CN101830815B - New cyclic compounds and method for preparing azepine spirocyclic compound by using same as intermediate - Google Patents
New cyclic compounds and method for preparing azepine spirocyclic compound by using same as intermediate Download PDFInfo
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- CN101830815B CN101830815B CN201010134587.7A CN201010134587A CN101830815B CN 101830815 B CN101830815 B CN 101830815B CN 201010134587 A CN201010134587 A CN 201010134587A CN 101830815 B CN101830815 B CN 101830815B
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 50
- 238000000034 method Methods 0.000 title claims abstract description 22
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 title abstract 2
- 150000001923 cyclic compounds Chemical class 0.000 title abstract 2
- 238000006243 chemical reaction Methods 0.000 claims description 25
- 238000002360 preparation method Methods 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 17
- 150000008627 azaspiro compounds Chemical class 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 15
- -1 C 1-4alkyl Chemical group 0.000 claims description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 125000004429 atom Chemical group 0.000 claims description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 6
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 238000007363 ring formation reaction Methods 0.000 claims description 4
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 claims description 3
- 235000011056 potassium acetate Nutrition 0.000 claims description 3
- 125000006239 protecting group Chemical group 0.000 claims description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 2
- 125000003368 amide group Chemical group 0.000 claims description 2
- 229910052751 metal Inorganic materials 0.000 claims description 2
- 239000002184 metal Substances 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims 2
- 239000012454 non-polar solvent Substances 0.000 claims 2
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical group O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 claims 2
- 150000003839 salts Chemical class 0.000 claims 2
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims 1
- LJCZNYWLQZZIOS-UHFFFAOYSA-N 2,2,2-trichlorethoxycarbonyl chloride Chemical compound ClC(=O)OCC(Cl)(Cl)Cl LJCZNYWLQZZIOS-UHFFFAOYSA-N 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- 230000002378 acidificating effect Effects 0.000 claims 1
- 125000002252 acyl group Chemical group 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 150000002170 ethers Chemical class 0.000 claims 1
- 150000005826 halohydrocarbons Chemical class 0.000 claims 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims 1
- 230000000802 nitrating effect Effects 0.000 claims 1
- 238000010992 reflux Methods 0.000 claims 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 4
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 abstract description 3
- 239000004599 antimicrobial Substances 0.000 abstract 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical class CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 238000007259 addition reaction Methods 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 229960004756 ethanol Drugs 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 0 *C(*)C1(CC1)C(*)C[N+]([O-])=O Chemical compound *C(*)C1(CC1)C(*)C[N+]([O-])=O 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- PGJSSOWNXNOBOO-VUUHIHSGSA-N C1(CC1)C(CN[C@H](C)C1=CC=CC=C1)[N+](=O)[O-] Chemical compound C1(CC1)C(CN[C@H](C)C1=CC=CC=C1)[N+](=O)[O-] PGJSSOWNXNOBOO-VUUHIHSGSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- IPCAGMYVDOFLFU-UHFFFAOYSA-N 2-nitroethenylcyclopropane Chemical group [O-][N+](=O)C=CC1CC1 IPCAGMYVDOFLFU-UHFFFAOYSA-N 0.000 description 2
- YPZJVWPQEAAMEJ-UHFFFAOYSA-N C(C)(=O)O.NCCCCCCC Chemical compound C(C)(=O)O.NCCCCCCC YPZJVWPQEAAMEJ-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- ZNZYKNKBJPZETN-WELNAUFTSA-N Dialdehyde 11678 Chemical class N1C2=CC=CC=C2C2=C1[C@H](C[C@H](/C(=C/O)C(=O)OC)[C@@H](C=C)C=O)NCC2 ZNZYKNKBJPZETN-WELNAUFTSA-N 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 150000002466 imines Chemical group 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 231100000957 no side effect Toxicity 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- ZICDZTXDTPZBKH-HNNXBMFYSA-N (1s)-2-(4-methylphenyl)-1-phenylethanamine Chemical compound C1=CC(C)=CC=C1C[C@H](N)C1=CC=CC=C1 ZICDZTXDTPZBKH-HNNXBMFYSA-N 0.000 description 1
