CN102002069A - Preparation method of dicyclic intermediate for synthesizing carbapenem side chains and application thereof - Google Patents
Preparation method of dicyclic intermediate for synthesizing carbapenem side chains and application thereof Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical group C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 title abstract description 3
- 230000002194 synthesizing effect Effects 0.000 title abstract description 3
- 125000002619 bicyclic group Chemical group 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 39
- 238000006243 chemical reaction Methods 0.000 claims abstract description 33
- -1 dicyclic compound Chemical class 0.000 claims abstract description 25
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 10
- 239000012190 activator Substances 0.000 claims abstract description 8
- 150000007530 organic bases Chemical class 0.000 claims abstract description 8
- 150000001412 amines Chemical class 0.000 claims abstract description 7
- 238000009833 condensation Methods 0.000 claims abstract description 6
- 230000005494 condensation Effects 0.000 claims abstract description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 claims description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- 239000000543 intermediate Substances 0.000 claims description 9
- IVRIRQXJSNCSPQ-UHFFFAOYSA-N propan-2-yl carbonochloridate Chemical compound CC(C)OC(Cl)=O IVRIRQXJSNCSPQ-UHFFFAOYSA-N 0.000 claims description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 8
- 230000035484 reaction time Effects 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 claims description 6
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical group [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 238000007363 ring formation reaction Methods 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 4
- 230000003213 activating effect Effects 0.000 claims description 4
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 4
- 150000001348 alkyl chlorides Chemical class 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 230000000694 effects Effects 0.000 claims description 4
- 150000002170 ethers Chemical class 0.000 claims description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 4
- 150000003141 primary amines Chemical class 0.000 claims description 4
- 150000003335 secondary amines Chemical class 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical compound OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 claims description 4
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical group ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 3
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 3
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 3
- 125000006239 protecting group Chemical group 0.000 claims description 3
- 235000010265 sodium sulphite Nutrition 0.000 claims 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 claims description 3
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 2
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 claims description 2
- 210000005252 bulbus oculi Anatomy 0.000 claims description 2
- 150000001805 chlorine compounds Chemical class 0.000 claims description 2
- PQLFROTZSIMBKR-UHFFFAOYSA-N ethenyl carbonochloridate Chemical group ClC(=O)OC=C PQLFROTZSIMBKR-UHFFFAOYSA-N 0.000 claims description 2
- 150000002460 imidazoles Chemical class 0.000 claims description 2
- DPLVEEXVKBWGHE-UHFFFAOYSA-N potassium sulfide Chemical compound [S-2].[K+].[K+] DPLVEEXVKBWGHE-UHFFFAOYSA-N 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- HYHCSLBZRBJJCH-UHFFFAOYSA-M sodium hydrosulfide Chemical compound [Na+].[SH-] HYHCSLBZRBJJCH-UHFFFAOYSA-M 0.000 claims description 2
- UJJDEOLXODWCGK-UHFFFAOYSA-N tert-butyl carbonochloridate Chemical compound CC(C)(C)OC(Cl)=O UJJDEOLXODWCGK-UHFFFAOYSA-N 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 2
- 238000009776 industrial production Methods 0.000 abstract 1
- 229910052979 sodium sulfide Inorganic materials 0.000 abstract 1
- GRVFOGOEDUUMBP-UHFFFAOYSA-N sodium sulfide (anhydrous) Chemical compound [Na+].[Na+].[S-2] GRVFOGOEDUUMBP-UHFFFAOYSA-N 0.000 abstract 1
- 238000000034 method Methods 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 150000003014 phosphoric acid esters Chemical class 0.000 description 5
- 239000013078 crystal Substances 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 230000004913 activation Effects 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- DMJNNHOOLUXYBV-PQTSNVLCSA-N meropenem Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)S[C@@H]1CN[C@H](C(=O)N(C)C)C1 DMJNNHOOLUXYBV-PQTSNVLCSA-N 0.000 description 2
- 229960002260 meropenem Drugs 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- BENKAPCDIOILGV-RQJHMYQMSA-N (2s,4r)-4-hydroxy-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(O)=O BENKAPCDIOILGV-RQJHMYQMSA-N 0.000 description 1
