CN114478437A - Method for preparing N-methyl-2-pyrrolidine ethylamine or salt thereof - Google Patents
Method for preparing N-methyl-2-pyrrolidine ethylamine or salt thereof Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 39
- 150000003839 salts Chemical class 0.000 title claims abstract description 8
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 title abstract description 16
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 title abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 29
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims description 38
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 13
- 239000002253 acid Substances 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 11
- 230000035484 reaction time Effects 0.000 claims description 11
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 10
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 6
- 238000005580 one pot reaction Methods 0.000 claims description 6
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 5
- 150000007522 mineralic acids Chemical class 0.000 claims description 5
- 150000007524 organic acids Chemical class 0.000 claims description 5
- 238000006467 substitution reaction Methods 0.000 claims description 5
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-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
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 4
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 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
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- 235000011054 acetic acid Nutrition 0.000 claims description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 2
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 2
- 229940043279 diisopropylamine Drugs 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 150000002170 ethers Chemical class 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 150000008282 halocarbons Chemical class 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 239000011976 maleic acid Substances 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- 235000006408 oxalic acid Nutrition 0.000 claims description 2
- 239000003880 polar aprotic solvent Substances 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 2
- 229940086542 triethylamine Drugs 0.000 claims description 2
- -1 aromatics Chemical class 0.000 claims 1
- 239000006227 byproduct Substances 0.000 abstract description 14
- 238000009776 industrial production Methods 0.000 abstract description 7
- 230000007613 environmental effect Effects 0.000 abstract description 2
- GYGYDOOXVKDZCF-UHFFFAOYSA-N n-methyl-2-pyrrolidin-1-ylethanamine Chemical compound CNCCN1CCCC1 GYGYDOOXVKDZCF-UHFFFAOYSA-N 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000001816 cooling Methods 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- 101100189582 Dictyostelium discoideum pdeD gene Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 208000010228 Erectile Dysfunction Diseases 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 101150098694 PDE5A gene Proteins 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 102100029175 cGMP-specific 3',5'-cyclic phosphodiesterase Human genes 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 201000001881 impotence Diseases 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- BAVYZALUXZFZLV-UHFFFAOYSA-N mono-methylamine Natural products NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- DOTPSQVYOBAWPQ-UHFFFAOYSA-N pyrazolo[4,3-d]pyrimidin-3-one Chemical class N1=CN=C2C(=O)N=NC2=C1 DOTPSQVYOBAWPQ-UHFFFAOYSA-N 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 208000014001 urinary system disease Diseases 0.000 description 1
- 208000020544 urinary system symptom Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention provides a method for preparing N-methyl-2-pyrrolidine ethylamine or a salt thereof, which comprises the following steps: c) reacting compound IV with compound V to form compound VI, d) de-bocating compound VI to give compound I, i.e. N-methyl-2-pyrrolidinoethylamine. The synthetic route has the advantages of high yield, few byproducts, environmental friendliness, economy and the like, and is suitable for being developed into an industrial production process.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry synthesis, in particular to a preparation method of N-methyl-2-pyrrolidine ethylamine and hydrochloride thereof, and a method for preparing TPN729 by using the method.
Background
TPN729, chemically 1-methyl-5- { 2-propoxy-5- [ [ 1-methyl-1- (2-pyrrolidin-1-yl) ethyl ] aminosulfonyl ] phenyl } -3-propyl-1, 6-dihydro-7H-pyrazolo [4,3-d ] pyrimidin-7-one, having the following specific structural formula:
WO2007/056955 discloses a class of pyrazolopyrimidinone derivatives, preparation methods and uses thereof. The derivatives have stronger PDE5 inhibition activity and lower toxicity proved by pharmacological tests, can be clinically used for improving or treating cardiovascular and cerebrovascular systems and urinary system symptoms or diseases, particularly for improving or treating symptoms or diseases including erectile dysfunction, and comprise TPN729 which shows extremely high activity and selectivity on PED5 enzyme in-vitro enzyme inhibitor screening tests.
The current preparation of synthetic TPN729 requires the passage of a key intermediate, N-methyl-2-pyrrolidinoethylamine, compound I shown below, including its free base and salt forms:
a previous synthetic route for compound I is as follows:
the main disadvantages of the route are that: (1) the intermediate 1 is not readily available in the market and can only be prepared by a preliminary reaction. (2) Thionyl chloride is needed for synthesizing the intermediate 2, and the industrial production has large pollution. (3) The same side reactions of the methyl amine substitution in the synthesized compound 3 are more, for example, impurities 3-a, 2 per se and 2 and 3 mutually form quaternary ammonium salt and the like generated by double substitution, so that the yield is low.
