-N Tamsulosine Chemical compound CCOC1=CC=CC=C1OCCN[C@H](C)CC1=CC=C(OC)C(S(N)(=O)=O)=C1 DRHKJLXJIQTDTD-OAHLLOKOSA-N 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 229960002613 tamsulosin Drugs 0.000 description 6
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 235000011114 ammonium hydroxide Nutrition 0.000 description 4
- 150000002168 ethanoic acid esters Chemical class 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- RQEUFEKYXDPUSK-SSDOTTSWSA-N (1R)-1-phenylethanamine Chemical compound C[C@@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-SSDOTTSWSA-N 0.000 description 2
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- GOFLNFPIFZZLIP-UHFFFAOYSA-N ethanol;2,2,2-trifluoroacetic acid Chemical compound CCO.OC(=O)C(F)(F)F GOFLNFPIFZZLIP-UHFFFAOYSA-N 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000004064 recycling Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000013022 venting Methods 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 208000001089 Multiple system atrophy Diseases 0.000 description 1
- 206010031127 Orthostatic hypotension Diseases 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 206010051482 Prostatomegaly Diseases 0.000 description 1
- 229910004298 SiO 2 Inorganic materials 0.000 description 1
- 206010043269 Tension headache Diseases 0.000 description 1
- 238000004176 ammonification Methods 0.000 description 1
- 150000003934 aromatic aldehydes Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- JXLHNMVSKXFWAO-UHFFFAOYSA-N azane;7-fluoro-2,1,3-benzoxadiazole-4-sulfonic acid Chemical compound N.OS(=O)(=O)C1=CC=C(F)C2=NON=C12 JXLHNMVSKXFWAO-UHFFFAOYSA-N 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- CBJYXYXOISWSDQ-UHFFFAOYSA-M cyclopenta-1,3-diene;1-cyclopenta-2,4-dien-1-ylideneethanolate;iron(2+) Chemical compound [Fe+2].C=1C=C[CH-]C=1.CC([O-])=C1C=CC=C1 CBJYXYXOISWSDQ-UHFFFAOYSA-M 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 206010013990 dysuria Diseases 0.000 description 1
- DRHKJLXJIQTDTD-HNNXBMFYSA-N ent-tamsulosin Chemical compound CCOC1=CC=CC=C1OCCN[C@@H](C)CC1=CC=C(OC)C(S(N)(=O)=O)=C1 DRHKJLXJIQTDTD-HNNXBMFYSA-N 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229910052500 inorganic mineral Chemical group 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 239000011707 mineral Chemical group 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000000955 prescription drug Substances 0.000 description 1
- 150000003147 proline derivatives Chemical class 0.000 description 1
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
Images
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a method for preparing tamsulosin hydrochloride asymmetrically. (R)-ferrocenyl ethylamine and 5-acetonyl-2-methoxyl benzene sulfonamide are dissolved in solvent for condensation reaction to obtain imine compound. (R)-5-(2-(N-ferrocenyl ethylamine) propyl)-2- methoxyl benzene sulfonamide is obtained by reduction reaction of the imine compound. The (R)-5-(2-(N-ferrocenyl ethylamine) propyl)-2- methoxyl benzene sulfonamide reacts with o-2-bromine ethoxyl phenetole under the action of alkali to form (R)-5-((2-[N-(2-ethoxyl-phenoxyl) ethyl)-N-ferrocenyl ethylamine) propyl)-2-methoxyl benzene sulfonamide after treatment. The (R)-5-((2-(N-(2-ethoxyl-phenoxyl) ethyl)-N-ferrocenyl ethylamine)propyl)-2-methoxyl benzene sulfonamide generates chiral amide compound and ferrocenyl ethanol carboxylic ester under the action of anhydride, and the chiral amide compound generates the tamsulosin hydrochloride after post treatment. The preparation method has simple operation and good yield and purity, is feasible and environmental-friendly and has the prospect of industrialized production.
Description
Technical field
The present invention relates to opticity medicine synthetic field, particularly the unilateral system Preparation Method of tamsulosin hydrochloride.
Background technology
1, chemical resolution method: this method comprises the Chiral Amine (structural formula is seen formula II) with racemization and the tamsulosin of compound M (structural formula is seen formula III) synthesising racemation, uses chiral acid then and carries out chemistry and split, and obtains tamsulosin hydrochloride at last.Chiral acid commonly used comprises camphorsulfonic acid, tartrate etc., and the shortcoming of this method is: waste 50% (S)-tamsulosin, and split process is because through recrystallization repeatedly, yield is lower, has only 30%, has both wasted raw material, and brings bigger environmental pollution to environment.
2, be the synthetic method of starting raw material with Chiral Amine (structural formula is seen formula II) with compound M (structural formula is seen formula III): by different technology synthetic hydrochloric acid tamsulosins.As: Gizur; the patent of Tibor application: WO 2004022532; being prepared as of the tamsulosin that this patent relates to: Chiral Amine obtains imines with different aromatic aldehyde reactions; imines through reduction again with the halogenide of compound M (structural formula is seen formula III), sulphonate reaction after, go the aryl protecting group can obtain tamsulosin hydrochloride.The shortcoming of this method is: chiral amine intermediates needs chemistry to split, and split process is owing to waste raw material through recrystallization, and operation is inconvenient, is unfavorable for the requirement of industrialization.