- JMJMJDNHVXYAOC-MNOVXSKESA-N (2s,4r)-4-hydroxy-1-[(4-nitrophenyl)methoxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound C1[C@H](O)C[C@@H](C(O)=O)N1C(=O)OCC1=CC=C([N+]([O-])=O)C=C1 JMJMJDNHVXYAOC-MNOVXSKESA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- JUZNIMUFDBIJCM-ANEDZVCMSA-N Invanz Chemical compound O=C([C@H]1NC[C@H](C1)SC=1[C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)NC1=CC=CC(C(O)=O)=C1 JUZNIMUFDBIJCM-ANEDZVCMSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- HMORXJGLDYBOEV-UHFFFAOYSA-N NC(C1)(C11NCCC1)O Chemical compound NC(C1)(C11NCCC1)O HMORXJGLDYBOEV-UHFFFAOYSA-N 0.000 description 1
- 0 [N+]=*C(CC[C@](C1)N2)=C[C@@]1C2=O Chemical compound [N+]=*C(CC[C@](C1)N2)=C[C@@]1C2=O 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 238000012658 bimolecular nucleophilic substitution Methods 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- XHFGWHUWQXTGAT-UHFFFAOYSA-N dimethylamine hydrochloride Natural products CNC(C)C XHFGWHUWQXTGAT-UHFFFAOYSA-N 0.000 description 1
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 229960002770 ertapenem Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/08—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/572—Five-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention relates to a preparation method of a dicyclic intermediate for synthesizing carbapenem side chains and application thereof. The reaction route is shown in the specification of the invention. A compound shown in a formula (III) reacts with a carboxyl activator under the action of organic base to generate a compound shown in a formula (IV); the compound shown in the formula (IV) reacts with the carboxyl activator under the action of organic base to generate a compound shown in a formula (V); the compound shown in the formula (V) and sodium sulfide are cyclized at low temperature to obtain a dicyclic compound (I); the compound shown in the formula (I) and amine are subjected to open-loop condensation to obtain a protected carbapenem side chain compound (II). The preparation method has the advantages of short reaction route, mild conditions and high reaction yield and is suitable for industrial production.
Description
Technical field
The present invention relates to the preparation method and the application of the key intermediate of the southern class side chain of a kind of synthetic training.
Background technology
Meropenem (Meropenem), ertabeinan carbapenem antibiotics such as (Ertapenem) on structure, all are to be formed through chemical condensation by the tetramethyleneimine side chain (II) of training southern parent nucleus and 2,4 replacements.Therefore, find a kind of method in common of synthetic above-mentioned tetramethyleneimine side chain compound (II), significant for the southern class microbiotic of synthetic training aspect.
Tetramethyleneimine side chain compound (II) synthetic, study many is to be starting raw material with the L-oxyproline, through N-protected, activated carboxylic, hydroxyl activation, 4-position generation bimolecular nucleophilic substitution (SN
2Reaction) steps such as upset configuration, activatory carboxyl and amine condensation, hydrolysis reaction obtain (II).Reaction scheme is as follows:
This preparation method often synthetic route is long, and preparation process complexity, total recovery are not high, and is not a kind of general simple and convenient preparation method.
In order to overcome the shortcoming of traditional method, also there are some document introductions to prepare training southern side chain compound in recent years by earlier synthetic dicyclo midbody compound (as shown in the formula (I)).But all coincidentally there are some defectives in these literature methods, as patent US5322952A1, have adopted the method cyclization of logical hydrogen sulfide, and this is unfriendly to environment, is not suitable for suitability for industrialized production; Patent US5648501A selects phenylbenzene phosphinylidyne ester for use to the activation of carboxyl, though yield is higher, the cost that costs an arm and a leg is too high, also is not suitable for scale operation.
Summary of the invention
The objective of the invention is to, the novel method of synthetic training southern side chain dicyclo intermediate (I) a kind of cheapness, that suitability for industrialized is produced is provided, and the method for synthesizing corresponding training southern side chain compound with this intermediate.
With trans-L-1,2-oxyproline is starting raw material, after N goes up protection, carries out with " one kettle way " that activated carboxylic, hydroxyl activate, cyclization obtains formula (I) compound again; The training southern side chain compound that formula (I) compound and corresponding amine condensation are protected, reaction scheme is as follows.
