CN116675707A - Method for synthesizing optical isomer of zilpate Luo Shunshi - Google Patents
Method for synthesizing optical isomer of zilpate Luo Shunshi Download PDFInfo
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- CN116675707A CN116675707A CN202310450563.XA CN202310450563A CN116675707A CN 116675707 A CN116675707 A CN 116675707A CN 202310450563 A CN202310450563 A CN 202310450563A CN 116675707 A CN116675707 A CN 116675707A
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- shunshi
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- 230000003287 optical effect Effects 0.000 title claims abstract description 26
- 238000000034 method Methods 0.000 title claims abstract description 22
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 20
- ZSTCZWJCLIRCOJ-DGCLKSJQSA-N Zilpaterol Chemical compound O[C@H]1[C@H](NC(C)C)CCN2C(=O)NC3=CC=CC1=C32 ZSTCZWJCLIRCOJ-DGCLKSJQSA-N 0.000 claims abstract description 21
- 229960000960 zilpaterol Drugs 0.000 claims abstract description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 16
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 6
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims abstract description 4
- 230000001105 regulatory effect Effects 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 39
- 238000006243 chemical reaction Methods 0.000 claims description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 23
- 238000003786 synthesis reaction Methods 0.000 claims description 20
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- 230000015572 biosynthetic process Effects 0.000 claims description 18
- 239000007787 solid Substances 0.000 claims description 15
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 12
- 239000002994 raw material Substances 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 9
- -1 anhydride di-tert-butyl carbonate Chemical class 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- 239000000047 product Substances 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 6
- 239000012074 organic phase Substances 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 5
- 238000001514 detection method Methods 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- 239000000758 substrate Substances 0.000 claims description 5
- 239000007858 starting material Substances 0.000 claims description 4
- UPULOMQHYQDNNT-UHFFFAOYSA-N 5h-1,3-oxazol-2-one Chemical compound O=C1OCC=N1 UPULOMQHYQDNNT-UHFFFAOYSA-N 0.000 claims description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 230000008859 change Effects 0.000 claims description 3
- 239000012295 chemical reaction liquid Substances 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 239000007791 liquid phase Substances 0.000 claims description 3
- 239000000741 silica gel Substances 0.000 claims description 3
- 229910002027 silica gel Inorganic materials 0.000 claims description 3
- 238000010898 silica gel chromatography Methods 0.000 claims description 3
- 239000011780 sodium chloride Substances 0.000 claims description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims description 3
- 239000000243 solution Substances 0.000 claims description 3
- 150000001408 amides Chemical class 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 238000010791 quenching Methods 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 claims description 2
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- GOXPSGTXTWQSQL-UHFFFAOYSA-N (1-amino-2-methylpropan-2-yl) formate Chemical compound NCC(C)(C)OC=O GOXPSGTXTWQSQL-UHFFFAOYSA-N 0.000 claims 1
- 229940126062 Compound A Drugs 0.000 claims 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims 1
- 230000000269 nucleophilic effect Effects 0.000 claims 1
- 230000000171 quenching effect Effects 0.000 claims 1
- 230000009471 action Effects 0.000 abstract description 3
- XBXCNNQPRYLIDE-UHFFFAOYSA-M n-tert-butylcarbamate Chemical compound CC(C)(C)NC([O-])=O XBXCNNQPRYLIDE-UHFFFAOYSA-M 0.000 abstract description 3
- ODCCJTMPMUFERV-UHFFFAOYSA-N ditert-butyl carbonate Chemical compound CC(C)(C)OC(=O)OC(C)(C)C ODCCJTMPMUFERV-UHFFFAOYSA-N 0.000 abstract description 2
- 230000003301 hydrolyzing effect Effects 0.000 abstract description 2
- 238000005650 intramolecular substitution reaction Methods 0.000 abstract 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 12
- YXCPDVDLUQEPKX-UHFFFAOYSA-N 2h-azulen-1-one Chemical compound C1=CC=CC=C2C(=O)CC=C21 YXCPDVDLUQEPKX-UHFFFAOYSA-N 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 238000010586 diagram Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 125000005605 benzo group Chemical group 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 102000051367 mu Opioid Receptors Human genes 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 108020001612 μ-opioid receptors Proteins 0.000 description 2
