CN117800962A - Method for synthesizing cinchona alkaloid dimer catalyst - Google Patents
Method for synthesizing cinchona alkaloid dimer catalyst Download PDFInfo
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- CN117800962A CN117800962A CN202211163841.5A CN202211163841A CN117800962A CN 117800962 A CN117800962 A CN 117800962A CN 202211163841 A CN202211163841 A CN 202211163841A CN 117800962 A CN117800962 A CN 117800962A
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- cinchona alkaloid
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- pyrimidine ring
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- 241000157855 Cinchona Species 0.000 title claims abstract description 35
- 235000021513 Cinchona Nutrition 0.000 title claims abstract description 32
- 229930013930 alkaloid Natural products 0.000 title claims abstract description 31
- 239000003054 catalyst Substances 0.000 title claims abstract description 28
- 150000003797 alkaloid derivatives Chemical class 0.000 title claims abstract description 24
- 239000000539 dimer Substances 0.000 title claims abstract description 21
- 238000000034 method Methods 0.000 title claims abstract description 19
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 31
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims abstract description 16
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims abstract description 16
- 125000000714 pyrimidinyl group Chemical group 0.000 claims abstract description 13
- LZCZIHQBSCVGRD-UHFFFAOYSA-N benzenecarboximidamide;hydron;chloride Chemical compound [Cl-].NC(=[NH2+])C1=CC=CC=C1 LZCZIHQBSCVGRD-UHFFFAOYSA-N 0.000 claims abstract description 8
- 230000009471 action Effects 0.000 claims abstract description 7
- FGYDHYCFHBSNPE-UHFFFAOYSA-N diethyl phenylmalonate Chemical compound CCOC(=O)C(C(=O)OCC)C1=CC=CC=C1 FGYDHYCFHBSNPE-UHFFFAOYSA-N 0.000 claims abstract description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- 229940125904 compound 1 Drugs 0.000 claims description 10
- -1 alkaloid compounds Chemical class 0.000 claims description 9
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 7
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 7
- 239000012312 sodium hydride Substances 0.000 claims description 7
- 239000012300 argon atmosphere Substances 0.000 claims 2
- 239000000758 substrate Substances 0.000 abstract description 6
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 abstract description 5
- 235000001258 Cinchona calisaya Nutrition 0.000 abstract description 3
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 abstract description 3
- 229960000948 quinine Drugs 0.000 abstract description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 238000007867 post-reaction treatment Methods 0.000 abstract 1
- 238000006467 substitution reaction Methods 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 20
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 239000007787 solid Substances 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 229910052786 argon Inorganic materials 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- 238000001291 vacuum drying Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000009987 spinning Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000001588 bifunctional effect Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012039 electrophile Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 238000006362 organocatalysis Methods 0.000 description 1
- 235000013930 proline Nutrition 0.000 description 1
- 150000003148 prolines Chemical class 0.000 description 1
- 125000003410 quininyl group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- SBYHFKPVCBCYGV-UHFFFAOYSA-N quinuclidine Chemical group C1CC2CCN1CC2 SBYHFKPVCBCYGV-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Catalysts (AREA)
Abstract
The invention discloses a method for synthesizing cinchona alkaloid dimer catalyst. According to the method, diethyl 2-phenylmalonate and benzamidine hydrochloride are firstly synthesized into a pyrimidine ring skeleton under the action of sodium methoxide, then hydroxyl on the skeleton and phosphorus oxychloride undergo substitution reaction to obtain a chlorinated product, and finally the chlorinated product reacts with quinine and various derivatives thereof to obtain the corresponding cinchona alkaloid dimer catalyst. The invention takes the quinine which is cheap and easy to obtain as a substrate, the synthesized pyrimidine ring is taken as a framework, the reaction path is simple, the reaction condition is mild, the post-reaction treatment is simple and convenient, and the invention can be applied to gram-level or even kilogram-level synthesis.
Description
Technical Field
The invention relates to a method for synthesizing a cinchona alkaloid dimer catalyst, and belongs to the technical field of organic catalysts.
Background
The 2021 nobel chemical prize awards Benjamin List and David w.c. macmillan to bring out their contributions in the field of asymmetric organocatalysis. The organic small molecule catalyst has the advantages of stable structure, low price, easy acquisition, environmental protection and the like, and is not possessed by the traditional metal organic catalyst. Common small organic molecule catalysts include: cinchona alkaloid, prolines and thiourea catalysts. They often fix substrates in a chiral environment by interactions such as hydrogen bonding, and thus induce the other substrate molecule to attack only from a single pathway (Handy, s.t. org.chem.,2000,4 (4): 363-395).
The basic skeleton of cinchona alkaloid comprises two rigid rings, a quinoline ring and a quinine ring, and are connected by two C-C single bonds. Studies of the asymmetric catalytic mechanism of cinchona have been calculated to show that it is often a bifunctional catalyst activation substrate (Cucinotta, C.S., kosa, M., melshiorre, P., et al chem. Eur. J.,2009,15 (32): 7913-7921). N on the quinuclidine ring serves as a base to activate the nucleophile, while the hydroxyl group activates the electrophile via hydrogen bonding, both functionalities accurately inducing the substrate to react via the optimal pathway. For some reactions, chiral environment provided by the cinchona alkaloid dimer catalyst is better than that of the cinchona alkaloid monomer catalyst, and the activity and the catalytic performance of the cinchona alkaloid dimer catalyst are often better. Therefore, the method for synthesizing cinchona alkaloid dimer type catalyst is very necessary.