3, asymmetric synthesis method.As: the patent of Yamanouchi application: EP 0257787, this patent is a chiral raw material with (the R)-phenyl-ethyl amine of chirality, after finishing chiral induction, method by catalyst decomposes (R)-phenyl-ethyl amine obtains Chiral Amine (structural formula is seen formula II), last synthetic hydrochloric acid tamsulosin, this technology is the most important method of synthetic hydrochloric acid tamsulosin at present, the key of this method obtains Chiral Amine (structural formula is seen formula II) by using noble metal catalyst hydrogenolysis chirality (R)-phenyl-ethyl amine, the shortcoming of this method is: not only can consume a large amount of chiral raw material, increase production cost, and contaminate environment.The patent of Narco.Pharma.Limited application: WO093227, this patent is a catalyzer with the sodium borohydride complex compound of non-natural proline derivative, imines is carried out catalytic reduction, it is catalyzer that this method adopts expensive natural proline(Pro), obtain tamsulosin, but its optical purity has only 39%, does not reach the requirement of industrialization far away.
Summary of the invention
The technical problem to be solved in the present invention provides a kind of highly selective, high yield, and environmental friendliness is easy to the unilateral system Preparation Method of the tamsulosin hydrochloride of industrialization.
For solving this technical problem, the technical solution used in the present invention is as follows:
The unilateral system Preparation Method of tamsulosin hydrochloride is characterized in that: with (R)-ferrocenyl ethamine and 5-acetonyl-2-methoxybenzenesulphoismide is raw material, synthetic through following steps successively:
(1) condensation reaction: under nitrogen protection, (R)-ferrocenyl ethamine and 5-acetonyl-2-methoxybenzenesulphoismide are dissolved in solvent S
1Or solvent S
2In carry out condensation reaction 3-6h, obtain group with imine moiety, (R)-mol ratio of ferrocenyl ethamine and 5-acetonyl-2-methoxybenzenesulphoismide is 1:1～2.5;
(2) reduction reaction: will obtain (R)-5-[2-(N-ferrocene ethamine) propyl group after the group with imine moiety reduction]-the 2-methoxybenzenesulphoismide; This compound has two chiral centres, and wherein the ratio of diastereomer is up to 95:5;
(3) alkylated reaction: (R)-5-[2-(N-ferrocene ethamine) propyl group]-the 2-methoxybenzenesulphoismide is dissolved in solvent S
2In, under the effect of alkali, react 10-40h down at 60-120 ℃ with adjacent 2-bromine oxethyl phenyl ethyl ether, obtain (R)-5-[[2-[N-(2-oxyethyl group-phenoxy group) ethyl through aftertreatment]-N ferrocene ethamine] propyl group]-the 2-methoxybenzenesulphoismide, (R)-5-[2-(N-ferrocene ethamine) propyl group]-mol ratio of 2-methoxybenzenesulphoismide and adjacent 2-bromine oxethyl phenyl ethyl ether is 1:1～3;
(4) remove reaction: under nitrogen protection, with (R)-5-[[2-[N-(2-oxyethyl group-phenoxy group) ethyl]-N ferrocene ethamine] propyl group]-the 2-methoxybenzenesulphoismide is dissolved in the acid anhydrides, in 50-100 ℃ of reaction 1.5-12h, obtain chiral amides compound and ferrocenyl alcohol carboxylate, (R)-5-[[2-[N-(2-oxyethyl group-phenoxy group) ethyl]-N ferrocene ethamine] propyl group]-mol ratio of 2-methoxybenzenesulphoismide and acid anhydrides is 1:10～50;
(5) hydrolysis reaction: the chiral amides compound is dissolved in S
1, add the hydrochloric acid of 6mol/L～12mol/L, carry out acidolysis reaction 5-12h in 50-100 ℃, the mol ratio of chiral amides compound and hydrochloric acid is: 1:30～60, pass through aftertreatment and obtain tamsulosin hydrochloride.
Also comprise step (6) aminating reaction further: the ferrocenyl alcohol carboxylate that step (4) obtains again with the strong aqua effect, mol ratio is 1:50～150, obtains initial chiral raw material: (R)-ferrocenyl ethamine.
Described solvent S
1Be alcohol.Described alcohol is C
1～C
10Monohydroxy-alcohol, C
2～C
8Dibasic alcohol or C
3～C
4Trivalent alcohol.Described C
1～C
10Monohydroxy-alcohol, as methyl alcohol, ethanol, propyl alcohol etc.; C
2～C
8Dibasic alcohol or C
3～C
4Trivalent alcohol, as ethylene glycol and glycerol etc.Wherein preferred solvent is methyl alcohol, ethanol, propyl alcohol etc.
Described solvent S
2Be ether or acetonitrile (CH
3CN), described ether is selected from a kind of in methyl tertiary butyl ether, butyl ether, tetrahydrofuran (THF) (THF), the dioxane.
The reductive agent that the described group with imine moiety reduction reaction of step (2) adopts comprises NaBH
4, LiBH
4, NaBH
3CN, wherein NaBH preferably
4Or NaBH
3CN.
Perhaps the described group with imine moiety reduction of step (2) is what to carry out under the effect of hydrogen and catalyzer, and this catalyzer comprises loading type and unsupported catalyzer, as Pd/C, Pd/SiO
2, Pd/BaSO
4, Pd/Al
2O
3, thunder Buddhist nun Ni etc., wherein preferably Pd/C or thunder Buddhist nun Ni.