- 108060003345 Adrenergic Receptor Proteins 0.000 description 1
- 102000017910 Adrenergic receptor Human genes 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 229940123257 Opioid receptor antagonist Drugs 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 208000020329 Zika virus infectious disease Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 102000030621 adenylate cyclase Human genes 0.000 description 1
- 108060000200 adenylate cyclase Proteins 0.000 description 1
- 239000000048 adrenergic agonist Substances 0.000 description 1
- 229940126157 adrenergic receptor agonist Drugs 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229960001117 clenbuterol Drugs 0.000 description 1
- STJMRWALKKWQGH-UHFFFAOYSA-N clenbuterol Chemical compound CC(C)(C)NCC(O)C1=CC(Cl)=C(N)C(Cl)=C1 STJMRWALKKWQGH-UHFFFAOYSA-N 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002169 ethanolamines Chemical class 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- YAMHXTCMCPHKLN-UHFFFAOYSA-N imidazolidin-2-one Chemical group O=C1NCCN1 YAMHXTCMCPHKLN-UHFFFAOYSA-N 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical group CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 229940087646 methanolamine Drugs 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
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen(.) Chemical compound [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- YJQZYXCXBBCEAQ-UHFFFAOYSA-N ractopamine Chemical compound C=1C=C(O)C=CC=1C(O)CNC(C)CCC1=CC=C(O)C=C1 YJQZYXCXBBCEAQ-UHFFFAOYSA-N 0.000 description 1
- 229940074095 ractopamine Drugs 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 229960002052 salbutamol Drugs 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/16—Peri-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/06—Peri-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses a method for synthesizing an optical isomer of zilpate Luo Shunshi, which comprises the following steps of: reacting a compound with a trans-ethanolamine structure with di-tert-butyl carbonate to generate tert-butyl carbamate; under the action of methanesulfonyl chloride, carrying out intramolecular substitution reaction to obtain a cis-oxazolinone ring intermediate; hydrolyzing the oxazoline ketone ring intermediate under alkaline condition, and regulating pH value by hydrochloric acid to obtain isomer of cis-ethanolamine structure. By using this method, the present invention successfully obtains the cis-optical isomer of zilpaterol in 33% of total yield, solving the problem that the cis-optical isomer of zilpaterol Luo Shunshi is difficult to obtain in the past.
Description
Technical Field
The invention relates to the field of organic synthesis, and relates to a method for synthesizing an optical isomer of zilpate Luo Shunshi.
Background
In the field of organic synthesis, the synthesis methods of cis-o-diol and cis-o-diamine structures are numerous, but the cis-o-amino alcohol structural unit is difficult to directly construct, and the products obtained by the way of ring opening of ethylene oxide and reduction of alpha-aminocarbonyl or alpha-hydroxyamide derivatives are all in a trans configuration. The current synthesis process of the zilpaterol adopts a reduction route, a trans-structure product is obtained with high selectivity, the dr value is more than 98%, and the zilpaterol Luo Shunshi optical isomer is difficult to obtain.
Zilpaterol is beta 2 Adrenergic receptor agonists and mu-opioid receptor antagonists. Agonizing beta 2 The adrenergic receptor can activate adenylate cyclase, so as to relax bronchial smooth muscle and achieve the aim of relieving asthma, and currently marketed drugs such as clenbuterol, ractopamine, salbutamol and the like are all used as targets; because the drug also acts on mu-opioid receptors, adverse reactions such as mental dependence and the like can be generated, and the clinical application of the drug is limited. The mother nucleus of the zilpaterol is benzo tetrahydrogen nitrogenAnd an imidazolidinone structure comprising 2 adjacent chiral centers, wherein the C6 and C7 positions are hydroxyl and isopropylamine groups, respectively, and are trans-structured. In recent years, zilpaterol cis (EWS/FLI) has been shown to inhibit proliferation of epstein-barr sarcoma (RDES, TC32, EW8, TC71 cells); in addition, it was found that it has anti-zika virus activity, and more biological activity and related action mechanisms are still to be studied more intensively.