Disclosure of Invention
The invention discloses a method for synthesizing cinchona alkaloid dimer catalyst. The method comprises the steps of attacking 2-phenyl diethyl malonate with benzamidine hydrochloride under the promotion of sodium methoxide to form a pyrimidine ring skeleton compound, carrying out nucleophilic substitution with phosphorus oxychloride to generate a chloro product, carrying out nucleophilic substitution with sodium alkoxide formed by a cinchona alkaloid compound and sodium hydride, and finally synthesizing the cinchona alkaloid dimer catalyst.
The technical scheme for realizing the purpose of the invention is as follows:
a method for synthesizing cinchona alkaloid dimer-based catalyst, comprising:
(1) A step of reacting diethyl 2-phenylmalonate with a methanol solution of benzamidine hydrochloride under the action of sodium methoxide to obtain a pyrimidine ring skeleton compound 1,
(2) A step of obtaining a chloro-substituted product 2 from the pyrimidine ring skeleton compound 1 under the action of phosphorus oxychloride,
(3) A step of reacting the chlorinated product 2 with cinchona alkaloid compounds under the action of sodium hydride to obtain a target product cinchona alkaloid dimer catalyst 3,
wherein,
preferably, in step 1, the reaction temperature is 75.+ -. 5 ℃.
Preferably, in the step 1, the molar ratio of benzamidine hydrochloride, diethyl 2-phenylmalonate and sodium methoxide is 1:1:3.
Preferably, in step 2, the reaction is carried out under an argon-protected atmosphere.
Preferably, in step 2, the reaction temperature is 110.+ -. 5 ℃.
Preferably, in step 2, the pyrimidine ring skeleton compound 1 is present at a concentration of 2.0M in phosphorus oxychloride.
Preferably, in step 3, the reaction is carried out under an argon-protected atmosphere.
Preferably, in step 3, the reaction is carried out in the presence of anhydrous DMF.
Preferably, in the step 3, the molar ratio of the sodium hydride, the cinchona alkaloid compound and the chlorinated product 2 is 2.5:2:1.
Compared with the prior art, the invention has the following advantages: (1) The invention has simple reaction condition and simple experimental operation steps. (2) The invention has simple reaction treatment steps, and the step 1 and the step 3 do not need post treatment, so that on one hand, the loss of products is reduced, and on the other hand, the cinchona alkaloid dimer catalyst can be produced on a large scale. (3) The invention has the advantages of cheap and easily obtained reaction raw materials and high economic benefit.
Drawings
FIG. 1 is a nuclear magnetic H spectrum of the cinchona alkaloid dimer type catalyst prepared in example 1.
FIG. 2 is a nuclear magnetic resonance C spectrum of the cinchona alkaloid dimer type catalyst prepared in example 1.
Detailed Description
The invention is further described below by way of examples and figures.
The method for synthesizing the cinchona alkaloid dimer catalyst comprises the following specific operation steps:
step 1, adding diethyl 2-phenylmalonate into a methanol solution of benzamidine hydrochloride at room temperature, then dropwise adding a methanol solution of sodium methoxide, carrying out reflux reaction for 3-4h at 75+/-5 ℃, after TLC monitoring is finished, pouring the reaction solution into ice water, adjusting the pH value of the reaction solution to about 4 by using 1M hydrochloric acid, filtering the reaction solution by using a sand core funnel, washing the filtered solid with methanol and n-hexane for three times respectively, and finally drying the filtered solid by using a vacuum drying box to obtain a pyrimidine ring skeleton compound 1;
step 2, directly and slowly dropwise adding phosphorus oxychloride into a pyrimidine ring skeleton compound 1 in an argon protection atmosphere, reacting for 4-5 hours at 110+/-5 ℃, slowly dropwise adding the reaction solution into ice water, extracting the obtained mixed solution with ethyl acetate, taking an organic layer, washing with saturated saline water, drying with anhydrous sodium sulfate, spinning to dry a solvent to obtain a crude product, and finally purifying by column chromatography to obtain a chlorinated product 2;
step 3, slowly dropwise adding DMF solution of cinchona alkaloid compound into DMF suspension of sodium hydride under the condition of ice bath under the protection of argon, slowly recovering to room temperature, stirring at the room temperature for 2-3h, dropwise adding DMF solution of chloro product 2, and continuing to react at the room temperature overnight. After TLC monitoring reaction is finished, the reaction solution is extracted by water, a large amount of white solid appears, the white solid is filtered by a sand core funnel, the filtered solid is washed by normal hexane, and finally the cinchona alkaloid dimer catalyst 3 is obtained by drying by a vacuum drying oven.
