CN102718711A - Novel method for preparing (R)-a-amino caprolactam hydrochloride - Google Patents
Novel method for preparing (R)-a-amino caprolactam hydrochloride Download PDFInfo
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- CN102718711A CN102718711A CN2011100785681A CN201110078568A CN102718711A CN 102718711 A CN102718711 A CN 102718711A CN 2011100785681 A CN2011100785681 A CN 2011100785681A CN 201110078568 A CN201110078568 A CN 201110078568A CN 102718711 A CN102718711 A CN 102718711A
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Abstract
The invention discloses a novel method for preparing besifloxacin important intermediate (R)-a-amino caprolactam hydrochloride (I). According to the method, a compound D-lysine monohydrochloride (II) or D-lysine (III) is used as a raw material, sodium hydroxide is used as alkali and alcohol is used as a solvent. The materials are subjected to heating reflux to prepare the compound (I). According to the invention, reagents and solvents used in the method have wide sources. The method is convenient and easy to operate and is suitable for industrialization.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, be specifically related to shellfish Xisha star midbody (
RThe new preparation process of)-alpha-amino group hexanolactam hydrochloride (I).
Background technology
Shellfish of the present invention Xisha star midbody be meant (
R)-alpha-amino group hexanolactam hydrochloride; This compound be the treatment bacterial conjunctivitis broad spectrum antimicrobicide shellfish Xisha star (Besifloxacin) building-up process in important midbody; DNA gyrase and the topoisomerase I V of shellfish Xisha star through acting on Gram-negative and positive bacteria; Interfere with bacterial DNA's is synthetic, thereby reaches the sterilization purpose.The structural formula of midbody is suc as formula shown in (I).
About the preparation (
RSynthesizing of)-alpha-amino group hexanolactam hydrochloride, following several method is arranged:
The patent No. is that the compound method of US20060014945A1 is as follows:
This method is to be starting material with D-Methionin mono-hydrochloric salts; Toluene is made solvent, and hexamethyldisilazane (Hexamethyldisilazane) is a catalyzer, and argon gas is as inert protective gas; One week of reflux, D-Methionin mono-hydrochloric salts close ring obtain target compound (
R)-alpha-amino group hexanolactam, salify not, yield 15%, this route reaction overlong time, and yield is very low is merely 15%, is not suitable for suitability for industrialized production.
Then mentioned other a kind of preparation method among the WO20050042489A1, reaction formula is following:
This method is a starting material with the N-α-tertbutyloxycarbonyl-D-Methionin of tertbutyloxycarbonyl protection; DMF is a solvent; Under BOP (BOP) effect, obtain D-tertbutyloxycarbonyl-alpha-amino group hexanolactam; Under 4 N HCl effects, slough the protective material tertbutyloxycarbonyl then, obtain target compound (
R)-alpha-amino group hexanolactam hydrochloride; The advantage of this route is not take place racemization, and two-step reaction obtains the target compound of single configuration, and the weak point one of this route is that starting material is not easy to obtain; The 2nd, this route is through two-step reaction; Aftertreatment is loaded down with trivial details, and the yield of target compound is lower, and cost is higher.
Summary of the invention
The object of the present invention is to provide a kind of comparatively simply the preparation (
RThe novel method of)-alpha-amino group hexanolactam hydrochloride.This method is used source reagent and solvent comparatively widely, and is easy to operate, is suitable for industriallization.
According to pertinent literature, use D-Methionin mono-hydrochloric salts or D-Methionin to be starting raw material, experiment confirm through method of the present invention can high efficiency, low cost prepare target compound.Concrete route is formula as follows:
This route uses suitable alcohol to be solvent, as initiator, adds proper amount of sodium hydroxide with D-Methionin mono-hydrochloric salts, and reflux self is closed ring and obtained target compound in solvent then.Post-treating method is simple, and suction filtration is removed by product NaCl, and filtrating obtains water with the aqueous hydrochloric acid reversed phase extraction, revolves inspissation and contracts and obtain bullion, and bullion uses methyl alcohol to pull an oar, and suction filtration can obtain the higher title product of purity.
Wherein solvent for use refers to Pentyl alcohol, n-hexyl alcohol, 1,2-Ucar 35 or their mixed solvent.Wherein preferred n-hexyl alcohol.
The temperature of reaction of required control is 120 ℃ to 185 ℃, preferred 155-175 ℃.
The practical implementation instance
Following embodiment is to specify the present invention, but should not be construed as limiting the invention.
Embodiment: (
RSynthesizing of)-alpha-amino group hexanolactam hydrochloride.