The dicyclo intermediates preparation of a kind of synthetic training southern side chain is characterized in that described dicyclo intermediate
The following reaction scheme of structural formula in formula (I) shown in:
Described preparation method is as follows:
1) the formula III compound generates the formula IV compound with the carboxyl activator reaction under the organic bases effect, and temperature of reaction is-30～-5 ℃, and the reaction times is 0.5～2h, and carboxyl activator is 2.0～1.2:1 with the amount of substance ratio of formula III compound;
Wherein, R
3Be the protecting group on the tetramethyleneimine N, be selected from tertbutyloxycarbonyl (t-BOC), to nitro carbobenzoxy-(Cbz) (PNZ), carbobenzoxy-(Cbz), to methoxyl group benzyloxy carbonyl, allyloxycarbonyl (AOC), carbobenzoxy-(Cbz) (Cbz), di-isopropyl phosphoryl (DIPP) etc.;
2) the formula IV compound is under the organic bases effect, and with hydroxy activating reagent reaction production (V) compound, temperature of reaction is-20～-5 ℃, and the reaction times is 0.5～2h, and the amount of substance of hydroxy activating reagent and formula IV compound is than 1.5～1.05:1;
3) formula (V) compound and sulfide at low temperatures cyclization obtain dicyclic compound (I), temperature of reaction is-20～0 ℃, the reaction times is 1～5h, the mol ratio of sulfide and formula (V) compound is 2～8:1.
Described carboxyl activator is sulfonyl chloride compound, sulphonic acid anhydride, alkyl chloride manthanoate, alkyl acyl chloride compound, N, N-carbonyl dimidazoles (CDI), dicyclohexylcarbodiimide (DCC), isopropyl chlorocarbonate or pivaloyl chloride, preferred isopropyl chlorocarbonate and pivaloyl chloride.
Described sulfonyl chloride compound is methane sulfonyl chloride, Tosyl chloride or benzene sulfonyl chloride; Described sulphonic acid anhydride is methylsulfonic acid acid anhydride or tosic acid acid anhydride; Described alkyl chloride manthanoate is Vinyl chloroformate, isopropyl chlorocarbonate or the chloroformic acid tert-butyl ester; Described chloride compounds is oxalyl chloride or pivaloyl chloride.
Described organic bases is triethylamine, diisopropylethylamine, pyridine, picoline, imidazoles or quinoline.
Described sulfide is sodium sulphite, Sodium sulfhydrate and potassium sulphide.
The solvent of using in each reactions steps is selected from ethers, halogenated alkane, second eyeball, toluene, ethyl acetate or DMF.
Described ethers is oxyethane, ether or tetrahydrofuran (THF); Described halogenated alkane is methylene dichloride, chloroform or 1, the 2-ethylene dichloride.
Described formula I application of compound is characterized in that, described formula I compound and amine open loop condensation obtain training southern side chain compound (II), and reaction formula is as follows:
Described amine is any primary amine or secondary amine, described primary amine such as NH
2PhCO
2H, NHBSO
2NH
2Deng; Described secondary amine is HN (CH
3)
2, HN (CH
3) C
2H
5Deng.
Solvent in the reaction is oxyethane, tetrahydrofuran (THF), ethyl acetate, toluene, acetone, acetate or DMF; Temperature of reaction is 0～40 ℃, and the reaction times is 30min～24h.
Advantage of the present invention: 1, dicyclo intermediate (I) compound is made by " one kettle way ", and synthetic route is brief, and is simple to operation; 2, this method versatility is good, goes up protecting group for tetramethyleneimine N and is BOC, PNZ, AOC, Cbz, DIPP, carbobenzoxy-(Cbz), methoxyl group benzyloxy carbonyl etc. all is suitable for; 3, adopt activation such as carboxyl isopropyl chlorocarbonate, pivaloyl chloride, use the method for sodium sulphite cyclization then, raw material is cheap and easy to get, yield is high, and greatly cost reduces; 4, this method reaction conditions gentleness, environmental friendliness are the routes that a suitability for industrialized is produced.
Embodiment
Below, the invention will be further described by following examples, and it will help to understand the present invention, but not limit content of the present invention.
