CN118047713A - Method for synthesizing boceprevir intermediate - Google Patents
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- 238000000034 method Methods 0.000 title claims abstract description 24
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 6
- MFBZMDIQWYXOSP-CIUDSAMLSA-N (1r,2s,5s)-6,6-dimethyl-3-[(2-methylpropan-2-yl)oxycarbonyl]-3-azabicyclo[3.1.0]hexane-2-carboxylic acid Chemical compound OC(=O)[C@H]1N(C(=O)OC(C)(C)C)C[C@@H]2C(C)(C)[C@H]12 MFBZMDIQWYXOSP-CIUDSAMLSA-N 0.000 title description 4
- -1 methyl ester hydrochloride Chemical class 0.000 claims abstract description 15
- 239000002994 raw material Substances 0.000 claims abstract description 14
- 230000008569 process Effects 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 42
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 36
- 238000006243 chemical reaction Methods 0.000 claims description 35
- 239000000243 solution Substances 0.000 claims description 26
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- 239000012074 organic phase Substances 0.000 claims description 14
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 11
- ZEOVXNVKXIPWMS-UHFFFAOYSA-N 2,2-dichloropropane Chemical compound CC(C)(Cl)Cl ZEOVXNVKXIPWMS-UHFFFAOYSA-N 0.000 claims description 10
- 239000012065 filter cake Substances 0.000 claims description 10
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 claims description 9
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- 230000009471 action Effects 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 238000012805 post-processing Methods 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 5
- 239000003054 catalyst Substances 0.000 claims description 5
- 238000009749 continuous casting Methods 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- 239000012467 final product Substances 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 4
- 239000011701 zinc Substances 0.000 claims description 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 3
- 239000008346 aqueous phase Substances 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- 238000001514 detection method Methods 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 3
- 238000011010 flushing procedure Methods 0.000 claims description 3
- 238000004321 preservation Methods 0.000 claims description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 3
- 238000010898 silica gel chromatography Methods 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims description 3
- 229910052725 zinc Inorganic materials 0.000 claims description 3
- 229940102001 zinc bromide Drugs 0.000 claims description 3
- MZMNEDXVUJLQAF-YUMQZZPRSA-N 1-o-tert-butyl 2-o-methyl (2s,4s)-4-hydroxypyrrolidine-1,2-dicarboxylate Chemical compound COC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C MZMNEDXVUJLQAF-YUMQZZPRSA-N 0.000 claims description 2
- ARITXYXYCOZKMU-UHFFFAOYSA-N 2,2-dibromopropane Chemical compound CC(C)(Br)Br ARITXYXYCOZKMU-UHFFFAOYSA-N 0.000 claims description 2
- BZRRQSJJPUGBAA-UHFFFAOYSA-L cobalt(ii) bromide Chemical compound Br[Co]Br BZRRQSJJPUGBAA-UHFFFAOYSA-L 0.000 claims description 2
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 claims description 2
- 238000007747 plating Methods 0.000 claims description 2
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- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- BEZVGIHGZPLGBL-UHFFFAOYSA-N 2,6-diacetylpyridine Chemical compound CC(=O)C1=CC=CC(C(C)=O)=N1 BEZVGIHGZPLGBL-UHFFFAOYSA-N 0.000 description 2
- 241000711549 Hepacivirus C Species 0.000 description 2
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- ABRWESLGGMHKEA-UHFFFAOYSA-N n-tert-butylaniline Chemical compound CC(C)(C)NC1=CC=CC=C1 ABRWESLGGMHKEA-UHFFFAOYSA-N 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 229910019131 CoBr2 Inorganic materials 0.000 description 1
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
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- 229920001184 polypeptide Polymers 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
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- 125000006239 protecting group Chemical group 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A method of synthesizing (1 r,2s,5 s) -6, 6-dimethyl-3-azabicyclo [3,1,0] hexyl-2-carboxylic acid methyl ester hydrochloride, the method route being as follows:
Description
Technical Field
The invention relates to the field of organic chemical synthesis, in particular to a method for synthesizing a boceprevir intermediate, namely (1R, 2S, 5S) -6, 6-dimethyl-3-azabicyclo [3,1,0] hexyl-2-carboxylic acid methyl ester hydrochloride.
