CN102952025A - Preparation method of (S)-1-amino-3-chloro-2-propyl alcohol hydrochloride - Google Patents
Preparation method of (S)-1-amino-3-chloro-2-propyl alcohol hydrochloride Download PDFInfo
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- CN102952025A CN102952025A CN2012103695817A CN201210369581A CN102952025A CN 102952025 A CN102952025 A CN 102952025A CN 2012103695817 A CN2012103695817 A CN 2012103695817A CN 201210369581 A CN201210369581 A CN 201210369581A CN 102952025 A CN102952025 A CN 102952025A
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- chloro
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- benzylamine
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 title claims abstract description 12
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000002994 raw material Substances 0.000 claims abstract description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 19
- 238000006243 chemical reaction Methods 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- 230000006837 decompression Effects 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 6
- 239000002253 acid Substances 0.000 abstract description 2
- 238000007259 addition reaction Methods 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000005580 one pot reaction Methods 0.000 abstract 2
- BRLQWZUYTZBJKN-GSVOUGTGSA-N (+)-Epichlorohydrin Chemical compound ClC[C@@H]1CO1 BRLQWZUYTZBJKN-GSVOUGTGSA-N 0.000 abstract 1
- 150000003839 salts Chemical class 0.000 abstract 1
- -1 phenyl aldehyde Chemical class 0.000 description 5
- 238000004821 distillation Methods 0.000 description 4
- 229960003907 linezolid Drugs 0.000 description 3
- TYZROVQLWOKYKF-ZDUSSCGKSA-N linezolid Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1N1CCOCC1 TYZROVQLWOKYKF-ZDUSSCGKSA-N 0.000 description 3
- 238000011017 operating method Methods 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical class O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 241000194033 Enterococcus Species 0.000 description 1
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 108010059993 Vancomycin Proteins 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 229960003085 meticillin Drugs 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 206010040872 skin infection Diseases 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 1
- 229960003165 vancomycin Drugs 0.000 description 1
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Abstract
The invention discloses a preparation method of (S)-1-amino-3-chloro-2-propyl alcohol hydrochloride, comprising the following steps of: carrying out addition reaction on S-epichlorohydrin which is taken as a raw material and benzylamine, and deprotecting under the acid condition to form into salt to prepare a target product by a one-pot method. According to the method, a midbody does not need to be separated, and the product can be prepared by the one-pot method at high yield, so that the preparation method is simple in technological operation, and easier for the large-scale industrial production.
Description
Technical field
The present invention relates to a kind of preparation of compound, the specifically one kettle way of (S)-1-amino-3-chloro-2-propylate hydrochlorate preparation.
Background technology
Linezolid (linezolid) is the brand-new chemosynthesis antimicrobial drug of a kind of structure, the G* bacterium and the mycobacterium tuberculosis infection that are used for the treatment of anti-multi-medicament, be a kind of novel oxazolidinone class antibacterials, its novel structure, mechanism of action uniqueness are without cross resistance.Can be used for treating the microbemia that vancomycin-resistant enterococcus (VRE) causes, the microbemia that the pneumonia that methicillin-resistant staphylococcus aureus (MRSA) causes and comprehensive skin infections and penicillin resistance pneumococcus (PRSP) cause.
(S)-and 1-amino-3-chloro-2-propylate hydrochlorate is the key intermediate of synthetic linezolid, its operational path is the international monopoly protection at present.The present invention is raw material with the S-epoxy chloropropane, and benzylamine is auxiliary reagent.With the one kettle way preparation, simplified operating procedure simultaneously.Avoid simultaneously the use of a large amount of ethanol in the former technique, reduced cost.
Summary of the invention
The objective of the invention is to develop a kind of new method preparation (S)-1-amino-3-chloro-2-propylate hydrochlorate.Former patent route reacts with S-epoxy chloropropane and ammoniacal liquor, and phenyl aldehyde is protective material, phenyl aldehyde is dissociated after complete again, dewaters with a large amount of ethanol distillations simultaneously.This technological operation is loaded down with trivial details, and final product is difficult for crystallization, needs to dewater with a large amount of ethanol distillations.The present invention replaces phenyl aldehyde with benzylamine, and deprotection and salify one kettle way can prepare.
Realize that above-mentioned purpose technical scheme of the present invention is, the preparation of a kind of (S)-1-amino of improvement-3-chloro-2-propylate hydrochlorate, described reaction is take the S-epoxy chloropropane as raw material, and benzylamine is auxiliary reagent, and ethanol and concentrated hydrochloric acid are solvent.This reaction can be used for lipid acid, fragrance and heterocyclic carboxylic acid.
