CN114085181B - Synthetic method and application of 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane - Google Patents

Synthetic method and application of 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane Download PDF

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CN114085181B
CN114085181B CN202210053918.7A CN202210053918A CN114085181B CN 114085181 B CN114085181 B CN 114085181B CN 202210053918 A CN202210053918 A CN 202210053918A CN 114085181 B CN114085181 B CN 114085181B
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陈剑
余长泉
顾榕
邱亚涛
祝俊
李丹
李斌
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Jindawei Biotechnology Jiangsu Co ltd
Nanjing Huaguan Biotechnology Co ltd
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Abstract

The invention discloses a 6, 6-dimethyl-3-azabicyclo [3.1.0]]The hexane is 6, 6-dimethyl-3-oxazole cyclo [ 3.1.0%]The 6, 6-dimethyl-3-azabicyclo [3.1.0] is prepared by taking hexane-2-ketone as a raw material and performing ring opening, aminolysis and reduction by using a chloro or bromo reagent]Hexane, said 6, 6-dimethyl-3-oxazolo cyclo [3.1.0]Hexane-2-ones of the formula
Figure 959470DEST_PATH_IMAGE001
The compound shown as 6, 6-dimethyl-3-azabicyclo [3.1.0]Hexane is of the formula
Figure 863972DEST_PATH_IMAGE002
The compound has the advantages that: the method has the advantages of cheap and easily obtained starting materials, simple and convenient operation of the preparation method, higher atom economy and low energy consumption and cost compared with the process of the caronic anhydride because only amide needs to be reduced, and is suitable for industrial production.

Description

Synthesis method and application of 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane
Technical Field
The invention relates to the technical field of drug intermediate synthesis, in particular to a synthesis method of 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane by taking 6, 6-dimethyl-3-oxazolylcyclo [3.1.0] hexane-2-ketone as a starting material and application thereof, wherein the synthesized compound is an important intermediate of a main antiviral component Nirmatrelvin (PF-07321332) of a new crown oral antiviral drug Paxlovid.
Background
COVID-19 caused by SARS-Cov-2 is spreading worldwide, has become a world epidemic disease, and brings a serious challenge to global public health defense and medical systems and an uncertain factor to the world economy. 5/11/2021, Pfizer company published the latest clinical trial results of its oral anti-neocoronaviruses in the development of therapy Paxlovid. Paxlovid reduces the risk of hospitalization or death by nearly 90% in a clinical trial at 2/3 in patients with COVID-19 who are at high risk of developing severe illness, and another clinical trial at 2/3 shows that Paxlovid also reduces the risk of hospitalization or death by 70% in people at lower risk of developing severe illness. Furthermore, in vitro biochemical experiments have shown that Paxlovid has the potential to retain potent antiviral activity against new coronavirus variants, including Omicron. Paxlovid appears as a specific drug for treating new coronavirus infection, and has great hope of making people afraid of the new coronavirus infection era. The FDA has urgently approved oral new crown drug Paxlovid for people over 12 years of age and having a weight of at least 40 kg for the united states local time of 12 months and 22 days for 12 months, and the british drug and health care administration (MHRA) has approved the use of the new crown oral drug Paxlovid by the company feverfew, and in addition, feverfew has started rolling submissions in several countries/regions including australia, new zealand and korea, and is planning to submit applications to other regulatory agencies around the world.
Paxlovid consists of the neocoronavirus 3CL protease inhibitor Nirmatrelvir (PF-07321332) and the antiviral therapy ritonavir (ritonavir). The nirmatrelvin disables the subsequent RNA replication process of the virus by blocking the activity of the new coronavirus 3CL protease. Ritonavir at low doses helps to reduce metabolism or degradation of the nitratrelvin, allows it to remain active in the body for longer periods of time, and helps to combat viruses. Wherein the structural formula of the Nirmatrelvir is as follows:
Figure 781459DEST_PATH_IMAGE001
it was confirmed by reverse synthetic analysis of Nirmatrelvin that the compound was obtained from the following 3 fragments by amide condensation reaction.
