CN101037402A - Preparation method of R-5-(2-Aminopropyl)-2-methoxybenzenesulfonyl with high optically active purity - Google Patents
Preparation method of R-5-(2-Aminopropyl)-2-methoxybenzenesulfonyl with high optically active purity Download PDFInfo
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- CN101037402A CN101037402A CN 200710068095 CN200710068095A CN101037402A CN 101037402 A CN101037402 A CN 101037402A CN 200710068095 CN200710068095 CN 200710068095 CN 200710068095 A CN200710068095 A CN 200710068095A CN 101037402 A CN101037402 A CN 101037402A
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- methoxybenzenesulphoismide
- aminopropyl
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- hydrochloride
- benzsulfamide
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- 238000002360 preparation method Methods 0.000 title claims description 17
- -1 R-5-(2-Aminopropyl)-2-methoxybenzenesulfonyl Chemical group 0.000 title description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000003960 organic solvent Substances 0.000 claims abstract description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 8
- 239000001257 hydrogen Substances 0.000 claims abstract description 8
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 7
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000003513 alkali Substances 0.000 claims abstract description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 23
- 238000006243 chemical reaction Methods 0.000 claims description 17
- 238000000711 polarimetry Methods 0.000 claims description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 8
- 239000000047 product Substances 0.000 claims description 8
- RQEUFEKYXDPUSK-UHFFFAOYSA-N 1-phenylethylamine Chemical compound CC(N)C1=CC=CC=C1 RQEUFEKYXDPUSK-UHFFFAOYSA-N 0.000 claims description 6
- 238000001953 recrystallisation Methods 0.000 claims description 5
- 239000012043 crude product Substances 0.000 claims description 4
- 238000004176 ammonification Methods 0.000 claims description 3
- 230000000694 effects Effects 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- VKEQBMCRQDSRET-UHFFFAOYSA-N Methylone Chemical compound CNC(C)C(=O)C1=CC=C2OCOC2=C1 VKEQBMCRQDSRET-UHFFFAOYSA-N 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 230000008719 thickening Effects 0.000 claims description 2
- 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 abstract description 11
- 229960002613 tamsulosin Drugs 0.000 abstract description 9
- 238000000034 method Methods 0.000 abstract description 6
- 230000003287 optical effect Effects 0.000 abstract description 6
- 239000003814 drug Substances 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract 1
- 229940117803 phenethylamine Drugs 0.000 abstract 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract 1
- 239000002994 raw material Substances 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 6
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 1
- 125000001539 acetonyl group Chemical group [H]C([H])([H])C(=O)C([H])([H])* 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000005516 engineering process Methods 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
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 235000021050 feed intake Nutrition 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229960003198 tamsulosin hydrochloride Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
A producing method for a R-5-(2-aminopropyl)-2-methoxybenzsulfamide is provided, which is including: catalyzed by Pd/C, doing an ammoniation hydrogenation reaction in the organic solvent making use of the chiral phenethylamine and 2-methoxy-5-(2-oxopropyl)benzsulfamide to get a product and acidifying to a hydrochlorate; removing the eshyl phenyl in a condition of hydrogen to get a R-5-(2-aminopropyl)-2-methoxybenzsulfamide hydrochlorate; further reacting with alkali to produce R-5-(2-aminopropyl)-2-methoxybenzsulfamide. The producing method is simple with a good yield and can obtain the product with a high optical purity and can be an industrial production method as the intermediate of the tamsulosin medicine.
Description
Technical field
The invention belongs to the field of chemical synthesis, relate to the preparation method of the high polarimetry purity R-5-of raw material (2-the aminopropyl)-2-methoxybenzenesulphoismide of a kind of tamsulosin (tamsulosin) medicine.
Background technology
Formula (1) R-5-(2-aminopropyl)-2-methoxybenzenesulphoismide is a kind of raw material of tamsulosin medicine.
The compound 5-[2-[[2-of formula (2) (2-ethoxy phenoxy) ethyl] amino] propyl group]-the 2-methoxybenzenesulphoismide,
It is the commercialization pharmaceutically active substance that is applicable to treatment cardiac insufficiency and benign prostatic hyperplasia.It is disclosed among EP34432 and the US 4731478, this molecule is a tamsulosin, (following formula marks with asterisk in (2) to have an asymmetric carbon, there are two kinds of enantiomorph: R or S enantiomorph, commercial product is the hydrochloride of R (-) enantiomorph of tamsulosin, and it is left-handed or (R) (-) tamsulosin hydrochloride.
EP34432 and US 4731478 disclose two kinds of general methods that tamsulosin can be provided.