This reaction may further comprise the steps:
(1) take ethanol as solvent, addition reaction at room temperature occurs in S-epoxy chloropropane and benzylamine;
(2) add the concentrated hydrochloric acid back flow reaction in the reaction solution of step (1), then decompression steams solvent, obtains (S)-1-amino-3-chloro-2-propylate hydrochlorate.
Wherein, whether fully reaction is to determine by gas phase or high performance liquid chromatography.
The present invention compared with prior art has following beneficial effect: (1) the present invention substitutes phenyl aldehyde with benzylamine, and the gained intermediate need not separate direct one kettle way can realize deprotection and salt-forming reaction.Simplify operating procedure, effectively reduced cost, be easier to large-scale industrial production; (2) avoided the use of a large amount of ethanol, aftertreatment is only to use reaction solvent steamed to obtain product.
Embodiment
For ease of the understanding of technical solution of the present invention, be introduced below in conjunction with concrete embodiment.
Operating procedure:
In the 10L four-hole bottle, add the 925gS-epoxy chloropropane, 2L ethanol, the lower control temperature of ice-water bath cooling is not higher than 15 degree, drips the 1070g benzylamine, complete rear stirring at normal temperature 4h.After the HPLC detection reaction is complete, add the 5L concentrated hydrochloric acid, temperature rising reflux reaction 10h.Ethanol and part moisture are removed in distillation, and bottle interior residual solvent amount for the treatment of stops distillation when being 3L.Be cooled to 0 degree, separate out white solid.Use cold washing with alcohol, drying obtains (S)-1-amino-3-chloro-2-propylate hydrochlorate 1200g, productive rate: 82.2%.MS?m/z145(M+H)
+[α]
20 D＝-22.3
Technique scheme has only embodied the optimal technical scheme of technical solution of the present invention, and some changes that those skilled in the art may make some part have wherein all embodied principle of the present invention, belong within protection scope of the present invention.
Claims (3)
1. the preparation method of (S)-1-amino-3-chloro-2-propylate hydrochlorate is characterized in that described reaction is take the S-epoxy chloropropane as raw material, and benzylamine and hydrochloric acid are auxiliary reagent.
2. reaction according to claim 1 is characterized in that, described reaction is one kettle way preparation (S)-1-amino-3-chloro-2-propylate hydrochlorate.
3. according to claim 1,2 or 3 described reactions, it is characterized in that described reaction may further comprise the steps:
(1) take ethanol as solvent, S-epoxy chloropropane and benzylamine react at normal temperatures, obtain the affixture intermediate;
(2) add the concentrated hydrochloric acid back flow reaction in the reaction solution of step (1), then decompression steams solvent, obtains (S)-1-amino-3-chloro-2-propylate hydrochlorate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012103695817A CN102952025B (en) | 2012-09-28 | 2012-09-28 | Preparation method of (S)-1-amino-3-chloro-2-propyl alcohol hydrochloride |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012103695817A CN102952025B (en) | 2012-09-28 | 2012-09-28 | Preparation method of (S)-1-amino-3-chloro-2-propyl alcohol hydrochloride |
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| Publication Number | Publication Date |
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| CN102952025A true CN102952025A (en) | 2013-03-06 |
| CN102952025B CN102952025B (en) | 2013-12-11 |
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| CN2012103695817A Active CN102952025B (en) | 2012-09-28 | 2012-09-28 | Preparation method of (S)-1-amino-3-chloro-2-propyl alcohol hydrochloride |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103467310A (en) * | 2013-08-15 | 2013-12-25 | 重庆惠健生物科技有限公司 | Separation and purification method for (S)-1-amino-3-chloro-2-propanol hydrochloride |
| CN103664673A (en) * | 2013-12-18 | 2014-03-26 | 成都医路康医学技术服务有限公司 | Preparation method of linezolid side chain |