Background
The (1R, 2S, 5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexyl-2-carboxylic acid methyl ester hydrochloride is an azabicyclo hexane derivative, is a new crown medicament, namely the high-added value intermediate of the Boprene Wei Qianzai, is widely used for preparing Hepatitis C Virus (HCV) NS3 serine protease inhibitors at present, and has an extremely important role in the field of biological pharmacy.
Boepprevir intermediate (1R, 2S, 5S) -6, 6-dimethyl-3-azabicyclo [3,1,0] hexyl-2-carboxylic acid methyl ester hydrochloride structural formula
At present, the preparation of (1R, 2S, 5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexyl-2-carboxylic acid methyl ester hydrochloride mainly comprises the following three synthetic routes:
Synthetic scheme 1, as shown in scheme one of the following patent reports. The route starting material A01 can be obtained from L-pyroglutamine alcohol through one step, so that the cost of the starting material is greatly reduced. But there are three disadvantages: (1) The whole route needs multi-step ultralow temperature reaction, so that the production condition is harsh; (2) The high-activity reagent is used for oxidation and reduction reactions in multiple steps, so that the operation risk is increased, phSeCl is high in price (5000/100 g), and the cost is increased; (3) there is no data on the optical purity of the final product in the literature.
Synthetic scheme 2, as shown in scheme two of the following patent report. The route resolution step is at the front end, which is beneficial to the control of the feeding equivalent of the subsequent experiment, and simultaneously avoids the problem that the enantiomer is difficult to resolve in the subsequent step as early as possible. However, there are also a number of disadvantages: (1) long route, low yield, and expensive starting materials; (2) Multiple use of highly risky reactions such as oxidation, cyanation, hydrogenation, etc.; (3) Resolution requires consideration of the other half of the isomer recovery problem.
Synthetic route 3, as shown in the following patent report route three. The synthesis route has the advantages of cheap and easily obtained starting materials, low cost, simple reaction and high yield. However, chiral resolution is required, the resolution step yield is less than 50%, and KCN with high toxicity harmful to human body is used.
In view of the above, the development of new crown drugs requires a potential high value-added intermediate, namely (1 r,2s,5 s) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexyl-2-carboxylic acid methyl ester hydrochloride, however, the current synthesis method has a large room for improvement.
Disclosure of Invention
Aiming at the problems of complicated steps, low yield, chiral resolution and the like in the existing synthetic route of (1R, 2S, 5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexyl-2-carboxylic acid methyl ester hydrochloride, the invention provides a method for preparing (1R, 2S, 5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexyl-2-carboxylic acid methyl ester hydrochloride with chiral self-contained and no resolution.
The invention discloses a novel method for synthesizing a boceprevir intermediate (1R, 2S, 5S) -6, 6-dimethyl-3-azabicyclo [3,1,0] hexyl-2-carboxylic acid methyl ester hydrochloride, which comprises the following reaction steps:
1) Dissolving a compound of the formula A01 in a dichloromethane solution, and then sequentially dropwise adding 2, 6-lutidine and trifluoromethanesulfonic anhydride at a low temperature (-65 ℃ to-78 ℃) for reaction to generate the compound of the formula A02;
2) Continuously dropwise adding 2, 6-lutidine into the compound of the formula A02 at a low temperature (-65 ℃ to-78 ℃) until the reaction is complete, and performing post-treatment to obtain the compound of the formula A03;
3) Reacting the compound of the formula A03 with zinc, zinc bromide and 2, 2-dichloropropane under the action of a catalyst, and obtaining the compound of the formula A04 after post treatment;
4) Removing Boc from the compound of formula A04 under the action of hydrogen chloride/methanol solution to obtain the compound of formula A0.