Embodiment one
In 2000 mL there-necked flasks, add D-Methionin mono-hydrochloric salts 55.0 g (300 mmol), add 1,2-Ucar 35 1200 mL make solvent, stir to add NaOH 12.0 g down; After stirring for some time, reflux 6.0 h, except that anhydrating, thin-layer chromatography monitoring (TLC) reaction finishes with water trap; Be cooled to room temperature, suction filtration is removed by product NaCl, in filtrating, adds 6 mol/L aqueous hydrochloric acids, 1200 mL, and " back extraction " separatory obtains water; Use 6 mol/L aqueous hydrochloric acids, 1200 mL " back extraction " separatory again, the water that obtains for twice is merged, organic phase reclaims through handling recycling, revolves inspissation and shrinks and obtain solid mutually; The solid that obtains is used the methyl alcohol making beating, suction filtration, filter cake uses methanol wash; Obtain white solid, it is single-point (iodine is smoked) that thin-layer chromatography detects this white solid, be (
R)-alpha-amino group hexanolactam hydrochloride, with it in 45 ℃ of dry 24h of vacuum, weighing 35.4 g, yield 72%.M.p.?292-294℃。
1H?NMR?(DMSO-
d 6 )?δ?1.21?(d,?
J?=?14.4?Hz,?1H),?1.52-1.64?(m,?2H),?1.74-1.78?(m,?1H),?1.87-1.93?(m,?2H),?3.05-3.10(m,?1H),?3.16-3.23?(m,?1H),?4.10?(d,?
J?=?14.4?Hz,?1H),?8.12?(br?s,?2H),?8.18?(br?s,?1H)。LC-MS：129.1?[M+1]
+。[α]
D 22?=26.5°。
Embodiment two
Adding D-Methionin mono-hydrochloric salts 55.0 g (300 mmol) in 2000 mL there-necked flasks add n-hexyl alcohol 1200 mL and make solvent, stir to add NaOH 12.0g down, after stirring for some time; Reflux 6.0 h, except that anhydrating, thin-layer chromatography monitoring (TLC) reaction finishes, and is cooled to room temperature with water trap; The suction filtration suction filtration is removed by product NaCl, in filtrating, adds 6 mol/L aqueous hydrochloric acids, 1200 mL, and " back extraction " separatory obtains water, uses 6 mol/L aqueous hydrochloric acids, 1200 mL " back extraction " separatory again; The water that obtains for twice is merged, and organic phase reclaims through handling recycling, revolves inspissation and shrinks and obtain solid mutually; The solid that obtains is used the methyl alcohol making beating, suction filtration, filter cake uses methanol wash; Obtain white solid, it is single-point (iodine is smoked) that thin-layer chromatography detects this white solid, be (
R)-alpha-amino group hexanolactam hydrochloride, with it in 45 ℃ of dry 24h of vacuum, weighing 39.4g, yield 80%.M.p.?292-294℃。
1H?NMR?(DMSO-
d 6 )?δ?1.21?(d,?
J?=?14.4?Hz,?1H),?1.52-1.64?(m,?2H),?1.74-1.78?(m,?1H),?1.87-1.93?(m,?2H),?3.05-3.10(m,?1H),?3.16-3.23?(m,?1H),?4.10?(d,?
J?=?14.4?Hz,?1H),?8.12?(br?s,?2H),?8.18?(br?s,?1H)。LC-MS：129.1?[M+1]
+。[α]
?D 22=26.5°。
Embodiment three
In 2000 mL there-necked flasks, add D-Methionin mono-hydrochloric salts 55.0 g (300 mmol), add Pentyl alcohol 1200 mL and make solvent, agitation condition adds NaOH 12.0 g down, after stirring for some time; Reflux 6.0 h constantly divide water during this, thin-layer chromatography monitoring (TLC) reaction finishes, and is cooled to room temperature; Except that anhydrating, thin-layer chromatography monitoring (TLC) reaction finishes, and is cooled to room temperature with water trap, and the suction filtration suction filtration is removed by product NaCl; In filtrating, add 6 mol/L aqueous hydrochloric acids, 1200 mL, " back extraction " separatory obtains water, uses 6 mol/L aqueous hydrochloric acids, 1200 mL " back extraction " separatory again; The water that obtains for twice is merged, and organic phase reclaims through handling recycling, revolves inspissation and shrinks and obtain solid mutually; The solid that obtains is used the methyl alcohol making beating, suction filtration, filter cake uses methanol wash; Obtain white solid, it is single-point (iodine is smoked) that thin-layer chromatography detects this white solid, be (
R)-alpha-amino group hexanolactam hydrochloride, with it in 45 ℃ of dry 24h of vacuum, weighing 29.5 g, yield 60%.M.p.?292-294℃。
1H?NMR?(DMSO-
d 6 )?δ?1.21?(d,?
J?=?14.4?Hz,?1H),?1.52-1.64?(m,?2H),?1.74-1.78?(m,?1H),?1.87-1.93?(m,?2H),?3.05-3.10(m,?1H),?3.16-3.23?(m,?1H),?4.10?(d,?
