CN1986548B - Industrial continuous preparing process of N-tert-butoxy carbonyl-5-aza-2-oxa-3-one-dicyclo-[2,2,1] heptane - Google Patents
Industrial continuous preparing process of N-tert-butoxy carbonyl-5-aza-2-oxa-3-one-dicyclo-[2,2,1] heptane Download PDFInfo
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- CN1986548B CN1986548B CN200510111853A CN200510111853A CN1986548B CN 1986548 B CN1986548 B CN 1986548B CN 200510111853 A CN200510111853 A CN 200510111853A CN 200510111853 A CN200510111853 A CN 200510111853A CN 1986548 B CN1986548 B CN 1986548B
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- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 title claims abstract description 66
- 238000000034 method Methods 0.000 title description 6
- 238000005886 esterification reaction Methods 0.000 claims abstract description 17
- 230000032050 esterification Effects 0.000 claims abstract description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 7
- 238000007273 lactonization reaction Methods 0.000 claims abstract description 5
- 230000007062 hydrolysis Effects 0.000 claims abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- 238000006243 chemical reaction Methods 0.000 claims description 32
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 11
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 10
- 239000007810 chemical reaction solvent Substances 0.000 claims description 10
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 9
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- SYBYTAAJFKOIEJ-UHFFFAOYSA-N 3-Methylbutan-2-one Chemical compound CC(C)C(C)=O SYBYTAAJFKOIEJ-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 6
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 229940043265 methyl isobutyl ketone Drugs 0.000 claims description 6
- 239000002994 raw material Substances 0.000 claims description 6
- -1 BOC acid anhydrides Chemical class 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 4
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 3
- 239000012346 acetyl chloride Substances 0.000 claims description 3
- 230000000903 blocking effect Effects 0.000 claims description 3
- 150000007524 organic acids Chemical class 0.000 claims description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 3
- 235000015320 potassium carbonate Nutrition 0.000 claims description 3
- 235000017550 sodium carbonate Nutrition 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 238000010189 synthetic method Methods 0.000 claims description 2
- 230000001681 protective effect Effects 0.000 claims 2
- 238000002360 preparation method Methods 0.000 abstract description 8
- 238000009776 industrial production Methods 0.000 abstract description 3
- 238000003912 environmental pollution Methods 0.000 abstract description 2
- 238000011097 chromatography purification Methods 0.000 abstract 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract 1
- 238000006277 sulfonation reaction Methods 0.000 abstract 1
- 239000000047 product Substances 0.000 description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 238000001953 recrystallisation Methods 0.000 description 8
- 230000002194 synthesizing effect Effects 0.000 description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000003810 Jones reagent Substances 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- GKOJGKLSWYPJCM-JEDNCBNOSA-N methyl (2s)-1-hydroxypyrrolidine-2-carboxylate;hydrochloride Chemical compound Cl.COC(=O)[C@@H]1CCCN1O GKOJGKLSWYPJCM-JEDNCBNOSA-N 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 229940117975 chromium trioxide Drugs 0.000 description 2
- WGLPBDUCMAPZCE-UHFFFAOYSA-N chromium trioxide Inorganic materials O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 2
- GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 description 2
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Chemical compound CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 238000011031 large-scale manufacturing process Methods 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000012450 pharmaceutical intermediate Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 150000003333 secondary alcohols Chemical class 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 238000006751 Mitsunobu reaction Methods 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
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- Pyrrole Compounds (AREA)
Abstract
The present invention relates to continuous industrial preparation process of N-tert-butoxy carbonyl-5-aza-2-oxa-3-one-dicyclo-[2, 2, 1] heptane. The present invention prepares N-tert-butoxy carbonyl-5-aza-2-oxa-3-one-dicyclo-[2, 2, 1] heptane with facile L-hydroxy praline as material, and through methyl esterification, tert-butoxy carbonyl radical protection, paratoluene sulfonation, hydrolysis and lactonization. The present invention has lowered cost, raised yield, less environmental pollution and no need of column chromatographic purification, and may be used in industrial production.
Description
Technical field:
The present invention relates to a kind of 5-azepine-2-oxa--3-ketone-dicyclo-[2 of N-protected; 2,1] preparation method of iieptanes pharmaceutical intermediate, particularly a kind of N-tertbutyloxycarbonyl-5-azepine-2-oxa--3-ketone-dicyclo-[2; 2,1] the continuous synthetic industrialized process for preparing of heptane.
