CN117801008A - Preparation method of vitamin D derivative A ring building block - Google Patents
Preparation method of vitamin D derivative A ring building block Download PDFInfo
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- 150000003710 vitamin D derivatives Chemical class 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 30
- 150000001875 compounds Chemical class 0.000 claims abstract description 29
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 claims abstract description 15
- -1 isopropyl Grignard reagent Chemical class 0.000 claims abstract description 12
- 239000007818 Grignard reagent Substances 0.000 claims abstract description 10
- 239000002994 raw material Substances 0.000 claims abstract description 10
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 9
- 229940125898 compound 5 Drugs 0.000 claims abstract description 7
- 239000003513 alkali Substances 0.000 claims abstract description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 9
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 8
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 8
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 239000007810 chemical reaction solvent Substances 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 5
- 150000007529 inorganic bases Chemical class 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical group [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 239000005051 trimethylchlorosilane Substances 0.000 claims description 4
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 3
- MENYRYNFSIBDQN-UHFFFAOYSA-N 5,5-dibromoimidazolidine-2,4-dione Chemical compound BrC1(Br)NC(=O)NC1=O MENYRYNFSIBDQN-UHFFFAOYSA-N 0.000 claims description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- 150000007530 organic bases Chemical class 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 239000012973 diazabicyclooctane Substances 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- DBTNVRCCIDISMV-UHFFFAOYSA-L lithium;magnesium;propane;dichloride Chemical compound [Li+].[Mg+2].[Cl-].[Cl-].C[CH-]C DBTNVRCCIDISMV-UHFFFAOYSA-L 0.000 claims description 2
- LVKCSZQWLOVUGB-UHFFFAOYSA-M magnesium;propane;bromide Chemical compound [Mg+2].[Br-].C[CH-]C LVKCSZQWLOVUGB-UHFFFAOYSA-M 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 claims description 2
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 21
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 150000002085 enols Chemical class 0.000 abstract description 4
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 2
- 239000000463 material Substances 0.000 abstract description 2
- 238000010438 heat treatment Methods 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 239000003208 petroleum Substances 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 229930003316 Vitamin D Natural products 0.000 description 5
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 235000019166 vitamin D Nutrition 0.000 description 5
- 239000011710 vitamin D Substances 0.000 description 5
- 229940046008 vitamin d Drugs 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- 150000004795 grignard reagents Chemical class 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 230000001766 physiological effect Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 241000510672 Cuminum Species 0.000 description 1
- 235000007129 Cuminum cyminum Nutrition 0.000 description 1
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- ZQBZAOZWBKABNC-UHFFFAOYSA-N [P].[Ca] Chemical compound [P].[Ca] ZQBZAOZWBKABNC-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229960002882 calcipotriol Drugs 0.000 description 1
- LWQQLNNNIPYSNX-UROSTWAQSA-N calcipotriol Chemical compound C1([C@H](O)/C=C/[C@@H](C)[C@@H]2[C@]3(CCCC(/[C@@H]3CC2)=C\C=C\2C([C@@H](O)C[C@H](O)C/2)=C)C)CC1 LWQQLNNNIPYSNX-UROSTWAQSA-N 0.000 description 1
- 229960005084 calcitriol Drugs 0.000 description 1
- 235000020964 calcitriol Nutrition 0.000 description 1
- 239000011612 calcitriol Substances 0.000 description 1
- GMRQFYUYWCNGIN-NKMMMXOESA-N calcitriol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C GMRQFYUYWCNGIN-NKMMMXOESA-N 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000006757 chemical reactions by type Methods 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 208000012839 conversion disease Diseases 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- FBPFZTCFMRRESA-GUCUJZIJSA-N galactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-GUCUJZIJSA-N 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 229940127554 medical product Drugs 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
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- 238000003541 multi-stage reaction Methods 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000003867 tiredness Effects 0.000 description 1
- 208000016255 tiredness Diseases 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a high-efficiency preparation method of a vitamin D derivative A ring building block, and belongs to the technical field of synthesis of medical intermediates. Taking a full-protection compound 8 as a raw material, and reacting with a brominating reagent in the presence of tetraisopropyl titanate and an isopropyl Grignard reagent to obtain a compound 4; then in the presence of organic alkali, heating to eliminate the reaction to obtain a compound 5; finally removing TMS in the presence of inorganic alkali to obtain the vitamin D derivative A ring building block. The invention replaces the enol-exposed intermediate with the fully-protected intermediate, and after the silyl ether is protected, the material stability is enhanced, the low-temperature solubility is good, and the reaction effect is greatly improved.