J?=?14.4?Hz,?1H),?8.12?(br?s,?2H),?8.18?(br?s,?1H)。LC-MS：129.1?[M+1]
+。[α]
?D ?22=26.4°。
Claims (5)
- One kind prepare shellfish Xisha star important intermediate ( RThe novel method of)-alpha-amino group hexanolactam hydrochloride (I) is characterized in that, with Compound D-Methionin mono-hydrochloric salts ( II) or D-Methionin (III) be raw material, sodium hydroxide is alkali, alcohol is solvent, reflux prepares compound (I)。
- 2. preparation method according to claim 1 is characterized in that, described alcohol is Pentyl alcohol, n-hexyl alcohol, 1,2-Ucar 35 or their mixed solvent.
- 3. preparation method according to claim 2 is characterized in that, described alcohol is n-hexyl alcohol.
- 4. preparation method according to claim 1 is characterized in that, the temperature of reflux is 120 ℃ to 185 ℃.
- 5. preparation method according to claim 4 is characterized in that, the temperature of reflux is 155-175 ℃.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103012264A (en) * | 2012-12-25 | 2013-04-03 | 常州市亚邦医药研究所有限公司 | Method for resolving 3-substituted amino-hexahydro-1H-azacycloheptane |
| CN103073498A (en) * | 2012-12-21 | 2013-05-01 | 北京万全德众医药生物技术有限公司 | Novel preparation method for (R)-Alpha-amino-e-caprolactam |
| CN106946779A (en) * | 2017-02-13 | 2017-07-14 | 广州仁恒医药科技股份有限公司 | A kind of amino hexahydro azepine * of R 3 preparation method |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2003206276A (en) * | 2002-01-07 | 2003-07-22 | Chisso Corp | METHOD FOR PRODUCING alpha-AMINO-epsilon-CAPROLACTAM |
| WO2005030730A1 (en) * | 2003-09-29 | 2005-04-07 | Yamakawa Chemical Industry Co., Ltd. | PROCESS FOR PRODUCING OPTICALLY ACTIVE α-AMINO-ϵ-CAPROLACTAM OR SALT THEREOF AND INTERMEDIATE FOR THE PRODUCTION |
| WO2006078753A1 (en) * | 2005-01-18 | 2006-07-27 | Elan Pharmaceuticals, Inc. | N-substituted heterocyclic sulfonamides |
| CN101035765A (en) * | 2004-07-13 | 2007-09-12 | 弗·哈夫曼-拉罗切有限公司 | Sulfonamide derivatives |
-
2011
- 2011-03-30 CN CN2011100785681A patent/CN102718711A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2003206276A (en) * | 2002-01-07 | 2003-07-22 | Chisso Corp | METHOD FOR PRODUCING alpha-AMINO-epsilon-CAPROLACTAM |
| WO2005030730A1 (en) * | 2003-09-29 | 2005-04-07 | Yamakawa Chemical Industry Co., Ltd. | PROCESS FOR PRODUCING OPTICALLY ACTIVE α-AMINO-ϵ-CAPROLACTAM OR SALT THEREOF AND INTERMEDIATE FOR THE PRODUCTION |
| CN101035765A (en) * | 2004-07-13 | 2007-09-12 | 弗·哈夫曼-拉罗切有限公司 | Sulfonamide derivatives |
| WO2006078753A1 (en) * | 2005-01-18 | 2006-07-27 | Elan Pharmaceuticals, Inc. | N-substituted heterocyclic sulfonamides |
Non-Patent Citations (1)
| Title |
|---|
| KENICHI SAKAI，等: "Practical continuous resolution of α-amino- ε-caprolactam by diastereomeric salt formation using a single resolving agent with a solvent switch method", 《TETRAHEDRON: ASYMMETRY》, vol. 14, 31 December 2003 (2003-12-31), pages 3713 - 3718, XP004474822, DOI: doi:10.1016/j.tetasy.2003.09.047 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103073498A (en) * | 2012-12-21 | 2013-05-01 | 北京万全德众医药生物技术有限公司 | Novel preparation method for (R)-Alpha-amino-e-caprolactam |
| CN103012264A (en) * | 2012-12-25 | 2013-04-03 | 常州市亚邦医药研究所有限公司 | Method for resolving 3-substituted amino-hexahydro-1H-azacycloheptane |
| CN103012264B (en) * | 2012-12-25 | 2018-01-19 | 常州亚邦制药有限公司 | The method for splitting of 3 substituted-amino hexahydro 1H azepans |
| CN106946779A (en) * | 2017-02-13 | 2017-07-14 | 广州仁恒医药科技股份有限公司 | A kind of amino hexahydro azepine * of R 3 preparation method |
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Application publication date: 20121010 |