Background technology:
The 5-azepine of N-protected-2-oxa--3-ketone-dicyclo-[2,2,1] heptane is the pharmaceutical intermediate of outbalance, but does not up to the present effectively prepare the industrial preparative method of this product.Once two kinds of preparation methods had been reported in the document, method one, with the L-oxyproline is raw material, at first through blocking group protection commonly used, obtain the 5-azepine-2-oxa--3-ketone-dicyclo-[2 of N-protected then by the Mitsunobu reaction, 2,1] (Heterocycles 1983,817-828) for heptane; Method two; the same L-of protection earlier oxyproline; using Jone ' s reagent oxidation secondary alcohol then is ketone; use sodium borohydride to obtain reduzate cis hydroxyl groups proline(Pro) afterwards; use dicyclohexylcarbodiimide (DCC) condensation to obtain the 5-azepine-2-oxa--3-ketone-dicyclo-[2 of N-protected at last; 2,1] heptane (Aust.J.Chem.1967,1493).
Document synthetic route 1:
a?PG＝Me
3COCO
b?PG＝PhCH
2OCO
c?PG＝MeC
6H
4SO
2
d?PG＝MeCO
Said synthesis route 1 is not suitable for the technical scale batch reaction, this be because:
(a) the raw material that uses expensive, the cost height for example, must be used diethyl azodiformate (DEAD) and triphenylphosphine and carry out Mitsunobu and react;
(b) reaction can generate more by product, causes the aftertreatment technology complexity, needs the last product of column chromatography purification, and resulting product yield and product purity can not be satisfactory for plant-scale preparation method.
Document synthetic route 2:
b?PG＝PhCH
2OCO
c?PG＝MeC
6H
4SO
2
d?PG＝MeCO
Said synthesis route 2 is not suitable for the technical scale batch reaction, this be because:
(a) using Jone ' s reagent oxidation secondary alcohol is ketone, and the requirement of protecting group is wanted high relatively: Jone ' s reagent (sulphuric acid soln of chromium trioxide) is highly acid, and so claimed base must be acidproof, has significant limitation like this for reaction;
(b) the by product environmental pollution of chromium trioxide is serious;
(c) the raw material that uses expensive, the cost height for example, is used dicyclohexylcarbodiimide (DCC) at last,
(d) by product that generates of reaction difficulty remove, also need the column chromatography purification product, yield has only 50～60%, can't realize the industrial production of mass-producing.
Summary of the invention:
The technical issues that need to address of the present invention are: having solved among existing N-tertbutyloxycarbonyl-5-azepine-2-oxa--3-ketone-dicyclo-[2,2,1] heptane preparation technology needs column chromatography purification, problem that can't large-scale production; The N-tertbutyloxycarbonyl that a kind of whole yield is higher, preparation cost is lower-5-azepine-2-oxa--3-ketone-dicyclo-continuous synthetic industrialized process for preparing of [2,2,1] heptane is provided.
Technical scheme of the present invention:
The present invention is a raw material with L-oxyproline conventional, that be easy to get, obtains N-tertbutyloxycarbonyl-5-azepine-2-oxa--3-ketone-dicyclo-[2,2,1] heptane by esterification, tertbutyloxycarbonyl protection, tosic acid esterification, hydrolysis with after lactonizing.
Concrete synthesis technique of the present invention is as follows:
In above-mentioned technological process, we at first adopt continuous synthetic method that the L-oxyproline is carried out esterification, tertbutyloxycarbonyl protection and tosic acid esterification.
Esterification reaction of organic acid, methyl alcohol is made reaction solvent, and reaction reagent is selected from a kind of in sulfur oxychloride, the vitriol oil and the Acetyl Chloride 98Min., and temperature of reaction is 0 ℃-60 ℃, and preferred initial reaction temperature is room temperature (20 ℃-25 ℃); Reacted crude product is directly gone up protection, blocking group reagent BOC acid anhydrides, and auxiliary addition agent is selected triethylamine for use, reaction solvent can be used methyl alcohol, 1, a kind of in 4-dioxane and the methylene dichloride, temperature of reaction is 0 ℃-70 ℃, preferred initial reaction temperature is room temperature (20 ℃-25 ℃); Last directly tosic acid esterification, adopt Tosyl chloride, auxiliary addition agent is selected pyridine or triethylamine for use, and reaction solvent is selected a kind of in tetrahydrofuran (THF), toluene and the methylene dichloride for use, temperature of reaction is 0 ℃-100 ℃, and preferred initial reaction temperature is room temperature (20 ℃-25 ℃).Three step yields are 81～89%.