US 4731478 generates the reaction of optically pure 5-((2-amino-2-methyl) ethyl)-2-methoxybenzenesulphoismide and 2-(O-ethoxyl oxygen base) monobromoethane corresponding (R) or (S) tamsulosin.Provide currently known methods (JP 58-18353, EP 257787, disclosed method among the JP 02-679248) synthetic route of described optically pure amine long and complicated.If raw material does not have required optical purity, the tamsulosin of generation correspondingly will prepare with the impure form of optics (mixture of enantiomers).The method of the product that not mentioned how this optics of purifying is impure.
In the preparation method of tamsulosin, require in synthesis step as far as possible early, to obtain the intermediate that optical purity surpasses 90%e.e., relate to too much and expensive purification step to avoid synthesis step afterwards.Therefore, the 5-of high polarimetry purity ((2-amino-2-methyl) ethyl)-2-methoxybenzenesulphoismide (formula 1) is synthetic particularly important.
Disclose the preparation method of chirality R-5-(2-aminopropyl)-2-methoxybenzenesulphoismide among the patent EP 87306543, used Raney Ni or PtO
2Make hydrogenation catalyst, the former Raney Ni usage quantity in reaction is very big, is 60% of raw materials quality, and Raney Ni property effect hydrogenation reaction, and storage inconvenience (easily catching fire during dry state) is not suitable for the suitability for industrialized production operation.PtO
2Make hydrogenation catalyst, cost an arm and a leg (about 250,000 yuan/kg), the production cost height has limited the commercial production advantage of this product.Therefore seek easy quick, with low cost and be suitable for suitability for industrialized production chirality R-5-(2-aminopropyl)-preparation method is extremely important for the 2-methoxybenzenesulphoismide.
Summary of the invention
The preparation method who the purpose of this invention is to provide high polarimetry purity R-5-(2-the aminopropyl)-2-methoxybenzenesulphoismide that is suitable for suitability for industrialized production.
High polarimetry purity R-5-(2-the aminopropyl)-2-methoxybenzenesulphoismide of the present invention's preparation, molecular formula (1):
The preparation method of the high polarimetry purity R-5-of formula (1) (2-aminopropyl)-2-methoxybenzenesulphoismide, be to do under the catalyzer condition at Pd/C, utilize phenylethylamine and 2-methoxyl group-5-(2-oxopropyl) benzsulfamide of chirality, in organic solvent, carry out the ammonification hydrogenation reaction, obtain the product acidifying and become hydrochloride; With the product crude product, further under logical hydrogen condition, take off ethylbenzene, then handle obtaining R-5-(2-aminopropyl)-2-methoxybenzenesulphoismide with yellow soda ash.
Reaction formula is as follows:
In the above-mentioned reaction formula: 3 is 2-methoxyl group-5-(2-oxopropyl) benzsulfamide;
4 is Chiral Amine α-(+) phenylethylamine;
5 is 5-(2-(1-phenyl-ethylamino) propyl group)-2-methoxybenzenesulphoismide;
6 is 5-(2-(1-phenyl-ethylamino) propyl group)-2-methoxybenzenesulphoismide hydrochloride;
7 is R-5-(2-aminopropyl)-2-methoxybenzenesulphoismide hydrochloride.
Above-mentioned preparation method's concrete steps are:
The first step: with 2-methoxyl group-5-(2-oxopropyl) benzsulfamide 3, Chiral Amine α-(+) phenylethylamine 4, catalyst P d/C, organic solvent mixes by a certain percentage, is heated to 50-60 ℃, reacted 40-60 hour, thickening filtration steams the crude product that solvent obtains product 5; Add HCl, be acidified to pH=4～5, use the organic solvent recrystallization, obtain 5-(2-(1-phenyl-ethylamino) propyl group)-2-methoxybenzenesulphoismide hydrochloride 6;
Second the step: with 5-(2-(1-phenyl-ethylamino) propyl group)-2-methoxybenzenesulphoismide hydrochloride 6 under Pd/C catalysis, logical hydrogen takes off ethylbenzene, be heated to 50 ℃ of reactions 24 hours, obtain high polarimetry purity R-5-(2-aminopropyl)-2-methoxybenzenesulphoismide hydrochloride 7, further obtain R-5-(2-aminopropyl)-2-methoxybenzenesulphoismide 1 with the alkali effect.
Raw material 2-methoxyl group-5-of the present invention (2-oxopropyl) benzsulfamide: the phenylethylamine molar equivalent is than 1: 1-1.10, the optimum proportion scope is 1: 1.01-1.05.