Figure 336069DEST_PATH_IMAGE002
Wherein fragment 1 is in turn composed of 6, 6-dimethyl-3-azabicyclo [3.1.0]]Hexane is obtained by oxidation and optionally cyano addition, from which it can be seen that 6, 6-dimethyl-3-azabicyclo [3.1.0]Hexane is an important intermediate of the main antiviral component of the new coronary oral drug Paxlovid, namely, the Nirmatrelvin (PF-07321332), and in addition, the intermediate is also widely applied to other organic synthesis fields, and the chemical formula of the intermediate is shown as the formula
Figure 485290DEST_PATH_IMAGE003
Shown in the figure:
Figure 834363DEST_PATH_IMAGE004
the general synthetic route for 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane is now as follows (WO 2007075790, WO2009073380, IN2010MU 02833):
Figure 803456DEST_PATH_IMAGE005
the route takes the caronic anhydride as a starting material, and is obtained by ammonolysis and carbonyl reduction, the raw material manufacturers are few, the price is high, two carbonyls need to be reduced, a large amount of reducing reagent is needed, the atom economy is poor, and the cost is too high. In addition, the caronic anhydride is cis-trans-caronic diacid obtained by oxidizing double bonds with methyl chrysanthemate, and the trans-diacid is isomerized into cis-diacid and then dehydrated into anhydride at 190 ℃ during the preparation of the caronic anhydride, so that the high-temperature reaction time is long and the energy consumption is high.
Disclosure of Invention
The invention aims to provide a method for synthesizing 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane by taking 6, 6-dimethyl-3-oxazolylcyclo [3.1.0] hexane-2-ketone as a starting material, wherein the starting material is cheap and easy to obtain, the preparation method is simple and convenient to operate, and compared with a process of caronic anhydride, the method only needs to reduce amide, has higher atom economy and low energy consumption and cost, and is suitable for industrial production.
A method of synthesizing 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane comprising the steps of:
Figure 630598DEST_PATH_IMAGE006
wherein R1 and R2 are the same or different and are selected from Cl or Br,
step 1: in a solvent, 6, 6-dimethyl-3-oxazolylcyclo [3.1.0] hexane-2-ketone is subjected to acylation reaction to obtain cis-2, 2-dimethylcyclopropane-4-halobutyryl halide;
step 2: in a solvent, cis-2, 2-dimethylcyclopropane-4-halobutyryl halide is subjected to ammonolysis reaction to obtain 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-ketone;
and step 3: reduction of 6, 6-dimethyl-3-azabicyclo [3.1.0] hexan-2-one in a solvent yields 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane.
Further, the acylation reagent used in the acylation reaction in the step 1 is selected from the group consisting of: one of phosphorus tribromide, phosphorus pentabromide, phosphorus oxybromide, dibromosulfoxide, thionyl chloride, hydrogen bromide, oxalyl bromide, hydrogen bromide, thionyl chloride and zinc chloride.
Further, the ammonolysis reaction in the step 2 is a compound
Figure 368747DEST_PATH_IMAGE007
Reacting with ammonia water to obtain 6, 6-dimethyl-3-azabicyclo [3.1.0]Hexane-2-ketone, and solvent is one or more of tetrahydrofuran, acetonitrile, 1, 4-dioxane, methanol, and ethanol.
Further, the compounds
Figure 121677DEST_PATH_IMAGE007
The molar ratio of the compound to ammonia water is 1: 1-1: 15
Figure 578066DEST_PATH_IMAGE007
Volume ratio to solvent was 0.2 mmο1 :0.5~1mL。
Further, the ammonolysis reaction in the step 2 is a compound
Figure 67953DEST_PATH_IMAGE007
Reacting with benzylamine in the presence of a base to obtain a compound
Figure 801554DEST_PATH_IMAGE007
B, compounds
Figure 617063DEST_PATH_IMAGE007
B debenzylation to give 6, 6-dimethyl-3-azabicyclo [3.1.0]Hexane-2-ketone, and the solvent is one or more of N, N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, dichloromethane, 1, 4-dioxane and acetonitrile.