Embodiment 1
1) di-isopropyl (1S, 4S)-6-oxo-5-sulphur-2-azabicyclo [2.2.1] heptan-2-base phosphoric acid ester
Add 90g(0.305mol in the reaction flask) the triethylamine of (2S 4R)-methylene dichloride of 1-(di-isopropyl phosphate)-4-hydroxyl pyrrolidine-2-formic acid and 430ml, adds 35g(0.347mol under the room temperature).Cool to bottle interior temperature≤-15 ℃ under the nitrogen protection, drip the pivaloyl chloride of 40.4g (0.335mol), stirring reaction 15 minutes.To the triethylamine that wherein adds 40g (0.396mol), drip methane sulfonyl chloride 41.7g (0.335mol), stirring reaction 15 minutes again.After temperature drops to below-10 ℃, add Na
2S
.9H
2O solution, stirring reaction 1 hour.Stream adds 3N HCl 200ml, leaves standstill phase-splitting, and water layer with the 120ml dichloromethane extraction once merges organic phase, adds 32g (0.317mol) triethylamine, reflux 2 hours.Temperature drops to 0 ℃, adds 1N HCl 200ml.Leave standstill phase-splitting, organic phase is water respectively, 5% aqueous sodium carbonate and saturated salt washing.Concentrating under reduced pressure evaporate to dryness, stream add the sherwood oil of 400ml, cool to 0 ℃, stir 2 hours, filter, and crystal is pulled an oar with MTBE, filter 40 ℃ of oven dry.Obtain product 82g (0.28mol, yield 91.8%) di-isopropyl (1S, 4S)-6-oxo-5-sulphur-2-azabicyclo [2.2.1] heptan-2-base phosphoric acid ester.
Mp:?89～90℃
1H?NMR(400MHz，CDCl
3)
1.27(d,?3H),?1.29(d,?3H),?1.30(d,?6H),?2.02(m,?1H),?2,13(m,?1H),?3.40(m,?1H),?3.71(m,?1H)?,?4.09(m,?1H),?4.20(m,?1H),?4.57(m,?2H)。
Embodiment 2
2) di-isopropyl (1S, 4S)-6-oxo-5-sulphur-2-azabicyclo [2.2.1] heptan-2-base phosphoric acid ester
The pivaloyl chloride of 40.4g among the embodiment 1 (0.335mol) is replaced with the isopropyl chlorocarbonate of 40g (0.327mol), other dosages are all identical with method, obtain 74.3g (0.253mol, yield 91.8%) di-isopropyl (1S, 4S)-6-oxo-5-sulphur-2-azabicyclo [2.2.1] heptan-2-base phosphoric acid ester.
Embodiment 3
3) (1S, 4S)-allyloxycarbonyl-6-oxo-5-sulphur-preparation of 2-azabicyclo [2.2.1] heptan-2-ester
With the 90g(0.305mol among the embodiment 1) (2S, 4R)-1-(di-isopropyl phosphate)-4-hydroxyl pyrrolidine-2-formic acid replaces with 65g(0.305mol) (2S, 4R)-1-allyloxycarbonyl-4-hydroxyl pyrrolidine-2-formic acid, other dosages are all identical with method, obtain oily matter 60.4g(0.283mol, yield 93%) (1S, 4S)-allyloxycarbonyl-6-oxo-5-sulphur-2-azabicyclo [2.2.1] heptan-2-ester.
1H?NMR(400MHz，CDCl
3)
2.18(m,?2H),?3.65(m,?1H),?3.85(d,?1H),?4.14(m,?1H),?4.63(d,?2H),?4.67(m,?1H),?5.22(d,?1H),?5.32(d,?1H),?5.92(m,?1H)。
Embodiment 4
4) (1S, 4S)-allyloxycarbonyl-6-oxo-5-sulphur-preparation of 2-azabicyclo [2.2.1] heptan-2-ester
Pivaloyl chloride among the embodiment 3 is replaced with the isopropyl chlorocarbonate of 40g (0.327mol), other dosages are all identical with method, obtain title compound oily matter 60.7g(0.284mol, yield 93.4%) (1S, 4S)-allyloxycarbonyl-6-oxo-5-sulphur-2-azabicyclo [2.2.1] heptan-2-ester.