Then, we are hydrolyzed continuously and react and lactonization reaction, in hydrolysis reaction, we select alkali commonly used and that be easy to get for use, and as sodium hydroxide, potassium hydroxide and lithium hydroxide etc., reaction solvent is selected from water, methyl alcohol, ethanol, a kind of in acetone and the tetrahydrofuran (THF), temperature is a room temperature to 78 ℃.Directly carry out lactonization reaction then, reaction reagent can be selected a kind of in yellow soda ash, salt of wormwood, sodium hydroxide and the potassium hydroxide for use, it is room temperature to 110 ℃ that reaction solvent can be used a kind of in acetone, methylethylketone, methyl isopropyl Ketone and the methyl iso-butyl ketone (MIBK), temperature of reaction.The two-step reaction yield is 82～87%.
Beneficial effect of the present invention:
Reaction process of the present invention is selected rationally; it has adopted, and economy is easy to get, the raw material L-oxyproline of energy large-scale production obtains N-tertbutyloxycarbonyl-5-azepine-2-oxa--3-ketone-dicyclo-[2 through esterification, tertbutyloxycarbonyl protection, tosic acid esterification, hydrolysis with after lactonizing; 2; 1] heptane; its overall yield reaches 66～77%, and the present invention reacts easy control, and preparation cost is lower; and intermediate can be purified by recrystallization, therefore can carry out large-scale industrial production.
Embodiment:
The following example helps to understand the present invention, but is not limited to content of the present invention.
Embodiment 1
Synthesizing of N-tertbutyloxycarbonyl-5-azepine-2-oxa--3-ketone-dicyclo-[2,2,1] heptane
The first step: N-tertbutyloxycarbonyl-O-tolysulfonyl-L-L-Hydroxyproline methyl ester synthetic
L-oxyproline (300g, 2.29mol) be dissolved in anhydrous methanol (2.0L), dripping thionyl chloride (335g under the room temperature, 2.8mol), reaction solution reflux to stir 1 hour, was concentrated into dried thick product L-L-Hydroxyproline methyl ester hydrochloride, directly it was dissolved in methyl alcohol (6.0L), add triethylamine (680g under the room temperature, 6.3mol) and the BOC acid anhydrides (520g 2.4mol), reacts after 1 hour, concentrate and do, obtain thick product N-tertbutyloxycarbonyl-L-L-Hydroxyproline methyl ester, it is dissolved in methylene dichloride (3L), add anhydrous pyridine (237g under the room temperature, 3.0mol) and Tosyl chloride (437g, 2.3mol), reacted 2 hours, add saturated sodium bicarbonate aqueous solution (3L), layering, organic phase water (3L) washing again is concentrated into dried crude product, behind methyl tertiary butyl ether (2.5L) recrystallization pure product N-tertbutyloxycarbonyl-O-tolysulfonyl-L-L-Hydroxyproline methyl ester (813g, 2.04mol), productive rate: 89%.
1H?NMR(400MHz，DMSO-d
6)：δ7.80(d，J＝8.0Hz，2H)，7.48(d，J＝8.0Hz，2H)，5.04(s，1H)，4.18(m，1H)，3.62(d，J＝9.2Hz，3H)，3.35～3.45(m，2H)，3.40(s，2H)，2.05～2.40(m，2H)，1.30(d，J＝9.2Hz，9H)；Ms(M
++1，400.1)。
Second step: N-tertbutyloxycarbonyl-5-azepine-2-oxa--3-ketone-dicyclo-[2,2,1]
Synthesizing of heptane
N-tertbutyloxycarbonyl-O-tolysulfonyl-L-L-Hydroxyproline methyl ester (710g, 1.78mol) be dissolved in methyl alcohol (3.5L), (5N 0.4L), stirs after 3 hours to add potassium hydroxide aqueous solution under the room temperature, it is 4～5 that 1N hydrochloric acid is regulated pH, separate out solid, filter, the thick product that obtains is dissolved in acetone (5L), add yellow soda ash (212g, 2.0mol), refluxed cool to room temperature 6 hours, add elutriation and go out solid, filter thick product, the methyl tertiary butyl ether recrystallization gets pure product N-tertbutyloxycarbonyl-5-azepine-2-oxa--3-ketone-dicyclo-[2,2,1] heptane (330g, 1.55mol). productive rate: 87%.