Disclosure of Invention
To solve 2 key problems in the prior art, namely that cis-o-amino alcohols are difficult to synthesize and that the optical isomer of the zilpate Luo Shunshi is difficult to obtain.
The invention provides a method for synthesizing an optical isomer of zilpate Luo Shunshi, a method strategy for synthesizing a cis-optical isomer of an anti-o-amino alcohol compound, and a method for synthesizing an optical isomer of zilpate Luo Shunshi, which solves the problem that the optical isomer of zilpate Luo Shunshi is difficult to obtain.
Successful synthesis of the cis optical isomer of zilpaterol also demonstrates the feasibility of synthetic methods by cis-o-amino alcohols.
The technical scheme provided by the invention is as follows:
a method of synthesizing an optical isomer of zilpate Luo Shunshi comprising the steps of:
reacting the trans-o-amino alcohol compound with di-tert-butyl carbonate to generate tert-butyl carbamate B;
under the action of methanesulfonyl chloride, carrying out intramolecular substitution reaction to obtain a cis-oxazole ring intermediate (C);
and (3) hydrolyzing the oxazole ring intermediate C under alkaline conditions, and regulating the pH value by using hydrochloric acid to obtain the cis-o-amino alcohol isomer D.
The principle of the strategy technology for synthesizing the cis optical isomer by taking a compound with a trans-o-amino alcohol structure as a raw material is described in detail:
trans-o-amino alcohol A and di-tert-butyl carbonate anhydride ((Boc) 2 O) reacting to obtain a tert-butyl carbamate intermediate B; the key step is that the benzyl hydroxyl of the intermediate B reacts with methanesulfonyl chloride to produce methanesulfonate, the methanesulfonate is a functional group which is easy to leave, the tert-butoxy of the intermediate B is just positioned on the back of the methanesulfonate, the oxygen atom of the intermediate B has nucleophilicity, and S can occur from back attack of the sulfonate group on benzyl C N 2 Affinity substitution reaction, thereby obtaining a cis-oxazolinone ring intermediate C; and (3) respectively carrying out ester and amide hydrolysis reaction on the intermediate C under alkaline conditions, and finally completing chiral inversion of hydroxyl to obtain the isomer of cis-o-amino alcohol.
A method for synthesizing an optical isomer of zilpaterol, comprising the steps of:
s1: synthesis of trans-6-hydroxy-1-oxo-1,2,6,7,8,9-hexahydro-2, 9 a-diazabenzo [ cd ]]-7-yl-carbamic acid tert-butyl ester (2);
s2: synthesis of cis-6, 77a,10 a-tetrahydro-10-oxa-4, 5a, 8-triazo benzo [ cd ]]Cyclopenta [ f ]]-5,9 (4 h,8 h) -dione (3);
s3: synthesis of cis-7-amino-6-hydroxy-6, 7,8, 9-tetrahydro-2, 9 a-diazabenzo [ cd ]]-1 (2H) -one (4);
s4: synthesis of cis-6-hydroxy-7- (isopropylamino) -6,7,8, 9-tetrahydro-2, 9 a-diazabenzo [ cd ]]-1 (2H) -one (5).
By optimizing the reaction conditions, S1 comprises the following sub-steps:
s1-1: substrate 1 (3.0 g,0.010mol,1.0 eq.) was dissolved in 50mL of methylene chloride in a 250mL round bottom flask and Et was added 3 N (3.6 g,0.036mol,3.0 eq.) was added dropwise via a constant pressure dropping funnel (Boc) 2 O(1.6g,0.016mol,1.3eq.)。
S1-2: after the dripping is finished, the reaction is carried out for 12 hours at room temperature (28 ℃), 40mL of water and 20mL of 10% citric acid are added after the HPLC detection of the raw material reaction is finished, and the reaction is quenched by stirring for 30 min.