Preferred embodiments of the invention:
The catalyst in the step 3) is 2, 2-dichloropropane or 2, 2-dibromopropane, preferably 2, 2-dichloropropane, and the higher yield is obtained by adopting the 2, 2-dichloropropane;
the required A03 compound in the step 3) can be generated by a continuous casting reaction of A01 or by a continuous casting reaction of N-Boc-cis-4-hydroxy-L-proline methyl ester (isomer of A01), preferably by the continuous casting reaction of A01.
In order to overcome the defects of complicated synthetic route, difficult chiral resolution, low resolution yield, harsh production conditions and the like of (1R, 2S, 5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexyl-2-carboxylic acid methyl ester hydrochloride, the invention develops a novel process route which comprises the following reaction steps:
1) Dissolving a compound of the formula A01 in a dichloromethane solution, and then sequentially dripping 2, 6-lutidine and trifluoromethanesulfonic anhydride at a low temperature (-65 ℃ to-78 ℃) for reaction to generate a compound of the formula A02;
2) Continuously dropwise adding 2, 6-lutidine into the compound of the formula A02 at a low temperature (-65 ℃ to-78 ℃) until the reaction is complete, and performing post-treatment to obtain the compound of the formula A03;
3) The compound of the formula A03 reacts with zinc, zinc bromide and 2, 2-dichloropropane under the action of a catalyst, and the compound of the formula A04 is obtained after post treatment.
4) Removing Boc from the compound of formula A04 under the action of hydrogen chloride/methanol solution to obtain the compound of formula A0.
According to one embodiment of the invention, the method comprises:
1) To a three-necked flask, the compound of formula A01 (1 eq.) and methylene chloride (10 vol.) were added, the temperature was lowered to-78℃under the protection of nitrogen, 2, 6-lutidine (2.0 eq.) was added dropwise at-65℃to-78℃and stirred for 0.5h at (-65℃to-78 ℃). Then, tf 2 O (1.5 eq.) is added dropwise after the temperature is kept at-65 ℃ to-78 ℃, the temperature is kept (-65 ℃ to-78 ℃) and stirred for reaction for 1 hour, then a spot plate is sampled, and the complete consumption of raw materials is confirmed, so that the compound of the formula A02 is obtained.
2) 2, 6-Lutidine (8.0 eq.) was added dropwise to the compound of formula A02 at-78deg.C, the temperature was kept at-65deg.C to-78deg.C, the reaction was allowed to proceed for 0.5 hours, and then the reaction was allowed to proceed slowly to room temperature, and after confirming the absence of the starting material, the post-treatment was performed.
The post-processing includes: citric acid (11.0 eq.) was dissolved in water (20 vol.), the prepared aqueous citric acid solution was slowly added dropwise to the reaction solution, the pH was adjusted to 5 to 6, the solution was separated, the organic phase was washed with saturated brine (10 vol..3), and the organic phase was concentrated to dryness to give a yellow liquid compound of formula a 03.
3) To a three-necked flask, a compound of formula a03 (1 eq.), cobalt bromide (0.1 eq.), 2-tBuPDI (0.1 eq.), zn (2.0 eq.), znBr 2 (1.0 eq.), THF (10 vol.), were added dropwise 2, 2-dichloropropane (2.0 eq.) under nitrogen protection, then slowly warmed to room temperature, reacted for 24 hours with heat preservation, and post-treatment was performed after confirming that there was no raw material.
The post-processing includes: filtration, washing of the filter cake with ethyl acetate (2 vol.)), concentration of the filtrate to component-free flow, addition of ethyl acetate (30 vol.)) and water (5 vol.)) to dissolve, separation of the liquid, extraction of the aqueous phase with ethyl acetate (10 vol..3.), washing of the organic phases with saturated aqueous sodium bicarbonate (5 vol.)), flash silica of the organic phases, concentration of the organic phases to component-free flow. The concentrated residue was purified by silica gel column chromatography to give the objective compound A04 (5.04 g, yield 85%).
4) The compound of formula a04 (1.0 eq.) and methanol (2 vol.) are added to a three-necked flask, cooled to 0-10 ℃, and a hydrogen chloride methanol solution (4 m,5 vol.) is slowly added dropwise, the temperature is slowly raised to room temperature after the dropwise addition, the mixture is stirred for 5 hours under heat preservation, then spot-plating detection is carried out, and after no raw material is confirmed, the post-treatment is carried out.