The described alkali of step (3) is for containing C
3～C
5Tertiary amine and mineral alkali, as triethylamine, Tributylamine, dipropyl ethamine, K
2CO
3, KHCO
3And Na
2CO
3Deng, wherein preferred alkali is triethylamine, KHCO
3, dipropyl ethamine, K
2CO
3Deng
The described acid anhydrides of step (4) is C
3～C
5Carboxylic acid anhydride, as diacetyl oxide, trifluoroacetic anhydride, propionic anhydride, first and second acid anhydrides etc.Wherein preferably diacetyl oxide, trifluoroacetic anhydride etc.
Step (3) or (5) described aftertreatment are: steam behind the organic solvent extraction again and desolventize, the thick product apparent purity that obtains requires to purify, and purification can be adopted current techiques such as recrystallization and chromatogram.
Raw material: 5-acetonyl-2-methoxybenzenesulphoismide can directly be buied from the market, (R)-the preparation reference literature Tetrahedron of ferrocenyl ethamine, 1997,53,7219. by ferrocenyl methyl ketone through the reduction of chirality reductive agent, esterification, ammonification obtains.
The structural formula of described (R)-ferrocenyl ethamine is seen formula (IV), 5-acetonyl-2-methoxybenzenesulphoismide structural formula is seen formula V, the structural formula of group with imine moiety is seen formula (VI), (R)-5-[2-(N-ferrocene ethamine) propyl group]-structural formula of 2-methoxybenzenesulphoismide sees formula (VII), (R)-5-[[2-[N-(2-oxyethyl group-phenoxy group) ethyl]-N ferrocene ethamine] propyl group]-structural formula of 2-methoxybenzenesulphoismide sees formula (VIII), the structural formula of chiral amides compound is seen formula (IX), and the structural formula of ferrocenyl alcohol carboxylate is seen formula (X).
In preparation method of the present invention, made full use of the characteristic of chiral ferrocene compounds.(R)-ferrocenyl ethamine with chirality is chiral raw material, through one row prepared in reaction tamsulosin hydrochloride, its cis-selectivity is better, in entire reaction course, after (R)-ferrocenyl ethamine of chirality has been finished chiral induction, got back at last and synthesized precursor compound---the ferrocene alcohol carboxylate of chirality of (R)-ferrocenyl ethamine, this compound and ammoniacal liquor reaction can obtain (R)-ferrocenyl ethamine again, have finished recycling of (R)-ferrocenyl ethamine like this.Easy and simple to handle, advantages such as reaction conditions is gentle, cis-selectivity good, environmental friendliness, product yield height, purity is good, cost is low that this synthesis technique has.And realized recycling of chiral raw material, and reduced the consumption of chiral raw material, alleviated pollution to environment, reduced production cost, be an eco-friendly synthetic route, have better industrialized production.
Description of drawings
Fig. 1 is the process flow sheet of the unilateral system Preparation Method of tamsulosin hydrochloride of the present invention.
Embodiment
Further illustrate the present invention below in conjunction with specific embodiment, but the present invention is not limited to following examples.Referring to Fig. 1:
Embodiment 1
Under nitrogen protection; 5-acetonyl-2-methoxybenzenesulphoismide 3.95g (16.25mmol) is dissolved in the 150ml methyl alcohol; slowly drip again 1.49g (6.5mmol) (R)-the methanol mixed solution of ferrocenyl ethamine; stir after 6 hours; form group with imine moiety, directly pour in the reaction under high pressure axe, add Raney-Ni; heat 50 ℃, hydrogenation is 48 hours under the 2.2MP normal atmosphere.Behind the excessive hydrogen of careful venting, elimination Raney-Ni concentrates and removes methyl alcohol, and with the ethyl acetate dilution, add the 20ml aqueous solution and stirred 30 fens, with ethyl acetate extraction three times, anhydrous Na
2SO
4Drying concentrates and removes solvent, and crude product obtains 1.6g safran solid promptly through purification by silica gel column chromatography: (R)-and 5-[2-(N-ferrocene ethamine) propyl group]-the 2-methoxybenzenesulphoismide.Eluent is an ethyl acetate: methyl alcohol (volume ratio)=5:2.Productive rate: 53%, m.p.92-95 ℃,
(c=1.0, CH
3OH).
(R)-5-[2-(N-ferrocene ethamine) propyl group]-2-methoxybenzenesulphoismide nuclear magnetic spectrogram is:
1HNMR (400MHz, CDCl
3) δ: 0.97 (d, J=6.4Hz, 3H), 1.30 (d, J=6.4Hz, 3H), 2.57 (m, 1H), 2.73 (m, 1H), 2.99 (m, 1H), 3.61 (m, 1H), 3.97 (s, 3H), 4.06-4.14 (m, 9H), 7.39-7.36 (m, 1H), 7.75 (d, J=2.2Hz, 1H).
Ultimate analysis is: C
22H
28FeN
2O
3The theoretical value of S: C, 57.90; H, 6.18; N, 6.14; S, 7.03. measured value: C, 57.86; H, 6.16; N, 6.13.S; 7.02.
With 1g (2.2mmol) (R)-5-[2-(N-ferrocene ethamine) propyl group]-the 2-methoxybenzenesulphoismide, the adjacent 2-bromine oxethyl of 0.8g (6.6mol) phenyl ethyl ether, a spot of KHCO
3With catalytic amount NaI, be dissolved in the methyl tertbutyl ethereal solution of 25ml, heat 60 ℃, reflux and stirred 40 hours.Cooling adds 10ml water, uses ethyl acetate extraction three times, anhydrous Na
2SO
4Drying concentrates and removes the solvent crude product through purification by silica gel column chromatography, obtains 1.1g safran oily liquids promptly: (R)-and 5-[[2-[N-(2-oxyethyl group-phenoxy group) ethyl]-N ferrocene ethamine] propyl group]-the 2-methoxybenzenesulphoismide.Productive rate: 78.5%,
(c=0.9, CH
3OH).