In view of the above-mentioned disadvantages of the conventional methods, it is of great practical significance to develop a preparation method which has a short synthetic route, high atom economy, low production cost and is easy for industrial production.
Disclosure of Invention
Technical problem
The technical problem to be solved by the invention is to overcome the defects of the prior art and provide a method for preparing N-methyl-2-pyrrolidine ethylamine, which has mild reaction conditions and simple and convenient process and is suitable for industrialization.
Therefore, the invention aims to provide the preparation method of the N-methyl-2-pyrrolidine ethylamine, which has the advantages of high yield, less by-products, environmental protection, economy and the like and is suitable for being developed into an industrial production process.
Technical scheme
According to one aspect, the present invention provides a process for the preparation of a compound of formula I or a salt thereof as described below, comprising the steps of:
c) carrying out substitution reaction on the compound IV and the compound V to generate a compound VI,
d) removing Boc from the compound VI to obtain a compound I,
wherein, Boc is tert-butyloxycarbonyl, and Ms is methylsulfonyl.
Advantageous effects
The invention firstly uses easily obtained chemicals as starting raw materials to prepare the N-methyl-2-pyrrolidine ethylamine and the hydrochloride thereof. The method has the advantages of few byproducts in the synthesis process, easy purification, high total yield, no pollution, suitability for development of industrial production process and accordance with the green economic principle.
Detailed Description
To make the features and effects of the present invention comprehensible to those having ordinary knowledge in the art, general description and definitions are made with respect to terms and phrases mentioned in the specification and claims. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
In this document, the terms "comprising," "including," "having," "containing," or any other similar term, are intended to be open-ended franslational phrase (open-ended franslational phrase) and are intended to cover non-exclusive inclusions. For example, a composition or article comprising a plurality of elements is not limited to only those elements recited herein, but may include other elements not expressly listed but generally inherent to such composition or article. In addition, unless expressly stated to the contrary, the term "or" is intended to mean an inclusive "or" rather than an exclusive "or". For example, the condition "a or B" is satisfied in any of the following cases: a is true (or present) and B is false (or not present), a is false (or not present) and B is true (or present), both a and B are true (or present). Furthermore, in this document, the terms "comprising," including, "" having, "" containing, "and" containing "are to be construed as specifically disclosed and to cover both closed and semi-closed conjunctions, such as" consisting of … "and" consisting essentially of ….
All features or conditions defined herein as numerical ranges or percentage ranges are for brevity and convenience only. Accordingly, the description of a range of values or percentages should be considered to cover and specifically disclose all possible subranges and individual values within the range, particularly integer values. For example, a description of a range of "1 to 8" should be considered to have specifically disclosed all subranges such as 1 to 7, 2 to 8, 2 to 6, 3 to 6, 4 to 8, 3 to 8, and so on, particularly subranges bounded by all integer values, and should be considered to have specifically disclosed individual values such as 1,2, 3, 4, 5, 6, 7, 8, and so on, within the range. Unless otherwise indicated, the foregoing explanatory methods apply to all matters contained in the entire disclosure, whether broad or not.
If an amount or other value or parameter is expressed as a range, preferred range, or a list of upper and lower limits, it is to be understood that all ranges subsumed therein for any pair of that range's upper or preferred value and that range's lower or preferred value, whether or not such ranges are separately disclosed, are specifically disclosed herein. Further, when a range of numerical values is recited herein, unless otherwise stated, the range is intended to include the endpoints thereof, and all integers and fractions within the range.
In this context, numerical values should be understood to have the precision of the number of significant digits of the value, provided that the object of the invention is achieved. For example, the number 40.0 should be understood to cover a range from 39.50 to 40.49.
In this document, where Markush group (Markush group) or Option language is used to describe features or examples of the invention, those skilled in the art will recognize that a sub-group of all elements or any individual element within a Markush group or list of options may also be used to describe the invention. For example, if X is described as "selected from the group consisting of1、X2And X3The group "also indicates that X has been fully described as X1Is claimed with X1And/or X2Claim (5). Furthermore, where Markush group or option terms are used to describe features or examples of the invention, those skilled in the art will recognize that any combination of sub-groups of all elements or individual elements within the Markush group or option list can also be used to describe the invention. Accordingly, for example, if X is described as "selected from the group consisting of1、X2And X3Group consisting of "and Y is described as" selected from Y1、Y2And Y3The group "formed indicates that X has been fully described as X1Or X2Or X3And Y is Y1Or Y2Or Y3Claim (5).