Description
Technical Field
The invention relates to a high-efficiency preparation method of a vitamin D derivative A ring building block, which can be used as a key intermediate of medical products such as vitamin D analogues and the like, and belongs to the technical field of medical intermediate synthesis.
Background
Vitamin D analogues are a class of compounds with defined physiological activity and therapeutic effects, such as calcitriol, calcipotriol, dulcitol, etc., and are widely used in clinic because of their physiological effects of regulating calcium-phosphorus metabolism, anti-inflammatory, antiproliferative, immunomodulation, etc. With reference to the pharmacodynamic characteristics of the vitamin D skeleton, the development of more novel-structure and better-indication drug molecules is pursued by the industry of cumin tiredness. In order to synthesize the compound with novel CD ring structure, a brand new compound I with A ring structure is designed and matched, and the compound I and boric acid ester II are subjected to catalytic coupling, so that the vitamin D analogues of IIIA type and IIIB type can be conveniently prepared.
As a key intermediate I, takeshi Hanazawa et al reported in J.org.chem.,2003,68,9767-9772 and org.Lett.,2003,5,523-525 that epichlorohydrin 1 was used as a starting material to produce chiral enol 2 via a multi-step reaction. The enol intermediate is subjected to grignard reagent and titanate co-catalysis to form ring/bromo/silyl ether protection/elimination and desilication protection, so that a brand new A ring structure compound I is prepared. Wherein: key reaction step compound 2 produced compound 4 in only 51% yield. The experimental operation condition of the method is harsh, the ether solvent and the Grignard reagent ether solution are used, the risk is high, and the scale is difficult to enlarge. The synthetic method has the defects of high purification process difficulty, low total yield, low economy and the like.
Disclosure of Invention
In order to overcome the technical defects, the invention aims to provide a preparation method of the compound shown in the general formula I. The preparation in the reaction process is more economical and efficient, and overcomes the defects of the prior synthesis technology, such as long route, complicated reaction types, high process safety risk and the like. Meanwhile, the starting materials used in the invention have a mature process based on the early technology, and are suitable for industrial scale-up production.
The invention provides a cyclohexane diene compound with a general formula I, which has a structural formula as shown in the specification, and is a chiral intermediate and a synthetic building block which are very important for synthesizing vitamin D compounds in biological medicines.
Wherein: r1 and R2 are each independently selected from TBS, TMS, me PhSi, i-Pr 3 Si、Et 3 Si。
The invention also provides a high-efficiency preparation method of the vitamin D derivative A ring building block, which comprises the following steps:
in the first step, the full-protection compound 8 is used as a raw material to react with a brominating reagent in the presence of tetraisopropyl titanate and an isopropyl Grignard reagent to obtain a compound 4.
In the second step, the compound 4 is heated to react and eliminate in the presence of organic alkali to obtain a compound 5.
And thirdly, removing TMS from the compound 5 in the presence of inorganic alkali to obtain a compound 6 (namely the vitamin D derivative A ring building block).
The reaction equation is expressed as follows:
further, in the above technical scheme, the first isopropyl grignard reagent is selected from isopropyl magnesium chloride, isopropyl magnesium bromide, isopropyl magnesium chloride-lithium chloride.
Further, in the above technical scheme, the brominating reagent of the first step is selected from NBS or dibromohydantoin.
Further, in the above technical scheme, the first step reaction solvent is tetrahydrofuran or 2-methyltetrahydrofuran; the reaction temperature is-78 ℃ to 30 ℃, and the reaction is carried out at ultralow temperature and then at room temperature.
Further, in the technical scheme, the molar ratio of the compound 8, the tetraisopropyl titanate, the isopropyl Grignard reagent and the brominating reagent in the first step is 1:1-1.5:3-4:1.5-3.5.
Further, in the above technical scheme, the organic base in the second step is DBU, DBN or DABCO.
Further, in the technical scheme, the reaction solvent in the second step is toluene, dioxane, tetrahydrofuran and the like, and the reaction temperature is 60-100 ℃.