The post-processing includes: vacuum concentrating the reaction solution until no component flows out, adding 5vol. methanol, heating to 60 ℃ for dissolving, keeping the temperature and stirring for 1h, then starting to slowly cool to 0 ℃, filtering, flushing a filter cake with a small amount of cold methanol at 0-10 ℃, and vacuum concentrating and drying the filter cake to obtain a final product A0.
The synthesis method of the invention is adopted to synthesize (1R, 2S, 5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexyl-2-carboxylic acid methyl ester hydrochloride, and the process route is novel; the raw materials are cheap and easy to obtain, and the raw materials have chirality, so that chiral resolution is avoided; the process steps are short, and the former two steps can be continuously thrown; high total yield (90%), high chemical purity (99.68%), etc.
Abbreviations and key term definitions:
boc-abbreviation of t-Butyloxy carbonyl, stands for "t-butoxycarbonyl", an amino protecting group commonly used in organic synthesis, in particular in polypeptide synthesis.
SM1:2, 6-diacetylpyridine; 2,6-DIACETYLPYRIDINE
SM2: t-butylaniline; tributylaniline; tert-Butylaniline
THF: tetrahydrofuran (THF)
DBU:1, 8-diazabicyclo [5.4.0] undec-7-ene
Tf 2 O: trifluoro methane sulfonic anhydride
DCM: dichloromethane (dichloromethane)
Detailed Description
The present invention will be further described in detail with reference to specific embodiments in order to make the objects, technical solutions and advantages of the present invention more apparent. Those skilled in the art will recognize that the present invention is not limited to the following examples.
Example 1
Step 1:
A01 (10 g,1 eq.) and DCM (100 mL,10 vol.) are added into a three-necked flask, the mixture is cooled to-78 ℃ under the protection of nitrogen, 2, 6-lutidine (8.74 g,2.0 eq.) is added dropwise at-65 ℃ to-78 ℃ and stirred for 0.5h at a temperature of (-65 ℃ to-78 ℃). Then Tf 2 O (17.25 g,1.5 eq.) is added dropwise after the temperature is kept at-65 ℃ to-78 ℃, the sample is taken after stirring reaction is carried out for 1h at the temperature of (-65 ℃ to-78 ℃), and the consumption of the raw materials is confirmed to be finished for the next step.
Step 2:
After confirming that the reaction system is free of A01, 2, 6-lutidine (8.74 g,8.0 eq.) is added dropwise at-78 ℃, the temperature is kept between-65 ℃ and-78 ℃, the reaction is carried out for 0.5h at the temperature of (-65 ℃ to-78 ℃), the reaction system is slowly warmed to room temperature, and after confirming that no raw material exists, the post-treatment is carried out.
Post-treatment: citric acid (86.16 g,11.0 eq.) was dissolved in water (200 ml,20 vol.) and the prepared aqueous citric acid solution was slowly added dropwise to the reaction solution, pH was adjusted to 5-6, the solution was separated, the organic phase was washed with saturated brine (100 ml x 3), and the organic phase was concentrated to dryness to give a yellow liquid.
1H NMR(400MHz,CDCl3):δ6.03-5.95(m,1H),5.79-5.71(m,1H),5.08-4.97 (m,1H),4.34-4.16(m,2H),3.76(s,1H),3.75(s,2H),1.50(s,3H),1.45(s,6H).
S1:2-tBuPDI ligand preparation
SM1 (3 g,1 eq), SM2 (10.97 g,4.0 eq.) and p-toluenesulfonic acid (0.32 g,0.1 eq.) were added to a three-necked flask, toluene (15 mL,5 vol.) was purged with nitrogen and the mixture was stirred at 135℃under reflux for 22 hours, and after confirming that there was no starting material SM1, the mixture was worked up.
Post-treatment: cooling to 20-25deg.C, concentrating the reaction solution until no component flows out, adding ethanol (3 mL,1 vol.) for pulping, filtering, and washing the filter cake with ethanol (1 mL). 5.15g of a yellow solid was obtained, and the structure was confirmed by 1 H NMR in 65.77% yield.