The following detailed description is merely exemplary in nature and is not intended to limit the invention or the application thereof. Furthermore, there is no intention to be bound by any theory presented in the preceding prior art or the summary of the invention or the following detailed description or examples.
According to one embodiment of the present disclosure, there is provided a method of preparing a compound represented by formula I or a salt thereof as described below, the method comprising the steps of:
c) carrying out substitution reaction on the compound IV and the compound V to generate a compound VI,
d) de-Boc compound VI to give compound I,
wherein, Boc is tert-butyloxycarbonyl, and Ms is methylsulfonyl.
By the method, the N-methyl-2-pyrrolidine ethylamine and the hydrochloride thereof are prepared by using readily available chemicals as starting materials. The method has the advantages of few byproducts in the synthesis process, easy purification, high total yield, no pollution, suitability for development of industrial production process and accordance with the green economic principle.
According to an embodiment of the present disclosure, in step c), the feeding molar ratio of the compound V to the compound IV is 1 to 3:1, preferably 1 to 1.3:1, and more preferably 1.05 to 1.1: 1. At the above-mentioned feed ratio, the reaction can be promoted to proceed smoothly in a desired direction, the conversion rate can be improved, and the production of by-products can be reduced.
According to one embodiment of the present disclosure, the reaction temperature of step c) is 30 ℃ to 70 ℃, preferably 45 ℃ to 55 ℃, and the reaction time is 8 hours to 24 hours, preferably 10 hours to 12 hours. At the above reaction temperature and reaction time, the reaction rate can be increased, the conversion rate can be increased, and the production of by-products can be reduced.
According to one embodiment of the present disclosure, the de-Boc of step d) may be performed under any suitable conditions without particular limitation as long as the de-Boc purpose can be achieved without significant adverse effects on the reaction product. For example, the Boc removal can be carried out in the presence of an acid. The acid may be an organic acid or an inorganic acid. The organic acid can be selected from formic acid, acetic acid, propionic acid, oxalic acid, maleic acid, citric acid, tartaric acid, methanesulfonic acid, and benzenesulfonic acid; the inorganic acid may be selected from hydrochloric acid, sulfuric acid and phosphoric acid. In particular, the acid is hydrochloric acid, in which case step d) may yield the hydrochloride salt of the compound of formula I. In the case of using the above-mentioned specific organic acid and inorganic acid, the selectivity can be improved and the production of other by-products can be reduced.
In the case where the de-Boc is carried out in the presence of an acid, a salt of the compound of formula I with the acid can be obtained.
In the case of Boc removal in the presence of an acid, the molar ratio of the acid used to the compound of the formula VI is 2-3: 1, preferably 2.3-2.7: 1, more preferably 2.4-2.6: 1. At the above-mentioned feed ratio, the reaction can be promoted to proceed smoothly in a desired direction, the conversion rate can be improved, and the production of by-products can be reduced.
According to one embodiment of the present disclosure, wherein the reaction temperature of step d) is-15 ℃ to 15 ℃, preferably-10 ℃ to 10 ℃; the reaction time is 1 to 2 hours. At the above reaction temperature and reaction time, the reaction rate can be increased, the conversion rate can be increased, and the production of by-products can be reduced.
According to another embodiment of the present disclosure, wherein the method further comprises, before step c):
a) reacting compound II with Boc anhydride to produce compound III,
b) reacting compound III with methanesulfonyl chloride to form compound IV,
that is, the general reaction formula of the process is as follows:
wherein step b) may be carried out under the action of an alkaline agent. The alkaline reagent can be one or a mixture of more of potassium tert-butoxide, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine and pyridine.
By using the compound II as a starting material, the intermediate is easy to carry out post-treatment operation after protective groups are introduced, and finally the protective groups are deprotected and salified simultaneously, so that the total yield of the 4-step reaction is 60%. The method has the advantages of few byproducts in the synthesis process, easy purification, high total yield of the four-step reaction, no pollution, suitability for developing an industrial production process and accordance with the green economic principle.
According to an embodiment of the disclosure, in step a), the feeding molar ratio of the Boc anhydride to the compound of formula II is 1 to 1.05:1, preferably 1 to 1.03:1, and more preferably 1 to 1.01: 1. At the above-mentioned feed ratio, the reaction can be promoted to proceed smoothly in a desired direction, the conversion rate can be improved, and the production of by-products can be reduced.
According to one embodiment of the present disclosure, wherein, in step a), the reaction temperature is preferably-15 ℃ to 15 ℃, more preferably-10 ℃ to 10 ℃; the reaction time is 0.5 to 1 hour.