(R)-5-[[2-[N-(2-oxyethyl group-phenoxy group) ethyl]-N ferrocene ethamine] propyl group]-2-methoxybenzenesulphoismide nuclear magnetic spectrogram is:
1H NMR (400MHz, CDCl
3) δ: 0.90 (d, J=6.0Hz, 3H), 1.24 (d, J=6.4Hz, 3H), 1.29 (t, J=6.6Hz3H), 2.47 (m, 1H), 2.69 (m, 1H), 2.91 (m, 1H), 3.28 (m, 2H), 3.55 (m, 2H), 3.75 (s, 3H), 3.80 (t, J=6.0Hz, 2H), 3.92 (m, 2H), and 4.01-4.11 (m, 9H), 6.73-6.81 (m, 5H), 7.20 (s, 1H), 7.74 (d, J=2.2Hz, 1H).
Ultimate analysis is: C
32H
40FeN
2O
5The theoretical value of S: C, 61.93; H, 6.50; N, 4.51; S, 5.17. measured value: C, 61.90; H, 6.49; N, 4.51; S, 5.18.
Under the nitrogen protection, with 0.6g (9.7mmol) (R)-5-[[2-[N-(2-oxyethyl group-phenoxy group) ethyl]-N ferrocene ethamine] propyl group]-the 2-methoxybenzenesulphoismide is dissolved in 10.3ml (97mmol) diacetyl oxide, heats 50 ℃, reacted 12 hours.Cooling adds 2MNaOH solution, uses ethyl acetate extraction three times, anhydrous Na
2SO
4Drying concentrates and removes solvent, and crude product obtains 0.26g chiral amides compound through purification by silica gel column chromatography, 0.15g ferrocenyl alcohol, acetic acid ester.Eluent is an ethyl acetate: sherwood oil (volume ratio)=1:1.Productive rate: 61.5%,
(c=1.0, CH
3OH)
0.23g (0.5mmol) chiral amides compound dissolution at 5ml ethanol, is added 2.5ml6mol/L HCl (15mmol), heat 50 ℃, reacted 12 hours.Cooling removes and to desolvate, and obtains crude product, through recrystallizing methanol to the 0.17g tamsulosin hydrochloride, productive rate: 83.3%, m.p.231-233 ℃,
(c=1.0, CH
3OH).
The tamsulosin hydrochloride nuclear magnetic spectrogram is:
1H NMR (400MHz, DMSO-d
6) δ: 1.16 (d, J=6.4Hz, 3H), 1.26 (d, J=7.0Hz, 3H), 2.67-2.73 (m, 1H), 3.31-3.35 (m, 3H), 3.55 (br, 1H), 3.89 (s, 1H), 4.02 (q, J=6.8Hz, 2H), 4.33 (t, J=4.8Hz, 2H), 6.09-7.02 (m, 3H), 7.07-7.08 (m, 3H), 7.18 (d, J=8.4Hz, 1H), 7.45-7.47 (m, 1H), 7.63 (d, J=2.0Hz, 1H).
Ultimate analysis is: the theoretical value of C18H24BrClN2O: C, 45.06; H, 5.04; N, 5.84; S, 7.21. measured value: C; 45.04H; 5.04, N; 5.83; S, 7.21.
0.1 (0.37mmol) gram ferrocenyl alcohol, acetic acid ester is dissolved in the 5ml methanol solution, adds 0.35ml (18.5mmol) ammoniacal liquor, stirring at room 48 hours.The concentrated methyl alcohol of removing adds ethyl acetate, 2mol/LHCl, organic layer is regulated pH with 2mol/L NaOH〉9, water layer ethyl acetate extraction three times merge organic phase, use the saturated common salt water washing, Na
2SO
4Drying concentrates and removes solvent, and crude product obtains 26mg yellow oily liquid promptly through purification by silica gel column chromatography: (R)-ferrocenyl ethamine, eluent is an ethyl acetate: methyl alcohol (volume ratio)=4: 1.Productive rate: 30.1%,
(c=1.0, C
2H
5OH)
(R)-ferrocenyl ethamine nuclear magnetic spectrogram is:
1H NMR (400MHz, CDCl
3) δ: 1.35 (d, 3H, J=6.5Hz), 1.74 (br, 2H), 3.80 (q, 1H, J=6.5Hz), 4.08-4.24 (m, 9H).
Ultimate analysis is: the theoretical value of C12H15FeN: C, 62.91; H, 6.60; N, 6.11 measured values: C, 62.89; H, 6.58; Fe, 24.38; N, 6.09.
Embodiment 2
Under nitrogen protection; 3.66g (15.0mmol) 5-acetonyl-2-methoxybenzenesulphoismide is dissolved among the exsiccant 150ml THF; then slowly drip again 2.12g (8.6mmol) (R)-the THF mixing solutions of ferrocenyl ethamine; reflux stirred after 4.5 hours; form group with imine moiety, add 640mg (34.4mmol) NaBH then
4, room temperature reaction 4h removes THF, uses ethyl acetate extraction three times, anhydrous Na
2SO
4Drying concentrates and removes solvent, and crude product obtains 1.76g safran solid promptly through purification by silica gel column chromatography: (R)-and 5-[2-(N-ferrocene ethamine) propyl group]-2-anisole sulphonyl, eluent is an ethyl acetate: methyl alcohol (volume ratio)=5:2.Productive rate: 45%, m.p.92.5-95 ℃.