- ZJEWDCBFLIGHLX-DGCLKSJQSA-N (7S)-N-[(1R)-1-phenylethyl]-5-azaspiro[2.4]heptan-7-amine Chemical compound C1(=CC=CC=C1)[C@@H](C)N[C@@H]1CNCC12CC2 ZJEWDCBFLIGHLX-DGCLKSJQSA-N 0.000 description 1
- RQEUFEKYXDPUSK-UHFFFAOYSA-N 1-phenylethylamine Chemical compound CC(N)C1=CC=CC=C1 RQEUFEKYXDPUSK-UHFFFAOYSA-N 0.000 description 1
- WJYIASZWHGOTOU-UHFFFAOYSA-N Heptylamine Chemical compound CCCCCCCN WJYIASZWHGOTOU-UHFFFAOYSA-N 0.000 description 1
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000001722 carbon compounds Chemical class 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 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
- LLYSBMNJRGHFBT-UHFFFAOYSA-N cyclopropane-1,1-dicarbaldehyde Chemical compound O=CC1(C=O)CC1 LLYSBMNJRGHFBT-UHFFFAOYSA-N 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- ZDYUUBIMAGBMPY-UHFFFAOYSA-N oxalic acid;hydrate Chemical compound O.OC(=O)C(O)=O ZDYUUBIMAGBMPY-UHFFFAOYSA-N 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
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- Indole Compounds (AREA)
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Abstract
The invention relates to two cyclic compounds shown in formulas III and IV and a method for preparing an azepine spirocyclic compound by using the same as an intermediate. The compounds can be used as raw materials for preparing a carbostyril antimicrobial compound.
Description
Technical field
The present invention relates to medical technical field, be specifically related to two kinds of ring compounds and using that it prepares the method for azaspiro compounds, their as intermediate.The azaspiro compounds, their obtaining can be used as the raw material use of preparing excellent antibacterial medicine carbostyril derivative.
Background of invention
7-S-[t-butoxycarbonyl amino] can be raw material by methyl aceto acetate make through polystep reaction is synthetic-5-azaspiro [2.4] heptane.By the separated required isomer of preparation property high performance liquid chromatography, then slough protecting group.But, if be applied to industrial production, also there is certain difficulty in this method complex operation.
Utilize Strake that reaction (Strecker) or enlightening gram to be subject to the preparation method of reaction (Oieckmann) to have certain improvement, but because reactions steps length and asymmetric synthesis are not easy to carry out, so still can not meet industrial needs.
The present invention has the nitrogen heterocyclic of the amino replacement of spirane structure by the reactions steps preparation of simplifying and shortening, azaspiro [2.4] heptane derivative that particularly optically active amino replaces, this method step is short, yield is high, and optical purity of products is high, is a kind of favourable industrial process.
Summary of the invention
In view of the foregoing, the compound that the inventor finds to take formula I as raw material can be easily with high yield preparation as the compound of general formula I I aldehyde-selectivity acetalation:
Wherein: R
2, R
3represent independently of one another C
1-4alkoxyl group;
And the compound of general formula I I is easy to be transformed into the compound as general formula III;
Wherein: R
2, R
3represent independently of one another C
1-4alkoxyl group.
The inventor also finds that the compound of general formula III is also easy to obtain as the compound of general formula I V by addition reaction:
Wherein: R
1hydrogen atom or group CR
αr
βr
γ, R wherein
α, R
β, R
γrepresent independently of one another hydrogen atom, C
1-4alkyl, phenyl or benzyl; R
2, R
3represent independently of one another C
1-4alkoxyl group.
The compound of general formula I V also can change into as the compound of general formula V:
Wherein: R
1hydrogen atom or group CR
αr
βr
γ, R wherein
α, R
β, R
γrepresent independently of one another hydrogen atom, C
1-4alkyl, phenyl or benzyl.