Embodiment 5
5) (1S, 4S)-tertbutyloxycarbonyl-6-oxo-5-sulphur-preparation of 2-azabicyclo [2.2.1] heptan-2-ester
With the 90g(0.305mol among the embodiment 1) (2S, 4R)-1-(di-isopropyl phosphate)-4-hydroxyl pyrrolidine-2-formic acid replaces with 70.4g(0.305mol) (2S, 4R)-1-(tertbutyloxycarbonyl)-4-hydroxyl pyrrolidine-2-formic acid, other dosages are all identical with method, obtain white solid 63.7g(0.278mol, yield 91.2%) (1S, 4S)-tertbutyloxycarbonyl-6-oxo-5-sulphur-2-azabicyclo [2.2.1] heptan-2-ester.
Mp:?91℃
1H?NMR(400MHz，CD
2Cl
2)
1.42(s,?9H),?2.07(dt,?1H),?2.13(m,?1H),?3.48-3.53(m,?1H),?3.74(m,?1H),?4.11(m,?1H),?4.42-4.53(d,?1H)。
Embodiment 6
6) (1S, 4S)-tertbutyloxycarbonyl-6-oxo-5-sulphur-preparation of 2-azabicyclo [2.2.1] heptan-2-ester
Pivaloyl chloride among the embodiment 5 is replaced with the isopropyl chlorocarbonate of 41.3g (0.337mol), triethylamine replaces with the diisopropylethylamine of a great deal of, other reactive modes are identical, obtain title compound white solid 65.6g(0.286mol, yield 94%) (1S, 4S)-tertbutyloxycarbonyl-6-oxo-5-sulphur-2-azabicyclo [2.2.1] heptan-2-ester.
Embodiment 7
7) (1S, 4S)-4-nitro carbobenzoxy-(Cbz)-6-oxo-5-sulphur-preparation of 2-azabicyclo [2.2.1] heptan-2-ester
With the 90g(0.305mol among the embodiment 1) (2S, 4R)-1-(di-isopropyl phosphate)-4-hydroxyl pyrrolidine-2-formic acid replaces with 94.5g(0.305mol) (2S, 4R)-1-((4-nitro benzyloxy) carbonyl)-4-hydroxyl pyrrolidine-2-formic acid, triethylamine substitutes with corresponding normal DIPEA, other dosages are all identical with method, obtain light yellow solid 79.4g(0.258mol, yield 84.5%) (1S, 4S)-4-nitro carbobenzoxy-(Cbz)-6-oxo-5-sulphur-2-azabicyclo [2.2.1] heptan-2-ester.
Mp:?102～103℃
1H?NMR(400MHz，CDCl
3)
2.11-2.27(m,?2H),?3.67-3.72(m,?1H),?3.85-3.90(m,?1H),?4.15-4.19(m,?1H),?4.62-4.70(m,?1H),?5.21(d,?1H),?5.31(d,?1H),?7.54(d,?2H)，8.23(d,?2H)。
Embodiment 8
8) (1S, 4S)-4-nitro carbobenzoxy-(Cbz)-6-oxo-5-sulphur-preparation of 2-azabicyclo [2.2.1] heptan-2-ester
With the pivaloyl chloride among the embodiment 7 with being that 40g (0.327mol) isopropyl chlorocarbonate substitutes, other dosages are identical with reaction method, obtain title compound light yellow solid 82.6g(0.268mol, yield 88%) (1S, 4S)-4-nitro carbobenzoxy-(Cbz)-6-oxo-5-sulphur-2-azabicyclo [2.2.1] heptan-2-ester.
Embodiment 9
9) 3-((3S, 5S)-1-(di-isopropyl phosphoryl)-3-mercapto pyrrolidine-5-formamido-) benzoic preparation
With 45.3g (0.148mol) di-isopropyl (1S; 4S)-and 6-oxo-5-sulphur-2-azabicyclo [2.2.1] heptan-2-base phosphoric acid ester and 22.7g(0.164mol) gavaculine is dissolved in the 250ml Glacial acetic acid; react 16h under the room temperature; to wherein adding 600ml methylene dichloride and 300ml 1M hydrochloric acid; the extracting organic layer; concentrate; with ethyl acetate and hexanaphthene recrystallization; get white crystal 59.2g(0.138mol; yield 93%) 3-((3S, 5S)-1-(di-isopropyl phosphoryl)-3-mercapto pyrrolidine-5-formamido-) phenylformic acid.