(c=1.0, CH
3OH).
(R)-5-[2-(N-ferrocene ethamine) propyl group]-2-methoxybenzenesulphoismide nuclear magnetic spectrogram is:
1HNMR (400MHz, CDCl
3) δ: 0.97 (d, J=6.4Hz, 3H), 1.30 (d, J=6.4Hz, 3H), 2.57 (m, 1H), 2.73 (m, 1H), 2.99 (m, 1H), 3.61 (m, 1H), 3.97 (s, 3H), 4.06-4.14 (m, 9H), 7.39-7.36 (m, 1H), 7.75 (d, J=2.2Hz, 1H).
Ultimate analysis is: C
22H
28FeN
2O
3The theoretical value of S: C, 57.90; H, 6.18; N, 6.14; S, 7.03. measured value: C, 57.86; H, 6.16; N, 6.13.S; 7.02.
With 1.5g (3.3mmol) (R)-5-[2-(N-ferrocene ethamine) propyl group]-the 2-methoxybenzenesulphoismide, the adjacent 2-bromine oxethyl of 1.6g (4.95mol) phenyl ethyl ether, a spot of K
2CO
3With catalytic amount NaI, be dissolved in the CH of 30ml
3In the CN solution, heat 82 ℃, reflux and stirred 25 hours.Cooling adds 15ml water, uses ethyl acetate extraction three times, anhydrous Na
2SO
4Drying concentrates and removes solvent, and crude product obtains 2.0g safran oily liquids promptly through purification by silica gel column chromatography: (R)-and 5-[[2-[N-(2-oxyethyl group-phenoxy group) ethyl]-N ferrocene ethamine] propyl group]-the 2-methoxybenzenesulphoismide, productive rate: 73.5%,
(c=0.9, CH
3OH)
(R)-5-[[2-[N-(2-oxyethyl group-phenoxy group) ethyl]-N ferrocene ethamine] propyl group]-2-methoxybenzenesulphoismide nuclear magnetic spectrogram is:
1H NMR (400MHz, CDCl
3) δ: 0.90 (d, J=6.0Hz, 3H), 1.24 (d, J=6.4Hz, 3H), 1.29 (t, J=6.6Hz3H), 2.47 (m, 1H), 2.69 (m, 1H), 2.91 (m, 1H), 3.28 (m, 2H), 3.55 (m, 2H), 3.75 (s, 3H), 3.80 (t, J=6.0Hz, 2H), 3.92 (m, 2H), and 4.01-4.11 (m, 9H), 6.73-6.81 (m, 5H), 7.20 (s, 1H), 7.74 (d, J=2.2Hz, 1H).
Ultimate analysis is: C
32H
40FeN
2O
5The theoretical value of S: C, 61.93; H, 6.50; N, 4.51; S, 5.17. measured value: C, 61.90; H, 6.49; N, 4.51; S, 5.18.
Under the nitrogen protection, with 1.2g (19.4mmol) (R)-5-[[2-[N-(2-oxyethyl group-phenoxy group) ethyl]-N ferrocene ethamine] propyl group]-the 2-methoxybenzenesulphoismide is dissolved in 40ml (0.424mol) diacetyl oxide, heats 80 ℃, reacted 6 hours.Cooling adds 2M NaOH solution, uses ethyl acetate extraction three times, anhydrous Na
2SO
4Drying concentrates and removes solvent, and crude product obtains 0.51g chiral amides compound through purification by silica gel column chromatography, 0.28g ferrocenyl alcohol, acetic acid ester.Eluent is an ethyl acetate: sherwood oil (volume ratio)=1:1.Productive rate: 58.4%,
(c=1.0, CH
3OH)
0.45g (1mmol) chiral amides compound dissolution at 10ml ethanol, is added 5ml8mol/LHCl (40mmol), heat 70 ℃, reacted 9 hours.Cooling removes and to desolvate, and obtains crude product, through recrystallizing methanol to the 0.35g tamsulosin hydrochloride, productive rate: 85.7%, m.p.231-233 ℃,
(c=1.0, CH
3OH).
The tamsulosin hydrochloride nuclear magnetic spectrogram is:
1H NMR (400MHz, DMSO-d
6) δ: 1.16 (d, J=6.4Hz, 3H), 1.26 (d, J=7.0Hz, 3H), 2.67-2.73 (m, 1H), 3.31-3.35 (m, 3H), 3.55 (br, 1H), 3.89 (s, 1H), 4.02 (q, J=6.8Hz, 2H), 4.33 (t, J=4.8Hz, 2H), 6.09-7.02 (m, 3H), 7.07-7.08 (m, 3H), 7.18 (d, J=8.4Hz, 1H), 7.45-7.47 (m, 1H), 7.63 (d, J=2.0Hz, 1H).
Ultimate analysis is: the theoretical value of C18H24BrClN2O: C, 45.06; H, 5.04; N, 5.84; S, 7.21. measured value: C; 45.04H; 5.04, N; 5.83; S, 7.21.