Further, in the technical scheme, the molar ratio of the compound 4 in the second step to the organic base is 1:3-5.
Further, in the above technical scheme, the inorganic base in the third step is sodium carbonate, potassium carbonate or cesium carbonate.
Further, in the technical scheme, the reaction solvent in the third step is DMF, DMSO, sulfolane and the like, and the reaction temperature is 0-40 ℃.
Further, in the technical scheme, the molar ratio of the compound 5 in the third step to the inorganic base is 1:3-5.
Further, in the technical scheme, the preparation method of the compound 8 comprises the step of reacting the compound 7 with n-butyllithium and trimethylchlorosilane at ultralow temperature to obtain the compound 8.
The ultralow temperature refers to the reaction temperature between-78 ℃ and-40 ℃.
The invention replaces the enol-exposed intermediate 2 with the fully-protected intermediate 8, the latter chiral hydroxyl is exposed to easily generate chiral racemization, magnesium salt is formed in the reaction, the solubility is poor, and the reaction conversion rate is affected at low temperature. After the protection of the silyl ether, the stability of the material is enhanced, the low-temperature solubility is good, and the reaction effect is greatly improved.
Compared with the prior art, the invention has the beneficial effects that:
1. the invention provides the method which uses 1a as the starting material, has simpler steps, better selectivity and higher yield, thereby improving the production efficiency of the A ring segment I and reducing the production cost.
2. The hydroxy protected eneyne fragment is used as a raw material, TMS protection reaction is carried out in high yield, and the compound 8 is subjected to ring closure and bromination under the action of isopropyl titanate and Grignard reagent. Because no hydroxyl groups are exposed, the reaction is milder and controllable, the yield is greatly improved, and the yield is improved to 75-80 percent from 51 percent (J.Org.chem., 2003,68,9767-9772 and Org.Lett.,2003,5,523-525supporting in formation) in the prior art.
3. Because no exposed hydroxyl is generated, the usage amount of the brominating reagent is reduced from 5.5eq to 3.4eq, the reagent is saved, and the burden of post-treatment purification and three wastes is also lightened.
4. The total yield is improved, the quantity of byproducts is reduced, and the product purification is more convenient.
Detailed Description
Example 1
Into a 100mL three-necked flask, compound 7 (4.0 g,10.85 mmol), 40mL of anhydrous tetrahydrofuran and trimethylchlorosilane (1.3 g,11.94 mmol) were sequentially added, the mixture was replaced with nitrogen, the temperature was lowered to-78 ℃, 6.5mL of 2M n-butyllithium was added dropwise under stirring, the mixture was kept at the temperature for half an hour after the addition, the cold bath was removed, and the reaction was carried out at room temperature for 1.5 hours. The system is cooled to about-10 ℃,30 mL of saturated ammonium chloride is added dropwise for quenching, after the temperature is returned, 20mL of petroleum ether is extracted twice, anhydrous sodium sulfate is dried, filtered, concentrated and purified by column chromatography, 4.7g of intermediate 8 is obtained for later use, and the yield is 98 percent. 1 H NMR(CDCl 3 )δ5.82(ddd,J＝17.2,10.3,7.0Hz,1H),5.18-5.09(m,1H),5.03(ddd,J＝10.3,1.6,0.9Hz,1H),4.22(d,J＝5.4Hz,1H),4.02-3.83(m,1H),2.39(dd,J＝5.9,3.0Hz,2H),1.86(ddd,J＝13.7,7.5,5.2Hz,1H),1.62(ddd,J＝13.8,6.6,5.3Hz,1H),0.89(d,J＝0.6Hz,18H),0.20–-0.06(m,21H).
Example 2
Into a 100mL three-necked flask, 7 (4.0 g,10.85 mmol), 50mL of n-heptane and trimethylchlorosilane (1.2 g,11.04 mmol) were sequentially added, the mixture was replaced with nitrogen, the temperature was lowered to-78 ℃, 6mL of 2M n-butyllithium was added dropwise under stirring, the temperature was kept for half an hour after the addition, the cold bath was removed, and the reaction was carried out at room temperature for 1.5 hours. The system is cooled to about-10 ℃,30 mL of saturated ammonium chloride is added dropwise for quenching, after the temperature is returned, 20mL of petroleum ether is extracted twice, anhydrous sodium sulfate is dried, filtered, concentrated and purified by column chromatography, 4.6g of intermediate 8 is obtained for later use, and the yield is 96%.