S1-3: 50mL×3 is extracted with dichloromethane, the organic phases are combined, dried over anhydrous sodium sulfate, and the solvent is evaporated under reduced pressure in a rotary manner to obtain 3.5g of intermediate 2 as a white solid; the yield thereof was found to be 99%.
By optimizing the reaction conditions, S2 comprises the following sub-steps:
s2-1: in a 100mL three-necked flask, intermediate 2 (2.0 g,0.0063mol,1.0 eq.) was dissolved with 40mL of methylene chloride with stirring, cooled to 0-5℃and added with Et 3 N (1.6 g,0.016mol,2.5 eq.) was slowly added dropwise MsCl (1.1 g,0.0095mol,1.5 eq.) and reacted at room temperature (25 ℃ C.) after the addition was completed, after every 30min the reaction was monitored by LC, after no significant change in intermediate 3 oxazolinone product was observed, the reaction was quenched with water.
S2-2: the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1.8g of a solid.
S2-3: finally separating V by silica gel column chromatography DCM :V MeOH :V Et3N =10:1:0.02, yielding intermediate 3 (1.3 g) in 77% yield.
By optimizing the reaction conditions, S3 comprises the following sub-steps:
s3-1: in a 100mL three-necked flask, intermediate 3 (2.0 g,0.008mol,1.0 eq.) was dissolved in 20mL of ethanol, and 10mL of a 15% aqueous sodium hydroxide solution was added to the mixture to react at 75℃for 8 hours.
S3-2: after the conversion of the raw materials is monitored by HPLC, the temperature is reduced to 0-5 ℃, hydrochloric acid (4M) is slowly added to adjust the pH to 3-4, the mixture is concentrated to constant weight under reduced pressure, methanol (15 mL) is added to be stirred for 30min for dissolution, and insoluble sodium chloride solid is filtered out; the filtrate was concentrated again to give 1.7g of pale yellow solid with a yield of 84%, dr >99%.
By optimizing the reaction conditions, S4 comprises the following sub-steps:
s4-1: in a 100mL three-necked flask, 30mL of intermediate 4 (2.0 g,0.008mol,1.0 eq.) was dissolved in methanol, and triethylamine (0.32 g,0.0032mol,0.4 eq.) and acetone (16 mL) were added.
S4-2: reacting for 30min, cooling to 0-5 ℃, and adding (CH 3 COO) 3 BHNa (2.5 g,0.012mol,1.5 eq.) was allowed to react at room temperature (27 ℃) for 30min, and HPLC checked that the starting material was still unconverted.
S4-3: cooling to 10-20deg.C, adding NaBH in batches 4 (0.6 g,0.016mol,2.0 eq.) for 2h at room temperature (27 ℃).
S4-4: the HPLC detection shows that a small amount of raw materials are converted, the pH is adjusted to 3-4 by hydrochloric acid (4M), the reaction liquid is dried by spin, and the high-efficiency liquid phase C18 reverse silica gel column is used for preparing and purifying to obtain 1.2g of target compound 5 as white solid, and the yield of the step is 51%.
The method for synthesizing the optical isomer of the zilpaterol Luo Shunshi has the following beneficial effects:
1. the invention provides a method for synthesizing cis-optical isomer by taking compound with trans-o-amino alcohol structure as raw material for the first time, trans-7-amino-6-hydroxy-6, 7,8, 9-tetrahydro-2, 9 a-diazabenzo [ cd ]]Synthesis of cis-7-amino-6-hydroxy-6, 7,8, 9-tetrahydro-2, 9 a-diazabenzo [ cd ] by using (1) 1 (2H) -keto dihydrochloride (1) as raw material]/>-1 (2H) -keto dihydrochloride (4) with a total reaction yield of 69% over 3 steps.