The consumption of catalyst P d/C of the present invention is the 1-5% of 2-methoxyl group-5-(2-oxopropyl) benzsulfamide quality, and optimum proportion is 1.5-3%
The organic solvent that recrystallization of the present invention is used: acetone, methyl alcohol, one or more mixed solvents of acetonitrile; Consumption (volume liter) with 2-methoxyl group-5-(2-oxopropyl) benzsulfamide molar equivalent ratio is: 4-4.5: 1, and optimum proportion 4-4.2: 1.
Ammonification hydrogenation of the present invention, hydrogen pressure are 5atm, and temperature of reaction is 52 ℃, 48 hours reaction times.
The present invention compares with existing synthetic method, have the following advantages: improved catalyzer and operating method, optical purity reaches more than 95%, the reaction conditions gentleness, the reagent operational safety is used cheap catalyzer, and it is simple with aftertreatment to feed intake, with low cost, make operational path be more suitable in suitability for industrialized production.
Embodiment
By following examples explanations but do not limit the present invention in any way:
Embodiment 1
The first step: (24.3g, 100mmol), the 12mL phenylethylamine after 0.4g 10%Pd/C and the 400mL methanol mixed, in autoclave, leads to H with 2-methoxyl group-5-(2-oxopropyl) benzsulfamide
2Replace three times, then keep still internal pressure 5atm, be heated to 50 ℃ of reactions 48 hours, stopped reaction is cooled to room temperature, filters, concentrate and obtain light yellow thickness oily matter, add HCl, be acidified to pH=4～5, and the concentrated light yellow solid that obtains of post-heating, with acetone 400mL recrystallization, obtain white solid, be 5-(2-(1-phenyl-ethylamino) propyl group)-2-methoxybenzenesulphoismide hydrochloride, productive rate 56%.
Second step: 5-(2-(1-phenyl-ethylamino) propyl group)-2-methoxybenzenesulphoismide hydrochloride (10mmol) and the 0.386g 10%Pd/C raw material of 3.86g are blended in the reaction flask logical H
2Replace three times, then the logical hydrogen of normal pressure is heated to 50 ℃ of reactions 24 hours, stopped reaction, be cooled to room temperature, filter, concentrate and obtain white solid, use washing with acetone, obtain white crystal, i.e. R-5-(2-aminopropyl)-2-methoxybenzenesulphoismide hydrochloride, productive rate 95%.The mensuration optical purity is 95%ee,
Embodiment 2
With reference to embodiment 1, different is that reaction raw materials 2-methoxyl group-5-(2-oxopropyl) benzsulfamide consumption is 24.3g in the first step, 100mmol, α-(+) phenylethylamine consumption is 13mL, catalyst P d/C consumption is 0.5g, and organic solvent ethanol consumption is 420mL, and recrystallization solvent acetonitrile consumption is 380mL, obtain 5-(2-(1-phenyl-ethylamino) propyl group)-2-methoxybenzenesulphoismide hydrochloride, productive rate 52%.
(2-(1-phenyl-ethylamino) propyl group)-2-methoxybenzenesulphoismide hydrochloride consumption is 3.86g to 5-in second step, and catalyst P d/C consumption is 0.3g, R-5-(2-aminopropyl)-2-methoxybenzenesulphoismide hydrochloride productive rate 94%.The mensuration optical purity is 95%ee.
Claims (6)
1, the preparation method of a kind of high polarimetry purity R-5-(2-aminopropyl)-2-methoxybenzenesulphoismide, be to do under the catalyzer condition at Pd/C, utilize phenylethylamine and 2-methoxyl group-5-(2-oxopropyl) benzsulfamide of chirality, in organic solvent, carry out the ammonification hydrogenation reaction, obtain the product acidifying and become hydrochloride; With the product crude product, further under logical hydrogen condition, take off ethylbenzene, obtain R-5-(2-aminopropyl)-2-methoxybenzenesulphoismide hydrochloride, reaction formula is as follows:
In the above-mentioned reaction formula: 3 is 2-methoxyl group-5-(2-oxopropyl) benzsulfamide;
4 is Chiral Amine α-(+) phenylethylamine;
5 is 5-(2-(2-phenyl-ethylamino) propyl group)-2-methoxybenzenesulphoismide;
6 is 5-(2-(2-phenyl-ethylamino) propyl group)-2-methoxybenzenesulphoismide hydrochloride;
7 is R-5-(2-aminopropyl)-2-methoxybenzenesulphoismide hydrochloride;
Above-mentioned preparation method's concrete steps are:
The first step: with 2-methoxyl group-5-(2-oxopropyl) benzsulfamide (3), Chiral Amine α-(+) phenylethylamine (4), catalyst P d/C, organic solvent mixes by a certain percentage, is heated to 50-60 ℃, reacted 40-60 hour, thickening filtration steams the crude product that solvent obtains product (5); Add HCl, be acidified to pH=4～5, use the organic solvent recrystallization, obtain 5-(2-(1-phenyl-ethylamino) propyl group)-2-methoxybenzenesulphoismide hydrochloride (6);
Second the step: with 5-(2-(1-phenyl-ethylamino) propyl group)-2-methoxybenzenesulphoismide hydrochloride 6 under Pd/C catalysis, logical hydrogen takes off ethylbenzene, be heated to 50-60 ℃ of reaction 24 hours, obtain high polarimetry purity R-5-(2-aminopropyl)-2-methoxybenzenesulphoismide hydrochloride (7), further obtain R-5-(2-aminopropyl)-2-methoxybenzenesulphoismide with the alkali effect.