In the compound of general formula V, the carbon atom of bonding amino is asymmetric, works as substituent R
1while having asymmetry, there is diastereomer in this compound.When the compound that the inventor finds to prepare general formula V is non-enantiomer mixture, at a certain temperature, have to a kind of isomer of configuration, and the isomer proportion of another kind of configuration is almost nil.Reaction conditions by heating makes a pair of diastereomer show different yields, based on above-mentioned discovery, has completed the present invention.
The preparation method who the present invention relates to is as described below:
The method of preparing general formula V compound, comprises
Wherein: R
1hydrogen atom or group CR
αr
βr
γ, R wherein
α, R
β, R
γrepresent independently of one another hydrogen atom, C
1-4alkyl, phenyl or benzyl;
The compound of preparing general formula III by condensation method:
Wherein: R
2, R
3represent independently of one another C
1-4alkoxyl group;
Compound of formula III makes the compound of general formula I V by addition reaction:
Wherein: R
1hydrogen atom or group CR
αr
βr
γ, R wherein
α, R
β, R
γrepresent independently of one another hydrogen atom, C
1-4alkyl, phenyl or benzyl; R
2, R
3represent independently of one another C
1-4alkoxyl group;
Under the existence of zinc powder/hydrochloric acid, the compound of general formula I V is prepared the compound of general formula V through reactions such as reduction, deprotection, closed loops:
Wherein: R
1hydrogen atom or group CR
αr
βr
γ, R wherein
α, R
β, R
γrepresent independently of one another hydrogen atom, C
1-4alkyl, phenyl or benzyl.
Embodiment of the present invention are as follows:
Below that the present invention is more specifically described.
In the present invention, term " optically-active is single ", " stereochemistry is single " refer to that compound has the structure of the multiple isomer of the existence of allowing, but it is any composition the in these isomer.This not only comprises that compound, completely not containing another kind of isomer, also comprises the compound containing this isomer of chemical scale.
Preparation method of the present invention will be described below.
Dialdehyde compounds suc as formula I is known.Under tosic acid exists, by dialdehyde compounds and acetalation reagent react, can obtain the monoacetal compound as general formula I I.The acetalation reagent using can be ortho-formiate etc.The monoacetal compound of general formula I I carries out addition reaction with Nitromethane 99Min. under the existence of catalyzer, obtains the compound as general formula III.The catalyzer using can be methylamine hydrochloride and potassium acetate etc.
To method that prepare general formula I V compound from compound of formula III be described below:
Wherein: R
1hydrogen atom or group CR
αr
βr
γ, R wherein
α, R
β, R
γrepresent independently of one another hydrogen atom, C
1-4alkyl, phenyl or benzyl; R
2, R
3represent independently of one another C
1-4alkoxyl group.
The amine of compound of formula III and general formula X carries out addition reaction, obtains the compound of general formula I V.
General formula X compound preferably has asymmetric carbon compound, more preferably has a kind of in two kinds of optically active isomers, that is to say optically-active single compound.
The example of general formula X compound comprises (R)-or (S)-1-styroyl amine, (R)-or (S)-1-hydrocinnamyl amine, (R)-or (S)-1-phenyl-2-p-methylphenyl ethylamine, (R)-or (S)-1-(1-naphthyl) ethamine, (R)-or (S)-1-(4-p-methoxy-phenyl) ethamine, (R)-or (S)-1-(4-chloro-phenyl-) ethamine, (R)-or (S)-1-(4-nitrophenyl) ethamine, (R)-or (S)-1-(2, 4-dichlorophenyl) ethamine, (R)-or (S)-1-(2, 4-dinitrophenyl) ethamine, (R)-or (S)-1-(3, 5-dichlorophenyl) ethamine and (R)-or (S)-1-(3, 5-dinitrophenyl) ethamine.
This reaction can be carried out under condition of no solvent, also can under any solvent condition that reaction is had no side effect, carry out, preferably condition of no solvent.