2. The invention successfully realizes the synthesis of the optical isomer of the zilpate Luo Shunshi for the first time, and the total yield is 35%.
3. The invention provides a material basis for researching the biological activity of the optical isomer of the zilpate Luo Shunshi and an important technical support for developing the synthesis methodology research of the cis-ethanolamine structure.
Drawings
FIG. 1 is a scheme of a method for synthesizing a cis-o-aminoalcohol structural compound of the present invention.
Fig. 2 is a block diagram of the optical isomers of zilpaterol and zilpaterol Luo Shunshi of the present invention.
FIG. 3 is a synthetic route diagram of the optical isomer of zilpaterol Luo Shunshi of the present invention.
FIG. 4 is a diagram of a method of synthesizing an ethanolamines and zilpaterol of the present invention.
Detailed Description
The following description of the embodiments of the present invention is provided to facilitate understanding of the present invention by those skilled in the art, but it should be understood that the present invention is not limited to the scope of the embodiments, and all the inventions which make use of the inventive concept are protected by the spirit and scope of the present invention as defined and defined in the appended claims to those skilled in the art.
Substrate (1) trans-7-amino-6-hydroxy-6, 7,8, 9-tetrahydro-2, 9 a-diazabenzo [ cd ] azulene-1 (2H) -one (1) reference was synthesized with dr >98% and the remaining reagents used were all analytically pure.
The synthesis steps are as follows:
1. trans-6-hydroxy-1-oxo-1,2,6,7,8,9-hexahydro-2, 9 a-diazabenzo [ cd ]]Synthesis of 7-yl-carbamic acid tert-butyl ester (2)
Substrate 1 (3.0 g,0.010mol,1.0 eq.) was dissolved in 50mL of methylene chloride in a 250mL round bottom flask and Et was added 3 N (3.6 g,0.036mol,3.0 eq.) was added dropwise via a constant pressure dropping funnel (Boc) 2 O (1.6 g,0.016mol,1.3 eq.) was reacted at room temperature (28 ℃ C.) for 12 hours after the completion of the dropwise addition. After the reaction of the raw materials is detected by HPLC, 40mL of water and 20mL of 10% citric acid are added, the mixture is stirred for 30min to quench the reaction, dichloromethane extraction (50 mL multiplied by 3) is carried out, the organic phases are combined, anhydrous sodium sulfate is dried, and the white solid of the intermediate 2 is obtained by decompression spin drying. The yield thereof was found to be 99%. 1 H NMR(400MHz,DMSO-d6)δ10.79(s,1H),6.98–6.87(m,3H),6.84(d,J＝8.2Hz,1H),5.53(d,J＝4.9Hz,1H),4.64(t,J＝5.2Hz,1H),4.02–3.88(m,2H),3.17(d,J＝5.2Hz,1H),2.26(q,J＝8.3,6.0Hz,1H),1.85–1.74(m,1H),1.38(s,9H)。m/z:320.0{[M+H] + }。
2. Cis-6, 7a,10 a-tetrahydro-10-oxa-4, 5a, 8-triazabenzo [ cd ]]Cyclopenta [ f ]]Synthesis of (E) -5,9 (4H, 8H) -dione (3)
The reaction is the core step of the whole synthetic route, and a methanesulfonylation intermediate of benzyl hydroxyl can be generated in the reaction process, and methanesulfonate is a good leaving group and can generate intramolecular S N 2 The target product is obtained through reaction, and benzyl positive ions can be obtained through direct leaving, so that byproducts are generated. Considering that the five-membered ring cyclization reaction may be advantageous in terms of thermodynamics, based on this, we first tried the reaction at low temperature, 1.5eq.mscl was added to the reaction by slow dropwise addition, and the target product was obtained after 0.5h of reaction, but the starting material remained in a large amount, the yield was only 25% (table 1, no. 1), and the reaction time was prolonged to 4.0h, but the yield of the reaction could not be improved yet (table 1, no. 3). Based on this, an attempt to raise the temperature to 25℃is to raise both the reaction yield and the conversion (Table 1, no. 5), but the reaction by-products are significantly increased at higher temperatures, which is disadvantageous for the post-reaction treatment. Finally, by adjusting MsCl and acid binding agent Et 3 N equivalent, the reaction yield is improvedTo 77% (Table 1, NO. 6), the optimal reaction conditions were determined: intermediate 2 (1.0 eq.), msCl (3.0 eq.), et 3 N (5.0 eq.) at 25℃for 0.5h. The experimental details are as follows.