0.2 (0.73mmol) gram ferrocenyl alcohol, acetic acid ester is dissolved in the 8ml methanol solution, adds 1.4ml (73mmol) ammoniacal liquor, stirring at room 48 hours.The concentrated methyl alcohol of removing adds ethyl acetate, 2mol/L HCl, organic layer is regulated pH with 2mol/L NaOH〉9, water layer ethyl acetate extraction three times merge organic phase, use the saturated common salt water washing, Na
2SO
4Drying concentrates and removes solvent, and crude product obtains 64.9mg yellow oily liquid promptly through purification by silica gel column chromatography: (R)-ferrocenyl ethamine, eluent is an ethyl acetate: methyl alcohol (volume ratio)=4: 1.Productive rate: 38.8%,
(c=1.0, C
2H
5OH)
(R)-ferrocenyl ethamine nuclear magnetic spectrogram is:
1H NMR (400MHz, CDCl
3) δ: 1.35 (d, 3H, J=6.5Hz), 1.74 (br, 2H), 3.80 (q, 1H, J=6.5Hz), 4.08-4.24 (m, 9H).
Ultimate analysis is: the theoretical value of C12H15FeN: C, 62.91; H, 6.60; N, 6.11 measured values: C, 62.89; H, 6.58; Fe, 24.38; N, 6.09.
Embodiment 3
Under nitrogen protection; 5-acetonyl-2-methoxybenzenesulphoismide 2.4g (10.0mmol) is dissolved among the exsiccant 100ml THF; slowly drip again 2.3g (10.0mmol) (R)-the THF mixing solutions of ferrocenyl ethamine; stir after 3 hours; form group with imine moiety, directly pour in the reaction under high pressure axe, add Pd/C; heat 50 ℃, hydrogenation is 30 hours under the 2.2MP normal atmosphere.Behind the excessive hydrogen of careful venting, elimination Pd/C concentrates and removes THF, and with the ethyl acetate dilution, add the 10ml aqueous solution and stirred 30 fens, with ethyl acetate extraction three times, anhydrous Na
2SO
4Drying concentrates and removes solvent, and crude product obtains 2.2g safran solid promptly through purification by silica gel column chromatography: (R)-and 5-[2-(N-ferrocene ethamine) propyl group]-the 2-methoxybenzenesulphoismide.Eluent is an ethyl acetate: methyl alcohol (volume ratio)=5:2.Productive rate: 48.2%, m.p.92.5-95 ℃.
(c=1.0, CH
3OH).
(R)-5-[2-(N-ferrocene ethamine) propyl group]-2-methoxybenzenesulphoismide nuclear magnetic spectrogram is:
1HNMR (400MHz, CDCl
3) δ: 0.97 (d, J=6.4Hz, 3H), 1.30 (d, J=6.4Hz, 3H), 2.57 (m, 1H), 2.73 (m, 1H), 2.99 (m, 1H), 3.61 (m, 1H), 3.97 (s, 3H), 4.06-4.14 (m, 9H), 7.39-7.36 (m, 1H), 7.75 (d, J=2.2Hz, 1H).
Ultimate analysis is: C
22H
28FeN
2O
3The theoretical value of S: C, 57.90; H, 6.18; N, 6.14; S, 7.03. measured value: C, 57.86; H, 6.16; N, 6.13.S; 7.02.
With 1g (2.2mmol) (R)-5-[2-(N-ferrocene ethamine) propyl group]-the 2-methoxybenzenesulphoismide, 0.54g (2.2mol) adjacent 2-bromine oxethyl phenyl ethyl ether, 1ml triethylamine and catalytic amount NaI are dissolved in the solution of 20ml dioxane, heat 120 ℃ and stir 10 hours.Cooling adds 10ml water, uses ethyl acetate extraction three times, anhydrous Na
2SO
4Drying concentrates and removes solvent, and crude product obtains 1.05g safran oily liquids promptly through purification by silica gel column chromatography: (R)-and 5-[[2-[N-(2-oxyethyl group-phenoxy group) ethyl]-N ferrocene ethamine] propyl group]-the 2-methoxybenzenesulphoismide, productive rate: 76.9%,
(c=0.9, CH
3OH).
(R)-5-[[2-[N-(2-oxyethyl group-phenoxy group) ethyl]-N ferrocene ethamine] propyl group]-2-methoxybenzenesulphoismide nuclear magnetic spectrogram is:
1H NMR (400MHz, CDCl
3) δ: 0.90 (d, J=6.0Hz, 3H), 1.24 (d, J=6.4Hz, 3H), 1.29 (t, J=6.6Hz3H), 2.47 (m, 1H), 2.69 (m, 1H), 2.91 (m, 1H), 3.28 (m, 2H), 3.55 (m, 2H), 3.75 (s, 3H), 3.80 (t, J=6.0Hz, 2H), 3.92 (m, 2H), and 4.01-4.11 (m, 9H), 6.73-6.81 (m, 5H), 7.20 (s, 1H), 7.74 (d, J=2.2Hz, 1H).
Ultimate analysis is: C
32H
40FeN
2O
5The theoretical value of S: C, 61.93; H, 6.50; N, 4.51; S, 5.17. measured value: C, 61.90; H, 6.49; N, 4.51; S, 5.18.
Under the nitrogen protection, with 0.6g (9.7mmol) (R)-5-[[2-[N-(2-oxyethyl group-phenoxy group) ethyl]-N ferrocene ethamine] propyl group]-the 2-methoxybenzenesulphoismide is dissolved in 62.1ml (0.485mol) trifluoroacetic anhydride, heats 100 ℃, reacted 1.5 hours.Cooling adds 2mol/LNaOH solution, uses ethyl acetate extraction three times, anhydrous Na
2SO
4Drying concentrates and removes solvent, and crude product obtains 0.27g chiral amides compound through purification by silica gel column chromatography, 0.16g ferrocenyl ethanol trifluoro-acetate.Eluent is an ethyl acetate: sherwood oil (volume ratio)=1:1.Productive rate: 55.2%,
(c=1.0, CH
3OH)
0.23g (0.5mmol) chiral amides compound dissolution at 5ml ethanol, is added 2.5ml12mol/LHCl (30mmol), heat 100 ℃, reacted 5 hours.Cooling removes and to desolvate, and obtains crude product, through recrystallizing methanol to the 0.19g tamsulosin hydrochloride.Productive rate: 93.1%, m.p.231-233 ℃,
(c=1.0, CH
3OH).