Example 3
Sequentially adding the intermediate 8 (4.0 g,9.07 mmol), 60mL of anhydrous tetrahydrofuran and tetraisopropyl titanate (3.9 g,13.72 mmol) into a 100mL three-necked flask, cooling the system to-50 ℃, dropwise adding 18mL of 2M isopropyl magnesium chloride, keeping the temperature for 1.5 hours after the addition, and confirming that the raw material conversion is finished by GC central control, wherein the three-necked flask is a three-necked flask with a three-necked flask structureThe method is to cool down to minus 78 ℃ again, add dibromohydantoin (4.4 g,15.39 mmol) tetrahydrofuran solution in batches, keep warm and stir for 0.5 hour, then naturally warm to room temperature, continue to react for 1.5 hours, keep the reaction in the GC, control the reaction to finish, cool down the system to minus 10 ℃ to minus 5 ℃, drop 40mL ammonium chloride to quench the reaction, extract 60mL of 2 petroleum ether twice, dry anhydrous sodium sulfate of the organic phase, filter, concentrate to obtain crude product, purify by column chromatography to obtain 4.4g intermediate 4, yield 81%. 1 H NMR(CDCl3)δ4.34-4.38(m,1H),3.97-4.08(m,1H),3.57-3.63(m,1H),3.38(d,J＝3.9Hz,1H),3.35(d,J＝8.4Hz,1H),2.79(dd,J＝4.5,13.8Hz,1H),1.92(dd,J＝10.8,13.8Hz,1H),1.82-1.90(m,1H),1.58(ddd,J＝2.4,10.5,12.9Hz,1H),0.89(s,9H),0.86(s,9H),0.29(s,9H),0.10(s,3H),0.07(s,3H),0.06(s,6H)；
Example 4
Intermediate 8 (4.0 g,9.07 mmol), anhydrous 2-methyltetrahydrofuran 60mL and tetraisopropyl titanate (3.9 g,13.72 mmol) are sequentially added into a 100mL three-port bottle, the system is cooled to-50 ℃, 18mL of 2M isopropyl magnesium chloride is dropwise added, the temperature is kept for 1.5 hours after the addition, the GC is controlled to confirm that the raw material conversion is finished, the system is cooled to-78 ℃ again, NBS (5.5 g,30.90 mmol) tetrahydrofuran solution is added in batches, the temperature is kept for 0.5 hour after stirring, the temperature is naturally kept at room temperature for 1.5 hours, the reaction is continued for 1.5 hours, the GC is controlled to confirm that the reaction is finished, the system is cooled to-10 to-5 ℃ and is quenched by dropwise adding 40mL of ammonium chloride, 60mL of 2 petroleum ether is extracted twice, the organic phase anhydrous sodium sulfate is dried, the crude product is obtained after filtration and concentration, 4.1g of intermediate 4 is obtained after column chromatography purification, and the yield is 75%.
Example 5
In a 50mL three-necked flask, intermediate 4 (3.0 g,4.99 mmol), 10mL of anhydrous toluene and DBU (2.7 g,17.47 mmol) were added sequentially, the mixture was heated to 80℃and kept at a temperature for 18 hours, the medium was controlled to confirm that the conversion of the raw materials was completed, the system was returned to room temperature, 30mL of petroleum ether was added, the organic phase was washed twice with 10mL of saturated ammonium chloride, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 2.7g of intermediate 5 as a crude product for use.
The intermediate 5, 15mL of anhydrous DMF and cesium carbonate (6.5 g,19.95 mmol) obtained above were added in sequence to a 50mL three-necked flask, stirred overnight at room temperature 25 ℃, the completion of the conversion of the raw materials was confirmed by central control, 60mL of petroleum ether was added, the organic phase was washed twice with ice water 10mL of x 2, dried over anhydrous sodium sulfate, filtered, concentrated to obtain crude product, and purified by column chromatography to obtain 2.0g A ring fragment 6 in 89% yield. 1 H NMR(CDCl3)δ6.03(d,J＝1.5Hz,1H),5.34(d,J＝1.5Hz,1H),5.16(d,J＝1.5Hz,1H),4.39-4.44(m,1H),4.14-4.21(m,1H),2.41(ddd,J＝1.5,3.6,13.5Hz,1H),2.23(dd,J＝6.3,13.5Hz,1H),1.73-1.87(m,2H),0.91(s,9H),0.88(s,9H),0.09(s,3H),0.08(s,3H),0.06(s,6H).