Mp:?95～96℃
1H?NMR(400MHz，CDCl
3)
1.16(s,?12H),?1.50(s,?1H),?2.07-2.32(m,?2H),?2.65-2.76(m,?1H),?2.90-2.94(m,?1H),?3.06-3.10(m,?1H),?3.57-3.65(m,?2H),?3.71-3.74(m,?1H),?7.45-7.48(m,?1H),?7.87-8.0(m,?3H),?8.50-8.53(m,?1H),?10.9(S,?1H)。
Embodiment 10
10) (2S, 4S)-preparation of 4-nitrobenzyl 2-(formyl-dimethylamino)-4-mercapto pyrrolidine-1-manthanoate
Add in the reaction flask 300ml acetone and 50g (0.162mol) (1S, 4S)-4-nitro carbobenzoxy-(Cbz)-6-oxo-5-sulphur-2-azabicyclo [2.2.1] heptan-2-ester, molten clear.Be cooled to 10 ℃, add 19.8g(0.244mol) dimethylamine hydrochloride.Controlled temperature drips the 24.6g triethylamine at 15 ~ 20 ℃, reacts after 30 minutes concentrating under reduced pressure acetone under uniform temp
To wherein adding 410ml ethyl acetate and 1N HCl, leave standstill phase-splitting.10% salt solution that adds 2.79g tributylphosphine, 180ml in organic phase, the saturated brine of 180ml concentrates organic phase, has a large amount of crystal to separate out.Centrifuging, vacuum drying, white crystal 52.2g (0.148mol, yield 87%) (2S, 4S)-4-nitrobenzyl 2-(formyl-dimethylamino)-4-mercapto pyrrolidine-1-manthanoate.
Mp:?117-119℃
1H?NMR(400MHz，CDCl
3)
1.56(d,?1H),?1.96-2.21(m,?2H),?2.65-2.71(m,?1H),?2.97(s,?3H),?3.08(s,?3H),?3.48-3.73(m,?2H),4.29-4.31(m,?1H),?5.19(s,?2H),?7.48(d,?2H),?8.15(d,?2H)。
Claims (9)
1. the dicyclo intermediates preparation of a synthetic training southern side chain is characterized in that described dicyclo intermediate
The following reaction scheme of structural formula in formula (I) shown in:
Described preparation method is as follows:
1) the formula III compound generates the formula IV compound with the carboxyl activator reaction under the organic bases effect, and temperature of reaction is-30～-5 ℃, and the reaction times is 0.5～2h, and carboxyl activator is 2.0～1.2:1 with the amount of substance ratio of formula III compound;
Wherein, R
3Be the protecting group on the tetramethyleneimine N, be selected from tertbutyloxycarbonyl, to nitro carbobenzoxy-(Cbz), carbobenzoxy-(Cbz), to methoxyl group benzyloxy carbonyl, allyloxycarbonyl, carbobenzoxy-(Cbz) or di-isopropyl phosphoryl;
2) the formula IV compound is under the organic bases effect, and with hydroxy activating reagent reaction production (V) compound, temperature of reaction is-20～-5 ℃, and the reaction times is 0.5～2h, and the amount of substance of hydroxy activating reagent and formula IV compound is than 1.5～1.05:1;
3) formula (V) compound and sulfide at low temperatures cyclization obtain dicyclic compound (I), temperature of reaction is-20～0 ℃, the reaction times is 1～5h, the mol ratio of sulfide and formula (V) compound is 2～8:1.
2. preparation method according to claim 1, it is characterized in that, described carboxyl activator is sulfonyl chloride compound, sulphonic acid anhydride, alkyl chloride manthanoate, alkyl acyl chloride compound, N, N-carbonyl dimidazoles or dicyclohexylcarbodiimide, pivaloyl chloride or isopropyl chlorocarbonate.