TABLE 1 influence of reaction temperature, msCl amount, time on 4 yield
In a 100mL three-necked flask, intermediate 2 (2.0 g,0.0063mol,1.0 eq.) was dissolved with 40mL of methylene chloride with stirring, cooled to 0-5℃and added with Et 3 N (1.6 g,0.016mol,2.5 eq.) was slowly added dropwise MsCl (1.1 g,0.0095mol,1.5 eq.) and reacted at room temperature (25 ℃ C.) after the addition was completed, after every 30min the reaction was monitored by LC, after no obvious change in intermediate 3 oxazolinone product was observed, the reaction was quenched with water; 40mL×2 was extracted with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1.8g of a solid; after that, the mixture was separated by silica gel column chromatography (V DCM :V MeOH :V Et3N =10:1:0.02) to afford intermediate 3 (1.3 g) in 77% yield. 1 H NMR(400MHz,DMSO-d6)δ11.03(s,1H),7.93(s,1H),7.05(s,1H),7.00(dd,J＝8.9,6.4Hz,1H),5.69(d,J＝7.9Hz,1H),4.36(dt,J＝7.6,3.5Hz,1H),3.10(qd,J＝7.3,4.8Hz,1H),1.97(dt,J＝7.2,3.4Hz,2H),1.18(t,J＝7.3Hz,2H)。MS m/z:246.0{[M+H]+}。
3. Cis-7-amino-6-hydroxy-6, 7,8, 9-tetrahydro-2, 9 a-diazabenzo [ cd ]]Synthesis of-1 (2H) -one 4
In a 100mL three-necked flask, 20mL of ethanol was used to dissolve intermediate 3 (2.0 g,0.008mol,1.0 eq.) and 10mL of 15% aqueous sodium hydroxide solution was added to the mixture to react at 75℃for 8 hours; after the conversion of the raw materials is monitored by HPLC, the temperature is reduced to 0-5 ℃, hydrochloric acid (4M) is slowly added to adjust the pH to 3-4, the mixture is concentrated to constant weight under reduced pressure, meOH (15 mL) is added to be stirred for 30min for dissolution, and insoluble sodium chloride solid is filtered out; the filtrate was concentrated again to give 1.7g of pale yellow solid with a yield of 84%, and a dr value of more than 99%. 1 H NMR(400MHz,DMSO-d6)δ11.06(s,1H),8.40(s,3H),7.04–6.93(m,3H),6.17(d,J＝5.0Hz,1H),5.04(dd,J＝4.9,2.5Hz,1H),4.15(ddd,J＝13.6,7.2,2.9Hz,1H),3.77–3.59(m,2H),2.38(ddt,J＝12.3,9.7,6.2Hz,1H),2.15(ddt,J＝14.5,7.0,3.2Hz,1H).13C NMR(100MHz，DMSO-d6)δ154.9,129.4(2C),128.7,123.1,122.3,121.3,109.0,71.4,54.0,26.6。m/z:201.9{[M+H] + }。
4. Cis-6-hydroxy-7- (isopropylamino) -6,7,8, 9-tetrahydro-2, 9 a-diazabenzo [ cd ]]Synthesis of (1 (2H) -one 5