Example 1
The quinine hydride is used as a substrate to synthesize the corresponding cinchona alkaloid dimer catalyst, and the structure is that
Step 1, adding diethyl 2-phenylmalonate (1.0 eq) into a methanol solution of benzamidine hydrochloride (1.0 eq) under the protection of argon gas at room temperature, then dropwise adding a methanol solution of sodium methoxide (3.0 eq), carrying out reflux reaction for 4 hours at 75+/-5 ℃, after TLC monitoring reaction is finished, pouring the reaction solution into ice water, adjusting the pH value of the reaction solution to about 4 by using 1M hydrochloric acid, filtering the reaction solution by using a sand core funnel, washing the filtered solid with methanol and n-hexane for three times respectively, and finally drying the mixture by using a vacuum drying box to obtain a pyrimidine ring skeleton compound 1;
step 2, directly and slowly dropwise adding phosphorus oxychloride into a pyrimidine ring skeleton compound 1 in an argon protection atmosphere, reacting for 5 hours at 110+/-5 ℃, slowly dropwise adding the reaction solution into ice water, extracting the obtained mixed solution with ethyl acetate, taking an organic layer, washing with saturated saline water, drying with anhydrous sodium sulfate, spinning to dry a solvent to obtain a crude product, and finally purifying by column chromatography to obtain a chlorinated product 2;
step 3, slowly dropwise adding a DMF solution of cinchona alkaloid compound (2.0 eq) into a DMF suspension of sodium hydride (2.5 eq) under the protection of argon under the ice bath condition, slowly recovering to room temperature, stirring for 2h at room temperature, then dropwise adding a DMF solution of a chloro product 2 (1.0 eq) into the DMF solution, and continuing to react overnight at room temperature. After TLC monitoring reaction is finished, the reaction solution is extracted by water, a large amount of white solid appears, the white solid is filtered by a sand core funnel, the filtered solid is washed by normal hexane, and finally the cinchona alkaloid dimer catalyst 3 is obtained by drying by a vacuum drying oven, wherein the total yield of the three steps is 56%, and dr is more than 20:1. The characterization map is shown in fig. 1 and 2.
1 H NMR(500MHz,Methanol-d 4 )δ8.71(d,J＝4.6Hz,2H),8.01(d,J＝9.2Hz,2H),7.79–7.77(m,2H),7.74–7.69(m,4H),7.61(d,J＝4.9Hz,3H),7.55(d,J＝2.6Hz,1H),7.53(d,J＝2.7Hz,1H),7.32(d,J＝7.7Hz,2H),7.23(s,2H),7.17(tt,J＝7.4,1.3Hz,1H),6.85(t,J＝7.7Hz,2H),4.00(s,6H),3.27–3.24(m,2H),3.00(t,J＝11.5Hz,2H),2.89(t,J＝11.3Hz,2H),2.79(dd,J＝13.0,8.6Hz,2H),2.70–2.65(m,2H),2.12(t,J＝11.4Hz,2H),1.69(s,2H),1.59-1.52(m,4H),1.42(d,J＝8.4Hz,2H),1.37–1.31(m,2H),0.78–0.65(m,10H). 13 C NMR(126MHz,Methanol-d 4 )δ166.08,160.98,158.93,146.91,144.79,143.78,135.81,130.74,130.59,130.52,130.33,129.01,128.33,127.60,127.43,126.63,122.62,118.07,105.04,101.11,75.39,58.64,55.50,50.60,49.25,36.24,25.63,25.34,23.78,19.76,11.31.。
Claims (9)
1. A method for synthesizing a cinchona alkaloid dimer-based catalyst, comprising:
(1) A step of obtaining a pyrimidine ring skeleton compound 1 by using a methanol solution of diethyl 2-phenylmalonate and benzamidine hydrochloride under the action of sodium methoxide,
(2) A step of obtaining a chloro-substituted product 2 from the pyrimidine ring skeleton compound 1 under the action of phosphorus oxychloride,
(3) A step of reacting the chlorinated product 2 with cinchona alkaloid compounds under the action of sodium hydride to obtain a target product cinchona alkaloid dimer catalyst 3,
wherein,
2. the method according to claim 1, wherein in step 1, the reaction temperature is 75±5 ℃.
3. The method according to claim 1, wherein in the step 1, the molar ratio of benzamidine hydrochloride, diethyl 2-phenylmalonate and sodium methoxide is 1:1:3.
4. The method according to claim 1, wherein in step 2, the reaction is performed under an argon atmosphere.
5. The method according to claim 1, wherein in step 2, the reaction temperature is 110±5 ℃.
6. The method according to claim 1, wherein in step 2, the pyrimidine ring skeleton compound 1 is present at a concentration of 2.0M in phosphorus oxychloride.
7. The method according to claim 1, wherein in step 3, the reaction is performed under an argon atmosphere.
8. The process according to claim 1, wherein in step 3, the reaction is carried out in the presence of anhydrous DMF.
9. The method according to claim 1, wherein in the step 3, the molar ratio of sodium hydride, cinchona alkaloid compound and chlorinated product 2 is 2.5:2:1.
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| CN202211163841.5A CN117800962A (en) | 2022-09-23 | 2022-09-23 | Method for synthesizing cinchona alkaloid dimer catalyst |
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