The tamsulosin hydrochloride nuclear magnetic spectrogram is:
1H NMR (400MHz, DMSO-d
6) δ: 1.16 (d, J=6.4Hz, 3H), 1.26 (d, J=7.0Hz, 3H), 2.67-2.73 (m, 1H), 3.31-3.35 (m, 3H), 3.55 (br, 1H), 3.89 (s, 1H), 4.02 (q, J=6.8Hz, 2H), 4.33 (t, J=4.8Hz, 2H), 6.09-7.02 (m, 3H), 7.07-7.08 (m, 3H), 7.18 (d, J=8.4Hz, 1H), 7.45-7.47 (m, 1H), 7.63 (d, J=2.0Hz, 1H).
Ultimate analysis is: the theoretical value of C18H24BrClN2O: C, 45.06; H, 5.04; N, 5.84; S, 7.21. measured value: C; 45.04H; 5.04, N; 5.83; S, 7.21.
0.1 (0.306mmol) gram ferrocenyl ethanol trifluoro-acetate is dissolved in the 5ml methanol solution, adds 0.9ml (45.9mmol) ammoniacal liquor, stirring at room 48 hours.Concentrate and remove methyl alcohol, add ethyl acetate, 2mol/LHCl, organic layer is regulated pH with 2mol/LNaOH〉9, water layer ethyl acetate extraction three times merge organic phase, use the saturated common salt water washing, Na
2SO
4Drying concentrates and removes solvent, and crude product obtains 27.3mg yellow oily liquid promptly through purification by silica gel column chromatography: (R)-and ferrocenyl ethamine.Eluent is an ethyl acetate: methyl alcohol (volume ratio)=4: 1.Productive rate: 38.9%,
(c=1.0, C
2H
5OH)
(R)-ferrocenyl ethamine nuclear magnetic spectrogram is:
1H NMR (400MHz, CDCl
3) δ: 1.35 (d, 3H, J=6.5Hz), 1.74 (br, 2H), 3.80 (q, 1H, J=6.5Hz), 4.08-4.24 (m, 9H).
Ultimate analysis is: the theoretical value of C12H15FeN: C, 62.91; H, 6.60; N, 6.11 measured values: C, 62.89; H, 6.58; Fe, 24.38; N, 6.09.
Claims (9)
1, the unilateral system Preparation Method of tamsulosin hydrochloride is characterized in that: with (R)-ferrocenyl ethamine and 5-acetonyl-2-methoxybenzenesulphoismide is raw material, synthetic through following steps successively:
(1) condensation reaction: under nitrogen protection, (R)-ferrocenyl ethamine and 5-acetonyl-2-methoxybenzenesulphoismide are dissolved in solvent S
1Or solvent S
2In carry out condensation reaction 3-6h, obtain group with imine moiety, (R)-mol ratio of ferrocenyl ethamine and 5-acetonyl-2-methoxybenzenesulphoismide is 1:1～2.5;
(2) reduction reaction: will obtain (R)-5-[2-(N-ferrocene ethamine) propyl group after the group with imine moiety reduction]-the 2-methoxybenzenesulphoismide;
(3) alkylated reaction: (R)-5-[2-(N-ferrocene ethamine) propyl group]-the 2-methoxybenzenesulphoismide is dissolved in solvent S
2In, under the effect of alkali, react 10-40h down at 60-120 ℃ with adjacent 2-bromine oxethyl phenyl ethyl ether, obtain (R)-5-[[2-[N-(2-oxyethyl group-phenoxy group) ethyl through aftertreatment]-N ferrocene ethamine] propyl group]-the 2-methoxybenzenesulphoismide, (R)-5-[2-(N-ferrocene ethamine) propyl group]-mol ratio of 2-methoxybenzenesulphoismide and adjacent 2-bromine oxethyl phenyl ethyl ether is 1:1～3;
(4) remove reaction: under nitrogen protection, with (R)-5-[[2-[N-(2-oxyethyl group-phenoxy group) ethyl]-N ferrocene ethamine] propyl group]-the 2-methoxybenzenesulphoismide is dissolved in the acid anhydrides, in 50-100 ℃ of reaction 1.5-12h, obtain chiral amides compound and ferrocenyl alcohol carboxylate, (R)-5-[[2-[N-(2-oxyethyl group-phenoxy group) ethyl]-N ferrocene ethamine] propyl group]-mol ratio of 2-methoxybenzenesulphoismide and acid anhydrides is 1:10～50;
(5) hydrolysis reaction: the chiral amides compound is dissolved in S
1, add the hydrochloric acid of 6mol/L～12mol/L, carry out acidolysis reaction 5-12h in 50-100 ℃, the mol ratio of chiral amides compound and hydrochloric acid is: 1:30～60, pass through aftertreatment and obtain tamsulosin hydrochloride.
2, preparation method according to claim 1 is characterized in that also comprising the steps:
(6) aminating reaction: the ferrocenyl alcohol carboxylate that step (4) obtains reacts with strong aqua again, and mol ratio is 1:50～150, obtains initial chiral raw material: (R)-and ferrocenyl ethamine.