1H NMR(400MHz,CDCl3):δ8.43(d,J＝8.0Hz,2H),7.96(t,J＝8.0Hz,1H), 7.46(d,J＝8.0Hz,2H),7.26-7.19(m,2H),7.13-7.09(m,2H),6.58(d,J＝8.0Hz, 2H),2.44(s,6H),1.40(s,18H).
Step 3: double bond addition
Scheme one: and adding A03(5g,1eq.),CoBr2(0.48g,0.1eq.),2-tBuPDI (0.94g,0.1eq.),Zn(2.88g,2.0eq.),ZnBr2(4.96g,1.0eq.),THF(50mL,10vol.), into a three-mouth bottle, and introducing nitrogen for protection. The reaction solution was cooled to 0 to 10 ℃, 2-dichloropropane (4.97 g,2.0 eq.) was added dropwise, then the reaction solution was slowly warmed to room temperature, reacted at a constant temperature for 24 hours, and after confirming that there was no raw material, post-treatment was performed. Post-treatment: filtration, washing of the filter cake with EA (25 mL), concentration of the filtrate to component free flow, addition of ethyl acetate (150 mL,30 vol.) and water (25 mL,5 vol.) to dissolve, separation, extraction of the aqueous phase with ethyl acetate (100 mL x 3), merging of the organic phases, washing with saturated aqueous sodium bicarbonate (50 mL), flash silica, merging of the organic phases, concentration to component free flow. The concentrated residue was purified by silica gel column chromatography to give the objective compound (5.04 g,85% yield).
1H NMR(400MHz,CDCl3):δ4.22-4.10(m,1H),7.77-7.76(m,3H),3.70-3.62 (m,1H),3.47-3.38(m,1H),1.45-1.37(m,11H),1.04(m,3H),0.99-0.98(m,3H).
Step 4: acidic Boc removal
A04 (5 g,1.0 eq.) and methanol (10 mL,2 vol.) were added to a three-necked flask, cooled to 0-10deg.C, and MeOH/HCl (4M, 25 mL) solution was slowly added dropwise, and after the dropwise addition was completed, the temperature was slowly raised to room temperature, and after stirring at a constant temperature for 5 hours, the plate was used for detection, and after confirming the absence of the raw material, the post-treatment was performed. Post-treatment: concentrating the reaction solution in vacuum until no component flows out, adding 30mL of methanol, heating to 60 ℃ for dissolving, keeping the temperature and stirring for 1h, then starting to slowly cool to 0 ℃, filtering, flushing a filter cake with a small amount of cold methanol at 0-10 ℃, and vacuum concentrating and drying the filter cake to obtain a final product A0.
1H NMR(400MHz,DMSO):δ9.94(brs,2H),4.14(s,1H),3.80(s,3H),2.60 (dd,J＝12.0,8.0Hz,1H),3.36(s,2H),3.05(dd,J＝12.0,4.0Hz,1H),1.90-1.88(m, 1H),1.78-1.74(m,1H),1.08(s,3H),1.04(s,3H).
Claims (8)
1. A method of synthesizing (1 r,2s,5 s) -6, 6-dimethyl-3-azabicyclo [3,1,0] hexyl-2-carboxylic acid methyl ester hydrochloride, the method route being as follows:
2. the method according to claim 1, characterized in that it comprises the following reaction steps:
1) Dissolving a compound of the formula A01 in a dichloromethane solution, and then sequentially dropwise adding 2, 6-lutidine and trifluoromethanesulfonic anhydride at a low temperature (-65 ℃ to-78 ℃) for reaction to generate the compound of the formula A02;
2) Continuously dropwise adding 2, 6-lutidine into the compound of the formula A02 at a low temperature (-65 ℃ to-78 ℃) until the reaction is complete, and performing post-treatment to obtain the compound of the formula A03;
3) Reacting the compound of the formula A03 with zinc, zinc bromide and 2, 2-dichloropropane under the action of a catalyst, and obtaining the compound of the formula A04 after post treatment;
4) Removing Boc from the compound of formula A04 under the action of hydrogen chloride/methanol solution to obtain the compound of formula A0.