Further, the alkali is one of sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate and potassium bicarbonate, and the compound is
Figure 436115DEST_PATH_IMAGE007
The molar ratio of the compound to the alkali is 1: 1-1: 3, and the compound
Figure 729693DEST_PATH_IMAGE007
The volume ratio of the water to the solvent is 0.2mm DEG O1: 0.5-1 mL.
Further, the benzylamine and the compound
Figure 52221DEST_PATH_IMAGE007
The molar ratio of (a) to (b) is 1:1 to 2: 1.
Further, the compounds
Figure 38631DEST_PATH_IMAGE007
And B, debenzylation adopts a palladium-carbon catalytic hydrogenation removal method.
Further, the reducing system in step 3 comprises a reducing agent and a Lewis acid, wherein the reducing agent is selected from one of lithium aluminum hydride, sodium borohydride, potassium borohydride, lithium borohydride, sodium cyanoborohydride, diborane, borane, bis (cyclopentadiene) zirconium hydride/pinacol borane, and the reducing agent is selected from one of lithium aluminum hydride, sodium borohydride, potassium borohydride, lithium borohydride, sodium cyanoborohydride, diborane, borane, bis (cyclopentadiene) zirconium hydride/pinacol boraneThe Lewis acid is selected from one of zinc chloride, lithium chloride, ferric chloride, cobalt chloride, magnesium chloride, aluminum chloride, boron trifluoride diethyl etherate, acetic acid, trifluoroacetic acid and sulfuric acid; reducing agents and compounds
Figure 866952DEST_PATH_IMAGE007
The molar ratio of (A) to (B) is 1.0-8.0: 1.0; the solvent in step 3 is one or more of tetrahydrofuran, dichloromethane, diethyl ether, toluene and acetonitrile
Figure 698641DEST_PATH_IMAGE008
The volume ratio of the water to the solvent is 0.2mm DEG O1: 0.5-1 mL.
The raw material 6, 6-dimethyl-3-oxazole cyclo [3.1.0] hexane-2-ketone adopted by the invention can be obtained by diazotizing and ring closing 3-methyl-2-alkene-1-glycine ester, and the route is shown as follows:
Figure 265889DEST_PATH_IMAGE009
。
the raw material 6, 6-dimethyl-3-oxazole cyclo [3.1.0] hexane-2-ketone adopted by the invention can also be obtained by Baeyer-Villiger rearrangement and hydrolysis of furfural to obtain 2(5H) -furanone and then Simmons-Smith reaction, and the route is shown as follows:
Figure 298567DEST_PATH_IMAGE010
。
another object of the invention is: including but not limited to the application of 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane synthesized by the method in the field of preparing a new novel oral crown drug, Paxlovid, as a main antiviral component, NirmatrelvirPF-07321332.
Has the advantages that:
the starting material 6, 6-dimethyl-3-oxazole cyclo [3.1.0] hexane-2-ketone in the invention is cheap and easy to obtain, the preparation method is simple and convenient to operate, and compared with the process of the caronic anhydride, the method only needs to reduce amide, has higher atom economy and low energy consumption and cost, and is suitable for industrial production.
Drawings
FIG. 1 is 6, 6-dimethyl-3-azabicyclo [3.1.0]]Process for preparing hexane1H NMR spectrum.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions. If the temperature is not particularly emphasized, the reaction is usually carried out at room temperature, and the room temperature in the present invention is 10 to 30 ℃.
The two synthetic routes involved in the invention have the following specific reaction formulas:
Figure 216844DEST_PATH_IMAGE011
compounds of the invention
Figure 993170DEST_PATH_IMAGE007
According to the selection of R1 and R2, three structures can be specifically selected, specifically compounds
Figure 555870DEST_PATH_IMAGE007
a. Compound IIb and compound
Figure 884083DEST_PATH_IMAGE007
c。
FIG. 1 is a 1H NMR spectrum of 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane.