This reaction under any circumstance, can be carried out in 0 to 100 ℃ of temperature range, preferably room temperature condition.
When this general formula X compound that reacts used is the single amine of optically-active, product is the compound that steric configuration is single, and the product of another kind of configuration almost can't detect.Enantio-selectivity is the feature of this reaction.For example, when general formula X compound used is (R)-1-styroyl amine, product is (2S)-2-(1-diethoxymethyl) cyclopropyl-2-{[(1R)-1-phenylethyl] amino } nitroethane, rising generation configuration conversion along with temperature of reaction, when temperature surpasses 70 ℃, the product of another kind of configuration gradates as principal product.
To method that prepare general formula V compound from general formula I V compound be described below:
Wherein: R
1hydrogen atom or group CR
αr
βr
γ, R wherein
α, R
β, R
γrepresent independently of one another hydrogen atom, C
1-4alkyl, phenyl or benzyl; R
2, R
3represent independently of one another C
1-4alkoxyl group.
Can be by being amido by the nitroreduction of general formula I V compound, deprotection, cyclization simultaneously generates group with imine moiety, restores imines and obtains general formula V compound.This reduction reaction can be carried out under metal/acid catalyst exists, preferably zinc powder/hydrochloric acid condition.
In this reaction, can use reaction is had no side effect and any solvent miscible with water, comprise alcohol (as methyl alcohol, ethanol, propyl alcohol or Virahol etc.), tetrahydrofuran (THF) and acetonitrile etc.Reaction can be carried out in 0 to 80 ℃ of temperature range.Reaction conditions preferably be take tetrahydrofuran (THF) as solvent, back flow reaction.
Embodiment
Be below embodiments of the invention, these embodiment are used for illustrating the present invention, but do not limit the present invention in any way.
Embodiment 1:1-diethoxymethyl cyclopanecarboxaldehyde
1,1-cyclopropane dialdehyde (49g, 0.5mol) is dissolved in toluene (500mL), adds tosic acid monohydrate (1.9g, 10mmol).At ice bath cooling and stir under, drip ethyl orthoformate (74g, 0.5mol).Gained mixture is at room temperature stirred 1 hour.In reaction solution, add saturated aqueous solution of sodium bicarbonate, be then extracted with ethyl acetate.Organic phase water and saturated brine wash successively, and anhydrous sodium sulfate drying filters, and then removes solvent under reduced pressure, obtains light red oily matter 68g, yield 78.9%.
1H-NMR(400MHz，CDCl
3)δ(ppm)：0.87-1.08(m，4H)，1.01(t，J=6.9Hz，1H)，3.25(q，J=6Hz，1H)，3.29(q，J=6.9Hz，1H)，3.45(q，J=6.9Hz，1H)，3.48(q，J=6.9Hz，1H)，4.96(s，1H)，9.36(s，1H).
Embodiment 2: trans 1-(1-diethoxymethyl) cyclopropyl-2-nitroethylene
1-diethoxymethyl cyclopanecarboxaldehyde (51.6g, 0.3mol) is dissolved in Nitromethane 99Min. (250ml).Add methylamine hydrochloride (2.0g, 0.03mol), potassium acetate (2.9g, 0.03mol), return stirring 3 hours, after gas chromatographic detection reacts completely, remove solvent under reduced pressure, in resistates, add water, ethyl acetate extraction, organic phase washing, saturated sodium-chloride is washed, anhydrous sodium sulfate drying, after steaming desolventizes, 78-80 ℃ of cut (1mmHg) 56.7g, yield 84% are collected in underpressure distillation.
Embodiment 3:2-(1-diethoxymethyl) cyclopropyl-2-{[(1R)-1-phenylethyl] amino } nitroethane
Trans 1-(1-diethoxymethyl) cyclopropyl-2-nitroethylene (22.5g, 0.1mol) and α-phenylethylamine (12.1g, 0.1mol) are mixed to rear stirring at room 24 hours.After HPLC monitoring reacts completely, add ethyl acetate, pass into carbon dioxide to separating out without solid, remove by filter after insolubles, remove solvent under reduced pressure, obtain colorless solid, filter, obtain target compound 30g, yield 79%.