In a 100mL three-necked flask, 30mL of intermediate 4 (2.0 g,0.008mol,1.0 eq.) was dissolved in methanol, triethylamine (0.32 g,0.0032mol,0.4 eq.) and acetone (16 mL) were added, reacted for 30min, cooled to 0 to 5℃and added in portions (CH) 3 COO) 3 BHNa (2.5 g,0.012mol,1.5 eq.) was allowed to react at room temperature (27 ℃) for 30min, and HPLC checked that the starting material was still unconverted. Cooling to 10-20deg.C, adding NaBH in batches 4 (0.6 g,0.016mol,2.0 eq.) for 2h at room temperature (27 ℃). The HPLC detection shows that a small amount of raw materials are converted, the pH is adjusted to 3-4 by hydrochloric acid (4M), the reaction liquid is dried by spin, and the high-efficiency liquid phase C18 reverse silica gel column is used for preparing and purifying to obtain 1.2g of target compound white solid, wherein the yield of the step is 51%. 1 H NMR(400MHz,DMSO-d6)δ11.05(s,1H),8.64(d,J＝56.7Hz,2H),7.04–6.96(m,3H),6.38(d,J＝5.0Hz,1H),5.11(t,J＝3.3Hz,1H),4.22(ddd,J＝13.7,7.2,2.6Hz,1H),3.86(d,J＝8.5Hz,1H),3.69(ddd,J＝13.2,10.1,2.5Hz,1H),3.53(p,J＝6.0Hz,1H),2.48–2.40(m,1H),2.19(ddt,J＝14.6,6.9,3.1Hz,1H),1.29(dd,J＝6.4,4.6Hz,6H).13CNMR(100MHz，DMSO-d6)δ154.7,129.3(2C),128.7,123.4,121.8,121.3,109.1,70.3,57.3,47.5,25.4,19.3,19.2。m/z:262.0{[M+H] + }。
Claims (6)
1. A method of synthesizing an optical isomer of zilpate Luo Shunshi, comprising the steps of:
step one: compound A is a trans-o-amino alcohol as a reaction starting substrate, and can be combined with the anhydride di-tert-butyl carbonate Boc 2 O reacts to form aminoTert-butyl formate intermediate B;
step two: the benzyl hydroxyl of the intermediate B reacts with methanesulfonyl chloride to generate methanesulfonate;
step three: the tert-butoxy group of intermediate B is located just behind the mesylate, its oxygen atom is nucleophilic, and it can attack benzyl position C from behind the sulfonate group to generate SN 2 Affinity substitution reaction, thereby obtaining a cis-oxazolinone ring intermediate C;
step four: and the intermediate C respectively generates ester and amide hydrolysis reaction under alkaline conditions, and the chiral inversion of hydroxyl is completed, so that the isomer of cis-o-amino alcohol, namely the optical isomer of zilpaterol Luo Shunshi, is obtained.
2. The method of synthesizing an optical isomer of zilpaterol Luo Shunshi as in claim 1, wherein the optical isomer of zilpaterol Luo Shunshi comprises the steps of:
s1: synthesis of trans-6-hydroxy-1-oxo-1,2,6,7,8,9-hexahydro-2, 9 a-diazabenzo [ cd ]]-7-yl-carbamic acid tert-butyl ester (2);
s2: synthesis of cis-6, 7a,10 a-tetrahydro-10-oxa-4, 5a, 8-triazabenzo [ cd ]]Cyclopenta [ f ]]-5,9 (4 h,8 h) -dione (3);
s3: synthesis of cis-7-amino-6-hydroxy-6, 7,8, 9-tetrahydro-2, 9 a-diazabenzo [ cd ]]-1 (2H) -keto-dihydrochloride (4);
s4: synthesis of cis-6-hydroxy-7- (isopropylamino) -6,7,8, 9-tetrahydro-2, 9 a-diazabenzo [ cd ]]-1 (2H) -one (5).