Example 1: compound (I)
Figure 397979DEST_PATH_IMAGE012
Synthesis of a
Figure 368209DEST_PATH_IMAGE013
Adding the compound to a three-necked bottle
Figure 785415DEST_PATH_IMAGE014
(10.00 g, 0.08 mol) was dissolved in toluene (200 mL), a mixed solution of thionyl chloride (11.90 g, 0.10 mol) and hydrogen bromide (8.09 g, 0.10 mol) in toluene (65 mL) was slowly added dropwise at room temperature, the reaction was continued for 8 hours with stirring, and the mixture was concentrated to give a compound
Figure 284529DEST_PATH_IMAGE007
a（16.35 g, 92%）。1H NMR (400 MHz, CDCl3) δ 3.43 – 3.31 (m, 2H), 2.95-2.81 (m, 1H), 2.29 – 2.21 (m, 1H), 1.12 (s, 3H), 1.07 (s, 3H)。
Example 2: compound (I)
Figure 521607DEST_PATH_IMAGE012
Synthesis of a
Figure 498790DEST_PATH_IMAGE015
Adding the compound to a three-necked flask at room temperature
Figure 36082DEST_PATH_IMAGE014
(50.00 g, 0.40 mol) and hydrobromic acid (122.61 g, 0.50 mol, 33% in H2O), heating to 30-80 ℃, stirring for reaction for 2-5 h, detecting by TLC (thin layer chromatography) to complete the reaction, adding water (250 mL) and ethyl acetate (250 mL), layering, extracting the water phase by ethyl acetate (250 mL multiplied by 2), combining the organic phases, concentrating under reduced pressure to obtain a crude product, adding the crude product into a three-neck bottle, dropwise adding thionyl chloride (59.49 g, 0.50 mol) at 0-5 ℃, heating to room temperature, stirring for 5-10 h after the addition is finished, detecting by TLC to complete the reaction, concentrating, distilling to obtain a compound
Figure 440518DEST_PATH_IMAGE007
a（84.38 g, 95%）。1H NMR (400 MHz, CDCl3) δ 3.43 – 3.31 (m, 2H), 2.95-2.81 (m, 1H), 2.29 – 2.21 (m, 1H), 1.12 (s, 3H), 1.07 (s, 3H)。
Example 3: compound (I)
Figure 555105DEST_PATH_IMAGE012
b Synthesis
Figure 709880DEST_PATH_IMAGE016
Adding the compound to a three-necked flask at room temperature
Figure 960733DEST_PATH_IMAGE014
(12.50 g, 0.10 mol) and dichloromethane (105 mL), thionyl chloride (14.87 g, 0.13 mol) and zinc chloride (13.63 g, 0.10 mol) were added thereto and heated to reflux for 5h, TLC checked for completion of reaction, cooled to room temperature, filtered under nitrogen, dichloromethane (25 mL. times.2) washed the solid, concentrated, and distilled to give the compound
Figure 677016DEST_PATH_IMAGE007
b（14.99 g, 84%）。1H NMR (400 MHz, CDCl3) δ 3.74 – 3.64 (m, 2H), 2.75-2.71 (m, 1H), 2.12 – 2.10 (m, 1H), 1.12 (s, 3H), 1.16 (s, 3H)。
Example 4: compound (I)
Figure 278899DEST_PATH_IMAGE012
c Synthesis
Figure 738830DEST_PATH_IMAGE017
Adding the compound to a three-necked flask at room temperature
Figure 375348DEST_PATH_IMAGE014
(50.00 g, 0.40 mol) and toluene (500 mL), to which phosphorus pentabromide (215.25 g, 0.50 mol) was added, stirred at room temperature for 8 h, TLC checked for completion, cooled to room temperature, filtered under nitrogen, the solid (250 mL. times.2) washed with toluene, concentrated, and distilled to give the compound
Figure 262533DEST_PATH_IMAGE007
c（97.75 g, 92%）。1H NMR (400 MHz, CDCl3) δ 3.44 – 3.28 (m, 2H), 2.96-2.87 (m, 1H), 2.33 – 2.23 (m, 1H), 1.16 (s, 3H), 1.11 (s, 3H)。