1H?NMR(400MHz，CDCl
3)：δ5.05(s，1H)，4.5(s，1H)，3.40～3.55(m，2H)，2.00～2.20(m，2H)，1.45(s，9H)；Ms(M
++1，214.1)。
Embodiment 2
Synthesizing of N-tertbutyloxycarbonyl-5-azepine-2-oxa--3-ketone-dicyclo-[2,2,1] heptane
The first step: N-tertbutyloxycarbonyl-O-tolysulfonyl-L-L-Hydroxyproline methyl ester synthetic
L-oxyproline (72g, 0.55mol) be dissolved in anhydrous methanol (0.48L), drip the vitriol oil (60g under the room temperature, 0.6mol), reaction solution stirring at room 5 hours is concentrated into dried thick product L-L-Hydroxyproline methyl ester hydrochloride, directly it is dissolved in methyl alcohol (1.44L), add triethylamine (163g under the room temperature, 1.5mol) and the BOC acid anhydrides (1245g 0.58mol), reacts after 1 hour, concentrate and do, obtain thick product N-tertbutyloxycarbonyl-L-L-Hydroxyproline methyl ester, it is dissolved in toluene (0.72L), add anhydrous pyridine (56.9g under the room temperature, 0.72mol) and Tosyl chloride (104g, 0.55mol), reacted 2 hours, add saturated sodium bicarbonate aqueous solution (0.72L), layering, organic phase water (0.72L) washing again is concentrated into dried crude product, behind methyl tertiary butyl ether (0.6L) recrystallization pure product N-tertbutyloxycarbonyl-O-tolysulfonyl-L-L-Hydroxyproline methyl ester (193g, 0.48mol), productive rate: 88%.Its test data is shown in above-mentioned embodiment 1 the first step.
Second step: N-tertbutyloxycarbonyl-5-azepine-2-oxa--3-ketone-dicyclo-[2,2,1]
Synthesizing of heptane
N-tertbutyloxycarbonyl-O-tolysulfonyl-L-L-Hydroxyproline methyl ester (852g, 2.14mol) be dissolved in tetrahydrofuran (THF) (6.0L), (1N 3L), stirs after 3 hours to add lithium hydroxide aqueous solution under the room temperature, it is 4～5 that 1N hydrochloric acid is regulated pH, separate out solid, filter, the thick product that obtains is dissolved in methylethylketone (6L), add potassium hydroxide (345g, 2.5mol), refluxed cool to room temperature 6 hours, add water (6L) and ethyl acetate (3L) layering, organic phase is concentrated into dried thick product, and the methyl tertiary butyl ether recrystallization gets pure product N-tertbutyloxycarbonyl-5-azepine-2-oxa--3-ketone-dicyclo-[2,2,1] heptane (381g, 1.8mol). productive rate: 84%.Its test data is shown in above-mentioned embodiment 1.
Embodiment 3
Synthesizing of N-tertbutyloxycarbonyl-5-azepine-2-oxa--3-ketone-dicyclo-[2,2,1] heptane
The first step: N-tertbutyloxycarbonyl-O-tolysulfonyl-L-L-Hydroxyproline methyl ester synthetic
L-oxyproline (3g, 22.9mmol) be dissolved in anhydrous methanol (20mL), dripping acetyl chloride (2.2g under the room temperature, 28mmol), reaction solution reflux to stir 1 hour, was concentrated into dried thick product L-L-Hydroxyproline methyl ester hydrochloride, directly it is dissolved in 1,4-dioxane (60mL), (6.8g is 63mmol) with BOC acid anhydrides (5.2g to add triethylamine under the room temperature, 24mmol), react after 1 hour, concentrate and do, obtain thick product N-tertbutyloxycarbonyl-L-L-Hydroxyproline methyl ester, it is dissolved in tetrahydrofuran (THF) (30mL), add under the room temperature anhydrous triethylamine (3.0g, 30mol) and Tosyl chloride (4.4g, 23mmol), reacted 2 hours, add saturated sodium bicarbonate aqueous solution (30mL), layering, organic phase water (30mL) washing again, be concentrated into dried crude product, behind methyl tertiary butyl ether (25mL) recrystallization pure product N-tertbutyloxycarbonyl-O-tolysulfonyl-L-L-Hydroxyproline methyl ester (7.6g, 19.0mmol), productive rate: 83%.Its test data is shown in above-mentioned embodiment 1.