2, the preparation method of high polarimetry purity R-5-according to claim 1 (2-aminopropyl)-2-methoxybenzenesulphoismide is characterized in that described 2-methoxyl group-5-(2-oxopropyl) benzsulfamide: Chiral Amine α-(+) phenylethylamine molar equivalent ratio is: 1: 1-1.10.
3, the preparation method of high polarimetry purity R-5-according to claim 1 (2-aminopropyl)-2-methoxybenzenesulphoismide, the consumption that it is characterized in that described catalyst P d/C is the 1-5% of 2-methoxyl group-5-(2-oxopropyl) benzsulfamide quality.
4, the preparation method of high polarimetry purity R-5-according to claim 1 (2-aminopropyl)-2-methoxybenzenesulphoismide is characterized in that described organic solvent is: acetone, methyl alcohol, one or more mixed solvents of acetonitrile.
5,, it is characterized in that described organic solvent volume rises and 2-methoxyl group-5-(2-oxopropyl) benzsulfamide molar equivalent ratio is: 4-4.5: 1 according to the preparation method of claim 1 or 4 described high polarimetry purity R-5-(2-aminopropyl)-2-methoxybenzenesulphoismide.
6, the preparation method of high polarimetry purity R-5-according to claim 1 (2-aminopropyl)-2-methoxybenzenesulphoismide is characterized in that described temperature of reaction is 52 ℃, and in 48 hours reaction times, hydrogen pressure is 5 normal atmosphere.
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| Application Number | Priority Date | Filing Date | Title |
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| CN 200710068095 CN101037402A (en) | 2007-04-24 | 2007-04-24 | Preparation method of R-5-(2-Aminopropyl)-2-methoxybenzenesulfonyl with high optically active purity |
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| CN 200710068095 CN101037402A (en) | 2007-04-24 | 2007-04-24 | Preparation method of R-5-(2-Aminopropyl)-2-methoxybenzenesulfonyl with high optically active purity |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101284807B (en) * | 2008-06-11 | 2010-12-08 | 药源药物化学（上海）有限公司 | Preparation method of tamsulosin |
| CN105002256A (en) * | 2015-08-05 | 2015-10-28 | 杭州人可生物制品有限公司 | Method for preparing optical pure R-(-) tamsulosin through composite enzymatic resolution |
| CN111320559A (en) * | 2018-12-14 | 2020-06-23 | 苏州盛迪亚生物医药有限公司 | Preparation method of tamsulosin hydrochloride |
| CN111876449A (en) * | 2020-07-29 | 2020-11-03 | 江苏苏利精细化工股份有限公司 | Preparation method of R- (-) -5- (2-aminopropyl) -2-methoxybenzenesulphonamide |
-
2007
- 2007-04-24 CN CN 200710068095 patent/CN101037402A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101284807B (en) * | 2008-06-11 | 2010-12-08 | 药源药物化学（上海）有限公司 | Preparation method of tamsulosin |
| CN105002256A (en) * | 2015-08-05 | 2015-10-28 | 杭州人可生物制品有限公司 | Method for preparing optical pure R-(-) tamsulosin through composite enzymatic resolution |
| CN105002256B (en) * | 2015-08-05 | 2018-02-23 | 杭州人可生物制品有限公司 | Combined-enzyme method, which is split, prepares the pure R- of optically-active（-）The method of tamsulosin |
| CN111320559A (en) * | 2018-12-14 | 2020-06-23 | 苏州盛迪亚生物医药有限公司 | Preparation method of tamsulosin hydrochloride |
| CN111876449A (en) * | 2020-07-29 | 2020-11-03 | 江苏苏利精细化工股份有限公司 | Preparation method of R- (-) -5- (2-aminopropyl) -2-methoxybenzenesulphonamide |
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