Example 5: compound (I)
Figure 820553DEST_PATH_IMAGE018
Synthesis of (2)
Figure 582710DEST_PATH_IMAGE019
At room temperature, to the compound
Figure 808155DEST_PATH_IMAGE007
c (30.00 g, 0.11 mol) ethanol (500 mL) was added, the reaction was heated to reflux with stirring for 2.5 hours, and ammonia (172.6 mL, 1.12 mol, 25% in H) was slowly added dropwise2O,) followed by reflux reaction for 5 hours, TLC detection of a small amount of the remaining starting material, concentration to remove ethanol, addition of water (300 mL), separation of layers, extraction of the aqueous phase with ethyl acetate (300 mL. times.2), combination of the organic phases, washing with saturated brine (300 mL), anhydrous Na2SO4Drying, concentrating the filtrate under reduced pressure to obtain compound
Figure 725296DEST_PATH_IMAGE008
（7.84 g，56%）。1H NMR (300 MHz, CDCl3) δ 3.50 (dd, J = 10.7, 6.0 Hz, 1H), 3.22 (d, J = 10.7 Hz, 1H), 1.71 (m, 2H), 1.12 (s, 6H)。
Example 6: compound (I)
Figure 177137DEST_PATH_IMAGE007
Synthesis of B
Figure 103504DEST_PATH_IMAGE020
To a solution of benzylamine (14.39 g, 0.13 mol) in dichloromethane (100 mL) at 0 deg.C was added potassium carbonate (18.58 g, 0.13 mol), followed by dropwise addition of the compound
Figure 58822DEST_PATH_IMAGE021
c (30.00 g, 0.11 mol) in dichloromethane (100 mL), heating to room temperature after completion of the dropwise addition, reacting for 3 hours, detecting by TLC that the reaction is complete, adding water (200 mL), separating the layers, extracting the aqueous phase with ethyl acetate (200 mL. times.2), combining the organic phases, washing with saturated saline (200 mL), anhydrous Na2SO4Drying, concentrating the filtrate under reduced pressure to obtain light yellow liquid compound
Figure 412443DEST_PATH_IMAGE021
B（19.51 g，81%）。1H NMR (300 MHz, CDCl3) δ 7.36 – 7.24 (m, 5H), 4.50 (d, J = 14.1 Hz, 1H), 4.16 (d, J = 14.8 Hz, 1H), 3.35 (dd, J = 10.8, 6.7 Hz, 1H), 2.99 (d, J = 10.8, 1H), 1.85 (dd, J= 6.6, 2.1 Hz, 1H), 1.58 (t, J=6.6 Hz, 1H), 1.09 (s, 3H), 0.95 (s, 3H)。
Example 7: compound (I)
Figure 86001DEST_PATH_IMAGE018
Synthesis of (2)
Figure 550480DEST_PATH_IMAGE022
Compound (I)
Figure 484938DEST_PATH_IMAGE007
Adding palladium carbon (3.00 g) into ethanol (250 mL) solution of B (30.00 g, 0.14 mol), replacing with hydrogen for three times, stirring at room temperature for 12 hours, filtering, concentrating and drying to obtain the compound
Figure 648941DEST_PATH_IMAGE008
（17.27 g, 99%）。
Example 8: synthesis of Compound IV
Figure 668850DEST_PATH_IMAGE023
The compound
Figure 812386DEST_PATH_IMAGE008
(50.00 g, 0.40 mol) is dissolved in THF (500 mL), the temperature is reduced to 0 ℃, sodium borohydride (60.53 g, 1.60 mol) is added in small amount in batches, then solution of iodine (203.05 g, 0.80 mol) in THF (300 mL) is added dropwise, after the dropwise addition, the reaction system is heated to 70 ℃ and reacts for 5 hours, the reaction is stopped, the reaction is cooled to room temperature, water (500 mL) is added, the layers are separated, the water phase is extracted by ethyl acetate (500 mL multiplied by 2), the organic phases are combined, washed by saturated saline (500 mL), and anhydrous Na is used as2SO4Drying, concentrating the filtrate under reduced pressure, rectifying and purifying to obtain a light yellow liquid compound IV (37.85 g, 85%).1H NMR (400 MHz, CDCl3): δ 3.06 (m, 2H), 2.87 (d, J = 11.2 Hz, 2H), 1.64 (br s, 1H), 1.22 (m, 2H), 0.98 (s, 3H), 0.96 (s, 3H)。MS (m/z): 112 (M++1)。