1H-NMR(400MHz，CDCl
3)δ(ppm)：0.15(m，1H)，0.48(m，2H)，0.74(m，1H)，1.22(t，J=6.SHz，3H)，1.25(d，J＝6.8Hz，3H)，1.27(t，J＝6.4Hz，3H)，2.22(s，1H)，2.53(dd，J＝3.2Hz，J＝10.4Hz，1H)，3.51(m，2H)，3.73(m，2H)，4.10(s，1H)，3.48(q，J＝6.9Hz，1H)，4.74(s，1H)，4.19(q，J=6.8Hz，1H)，4.44(dd，J＝3.6Hz，J＝12Hz，1H)，4.71(dd，J＝10.4Hz，J＝12Hz，1H)，7.26(m，5H).
Embodiment 4:(S)-N-[(1R)-1-phenylethyl]-5-azaspiro [2.4] heptane-7-amine
By 2-(1-diethoxymethyl) cyclopropyl-2-{[(1R)-1-phenylethyl] amino } nitroethane (100g, 0.3mmol) is dissolved in 2L tetrahydrofuran (THF).Add zinc powder (195g, 3mol), 2M hydrochloric acid (1.5L, 3mol) back flow reaction 10 hours.After reacting completely, be cooled to room temperature, add salt of wormwood then to stir after 10 minutes, filter, separate organic layer, tetrahydrofuran (THF) extraction 2 times for water layer, merges organic layer, remove under reduced pressure after solvent, add dehydrated alcohol, after elimination insolubles, add oxalic acid-hydrate (37g, 0.3mol), produce a large amount of white solids, filter, filter cake washing with alcohol, is dried to obtain white powder solid 68g, yield 75%.
1H-NMR(400MHz，CDCl
3)δ(ppm)：0.50(m，2H)，0.59(m，1H)，0.82(m，1H)，1.30(d，J＝6.4Hz，3H)，1.89(s，2H)，3.06(d，J=12Hz，1H)，3.23(d，J=12.8Hz，1H)，4.47(q，J=6.8Hz，1H)，7.28(m，5H).
Embodiment 5:7-S-[(1R)-1-phenylethyl is amino]-5-N-benzoyl azaspiro [2.4] heptane
By (S)-N-[(1R)-1-phenylethyl]-5-azaspiro [2.4] heptane-7-amine (33g, 0.15mol) be dissolved in 300mL dry methylene chloride, add triethylamine (18.5g, 0.18mol), under ice bath, add Benzoyl chloride (21g, 0.15mol) at this temperature, react 1 hour, thin layer detection reaction is complete, add 100mL frozen water termination reaction, divide water-yielding stratum, organic layer adds 1M hydrochloric acid to pH1-2, divide water-yielding stratum, with 1M sodium hydroxide, be adjusted to neutrality, there are a large amount of solids to separate out, filter, obtain yellow solid 49g, ethyl alcohol recrystallization obtains colourless crystallization 41g, yield 85%.
1H-NMR(400MHz，CDCl
3)δ(ppm)：0.61(m，4H)，1.32(d，3H)，2.76(t，1H)，3.10(d，1H)，3.40(m，2H)，3.68(m，1H)，3.82(d，1H)，7.37(m，10H).
Embodiment 6:(S)-5-N-benzoyl azaspiro [2.4] heptane-7-amine acetate
By 7-S-[(1R)-1-phenylethyl amino]-5-N-benzoyl azaspiro [2.4] heptane (38g, 0.12mol), 20%Pd-C (4g), 500mL acetic acid is placed in autoclave, nitrogen atmosphere (5atm) stirring at room 12 hours.After thin layer detection reaction is complete, remove by filter catalyzer, reaction solution concentrating under reduced pressure obtains white solid 31g, yield 95%.