3. preparation method according to claim 2 is characterized in that, described sulfonyl chloride compound is methane sulfonyl chloride, Tosyl chloride or benzene sulfonyl chloride; Described sulphonic acid anhydride is methylsulfonic acid acid anhydride or tosic acid acid anhydride; Described alkyl chloride manthanoate is Vinyl chloroformate, isopropyl chlorocarbonate or the chloroformic acid tert-butyl ester; Described chloride compounds is oxalyl chloride or pivaloyl chloride.
4. preparation method according to claim 1 is characterized in that, described organic bases is triethylamine, diisopropylethylamine, pyridine, picoline, imidazoles or quinoline.
5. preparation method according to claim 1 is characterized in that, described sulfide is sodium sulphite, Sodium sulfhydrate or potassium sulphide.
6. preparation method according to claim 1 is characterized in that, the solvent of using in each reactions steps is selected from ethers, halogenated alkane, second eyeball, toluene, ethyl acetate or DMF.
7. preparation method according to claim 6 is characterized in that, described ethers is oxyethane, ether or tetrahydrofuran (THF); Described halogenated alkane is methylene dichloride, chloroform or 1, the 2-ethylene dichloride.
8. the described formula I application of compound of claim 1 is characterized in that, described formula I compound and amine open loop condensation obtain training southern side chain compound (II), and reaction formula is as follows:
Described amine is any primary amine or secondary amine;
Solvent in the reaction is oxyethane, tetrahydrofuran (THF), ethyl acetate, toluene, acetone, acetate or DMF; Temperature of reaction is 0～40 ℃, and the reaction times is 30min～24h.
9. described according to Claim 8 formula I application of compound is characterized in that described primary amine is NH
2PhCO
2H or NHBSO
2NH
2Described secondary amine is HN (CH
3)
2Or HN (CH
3) C
2H
5
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2012062036A1 (en) * | 2010-11-12 | 2012-05-18 | 上海巴迪生物医药科技有限公司 | Preparation method and applications of a two-ring intermediate including a penem-type side chain |
| CN102976994A (en) * | 2012-12-27 | 2013-03-20 | 天津市敬业精细化工有限公司 | Crystal form meropenem side chain and preparation method thereof |
| CN110386942A (en) * | 2019-07-12 | 2019-10-29 | 天津大学 | A kind of preparation method of Meropenem side chain intermediate mercaptan lactone |
| CN111484506A (en) * | 2020-04-16 | 2020-08-04 | 天津大学 | Preparation method of improved meropenem side chain intermediate thiolactone by adding surfactant |
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| CN114773248A (en) * | 2022-05-11 | 2022-07-22 | 湖北华洲药业有限公司 | Continuous production method and device for meropenem side chain |
| CN115490625A (en) * | 2022-11-18 | 2022-12-20 | 山东鑫泉医药有限公司 | Synthesis and refining method of meropenem side chain |
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| CN102134249B (en) * | 2010-12-30 | 2015-11-25 | 天津市敬业精细化工有限公司 | A kind of chirality 5-protects the preparation method of-2-thia-5-azabicyclo [2.2.1]-3-in heptan ketone |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2012062036A1 (en) * | 2010-11-12 | 2012-05-18 | 上海巴迪生物医药科技有限公司 | Preparation method and applications of a two-ring intermediate including a penem-type side chain |
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| CN110386942A (en) * | 2019-07-12 | 2019-10-29 | 天津大学 | A kind of preparation method of Meropenem side chain intermediate mercaptan lactone |
| CN111484506A (en) * | 2020-04-16 | 2020-08-04 | 天津大学 | Preparation method of improved meropenem side chain intermediate thiolactone by adding surfactant |
| CN114437043A (en) * | 2022-02-02 | 2022-05-06 | 浙江乐普药业股份有限公司 | Preparation method of anti-neocorolla drug Nirmatrelvir |
| CN114773248A (en) * | 2022-05-11 | 2022-07-22 | 湖北华洲药业有限公司 | Continuous production method and device for meropenem side chain |
| CN114773248B (en) * | 2022-05-11 | 2023-11-03 | 湖北华洲药业有限公司 | Continuous production method and device for meropenem side chain |
| CN115490625A (en) * | 2022-11-18 | 2022-12-20 | 山东鑫泉医药有限公司 | Synthesis and refining method of meropenem side chain |
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