| CN106966940A (en) * | 2015-07-30 | 2017-07-21 | 新发药业有限公司 | A kind of preparation method of Sitagliptin phosphate intermediate N arylmethyls 2S cyano methyl acridines |
| CN112300149A (en) * | 2019-08-01 | 2021-02-02 | 北京弘德信医药科技有限公司 | Preparation method of arotinolol hydrochloride |
| CN115219632A (en) * | 2022-07-29 | 2022-10-21 | 山东达因海洋生物制药股份有限公司 | HPLC-ELSD detection method of (S) -1-amino-3-chloro-2-propanol hydrochloride |
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|---|---|---|---|---|
| US4310697A (en) * | 1979-08-14 | 1982-01-12 | Produits Chimiques Ugine Kuhlmann | Process for the manufacture of dimethylethylamine |
| CN1140163A (en) * | 1994-04-28 | 1997-01-15 | Basf公司 | Preparation of stable-colored dialkylaminoethanol |
| US6362188B1 (en) * | 1998-12-18 | 2002-03-26 | Schering Corporation | Farnesyl protein transferase inhibitors |
| CN101830812A (en) * | 2009-12-31 | 2010-09-15 | 茂名云龙工业发展有限公司 | Process for continuously producing N-monomethylethanolamine |
-
2012
- 2012-09-28 CN CN2012103695817A patent/CN102952025B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4310697A (en) * | 1979-08-14 | 1982-01-12 | Produits Chimiques Ugine Kuhlmann | Process for the manufacture of dimethylethylamine |
| CN1140163A (en) * | 1994-04-28 | 1997-01-15 | Basf公司 | Preparation of stable-colored dialkylaminoethanol |
| US6362188B1 (en) * | 1998-12-18 | 2002-03-26 | Schering Corporation | Farnesyl protein transferase inhibitors |
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Non-Patent Citations (2)
| Title |
|---|
| 《ARKIVOC》 20030630 Mirosław Soroka等 Tritylamine (triphenylmethylamine) in organic synthesis; II. The reaction of tritylamine with oxiranes-synthesis of N-trityl-beta-aminoalcohols 第33页第1-7行 1-2 , 第12期 * |
| MIROSłAW SOROKA等: "Tritylamine (triphenylmethylamine) in organic synthesis; II. The reaction of tritylamine with oxiranes–synthesis of N-trityl-β-aminoalcohols", 《ARKIVOC》, no. 12, 30 June 2003 (2003-06-30) * |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103467310A (en) * | 2013-08-15 | 2013-12-25 | 重庆惠健生物科技有限公司 | Separation and purification method for (S)-1-amino-3-chloro-2-propanol hydrochloride |
| CN103467310B (en) * | 2013-08-15 | 2015-05-27 | 重庆惠健生物科技有限公司 | Separation and purification method for (S)-1-amino-3-chloro-2-propanol hydrochloride |
| CN103664673A (en) * | 2013-12-18 | 2014-03-26 | 成都医路康医学技术服务有限公司 | Preparation method of linezolid side chain |
| CN103664673B (en) * | 2013-12-18 | 2016-06-08 | 成都医路康医学技术服务有限公司 | A kind of preparation method of linezolid side chain |
| CN106966940A (en) * | 2015-07-30 | 2017-07-21 | 新发药业有限公司 | A kind of preparation method of Sitagliptin phosphate intermediate N arylmethyls 2S cyano methyl acridines |
| CN106966940B (en) * | 2015-07-30 | 2019-03-19 | 新发药业有限公司 | A kind of preparation method of Sitagliptin phosphate intermediate N arylmethyl -2S- cyano methyl acridine |
| CN112300149A (en) * | 2019-08-01 | 2021-02-02 | 北京弘德信医药科技有限公司 | Preparation method of arotinolol hydrochloride |
| CN115219632A (en) * | 2022-07-29 | 2022-10-21 | 山东达因海洋生物制药股份有限公司 | HPLC-ELSD detection method of (S) -1-amino-3-chloro-2-propanol hydrochloride |
| CN115219632B (en) * | 2022-07-29 | 2024-04-05 | 山东达因海洋生物制药股份有限公司 | HPLC-ELSD detection method for (S) -1-amino-3-chloro-2-propanol hydrochloride |
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| Publication number | Publication date |
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| CN102952025B (en) | 2013-12-11 |
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Effective date of registration: 20240222 Address after: No. 4 Xi'an Road, South District, Jinghai Economic Development Zone, Jinghai District, Tianjin City, 301699 Patentee after: TIANJIN HESHENG MEDICAL TECHNOLOGY DEVELOPMENT Co.,Ltd. Country or region after: China Address before: Room 501, Building F, Green Industry Base, No. 6 Haitai Development Road, Huayuan Industrial Park (Outer Ring), Xiqing District, Tianjin, 300381 Patentee before: TIANJIN SCIPHARMACN Ltd. Country or region before: China |