1H-NMR(400MHz，D
2O)δ(ppm)：0.83(m，8H)，1.82(s，6H)，3.17(d，J=11.6Hz，1H)，3.36(m，2H)，3.50(d，J=5.6Hz，1H)，3.63(d，J=12.8Hz，1H)，3.90(m，3H)，4.11(m，2H)，7.48(m，10H).
Embodiment 7:7-S-[tertbutyloxycarbonyl base is amino]-5-N-benzoyl azaspiro [2.4] heptane
(S)-5-N-benzoyl azaspiro [2.4] heptane-7-amine acetates (45g, 0.16mol) are dissolved in 450mL ethanol, add triethylamine (36g; 0.36mol), di-tert-butyl dicarbonic acid ester (39g, 0.18mol); stirring at room 1 hour; thin layer monitoring reacts completely, and steams solvent, and chloroform and sodium bicarbonate aqueous solution extraction separatory are removed resistates; organic phase anhydrous sodium sulfate drying; filter, steam solvent and obtain colorless solid 51g, yield 98%.
1H-NMR(400MHz，CDCl
3)δ(ppm)：0.48-0.88(m，4H)，1.38(s，9H)，3.18-4.02(m，5H)，4.66(s，1H)，7.38-7.52(m，5H).
Embodiment 8:7-S-[tertbutyloxycarbonyl base is amino]-5-azaspiro [2.4] heptane
7-S-[tertbutyloxycarbonyl base is amino]-5-N-benzoyl azaspiro [2.4] heptane (24g); be dissolved in 150mL ethanol; add 5M aqueous sodium hydroxide solution 150mL; 50 ℃ are reacted 24 hours, steam solvent, and chloroform and sodium bicarbonate aqueous solution extraction separatory are removed resistates; organic phase anhydrous sodium sulfate drying; filter, steam solvent and obtain colorless solid 14g, yield 90%.
1H-NMR(400MHz，CDCl
3)δ(ppm)：0.52(m，2H)，0.77(m，2H)，1.43(s，9H)，2.04(s，1H)，2.73(d，J＝10.8Hz，1H)，2.93(dd，J＝3.6Hz，J＝11.6Hz，1H)，2.92(d，J＝10.8Hz，1H)，3.00(dd，J=3.2Hz，J＝10.4Hz，1H)，3.33(dd，J=5.6Hz，J=11.6Hz，1H)，3.66(s，1H)，4.76(s，1H).
Claims (15)
1. suc as formula ring compound or its salt of IV:
Wherein:
R
1hydrogen atom or group CR
αr
βr
γ, R wherein
α, R
β, R
γrepresent independently of one another hydrogen atom, C
1-4alkyl, phenyl or benzyl;
R
2, R
3represent independently of one another C
1-4alkoxyl group.
2. compound or its salt as claimed in claim 1, wherein the ring compound suc as formula IV has following configuration:
R wherein
1, R
2and R
3as claim 1 defines.
3. as the ring compound of formula III:
Wherein:
R
2, R
3represent independently of one another C
1-4alkoxyl group.
As follows ring compound of usining formula III, IV as intermediate preparation the method suc as formula the azaspiro compounds, their of IX:
Wherein:
R
1hydrogen atom or group CR
αr
βr
γ, R wherein
α, R
β, R
γrepresent independently of one another hydrogen atom, C
1-4alkyl, phenyl or benzyl;
R
2, R
3represent independently of one another C
1-4alkoxyl group;
R
4be conventional amido protecting group, described conventional amino protecting group is selected from formyl radical, ethanoyl, chloracetyl, trifluoroacetyl group, unsubstituting phenenyl formyl radical, unsubstituting phenenyl ethanoyl, methoxy methyl acyl group, ethoxy acetyl, Boc, Fmoc, Troc.
5. preparation as claimed in claim 4 is suc as formula the method for the azaspiro compounds, their of IX, and wherein step 2 nitrating agent used is Nitromethane 99Min..