Second step: N-tertbutyloxycarbonyl-5-azepine-2-oxa--3-ketone-dicyclo-[2,2,1]
Synthesizing of heptane
N-tertbutyloxycarbonyl-O-tolysulfonyl-L-L-Hydroxyproline methyl ester (64g, 0.16mol) add aqueous sodium hydroxide solution (5N under the room temperature, 0.04L), stir after 3 hours, it is 4～5 that 1N hydrochloric acid is regulated pH, separates out solid, filter, the thick product that obtains is dissolved in methyl iso-butyl ketone (MIBK) (0.5L), and adding salt of wormwood (25g, 0.18mol), refluxed 6 hours, cool to room temperature adds water (300mL) layering, and organic phase is concentrated into dried thick product, the methyl tertiary butyl ether recrystallization gets pure product N-tertbutyloxycarbonyl-5-azepine-2-oxa--3-ketone-dicyclo-[2,2,1] heptane (28g, 0.13mol). productive rate: 82%.Its test data is shown in above-mentioned embodiment 1.
Embodiment 4
Synthesizing of N-tertbutyloxycarbonyl-5-azepine-2-oxa--3-ketone-dicyclo-[2,2,1] heptane
The first step: N-tertbutyloxycarbonyl-O-tolysulfonyl-L-L-Hydroxyproline methyl ester synthetic
Prepare corresponding product according to the described continuous esterification of the first step in the foregoing description 1, tertbutyloxycarbonyl protection and tosic acid esterification technique condition and operation steps, its test data is shown in above-mentioned example 1.
Second step: N-tertbutyloxycarbonyl-5-azepine-2-oxa--3-ketone-dicyclo-[2,2,1]
Synthesizing of heptane
N-tertbutyloxycarbonyl-O-tolysulfonyl-L-L-Hydroxyproline methyl ester (42.6g, 0.11mol) be dissolved in ethanol (0.2L), (5N 0.3L), stirs after 3 hours to add aqueous sodium hydroxide solution under the room temperature, it is 4～5 that 1N hydrochloric acid is regulated pH, separate out solid, filter, the thick product that obtains is dissolved in methyl isopropyl Ketone (0.3L), add sodium hydroxide (4.8g, 0.12mol), refluxed cool to room temperature 6 hours, add water (3L) layering, organic phase is concentrated into dried thick product, and the methyl tertiary butyl ether recrystallization gets pure product N-tertbutyloxycarbonyl-5-azepine-2-oxa--3-ketone-dicyclo-[2,2,1] heptane (19g, 0.09mol). productive rate: 84%.Its test data is shown in above-mentioned embodiment 1.
Claims (8)
1.N-tertbutyloxycarbonyl-5-azepine-2-oxa--3-ketone-dicyclo-[2; 2; 1] the continuous synthetic industrialized process for preparing of heptane; with routine; the L-oxyproline that is easy to get is a raw material; it is characterized in that; with continuous synthetic method the L-oxyproline is carried out esterification; tertbutyloxycarbonyl protection and tosic acid esterification; then hydrolysis and lactonize after obtain N-tertbutyloxycarbonyl-5-azepine-2-oxa--3-ketone-dicyclo-[2; 2; 1] heptane; described hydrolysis reaction and lactonization reaction carry out continuously, and in hydrolysis reaction, used alkali is selected from sodium hydroxide; a kind of in potassium hydroxide and the lithium hydroxide; reaction solvent is selected from water; methyl alcohol; ethanol, a kind of in acetone and the tetrahydrofuran (THF), temperature of reaction is a room temperature to 78 ℃; directly carry out lactonization reaction then; reaction reagent is selected from yellow soda ash; salt of wormwood; a kind of in sodium hydroxide and the potassium hydroxide, reaction solvent is selected from acetone; methylethylketone; a kind of in methyl isopropyl Ketone and the methyl iso-butyl ketone (MIBK), temperature of reaction is a room temperature to 110 ℃.