3. The method of synthesizing the optical isomer of zilpaterol Luo Shunshi as recited in claim 2, wherein S1 comprises the sub-steps of:
s1-1: substrate 1 (3.0 g,0.010mol,1.0 eq.) was dissolved in 50mL of methylene chloride in a 250mL round bottom flask and Et was added 3 N (3.6 g,0.036mol,3.0 eq.) was added dropwise via a constant pressure dropping funnel (Boc) 2 O(1.6g,0.016mol,1.3eq.)；
S1-2: after the dripping is finished, reacting for 12 hours at the room temperature of 28 ℃, adding 40mL of water and 20mL of 10% citric acid after the HPLC detection raw material is finished, stirring for 30min, and quenching;
s1-3: dichloromethane extraction (50 mL x 3), combined organic phases, dried over anhydrous sodium sulfate, and spun-dried under reduced pressure to afford intermediate 2 as a white solid, 3.5g; the yield thereof was found to be 99%.
4. The method of synthesizing the optical isomer of zilpaterol Luo Shunshi as recited in claim 2, wherein S2 comprises the sub-steps of:
s2-1: in a 100mL three-necked flask, intermediate 2 (2.0 g,0.0063mol,1.0 eq.) was dissolved with 40mL of methylene chloride with stirring, cooled to 0-5℃and added with Et 3 N (1.6 g,0.016mol,2.5 eq.) was slowly added dropwise MsCl (1.1 g,0.0095mol,1.5 eq.) and reacted at room temperature (25 ℃ C.) after the addition was completed, after every 30min the reaction was monitored by LC, after no obvious change in intermediate 3 oxazolinone product was observed, the reaction was quenched with water;
s2-2: 40mL×2 was extracted with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1.8g of a solid;
s2-3: finally separating V by silica gel column chromatography DCM :V MeOH :V Et3N =10:1:0.02, yielding intermediate 3 (1.3 g) in 77% yield.
5. The method of synthesizing the optical isomer of zilpaterol Luo Shunshi as recited in claim 2, wherein S3 comprises the sub-steps of:
s3-1: in a 100mL three-necked flask, 20mL of ethanol was used to dissolve intermediate 3 (2.0 g,0.008mol,1.0 eq.) and 10mL of 15% aqueous sodium hydroxide solution was added to the mixture to react at 75℃for 8 hours;
s3-2: after the conversion of the raw materials is monitored by HPLC, the temperature is reduced to 0-5 ℃, hydrochloric acid (4M) is slowly added to adjust the pH to 3-4, the mixture is concentrated to constant weight under reduced pressure, meOH (15 mL) is added to be stirred for 30min for dissolution, and insoluble sodium chloride solid is filtered out; the filtrate was concentrated again to give 1.7g of pale yellow solid in 84% yield (dr > 99%).
6. The method of synthesizing the optical isomer of zilpaterol Luo Shunshi as recited in claim 2, wherein S4 comprises the sub-steps of:
s4-1: in a 100mL three-necked flask, 30mL of intermediate 4 (2.0 g,0.008mol,1.0 eq.) was dissolved in methanol, triethylamine (0.32 g,0.0032mol,0.4 eq.) and acetone (16 mL) were added;
s4-2: reacting for 30min, cooling to 0-5 ℃, and adding (CH 3 COO) 3 BHNa (2.5 g,0.012mol,1.5 eq.) was allowed to react at room temperature (27 ℃ C.) for 30min, and HPLC checked that the starting material was still unconverted;
s4-3: cooling to 10-20deg.C, adding NaBH in batches 4 (0.6 g,0.016mol,2.0 eq.) for 2h at room temperature (27 ℃);
s4-4: a small amount of raw materials are converted by HPLC detection, the pH value is regulated to 3-4 by hydrochloric acid (4 mol/L), the reaction liquid is dried by spin, and a high-efficiency liquid phase C18 reverse silica gel column is used for preparing and purifying to obtain 1.2g of a white solid of the target compound, wherein the yield of the step is 50%.
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