According to an embodiment of the present disclosure, in step b), the charging molar ratio of methanesulfonyl chloride to compound III is 1 to 1.05:1, preferably 1 to 1.03:1, and more preferably 1 to 1.01: 1. At the above-mentioned feed ratio, the reaction can be promoted to proceed smoothly in a desired direction, the conversion rate can be improved, and the production of by-products can be reduced.
According to an embodiment of the present disclosure, in step b), the feeding molar ratio of the alkaline agent to the compound III is 1 to 1.05:1, preferably 1 to 1.03:1, and more preferably 1 to 1.02: 1. At the above-mentioned feed ratio, the reaction can be promoted to proceed smoothly in a desired direction, the conversion rate can be improved, and the production of by-products can be reduced.
According to one embodiment of the present disclosure, wherein, in step b), the reaction temperature is from-15 ℃ to 15 ℃, preferably from-10 ℃ to 10 ℃; the reaction time is 0.5 to 2 hours. At the above reaction temperature and reaction time, the reaction rate can be increased, the conversion rate can be increased, and the production of by-products can be reduced.
According to an embodiment of the present disclosure, the steps a) to d) are performed by a one-pot method, and the solvent used in the one-pot method is one or a mixture of two or more selected from alkanes, aromatic hydrocarbons, halogenated hydrocarbons, esters, ethers, polar aprotic solvents, preferably dichloromethane and toluene.
According to an embodiment of the present disclosure, the mass-to-volume ratio of the solvent to the compound of formula II is 5 to 12:1, preferably 7 to 11:1, and more preferably 8 to 10: 1.
In the case of using the one-pot method, and using the above-mentioned specific solvent and solvent content, the one-pot reaction can be smoothly performed, and the consumption of the intermediate purification step and the like can be reduced.
The advantages of the present invention will now be further described by the following examples, which are to be understood as being illustrative only and not limiting to the scope of the invention, and that variations and modifications apparent to those of ordinary skill in the art in light of the present invention are intended to be included within the scope of the invention.
EXAMPLE 1 Synthesis of Compound III
Dissolving the compound II in toluene solvent, cooling to 0-10 ℃ in ice water bath, and dropwise adding Boc2O, gas is released in the dripping process, the temperature is controlled to be lower than 20 ℃, the mixture is stirred for 30min at about 0-10 ℃ after the dripping is finished, and the next step is directly carried out after the TLC shows that the reaction is finished;1h NMR (400MHz, chloroform-d) δ 3.74(t, J ═ 5.4Hz,2H),3.39(t, J ═ 5.4Hz,2H),2.92(s,3H),2.66(s,1H),1.46(s,9H).13C NMR (101MHz, chloroform-d) delta 157.04,79.79,60.75,51.17,35.34,28.33.
EXAMPLE 2 Synthesis of Compound IV
Cooling the reaction liquid to 0-10 ℃, adding triethylamine, dropwise adding MsCl, controlling the temperature to be less than 20 ℃ in the dropwise adding process, separating out white solids, and stirring for 30min after dropwise adding. TLC shows that the reaction is finished, the reaction solution is filtered, the filter cake is washed by toluene, and the filtrate is directly carried out in the next step;
EXAMPLE 3 Synthesis of Compound VI
And (2) replacing the filtrate with nitrogen for three times, controlling the temperature to be lower than 20 ℃, dropwise adding pyrrolidine, raising the temperature to 35-45 ℃ after dropwise adding, stirring for more than 16h, and after TLC (thin layer chromatography) shows that the reaction of the raw material IV is finished, performing aftertreatment: cooling the reaction solution to about 20 ℃, and adding waterStirring and layering, washing an organic layer for 2 times by using water, concentrating the organic layer to remove water, filtering, and concentrating and drying filtrate to obtain a light-colored oily substance VI with the mass yield: 170-.1H NMR (400MHz, chloroform-d) δ 3.43-3.31 (m,2H),2.88(s,3H),2.60 (d, J ═ 10.7Hz,6H),1.78(m, J ═ 3.1Hz,4H),1.46(s,9H).13C NMR (101MHz, chloroform-d) delta 155.57,79.16,54.20,53.85,53.44,48.07,47.65,34.51,28.36,23.37
EXAMPLE 4 Synthesis of Compound I
Cooling VI to 0-10 ℃, dropwise adding concentrated hydrochloric acid, controlling the temperature to be less than 40 ℃, discharging gas in the dropwise adding process, heating to 55-65 ℃ after dropwise adding, reacting for 1h, monitoring the VI by TLC to react completely, concentrating to remove water, adding isopropanol to disperse, concentrating to remove a solvent, adding 5 times of isopropanol, heating, refluxing, dissolving, cooling to separate out a solid, stirring for 3-4h at about 20 ℃, filtering, washing a filter cake by using isopropanol, and drying at 60 ℃ to obtain a white-like solid I, wherein the mass yield is as follows: 60 to 85 percent.1H NMR (400MHz, chloroform-d) δ 3.53-3.31 (dt, J ═ 79.2,6.8Hz 8H),3.07(s,1H), 2.56(s,3H),1.93(s,4H).13C NMR(101MHz,DMSO-d6)δ53.54,49.47,43.95, 32.65,23.13.