3, preparation method according to claim 1 and 2 is characterized in that: described solvent S
1Be alcohol.
4, preparation method according to claim 3 is characterized in that described alcohol is methyl alcohol or ethanol or propyl alcohol.
5, preparation method according to claim 1 and 2 is characterized in that: described solvent S
2Be selected from a kind of in methyl tertiary butyl ether, butyl ether, tetrahydrofuran (THF), dioxane, the acetonitrile.
6, preparation method according to claim 1 and 2 is characterized in that: the reductive agent that the described group with imine moiety reduction reaction of step (2) adopts is NaBH
4Or NaBH
3CN.
7, preparation method according to claim 1 and 2 is characterized in that: the described group with imine moiety reduction of step (2) is what to carry out under the effect of hydrogen and catalyzer, and this catalyzer is Pd/C or thunder Buddhist nun Ni.
8, preparation method according to claim 1 and 2 is characterized in that the described alkali of step (3) is selected from triethylamine, KHCO
3, dipropyl ethamine, K
2CO
3In a kind of.
9, preparation method according to claim 1 and 2 is characterized in that: the described acid anhydrides of step (4) is C
3～C
5Carboxylic acid anhydride.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2009100956419A CN101462987A (en) | 2009-01-15 | 2009-01-15 | Novel unsymmetrical preparation of tamsulosin hydrochloride |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2009100956419A CN101462987A (en) | 2009-01-15 | 2009-01-15 | Novel unsymmetrical preparation of tamsulosin hydrochloride |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101462987A true CN101462987A (en) | 2009-06-24 |
Family
ID=40803807
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2009100956419A Pending CN101462987A (en) | 2009-01-15 | 2009-01-15 | Novel unsymmetrical preparation of tamsulosin hydrochloride |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101462987A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102898336A (en) * | 2012-10-16 | 2013-01-30 | 北京悦康科创医药科技有限公司 | Preparation method of tamsulosin hydrochloride |
| CN104926699A (en) * | 2015-07-02 | 2015-09-23 | 成都丽凯手性技术有限公司 | Preparation method of tamsulosin hydrochloride with high optical purity |
| CN111662285A (en) * | 2019-03-07 | 2020-09-15 | 江苏豪森药业集团有限公司 | Process for the preparation of 2-oxo-1, 3-oxazepine derivatives |
-
2009
- 2009-01-15 CN CNA2009100956419A patent/CN101462987A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102898336A (en) * | 2012-10-16 | 2013-01-30 | 北京悦康科创医药科技有限公司 | Preparation method of tamsulosin hydrochloride |
| CN104926699A (en) * | 2015-07-02 | 2015-09-23 | 成都丽凯手性技术有限公司 | Preparation method of tamsulosin hydrochloride with high optical purity |
| CN111662285A (en) * | 2019-03-07 | 2020-09-15 | 江苏豪森药业集团有限公司 | Process for the preparation of 2-oxo-1, 3-oxazepine derivatives |
| CN111662285B (en) * | 2019-03-07 | 2023-05-16 | 江苏豪森药业集团有限公司 | Process for preparing 2-oxo-1, 3-oxazepine derivatives |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2018309043B2 (en) | Processes for preparing pyrrolidine compounds | |
| JP5923105B2 (en) | Chiral spiro-pyridylamidophosphine ligand compound, synthesis method thereof and use thereof | |
| CN101993406B (en) | Indoline compound with optical activity and preparation method thereof | |
| CN104447445A (en) | Preparation method for synthesizing apremilast intermediate | |
| CN111592467B (en) | Nilaparib intermediate, preparation method and application thereof, and synthetic method of nilapab | |
| CN115160158B (en) | Preparation method of chiral tertiary leucinol | |
| JP4718452B2 (en) | Optically active transition metal-diamine complex and method for producing optically active alcohols using the same | |
| CN102532196A (en) | Phosphine ligand and enantiomer or racemic body thereof and preparation methods thereof | |
| CN103664677A (en) | Asymmetric synthesis method of (R,R)-formoterol tartrate | |
| WO2016055015A1 (en) | Method for preparing sitagliptin intermediate via asymmetrical reduction method | |
| JP4194865B2 (en) | Process for producing enantiomerically enriched arylaminopropanol | |
| CN101462987A (en) | Novel unsymmetrical preparation of tamsulosin hydrochloride | |
| CN104961640A (en) | Preparation method of optically pure 3-amino-1-butanol | |
| CN114349648A (en) | Preparation method of chiral amine compound | |
| CN110885292A (en) | β -amino alcohol compound synthesis method | |
| CN101747252A (en) | Synthetic method of R-structured Rolipram | |
| CN112174837B (en) | Method for synthesizing (R) -4-methoxy-alpha-methylphenethylamine | |
| CN101723879B (en) | Method for synthesizing (R)-3-ethyl piperidine hydrochloride | |
| CN109705014B (en) | Novel chiral amine oxide ligand and preparation method thereof | |
| CN100554252C (en) | A kind of preparation method of Sumatriptan Succinate | |
| CN115872887B (en) | Preparation method of agomelatine | |
| CN107827916A (en) | A kind of (R)（The methyl of 1 amino 3）The synthetic method of the boric acid pinane diol ester of butyl 1 | |
| CN112441934B (en) | Halogenated oxaallylamine compound and preparation method and application thereof | |
| CN106588778A (en) | Preparation process of dexmedetomidine hydrochloride for ICU (intensive care unit) sedation and analgesia | |
| JP4529419B2 (en) | Optically active fluorine-containing compounds and methods for producing them |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Open date: 20090624 |