6. preparation as claimed in claim 4 is suc as formula the method for the azaspiro compounds, their of IX, and wherein step 2 catalyzer used is selected from methylamine hydrochloride, potassium acetate.
7. preparation as claimed in claim 4 is suc as formula the method for the azaspiro compounds, their of IX, and wherein step 2 solvent used is selected from Nitromethane 99Min., methyl alcohol, ethanol, propyl alcohol, Virahol.
8. as the method for the preparation of claim 4 or 7 suc as formula the azaspiro compounds, their of IX, wherein step 2 solvent used is methyl alcohol.
9. preparation as claimed in claim 4 is suc as formula the method for the azaspiro compounds, their of IX, and wherein step 3 is solvent-free or use non-polar solvent.
10. as the method for the preparation of claim 4 or 9 suc as formula the azaspiro compounds, their of IX, wherein step 3 non-polar solvent used is selected from halohydrocarbon and ethers.
11. preparations as claimed in claim 4 are suc as formula the method for the azaspiro compounds, their of IX, and wherein the compound of intermediate formula III is three-dimensional Focus compound.
12. preparations as claimed in claim 4 are suc as formula the method for the azaspiro compounds, their of IX, and wherein step 4 cyclization reagent used is metal/acid system.
13. as the method for the preparation of claim 4 or 12 suc as formula the azaspiro compounds, their of IX, and wherein step 4 cyclization reagent used is zinc powder/hydrochloric acid system.
14. preparations as claimed in claim 4 are suc as formula the method for the azaspiro compounds, their of IX, and wherein the ring-closure reaction of step 4 is carried out under acidic conditions.
15. preparations as claimed in claim 4 are suc as formula the method for the azaspiro compounds, their of IX, and wherein the reaction conditions of step 4 is reflux.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1426399A (en) * | 2000-02-25 | 2003-06-25 | 第一制药株式会社 | Process for producing quinolonecarboxylic acids and intermediates thereof |
| CN1580044A (en) * | 2003-07-31 | 2005-02-16 | 上海新创医药科技有限公司 | 7-tert-butoxy-carbonyl-amino-5-azaspiro[2,4] heptane and its pure stereo-isomer preparing method |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1426399A (en) * | 2000-02-25 | 2003-06-25 | 第一制药株式会社 | Process for producing quinolonecarboxylic acids and intermediates thereof |
| CN1580044A (en) * | 2003-07-31 | 2005-02-16 | 上海新创医药科技有限公司 | 7-tert-butoxy-carbonyl-amino-5-azaspiro[2,4] heptane and its pure stereo-isomer preparing method |
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| Title |
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| Koji SATOH等.An efficient Synthesis of a Key Intermediate of DU-6859a via Asymmetric Microbial Reduction.《Chemical & Pharmaceutical Bulletin》.1998,第46卷(第4期),第587-590页. |
| Koji SATOH等.An efficient Synthesis of a Key Intermediate of DU-6859a via Asymmetric Microbial Reduction.《Chemical & * |
| Pharmaceutical Bulletin》.1998,第46卷(第4期),第587-590页. * |
| Youichi Kimura等.(Fluorocyclopropy1)quinolones. 2.l Synthesis and Stereochemical Structure-Activity Relationships of Chiral 7-(7 -Amino-5-azaspiro2[ .41 heptan-5-y1)1- -(2 -fluorocyclopropyl)quinolone Antibacterial Agents.《Journal of Medicinal Chemistry》.1994,第37卷第3344-3352页. |
| Youichi Kimura等.(Fluorocyclopropy1)quinolones. 2.l Synthesis and Stereochemical Structure-Activity Relationships of Chiral 7-(7-Amino-5-azaspiro2[ .41 heptan-5-y1)1--(2-fluorocyclopropyl)quinolone Antibacterial Agents.《Journal of Medicinal Chemistry》.1994,第37卷第3344-3352页. * |
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