Claims (10)
1. A process for preparing a compound of formula I or a salt thereof as described below, comprising the steps of:
c) carrying out substitution reaction on the compound IV and the compound V to generate a compound VI,
d) removing Boc from the compound VI to obtain a compound I,
wherein, Boc is tert-butyloxycarbonyl, and Ms is methylsulfonyl.
2. The process according to claim 1, wherein in step c), the charged molar ratio of compound V to compound IV is 1-3: 1, preferably 1-1.3: 1, more preferably 1.05-1.1: 1,
wherein the reaction temperature of the step c) is 30-70 ℃, preferably 45-55 ℃, and the reaction time is 8-24 hours, preferably 10-12 hours.
3. The process according to claim 1, wherein the de-Boc in step d) is carried out in the presence of an acid, said acid being an organic or inorganic acid, said organic acid being selected from the group consisting of formic acid, acetic acid, propionic acid, oxalic acid, maleic acid, citric acid, tartaric acid, methanesulfonic acid and benzenesulfonic acid; the inorganic acid is selected from the group consisting of hydrochloric acid, sulfuric acid and phosphoric acid, in particular, the acid is hydrochloric acid.
4. The process according to claim 1, wherein the molar ratio of acid used in step d) to compound of formula VI is 2-3: 1, preferably 2.3-2.7: 1, more preferably 2.4-2.6: 1,
wherein the reaction temperature of step d) is from-15 ℃ to 15 ℃, preferably from-10 ℃ to 10 ℃; the reaction time is 1 to 2 hours.
5. The method of claim 1, wherein the method further comprises, prior to step c):
a) reacting compound II with Boc anhydride to produce compound III,
b) reacting compound III with methanesulfonyl chloride to form compound IV,
that is, the general reaction formula of the process is as follows:
in particular, step b) is carried out in the presence of a basic agent, preferably a mixture of one or more selected from potassium tert-butoxide, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine.
6. The process of claim 5, wherein in step a), the feeding molar ratio of Boc anhydride to the compound of formula II is 1-1.05: 1, preferably 1-1.03: 1, more preferably 1-1.01: 1,
wherein, in step a), the reaction temperature is preferably-15 ℃ to 15 ℃, more preferably-10 ℃ to 10 ℃; the reaction time is 0.5 to 1 hour.
7. The method according to claim 5, wherein in step b), the feeding molar ratio of methanesulfonyl chloride to the compound III is 1-1.05: 1, preferably 1-1.03: 1, more preferably 1-1.01: 1,
wherein, in step b), the reaction temperature is from-15 ℃ to 15 ℃, preferably from-10 ℃ to 10 ℃; the reaction time is 0.5 to 2 hours.
8. The method according to claim 5, wherein in step b), the molar ratio of the alkaline agent to the compound III is 1-1.05: 1, preferably 1-1.03: 1, and more preferably 1-1.02: 1.
9. The method according to claim 5, wherein the steps a) to d) are performed using a one-pot method, and the solvent used in the one-pot method is one or a mixture of two or more selected from the group consisting of alkanes, aromatics, halogenated hydrocarbons, esters, ethers, polar aprotic solvents, preferably dichloromethane and toluene.
10. The method according to claim 5, wherein the mass-to-volume ratio of the solvent to the compound of formula II is 5-12: 1, preferably 7-11: 1, and more preferably 8-10: 1.
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| WO2007056955A1 (en) * | 2005-11-17 | 2007-05-24 | Topharman Shanghai Co., Ltd. | Pyrazolopyrimidinone derivatives, their preparation and their use |
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| WO2007056955A1 (en) * | 2005-11-17 | 2007-05-24 | Topharman Shanghai Co., Ltd. | Pyrazolopyrimidinone derivatives, their preparation and their use |
| CN110088096A (en) * | 2016-10-20 | 2019-08-02 | 阿尔麦克探索有限公司 | The piperidine derivative of inhibitor as ubiquitin-specific protease 7 |
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