Example 9 Synthesis of Compound IV
Figure 866930DEST_PATH_IMAGE023
The compound
Figure 296774DEST_PATH_IMAGE008
(10.00 g, 0.08 mol) in THF (160 mL), cooling to 0 deg.C, adding zinc chloride (21.81 g, 0.16 mol), then adding small amount of potassium borohydride (12.95 g, 0.24 mol) in portions, heating to room temperature and continuing stirring for reaction for 3 hours, cooling to 0 deg.C, quenching the reaction with saturated aqueous sodium bicarbonate solution (100 mL), layering, extracting the aqueous phase with ethyl acetate (100 mL. times.2), combining the organic phases, washing with saturated saline (100 mL), anhydrous Na2SO4Drying, concentrating the filtrate under reduced pressure, rectifying and purifying to obtain a light yellow liquid compound IV (6.93 g, 78%).
Example 10: compound (I)
Figure 944924DEST_PATH_IMAGE024
Synthesis of (2)
Figure 16786DEST_PATH_IMAGE023
Under the protection of argon, the compound is added
Figure 801202DEST_PATH_IMAGE008
(50.00 g, 0.40 mol) in THF (200 mL), cooling to 0 deg.C, slowly adding borane tetrahydrofuran complex (800 mL, 0.80 mol, 1M in THF) dropwise, heating to 30 deg.C for 24 hours, detecting by TLC that the reaction is complete, quenching the reaction with methanol (100 mL), removing the solvent under reduced pressure, adding ethyl acetate (500 mL) and water (500 mL), separating the layers, extracting the aqueous phase with ethyl acetate (500 mL. times.2), combining the organic phases, washing with saturated brine (500 mL), anhydrous Na2SO4Drying, concentrating the filtrate under reduced pressure, rectifying and purifying to obtain a light yellow liquid compound IV (36.86 g, 83%).
Example 11: synthesis of Compound IV
Figure 933106DEST_PATH_IMAGE023
Under the protection of argon, the compound is added
Figure 35929DEST_PATH_IMAGE008
(75.00 g, 0.60 mol) was dissolved in THF (300 mL), bis (cyclopentadienyl) zirconium dihydride (6.71 g, 0.03 mol) was added thereto and the temperature was lowered to 0 deg.C, pinacolborane (230.37 g, 1.80 mol) was slowly added dropwise and the reaction was allowed to warm to room temperature for 12 hours, TLC was used to check completion of the reaction, the reaction was quenched with methanol (150 mL), the solvent was removed under reduced pressure, ethyl acetate (500 mL) and water (500 mL) were added, the layers were separated, the aqueous phase was extracted with ethyl acetate (500 mL. times.2), the organic phases were combined, washed with saturated brine (500 mL), anhydrous Na2SO4Drying, concentrating the filtrate under reduced pressure, rectifying and purifying to obtain light yellow liquid compound IV (49.97 g, 75%).
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present invention should be subject to the appended claims.