Example 6
Intermediate 4 (3.0 g,4.99 mmol), 10mL of anhydrous toluene and DBU (3.8 g,24.96 mmol) are sequentially added into a 50mL three-necked flask, the mixture is heated to 80 ℃ and kept for 18 hours, the medium control confirms that the raw material conversion is finished, the system is returned to room temperature, 30mL of petroleum ether is added, the organic phase is washed twice with 10mL of saturated ammonium chloride, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 2.9g of crude intermediate 5 for later use.
The obtained intermediate 5, 10mL of anhydrous DMSO and potassium carbonate (2.06 g,14.97 mmol) are sequentially added into a 50mL three-necked flask, stirred overnight at room temperature and 25 ℃, 50mL of petroleum ether is added for central control to confirm that the raw material conversion is finished, the organic phase is washed twice with 10mL of ice water and 2, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, and column chromatography is performed to obtain a 1.9g A ring segment 6, and the yield is 85%.
The foregoing embodiments illustrate the basic principles, principal features and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the above-described embodiments, and that the above-described embodiments and descriptions are merely illustrative of the principles of the present invention, and various changes and modifications may be made without departing from the scope of the principles of the invention, which are defined in the appended claims.
Claims (10)
1. The cyclohexane diene compound of the general formula I is characterized by having the following structural formula:
wherein: r is R 1 ,R 2 Each independently selected from TBS, TMS, me PhSi, i-Pr 3 Si、Et 3 Si。
2. The preparation method of the vitamin D derivative A ring building block is characterized by comprising the following steps of:
firstly, taking a full-protection compound 8 as a raw material, and reacting with a brominating reagent in the presence of tetraisopropyl titanate and an isopropyl Grignard reagent to obtain a compound 4;
step two, the compound 4 is heated to react and eliminate in the presence of organic alkali to obtain a compound 5;
and thirdly, removing TMS from the compound 5 in the presence of inorganic base to obtain a compound 6.
3. The method for preparing the vitamin D derivative A ring block according to claim 2, wherein: the first isopropyl grignard reagent is selected from the group consisting of isopropyl magnesium chloride, isopropyl magnesium bromide, isopropyl magnesium chloride-lithium chloride.
4. The method for preparing the vitamin D derivative A ring block according to claim 2, wherein: the brominating reagent in the first step is selected from NBS or dibromohydantoin; the reaction solvent is tetrahydrofuran or 2-methyltetrahydrofuran; the reaction temperature is-78 ℃ to 30 ℃.
5. The method for preparing the vitamin D derivative A ring block according to claim 2, wherein: the molar ratio of the compound 8, the tetraisopropyl titanate, the isopropyl Grignard reagent and the brominating reagent in the first step is 1:1-1.5:3-4:1.5-3.5.
6. The method for preparing the vitamin D derivative A ring block according to claim 2, wherein: the organic alkali in the second step is DBU, DBN or DABCO; the reaction solvent is toluene, dioxane and tetrahydrofuran, and the reaction temperature is 60-100 ℃.
7. The method for preparing the vitamin D derivative A ring block according to claim 2, wherein: the molar ratio of the compound 4 in the second step to the organic base is 1:3-5.
8. The method for preparing the vitamin D derivative A ring block according to claim 2, wherein: the third step of inorganic base is sodium carbonate, potassium carbonate or cesium carbonate; the reaction solvent is DMF, DMSO, sulfolane, etc. and the reaction temperature is 0-40 ℃.
9. The method for preparing the vitamin D derivative A ring block according to claim 2, wherein: the molar ratio of the compound 5 in the third step to the inorganic base is 1:3-5.
10. The method for preparing the vitamin D derivative A ring block according to claim 2, wherein:
the preparation method of the compound 8 comprises the step of reacting the compound 7 with n-butyllithium and trimethylchlorosilane at ultralow temperature to obtain the compound 8.
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