2. the N-tertbutyloxycarbonyl according to claim 1-5-azepine-2-oxa--3-ketone-dicyclo-continuous synthetic industrialized process for preparing of [2,2,1] heptane is characterized in that the reaction formula of above-mentioned reaction is:
3. N-tertbutyloxycarbonyl according to claim 1-5-azepine-2-oxa--3-ketone-dicyclo-[2,2,1] the continuous synthetic industrialized process for preparing of heptane, it is characterized in that, in described esterification reaction of organic acid, reaction solvent is a methyl alcohol, and reaction reagent is selected from a kind of in sulfur oxychloride, the vitriol oil and the Acetyl Chloride 98Min., and temperature of reaction is 0 ℃-60 ℃.
4. the N-tertbutyloxycarbonyl according to claim 3-5-azepine-2-oxa--3-ketone-dicyclo-continuous synthetic industrialized process for preparing of [2,2,1] heptane is characterized in that the initial reaction temperature of esterification reaction of organic acid is a room temperature.
5. N-tertbutyloxycarbonyl according to claim 1-5-azepine-2-oxa--3-ketone-dicyclo-[2; 2; 1] the continuous synthetic industrialized process for preparing of heptane; it is characterized in that, in the tertbutyloxycarbonyl protective reaction, blocking group reagent BOC acid anhydrides; auxiliary addition agent is selected triethylamine for use; reaction solvent is selected from methyl alcohol, 1, a kind of in 4-dioxane and the methylene dichloride, and temperature of reaction is 0 ℃-70 ℃.
6. the N-tertbutyloxycarbonyl according to claim 5-5-azepine-2-oxa--3-ketone-dicyclo-continuous synthetic industrialized process for preparing of [2,2,1] heptane is characterized in that the initial reaction temperature of tertbutyloxycarbonyl protective reaction is a room temperature.
7. N-tertbutyloxycarbonyl according to claim 1-5-azepine-2-oxa--3-ketone-dicyclo-[2,2,1] the continuous synthetic industrialized process for preparing of heptane, it is characterized in that, in the tosic acid esterification reaction, adopt Tosyl chloride, auxiliary addition agent is selected pyridine or triethylamine for use, reaction solvent is selected a kind of in tetrahydrofuran (THF), toluene and the methylene dichloride for use, and temperature of reaction is 0 ℃-100 ℃.
8. the N-tertbutyloxycarbonyl according to claim 7-5-azepine-2-oxa--3-ketone-dicyclo-continuous synthetic industrialized process for preparing of [2,2,1] heptane is characterized in that, the initial reaction temperature of tosic acid esterification reaction is a room temperature.
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| CN115572251B (en) * | 2022-10-18 | 2024-03-22 | 苏州爱玛特生物科技有限公司 | Preparation method of (4S) -1-fluorenylmethoxycarbonyl-4-tert-butoxycarbonylamino-D-proline |
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| US4912231A (en) * | 1987-06-15 | 1990-03-27 | E. R. Squibb & Sons, Inc. | Process for preparing (trans)-4-phenyl-L-proline derivatives |
| JP2005220079A (en) * | 2004-02-05 | 2005-08-18 | Shionogi & Co Ltd | Synthesis of pyrrolidine compound and crystal therefor |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4912231A (en) * | 1987-06-15 | 1990-03-27 | E. R. Squibb & Sons, Inc. | Process for preparing (trans)-4-phenyl-L-proline derivatives |
| JP2005220079A (en) * | 2004-02-05 | 2005-08-18 | Shionogi & Co Ltd | Synthesis of pyrrolidine compound and crystal therefor |
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| Title |
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| Margaret M. et al.A SHORT INPROVED SYNTHESIS OF N-SUBSTITUTED 5-AZA-2-OXA-BICYCLO[2.2.1] HEPTANES.HETEROCYCLES20 5.1983,20(5),817-828. |
| Margaret M.et al.A SHORT INPROVED SYNTHESIS OF N-SUBSTITUTED 5-AZA-2-OXA-BICYCLO[2.2.1] HEPTANES.HETEROCYCLES20 5.1983,20(5),817-828. * |
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