Claims (6)

1. A method of synthesizing 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane, comprising the steps of:
Figure DEST_PATH_IMAGE001
wherein R1 and R2 are the same or different and are selected from Cl or Br,
step 1: in a solvent, 6, 6-dimethyl-3-oxazolylcyclo [3.1.0] hexane-2-ketone is subjected to acylation reaction to obtain cis-2, 2-dimethylcyclopropane-4-halobutyryl halide;
step 2: in a solvent, cis-2, 2-dimethylcyclopropane-4-halobutyryl halide is subjected to ammonolysis reaction to obtain 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-ketone;
and step 3: reducing 6, 6-dimethyl-3-azabicyclo [3.1.0] hexan-2-one in a solvent to give 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane;
when R1, R2 are the same, the reagents used in the acylation reaction in step 1 are selected from: one of phosphorus tribromide, phosphorus pentabromide, phosphorus oxybromide, dibromo sulfoxide, thionyl chloride, hydrogen bromide and oxalyl bromide,
when R1 and R2 are different, the reagents used in the acylation reaction in the step 1 are selected from: thionyl chloride and hydrogen bromide;
the ammonolysis reaction in the step 2 is a compound
Figure DEST_PATH_IMAGE002
Reacting with ammonia water to obtain 6, 6-dimethyl-3-azabicyclo [3.1.0]Hexane (C)-2-ketone, solvent is one or more of tetrahydrofuran, acetonitrile, 1, 4-dioxane, methanol, ethanol;
said compounds
Figure 171093DEST_PATH_IMAGE002
The molar ratio of the compound to ammonia water is 1: 1-1: 15
Figure 760337DEST_PATH_IMAGE002
The volume ratio of the solvent to the solvent is 0.2mmol: 0.5-1 ml.
2. A 6, 6-dimethyl-3-azabicyclo [3.1.0] according to claim 1]The synthesis method of the hexane is characterized by comprising the following steps: the ammonolysis reaction in the step 2 is a compound
Figure 71233DEST_PATH_IMAGE002
Reacting with benzylamine in the presence of a base to obtain a compound
Figure 132687DEST_PATH_IMAGE002
B, compounds of
Figure 353584DEST_PATH_IMAGE002
B debenzylation to give 6, 6-dimethyl-3-azabicyclo [3.1.0]Hexane-2-ketone, solvent is one or more of N, N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, dichloromethane, 1, 4-dioxane and acetonitrile;
the reaction formula is as follows:
Figure DEST_PATH_IMAGE004
。
3. a 6, 6-dimethyl-3-azabicyclo [3.1.0] according to claim 2]The synthesis method of the hexane is characterized by comprising the following steps: the alkali is one of sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate and potassium bicarbonate, and the compound is
Figure 379309DEST_PATH_IMAGE002
The molar ratio of the compound to the alkali is 1:1 to 1:3
Figure 584025DEST_PATH_IMAGE002
The volume ratio of the solvent to the solvent is 0.2mmol: 0.5-1 ml.
4. A 6, 6-dimethyl-3-azabicyclo [3.1.0] according to claim 2]The synthesis method of the hexane is characterized by comprising the following steps: said benzylamines and compounds
Figure 455029DEST_PATH_IMAGE002
The molar ratio of (a) to (b) is 1:1 to 2: 1.
5. A 6, 6-dimethyl-3-azabicyclo [3.1.0] according to claim 2]The synthesis method of the hexane is characterized by comprising the following steps: said compounds
Figure 655066DEST_PATH_IMAGE002
And B, debenzylation adopts a palladium-carbon catalytic hydrogenation removal method.
6. A 6, 6-dimethyl-3-azabicyclo [3.1.0] according to claim 1]The synthesis method of the hexane is characterized by comprising the following steps: the reducing system in the step 3 comprises a reducing agent and a Lewis acid, wherein the reducing agent is selected from one of lithium aluminum hydride, sodium borohydride, potassium borohydride, lithium borohydride, sodium cyanoborohydride, diborane, borane and bis (cyclopentadienyl) zirconium dihydride/pinacol borane, and the Lewis acid is selected from one of zinc chloride, lithium chloride, ferric chloride, cobalt chloride, magnesium chloride, aluminum chloride, boron trifluoride diethyl etherate, acetic acid, trifluoroacetic acid and sulfuric acid; reducing agents and compounds
Figure 54955DEST_PATH_IMAGE002
The molar ratio of (A) to (B) is 1.0-8.0: 1.0; the solvent in step 3 is one or more of tetrahydrofuran, dichloromethane, diethyl ether, toluene and acetonitrile
Figure DEST_PATH_IMAGE005
The volume ratio of the solvent to the solvent is 0.2mmol: 0.5-1 ml.
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