3. Process according to claim 1 or 2, characterized in that the catalyst in step 3) is 2, 2-dichloropropane or 2, 2-dibromopropane, preferably 2, 2-dichloropropane.
4. The process according to claim 1 or 2, wherein the compound a03 required in step 3) is produced by a continuous casting reaction of a01 or by a continuous casting reaction of the compound N-Boc-cis-4-hydroxy-L-proline methyl ester (isomer of a 01), i.e. step 1) to give a mixture comprising the compound a02, which is directly subjected to the next reaction without subsequent work-up.
5. The method according to claim 1 or 2, characterized in that the method comprises:
1) Adding a compound (1 eq.) of formula A01 and methylene dichloride (10 vol.) into a three-necked flask, cooling to-78 ℃ under the protection of nitrogen, dropwise adding 2, 6-lutidine (2.0 eq.) at the temperature of-65 ℃ to-78 ℃, and stirring for 0.5h at the temperature of (-65 ℃ to-78 ℃); then, dropwise adding Tf 2 O (1.5 eq.) at the temperature of-65 ℃ to-78 ℃, keeping the temperature (-65 ℃ to-78 ℃) and stirring for reacting for 1 hour, and then sampling a spot plate, and confirming that the raw material consumption is complete to obtain a compound of a formula A02;
2) 2, 6-lutidine (8.0 eq.) is added dropwise to the compound of formula A02 at-78deg.C, the temperature is kept at-65deg.C to-78deg.C, the reaction time is 0.5h, the reaction time is slowly raised to room temperature, and after no raw material is confirmed, the post treatment is performed;
3) Adding a compound (1 eq.), cobalt bromide (0.1 eq.), 2-tBuPDI (0.1 eq.), zn (2.0 eq.), znBr 2 (1.0 eq.), THF (10 vol.), cooling to 0-10 ℃ under the protection of nitrogen, dropwise adding 2, 2-dichloropropane (2.0 eq.), then slowly heating to room temperature, keeping the temperature for reaction for 24 hours, and carrying out post-treatment after confirming no raw material;
4) The compound of formula a04 (1.0 eq.) and methanol (2 vol.) are added to a three-necked flask, cooled to 0-10 ℃, and a hydrogen chloride methanol solution (4 m,5 vol.) is slowly added dropwise, the temperature is slowly raised to room temperature after the dropwise addition, the mixture is stirred for 5 hours under heat preservation, then spot-plating detection is carried out, and after no raw material is confirmed, the post-treatment is carried out.
6. The method according to claim 5, wherein the post-processing in step 2) comprises: citric acid (11.0 eq.) was dissolved in water (20 vol.), the prepared aqueous citric acid solution was slowly added dropwise to the reaction solution, the pH was adjusted to 5 to 6, the solution was separated, the organic phase was washed with saturated brine (10 vol. Times.3), and the organic phase was concentrated to dryness to give a yellow liquid compound a 03.
7. The method of claim 5, wherein the post-processing in step 3) comprises: filtering, washing the filter cake with ethyl acetate (2 vol.), concentrating the filtrate until no component flows out, adding ethyl acetate (30 vol.) and water (5 vol.)) to dissolve, separating the liquid, extracting the aqueous phase with ethyl acetate (10 vol.: 3), combining the organic phases, washing with saturated aqueous sodium bicarbonate solution (5 vol.)), washing the organic phases with silica gel, combining the organic phases, and concentrating until no component flows out; the concentrated residue was purified using silica gel column chromatography to give the objective compound a04.
8. The method according to claim 5, wherein the post-processing in step 4) comprises: vacuum concentrating the reaction solution until no component flows out, adding 5vol. methanol, heating to 60 ℃ for dissolving, keeping the temperature and stirring for 1h, then starting to slowly cool to 0 ℃, filtering, flushing a filter cake with a small amount of cold methanol at 0-10 ℃, and vacuum concentrating and drying the filter cake to obtain a final product A0.
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